chronic lymphocytic leukemia: diagnosis and treatmentcllcanada.ca/2010/pages/mayo clinic cll...

Mayo Clin Proc. • August 2006;81(8):1105-1129 • www.mayoclinicproceedings.com 1105

CHRONIC LYMPHOCYTIC LEUKEMIA

From the Department of Leukemia, University of Texas M. D. Anderson CancerCenter, Houston, Tex.

Dr Yee was supported in part by a Cancer Care Ontario Fellowship.

Address correspondence to Susan M. O’Brien, MD, Department of Leukemia,University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box428, Houston, TX 77030 (e-mail: [email protected]). Individual re-prints of this article and a bound booklet of the entire Symposium on OncologyPractice: Hematological Malignancies will be available for purchase from ourWeb site www.mayoclinicproceedings.com.

© 2006 Mayo Foundation for Medical Education and Research

SYMPOSIUM ON ONCOLOGY PRACTICE: HEMATOLOGICAL MALIGNANCIES

Chronic Lymphocytic Leukemia: Diagnosis and Treatment

KAREN W. L. YEE, MD, AND SUSAN M. O’BRIEN, MD

Traditionally, the goal of therapy in chronic lymphocytic leukemia(CLL) has been palliative, with first-line therapy using alkylatingagents and/ or involved field radiotherapy (depending on the stageof disease and sites of involvement) because of the older age ofaffected patients and the low rate of complete remissions (CRs)with no improvement in overall survival despite treatment. Withincreasing knowledge about the biology, molecular genetics, andprognostic factors of the disease, the philosophy of care forpatients with CLL has evolved from palliation to aiming for apotential cure, especially in younger patients. Furthermore, mul-tiple treatment options have emerged, including purine analogues,monoclonal antibodies, and potentially stem cell transplantation.These have been associated with higher frequencies of CRs andlonger durations of responses compared to conventional chemo-therapy. In addition, a subset of patients treated with chemo-immunotherapy can achieve durable CRs and molecular remis-sions. This may translate into improved disease-free survival andpotentially a “cure.” Because of the heterogeneous nature of CLL,new prognostic markers are currently being incorporated intoclinical trials to determine their role in routine clinical practice.This review summarizes current therapeutic regimens that arebeing evaluated in patients with CLL and management of disease-related complications.

Mayo Clin Proc. 2006;81(8):1105-1129

Chronic lymphocytic leukemia (CLL) is the most com-mon form of leukemia in adults in the Western world,

accounting for nearly 25% of all leukemias with an esti-mated annual age-adjusted incidence of 3 per 100,000 per-sons in the United States.1,2 The median age at diagnosis isapproximately 70 years, with 81% of the patients beingdiagnosed at age 60 years or older.1 Under the WorldHealth Organization classification, CLL is a B-cell neo-plasm, and the entity T-cell CLL has been reclassified as T-cell prolymphocytic leukemia (PLL).3 Recent data from theSurveillance, Epidemiology, and End Results cancer statis-

tics indicate that the 5-year survival of patients with CLL is73%.4

ETIOLOGYThe cause of CLL is unknown. It is the only leukemia notassociated with exposure to ionizing radiation, drugs, orchemicals.5-7 No convincing evidence exits for a viral etiol-ogy.8 Epidemiological studies have shown that the risk ofCLL, and other primary cancers, is increased in relatives ofpatients with CLL and therefore strongly suggest that ge-netic susceptibility to CLL occurs in 5% to 10% of pa-tients.9-17 At present, no genes have unambiguously beenshown to confer an increased risk of CLL.18-22 Some, butnot all, studies have indicated that the mean age at diagno-sis of offsprings is approximately 10 to 20 years earlierthan that of their parents (ie, anticipation).10,11,13,17,23-27 Nodifferences in biology (eg, immunoglobulin heavy chainvariable region [IgVH] gene mutational status, IgVH use,ZAP-70 expression, CD38 expression, or cytogenetics) orrates of transformation to non-Hodgkin lymphoma (NHL)have been demonstrated between familial and sporadiccases of CLL.13,24,25,28,29 No data are available comparingtreatment responses between familial and sporadic cases ofCLL.

CLINICAL PRESENTATIONApproximately 50% of patients with CLL are asymptom-atic at the time of presentation and are found to have anisolated peripheral lymphocytosis on blood work ob-tained for an unrelated indication.30-32 Constitutionalsymptoms are present in approximately 15% of patients atdiagnosis, with night sweats, weight loss, and fatiguebeing more frequent than disease-related fever.33 Themost common physical findings are lymphadenopathyfollowed by splenomegaly and then hepatomegaly.33 Ex-

AIHA = autoimmune hemolytic anemia; AML = acute myeloid leuke-mia; CALGB = Cancer and Leukemia Group B; CAP = cyclophospha-mide, doxorubicin (Adriamycin), and prednisone; CHOP = cyclophos-phamide, hydroxydaunomycin (doxorubicin), vincristine (Oncovin) andprednisone; CLL = chronic lymphocytic leukemia; CMV = cytomega-lovirus; CR = complete response; DAT = direct antiglobulin test;GCLLSG = German CLL Study Group; GVHD = graft-vs-host disease;GVL = graft-vs-leukemia; IgVH = immunoglobulin heavy chain variableregion; IVIG = intravenous immunoglobulin; MBL = monoclonal B-celllymphocytosis; MDS = myelodysplasia; MRD = minimal residual dis-ease; NCI = National Cancer Institute; NHL = non-Hodgkin lymphoma;NMA = nonmyeloablative; NPR = nodular partial remission; OR =overall response; OS = overall survival; PCR = polymerase chainreaction; PFS = progression-free survival; PLL = prolymphocytic leu-kemia; PR = partial response; PRCA = pure red cell aplasia; RS =Richter syndrome; SCT = stem cell transplantation; SLL = smalllymphocytic leukemia; TRM = treatment-related mortality; TTP = timeto progression

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

Mayo Clin Proc. • August 2006;81(8):1105-1129 • www.mayoclinicproceedings.com1106


tranodal involvement of the tonsils and skin has been ob-served, whereas involvement of the gastrointestinal tract,lungs, pleura, central nervous system, kidneys, and bones isuncommon.33

DIAGNOSISThe current diagnosis of CLL is based on minor modifica-tions of the criteria originally proposed by the National

Cancer Institute (NCI) (Table 1).34,35 An absolute bloodlymphocytosis, lymphocyte count of less than 5 × 109/L, isacceptable provided it is chronic with the characteristicmorphology and immunophenotype.35 A bone marrowevaluation is no longer required for diagnosis but is usefulto determine the extent and pattern of involvement and toclarify the etiology of the cytopenias.35

The morphology and immunophenotype are adequatefor diagnosis and to distinguish CLL from other disorders(Table 2).36 Although the typical B-cell CLL immuno-phenotype is CD5+, CD19+, CD23+, FMC7–, with weakor negative expression of CD22, CD79b, and surface mem-brane immunoglobulin, there can be some variability in theexpression of these surface markers.37-40 Therefore, animmunophenotypic scoring system is often used to aid inthe diagnosis and differentiation from other B-cell malig-nancies41-47 (Tables 3 and 4).

Using a highly sensitive flow cytometric technique, amonoclonal B-cell lymphocytosis (MBL) can be detectedin 2% to 3% of the general population, increasing to morethan 5% for adults aged 60 years or older.48 The B-cellclones may have a CLL-like immunophenotype or that ofother B-cell lymphoproliferative disorders (Table 5). Ahigher incidence of MBL (15.0%-57.5%) has been ob-served in healthy first-degree relatives of individuals af-fected with CLL, 13.5% to 18.0% of whom have a CLL-like immunophenotype.49,50 After a median follow-up of 5years, approximately 5% of these first-degree relativeswith MBL have required treatment.48

PROGNOSISThe natural history of CLL is highly variable. Survival hasbeen shown to correlate with clinical staging. Patients canbe classified into low-, intermediate-, and high-risk groups(ie, Rai or Binet classification) on the basis of presenting

TABLE 1. Criteria for the Diagnosis of Chronic Lymphocytic Leukemia*

Criteria NCI-WG 199634 IWCLL 200535

Peripheral blood lymphocytes (× 109/L) >5 Not specified†Morphology Not specified Small mature lymphocytes without visible

nucleoli; smudge cells are characteristicImmunophenotype of lymphocytes 1 B-cell marker (CD19, CD20, or CD23) 1 B-cell marker (CD19, CD20, or CD23)

and CD5 positivity in the absence of other and CD5 positivity in the absence of otherpan-T-cell marker pan-T-cell marker

Monoclonal expression of either κ or γ chain Monoclonal expression of either κ or γ chainLow-density surface Ig Low-density surface Ig

Atypical cells (eg, prolymphocytes) <55% and/or <15 × 109/L <55% and/or <15 × 109/LDuration of lymphocytosis None required Not specified but needs to be chronicBone marrow lymphocytes (%) 30 Bone marrow evaluation not required‡

*IWCLL = International Workshop on Chronic Lymphocytic Leukemia; NCI-WG = National Cancer Institute–sponsored Working Group.†A lower value than 5 × 109/L is acceptable provided there is a chronic, absolute increase in blood lymphocytes with the characteristic

morphology and immunophenotype.‡Bone marrow evaluation is no longer required for diagnosis but useful to determine extent and pattern of involvement and clarification of

etiology of cytopenias.

TABLE 2. Differential Diagnosis of Chronic Lymphocytic Leukemia

Benign causesB cell

PostsplenectomyHyperreactive malarial splenomegalyPersistent polyclonal B-cell lymphocytosis (eg, in smokers)

T cellBacterial (eg, tuberculosis, syphilis)Viral (eg, infectious mononucleosis, cytomegalovirus)Serum sicknessThyrotoxicosisAddison diseasePostsplenectomy

Malignant causesB cell

Chronic lymphocytic leukemiaProlymphocytic leukemiaLeukemic phase of non-Hodgkin lymphoma

Mantle cell lymphomaFollicular small cleaved cell lymphomaSplenic lymphoma with villous lymphocytesMarginal zone lymphomasLarge cell lymphoma

Hairy cell leukemiaWaldenström macroglobulinemia

T cellT-cell prolymphocytic leukemiaProlymphocytic leukemiaAdult T-cell leukemia/lymphomaSézary syndromeLarge granular lymphocytic leukemiaPeripheral T-cell lymphoma




features (ie, lymphadenopathy, hepatosplenomegaly, ane-mia, and thrombocytopenia) with median survivals of morethan 10 years, 7 to 9 years, and 2 years, respectively(Tables 6 and 7).34,51,52 However, there is still marked het-erogeneity in outcome between different individuals withinthe same stage.53

Risk may be further refined by the presence of otheradverse prognostic factors, including a lymphocyte dou-bling time of less than 12 months, atypical morphology,elevated serum β2-microglobulin levels, high levels ofsoluble CD23, elevated serum thymidine kinase levels, anddeletions or mutations of the p53 gene (Table 8).42,54,55

Chromosomal abnormalities are detected in 30% to 50%and in more than 80% of patients by cytogenetic or fluores-cence in situ hybridization analyses, respectively.56,57 Me-dian survival times for patients with 17p–, 11q–, trisomy12q, normal karyotype, and 13q– as the sole abnormalitywere 32, 79, 114, 111, and 133 months, respectively.57 Inmultivariate analysis, 17p– and 11q– were associated withshorter overall survival (OS).57 Recent data suggest thatchromosomal translocations may also be an independentprognostic factor for inferior overall survival.58

The presence of unmutated IgVH genes has been associ-ated with high-risk cytogenetics,59,60 a need for chemo-therapy,61 and shortened survival.60-62 Also, IgVH muta-

tional status can segregate the different stages of Binetclassification into distinct groups with different survivalpatterns.60,62 However, it is unclear what degree of homol-ogy of IgVH genes to germline sequences (ie, 95% or98%) should be used to define an unmutated phenotype.63

Recent data suggest that the use of specific IgVH genesegments, such as the VH3-21 gene, may be associated withan inferior outcome regardless of mutational status.64

In multivariate analysis, unmutated IgVH status, 17pdeletion, 11q deletion, age, white blood cell count, andlactate dehydrogenase levels were independent prognosticfactors for survival.59 Two other series have indicated thatunmutated IgVH status and p53 mutation, loss, or dysfunc-tion were independent adverse prognostic factors.63,65 Pa-tients with an unmutated IgVH status and/or high-risk inter-phase cytogenetics may have a shorter progression-freesurvival (PFS) and OS after therapy with fludarabine andrituximab.66

Because of the difficulty in sequencing IgVH genes in aclinical laboratory, surrogate markers for IgVH mutationalstatus have been evaluated. CD38 expression correlateswith unmutated IgVH genes but is not a surrogate markerfor IgVH mutational status; however, it may serve as an inde-pendent prognostic variable in patients with CLL.61,63,65,67,68

The optimum cutoff level defining CD38-positivity is un-clear.61,63,67,69 Furthermore, CD38 expression may vary dur-ing the course of the disease.67

Gene expression profiles of CLL cells with unmutatedIgVH genes are similar to those with mutated IgVH genes,with a limited number of genes being differentially ex-pressed in the subgroups.70,71 One such gene is the intracel-lular protein tyrosine kinase ZAP-70, which plays a criticalrole in T-cell receptor signaling. The function of ZAP-70 inCLL is unclear but has been postulated to enhance IgMsignaling and thereby contribute to the aggressive clinicalcourse of patients with CLL and unmutated IgVH genes.72

ZAP-70 expression appears to correlate with an unmutatedIgVH gene status and inferior outcome.73-76 However, its

TABLE 3. Scoring System for Diagnosisof Chronic Lymphocytic Leukemia*

Score for marker intensity

Marker 1 0

Surface immunoglobulin Weak StrongCD5 Positive NegativeCD23 Positive NegativeCD22 or CD79b Weak StrongFMC7 Negative Positive

*Diagnosis of chronic lymphocytic leukemia requires a score of >3 (withmost cases having scores of 4 or 5), whereas in other B-cell malignan-cies, the scores are usually <3.

From Br J Haematol,43 with permission from Blackwell Publishing.

TABLE 4. Immunophenotype of Chronic Lymphocytic Leukemia and Other Chronic B-cell Lymphoproliferative Disorders*

Disease sIg CD5 CD10 CD11c CD19 CD20 CD22 CD23 CD25 CD79b CD103 FMC7

Chronic lymphocytic leukemia Dim ++ – –/+ ++ Dim –/+ ++ –/+ – – –/+Follicular lymphoma ++ – ++ – ++ ++ ++ – − ++ – ++Hairy cell leukemia +++ – – ++ +++ +++ +++ – +++ ++ +++ ++Mantle cell lymphoma ++ ++ – – ++ ++ ++ – – ++ – +Marginal zone lymphoma ++ – – +/− ++ ++ +/− +/– – ++ – +Prolymphocytic leukemia +++ –/+ –/+ –/+ ++ +++ ++ –/+ +/− ++ – ++Splenic lymphoma with villous

lymphocytes ++ –/+ –/+ +/– ++ ++ ++ +/– +/− ++ +/− ++Waldenström

macroglobulinemia ++ – – –/+ ++ ++ + – –/+ + – +

*sIg = surface immunoglobulin; – = not expressed; –/+ = usually is not expressed; +/– = usually is expressed; + to +++ = varying degrees of strength ofexpression. Dim indicates that most patients with chronic lymphocytic leukemia will express CD20 and sIg albeit with a low level of expression.

Adapted from Wintrobe’s Clinical Hematology,47 with permission from Lippincott Williams and Wilkins.




validity as a surrogate marker for IgVH mutational status isunclear because (1) approximately 6% to 29% of casesshow discordant status for ZAP-70 expression and IgVHmutational phenotype, (2) the optimum cutoff level defin-ing ZAP-70 positivity remains to be defined, and (3) care-ful separation of T cells is required.73-77 Furthermore, repro-ducible results between laboratories have been marred bytechnical difficulties with the standardization of flowcytometric methods for assessing ZAP-70 expression.78

Also, prospective trials are required to verify and establishthe role of these prognostic markers in determining theneed for therapy79 and in selecting the type of therapy.80

INDICATIONS FOR TREATMENTThe indications for initiation of therapy for CLL are thoserecommended by the NCI–sponsored Working Group

(Table 9).34 Criteria for therapy include B symptoms (ie,fevers, sweats, or weight loss), progressive enlargement oflymph nodes or hepatosplenomegaly, obstructive adenop-athy, development of or worsening thrombocytopenia andanemia, immune hemolysis or thrombocytopenia not re-sponsive to corticosteroids, and rapid lymphocyte doublingtime. Hyperviscosity due to a high lymphocyte count isuncommon; therefore, a high lymphocyte count in the ab-sence of a rapid doubling time is not an indication fortherapy.

ASSESSMENT OF RESPONSEEvaluation of response to therapy is based on criteria setforth by the NCI–sponsored Working Group (Table 10).34

Since the publication of these criteria, newer therapeuticmodalities, such as purine analogues, monoclonal antibod-ies, and stem cell transplantation (SCT), have yieldedhigher frequencies of complete responses (CRs) and longerdurations of responses. The quality of these remissions hasbeen evaluated using a variety of techniques capable ofdetecting minimal residual disease (MRD). The 2 mainapproaches for detecting MRD have been multiparametricflow cytometry based on the immunophenotype of the CLLcell and polymerase chain reaction (PCR)-based strategiesusing either the qualitative consensus IgH PCR or thequantitative allele specific oligonucleotide (to the comple-mentarity determining region 3) PCR, with reported sensi-tivities of 1 monoclonal B cell in 104 normal cells, 1 in 102

to 104 normal cells, and 1 in 104 to 105 normal cells,respectively.81,82 Eradication of detectable MRD after au-tologous SCT and chemotherapy or chemoimmunotherapyis associated with an improved outcome, whereas MRDkinetics are more important than absolute MRD levels afterallogeneic SCT.81-91 Techniques for assessing MRD requirestandardization, and prospective clinical studies are neededto validate the role of MRD negativity as a surrogate marker

TABLE 5. Criteria for Diagnosis of Monoclonal B-cellLymphocytosis* 48

Criteria

Immunophenotype Disease-specific immunophenotypeof lymphocytes Monoclonal expression of either κ or γ chain

Absent or low-density surface immunoglobulinin >25% of B cells

Exclusion criteria Lymphadenopathy and organomegaly, orAssociated autoimmune/infectious disease, orB-cell lymphocyte count >5 × 109/L, orAny other feature diagnostic of a B-cell lympho-

proliferative disorder (except possibly for aparaprotein that may be present or associatedwith monoclonal B-cell lymphocytosis)

Duration ofmonoclonalB-cell population 3 mo

Subclassification (1) CD5+ CD23+ corresponds to CLL phenotype(2) CD5+ CD23– corresponds with atypical CLL

(correlate CD20 and CD79b expression)(3) CD5– corresponds to non-CLL

lymphoproliferative disease

*CLL = chronic lymphocytic leukemia.

TABLE 6. Modified Rai Clinical Staging System34,51

Median survivalRisk level Stage Clinical features (y)

Low 0 Lymphocytosis only (in blood and bone marrow)* 10Intermediate I Lymphocytosis* with lymphadenopathy 7

II Lymphocytosis* with splenomegaly and/or 7hepatomegaly with or without lymphadenopathy

High III Lymphocytosis* with anemia† (hemoglobin <11 g/dL ) 1.5-4with or without lymphadenopathy, splenomegaly, orhepatomegaly

IV Lymphocytosis* with thrombocytopenia† 1.5-4(platelets <100 × 109/L) with or without anemia and/orlymphadenopathy, splenomegaly, or hepatomegaly

*Lymphocytes >5 × 109/L in the peripheral blood and comprising >30% of nucleated cells in the bonemarrow.

†Excluding immune-mediated anemia or thrombocytopenia.




for disease eradication and/or improved survival before itsincorporation into routine clinical practice.

TREATMENTINITIAL THERAPYDespite the failure of randomized trials to demonstrate animprovement in OS between the different treatment regi-mens and the paucity of data evaluating different thera-peutic strategies and achievement of CR on patient qual-ity of life, treatment rationales have been based on obser-vations that patients who achieve a CR are more likely tohave a prolonged PFS and OS92 and the assumption thatprolonged time to treatment failure is associated withimproved quality of life. Therefore, front-line treatmentdecisions are usually geared to achieving a CR withoutincreased toxicity.

Alkylating Agents. An individual patient data meta-analysis indicated that immediate treatment with chloram-bucil with or without corticosteroids did not result in asurvival advantage over deferred chemotherapy (10-yearsurvival rate, 44% vs 47%, respectively; P>.10) in patientswith early-stage disease (Rai stages I or II; Binet stage A).93

Therefore, treatment of asymptomatic early-stage diseasewith alkylating agents is not warranted. At this time, it isunclear whether (1) therapy with nucleoside analogues willbe superior to observation in this group of patients, or (2)asymptomatic patients with early-stage disease and leuke-mic cells expressing CD38 and unmutated IgVH genesshould be treated.

This same individual patient data meta-analysis alsodemonstrated that no difference existed in 5-year OS forpreviously untreated patients with CLL (primarily Binetstage B or C disease) who received combination therapy(ie, COP [cyclophosphamide, vincristine {Oncovin}, and

prednisone], CHOP [cyclophosphamide, hydroxydauno-mycin {doxorubicin}, vincristine {Oncovin}, and pred-nisone], or chlorambucil and epirubicin) compared withthose who received chlorambucil with or without cortico-steroids (48% vs 48%, respectively; P>0.10).93 Early inclu-sion of an anthracycline did not improve 5-year survival.Subgroup analyses that assessed for an interaction between

TABLE 7. Binet Classification34,52

Equivalent Median survivalStage Clinical features Rai staging (y)

A Lymphocytosis (in blood and bone marrow)* with <3 areas 0-II 12of nodal involvement†

No anemia or thrombocytopeniaB Lymphocytosis* with 3 areas of nodal involvement,† I-II 7

with or without splenomegaly and/or hepatomegalyNo anemia or thrombocytopenia

C Lymphocytosis* with anemia‡ (hemoglobin <11 g/dL in men III-IV 2-4and <10 g/dL in women) or thrombocytopenia‡(platelets <100 × 109/L) regardless of the number of areasof nodal involvement, splenomegaly, or hepatomegaly

*Lymphocytes >5 × 109/L in the peripheral blood and comprising >30% of total nucleated cells in the bonemarrow.

†Each cervical, axillary, and inguinal area (whether unilateral or bilateral), spleen, and liver count as 1 area.Therefore, the number of areas of nodal involvement ranges from 1 to 5.

‡Excluding immune-mediated anemia or thrombocytopenia.

TABLE 8. Prognostic Factors forChronic Lymphocytic Leukemia*

Clinical risk

Prognostic factor Low High

Clinical featuresSex Female MaleClinical stage Binet A/Rai 0 Binet C/Rai III-IV

MorphologyLymphocyte morphology Typical AtypicalPattern of marrow Nodular or Diffuse

trephine infiltration interstitialChromosomal abnormalities Normal 17p–

Trisomy 12 11q–13q– (sole)

CD38 expression <20%-30% >20%-30%ZAP-70 expression <20%-30% >20%-30%IgVH gene status Mutated UnmutatedMarkers of tumor burden or

proliferationLymphocyte doubling

time >12 mo 12 moβ2-microglobulin levels Low or normal HighThymidine kinase Low or normal HighLactate dehydrogenase Low or normal HighSoluble CD23 levels Low or normal High

Markers of angiogenesisMicrovessel density Low or normal HighSerum VEGF levels Low or normal High

Tumor suppressors or Normal Loss or mutation/oncogenes p53 dysfunction

*IgVH = immunoglobulin heavy chain variable region; VEGF = vascularendothelial growth factor.

Adapted from Br J Haematol,43 with permission from Blackwell Publishing.




type of treatment (ie, combination chemotherapy vschlorambucil with or without corticosteroids) and age, sex,or Binet stage demonstrated no differences in survival.

Purine Analogues. Fludarabine. Four randomized tri-als that compared fludarabine monotherapy to alkylator-based chemotherapy (ie, chlorambucil, mini-ChOP, andCAP [cyclophosphamide, doxorubicin {Adriamycin}, andprednisone]) in previously untreated patients with activeCLL consistently demonstrated higher overall response(OR) and CR rates with fludarabine compared withalkylator-based chemotherapy regimens (Table 11).94-97 Inthe French Cooperative Group study that comparedfludarabine with CAP and mini-ChOP (lower-dose doxoru-bicin), enrollment in the CAP arm was prematurely closedwhen interim analysis demonstrated lower response andsurvival rates with CAP.96 Therapy with fludarabine was

associated with an improved PFS.94-96 However, no differ-ences in OS have been detected. More myelosuppressionwas seen with fludarabine,95-97 and higher incidences ofadverse effects (all grades) were seen in older patientsreceiving fludarabine.97 The lack of survival differencemay partly be due to (1) allowing crossover to the other armif there was no response or disease progression,95,96 with ahigher likelihood of achieving a response to subsequenttreatment with fludarabine in the alkylator arm than with analkylating agent in the fludarabine arm,95 (2) lack of signifi-cant high-quality responses achieved,94-97 and (3) heteroge-neity in other unmeasured prognostic variables (eg, propor-tion of patients with CD38-positive leukemic cells andunmutated IgVH genes).

In an attempt to improve on these response rates and toprevent the development of resistance, fludarabine hasbeen combined with chemotherapeutic agents and/ormonoclonal antibodies. Phase 2 studies that have evaluatedfludarabine plus cyclophosphamide, administered in a vari-ety of different schedules and dosing, in untreated patientswith CLL have demonstrated OR rates of 76% to 100% andCR rates of 21% to 60%,99,105-108 with a higher proportion ofcomplete responders lacking detectable disease by flowcytometry (ie, <1% CD5+/CD19+ cells) (Table 11).106-108

Five randomized trials have compared fludarabine aloneto fludarabine and cyclophosphamide, fludarabine andepirubicin, or fludarabine and chlorambucil in untreated pa-tients with active CLL.95,98-101 Fludarabine and epirubicin andfludarabine and cyclophosphamide demonstrated superiorresponse rates and PFS compared to single-agent fludarabine

TABLE 10. Response Criteria* 34

NodularCriteria Complete response partial response Partial response Progressive disease

Symptoms Absent Absent Absent or present Not specifiedLymphadenopathy Absent Absent 50% reduction 50% increase† or

new nodesHepatomegaly and/or splenomegaly Absent Absent 50% reduction 50% increase or new

hepatomegaly and/orsplenomegaly

Neutrophils (× 109/L) 1.5 1.5 1.5 or 50% improvement Not specifiedfrom baseline

Lymphocytes (× 109/L) <4 <4 >50% reduction from 50% increase tobaseline at least 5 × 109/L

Platelets (× 109/L) >100 >100 >100 or 50% improvement Not specifiedfrom baseline

Hemoglobin (g/dL) (untransfused) >11 >11 >11 or 50% improvement Not specifiedfrom baseline

Bone marrow aspirate and biopsy Normocellular Normocellular May be normal (ie, <30% Not specified<30% lymphocytes <30% lymphocytes lymphocytes withoutNo interstitial or Nodular infiltrates interstitial or nodular

nodular infiltrates infiltrates) or persistentdisease

Other NA NA NA Transformation to RSor PLL

*NA = not applicable; PLL = prolymphocytic leukemia (with >55% prolymphocytes); RS = Richter syndrome.†Sum of the products of at least 2 lymph nodes.

TABLE 9. Indications for Treatment34

Disease-related systemic symptoms*Weight loss >10% within the previous 6 moExtreme fatigueFevers >38C for 2 wkNight sweats

Progressive marrow failure with development or worsening of anemiaand/or thrombocytopenia

Autoimmune cytopeniasMassive (>6 cm below the costal margin) or progressive splenomegalyMassive (>10 cm) or progressive lymphadenopathyProgressive lymphocytosis

>50% increase over 2 moLymphocyte doubling time <6 mo

*Exclude other causes, eg, infection.




and/or single-agent chlorambucil (Table 11).98-101 However,no differences in OS have been detected. Although morefrequent and severe leukopenia was observed in thefludarabine and cyclophosphamide arm compared tofludarabine alone,98,99 the incidence of serious infections wassimilar in both arms.98-100 No toxicity data were available forthe trial that compared fludarabine to fludarabine andepirubicin.101 In the United Kingdom CLL4 trial that com-pared single-agent chlorambucil, single-agent fludarabine,and fludarabine and cyclophosphamide, more hemolyticanemias were observed with chlorambucil therapy.98 In theCancer and Leukemia Group B (CALGB) trial that com-pared single-agent fludarabine, single-agent chlorambucil,

and fludarabine and chlorambucil, the fludarabine and chlor-ambucil arm was prematurely closed because of excessiverates of life-threatening toxicities, including major infec-tions.95,109 More recently, an increased frequency of therapy-related myelodysplasia (MDS) and/or acute myeloid leuke-mia (AML) was observed in the patients treated withfludarabine and chlorambucil (0.5% vs 0% vs 3.5%, respec-tively) after a median follow-up of 4.2 years.110 Similarfindings have not been reported in trials using a combinationof fludarabine (or cladribine) and cyclophosphamide orcladribine and chlorambucil therapy.98-100,106-108,111-114

Treatment with fludarabine and mitoxantrone does notappear to yield higher response rates (OR, 83%; CR,

TABLE 11. Results of Randomized Trials Using Purine Analogues in Previously Untreated Patients* †

Median Rai or Binet Median Chemo-No. of age stage follow-up therapeutic Response rate Disease control OS

Reference patients (y) (%) (mo) regimen (%) (median) (median)

Fludarabine monotherapyJohnson et al,94 100‡ 62-63§ A (1), B (54), 34 F vs CAP OR, 71 vs 60‡⁄⁄ PFI not reached Not reached

1996 C (45)§ CR, 23 vs 17‡⁄⁄ vs 6.9 mo‡⁄⁄ vs 52.7 mo‡⁄⁄

Rai et al,95 2000 507¶ 62-63 I-II (60), 62 F vs CB vs OR, 63 vs 37 vs 61 TTP, 20 mo vs 14 mo 66 mo vs 56 moIII-IV (40) F/CB CR, 20 vs 4 vs 20 vs 55 mo⁄⁄

Leporrier et al,96 924 60-65 B (69), C (31) 70 F vs CAP vs OR, 71 vs 58 vs 72 TTP, 31.7 mo vs 5-y OS, 58.4%2001 ChOP CR, 40 vs 15 vs 30 27.7 mo vs 29.5 mo⁄⁄ vs 59.8% vs

57.3%⁄⁄69 mo vs 70 mo

vs 67 mo⁄⁄

Eichhorst et al,97 179 71 A (9), B (42), NR F vs CB OR, 89 vs 65 PFS⁄⁄# NR2003 C (32)** CR, 11 vs 0

Catovsky et al,98 661 NR A (25), B (45), NR F vs CB vs FC OR, 77 vs 69 vs 91 3-y PFS, 31% vs No difference2005 C (35) CR, 15 vs 18 vs 38 23% vs 62%

Fludarabine in combination with other agentsEichhorst et al,99 362 56.5 A (9), B (56), 22 F vs FC OR, 83 vs 94 PFS, 20 mo vs 48 mo 5-y OS, 80.7%

2006 C (359) CR, 7 vs 24 vs 80.3%⁄⁄

Flinn et al,100 278 62 0-II (56), NR F vs FC OR, 50 vs 70 PFS, 17.7 mo vs 41 mo NR2004 III-IV (44) CR, 6 vs 22

Rummel et al,101 150§ 62 B (57), C (43) NR F vs FE OR, 73 vs 88§ PFS, 20 mo vs 26 mo§ 63 mo vs2005 CR, 29 vs 9§ EFS, 19 mo vs 30 mo 76 mo§

Byrd et al,102 104 64 I-II (59), 43 F + R OR, 77 vs 90 Not reached for both Not reached2003 III-IV (41) consolidation Induction CR, arms; 2-y PFS, for both arms

vs FR + R 15 vs 33 70% vs 70%⁄⁄consolidation Overall CR, 28 vs 47

CladribineRobak et al,103 229 61-62 0 (14), I-II (53), NR 2-CdA/P vs OR, 87 vs 57 PFS, 21 mo vs 18 mo⁄⁄ 2-y OS, 78% vs

2000 III-IV (33) CB/P CR, 47 vs 12 2-y PFS, 46% vs 33% 82%⁄⁄EFS⁄⁄

Robak et al,104 508 59-62 0 (2), I-II (52), NR 2-CdA vs OR, 78 vs 83 vs 80 PFS, 23.5 mo vs 51.2 mo vs not2006 III-IV (40) 2-CdA/C CR, 21 vs 29 vs 36 22.4 mo vs 23.6 mo⁄⁄ reached vs

vs 2-CdA/CM not reached⁄⁄

*2-CdA = cladribine; 2-CdA/C = cladribine and cyclophosphamide; 2-CdA/CM = cladribine, cyclophosphamide, and mitoxantrone; 2-CdA/P = cladribine and prednisone; CAP =cyclophosphamide, doxorubicin (Adriamycin), and prednisone; CB = chlorambucil; CB/P = chlorambucil and prednisone; ChOP = cyclophosphamide, hydroxydaunomycin(doxorubicin [low-dose]), vincristine (Oncovin), and prednisone; CR = complete response; F = fludarabine; F/CB = fludarabine and chlorambucil; FE = fludarabine and epirubicin;NR = not reported; NS = not significant; OR = overall response; OS = overall survival; PFI = progression-free interval; PFS = progression-free survival; R = rituximab; TTP = timeto progression.

†Unless otherwise specified, P<.05.‡Untreated patients.§Includes untreated and previously treated patients.⁄⁄P=NS.¶507 patients were evaluable for survival and 474 for response.#Actual data not provided.**Staging available for only 148 patients.

Patient characteristicsResponse




20%)115 compared to historical results achievable withsingle-agent fludarabine, fludarabine and cyclophospha-mide, or fludarabine and epirubicin. In contrast, treatmentof 64 untreated patients with CLL (83% advanced stage,62% ZAP-70 positive) with a combination of fludarabine,cyclophosphamide, and mitoxantrone yielded an OR rateof 88% (MRD-negative CR, 24%; MRD-positive CR,23%; nodular partial remission [NPR], 22%; partial re-sponse [PR], 11%).116 Duration of response was 55% at 36months. Whether the combination of fludarabine, cyclo-phosphamide, and mitoxantrone is truly superior to fludar-abine and cyclophosphamide, fludarabine and epirubicin,or single-agent fludarabine remains to be determined.

Cladribine. Cladribine with or without corticosteroids hasbeen evaluated in previously untreated patients with CLL,with OR rates of 49% to 86% (CR, 10%-47%).103,104,117,118

These results are comparable to those obtained with single-agent fludarabine. A phase 3 trial compared cladribine plusprednisone vs chlorambucil plus prednisone in previouslyuntreated patients with CLL (Table 11).103 Cross over to theother arm was permitted if there was no response or diseaseprogression. Overall response and CRs were superior in thecladribine arm (87% and 47% vs 57% and 12%, respec-tively; P.0001). At 2 years, PFS was significantly improvedin the cladribine arm (46% vs 33%, respectively; P=.01).However, there was no survival difference. Treatment withcladribine combined with chlorambucil does not yield du-rable responses.111 After a median follow-up of 5 years, morethan 80% of responders had experienced relapse.112

A phase 3 trial compared single-agent cladribine tocladribine plus cyclophosphamide and cladribine plus cy-clophosphamide and mitoxantrone (Table 11).104 Signifi-cantly higher CR rates were obtained in the cladribine pluscyclophosphamide and mitoxantrone arm compared withcladribine alone (36% vs 21%, respectively; P=.004),whereas only a trend for a higher CR was observed withcladribine plus cyclophosphamide compared with cladri-bine alone (29% vs 21%, respectively; P=.08). Eradicationof MRD, as evaluated by immunophenotyping, was higherin the cladribine plus cyclophosphamide and mitoxantronearm compared with cladribine alone (23% vs 14%, respec-tively; P=.042). There were no detectable differences inOR, PFS, and OS among the 3 groups.

Pentostatin (Deoxycoformycin). Limited data are avail-able on the use of single-agent pentostatin in untreatedpatients with CLL (OR, 46%; CR, 0%).119

Rituximab. Induction Therapy. Previously untreatedpatients with CLL/small lymphocytic leukemia (SLL) whoreceived single-agent rituximab, a chimeric human-murineanti-CD20 monoclonal antibody, as first-line and mainte-nance therapy achieved OR rates of 57% (CR, 9%).120,121

Higher response rates (OR, 90%; CR, 19%) may be ob-

tained when standard-dose rituximab is administered for 8weeks, instead of 4 weeks, in untreated patients with lowtumor burden (Rai stage 0-II).122 It is unclear whether theseresponses will be durable because median follow-up isrelatively short.

The combination of fludarabine, cyclophosphamide,and rituximab has been assessed in 224 previously un-treated patients with CLL.107 Overall response was 95%(CR, 70%; NPR, 10%; PR, 15%) with 120 (78%) of 153complete responders having less than 1% CD5+/CD19+

cells in the marrow by immunophenotyping. Twenty-sixpercent of patients could not complete all 6 cycles oftherapy. Early discontinuation of therapy was significantlyassociated with advanced Rai or Binet stage, age older than65 years, hemoglobin level less than 11 g/dL, serum creati-nine level greater than 1.4 mg/dL, and β2-microglobulinlevels greater than 4 mg/dL (P<.05). Median time to pro-gression (TTP) and OS had not yet been reached after morethan 36 months. The proportion of patients achieving a CRand less than 1% CD5+/CD19+ cells was significantlyhigher than that historically achieved with fludarabine andcyclophosphamide therapy.106 The addition of 3 doses ofrituximab to the fludarabine and cyclophosphamide regi-men, in lieu of the single dose administered in the fludara-bine, cyclophosphamide, and rituximab regimen, does notappear to improve responses.123 A phase 3 German CLLStudy Group (GCLLSG) trial is currently comparing thecombination of fludarabine and cyclophosphamide vs thatof fludarabine, cyclophosphamide, and rituximab as front-line therapy in previously untreated patients with CLL.However, a formal comparision of these 2 regimens102,124 isalso needed to determine which is more efficacious withoutincreased toxicity.

The combination of pentostatin, cyclophosphamide, andrituximab appears to yield comparable OR rates (97%) butlower CR rates (33%) compared with that of fludarabine,cyclophosphamide, and rituximab, with eradication ofMRD in some patients.125 However, median follow-up wasonly 8.6+ months.

Induction and Consolidation Therapy. The CALGBconducted a randomized phase 2 trial of fludarabine withconcurrent vs sequential treatment with rituximab in 104symptomatic, previously untreated patients with CLL.114,126

Patients were randomized to either 6 cycles of standard-dose and schedule fludarabine alone or 6 cycles of stan-dard-dose and schedule fludarabine plus rituximab. After a2-month observation period, patients with stable disease orbetter (ie, CR or PR) were treated with rituximab for 4weeks. The OR and CR rates after induction therapy were90% and 33% vs 77% and 15%, respectively. These re-sponses increased to 90% and 47% vs 77% and 28%, respec-tively, after consolidation therapy with rituximab. Median




follow-up was 43 months. The estimated 2-year PFS was70% for each arm. Overall survival was similar in both arms.

Using data generated from the aforementioned study102

and a prior randomized trial,95 CALGB performed a retro-spective comparison of fludarabine monotherapy to fludar-abine and rituximab (sequential and concurrent) in previ-ously untreated patients with CLL.126 Baseline features ofthe patients were similar with respect to age, sex, stage, andpresence of organomegaly. Therapy with fludarabine andrituximab was associated with significantly more ORs(84% vs 63%, respectively; P=.0003) and CRs (38% vs20%, respectively; P=.002). The combination of fludar-abine and rituximab resulted in a significant difference inPFS (67% vs 45%, respectively; P<.0001) and OS (93% vs81%, respectively; P=.0006) at 2 years.

Consolidation Therapy. Two groups have evaluated theefficacy of rituximab for the treatment of MRD after che-motherapy (ie, chlorambucil and prednisone or fludarabinefollowed by high-dose cyclophosphamide).127,128 Serial im-provements in response were observed after each phase oftherapy,128 with OR rates of 86% to 100% (CR, 57%-68%).127,128 The role of rituximab as consolidative therapyneeds to be formally evaluated before its incorporation intoroutine clinical practice.

Alemtuzumab. Induction Therapy. Subcutaneous al-emtuzumab, a humanized unconjugated anti-CD52 mono-clonal antibody, can produce OR rates of 87% (CR, 19%)as front-line therapy in patients with CLL.129 Response bytumor site demonstrated that in most patients (95%), theCLL cells were cleared from the blood and that 66%achieved a CR or NPR in the bone marrow. Although 86%of patients with adenopathy had a response, only 29%achieved a CR (all of whom had lymph nodes of <2 cm indiameter). Most responses occurred after 18 weeks oftherapy. The median time to treatment failure had not beenreached yet (18+ months). No survival data were reported.First-dose reactions typically associated with intravenousadministration (ie, rash, nausea, dyspnea, and hypoten-sion) were absent. Reactivation of cytomegalovirus (CMV)occurred in 10% of patients, with 3 patients requiringganciclovir.

A phase 3 trial indicated that superior responses areobtained with single-agent intravenous alemtuzumab com-pared with chlorambucil as first-line therapy for CLL pa-tients with active disease (OR, 82.6% vs 54.7%, respec-tively; P<.001; CR, 22% vs 2%, respectively; P<.0001).130

However, higher incidences of grade 3 or 4 neutropenia,infections, and CMV infections were noted in patientsreceiving alemtuzumab. Overall survival was not reported.

Consolidation Therapy. Consolidation with single-agent alemtuzumab appears to improve responses (ie, PRor better) obtained with fludarabine in patients with CLL.131

Alemtuzumab was administered a median of 5 months afterfludarabine therapy. Nine of 11 patients were convertedfrom NPR to CR (with 5 achieving a molecular CR), 12 of14 patients in PR to either an NPR (n=2) or a CR (n=10)(with 6 achieving a molecular CR), and 7 of 10 patients inCR to a molecular CR. Although there were no cases ofCMV disease, oral ganciclovir was used to treat CMVreactivation in 15 (57%) patients.

The efficacy of alemtuzumab for the treatment of MRDis being evaluated further in 2 phase 2 trials; alemtuzumabwas administered (intravenously or subcutaneously) for 6weeks following 4 months of standard-dose and schedulefludarabine.132,133 Cytomegalovirus reactivation occurred in14% (with 1 fatality and 1 persistent disease despite ther-apy) and 17% of patients receiving intravenous or subcuta-neous alemtuzumab, respectively. Alemtuzumab was ableto convert a proportion of patients with stable disease or PRafter fludarabine to PRs and/or CRs. Although higher ORrates were achieved in patients receiving alemtuzumab in-travenously (OR, 92% vs 66%, and CR, 42% vs 22%,respectively), it is unclear whether intravenous administra-tion of alemtuzumab is superior to subcutaneous adminis-tration because lower response rates were obtained withfludarabine treatment in the patients who received alem-tuzumab subcutaneously. Less infusion-related toxicitieswere seen with subcutaneous administration.

The GCLLSG assessed the safety and efficacy ofalemtuzumab consolidation in patients with CLL in firstremission.134 Twenty-three patients responding to first-linetherapy with fludarabine alone or fludarabine and cyclo-phosphamide were randomized to either standard-dosealemtuzumab for 12 weeks or observation only. Of the 21evaluable patients, 11 were randomized to the alem-tuzumab arm before the study was prematurely stoppedbecause of grade 3 to 4 infections (64%) and grade 4hematologic toxicities in the alemtuzumab arm (36%). Allinfections were successfully treated. Five of 6 patients inthe alemtuzumab arm achieved a molecular remission inthe peripheral blood compared to 0 of 3 patients in theobservation arm (P=.048). After a median follow-up of21.4 months, PFS was superior in the alemtuzumab armcompared to the observation arm (ie, no progression vs24.7 months, respectively; P=.036). The increased inci-dence of non-CMV infections observed in the GCLLSG134

and the CALGB132 studies compared to the Italian131 andMD Anderson135,136 studies (27% and 33% vs <10%, re-spectively) may be due to the shorter interval betweenchemotherapy and alemtuzumab administration (2 monthsvs 5-6 months, respectively). Although alemtuzumab con-solidation holds promise, the optimal regimen remains tobe determined, and its efficacy needs to be verified in arandomized trial.




SALVAGE THERAPYBecause retrospective data have indicated that response tosalvage therapies appears to be strongly associated withresponse to prior therapies and most patients have been orwill be treated with fludarabine or fludarabine-based regi-mens, relapsed patients have generally been classified into2 groups based on prior response or exposure to fludara-bine: fludarabine naive or fludarabine sensitive and fludar-abine refractory. However, the choice of appropriate salvagetherapy in relapsed patients is hampered by (1) the lack ofrandomized trials, including those involving SCT, of pa-tients who have been previously exposed to purine analogue-based regimens94,101 and monoclonal antibodies; (2) incom-plete data in the currently reported phase 2 studies withrespect to prior sensitivity or resistance to purine analogue-and/or monoclonal antibody–based treatment regimens; and(3) usually inclusion of both purine analogue-sensitive andanalogue-resistant patients and/or alkylator-sensitive andalkylator-resistant patients in the same clinical trial.

Fludarabine (Purine Analogue)-Naive or Fludarabine(Purine Analogue)-Sensitive Patients

Alkylating Agents. Although re-treatment of patients,who have received prior therapy with an alklyating agent,with an alkylator-based regimen may induce responsesin 21% to 62%, the quality of responses is low (CR, 0%-31%) and the duration of responses usually short (2-18months).94,137-140 In patients who experience relapse after orwere refractory to therapy with fludarabine, alkylator-based therapy can induce OR rates of 7% to 44% with CRrates of 6% to 22%.92,94,95

Purine Analogues. Fludarabine. In previously treatedpatients with CLL, most experienced failure with analkylator-based regimen; OR rates of 12% to 58% with CRrates of 0% to 26% can be obtained with single-agentfludarabine.141-146 Overall survival strongly correlated withquality of response achieved (ie, CR vs PR vs no re-sponse).143,144 Long-term follow-up of 174 patients who

received first-line therapy with single-agent fludarabineindicated that 67% who experience relapse will respond tosalvage therapy with a fludarabine-based regimen, with74% of patients responding to rechallenge with single-agent fludarabine.92 However, no patient who initiallyfailed to respond to fludarabine responded to re-treatmentwith a fludarabine-containing regimen.

A single phase 3 study compared fludarabine alone toCAP in previously treated and untreated patients with CLL(Table 12).94 Patients were stratified based on prior or noprior therapy. However, the proportion of patients whoreceived prior fludarabine was not specified. Subgroupanalysis of the previously treated patients demonstrated asuperior response rate in favor of fludarabine (OR, 48% vs27%; P=.036; CR, 13% vs 6%; P value, not significant).However, there was no significant difference in responseduration or OS.

Several phase 2 studies have evaluated the efficacy offludarabine in combination with alkylators (eg, fludarabineand cyclophosphamide),106,147,148 anthracyclines/anthra-quinones (eg, fludarabine and doxorubicin or fludarabineand mitoxantrone),115,149 both alkylators and anthracyclines/anthraquinones (eg, fludarabine, cyclophosphamide, andmitoxantrone),103 or other nucleoside analogues. Therapywith fludarabine and cyclophosphamide yielded OR ratesof 60% to 94% (CR, 10%-29%) in previously treated pa-tients, a proportion of whom had received prior fludarabinetherapy (14%-79%).106,147,148 Treatment with fludarabineplus doxorubicin149 or fludarabine plus mitoxantrone115 ap-pears to yield inferior results to those obtained with flu-darabine plus cyclophosphamide. However, most of thesepatients (72%-83%) had received prior fludarabine in con-trast to patients treated with fludarabine plus cyclophos-phamide. Treatment with fludarabine, cyclophosphamide,and mitoxantrone appears to yield higher-quality responserates (CR, 50%, with 33% having no detectable disease byflow cytometry and PCR analysis) in patients who have not

TABLE 12. Results of Randomized Trials Using Fludarabine Regimens in Previously Treated PatientsWith Chronic Lymphocytic Leukemia* †

Median Binet Median Chemo-No. of age stage Prior F follow-up therapeutic Response rate Disease control OS

Reference patients (y) (%) (%) (mo) regimen (%) (median) (median)

Johnson et al,94 96‡ 62-63§ A (1), B (54), NR 34 F vs CAP OR, 48 vs 27‡⁄⁄ Response duration, 24.3 mo vs1996 C (45)§ CR, 13 vs 6‡ 10.8 mo vs 6 mo‡ 24.4 mo‡

Rummel et al,101 150§ 62 B (57), C (43) NR NR F vs FE OR, 73 vs 88§¶ PFS, 20 mo vs 26 mo§ 63 mo vs 76 mo§2005 CR, 29 vs 9§ EFS, 19 mo vs 30 mo#

*CAP = cyclophosphamide, doxorubicin (Adriamycin), and prednisone; CR = complete response; EFS = event-free survival; F = fludarabine; FE = fludarabine andepirubicin; NR = not reported; OR = overall response; OS = overall survival; PFS = progression-free survival.

†P value was not significant unless otherwise specified.‡Previously treated patients.§Includes untreated and previously treated patients.⁄⁄P=.036.¶P=.0026.#P=.0048.

ResponsePatient characteristics




received prior fludarabine but may be associated with moremyelosuppression.113 Although fludarabine, ara-C, mitox-antrone, and dexamethasone chemotherapy can induceCRs of 60% in previously treated patients (87% who hadreceived prior fludarabine, with at least 19% being fludar-abine refractory), granulocyte-colony stimulating factorwas required to treat severe myelosuppression.150 It is un-clear whether these results will be durable because 25% to30% of the patients treated underwent SCT.

Preliminary results for a randomized trial comparingfludarabine alone to fludarabine and epirubicin in previ-ously treated and untreated patients with CLL have beenpresented (Table 12).101 The proportion of patients whoreceived prior fludarabine was not specified. Treatmentwith fludarabine and epirubicin yielded superior responserates (OR, 88% vs 73%, respectively; P=.026; CR, 29% vs9%, respectively; P=.0029). The combination of fludara-bine and epirubicin resulted in a higher PFS (26 months vs20 months, respectively; P=.085); however, this did nottranslate into an improved OS (76 months vs 63 months,respectively; P=.10). Subgroup analysis of the previouslytreated patients has not been performed. Although responseduration and/or OS after fludarabine-based salvage thera-pies appears to be strongly associated with response toprior therapies (ie, prior alkylating agents only, prior alky-lating agents and fludarabine [fludarabine sensitive butrelapsed], and prior alkylating agents and fludarabine[alkylator refractory and fludarabine refractory]),106,113 thetrue magnitude of the efficacy of the various treatmentregimens is hampered by incomplete data concerning pa-tient refractoriness to prior alkylator and/or fludarabinetherapies.

Cladribine. Cladribine with or without corticosteroidscan induce OR rates of 31% to 68% with CRs of 0% to 31%in previously treated patients with CLL.118,151-154 These re-sults appear to be comparable to those with single-agentfludarabine, although the duration of responses appears tobe shorter with cladribine (4-20 months vs >18 months forfludarabine). However, 7% to 43% of these patients hadreceived prior fludarabine.151-153 The European Organisa-tion for Research and Treatment of Cancer performed arandomized controlled trial that compared fludarabine tocladribine in previously treated patients with CLL, but noresults have been reported to date.

A small number of patients with CLL have receivedtherapy with cladribine and cyclophosphamide or cladri-bine, cyclophosphamide, and mitoxantrone.155-157 Treat-ment with cladribine and cyclophosphamide yielded ORsof 45% to 62% (CR, 8%-15%),155,156 similar to those ob-tained with fludarabine and cyclophosphamide therapy.However, these responses do not appear to be as durable(median, 11-12 months) as those obtained with fludarabine

and cyclophosphamide, but a higher proportion of patients(85%-95%) had received prior fludarabine therapy. Ther-apy with cladribine, cyclophosphamide, and mitoxantroneappears to be inferior to both cladribine and cyclophospha-mide and fludarabine, cyclophosphamide, and mitoxan-trone, with an OR of only 37% (CR, 5%) and medianresponse duration of 5 months.157

Pentostatin. Extremely poor results were seen whenpentostatin monotherapy was used in patients with previ-ously treated CLL (OR, 15%-29%; CR, 0%-8%).119,158,159

However, 59% of the patients in at least 1 study had beenexposed to prior fludarabine.159 Twenty-one patients withCLL were treated with pentostatin plus cyclophospha-mide.160 Most had advanced disease, and 87% had receivedprior fludarabine. Overall survival was 81% (CR, 19%)with a median response duration of only 7 months. Similarto what has been observed with fludarabine-based regi-mens, response to salvage therapy with cladribine- orpentostatin-based regimens appears to be affected by priorfludarabine exposure.

Rituximab. Induction Therapy. Single-agent rituxi-mab administered at the standard-dose and schedule yieldedunimpressive responses in previously treated patients withCLL/SLL (OR, 0%-35%; CR, 0%).161-164 Alternative dos-ages (up to 2250 mg/m2 per week) and schedules of admin-istration (3 times a week) have improved response rates ofsingle-agent rituximab induction therapy (OR, 36% and52%, and CR, 0% and 4%, respectively) with median TTPof 8 to 11 months.165,166

The GCLLSG evaluated fludarabine and rituximab ther-apy in previously untreated (n=20) and treated (n=11) pa-tients with CLL.124 Of the 11 previously treated patients,OR was 90% (CR, 27%; complete remission unconfirmed,18%). Median duration of response for this subset of pa-tients was not stated. No survival data were reported. Infe-rior results were obtained when rituximab was combinedwith either pentostatin or cladribine.167,168

The combination of fludarabine, cyclophosphamide,and rituximab was evaluated in 177 previously treatedpatients with CLL.169 An OR of 73% (CR, 25%; NPR, 16%;PR, 32%) was obtained. Of 35 patients, 25 (71%) in CRhad less than 1% CD5+/CD19+ cells in the marrow by flowcytometry, and 12 (32%) of 37 patients in CR achieved amolecular remission. With a follow-up of 28 months, theestimated median survival was 42 months. These resultshave been compared to historical controls treated with thecombination of fludarabine and cyclophosphamide andfludarabine with or without prednisone.170 Overall responseand CR for fludarabine and cyclophosphamide andfludarabine with or without prednisone were 67% and 12%and 59% and 13%, respectively. Estimated median survivalwas 31 months and 19 months, respectively. Multivariate




analysis showed that the fludarabine, cyclophosphamide,and rituximab group had a significantly higher CR rate andlonger survival compared to the fludarabine and cyclo-phosphamide and fludarabine with or without prednisonegroup (P=.0001 and P<.0001, respectively). Median sur-vival for the nonresponders was similar for all 3 groups,suggesting that improved supportive care over time did nothave a major impact on survival. A phase 3 trial comparingfludarabine, cyclophosphamide, and rituximab with fludar-abine and cyclophosphamide in previously treated patientswith CLL is currently under way. The OR rates obtainedwith fludarabine, cyclophosphamide, and rituximab appearcomparable to those obtained with fludarabine and ri-tuximab therapy, albeit in a significantly smaller cohort ofpreviously treated patients.124 However, in that study, MRDwas not evaluated, and follow-up was too short to drawconclusions about survival.124 A formal comparision ofthese 2 regimens is warranted.

Therapy with pentostatin, cyclophosphamide, and ritux-imab can yield OR rates of 75% (CR, 25%), which appearto be comparable to those obtained with fludarabine, cyclo-phosphamide, and rituximab therapy, although the propor-tion of patients who had received prior fludarabine was notspecified.171 Median response duration and time to treat-ment failure were 25 months and 40 months, respectively.Median survival was 44 months.

Alemtuzumab. Induction Therapy. Alemtuzumab hasbeen approved for the treatment of patients with refractoryCLL.172-175 Most of these patients had advanced stage dis-ease, had received prior fludarabine (55%-100%), and hadreceived 3 or fewer prior therapies. Overall response rateswere 31% to 70% with CRs of 0% to 30%. Patients wereless likely to respond if they had high-risk disease172,173;enlarged lymph nodes, especially greater than 5 cm indiameter172,173,176; World Health Organization performancestatus of 2172; and received more than 5 prior therapeuticregimens.174 The higher quality of the responses (CR, 30%and 26%, with no detectable bone marrow disease byimmunophenotyping in 16% of complete responders)achieved in 2 trials may be due to differences in patientcharacteristics and the duration of therapy with alemtuz-umab.83,177 Median OS was reported in only 2 studies andranged from 16 months to 27.5 months.172,173 Major toxicitieswere infusion-related events, infections (including CMV re-activation), neutropenia, and thrombocytopenia.

In an attempt to improve on results obtained with thecombination of fludarabine, cyclophosphamide, and ritux-imab in previously treated patients, alemtuzumab wasadded to the regimen.178 Of 66 patients with relapsed orrefractory CLL who had received treatment, 36% werefludarabine refractory. Of 44 evaluable patients, the ORrate was 65% (CR, 27%; PR, 38%). Higher OR and CR

rates were observed in fludarabine-sensitive patients.Eradication of MRD occurred in 92% of patients in CR.Estimated median TTP and OS were 19 months and 16months, respectively. The study is currently ongoing.

Three studies have evaluated the efficacy and safe-ty of alemtuzumab combined with rituximab in patientswith relapsed or refractory CLL (OR, 0%-67%; CR, 0%-44%).179-181 No responses were seen in 1 study,179 possiblybecause 6 of 12 patients received lower doses of alem-tuzumab, and only 1 course of therapy was administered.179

Responses may be higher in patients who are not refractoryto fludarabine/purine analogues180,181 and have less ad-vanced disease.181 No study reported response duration orOS. In general, a higher frequency and severity of adverseevents were seen with alemtuzumab than with rituxi-mab. Cytomegalovirus reactivation occurred in up to 27%of patients.

Consolidation Therapy. Administration of alemtuzu-mab consolidation therapy to patients with CLL who haveachieved a PR, NPR, or CR after chemotherapy can im-prove response rates.135,136 The OR rate was 53% with aresponse rate of 39% with the 10-mg dose three times aweek compared with 65% with the 30-mg dose three timesa week (P=.066). Forty-seven percent of patients in NPRachieved CR, and 46% in PR achieved NPR or CR. Re-sidual bone marrow disease cleared in most patients, with11 (38%) of 29 patients achieving a molecular remission.After a median follow-up of 24 months, median TTP hasnot been reached in responders. Subgroup analysis indi-cated a longer TTP in patients with no detectable MRD (notreached vs 15 months, respectively) after a median follow-up of 18 months. Toxicities included grade 1 to 2 infusion-related events (common) and infections (mainly CMV re-activation). One patient died of pneumonia, and 3 patientsdeveloped Epstein-Barr virus–positive large cell lym-phoma (the disease resolved in all 3 patients: spontane-ously in 2 and after treatment with cidofovir and immuno-globulin in 1).

Fludarabine-Refractory PatientsUp to 37% of previously untreated and 76% of previ-

ously treated patients with CLL will not respond to single-agent fludarabine (they will either fail to achieve PR or CRwhile taking at least 1 fludarabine-containing regimen orexperience disease progression while taking fludarabinetreatment),92,94-97,141-146 and an additional 7% to 14% of pa-tients who were initially sensitive to fludarabine (ie, CR orPR) will experience relapse within 6 months of ther-apy.94,95,145,146 Treatment of fludarabine-refractory patientshas had limited success. Historically, OR rates of 22% (CR,1%) with a median survival of 10 months have been obtainedafter first salvage therapy with a variety of agents, includingsingle-agent purine analogues, purine analogues combined




with alkylators or other chemotherapeutic agents, andanthracycline-based regimens.182 This contrasts with resultsobtained in patients with fludarabine-sensitive disease, inwhich ORs of 50% to 80% (CR, 12%-30%) and mediansurvivals of 21 to 36 months can be achieved.101,112,169

In a very select group of fludarabine-refractory patients(ie, those with intermediate-stage disease, good baselinehematological parameters, 3 prior types of therapy, and6 cycles of fludarabine), a modest response may be seen(OR, 32%; CR, 0%) with an OS of 26 months with single-agent cladribine.183 However, few patients will fulfill thesecharacteristics, as demonstrated by an accrual time of 4years for 28 patients. In a small series of patients, thecombination of pentostatin and cyclophosphamide appearsto improve OR rates (77%) with few CRs (8%),160 but thedurability of these responses and effect on OS are un-known.

Modest responses of short duration have been achievedwith single-agent rituximab.165,166 Higher response rates(OR, 59%) can be obtained with fludarabine, cyclophos-phamide, and rituximab therapy; however, CRs are infre-quent (5%), and the durability of responses is unknown.169

Responses have also been observed with the combinationof pentostatin, cyclophosphamide, and rituximab171 andwith rituximab plus CHOP chemotherapy.184 Single-agentalemtuzumab has activity in this group of patients (OR,31%-46%; CR, 0%-29%),83,172,173,176,185 with a proportion ofcomplete responders having no detectable bone marrowdisease by immunophenotyping.83 Higher responses wereseen in patients who had received fewer than 3 prior typesof therapy83 with no significant adenopathy (none or nodes<2 cm in diameter).83,172 The combination of alemtuzumaband fludarabine may yield higher responses, even in pa-tients refractory to single-agent alemtuzumab and single-agent fludarabine (OR, 83%; CR, 16%; PR, 67%).186 At thistime, it is unclear whether the addition of rituximab toalemtuzumab will improve these results.179,180 Because noeffective therapies currently exist for patients in whomfludarabine therapy fails, these patients should be encour-aged to participate in clinical trials that address this issue.

HEMATOPOIETIC SCTAutologous SCT. The rationale behind autologous SCT

is extrapolated from a linear dose efficacy observed withsome chemotherapeutic agents, with higher doses resultingin higher tumor kill. Limitations include potential forreinfusion of the tumor cells, development of secondaryMDS, and lack of graft-vs-leukemia (GVL) effect. Con-trary to previous reports, administration of fludarabine asfirst-line therapy does not appear to be associated with apoor collection of peripheral blood stem cells providedmobilization is performed using chemotherapy and granu-

locyte-colony stimulating factor and an adequate time in-terval has elapsed between the last dose of fludarabine andleukapheresis.187-189

Although autologous SCT is associated with lowertreatment-related mortality (TRM) (1%-7%) and can pro-duce molecular remissions,86,187,190 it is unlikely to providea cure because no evidence exists of a plateau in PFS(Table 13).86,89,187,194,197 Purging of the autograft, CD34+-positive selection or double selection (CD34+-positive se-lection followed by CD19+-/CD20+-negative selection), hasnot been shown to improve relapse rates.198 Second malig-nancies, including MDS, skin cancers, lung cancer, NHL,and colorectal and breast cancers, have developed in up to21% of patients191,196,197; development of MDS occurred in9% to 15% of patients, with 5-year and 8-year actuarial risksposttransplantation being approximately 12%.191,197

To identify subgroups of patients who may potentiallybenefit from an autotransplant, several variables have beenevaluated. Predictors of an improved disease-free survivaland OS have included a short interval from diagnosis totransplantation, minimal disease (eg, CR) at transplanta-tion, mutated VH status, tumor chemosensitivity, and use oftotal body irradiation–conditioning regimens.86,187,194,197,199

Three randomized trials are under way comparing au-totransplantation to chemotherapy in previously untreatedpatients with advanced CLL (www.ebmt.org/5workingparties/clwp/clwp6.html).192,193 Preliminary results from 2 of thesetrials in younger (ie, <60-66 years) patients with advancedCLL have been reported.192,193 Only 1 reported event-freesurvival outcomes in favor of autotransplantation (median,63.1 months vs 23.6 months, respectively; P<.001),192 andnone reported OS. Furthermore, up to 30% of patients didnot receive the intended autotransplant.192 Analysis of mu-tational VH status is ongoing for both trials because it isunclear whether autologous SCT is superior to standardtreatment, especially in high-risk patients, eg, those withunmutated VH gene status.196,200 Longer-term follow-up isrequired to determine impact of autotransplantation in pa-tients with advanced-stage and/or high-risk disease. Cur-rently, the use autotransplantation is not recommendedoutside of a clinical trial.

Allogeneic SCT. The underlying principles of the appli-cation of allogeneic SCT are the higher antitumor activitywith increased doses of chemotherapy, the GVL effect, andthe absence of stem cell contamination. However, alloge-neic SCT is associated with increased morbidity and mor-tality (TRM, up to 50%) because of toxicities from theconditioning regimen, the presence of graft-vs-host disease(GVHD), and infectious complications. Furthermore, fea-sibility is limited by age restrictions and donor availability.Because first-degree relatives of patients with CLL mayharbor a monoclonal population of B cells with a CLL-like




immunophenotype,49,50 all potential HLA-identical relateddonors should have peripheral blood evaluated by flowcytometry.

In contrast to autologous SCT, allotransplantation isassociated with a plateau in disease-free survival and OS(Table 14),89,202,203,205-207 suggesting that allotransplantationmay be curative for some patients. Furthermore, unlikeautotransplantation in which disease chemosensitivity isrequired for the success of the procedure, allogeneic SCTcan induce sustained CRs, potentially via a GVL effect, inpatients with chemorefractory disease.203,206,207

Allogeneic SCT may also be superior to standard treat-ment and/or autotransplantation in CLL patients with anunmutated VH gene status.200,208 Recent data suggest thatpatients with negative MRD status have an improved sur-vival rate compared to those with MRD positivity.83 How-ever, it is unclear whether SCT offers any additional ben-efit to patients who have already achieved MRD negativityafter chemoimmunotherapy.208 No published randomizedtrials have compared allogeneic SCT to standard chemo-therapy and/or autologous SCT in patients with CLL. Theoptimal source of stem cells (ie, bone marrow vs peripheral

blood), the best conditioning regimen, the timing of trans-plantation, and patient selection (eg, unfavorable featuressuch as unmutated IgVH, refractory disease) remain to bedefined. In younger patients with relapsed disease or high-risk features, allotransplantation may offer a potential for acure, but the potential gains have to be balanced by the hightreatment-related mortality and morbidity.

Nonmyeloablative SCT. Nonmyeloablative (NMA) al-logeneic transplantation was developed to minimize thetoxicity of the preparative regimen and to exploit the poten-tial for immune-mediated GVL effect. The low-dose NMApreparative regimen (usually fludarabine based) is de-signed not to eradicate the leukemia but to provide suffi-cient immunosuppression to allow engraftment of donorstem cells and development of a GVL effect. This strategyallows for treatment of patients who are older and/or havecomorbidities that prevent use of standard high-dose abla-tive conditioning regimens.

Although follow-up is relatively short, NMA SCT isassociated with a much lower cumulative and 100-dayTRM compared with myeloablative SCT (16%-26% and0%-5%, repectively, vs 38%-50% and 11%-29%, respec-

TABLE 13. Selected Autologous Stem Cell Transplantation Trials*

Rai Time from Stem cellMedian or Binet diagnosis to purging/CD34 Median TRM

No. of age stage autoSCT selection follow-up at 100 d OSReference patients (y) (%) (range, mo) (%) (y) (%) Disease control (%)

Front-line therapyPilot study

Milligan et al,191 65 49† B (58.1); NR 17‡ 3 1.5 5-y DFS, 48.9% 5-y OS, 79.52005 (MRC) C (18.8)†

Phase 3 trialsBrion et al,192 2005 79§ 53 B (67); NR 69 2.5 NR Median EFS, 2 y NR

(GOELAMS) C (25) vs 5.2 y (P<.001)Sutton et al,193 100¶ 55⁄⁄ B (77); NR 0 NR NR NR, too early NR

2005 C (22)⁄⁄Front-line and salvage therapy

Montserrat et al,1941999 107# 50 NR 38 (5-218) 59 NR 7 Median, DFS, 3.1 y 5-y OS, 59(International Project (time NS) on CLL)

Horowitz et al,195 2000(IBMTR and ABMTR) 83# 50 NR 46 (2-214)** 72 NR NR NR 3-y OS, 87

Dreger et al,190 2000 321# 51 NR 27 (4-215) 50 1.2 6 NR 2-y OS, 83(EBMT) (time NS)

Dreger et al,196 2004 98 51†† B (61); NR 100 3 5 Median PFS, 4-y OS, 84††(GCLLSG) C (24)†† (time NS) 4.9 y††

Gribben et al,197 2005 137‡‡ 51 NR¶ 46 (7-212) 100 6.5 4 6-y PFS, 30% 6-y OS, 58

*ABMTR = Autologous Blood and Marrow Transplant Registry; autoSCT = autologous stem cell transplantation; CHOP = cyclophosphamide, hydroxydaunomycin (doxorubicin),vincristine (Oncovin) and prednisone; CLL = chronic lymphocytic leukemia; DFS = disease-free survival; EBMTR = European Bone Marrow Transplant Registry; EFS = event-free survival; F = fludarabine; FC = fludarabine and cyclophosphamide; GCLLSG = German CLL Study Group; GOELAMS = Groupe Ouest Est d’etude des Leucemies etAutres Maladies du Sang; IBMTR = International Bone Marrow Transplant Registry; MRC = Medical Research Council; NR = not reported; NS = not specified; OS = overallsurvival; PFS = progression-free survival; TRM = treatment-related mortality.

†117 patients enrolled (only 65 proceeded to autoSCT).‡Proportion of chemotherapy-naive patients not specified.§CHOP F vs autoSCT. Of 41 patients, 28 underwent autoSCT.⁄⁄There were 142 patients.¶48 patients in CR (after miniChOP and F) randomized to autoSCT or observation, whereas 52 patients not in CR randomized to autoSCT or FC.#CD34 selection performed in 15 of 88 patients.**There were 325 patients (of which 83 underwent autoSCT).††There were 128 of which 86% were chemotherapy-naive at study entry (only 98 proceeded to autoSCT).‡‡At least 41 patients had no prior therapy;

Patient characteristicsResponse and toxicity




tively) (Table 15).202-205,207,211,216 However, the incidences ofgrade 2 to grade 4 acute GVHD and chronic GVHD appearto be comparable in patients undergoing NMA or myelo-ablative SCT (9%-63% and 33%-75%, respectively, vs37%-56% and 40%-85%, respectively).195,201-207,209-216 Datasuggest that NMA SCT may overcome the negative prog-nostic impact of ZAP-70 positivity, unmutated VH genestatus, and/or chromosomal abnormalities (such as 11q–and 17p–).213,217 The optimal conditioning regimen andstrategy for prophylaxis of GVHD are unknown. Longerfollow-up is required to determine whether remissions aredurable, whether rates of relapse or disease progression arecomparable to those achieved with myeloablative SCT,and whether the use of donor leukocyte infusions toachieve either full donor chimerism or control diseaseposttransplantation is effective. Controlled trials are re-quired to determine whether NMA SCTs are superior toconventional chemotherapy in older patients and/or thosenot otherwise eligible for myeloablative SCT who haveadverse prognostic factors. In view of these uncertainties,NMA SCT should be performed in the context of a clinicaltrial.

COMPLICATIONSIMMUNE-MEDIATED CYTOPENIAS

Autoimmune Hemolytic Anemia. The prevalence ofpositive direct antiglobulin test (DAT) results in patientswith CLL varies from 2% to 35%, with a higher prevalence

with more advanced disease.217-219 Clinically detectable au-toimmune hemolytic anemia (AIHA) has been observed in3% to 37% of patients, usually those with advanced-stageCLL.99,218-223 Older age, male sex, and a higher lymphocytecount have also been associated with an increased rate ofAIHA at CLL diagnosis.221 In approximately one third ofpatients, AIHA will be diagnosed concurrently with thediagnosis of CLL.221 However, the development of AIHAdoes not have a negative impact on OS.221,222

The precise pathogenesis of AIHA in patients with CLLis unclear.219,220 Most patients have a warm AIHA mediatedby IgG antierythrocyte antibodies directed against antigensof the Rhesus system on red blood cells, whereas the re-maining have a cold AIHA mediated by monoclonal IgMantibodies that can fix and activate complement219-221,224;rarely, patients will have a mixed type AIHA, with a com-bination of warm and cold autoantibodies.225,226

Autoimmune hemolytic anemia and CLL should betreated independently.219,220 For warm AIHA, corticosteroidsare the standard initial therapy.219,220 If there is no response tocorticosteroids, intravenous immunoglobulin (IVIG) shouldbe added; however, response is usually transient, but re-treatment is effective. Cyclosporine is a reasonable choicewhen corticosteroids and IVIG have failed.219,220,227 Therapywith alemtuzumab alone or in combination with fludarabine,rituximab alone or in combination with fludarabine andcyclophosphamide or cyclophosphamide and dexametha-sone, and splenectomy or splenic irradiation may be effec-tive in refractory AIHA.219,220,228-234

TABLE 14. Selected Myeloablative Allogeneic Stem Cell Transplantation Trials*

Time fromMedian diagnosis Status before Median

No. of age to SCT SCT MUD follow-up TRM Disease control OSReference patients (y) (range, mo) (%) (%) (y) (%) (%) (%)

Horowitz et al,195 2000(IBMTR and ABMTR) 242 47 46 (2-214)† CR/stage 0 (16) 12 NR NR NR 3-y OS, 41-49

Michallet et al,201 1996(EBMTR and IBMTR) 54 41 37 (5-130) Stage III-IV (54) 0 NR >39 CRu 91 3-y OS, 46

Michallet et al,202 1999 187 43 42 (2-162) CR + PR (60) 5 NR 50 3-y relapse 3-y OS, 45(EBMTR) risk, 16

Pavletic et al,203 2000 23 46 19 (4-160) Refractory (61); 13 2.2 17 at 100 d CR 87;stage III-IV (56) 5-y FFS, 65 5-y OS, 62

Khouri et al,204 2002 28 43 NR Refractory (68); 5-y PFS, 42stage III-IV (71) 25 5.5‡ 11 at 100 d 5-y PFS, 42 5-y OS, 45

Doney et al,205 2002 25§ 46.6 61.2 (14.4-198) Refractory (64); 0 NR 28 NRM at CR, 52 5-y OS, 32stage III-IV (68) 100 d

Toze et al,206 2005 30 48 57.6 (3.6-156) NR 33 4.3 NRM, 47 5-y EFS, 39 5-y OS, 39Pavletic et al,207 2005 38 45 51 (8-213) Refractory (55); 100 6 29 at 100 d; CR, 58; 5-y OS, 33

stage III-IV (47) 5-y TRM, 38 PR, 11;5-y FFS, 30

*ABMTR = Autologous Blood and Marrow Transplant Registry; CR = complete remission; CRu = complete remission unconfirmed; EBMTR = European Bone MarrowTransplant Registry; EFS = event-free survival; FFS = failure-free survival; IBMTR = International Bone Marrow Transplant Registry; MUD = matched unrelated donor;NR = not reported; NRM = nonrelapse mortality; OS = overall survival; PFS = progression-free survival; PR = partial response; SCT = stem cell transplantation; TRM =treatment-related mortality.

†There were 325 patients (of 242 whom underwent autologous SCT).‡For 10 surviving patients only.§4 patients did not have immunophenotyping to confirm diagnosis.

Response and toxicity

Patient characteristics




Blood transfusions may be required for symptomaticAIHA before a response occurs to primary therapy. Trans-fusion therapy may be complicated by phenotyping prob-lems due to the presence of the autoantibodies, whichtypically reacts with all donor red blood cells. These au-toantibodies can mask alloantibodies stimulated by previ-ous transfusions or pregnancies and may contribute to al-lergic and febrile nonhemolytic transfusion reactions.235

Nonetheless, donor blood can be safely and expeditiouslyprovided.236,237

Immune-Mediated Thrombocytopenia. The true inci-dence of autoantibodies to platelets and other hematopoi-etic cells in patients with CLL is unknown because of thelack of available sensitive and reliable detection as-says.219,238 Despite this, the presence of autoantibodies toplatelets has been observed in 74% to 85% of patients withCLL,239,240 which is greater than the reported incidence ofimmune-mediated thrombocytopenia in patients with CLL(2%-4%).219,220,222 About one third of patients with CLL andimmune thrombocytopenia will also have either a positiveDAT result or AIHA (ie, Evan syndrome).220 The develop-ment of immune-mediated thrombocytopenia does notcompromise survival.222

The precise pathogenesis of thrombocytopenia in pa-tients with CLL is unknown.219,220 Optimal therapy for im-mune-mediated thrombocytopenia is unclear given thesmall number of patients. Immune-mediated thrombocy-topenia and CLL should be treated independently.219,220 Thetreatment strategy is based on recommendations made bythe American Society of Hematology for the treatment ofidiopathic thrombocytopenic purpura, with first-line ther-apy being corticosteroids.241 Refractory autoimmune throm-bocytopenia may respond to therapy with alemtuzumab orrituximab.242,243

Pure Red Cell Aplasia. Unlike AIHA, which ischaracterized by an increased number of reticulocytes,positive DAT, and elevated serum lactate dehydrogenaselevel, pure red cell aplasia (PRCA) is associated withreticulocytopenia and the absence of erythroid precursorsin the bone marrow.220 Pure red cell aplasia occurs in 1% to6% of patients with CLL; however, the true incidence maybe underestimated because patients are usually receivingmyelosuppressive therapy or may have a positive DAT or alarge spleen suggestive of hypersplenism.219,220,222,244 It mayoccur at the time of or several years after the diagnosis ofCLL, regardless of the type of prior therapy, and does not

TABLE 15. Selected Nonmyeloablative Stem Cell Transplantation Trials*

Time fromMedian diagnosis Status before Median

No. of age to SCT SCT MUD follow-up TRM Disease control OSReference patients (y) (range, mo) (%) (%) (y) (%) (%) (%)

Dreger et al,209

2003 (EBMTR) 77 54 49 (8-146) CR (10); 18 1.5 1-y TRM, 18 CR, 69; 2-y OS, 73PR (55) PR, 22;

2-y EFS, 56Schetelig et al,210 30† 50 48 (12-204) Refractory (46) 50 2 2-y NRM, 15 CR, 40; 2-y OS, 72

2003 PR, 53;2-y PFS, 67

Khouri et al,211 17 54 67 (22-168) Refractory (53) 0 1.8 0 at 100 d; CR, 71; 2-y OS, 802004 2-y TRM, 22 PR, 24;

2-y PFS, 60Sorror et al, 212 64‡ 56 52.8 (7.2-300) Refractory (53) 31 2 2-y NRM, 22 CR, 50; 2-y OS, 60

2005 2-y DFS, 52Caballero et al,213 30§ 53 44 (6-201) Refractory (20); 0 3.9 5.7-y NRM, 22 5-y DFS, 93 5-y OS, 72

2005 CR (17);PR (63)

Schetelig et al,214

2004 20 54 NR NR 80 1.1 NR 1-y PFS, 50 1-y OS, 75Brown et al,215 50 53 76.8 (2.4-176.4) Refractory (6); 62 1⁄⁄ NR 2-y PFS, 28⁄⁄ 2-y OS, 48⁄⁄

2005 CR (16);PR (26)

Delgado et al,216 41 54 54 (10-164) Refractory (17); 42 1.2 5 at 100 d; 2-y PFS, 45 2-y OS, 512006 CR (12); 2-y TRM, 26

PR (70)

*CLL = chronic lymphocytic leukemia; PLL = prolymphocytic leukemia; SLL = small lymphocytic leukemia. For expansions of all other abbreviations,please see Table 14.

†Includes 1 patient with PLL.‡Includes patients with CLL/SLL (n=5) and CLL/PLL (n=3).§Includes 2 patients with Richter syndrome.⁄⁄Surviving patients only (n=31).

Patient characteristics

Response and toxicity




appear to affect prognosis.244 T-cell mediated inhibition oferythropoiesis plays a major role in the development ofPRCA.220,244

Given the rarity of PRCA, assessing treatment efficacyis difficult. The underlying CLL must be treated concur-rently to achieve long-term control of the PRCA.220 Ini-tially, PRCA is treated with corticosteroids. If no responseoccurs, cyclosporine is added. After normalization of thehemoglobin level, the corticosteroids are tapered and dis-continued, and cyclosporine is continued for 5 to 7 monthsfollowed by a slow taper.220 Also, PRCA may respond totherapy with rituximab and alemtuzumab.242,243,245

Therapy-Related Autoimmunity. Alkylating agents,radiotherapy, and purine analogues may trigger hemolysis,PRCA, and/or immune thrombocytopenia.95,96,98,219,223,246

Most cases of AIHA associated with fludarabine have oc-curred in heavily pretreated patients, usually in those whohave received a prior alkylating agent, irrespective ofDAT status.219,220,247 Most patients were responding totherapy at the time of development of AIHA; some, butnot all, patients had a history of AIHA.247 Development oftreatment-associated AIHA and/or immune thrombocy-topenia may be related to immunosuppression with adisturbance in the immunoregulatory T cells; immune toler-ance is impaired with an inability to recognize self-anti-gens.219,220,248 Recent data suggest that AIHA may occur morefrequently in previously untreated patients who receive analkylating agent than in those receiving fludarabine; flu-darabine and cyclophosphamide chemotherapy may have aprotective effect against the development of AIHA. 98,99,223

Successful treatment of autoimmunity after fludarabinetherapy has been reported with use of corticosteroids,rituximab, and cyclosporine.227,247,249-252 Recurrence ofAIHA or immune thrombocytopenia after reexposure topurine analogues has been reported.220,247,248,253 It is unclearwhether this can be prevented by administering purineanalogues with an alkylating agent or cyclosporine.227 Be-cause life-threatening and sometimes fatal AIHA has beenreported, it would appear prudent not to rechallenge thesepatients with a purine analogue.219

INFECTIONSThe types of infections, risk factors, and therapy-associatedimmune defects in patients with CLL have been exten-sively reviewed recently.254-256 It is estimated that up to 70%of patients will develop infections, with incidences varyingfrom as low as 0.009 per patient-year to as high as 1.82 perpatient-year depending on the group of CLL patients. Fur-thermore, up to 55% of deaths in patients with CLL areattributed to infections.

Because of the lack of randomized trials, strategies forpreventing infections in patients with CLL should be

guided by the patient’s age, stage of disease, extent of priortherapy, and immunosuppressive properties of the anti-neoplastic agent being administered. Intravenous immuno-globulin has been shown to decrease the incidence of bacte-rial infections in patients with CLL.257,258 However, giventhe expense, lack of improvement in OS, and the effective-ness of less-expensive antibiotics, the role of IVIG islimited in patients with CLL259 but may be warranted inpatients with hypogammaglobulinemia and recurrent sino-pulmonary infections.254-256 Growth factors may reduce theseverity and duration of neutropenia associated withnucleoside analogues; however, their routine use remainsto be established.255 Concomitant use of nucleoside ana-logues and corticosteroids should be avoided. Despite thelack of randomized trials demonstrating the effectivenessof Pneumocystis jirovecii (formerly P carinii) prophylaxisin this patient population, some have advocated prophy-laxis for all patients receiving purine analogues and/oralemtuzumab because of the high mortality rate in infectedindividuals.254 Similarly, given the morbidity associatedwith varicella zoster viral infections, prophylaxis in olderseropositive patients with low CD4 counts and those re-ceiving therapy with alemtuzumab may be warranted.256,260

Patients should also be screened before and monitoredduring and after alemtuzumab therapy for CMV reactiva-tion and infections.260 Recent data from a single-centerrandomized study indicated that valganciclovir can effec-tively prevent CMV reactivation compared with valacy-clovir (0% vs 35%; P=.004).261

SECOND MALIGNANCIESSecond cancers, including Kaposi sarcoma, malignantmelanoma, cancers of the larynx and lung, brain cancer,and cancers of the stomach and bladder, have been ob-served in up to 11% of patients with CLL.92,262-265 Theoverall risk of developing a second cancer was modestlybut significantly elevated, independent of initial treatment,in patients with CLL compared with those in the generalpopulation. Differences in cancer distribution have beenassociated with sex and age.262-264 The increased incidenceof second neoplasms in patients with CLL may be relatedto immunologic impairment associated with CLL255 and/orheightened responses to carcinogens, such as tobaccosmoke and excessive sunlight, but does not appear to berelated to therapy.262,264,265 Given the long survival of pa-tients with CLL, they should be monitored for the occur-rence of second malignancies and urged to avoid exposuresto carcinogens, such as tobacco smoke and excessive sun-light.

The development of AML or MDS in patients with CLLis uncommon (1%), but it has been reported in bothuntreated and treated patients and can be detected concur-




rently.53,265-273 It is unclear whether the development ofMDS or AML occurs from clonal evolution or independenttransforming events.269,271,273 An increased frequency oftherapy-related MDS and/or AML has been observed inpatients treated with fludarabine and chlorambucil therapycompared with single-agent fludarabine or chlorambu-cil.95,107 Patients with CLL in whom AML or MDS devel-ops appear to have prognoses similar to those with de novoAML or MDS.266

DISEASE TRANSFORMATIONTransformation of CLL to an aggressive form of disease,either PLL (with >55% circulating prolymphocytes) orRichter syndrome (RS) (large cell lymphoma or immuno-blastic lymphoma), occurs in a small proportion of pa-tients.274-282 Transformation to acute lymphocytic leukemia,Hodgkin lymphoma, and multiple myeloma has also beendescribed.282

Richter Syndrome. Up to 10% of patients with B-CLL/SLL will undergo histological transformation to RS. Fea-tures associated with RS include systemic symptoms, rap-idly progressive lymphadenopathy, extranodal disease,monoclonal gammopathy, and an elevated lactate dehydro-genase level. Other findings include hepatosplenomegaly,anemia, thrombocytopenia, and atypical extranodal sites ofinvolvement (eg, brain, respiratory tract, skin, and gas-trointestinal tract).282,283 Although these features are un-usual in CLL, none are pathognomic for RS. The patho-physiology has been extensively reviewed.274,282

Treatment of RS has commonly involved chemothera-peutic regimens traditionally used for NHL, such as thealkylating agent-based, anthracycline-based, and cytarabine/platinum regimens, as well as therapies for the treatment ofHodgkin lymphoma. These regimens have produced ORrates of 25% to 41% (PR, 6%-15%; CR, 10%-34%).274 How-ever, median survival after transformation to RS is less than6 months. Therapy with newer regimens, eg, hyperCVXD(fractionated cyclophosphamide, vincristine, liposomaldaunorubicin [daunoXome], and dexamethasone) aug-mented hyperCVXD, and yttrium-90 ibritumomab tiuxetan,has not produced major improvements in response rates orOS.

In a small series of 12 patients treated with allogeneicSCT, 3 patients remained alive and in remission at 14, 47,and 67 months, respectively.211,284-286 At the time of transplan-tation, only 3 patients had achieved a CR or PR, including 2of the 3 patients who were still alive after allogeneic SCT.These favorable results compared to those obtained withchemotherapy alone need to be confirmed in a larger seriesof patients.

Prolymphocytic Leukemia. Because of the relative rar-ity of cases,275-281 discrepancies in the percentage of circulat-

ing prolymphocytes required for a diagnosis of PLL trans-formation, and lack of serial blood work available for assess-ment,277,278,281 data are extremely limited with respect to notonly the incidence of PLL transformation but also the me-dian time to transformation, OS, and optimal therapy.277-280 Ina small series of patients with typical CLL who had serialblood films available for review, most had minor variationsor transient increases in the percentage of circulatingprolymphocytes, and one third had a steady increase in theproportion of prolymphocytes (but always <55%).287 In con-trast, 19% of patients with CLL/PLL (defined by the pres-ence of 11%-55% prolymphocytes) had progression to aPLL-like picture.287

Features associated with transformation include leuko-cytosis (white blood cell count >100 × 109/L), spleno-megaly, hepatomegaly, and lymphadenopathy; centralnervous system involvement288-290 and development of ma-lignant ascites, pleural effusions, and periorbital swellinghave been described.291,292 Median age at transformationwas 76 years (range, 64-82 years).275-280 Median time totransformation and survival from the time of transforma-tion were 38 months (range, 15-192 months) and 5 months(range, <1-27.5 months), respectively.275-280 Optimal ther-apy, including the role of SCT, is unclear. 176,293-299

SUMMARYImportant changes in the understanding and managementof CLL have occurred in the past 2 decades. With theadvent of newer treatment modalities, such as purine ana-logues and monoclonal antibodies, substantial improve-ments have been made in achieving CRs, with a proportionachieving molecular remissions and durable responses,which may translate into increased survival for these pa-tients. Allogeneic myeloablative SCT may benefit youngerpatients but is still associated with pronounced treatment-related mortality and morbidity. Nonmyeloablative SCT isassociated with less toxicity, but its role in the treatment ofCLL remains to be defined. Future therapy will be modi-fied by the integration of prognostic factors into the treat-ment alogorithm.

REFERENCES1. Diehl LF, Karnell LH, Menck HR, the American College of Surgeons

Commission on Cancer and the American Cancer Society. The NationalCancer Data Base report on age, gender, treatment, and outcomes of patientswith chronic lymphocytic leukemia. Cancer. 1999;86:2684-2692.

2. US Cancer Statistics Working Group. United States Cancer Statistics:2000 Incidence. Atlanta, Ga: Department of Health and Human Services,Centers for Disease Control and Prevention, and National Cancer Institute;2003.

3. Jaffe ES, ed. Pathology and Genetics of Tumours of Haematopoieticand Lymphoid Tissues. Lyon, France: IARC Press; 2001.

4. Jemal A, Clegg LX, Ward E, et al. Annual report to the nation on thestatus of cancer, 1975-2001, with a special feature regarding survival. Cancer.2004;101:3-27.




5. Cronkite EP. An historical account of clinical investigations on chroniclymphocytic leukemia in the Medical Research Center, Brookhaven NationalLaboratory. Blood Cells. 1987;12:285-295.

6. Zahm SH, Weisenburger DD, Babbitt PA, Saal RC, Vaught JB, Blair A.Use of hair coloring products and the risk of lymphoma, multiple myeloma,and chronic lymphocytic leukemia. Am J Public Health. 1992;82:990-997.

7. Inskip PD, Kleinerman RA, Stovall M, et al. Leukemia, lymphoma, andmultiple myeloma after pelvic radiotherapy for benign disease. Radiat Res.1993;135:108-124.

8. Faguet GB. Chronic lymphocytic leukemia: an updated review. J ClinOncol. 1994;12:1974-1990.

9. Horwitz M, Goode EL, Jarvik GP. Anticipation in familial leukemia.Am J Hum Genet. 1996;59:990-998.

10. Yuille MR, Houlston RS, Catovsky D. Anticipation in familial chroniclymphocytic leukaemia. Leukemia. 1998;12:1696-1698.

11. Goldin LR, Sgambati M, Marti GE, Fontaine L, Ishibe N, Caporaso N.Anticipation in familial chronic lymphocytic leukemia. Am J Hum Genet.1999;65:265-269.

12. Yuille MR, Matutes E, Marossy A, Hilditch B, Catovsky D, HoulstonRS. Familial chronic lymphocytic leukaemia: a survey and review of publishedstudies. Br J Haematol. 2000;109:794-799.

13. Ishibe N, Sgambati MT, Fontaine L, et al. Clinical characteristics offamilial B-CLL in the National Cancer Institute Familial Registry. LeukLymphoma. 2001;42:99-108.

14. Rai KR, Driscoll N, Janson D, et al. Incidence of CLL and other cancersin families of CLL patients [abstract]. Blood. 2003;102:188a. Abstract 655.

15. Capalbo S, Trerotoli P, Ciancio A, Battista C, Serio G, Liso V.Increased risk of lymphoproliferative disorders in relatives of patients with B-cell chronic lymphocytic leukemia: relevance of the degree of familial linkage.Eur J Haematol. 2000;65:114-117.

16. Capalbo S, Callea V, Musolino C, et al. Familial B-cell chroniclymphocytic leukemia in a population of patients from Southern Italy. Int JHematol. 2004;79:354-357.

17. Jonsson V, Houlston RS, Catovsky D, et al. CLL family ‘Pedigree 14’revisited: 1947-2004. Leukemia. 2005;19:1025-1028.

18. Houlston RS, Catovsky D, Yuille MR. Genetic susceptibility to chroniclymphocytic leukemia. Leukemia. 2002;16:1008-1014.

19. Ishibe N, Prieto D, Hosack DA, et al. Telomere length and heavy-chainmutation status in familial chronic lymphocytic leukemia. Leuk Res. 2002;26:791-794.

20. Benzow KA, Koob MD, Condie A, et al. Instability of CAG-trinucleotide repeats in chronic lymphocytic leukemia. Leuk Lymphoma. 2002;43:1987-1990.

21. Sellick GS, Webb EL, Allinson R, et al. A high-density SNP genome-wide linkage scan for chronic lymphocytic leukemia-susceptibility loci. Am JHum Genet. 2005 Sep;77:420-429. Epub 2005 Aug 2.

22. Dao-Ung LP, Fuller SJ, Sluyter R, et al. Association of the 1513Cpolymorphism in the P2X7 gene with familial forms of chronic lymphocyticleukaemia. Br J Haematol. 2004;125:815-817.

23. Wiernik PH, Ashwin M, Hu XP, Paietta E, Brown K. Anticipation infamilial chronic lymphocytic leukaemia. Br J Haematol. 2001;113:407-414.

24. Rassenti LZ, Toy TL, Huynh L, et al. High similarity between familialand sporadic cases of chronic lymphocytic leukemia [abstract]. Blood. 2003;102:670a. Abstract 2481.

25. Haddad TC, Shanafelt TD, Slager SL, et al. Familial chronic lympho-cytic leukemia (CLL): the Mayo Clinic experience [abstract]. Blood. 2004;102:527a. Abstract 1906.

26. Goldin LR, Pfeiffer RM, Li X, Hemminki K. Familial risk oflymphoproliferative tumors in families of patients with chronic lymphocyticleukemia: results from the Swedish Family-Cancer Database. Blood. 2004 Sep15;104:1850-1854. Epub 2004 May 25.

27. Daugherty SE, Pfeiffer RM, Mellemkjaer L, Hemminki K, Goldin LR.No evidence for anticipation in lymphoproliferative tumors in population-based samples. Cancer Epidemiol Biomarkers Prev. 2005;14:1245-1250.

28. Sakai A, Marti GE, Caporaso N, et al. Analysis of expressed immuno-globulin heavy chain genes in familial B-CLL. Blood. 2000;95:1413-1419.

29. Pritsch O, Troussard X, Magnac C, et al. VH gene usage by familymembers affected with chronic lymphocytic leukaemia. Br J Haematol. 1999;107:616-624.

30. Rozman C, Montserrat E. Chronic lymphocytic leukemia [publishedcorrection appears in N Engl J Med. 1995;333:1515]. N Engl J Med. 1995;333:1052-1057.

31. Molica S, Levato D. What is changing in the natural history of chroniclymphocytic leukemia? Haematologica. 2001;86:8-12.

32. Rozman C, Bosch F, Montserrat E. Chronic lymphocytic leukemia: achanging natural history? Leukemia. 1997;11:775-778.

33. Pangalis GA, Vassilakopoulos TP, Dimopoulou MN, Siakantaris MP,Kontopidou FN, Angelopoulou MK. B-chronic lymphocytic leukemia:practical aspects. Hematol Oncol. 2002;20:103-146.

34. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia:revised guidelines for diagnosis and treatment. Blood. 1996;87:4990-4997.

35. Binet JL, Caligaris-Cappio F, Catovsky D, et al, InternationalWorkshop on Chronic Lymphocytic Leukemia (IWCLL). Perspectives on theuse of new diagnostic tools in the treatment of chronic lymphocytic leukemia.Blood. 2006 Feb 1;107:859-861. Epub 2005 Oct 13.

36. Harris NL, Jaffe ES, Stein H, et al. A revised European-Americanclassification of lymphoid neoplasms: a proposal from the InternationalLymphoma Study Group. Blood. 1994;84:1361-1392.

37. Geisler CH, Larsen JK, Hansen NE, et al. Prognostic importance of flowcytometric immunophenotyping of 540 consecutive patients with B-cellchronic lymphocytic leukemia. Blood. 1991;78:1795-1802.

38. Monaghan SA, Peterson LC, James C, et al. Pan B-cell markers are notredundant in analysis of chronic lymphocytic leukemia (CLL). Cytometry BClin Cytom. 2003;56:30-42.

39. Criel A, Michaux L, De Wolf-Peeters C. The concept of typical andatypical chronic lymphocytic leukaemia. Leuk Lymphoma. 1999;33:33-45.

40. Kurec AS, Threatte GA, Gottlieb AJ, Smith JR, Anderson J, Davey FR.Immunophenotypic subclassification of chronic lymphocytic leukaemia (CLL).Br J Haematol. 1992;81:45-51.

41. Moreau EJ, Matutes E, A’Hern RP, et al. Improvement of the chroniclymphocytic leukemia scoring system with the monoclonal antibody SN8(CD79b). Am J Clin Pathol. 1997;108:378-382.

42. Matutes E, Polliack A. Morphological and immunophenotypic featuresof chronic lymphocytic leukemia. Rev Clin Exp Hematol. 2000;4:22-47.

43. Oscier D, Fegan C, Hillmen P, et al, Guidelines Working Group of theUK CLL Forum, British Committee for Standards in Haematology. Guidelineson the diagnosis and management of chronic lymphocytic leukaemia. Br JHaematol. 2004;125:294-317.

44. Gascoyne RD. Differential diagnosis of the chronic B-cell lymphoidleukemias. In: Cheson BD, ed. Chronic Lymphoid Leukemias. 2nd ed. NewYork, NY: Marcel Dekker; 2001:209-230.

45. Rozman C, Montserrat E, Vinolas N. Serum immunoglobulins in B-chronic lymphocytic leukemia: natural history and prognostic significance.Cancer. 1988;61:279-283.

46. DiGiuseppe JA, Borowitz MJ. Clinical utility of flow cytometry in thechronic lymphoid leukemias. Semin Oncol. 1998;25:6-10.

47. Johnston JB. Chronic lymphocytic leukemia. In: Greer JP, Foerster JF,Lukens JN, Rodgers GM, Paraskevas F, Glader B, eds. Wintrobe’s ClinicalHematology. Vol 2. 11th ed. Philadelphia, Pa: Lippincott Williams & Wilkins;2004:2429-2463.

48. Marti GE, Rawstron AC, Ghia P, et al, The International Familial CLLConsortium. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br JHaematol. 2005;130:325-332.

49. Rawstron AC, Yuille MR, Fuller J, et al. Inherited predisposition toCLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood.2002;100:2289-2290.

50. Marti GE, Carter P, Abbasi F, et al. B-cell monoclonal lymphocytosisand B-cell abnormalities in the setting of familial B-cell chronic lymphocyticleukemia. Cytometry B Clin Cytom. 2003;52:1-12.

51. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, PasternackBS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219-234.

52. Binet JL, Auquier A, Dighiero G, et al. A new prognostic classificationof chronic lymphocytic leukemia derived from a multivariate survival analysis.Cancer. 1981;48:198-206.

53. Dighiero G, Maloum K, Desablens B, et al, French Cooperative Groupon Chronic Lymphocytic Leukemia. Chlorambucil in indolent chroniclymphocytic leukemia. N Engl J Med. 1998;338:1506-1514.

54. Shanafelt TD, Geyer SM, Kay NE. Prognosis at diagnosis: integratingmolecular biologic insights into clinical practice for patients with CLL. Blood.2004 Feb 15;103:1202-1210. Epub 2003 Oct 23.

55. Melo JV, Catovsky D, Gregory WM, Galton DA. The relationshipbetween chronic lymphocytic leukaemia and prolymphocytic leukaemia, IV:analysis of survival and prognostic features. Br J Haematol. 1987;65:23-29.

56. Juliusson G, Merup M. Cytogenetics in chronic lymphocytic leukemia.Semin Oncol. 1998;25:19-26.




57. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations andsurvival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-1916.

58. Mayr C, Speicher MR, Kofler DM, et al. Chromosomal translocationsare associated with poor prognosis in chronic lymphocytic leukemia. Blood.2006 Jan 15;107:742-751. Epub 2005 Sep 22.

59. Krober A, Seiler T, Benner A, et al. V(H) mutation status, CD38expression level, genomic aberrations, and survival in chronic lymphocyticleukemia. Blood. 2002;100:1410-1416.

60. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK.Unmutated Ig V(H) genes are associated with a more aggressive form ofchronic lymphocytic leukemia. Blood. 1999;94:1848-1854.

61. Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38expression as novel prognostic indicators in chronic lymphocytic leukemia.Blood. 1999;94:1840-1847.

62. Vasconcelos Y, Davi F, Levy V, et al. Binet’s staging system and VHgenes are independent but complementary prognostic indicators in chroniclymphocytic leukemia. J Clin Oncol. 2003;21:3928-3932.

63. Lin K, Sherrington PD, Dennis M, Matrai Z, Cawley JC, Pettitt AR.Relationship between p53 dysfunction, CD38 expression, and IgV(H)mutation in chronic lymphocytic leukemia [published correction appears inBlood. 2002;100:2291]. Blood. 2002;100:1404-1409.

64. Tobin G, Thunberg U, Johnson A, et al. Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood.2002;99:2262-2264.

65. Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis ofprognostic factors in CLL: clinical stage, IGVH gene mutational status, andloss or mutation of the p53 gene are independent prognostic factors. Blood.2002;100:1177-1184.

66. Byrd JC, Gribben JG, Peterson BL, et al. Select high-risk geneticfeatures predict earlier progression following chemoimmunotherapy withfludarabine and rituximab in chronic lymphocytic leukemia: justification forrisk-adapted therapy. J Clin Oncol. 2006 Jan 20;24:437-443. Epub 2005 Dec12.

67. Hamblin TJ, Orchard JA, Ibbotson RE, et al. CD38 expression andimmunoglobulin variable region mutations are independent prognosticvariables in chronic lymphocytic leukemia, but CD38 expression may varyduring the course of the disease. Blood. 2002;99:1023-1029.

68. Thunberg U, Johnson A, Roos G, et al. CD38 expression is a poorpredictor for VH gene mutational status and prognosis in chronic lymphocyticleukemia. Blood. 2001;97:1892-1894.

69. Gentile M, Mauro FR, Calabrese E, et al. The prognostic value of CD38expression in chronic lymphocytic leukaemia patients studied prospectively atdiagnosis: a single institute experience. Br J Haematol. 2005;130:549-557.

70. Rosenwald A, Alizadeh AA, Widhopf G, et al. Relation of geneexpression phenotype to immunoglobulin mutation genotype in B cell chroniclymphocytic leukemia. J Exp Med. 2001;194:1639-1647.

71. Klein U, Tu Y, Stolovitzky GA, et al. Gene expression profiling of Bcell chronic lymphocytic leukemia reveals a homogeneous phenotype relatedto memory B cells. J Exp Med. 2001;194:1625-1638.

72. Chen L, Apgar J, Huynh L, et al. ZAP-70 directly enhances IgMsignaling in chronic lymphocytic leukemia. Blood. 2005 Mar 1;105:2036-2041. Epub 2004 Oct 28.

73. Orchard JA, Ibbotson RE, Davis Z, et al. ZAP-70 expression andprognosis in chronic lymphocytic leukaemia. Lancet. 2004;363:105-111.

74. Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immuno-globulin heavy-chain gene mutation status as a predictor of disease progressionin chronic lymphocytic leukemia. N Engl J Med. 2004;351:893-901.

75. Crespo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogatefor immunoglobulin-variable-region mutations in chronic lymphocyticleukemia. N Engl J Med. 2003;348:1764-1775.

76. Wiestner A, Rosenwald A, Barry TS, et al. ZAP-70 expressionidentifies a chronic lymphocytic leukemia subtype with unmutated immuno-globulin genes, inferior clinical outcome, and distinct gene expression profile.Blood. 2003 Jun 15;101:4944-4951. Epub 2003 Feb 20.

77. Orchard J, Ibbotson R, Best G, Parker A, Oscier D. ZAP-70 in B cellmalignancies. Leuk Lymphoma. 2005;46:1689-1698.

78. Kay S, Herishanu Y, Pick M, et al. Quantitative flow cytometry of ZAP-70 levels in chronic lymphocytic leukemia using molecules of equivalentsoluble fluorochrome. Cytometry B Clin Cytom. 2006 Feb 2; [Epub ahead ofprint].

79. Bergmann M, Eichhorst B, Busch R, Hallek M. Elevated thymidinekinase and short lymphocyte doubling time in combination with unfavorablecytogenetics or unmutated IgVH status are strong predictors for high individual

risk for rapid disease progression in patients with B-CLL in Binet Stage A: aninterim report from the CLL1 protocol of the German CLL Study Group(GCLLSG) [abstract]. Blood. 203:102:665a. Abstract 2464.

80. Stilgenbauer S, Kröber A, Busch R, et al. 17p deletion predicts forinferior overall survival after fludarabine-based first line therapy in chroniclymphocytic leukemia: first analysis of genetics in the CLL4 trial of theGCLLSG [abstract]. Blood. 2005;106:212a. Abstract 715.

81. Bottcher S, Ritgen M, Pott C, et al. Comparative analysis of minimalresidual disease detection using four-color flow cytometry, consensus IgH-PCR, and quantitative IgH PCR in CLL after allogeneic and autologous stemcell transplantation. Leukemia. 2004;18:1637-1645.

82. Moreno C, Villamor N, Colomer D, et al. Clinical significance ofminimal residual disease, as assessed by different techniques, after stem celltransplantation for chronic lymphocytic leukemia. Blood. 2006 Jun 1;107:4563-4569. Epub 2006 Jan 31.

83. Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residualdisease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy isassociated with prolonged survival. J Clin Oncol. 2005 May 1;23:2971-2979.Epub 2005 Feb 28.

84. Rawstron AC, Kennedy B, Evans PA, et al. Quantitation of minimaldisease levels in chronic lymphocytic leukemia using a sensitive flowcytometric assay improves the prediction of outcome and can be used tooptimize therapy. Blood. 2001;98:29-35.

85. Del Poeta G, Del Principe MI, Consalvo MA, et al. The addition ofrituximab to fludarabine improves clinical outcome in untreated patients withZAP-70-negative chronic lymphocytic leukemia. Cancer. 2005;104:2743-2752.

86. Milligan DW, Fernandes S, Dasgupta R, et al, National CancerResearch Institute Haematological Studies Group. Results of the MRC pilotstudy show autografting for younger patients with chronic lymphocyticleukemia is safe and achieves a high percentage of molecular responses. Blood.2005 Jan 1;105:397-404. Epub 2004 Apr 29.

87. Meloni G, Proia A, Mauro F, et al. Unmanipulated peripheral bloodstem cell autograft in chronic lymphocytic leukemia: clinical findings andbiological monitoring. Haematologica. 2000;85:952-960.

88. Esteve J, Villamor N, Colomer D, Montserrat E. Different clinical valueof minimal residual disease after autologous and allogenic stem celltransplantation for chronic lymphocytic leukemia. Blood. 2002;99:1873-1874.

89. Esteve J, Villamor N, Colomer D, et al. Stem cell transplantation forchronic lymphocytic leukemia: different outcome after autologous andallogeneic transplantation and correlation with minimal residual disease status.Leukemia. 2001;15:445-451.

90. Provan D, Bartlett-Pandite L, Zwicky C, et al. Eradication ofpolymerase chain reaction-detectable chronic lymphocytic leukemia cells isassociated with improved outcome after bone marrow transplantation. Blood.1996;88:2228-2235.

91. Dreger P, Ritgen M, Bottcher S, Schmitz N, Kneba M. The prognosticimpact of minimal residual disease assessment after stem cell transplantationfor chronic lymphocytic leukemia: is achievement of molecular remissionworthwhile? Leukemia. 2005;19:1135-1138.

92. Keating MJ, O’Brien S, Lerner S, et al. Long-term follow-up of patientswith chronic lymphocytic leukemia (CLL) receiving fludarabine regimens asinitial therapy. Blood. 1998;92:1165-1171.

93. CLL Trialists’ Collaborative Group. Chemotherapeutic options inchronic lymphocytic leukemia: a meta-analysis of the randomized trials. J NatlCancer Inst. 1999;91:861-868.

94. Johnson S, Smith AG, Loffler H, et al, The French Cooperative Groupon CLL. Multicentre prospective randomised trial of fludarabine versuscyclophosphamide, doxorubicin, and prednisone (CAP) for treatment ofadvanced-stage chronic lymphocytic leukaemia. Lancet. 1996;347:1432-1438.

95. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared withchlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl JMed. 2000;343:1750-1757.

96. Leporrier M, Chevret S, Cazin B, et al, French Cooperative Group onChronic Lymphocytic Leukemia. Randomized comparison of fludarabine,CAP, and ChOP in 938 previously untreated stage B and C chroniclymphocytic leukemia patients. Blood. 2001;98:2319-2325.

97. Eichhorst BF, Busch R, Stauch M, et al. Fludarabine (F) induces higherresponse rates in first line therapy of older patients (pts) with advanced chroniclymphocytic leukemia (CLL) than chlorambucil: interim analysis of a phase IIIstudy of the German CLL Study Group (GCLLSG) [abstract]. Blood.2003;102:109a. Abstract 369.




98. Catovsky D, Richards S, Hillmen P. Early results from LRF CLL4: a UKmulticenter randomized trial [abstract]. Blood. 2005;106:212a. Abstract 716.

99. Eichhorst BF, Busch R, Hopfinger G, et al, German CLL Study Group.Fludarabine plus cyclophosphamide versus fludarabine alone in first-linetherapy of younger patients with chronic lymphocytic leukemia. Blood. 2006Feb 1;107:885-891. Epub 2005 Oct 11.100. Flinn IW, Kumm E, Grever MR, et al. Fludarabine and cyclophospha-

mide produces a higher complete response rate and more durable remissionsthan fludarabine in patients with previously untreated CLL: Intergroup TrialE2997 [abstract]. Blood. 2004;104:139a. Abstract 475.101. Rummel MJ, Stilgenbauer S, Gamm H, et al. Fludarabine versus

fludarbine plus epirubicin in the treatment of chronic lymphocytic leukemia:final results of a German randomized phase-III study [abstract]. Blood.2005;106:600a. Abstract 2123.102. Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study

of fludarabine with concurrent versus sequential treatment with rituximab insymptomatic, untreated patients with B-cell chronic lymphocytic leukemia:results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003Jan 1;101:6-14. Epub 2002 Jul 5.103. Robak T, Blonski JZ, Kasznicki M, et al. Cladribine with prednisone

versus chlorambucil with prednisone as first-line therapy in chronic lympho-cytic leukemia: report of a prospective, randomized, multicenter trial. Blood.2000;96:2723-2729.104. Robak T, Blonski JZ, Gora-Tybor J, et al. Cladribine alone and in

combination with cyclophosphamide or cyclophosphamide plus mitoxantronein the treatment of progressive chronic lymphocytic leukemia: report ofprospective, multicenter, randomized trial of the Polish Adult Leukemia Group(PALG CLL2). Blood. 2006 Mar 21; [Epub ahead of print].105. Weiss MA, Glenn M, Maslak P, et al. Consolidation therapy with high-

dose cyclophosphamide improves the quality of response in patients withchronic lymphocytic leukemia treated with fludarabine as induction therapy.Leukemia. 2000;14:1577-1582.106. O’Brien SM, Kantarjian HM, Cortes J, et al. Results of the fludarabine

and cyclophosphamide combination regimen in chronic lymphocyticleukemia. J Clin Oncol. 2001;19:1414-1420.107. Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoimmu-

notherapy regimen of fludarabine, cyclophosphamide, and rituximab as initialtherapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23:4079-4088. Epub 2005 Mar 14.108. Cazin BF, Maloum K, Créteil MD, et al. Oral fludarabine phosphate and

cyclophosphamide in previously untreated CLL: final response and follow-upin 75 patients [abstract]. Blood. 2003;102:438a. Abstract 1598.109. Morrison VA, Rai KR, Peterson BL, et al. Impact of therapy with

chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections inpatients with chronic lymphocytic leukemia: Intergroup Study Cancer andLeukemia Group B 9011. J Clin Oncol. 2001;19:3611-3621.110. Morrison VA, Rai KR, Peterson BL, et al. Therapy-related myeloid

leukemias are observed in patients with chronic lymphocytic leukemia af-ter treatment with fludarabine and chlorambucil: results of an intergroupstudy, cancer and leukemia group B 9011. J Clin Oncol. 2002;20:3878-3884.111. Tefferi A, Levitt R, Li CY, et al. Phase II study of 2-chlorodeoxy-

adenosine in combination with chlorambucil in previously untreated B-cellchronic lymphocytic leukemia. Am J Clin Oncol. 1999;22:509-516.112. Tefferi A, Li CY, Reeder CB, et al. A phase II study of sequential

combination chemotherapy with cyclophosphamide, prednisone, and 2-chlorodeoxyadenosine in previously untreated patients with chronic lympho-cytic leukemia. Leukemia. 2001;15:1171-1175.113. Bosch F, Ferrer A, Lopez-Guillermo A, et al, GELCAB (Grup per

l’Estudi dels Limfomes a Catalunya i Balears). Fludarabine, cyclophospha-mide and mitoxantrone in the treatment of resistant or relapsed chroniclymphocytic leukaemia. Br J Haematol. 2002;119:976-984.114. Schmitt BF, Franke A, Burkhard O, et al. Fludarabine, mitoxantrone

and cyclophosphamide combination therapy in relapsed chronic lymphocyticleukemia (CLL) with or without G-CSF: results of the first interim ana[n]lysisof a phase III study of the German CLL Study Group (GCLLSCG) [abstract].Blood. 2002;100:364b. Abstract 5015.115. Tsimberidou AM, Keating MJ, Giles FJ, et al. Fludarabine and mitox-

antrone for patients with chronic lymphocytic leukemia. Cancer. 2004;100:2583-2591.

116. Bosch F, Ferrer A, Villamor N, et al. Combination chemotherapy withfludarabine, cyclosphosphamide and mitoxantrone (FCM) induced a highresponse rate in previously untreated CLL [abstract]. Blood. 2005;106:213a.Abstract 718.

117. Saven A, Lemon RH, Kosty M, Beutler E, Piro LD. 2-Chlorodeoxy-adenosine activity in patients with untreated chronic lymphocytic leukemia. JClin Oncol. 1995;13:570-574.118. Robak T, Blonski JZ, Kasznicki M, et al. Cladribine with or without

prednisone in the treatment of previously treated and untreated B-cell chroniclymphocytic leukaemia: updated results of the multicentre study of 378patients. Br J Haematol. 2000;108:357-368.119. Dillman RO, Mick R, McIntyre OR. Pentostatin in chronic lymphocytic

leukemia: a phase II trial of Cancer and Leukemia group B. J Clin Oncol. 1989;7:433-438.120. Hainsworth JD, Burris HA III, Morrissey LH, et al. Rituximab mono-

clonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. Blood. 2000;95:3052-3056.121. Hainsworth JD, Litchy S, Barton JH, et al, Minnie Pearl Cancer

Research Network. Single-agent rituximab as first-line and maintenancetreatment for patients with chronic lymphocytic leukemia or small lymphocyticlymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. JClin Oncol. 2003;21:1746-1751.122. Thomas DA, O’Brien S, Giles FJ, et al. Single agent Rituxan in early

stage chronic lymphocytic leukemia (CLL) [abstract]. Blood. 2001;98:364a.Abstract 1533.123. O’Brien S, Wierda WG, Faderl S, et al. FCR-3 as frontline therapy for

patients with chronic lymphocytic (CLL) [abstract]. Blood. 2005;106:599a.Abstract 2117.

124. Schulz H, Klein SK, Rehwald U, et al, German CLL Study Group. Phase2 study of a combined immunochemotherapy using rituximab and fludarabine inpatients with chronic lymphocytic leukemia. Blood. 2002;100:3115-3120.125. Kay NE, Geyer SM, Lin T, et al. Combination chemotherapy with

pentostatin, cyclophosphamide and rituximab induces high rates of remissionincluding complete reponses and achievement of minimal residual disease inpreviously untreated B-chronic lymphocytic leukemia [abstract]. Blood. 2004;104:100a. Abstract 339.126. Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine

may prolong progression-free survival and overall survival in patients withpreviously untreated chronic lymphocytic leukemia: an updated retrospectivecomparative analysis of CALGB 9712 and CALGB 9011. Blood. 2005 Jan1;105:49-53. Epub 2004 May 11.127. Mauro FR, Gentile M, De Propris MS, et al. Postremissional rituximab

administration for the treatment of older chronic lymphocytic leukemia (CLL)patients responsive to first line therapy with chlorambucil and prednisone[abstract]. Blood. 2003;102:674a. Abstract 2497.128. Lamanna N, Wiess MA, Maslak PG, et al. Sequential therapy with

fludarabine, high dose cyclophosphamide, and rituximab induces a highincidence of complete response in patients with chronic lymphocytic leukemia(CLL) [abstract]. Blood. 2003;102:440a. Abstract 1603.129. Lundin J, Kimby E, Bjorkholm M, et al. Phase II trial of subcutaneous

anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-linetreatment for patients with B-cell chronic lymphocytic leukemia (B-CLL).Blood. 2002;100:768-773.130. Hillmen P, Skotnicki A, Robak T, et al. Preliminary phase III efficacy

and safety of alemtuzumab vs chlorambucil as front-line therapy for patientswith progressive B-cell chronic lymphocytic leukemia (BCLL) [abstract]. JClin Oncol. 2006;24(suppl):339s. Abstract 6511.131. Montillo M, Tedeschi A, Rossi V, et al. Alemtuzumab as consolidation

after a response to fludarabine is effective to purge residual disease in patientswith chronic lymphocytic leukemia [abstract]. Blood. 2004;104:140a. Abstract479.

132. Rai KR, Byrd JC, Peterson BL, et al. A phase II trial of fludarabinefollowed by alemtuzumab (Campath-1H) in previously untreated chroniclymphocytic leukemia (CLL) patients with active disease: Cancer and LeukemiaGroup B (CALGB) Study 19901 [abstract]. Blood. 2002;100:205a. Abstract 772.133. Rai KR, Byrd JC, Peterson BL, et al. Subcutaneous alemtuzumab

following fludarabine for previously untreated patients with chronic lympho-cytic leukemia (CLL): CALGB Study 19901 [abstract]. Blood. 2003;102:676a. Abstract 2506.134. Wendtner CM, Ritgen M, Schweighofer CD, et al, German CLL Study

Group (GCLLSG). Consolidation with alemtuzumab in patients with chroniclymphocytic leukemia (CLL) in first remission: experience on safety andefficacy within a randomized multicenter phase III trial of the German CLLStudy Group (GCLLSG). Leukemia. 2004;18:1093-1101.135. O’Brien SM, Kantarjian HM, Thomas DA, et al. Alemtuzumab as

treatment for residual disease after chemotherapy in patients with chroniclymphocytic leukemia. Cancer. 2003;98:2657-2663.




136. O’Brien SM, Gribben JG, Thomas DA, et al. Alemtuzumab for minimalresidual disease in CLL [abstract]. Blood. 2003;102:109a. Abstract 371.137. Sawitsky A, Rai KR, Glidewell O, Silver RT. Comparison of daily

versus intermittent chlorambucil and prednisone therapy in the treatment ofpatients with chronic lymphocytic leukemia. Blood. 1977;50:1049-1059.138. Montserrat E, Alcala A, Alonso C, et al. A randomized trial comparing

chlorambucil plus prednisone vs cyclophosphamide, melphalan, and pred-nisone in the treatment of chronic lymphocytic leukemia stages B and C. NouvRev Fr Hematol. 1988;30:429-432.139. Itala M, Remes K. The COP regimen is not a feasible treatment for

advanced, refractory chronic lymphocytic leukemia. Leuk Lymphoma. 1996;23:137-141.140. Liepman M, Votaw ML. The treatment of chronic lymphocytic

leukemia with COP chemotherapy. Cancer. 1978;41:1664-1669.141. Grever MR, Kopecky KJ, Coltman CA, et al. Fludarabine monophos-

phate: a potentially useful agent in chronic lymphocytic leukemia. Nouv Rev FrHematol. 1988;30:457-459.142. Puccio CA, Mittelman A, Lichtman SM, et al. A loading dose/con-

tinuous infusion schedule of fludarabine phosphate in chronic lymphocyticleukemia. J Clin Oncol. 1991;9:1562-1569.143. Keating MJ, O’Brien S, Kantarjian H, et al. Long-term follow-up of

patients with chronic lymphocytic leukemia treated with fludarabine as a singleagent. Blood. 1993;81:2878-2884.144. Kemena A, O’Brien S, Kantarjian H, et al. Phase II clinical trial of

fludarabine in chronic lymphocytic leukemia on a weekly low-dose schedule.Leuk Lymphoma. 1993;10:187-193.145. Sorensen JM, Vena DA, Fallavollita A, Chun HG, Cheson BD.

Treatment of refractory chronic lymphocytic leukemia with fludarabinephosphate via the group C protocol mechanism of the National CancerInstitute: five-year follow-up report. J Clin Oncol. 1997;15:458-465.146. Zinzani PL, Bendandi M, Magagnoli M, et al. Long-term follow-up

after fludarabine treatment in pretreated patients with chronic lymphocyticleukemia. Haematologica. 2000;85:1135-1139.147. Hallek M, Schmitt B, Wilhelm M, et al, German Chronic Lymphocytic

Leukaemia Study Group. Fludarabine plus cyclophosphamide is an efficienttreatment for advanced chronic lymphocytic leukaemia (CLL): results of a phaseII study of the German CLL Study Group. Br J Haematol. 2001;114:342-348.148. Gonzalez H, Maloum K, Tezenas du Montcel S, et al. Fludarabine +

cyclophosphamide in chronic lymphoproliferative disorders [abstract]. Blood.2003;102:357b. Abstract 5153.149. Robertson LE, O’Brien S, Kantarjian H, et al. Fludarabine plus

doxorubicin in previously treated chronic lymphocytic leukemia. Leukemia.1995;9:943-945.150. Mauro FR, Foa R, Meloni G, et al. Fludarabine, ara-C, novantrone and

dexamethasone (FAND) in previously treated chronic lymphocytic leukemiapatients. Haematologica. 2002;87:926-933.151. Tallman MS, Hakimian D, Zanzig C, et al. Cladribine in the treatment

of relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 1995;13:983-988.152. Juliusson G, Liliemark J. Long-term survival following cladribine (2-

chlorodeoxyadenosine) therapy in previously treated patients with chroniclymphocytic leukemia. Ann Oncol. 1996;7:373-379.153. Rondelli D, Lauria F, Zinzani PL, et al. 2-Chlorodeoxyadenosine in the

treatment of relapsed/refractory chronic lymphoproliferative disorders. Eur JHaematol. 1997;58:46-50.154. Betticher DC, Ratschiller D, Hsu Schmitz SF, et al, Swiss Group for

Clinical Cancer Research (SAKK). Reduced dose of subcutaneous cladribineinduces identical response rates but decreased toxicity in pretreated chroniclymphocytic leukaemia. Ann Oncol. 1998;9:721-726.155. Van Den Neste E, Louviaux I, Michaux JL, et al. Phase I/II study of 2-

chloro-2'-deoxyadenosine with cyclophosphamide in patients with pretreatedB cell chronic lymphocytic leukemia and indolent non-Hodgkin’s lymphoma.Leukemia. 2000;14:1136-1142.156. Montillo M, Tedeschi A, O’Brien S, et al. Phase II study of cladribine

and cyclophosphamide in patients with chronic lymphocytic leukemia andprolymphocytic leukemia. Cancer. 2003;97:114-120.157. Robak T, Gora-Tybor J, Lech-Maranda E, Blonski JZ, Kasznicki M.

Cladribine in combination with mitoxantrone and cyclophosphamide (CMC)in the treatment of heavily pre-treated patients with advanced indolentlymphoid malignancies. Eur J Haematol. 2001;66:188-194.158. Ho AD, Thaler J, Stryckmans P, et al. Pentostatin in refractory chronic

lymphocytic leukemia: a phase II trial of the European Organization forResearch and Treatment of Cancer. J Natl Cancer Inst. 1990;82:1416-1420.

159. Johnson SA, Catovsky D, Child JA, Newland AC, Milligan DW,Janmohamed R. Phase I/II evaluation of pentostatin (2ʹ′-deoxycoformycin) in afive day schedule for the treatment of relapsed/refractory B-cell chroniclymphocytic leukaemia. Invest New Drugs. 1998;16:155-160.160. Weiss MA, Maslak PG, Jurcic JG, et al. Pentostatin and cyclophos-

phamide: an effective new regimen in previously treated patients with chroniclymphocytic leukemia. J Clin Oncol. 2003;21:1278-1284.161. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric

anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: halfof patients respond to a four-dose treatment program. J Clin Oncol.1998;16:2825-2833.162. Foran JM, Rohatiner AZ, Cunningham D, et al. European phase II study

of rituximab (chimeric anti-CD20 monoclonal antibody) for patients withnewly diagnosed mantle-cell lymphoma and previously treated mantle-celllymphoma, immunocytoma, and small B-cell lymphocytic lymphoma[published correction appears in J Clin Oncol. 2000;18:2006]. J Clin Oncol.2000;18:317-324.163. Huhn D, von Schilling C, Wilhelm M, et al, German Chronic

Lymphocytic Leukemia Study Group. Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood. 2001;98:1326-1331.164. Itala M, Geisler CH, Kimby E, et al. Standard-dose anti-CD20 antibody

rituximab has efficacy in chronic lymphocytic leukaemia: results from aNordic multicentre study. Eur J Haematol. 2002;69:129-134.165. Byrd JC, Murphy T, Howard RS, et al. Rituximab using a thrice weekly

dosing schedule in B-cell chronic lymphocytic leukemia and smalllymphocytic lymphoma demonstrates clinical activity and acceptable toxicity.J Clin Oncol. 2001;19:2153-2164.

166. O’Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalationtrial in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:2165-2170.167. Drapkin R, Di Bella NJ, Cuasay LC, et al. Phase II multicenter trial of

pentostatin and rituximab in patients with previously treated or untreatedchronic lymphocytic leukemia [abstract]. Blood. 2002;100:803a. Abstract 3171.168. Robak T, Smolewski P, Urbanska-Rys H, Gora-Tybor J, Blonski JZ,

Kasznicki M. Rituximab followed by cladribine in the treatment of heavilypretreated patients with indolent lymphoid malignancies. Leuk Lymphoma.2004;45:937-944.169. Wierda W, O’Brien S, Wen S, et al. Chemoimmunotherapy with

fludarabine, cyclophosphamide, and rituximab for relapsed and refractorychronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23:4070-4078. Epub2005 Mar 14.170. Wierda W, O’Brien S, Faderl S, et al. A retrospective comparison of

three sequential groups of patients with Recurrent/Refractory chroniclymphocytic leukemia treated with fludarabine-based regimens. Cancer. 2006;106:337-345.171. Lamanna N, Kalaycio M, Maslak P, et al. Pentostatin, cyclophos-

phamide, and rituximab is an active, well-tolerated regimen for patients withpreviously treated chronic lymphocytic leukemia. J Clin Oncol. 2006 Apr 1;24:1575-1581. Epub 2006 Mar 6.172. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab

(Campath-1H) in patients who have failed fludarabine: results of a largeinternational study. Blood. 2002;99:3554-3561.173. Rai KR, Freter CE, Mercier RJ, et al. Alemtuzumab in previously

treated chronic lymphocytic leukemia patients who also had receivedfludarabine. J Clin Oncol. 2002;20:3891-3897.174. Rai KR, Keating MJ, Coutre S, et al. Patients with refractory B-CLL

and T-PLL treated with alemtuzumab (Campath) on a compassionate basis: areport on efficacy and safety of CAM 511 trial [abstract]. Blood. 2002;100:802a. Abstract 3165.175. Rai KR, Coutre S, Rizzieri D, et al. Efficacy and safety of alemtuzumab

(Campath-1H) in refractory B-CLL patients treated on a compassionate basis[abstract]. Blood. 2001;98:365a. Abstract 1538.

176. Ferrajoli A, O’Brien SM, Cortes JE, et al. Phase II study of alemtuzumabin chronic lymphoproliferative disorders. Cancer. 2003;98:773-778.177. Ciolli S, Gigli F, Mannelli F, et al. High response rates and reduced

first-dose reactions with subcutaneous alemtuzumab in patients with relapsedand refractory CLL [abstract]. Blood. 2003;102:357b. Abstract 5156.178. Wierda WG, O’Brien S, Ferrajoli A, et al. Salvage therapy with

combined cyclophosphamide (C), fludarabine (F), alemtuzumab (A), andrituximab (R) (CFAR) for heavily pre-treated patients with CLL [abstract].Blood. 2005;106:213a. Abstract 719.179. Nabhan C, Patton D, Gordon LI, et al. A pilot trial of rituximab and

alemtuzumab combination therapy in patients with relapsed and/or refractorychronic lymphocytic leukemia (CLL). Leuk Lymphoma. 2004;45:2269-2273.




180. Faderl S, Thomas DA, O’Brien S, et al. Experience with alemtuzumabplus rituximab in patients with relapsed and refractory lymphoid malignancies.Blood. 2003 May 1;101:3413-3415. Epub 2003 Jan 9.181. Faderl S, Ferrajoli A, Wierda W, et al. Continuous infusion/subcu-

taneous alemtuzumab (Campath-1H) plus rituximab is active for patients withrelapsed/refractory chronic lymphocytic leukemia (CLL) [abstract]. Blood.2005;106:831a. Abstract 2963.182. Keating MJ, O’Brien S, Kontoyiannis D, et al. Results of first salvage

therapy for patients refractory to a fludarabine regimen in chronic lymphocyticleukemia. Leuk Lymphoma. 2002;43:1755-1762.183. Byrd JC, Peterson B, Piro L, et al. A phase II study of cladribine

treatment for fludarabine refractory B cell chronic lymphocytic leukemia:results from CALGB Study 9211. Leukemia. 2003;17:323-327.184. Eichhorst BF, Busch R, Duehrsen U, et al. CHOP plus rituximab

(CHOP-R) in fludarabine (F) refractory chronic lymphocytic leukemia (CLL)or CLL with autoimmune hemolytic anemia (AIHA) or Richter’stransformation (RT): first interim analysis of a phase II trial of the German CLLStudy Group (GCLLSG) [abstract]. Blood. 2005;106:601a. Abstract 2126.185. Stilgenbauer S, Winkler D, Kröber A, et al. Subcutaneous campath-1H

(alemtuzumab) in fludarabine-refractory CLL: interim analysis of the CLL2hstudy of the German CLL Study Group (GCLLSG) [abstract]. Blood.2004;104:140a. Abstract 478.186. Kennedy B, Rawstron A, Carter C, et al. Campath-1H and fludarabine

in combination are highly active in refractory chronic lymphocytic leukemia.Blood. 2002;99:2245-2247.187. Dreger P, van Biezen A, Brand R, et al. Prognostic factors for survival

after autologous stem cell transplantation for chronic lymphocytic leukemia(CLL): the EBMT experience [abstract]. Blood. 2000;96:482a. Abstract 2071.188. Montillo M, Tedeschi A, Rossi V, et al. Successful CD34+ cell

mobilization by intermediate-dose Ara-C in chronic lymphocytic leukemiapatients treated with sequential fludarabine and Campath-1H. Leukemia. 2004;18:57-62.189. Lysak D, Koza V, Steinerova K, Jindra P, Vozobulova V, Schutzova M.

Mobilization of peripheral blood stem cells in CLL patients after front-linefludarabine treatment. Ann Hematol. 2005 Jul;84:456-461. Epub 2005 Mar 16.190. Dreger P, von Neuhoff N, Sonnen R, et al. Efficacy and prognostic

implications of early autologous stem cell transplantation for poor-risk chroniclymphocytic leukemia (CLL) [abstract]. Blood. 2000;96:483a. Abstract 2076.191. Milligan D, Kochethu G, Dearden C, Matutes E, MacConkey C,

Catovsky D. High incidence of myelodysplasia and secondary leukemia in theUK MRC pilot study of autografting in chronic lymphocytic leukemia[abstract]. Blood. 2005;106:48a. Abstract 153.192. Brion A, Mahe B, Kolb B, et al. Preliminary results of a prospective

randomized study comparing first line conventional therapy versus high dosetherapy with autologous CD34+ purified progenitor cell support in B CLLpatients with B and C Binet stages: the GOELAMS LLC98 study [abstract].Blood. 2005;106:48a. Abstract 152.193. Sutton L, Diviné M, Travade P, et al. Autologous stem cell trans-

plantation (ASCT) versus standard treatments for CLL patients: first interimanalysis of a prospective randomized study from the French Cooperative StudyGroup on CLL [abstract]. Blood. 2005;106:455b. Abstract 5471.194. Montserrat E, Esteve J, Schmitz N, et al. Autologous stem-cell trans-

plantation (ASCT) for chronic lymphocytic leukemia (CLL): results in 107patients [abstract]. Blood. 1999;92:397a. Abstract 1758.195. Horowitz MM, Montserrat E, Sobocinski K, Giralt S, Khouri IF,

Schmitz N, Chronic Leukemia Working Committee. Haematopoietic stem celltransplantation (SCT) for chronic lymphocytic leukemia (CLL) [abstract].Blood. 2000;96:522a. Abstract 2245.196. Dreger P, Busch R, Stilgenbauer S, et al. Early autologous stem cell

transplantation (SCT) in genetically poor-risk chronic lymphocytic leukemia isfeasible and effective: results from a prospective multicenter study (GCLLSGCLL3 Protocol) [abstract]. Blood. 2004;104:45a. Abstract 146.197. Gribben JG, Zahrieh D, Stephans K, et al. Autologous and allogeneic

stem cell transplantations for poor-risk chronic lymphocytic leukemia. Blood.2005 Dec 15;106:4389-4396. Epub 2005 Aug 30.198. Fouillard L, Michallet M, Van-Biezen A, et al. In vitro purging in

autologous stem cell transplantation for chronic lymphocytic leukaemia: aretrospective analysis on behalf of the Chronic Leukaemia Working Party ofthe EBMT [abstract]. Blood. 2004;104:45a-46a. Abstract 148.199. Ritgen M, Lange A, Stilgenbauer S, et al. Unmutated immunoglobulin

variable heavy-chain gene status remains an adverse prognostic factor afterautologous stem cell transplantation for chronic lymphocytic leukemia. Blood.2003 Mar 1;101:2049-2053. Epub 2002 Oct 31.

200. Moreno C, Villamor N, Colomer D, et al. Allogeneic stem-celltransplantation may overcome the adverse prognosis of unmutated VH gene inpatients with chronic lymphocytic leukemia. J Clin Oncol. 2005 May 20;23:3433-3438. Epub 2005 Apr 4.201. Michallet M, Archimbaud E, Bandini G, et al, European Group for

Blood and Marrow Transplantation and the International Bone MarrowTransplant Registry. HLA-identical sibling bone marrow transplantation inyounger patients with chronic lymphocytic leukemia. Ann Intern Med. 1996;124:311-315.202. Michallet M, Van Biezen A, Bandini G, et al. Allotransplants and

autotransplants in chronic lymphocytic leukemia (CLL) [abstract]. BoneMarrow Transplant. 1999;23:S53. Abstract 170.203. Pavletic ZS, Arrowsmith ER, Bierman PJ, et al. Outcome of allogeneic

stem cell transplantation for B cell chronic lymphocytic leukemia. BoneMarrow Transplant. 2000;25:717-722.204. Khouri IF, Keating MJ, Saliba RM, Champlin RE. Long-term follow-up

of patients with CLL treated with allogeneic hematopoietic transplantation.Cytotherapy. 2002;4:217-221.205. Doney KC, Chauncey T, Appelbaum FR, Seattle Bone Marrow

Transplant Team. Allogeneic related donor hematopoietic stem cell trans-plantation for treatment of chronic lymphocytic leukemia. Bone MarrowTransplant. 2002;29:817-823.206. Toze CL, Galal A, Barnett MJ, et al. Myeloablative allografting for

chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemiaeffect associated with graft-versus-host disease. Bone Marrow Transplant.2005;36:825-830.207. Pavletic SZ, Khouri IF, Haagenson M, et al. Unrelated donor marrow

transplantation for B-cell chronic lymphocytic leukemia after usingmyeloablative conditioning: results from the Center for International Bloodand Marrow Transplant research. J Clin Oncol. 2005 Aug 20;23:5788-5794.Epub 2005 Jul 25.208. Ritgen M, Stilgenbauer S, von Neuhoff N, et al. Graft-versus-leukemia

activity may overcome therapeutic resistance of chronic lymphocytic leukemiawith unmutated immunoglobulin variable heavy-chain gene status: impli-cations of minimal residual disease measurement with quantitative PCR.Blood. 2004 Oct 15;104:2600-2602. Epub 2004 Jun 17.209. Dreger P, Brand R, Hansz J, et al, Chronic Leukemia Working Party of

the EBMT. Treatment-related mortality and graft-versus-leukemia activityafter allogeneic stem cell transplantation for chronic lymphocytic leukemiausing intensity-reduced conditioning. Leukemia. 2003;17:841-848.210. Schetelig J, Thiede C, Bornhäuser M, et al, Cooperative German

Transplant Study Group. Evidence of a graft-versus-leukemia effect in chroniclymphocytic leukemia after reduced-intensity conditioning and allogeneicstem-cell transplantation: the Cooperative German Transplant Study Group. JClin Oncol. 2003;21:2747-2753.211. Khouri IF, Lee MS, Saliba RM, et al. Nonablative allogeneic stem cell

transplantation for chronic lymphocytic leukemia: impact of rituximab onimmunomodulation and survival. Exp Hematol. 2004;32:28-35.

212. Sorror ML, Maris MB, Sandmaier BM, et al. Hematopoietic celltransplantation after nonmyeloablative conditioning for advanced chronic lym-phocytic leukemia. J Clin Oncol. 2005 Jun 1;23:3819-3829. Epub 2005 Apr 4.213. Caballero D, Garcia-Marco JA, Martino R, et al. Allogeneic transplant

with reduced intensity conditioning regimens may overcome the poorprognosis of B-cell chronic lymphocytic leukemia with unmutated immu-noglobulin variable heavy-chain gene and chromosomal abnormalities (11q–and 17p–). Clin Cancer Res. 2005;11:7757-7763.214. Schetelig J, Bornhaeuser M, Thiede C, et al. Reduced-intensity

conditioning (RIC) with busulfan, fludarabine and Campath-1H is complicatedby a high rate of graft failure and severe viral complications in patients withCLL [abstract]. Blood. 2004;104:353b. Abstract 5080.215. Brown JR, Li S, Kim H, et al. High levels of early donor chimerism and

treatment-responsive disease predict improved progression-free survivalfollowing non-myeloablative transplantation for advanced CLL [abstract].Blood. 2005;106:166a-167a. Abstract 560.216. Delgado J, Thomson K, Russell N, et al, British Society of Blood and

Marrow Transplantation. Results of alemtuzumab-based reduced-intensityallogeneic transplantation for chronic lymphocytic leukemia: a British Societyof Blood and Marrow Transplantation Study. Blood. 2006 Feb 15;107:1724-1730. Epub 2005 Oct 20.217. Khouri IF, Saliba RM, Keating MJ, et al. ZAP-70 status may not predict

outcome after non-myeloablative allogeneic transplantation (NMT) in patientswith chronic lymphocytic leukemia (CLL) who failed conventional chemo-therapy [abstract]. Blood. 2005;106:577a. Abstract 2038.




218. Hamblin TJ, Oscier DG, Young BJ. Autoimmunity in chroniclymphocytic leukaemia. J Clin Pathol. 1986;39:713-716.219. Hamblin T. Autoimmune disease and its management in chronic

lymphocytic leukemia. In: Cheson BD, ed. Chronic Lymphoid Leukemias. 2nded. New York, NY: Marcel Dekker Inc; 2001:435-458.220. Diehl LF, Ketchum LH. Autoimmune disease and chronic lymphocytic

leukemia: autoimmune hemolytic anemia, pure red cell aplasia, andautoimmune thrombocytopenia. Semin Oncol. 1998;25:80-97.221. Mauro FR, Foa R, Cerretti R, et al. Autoimmune hemolytic anemia in

chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features.Blood. 2000;95:2786-2792.222. Kyasa MJ, Parrish RS, Schichman SA, Zent CS. Autoimmune cyto-

penia does not predict poor prognosis in chronic lymphocytic leukemia/smalllymphocytic lymphoma. Am J Hematol. 2003;74:1-8.223. Catovsky D, Richards S. Incidence of hemolytic anemia after chemo-

therapy in the CLL4 trial: a possible protective role for fludarabine plus cyclo-phosphamide [abstract]. Blood. 2004;104:140a. Abstract 480.224. Sthoeger ZM, Wakai M, Tse DB, et al. Production of autoantibodies by

CD5-expressing B lymphocytes from patients with chronic lymphocyticleukemia. J Exp Med. 1989;169:255-268.225. Vick DJ, Byrd JC, Beal CL, Chaffin DJ. Mixed-type autoimmune

hemolytic anemia following fludarabine treatment in a patient with chroniclymphocytic leukemia/small cell lymphoma. Vox Sang. 1998;74:122-126.226. Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis: an 18-year

study of 865 cases referred to a regional transfusion centre. Br Med J (Clin ResEd). 1981;282:2023-2027.227. Cortes J, O’Brien S, Loscertales J, et al. Cyclosporin A for the treatment

of cytopenia associated with chronic lymphocytic leukemia. Cancer. 2001;92:2016-2022.228. Hill J, Walsh RM, McHam S, Brody F, Kalaycio M. Laparoscopic

splenectomy for autoimmune hemolytic anemia in patients with chroniclymphocytic leukemia: a case series and review of the literature. Am J Hematol.2004;75:134-138.229. Lundin J, Celsing F, Karlsson C, Osterborg A. Treatment of refractory

autoimmune hemolytic anemia in B-CLL with alemtuzumab (humanizedCD52 MAb) [abstract]. Blood. 2005;106:832a. Abstract 2967.230. Zaja F, Vianelli N, Sperotto A, et al. Anti-CD20 therapy for chronic

lymphocytic leukemia-associated autoimmune diseases. Leuk Lymphoma.2003;44:1951-1955.

231. Elter T, Bochmann P, Schulz H, et al. FluCam: a new, 4-weeklycombination of fludarabine and alemtuzumab for patients with relapsed chroniclymphocytic leukemia [abstract]. Blood. 2004;104:690a. Abstract 2517.232. Donthireddy V, Shurafa MS, Saleh M, Kamboj G, Wang D, Jana-

kiraman N. The treatment of complicated and high risk chronic lymphocyticleukemia (CLL) with fludarabine, cyclophosphamide and rituximab (FCR)[abstract]. Blood. 2005;106:341b. Abstract 5038.233. Gupta N, Kavuru S, Patel D, et al. Rituximab-based chemotherapy for

steroid-refractory autoimmune hemolytic anemia of chronic lymphocyticleukemia. Leukemia. 2002;16:2092-2095.234. Shvidel L, Shtalrid M, Berrebi A. Intractable autoimmune hemolytic

anemia in B cell chronic lymphocytic leukemia resolved by rituximab. LeukLymphoma. 2004;45:1493-1494.235. King KE, Ness PM. Treatment of autoimmune hemolytic anemia.

Semin Hematol. 2005;42:131-136.236. Petz LD. “Least incompatible” units for transfusion in autoimmune

hemolytic anemia: should we eliminate this meaningless term? a commentaryfor clinicians and transfusion medicine professionals. Transfusion. 2003;43:1503-1507.237. Shirey RS, Boyd JS, Parwani AV, Tanz WS, Ness PM, King KE.

Prophylactic antigen-matched donor blood for patients with warm autoanti-bodies: an algorithm for transfusion management. Transfusion. 2002;42:1435-1441.238. Rustagi P, Han T, Ziolkowski L, Currie M, Logue G. Antigranulocyte

antibodies in CLL and other chronic lymphoproliferative disorders [abstract].Blood. 1983;62:106a. Abstract 328.239. Garvey MB, Freedman J. Indirect platelet radioactive antiglobulin test

in patients with lymphoproliferative disease. J Lab Clin Med. 1986;107:123-128.240. De Rossi G, Granati L, Girelli G, et al. Prognostic value of autoanti-

bodies against erythrocytes and platelets in chronic lymphocytic leukemia(CLL). Tumori. 1991;77:100-104.241. The American Society of Hematology ITP Practice Guideline Panel.

Diagnosis and treatment of idiopathic thrombocytopenic purpura:

recommendations of the American Society of Hematology. Ann Intern Med.1997;126:319-326.242. Rodon P, Breton P, Courouble G. Treatment of pure red cell aplasia and

autoimmune haemolytic anaemia in chronic lymphocytic leukaemia withCampath-1H. Eur J Haematol. 2003;70:319-321.243. Ru X, Liebman HA. Successful treatment of refractory pure red cell

aplasia associated with lymphoproliferative disorders with the anti-CD52monoclonal antibody alemtuzumab (Campath-1H). Br J Haematol. 2003;123:278-281.244. Chikkappa G, Zarrabi MH, Tsan MF. Pure red-cell aplasia in patients

with chronic lymphocytic leukemia. Medicine (Baltimore). 1986;65:339-351.245. Narra K, Borghaei H, Al-Saleem T, Hoglund M, Smith MR. Pure red

cell aplasia in B-cell lymphoproliferative disorder treated with rituximab:report of two cases and review of the literature. Leuk Res. 2006 Jan;30:109-114. Epub 2005 Jul 25.

246. Chasty RC, Myint H, Oscier DG, et al. Autoimmune haemolysis inpatients with B-CLL treated with chlorodeoxyadenosine (CDA). LeukLymphoma. 1998;29:391-398.247. Di Raimondo F, Giustolisi R, Cacciola E, et al. Autoimmune hemolytic

anemia in chronic lymphocytic leukemia patients treated with fludarabine.Leuk Lymphoma. 1993;11:63-68.248. Myint H, Copplestone JA, Orchard J, et al. Fludarabine-related auto-

immune haemolytic anaemia in patients with chronic lymphocytic leukaemia.Br J Haematol. 1995;91:341-344.249. Paydas S. Fludarabine-induced hemolytic anemia: successful treatment

by rituximab. Hematol J. 2004;5:81-83.250. Ghazal H. Successful treatment of pure red cell aplasia with rituximab

in patients with chronic lymphocytic leukemia. Blood. 2002;99:1092-1094.251. Hegde UP, Wilson WH, White T, Cheson BD. Rituximab treatment of

refractory fludarabine-associated immune thrombocytopenia in chroniclymphocytic leukemia. Blood. 2002;100:2260-2262.252. Fernandez MJ, Llopis I, Pastor E, Real E, Grau E. Immune thrombo-

cytopenia induced by fludarabine successfully treated with rituximab.Haematologica. 2003;88:ELT02.253. Leach M, Parsons RM, Reilly JT, Winfield DA. Autoimmune thrombo-

cytopenia: a complication of fludarabine therapy in lymphoproliferativedisorders. Clin Lab Haematol. 2000;22:175-178.254. Tsiodras S, Samonis G, Keating MJ, Kontoyiannis DP. Infection and

immunity in chronic lymphocytic leukemia. Mayo Clin Proc. 2000;75:1039-1054.255. Ravandi F, O’Brien S. Immune defects in patients with chronic lympho-

cytic leukemia. Cancer Immunol Immunother. 2006 Feb;55:197-209. Epub2005 Jul 16.256. O’Brien SN, Blijlevens NM, Mahfouz TH, Anaissie EJ. Infections in

patients with hematological cancer: recent developments. Hematology Am SocHematol Educ Program. 2003:438-472.257. Cooperative Group for the Study of Immunoglobulin in Chronic

Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention ofinfection in chronic lymphocytic leukemia: a randomized, controlled clinicaltrial. N Engl J Med. 1988;319:902-907.258. Molica S, Musto P, Chiurazzi F, et al. Prophylaxis against infections

with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocyticleukemia: results of a crossover study. Haematologica. 1996;81:121-126.259. Weeks JC, Tierney MR, Weinstein MC. Cost effectiveness of

prophylactic intravenous immune globulin in chronic lymphocytic leukemia. NEngl J Med. 1991;325:81-86.260. Thursky KA, Worth LJ, Seymour JF, Miles Prince H, Slavin MA.

Spectrum of infection, risk and recommendations for prophylaxis andscreening among patients with lymphoproliferative disorders treated withalemtuzumab. Br J Haematol. 2006;132:3-12.261. O’Brien S, Ravandi-Kashani F, Wierda WG, et al. A randomized trial of

valacyclovir versus valganciclovir to prevent CMV reactivation in patientswith CLL receiving alemtuzumab [abstract]. Blood. 2005;106:830a. Abstract2960.262. Hisada M, Biggar RJ, Greene MH, Fraumeni JF Jr, Travis LB. Solid

tumors after chronic lymphocytic leukemia. Blood. 2001;98:1979-1981.263. Mauro FR, Foa R, Giannarelli D, et al. Clinical characteristics and

outcome of young chronic lymphocytic leukemia patients: a single institutionstudy of 204 cases. Blood. 1999;94:448-454.264. Cheson BD, Vena DA, Barrett J, Freidlin B. Second malignancies as a

consequence of nucleoside analog therapy for chronic lymphoid leukemias. JClin Oncol. 1999;17:2454-2460.




End of Symposium on Oncology Practice: Hematological Malignancies.

265. Robak T. Second malignancies and Richter’s syndrome in patients withchronic lymphocytic leukemia. Hematology. 2004;9:387-400.266. Robertson LE, Estey E, Kantarjian H, et al. Therapy-related leukemia

and myelodysplastic syndrome in chronic lymphocytic leukemia. Leukemia.1994;8:2047-2051.267. Stern N, Shemesh J, Ramot B. Chronic lymphatic leukemia terminating

in acute myeloid leukemia: review of the literature. Cancer. 1981;47:1849-1851.268. Yagci M, Sucak GT, Ogur G, Haznedar R. Therapy-related refractory

anemia with ringed sideroblasts in chronic lymphocytic leukemia: involvementof 3q21 region. Cancer Genet Cytogenet. 2001;129:43-46.269. Miller MK, Strauchen JA, Nichols KT, Phelps RG. Concurrent chronic

lymphocytic leukemia cutis and acute myelogenous leukemia cutis in a patientwith untreated CLL. Am J Dermatopathol. 2001;23:334-340.270. Barresi GM, Albitar M, O’Brien SM. Acute myeloid leukemia,

inversion 16, occurring in a patient with chronic lymphocytic leukemia. LeukLymphoma. 2000;38:621-625.271. Aviv H, Tang D, Das K, Harrison JS, Hameed M, Varma M.

Simultaneous appearance of trisomy 8 and trisomy 12 in different cellpopulations in a patient with untreated B-cell chronic lymphocytic leukemiaand myelodysplasia. Leuk Lymphoma. 2004;45:1279-1283.

272. Muta T, Okamura T, Niho Y. Acute myelogenous leukemia concurrentwith untreated chronic lymphocytic leukemia. Int J Hematol. 2002;75:187-190.273. Mossafa H, Fourcade C, Pulic M, et al. Chronic lymphocytic leukemia

associated with myelodysplastic syndrome and/or chronic myeloid leukemia:evidence for independent clonal chromosomal evolution. Leuk Lymphoma.2001;41:337-341.274. Yee KW, O’Brien SM, Giles FJ. Richter’s syndrome: biology and

therapy. Cancer J. 2005;11:161-174.275. Enno A, Catovsky D, O’Brien M, Cherchi M, Kumaran TO, Galton DA.

‘Prolymphocytoid’ transformation of chronic lymphocytic leukaemia. Br JHaematol. 1979;41:9-18.276. Kjeldsberg CR, Marty J. Prolymphocytic transformation of chronic

lymphocytic leukemia. Cancer. 1981;48:2447-2457.277. Stark AN, Limbert HJ, Roberts BE, Jones RA, Scott CS. Prolympho-

cytoid transformation of CLL: a clinical and immunological study of 22 cases.Leuk Res. 1986;10:1225-1232.278. Ghani AM, Krause JR, Brody JP. Prolymphocytic transformation of

chronic lymphocytic leukemia: a report of three cases and review of theliterature. Cancer. 1986;57:75-80.279. Roberts JD, Tindle BH, MacPherson BR. Prolymphocytic

transformation of chronic lymphocytic leukemia: a case report of lengthysurvival after intensive chemotherapy. Am J Hematol. 1989;31:131-132.280. Jones R, Pipas JM, Kritz AD. Tumor lysis syndrome provides evidence

for dose-intense response for corticosteroids in prolymphocytic leukemia.Blood. 1993;81:1107.281. Scott CS, Stark AN, Head C, Roberts BE. Diagnostic features and

survival in typical and prolymphocytoid variants of chronic lymphocyticleukemia. Hematol Oncol. 1989;7:175-179.282. Giles FJ, O’Brien SM, Keating MJ. Chronic lymphocytic leukemia in

(Richter’s) transformation. Semin Oncol. 1998;25:117-125.283. Foon KA, Thiruvengadam R, Saven A, Bernstein ZP, Gale RP. Genetic

relatedness of lymphoid malignancies: transformation of chronic lymphocyticleukemia as a model. Ann Intern Med. 1993;119:63-73.

284. Khouri IF, Keating M, Korbling M, et al. Transplant-lite: induction ofgraft-versus-malignancy using fludarabine-based nonablative chemotherapyand allogeneic blood progenitor-cell transplantation as treatment for lymphoidmalignancies. J Clin Oncol. 1998;16:2817-2824.285. Rodriguez J, Keating MJ, O’Brien S, Champlin RE, Khouri IF.

Allogeneic haematopoietic transplantation for Richter’s syndrome. Br JHaematol. 2000;110:897-899.286. Khouri IF, Albitar M, Saliba RM, et al. Low-dose alemtuzumab

(Campath) in myeloablative allogeneic stem cell transplantation for CD52-positive malignancies: decreased incidence of acute graft-versus-host-diseasewith unique pharmacokinetics. Bone Marrow Transplant. 2004;33:833-837.287. Melo JV, Catovsky D, Galton DA. The relationship between chronic

lymphocytic leukaemia and prolymphocytic leukaemia, II: patterns of evolu-tion of ‘prolymphocytoid’ transformation. Br J Haematol. 1986;64:77-86.288. Gobbi M, Tazzari PL, Raspadori D, Cavo M, Pileri S, Tura S. Men-

ingeal leukemia complicating prolymphocytoid transformation of B-chroniclymphocytic leukemia. Acta Haematol. 1985;74:205-207.289. Thiruvengadam R, Bernstein ZP. Central nervous system involvement

in prolymphocytic transformation of chronic lymphocytic leukemia. ActaHaematol. 1992;87:163-164.290. Kuwabara H, Kanamori H, Takasaki H, et al. Involvement of central

nervous system in prolymphocytoid transformation of chronic lymphocyticleukemia. Leuk Lymphoma. 2003;44:1235-1237.291. Shimoni A, Shvidel L, Shtalrid M, Klepfish A, Berrebi A. Prolympho-

cytic transformation of B-chronic lymphocytic leukemia presenting asmalignant ascites and pleural effusion. Am J Hematol. 1998;59:316-318.292. Gujral S, Jain P, Bhutani M, Kochupillai V, Kumar R, Sahoo M.

Prolymphocytic transformation in chronic lymphocytic leukemia presenting asbilateral periorbital swelling. Am J Hematol. 1998;59:98-99.293. Dohner H, Ho AD, Thaler J, et al. Pentostatin in prolymphocytic

leukemia: phase II trial of the European Organization for Research andTreatment of Cancer Leukemia Cooperative Study Group. J Natl Cancer Inst.1993;85:658-662.294. Byrd JC, Waselenko JK, Maneatis TJ, et al. Rituximab therapy in

hematologic malignancy patients with circulating blood tumor cells:association with increased infusion-related side effects and rapid blood tumorclearance. J Clin Oncol. 1999;17:791-795.295. Hercher C, Robain M, Davi F, et al, Groupe Francais d’Hematologie

Cellulaire. A multicentric study of 41 cases of B-prolymphocytic leukemia:two evolutive forms. Leuk Lymphoma. 2001;42:981-987.296. van Besien KW, de Lima M, Giralt SA, et al. Management of

lymphoma recurrence after allogeneic transplantation: the relevance of graft-versus-lymphoma effect. Bone Marrow Transplant. 1997;19:977-982.297. Mehta J, Powles R, Singhal S, Iveson T, Treleaven J, Catovsky D.

Clinical and hematologic response of chronic lymphocytic and prolymphocyticleukemia persisting after allogeneic bone marrow transplantation with theonset of acute graft-versus-host disease: possible role of graft-versus-leukemia.Bone Marrow Transplant. 1996;17:371-375.298. Castagna L, Sarina B, Todisco E, Mazza R, Santoro A. Allogeneic

peripheral stem-cell transplantation with reduced-intensity conditioningregimen in refractory primary B-cell prolymphocytic leukemia: a long-termfollow-up. Bone Marrow Transplant. 2005;35:1225.299. Shvidel L, Shtalrid M, Klepfish A, Haran M, Berrebi A. Successful

autologous stem cell transplantation in aggressive prolymphocytic leukemia.Am J Hematol. 2000;63:230-231.


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