hanan.a.eltib 2014 chronic lymphocytic leukemia
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HANAN.A.ELTIB2 0 1 4
Chronic lymphocytic leukemia
OVERVIEW
The most prevalent type of adult leukemia in western countries
Median age of diagnosis of CLL is ~ 72 years, with only 10% of patients younger than 50 years of age
CLL morbidity rapidly increases with age
More common in men than women (2:1 ratio)
Pathophysiology
Historically CLL considered disease of accumulation due to defect in apoptosis
CLL more proliferative disease than previously thought
CLL cells up regulate gene signature consistent with BCR and NF-KB pathway activation
Diagnosis
CBC: at least 5000 monoclonal B-lymphocytes/cml in the peripheral blood
Morphologically :small mature lymphocytes
N.B :Fewer clonal B-Cells LNS less 1.5 cm no anemia or thromocytopenia +/_ the immunophenotybe of the CLL ALymphoproliferative disorders :monoclonal B-
lymphocytosis(MPL)
CLL/SLL
Different manifestation of the same disease managed in the same way
The major difference SLL: the abnormal lymphocytes are
predominantly found in the LNS-diagnosis mainly by LN biopsy-no more than 5000 clonal B-cells in the peripheral blood
CLL: significant number of the abnormal lymphocytes are also found in the BM and blood
Initial Work-up of CLL Patients
Flow cytometry of the peripheral blood Kappa/lambda CD5 + CD19 + CD23 + CD10 - CD20 dim Surface IG dim Cycline D1 –
Atypical CLL : t(11;14) by FISH :LN biopsy with IHC CD3 CD5
CD10 CD20 CD23 Cyclin D1
Anemic pt : RC count - direct combs‘ test
LN biopsy only if diagnosis not confirmed by flowcytometry
Bone marrow aspirate and biobsy not necessary in absence of cytopenias
No CT scan unless symptoms are present; PET scan can be helpful if Richter’s suspected
Informative for prognostic and/or therapy determination flowcytometry or IHC: CD38-CD70 cytogenetics analysis : +12, del(13q), del(17p)and del(11q) mollecular analysis : IGVH gene status assessment-TP53 serum level : β2-microglobulin
Initial Work-up of CLL Patients
Physical Exam LNs : size-symptoms liver-spleen size
B-symptoms
Performance
Useful under certain circumstaces haptoglobin Serum QIG level uric acid LDH HBV
Initial Work-up of CLL Patients
RAI’s CLINICAL STAGING SYSTEM
Stage Clinical Features at Diagnosis Median Survival (years)
0Low risk
Blood lymphocytosis>5000/mcl,Bone marrow lymphocytosis>30%
>12,5
IIntermediate risk
Stage 0and enlarged lymph node(s)
8
IIIntermediate risk
Stage 0-Iand enlarged spleen and/or liver
6
IIIHigh risk
Stage0-IIand anemia (Hb < 11g/dl)
1,5-2
IVHigh risk
Stage0-IIIand thrombocytopenia(< 100 000 /mcl)
1,5-2
When to Treat CLL Patient
No advantage to treating CLL until symptoms develop
Constitutional symptoms due to disease (fatigue, B symptoms)
Enlarging, symptomatic lymph nodes (> 10 cm)
Enlarging, symptomatic spleen (> 6 cm BCM)
Cytopenias due to CLL (hemoglobin < 11 g/dL, platelets < 100,000 cells/μL)
Poorly controlled AIHA or ITP
Absolute lymphocytic count alone is not indication for treatment unless above 200-300×109/L Or symptoms related to leukostasis
Treatment options
Alkylating agents
Purine anologue vs Alkylators Higher RR and PFS Better QOL Not OS
Purine/alkylator combo vs. purine: Higher RR and PFS Not OS
Treatment options
CLL8 study ;chemoimmunotherpy : FCR VS FC
• More neutropenia
• A better therapy for young –physically fit pt
• Significantly improves ORR and CR
• Significantly improves PFS
• Significantly improves OS 7% Most genetic groups benefit from FCR therapy
except for del(17p13)
Treatment options
CLL10 study; FCR VS BR
Bendamastin: An Alkylator agent with apurine like benzimidazole ring component Identical ORR Higher CR rates observed with FCRPFS significantly longer with FCRAcute (and long-term?) toxicity greater with BR
PCR Pentostatin: purine analog No advantage over FCR Cyclophoshamide is an important component
AlemtuzumabHuminazied Monoclonal Ab target CD52Not as afirst line treatment option except in the setting of del (17p)
In elderly: Treatment options
FCR not well tolerated –less effective by pts 70 ys
Fludrabine vs chloreambucil 65 ys Better ORR CR TTTF QOL analysis favoured fludrabine NO PFS OS difference SO Chloreambucil is avalid option
In elderly: Treatment options
Bendamastin vs chlorambucil Higher RR/PFS
Higher toxicity CLL11 study :Obinituzumab + chlorambucil is
an effective, well-tolerated therapy Most appropriate for elderly ? question of whether obinituzumab is superior to rituximab
in other clinical contexts
First line therapy
Fit patient Chemoimmunotherapy e.g FCR/FR/BR/PCR
Elderly pt-comorbidity Chlorambucil+/- R Fludarabine+/- R Cyclophosphamide , prednisolone+/-R Bendamastin+/-R Rituximab
First line therapy
Frail pt Chlorambucil Pulse steroides Rituximab
Molecular guided therapy
Pt with del(17p) Trial FCR HDM+R Alemtuzumab+/-R Ibrutinib for patients with
relapsed/refractory disease Pt with del(11q) Regimens containing an alkylator
Considerations for Relapsed CLL
Outcome of patients at time of relapse dependent on: – Interphase cytogenetics, β2-microglobulin, and stage – Previous therapy (ie, monotherapy or chemoimmunotherapy) – Time of remission with last treatment Treat relapsed patients when symptomatic only Interphase cytogenetics should be repeated prior to initiating salvage therapy All patients with cytopenias should have repeat bone marrow to assess for MDS if prior FCR given Transplant evaluation should be considered early in this population if any unfavorable features present
Salvage therapy
IbrutinibChemoimmunotherapyOfatumabLenalidomide+/- RAlemtuzumab+/- R
Supportive Care for pts with CLL
1-Recurrent infection Antimicrobials as appropriate IVIG, if <500mg/dl2-Antinfective prophylaxis PCP-Herpes virus CMV HBV3-vaccination Annual INFLUENZA vaccine Pneumococcal vaccine/5y
Supportive Care for pts with CLL
Blood product :irradiate all blood productTumor lysis syndromeTumor flare reaction :lenalidomideThromboprophylaxis :lenalidomideAutoimmune cytopenias - Steroides - IVIG - Cyclosporin A - Rituximab - Splenectomy
In clinical practice)) Follow up
Constitutional symptomsPhysical Examination Organomegally LNSBlood parameters blood counts+/_BM
Richter's syndrome))Histological Transformation
DLBCL or HL2-5 %Increase with NO. of prior regimensPoor prognosis Extra nodal involvement, Sharp rise in LDHChemoimmunotherapy e.g R-CHOP/ R-HYPERCYVAD Allogeneic HSCT, considered following initial therapy
Prolymphoctic leukemia. > 55% increase in prolymphocytes Progression of splenomegaly & cytopenias Refractoriness to treatment.
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