acute myeloid leukemia

98 American Society of Hematology

Acute Myeloid Leukemia

Richard M. Stone, Margaret R. O’Donnell, and Mikkael A. Sekeres

Advances in our understanding of the patho-physiology of acute myeloid leukemia (AML)have not yet led to major improvements indisease-free and overall survival of adults withthis disease. Only about one-third of thosebetween ages 18–60 who are diagnosed with AMLcan be cured; disease-free survival is rare andcurrent therapy devastating in older adults. Inthis chapter, challenges in the management ofthe adult with AML are discussed, includingongoing questions concerning the optimalchoice of induction and postremission therapysuch as the rationale for and role of allogeneicand autologous stem cell transplantation in avariety of settings, the special considerationspertaining to the older patient, and the develop-ment of new, so-called targeted therapies.

In Section I, Dr. Richard Stone reviews state-of the-art therapy in AML in the era of changefrom a morphological to a genetically basedclassification system. Questions being addressedin ongoing randomized cooperative group trialsinclude anthracycline dose during induction, theefficacy of drug-resistance modulators, and theutility of pro-apoptotic agents such as the anti-bcl-2 antisense oligonucloetide. Developmentaltherapeutics in AML include drug resistancemodulation, anti-angiogenic strategies, immuno-therapy, and signal transduction-active agents,particularly the farnesyl transferase inhibitors aswell as those molecules that inhibit the FLT3

tyrosine kinase, activated via mutation in 30% ofpatients.

In Section II Dr. Margaret O’Donnell dis-cusses the role of stem cell transplantation inAML. Several advances including expandeddonor pools, the movement toward peripheralblood stem cell collection, newer immunosup-pressive drugs and antifungals, and particularlythe advent of nonmyeloablative transplant havemade the allogeneic option more viable. Thesubset-specific role for high-dose chemotherapywith autologous stem cell support and/or forallogeneic transplant in AML patients in firstremission is outlined. Although preconceivednotions about the role of transplant abound, theclinical data supporting a risk-adapted approachare covered. Finally, guidance concerning theuse of nonmyeloablative or reduced-intensityallogeneic transplantation is provided.

In Section III Dr. Mikkael Sekeres reviews theapproach to the older patient with AML. Uniquebiological and therapeutic considerations makeAML in this age group a vastly different diseasethan that in younger adults. The outcome data,including the role of specific anthracylines,hematopoietic growth factors, and drug-resis-tance modulators, are summarized. Communicat-ing with older adults with AML and their familiesregarding selection of the optimal treatmentstrategy, often a stark choice between inductionchemotherapy and palliative care, is covered.

* Dana-Farber Cancer Institute, 44 Binney Street, Room D-840,Boston MA 02115-6084

I. AML: C URRENT LANDSCAPE

AND FUTURE DIRECTIONS

Richard M. Stone, MD*

Acute myeloid leukemia (AML) represents a group ofclonal hematopoietic stem cell disorders in which bothfailure to differentiate and overproliferation in the stemcell compartment result in accumulation of non-func-tional cells termed myeloblasts. While the specific causefor this biological abnormality in any individual pa-tient is usually unknown, the burgeoning understand-

ing of the genetic underpinnings of leukemia is begin-ning to lead to a wide array of so-called targeted thera-pies, many of which are in clinical development.

Despite current optimism, most patients with AMLwill die of their disease. The basic therapeutic approachto patients with AML has changed little over the last 20years. Nonetheless, before beginning to introduce noveltherapies in the clinic, a thorough understanding of the

Hematology 2004 99

current approach to treatment is required. The evolu-tion of the classification system in AML from mor-phology to cytogenetic/genetic-based reflects the rec-ognition of the importance of subtype-specific biology.1

The two major prognostic factors in newly diagnosedAML, patient age and chromosome status, form thebasis of important treatment decisions. Recently, sev-eral molecularly based prognostic factors, such as theadverse impact of an FLT3 tyrosine kinase gene length(or ITD) mutation (repeat of 3–30 amino acids in thejuxtamembrane region,2 leading to constitutive activa-tion) and duplication of the MLL gene on the long armof chromosome 113 have been described; however, theimpact of such findings on treatment decisions remainsunclear. Patients with treatment-related AML requirespecial consideration because, in the absence of bal-anced translocations known to carry a favorable prog-nostic impact, such patients fare poorly with standardapproaches. The management of AML in older adults,who have a highly inferior prognosis and an increasedrate of treatment morbidity and mortality, is highlightedin Section III.

The approach to adults aged 18–60 years with AML

classically involves separate treatment phases. The firstconsists of induction chemotherapy in which the goalof myelosuppressive chemotherapy is to “empty” thebone marrow of all hematopoietic elements (both be-nign and malignant) and to allow repopulation of themarrow with normal cells, thereby yielding remission(< 5% marrow blasts). The primacy of the standardregimen of 3 days of an anthracycline and 7 days ofcytarabine has not been definitely altered despite clini-cal trials that have substituted alternative anthracyclinessuch as idarubicin, added or substituted high-dosecytarabine, or added etoposide. Recent trials by theCancer and Leukemia Group B (CALGB) have em-ployed high doses of daunorubicin and etoposide.4 Whiletolerable, whether such higher doses offer disease-freeor overall survival benefits remains to be proven byongoing clinical trials (Table 1). Given the high (75%–80%) complete remission rate typically achieved inyounger adults with standard chemotherapy, an ex-tremely large trial or a highly effective agent would berequired to show superiority over conventional chemo-therapy. Most of the trials that have reported an im-provement with a new chemotherapeutic agent or with

Table 1. Selected clinical trials in acute myeloid leukemia (AML).

US Intergroup APL: ATRA/daunorubicin/ara-C induction, followed by As203 + daunorubicin/ATRA x 2 vs daunorubicin/ATRA x 2 consolidation, followed by ATRA/6MP/methotrexate vs ATRA x 1 yr for maintenance.

AML (age > 70 years and not a candidate for chemotherapy): Oral tipifarnib (R115777) at 2 doses and 2schedules

CALGB AML (age > 60): dauno/ara-C vs dauno/ara-C/oblimersenAML (age < 60): dauno/ara-C/etoposide, followed by post-chemotherapy/PBSCT, followed by IL-2 vs observation

ECOG AML (age > 60): dauno/ara-C ± MDR modulator (LY335979)

AML (age < 60): daunorubicin (45 mg/m2 x 3 d)/ara-C vs daunorubicin (90 mg/m2 x 3 d)/ara-C, followed by± gemtuzumab ozogamicin (GO) prior to autoPBSCT (if no sib donor)

SWOG AML (age > 55): continuous infusion daunorubicin/ara-C ± cyclosporine A followed by assignment to mini-allo BMT(if HLA-matched sibling donor)

AML (age < 55): daunorubicin/ara-C vs daunorubicin/ara-C + GO

EORTC AML (age > 60): ida/ara-C vs ida/ara-C/GO

AML (age < 60): ida/ara-C vs ida/high dose ara-C, followed by intensive consolidation/allogeneic BMT,followed by IL-2

HOVON AML (age > 60): dauno (45 mg/m2)/ara-C vs dauno (90 mg/ m2)/ara-C f/b intermediate dose ara-C,followed by GO x 4 vs observation

AML (age < 60): ida/ara-C ± G-CSF vs ida/high-dose ara-C ± G-CSF, followed by mitoxantrone/etoposide(good risk) or Mito/etop vs autoBMT or alloBMT (if sibling donor)

MRC APL: ATRA/dauno/high-dose ara-C/6-thioguanine (MRC) vs ATRA/ida (Spanish), followed by MRC or Spanishchemo ± GO

AML (age > 60): intensive chemo (dauno/ara-c at various doses) vs non-intensive chemo (hydroxyurea/low dose ara-C ± ATRA)

AML (age < 60): dauno/high dose ara-C/6-thioguanine vs fludarabine/ara-C/G-CSF/ida +/- GO, followed byallo BMT (if sibling; and will be nonmyeloablative if > 50, ‘full’ if under 35 years old)

Abbreviations: APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; ara-C, cytosine arabinoside; 6MP, 6-mercapto-purine; AML, acute myeloid leukemia; PBSCT, peripheral blood stem cell transplantation; IL, interleukin; MDR, multidrug resistance;BMT, bone marrow transplantation; G-CSF, granulocyte colony-stimulating factor


a higher dose of a standard drug during induction havedocumented a disease-free survival benefit, implyingthat such remissions yield a lower disease burden. How-ever, the inability to translate such benefits into overallsurvival improvements suggests a limited ability to af-fect a major difference in the depth of remission.

It is definitely clear that once remission is achieved,additional therapy is required to reduce the undetect-able burden of leukemic cells to a level low enoughthat long-term disease-free survival (i.e., cure) mightbe possible. The most effective anti-leukemic approachis allogeneic stem cell transplantation. However, thistechnique carries a high degree of initial mortality anda significant degree of long-term morbidity in the formof chronic graft-versus-host disease (GVHD), tendingto offset the low likelihood of disease relapse. Chemo-therapy-based approaches with or without autologousstem cell rescue can be performed relatively safely, butthere remains a high chance for disease recurrence. Someof the patients who relapse after chemotherapy or evenhigh-dose chemotherapy with autologous stem cell res-cue can be salvaged with an allogeneic transplant per-formed in early relapse or second remission. The roleof autologous and allogeneic (both standard and reducedintensity) strategies in the post-remission management ofAML patients with various risks of disease relapse basedon karyotype at diagnosis is discussed in Section II.

Specific therapies have proven benefit for smallsubsets of patients defined by recurring cytogenetic ab-normalities. Post-remission chemotherapy with high-dose cytarabine is generally accepted as the best ap-proach for the 15% of patients with favorable progno-sis chromosome abnormalities [e.g., t(8:21); orinv(16)].5 While the optimal number of such cycles re-mains to be defined, at least three are probably required.6

Whether the high-dose cytarabine or repetitive cyclesof intensive chemotherapy is the critical factor remainsdebatable; however, a cure rate of 60%–70% with che-motherapy suggests that the more risky strategy of al-logeneic transplant should be reserved for early relapseor second complete remission in this subset of patients.Patients who present with acute promyelocytic leuke-mia (APL; another 8%–12% of patients) should betreated with all-trans retinoic acid (ATRA) and ananthracycline in induction.7,8 Although many still em-ploy cytarabine in the induction and postremission man-agement of APL patients, its use is probably not neces-sary.7 ATRA/anthracycline-based postremission therapyshould be augmented with a year of maintenance therapy,not generally thought effective in other AML subtypes,with ATRA, probably in combination with oral anti-metabolites.9 APL is the one subtype of APL in whichmolecular monitoring after achievement of complete

response (CR) has proven useful. Few patients whoachieve polymerase chain reaction (PCR)-negative sta-tus after postremission chemotherapy relapse; whereasthose with persistently detectable PML-RARα fusiontranscripts have a 25% risk of relapse,10 yet whethersuch relapses can be prevented with additional therapyremains unclear. While the cure rate in APL with “stan-dard” therapy is favorable (60%–70%), the problemsof secondary myelodysplasia11 and late central nervoussystem (CNS) relapses8 have recently been described.

In summary, the young adult who presents withAML should have studies performed on leukemic cellsleading to morphologic and cytogenetic classification.Those with non-APL AML should receive inductiontherapy with 3 days of an anthracyline and 7 days ofinfusional cytarabine followed by risk-adapted post-remission therapy [intensive chemotherapy for thosewith inv 16 or t(8;21)], allogeneic transplant for thosewith high-risk cytogenetics, and either intensive che-motherapy, high-dose chemotherapy with autologousstem cell rescue or sibling-matched allogeneic trans-plant for the remainder. That a “standard approach” tothe treatment of AML in the 18–60 year old patient canbe described is still compatible with the notion that allshould be referred for a clinical trial. Many questionsneed to be answered, even for those with so-called ‘fa-vorable’ prognoses, that usually involve the addition ofa new agent onto a backbone of “standard” therapy.The ideal candidates for investigational therapy, manyof whom are described subsequently, with a single agentare those likely to fare poorly with induction chemo-therapy, including older adults and those with diseaserelapse less than a year from diagnosis. While manydifferent chemotherapy regimens exist for AML in re-lapse, the choice of regimen is less important than theduration of first remission. Those who relapse morethan one year after diagnosis have good chance to achievea second remission after administration of the originalinduction regimen, or at least one of similar intensity.However a second remission is achieved, the only post-remission therapy with significant utility is allogeneictransplant if possible, or high-dose chemotherapy withautologous stem cell rescue.

Developmental Therapeutics in AMLThe increased understanding of the pathophysiology ofAML has led to the development of a host of new so-called targeted therapies. The success of imatinib in thetreatment of chronic myeloid leukemia (CML) and otherdiseases pathophysiologically based on the constitutiveactivation of a tyrosine kinase that is inhibited by thedrug has spurred the search for similarly effective agentsin AML. Table 2 lists some of the newer therapies ac-

Hematology 2004 101

cording to their proposed mechanism of action. Whetherany of these will prove to alter the natural history ofAML when used either alone or in combination witheach other or with standard chemotherapy remains tobe determined. That there are so many therapies in de-velopment is certainly positive; the challenge posed bythis surfeit in a relatively rare disease for which fairlyeffective therapy already exists remains daunting. Im-munological therapies in AML based on enhancementof the host immunity or elegant strategies of makingAML cells “visible” to the immune system are men-tioned in Section II.

Two agents have recently been approved for use inAML: arsenic trioxide12 and gemtuzumab ozogamicin.13

Their place in the therapeutic armamentarium is nowbeing better defined. Both could be considered modelsfor other new therapies, because they were shown to beeffective (in highly varying degrees) in relapsed pa-tients. Post-approval studies are being done to definetheir role in newly diagnosed patients to increase theiroverall impact. Arsenic trioxide leads to a four-log re-duction in the acute promyelocytic leukemia diseaseburden in heavily pre-treated relapsed patients12 and isnow being evaluated to consolidate first remissions(Table 1). Gemtuzumab ozogamicin is an anti-CD33immunotoxin conjugate that was approved based on a30% response rate (half of whom were patients whonever fully recovered their platelet count) in patients

with untreated first relapse who had, in most cases, afirst remission of 6 months or longer.13 Disappointmentwith this drug due to its low single-agent efficacy intreatment of patients with refractory AML as well as itsassociation with hepatic veno-occlusive disease whenadministered proximal to or following a bone marrowtransplant14 has dampened enthusiasm. Nonetheless,based on the apparent safety of combining this agentwith chemotherapy in newly diagnosed patients,15 im-portant studies are now underway to determine ifgemtuzumab ozogamicin combined with induction orconsolidation chemotherapy, or as a single agent in thepost-remission setting in older adults might lead to abetter outcome (Table 1).

Agents Not Expected to Be Effective as Single Drugs

Drug-resistant modulatorsThe notion that blasts from AML patients, and particu-larly from older individuals, are likely to express genescapable of mediating drug resistance, most notably theGP170 drug efflux pump, has prompted clinical trialswith so-called reversing agents that inhibit this func-tion. Since many of these agents also inhibit the me-tabolism of chemotherapeutic drugs like anthracyclines,pharmacokinetic considerations are important. Most ofthe trials that have compared chemotherapy with orwithout a drug-resistant modulator (DRM) have shownno benefit or have been terminated early due to excesstoxicity.16 However, a randomized clinical trial involv-ing cyclosporine A as a reversing agent has been posi-tive,17 prompting the Southwest Oncology Group to treatolder adults with chemotherapy (using a novel regimenincluding continuous infusion daunorubicin) with andwithout cyclosporine A. Secondly, trials with newerDRMs that do not have pharmacological effects on che-motherapy are also underway (Table 1).

A problem with these drugs as well as with manynovel approaches is that the mechanism of resistance islikely to be pleiotropic. The inability to initiate celldeath in response to chemotherapy is another potentialmechanism of resistance. Overexpression of the bcl-2anti-apoptotic gene has been associated with poor prog-nosis in AML patients. Preclinical data documentingsynergism between chemotherapy and the antisense 18-mer oligonucleotide oblimersen (G3139) have promptedPhase I clinical trials documenting the safety of induc-tion chemotherapy with this agent.18 The CALGB hasbegun a randomized a trial in older adults that com-pares chemotherapy alone to chemotherapy adminis-tered with oblimersen (Table 1). Synergistic antileuke-mic activity between chemotherapy agents and theproteosome inhibitor bortezomib19 has spurred the clini-

Table 2. Categories of novel therapies for acute myeloidleukemia (AML).

Drug-resistance modifiers

Proteosome inhibitors

Pro-apoptotic approaches

Signal transduction inhibitors

“RAS”-targeted (e.g., farnesyl transferase inhibitors)

Tyrosine kinase targeted (e.g., FLT3, c-kit)

Downstream signal inhibitors

Immunotherapeutic approaches

Antigens known

anti-CD33

anti-GM-CSF receptor

Antigens unknown

stimulate immune system (IL-2, GM-CSF)

present tumor antigens effectively

dendritic cell fusion

transfer hematopoietic growth factor genes

Abbreviations: IL, interleukin; GM-CSF, granulocyte-macroph-age colony-stimulating factor


cal development of this agent in conjunction with che-motherapy in AML.

The use of hematopoietic growth factors (HGFs)in AML has received much attention. Once concernsdiminished that growth factors would enhance diseaseresistance via their known ability to stimulate leukemiacells to enter S-phase, a host of clinical trials examinedthe ability of HGFs to shorten the period of neutrope-nia and reduce infectious mortality. While the durationof neutropenia was reduced by several days when G-CSF or granulocyte-macrophage colony-stimulatingfactor (GM-CSF) was used in the postchemotherapyperiod, the inability of these agents to alter the nadir,allay mucositis, or decrease the death rate diminishedtheir utility. Perhaps more interesting is the use of theseagents before or during chemotherapy in an effort toincrease the S-phase fraction of cells, thereby using themas chemosensitizing agents. Although most of the trialsusing HGFs in this fashion have been disappointing, arecent randomized study in which G-CSF was used be-fore and during chemotherapy, yielding a disease freesurvival benefit,20 has prompted renewed interest in thisstrategy. At the present time the use of G- or GM-CSFcan be considered optional using supportive care guide-lines for neutropenic fever while their use as chemo-therapy-enhancing agents needs to be explored furtherbefore routine use is warranted.

Agents That Promote DifferentiationAlmost a quarter century has elapsed since clinical tri-als suggested that low-dose cytarabine’s effect in AMLand myelodysplasia resulted from hematopoietic celldifferentiation. In the ensuing years, the enthusiasm forlow-dose cytarabine as an effective therapy that inducesmaturation of AML cells has waned. However, an in-creased understanding of how the transcription of dif-ferentiation-associated genes is regulated has promptedthe exploration of new and potentially effective thera-pies. Among the many biochemical events that mustoccur as a cell changes from a stem cell to a maturefunctional blood cell are removal of methyl groups fromDNA bases and addition of acetyl groups to the histoneDNA protein coat. Such effects change the conforma-tion of the DNA and allow transcription of certain genes.The DNA hypomethylating agent azacitidine21 was re-cently approved by the US Food and Drug Administra-tion (FDA) for use in all subtypes of myelodysplasticsyndrome. Many clinical trials are now underway withso-called histone deacetylase inhibitors, although out-come data are sparse. Given the general hypothesis thatAML results from a combination of over proliferationof the stem cell compartment as well as failure to dif-ferentiate, it is rational to consider the future use of

these differentiating agents in combination with agentsthat inhibit mitogenic signals.

Signal Transduction InhibitionThe mechanism by which cells receive and transmitmitogenic signals is complex and involves the coordi-nated action of many different proteins, commonly rep-resented by so-called signal transduction cascades. In-sofar as such cascades might be overactive in leukemiacells compared to normal hematopoietic cells, a thera-peutic opportunity is provided. Moreover, an activat-ing mutation in one of the proteins responsible for trans-mitting proliferative signals in AML defines a poten-tial target. Mutations in one of the RAS family pro-teins, 21-KD guanine-nucleotide binding proteins, havebeen described in 10%–50% of AML patients. Suchactivating mutations are thought to allow autonomousgrowth. RAS proteins require several post-translationalmodification steps including addition of a farnesyl lipidmoiety that allows translocation to the plasma mem-brane and activation. Farnesyl transferase inhibitors(FTIs) have been shown to inhibit the growth of mu-tant RAS-transformed cell lines. The FTI in furthestdevelopment in AML, tipifarnib (R115777), was asso-ciated with responses in advanced-stage patients in aPhase I trial.22 Despite disappointing results in an inter-national Phase II trial in refractory/relapsed patients(although RAS mutations were not required), the drughas been administered to over 100 chemotherapy-naïveAML patients. A preliminary report documented a 20%complete remission rate in this group of poor progno-sis, largely older patients who received this oral agentas their initial therapy.23 These exciting results, if con-firmed, might provide a new and less toxic therapy com-pared to chemotherapy for older adults with AML. FTIsare also being evaluated in younger patients in earlierdisease states and in combination with chemotherapy.An active area of current research in AML is the devel-opment of agents known as FLT3 inhibitors. FLT3 is atransmembrane tyrosine kinase. Approximately 30% ofAML patients can be shown to have an activating mu-tation that generally carries a poor prognosis.2 The ac-tivating mutation may be a duplication of between 3and 60 amino acids in the juxtamembrane region or,less commonly, a point mutation in the activation loop.2

Activating mutations of the FLT3 tyrosine kinase trans-form leukemic cell lines into growth factor indepen-dence and cause a fatal myeloproliferative syndrome ina murine bone marrow transplant model. Small mol-ecules capable of inhibiting FLT3 enzyme activity canselectively kill such transformed cell lines and improvesurvival in the murine model.2 Thus, the preclinicaldata supporting the development of these drugs as thera-

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peutic agents in AML is at least as strong as that used tosupport clinical trials with imatinib in patients withCML. There are two major differences between imat-inib’s development and that of the FLT3 inhibitors: 1)CML in chronic phase is probably based solely on theactivation of bcr-abl, whereas AML is almost certainlya “multi-hit” disease; 2) Multiple agents and drug com-panies are developing FLT3 inhibitors. However, justas was the case for imatinib, these drugs have a spec-trum of activity beyond FLT3 inhibition alone. Forexample, PKC-412 (N-benzoylstaurosporine) inhibitsFLT3 as well as protein kinase C and the vascular en-dothelial growth factor receptor. Such a wide spec-trum of activity could have positive or negative conse-quences. SU5416, which inhibits FLT3 reasonably po-tently, was developed as a c-kit inhibitor. The drug dem-onstrated modest activity in AML, but no activity wasobserved in the 7 patients who retrospectively werefound to have an activating mutation of FLT3 in theirmyeloblasts.24 Minor responses have been observed inpatients without known FLT3 mutations who have re-ceived PKC-412. Available clinical data from early tri-als with the three drugs specifically developed as FLT3inhibitors, PKC-412,25 CEP-701,26 and MLN-518,27 are

summarized in Table 3. Biological responses, demon-strated by a major reduction in peripheral blast count,have occurred with each of these drugs. However, theyhave minimal ability to reduce the bone marrow blastcount, and therefore, complete remissions have occurredin 1/42 reported patients. Moreover, the duration ofresponse has been brief. Although much more workwith these oral agents needs to be done, initial impres-sions suggest that (1) the multiplicity of genetic lesionsin the typical AML cell may be problematic for expect-ing these agents to work alone; (2) pharmacokineticissues require prolonged therapeutic drug levels and theability to get to the target leukemia progenitor cell; and(3) the contribution of alternative enzymes and path-ways are important.28

Nonetheless, further development of these drugs atdifferent doses and schedules and in combination withother signal transduction inhibitors and/or chemotherapyis warranted. Other tyrosine kinase inhibitors, includ-ing those that inhibit the vascular endothelial growthfactor receptor, are also in clinical trials in AML.29

Table 3. FLT3 inhibitors in clinical development (modified from Wadleigh et al 29).

Tyrosine ReceptorKinase Inhibitor Clinical Trials/Inhibitor C lass Activity† FLT3 IC 50 ‡ Comments To xicity

PKC-412 Benzoylstaurosporine PKC Phase II: AML with/without FLT3-ITD Nausea,PDGFR In FLT 3 mut pts (n = 20), 35% emesis, fatigueKDR significant reduction in blastKIT count25

FLT3 528 nMABL

CEP-701 Indolocarbazole FLT3 2–3 nM Phase II: AML with FLT3-ITD Nausea,TRKA Several pts had reduced blast emesis, fatigueKDR counts, autophosphorylationPKC inhibited26

PDGFREGFR

MLN-518 Piperazinyl quinazoline KIT Phase I: AML/MDS with/without GeneralizedPDGFR FLT3-ITD weakness,FLT3 170–220 nM Phase II: AML with FLT3-ITD fatigue, nauseaFMS A few pts with FLT3 ITD treated and vomiting

at higher doses had biologicalresponse27

SU5416 Indolinone FLT3 250 nM Phase II: Refractory Fatigue,KDR AML/MDS/MPD/MM nausea, sepsisKIT Phase II: Refractory AML (c-KIT and bone pain

positive). No responses inFLT3 ITD pts.24

† Receptor inhibitor activity in descending order of potency‡ FLT3 autophosphorylation in vitro 1

Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; MPD, myeloproliferative disease; MM, multiplemyeloma


II. T HE ROLE OF AUTOLOGOUS AND ALLOGENEIC

(“F ULL ” AND “M INI ”) STEM CELL

TRANSPLANTATION IN AML

Margaret R. O’Donnell, MD*

Hematopoietic cell transplantation (HCT) is an effec-tive therapy for AML. Obstacles to broad applicabilityof HCT therapy for the majority of patients with AMLhave included inability to control leukemia with pri-mary induction therapy, lack of suitable hematopoieticcell donors, toxicities of HCT conditioning regimensand long-term complications of the transplant proce-dure. While all antileukemia therapies are complicatedby the problems of chemotherapy-related toxicities anddisease relapse, allogeneic HCT also exposes patientsto the risks of potential failure of engraftment; organtoxicities caused by GVHD and prolonged immuno-suppression with its attendant risks of post-HCT infec-tious complications.

In the last decade, several developments have madeallogeneic HCT a more “user-friendly” treatment mo-dality. Expansion of the pool of donors in national andinternational registries as well as the establishment ofcord blood banks has vastly increased the likelihood ofsuccess in identifying a suitable HLA match for pa-tients who lack matched family donors, although cordblood HCT is still utilized primarily for pediatric re-cipients. The refinement of tissue typing using molecu-lar probes permits better matching of unrelated donor-recipient pairs, thereby decreasing the risks of both graftrejection and GVHD.

There has also been a recent change in the type ofhematopoietic progenitor cell (HPC) product used forgraft reconstitution. Autologous transplant procedureshad transitioned from marrow to cytokine-primed (G-CSF and/or GM-CSF) peripheral blood stem cells(PBSC) for ease of collection and rapid engraftment bythe early 1990s. However, expectation of higher ratesof GVHD due to the 10-fold increase in T cells in PBSCproducts delayed their use in allogeneic settings untilthe latter-half of the 1990s. In 2003, National MarrowDonor Program (NMDP) statistics showed 60% of un-related donor products collected for transplants for AMLwere PBSC. Collection via apheresis is physically easierfor many donors. The 4- to 5-fold higher number ofCD34+ cells in a PBSC product facilitates more rapidengraftment in comparison with a marrow product (me-dian of 17 days versus 24 days for granulocytes and

median of 28 days versus 47 days for platelets, respec-tively), which decreases the risk for bacterial infectionsin the early post-transplant period.1 Despite initial con-cerns that a 10-fold increase in the number of CD3+

cells in the PBSC graft would lead to higher incidenceof severe GVHD, this has not been demonstrated inclinical trials. Several studies have shown no signifi-cant difference in the incidence of acute GVHD; how-ever, higher rates of late onset chronic GVHD (beyond6 months) have been reported.2 In both a large random-ized trial and a retrospective review of InternationalBone Marrow Transplant Registry (IBMTR) data, PBSCgrafts were associated with improved relapse-free sur-vival in patients with leukemia beyond first remission(CR1).1,3,4 In addition to producing a HPC product thatresults in more rapid engraftment, G-CSF exposure alsoshifts donor T cells to Type 2 cytokine secretion(interleukin [IL]-4 and IL-10) and downregulates Type1 (IL-2 and interferon γ ) cytokine production, phe-nomena which may be associated with less severe acuteGVHD.

Improvements in post-transplant supportive careand the development of newer immunosuppressiveagents have also had an impact on transplant-relatedtoxicities. More refined PCR-based screening for cy-tomegalovirus reactivation allows pre-emptive therapytailored to viral load. Newer less toxic antifungal agentssuch as voriconazole and caspofungin have decreasedearly mycotic infections and make it feasible to pro-vide long-term fungal prophylaxis in patients at highrisk due to chronic GVHD. Newer immunosuppressiveagents, such as sirolimus and mycophenolate mofetil(MMF) are being incorporated into GVHD prophylac-tic regimens to decrease the incidence of acute and chronicGVHD in high-risk populations including unrelated do-nor recipients and older (> 50 years) patients.5,6

However, the change that may have the greatestimpact on AML treatment is the advent of reduced in-tensity or nonmyeloablative HCT. Reduced-intensityHCT relies upon the graft-versus-leukemia effect ofthe allograft rather than the direct tumoricidal activityof the conditioning regimen. Because of the paucity ofany direct antileukemic effect of the conditioning regi-mens, the truly nonmyeloablative (NMABT) regimenscan only be used in patients with low volumes of dis-ease, whereas the reduced-intensity conditioning regi-mens, which usually contain fludarabine and some alky-lating agent, do have direct antileukemia activity andcan be used with more extensive disease. The shortenedduration of cytopenias and the minimal mucosal toxic-ity of the newer reduced-intensity conditioning regi-mens provide a reasonably safe transplant option forpatients two decades older than the population that was

* City of Hope National Medical Center, 1500 East DuarteRoad, Duarte CA 91010

Hematology 2004 105

treated with traditional fully ablative high-dose chemo-radiotherapy regimens.

Choosing the Type and Timing of HCT(To Transplant or Not to Transplant)

The possible need for HCT as a component of futuretherapy should be acknowledged at diagnosis in AML.For all patients under age 56 who do not have signifi-cant co-morbid conditions, HLA typing should be partof the patient’s initial evaluation, and family typingshould be initiated when the cytogenetic information isavailable. Only a minority of patients will have a fa-vorable karotype that would obviate consideration ofallogeneic HCT either as part of consolidation or forsalvage of resistant disease. For patients with poor-riskcytogenetics, antecedent myelodysplasia or therapy-related AML, an unrelated donor search should bepromptly instituted in patients lacking a family donor.Early donor identification allows optimal timing forHCT as consolidation or salvage therapy. In older pa-tients (56–70 years), however, it is reasonable to delayHLA typing of family members until remission isachieved and the patient has recovered a good perfor-mance status since there is substantial attrition in therank of candidates for the investigational use of reduced-intensity or nonmyeloablative HCT as consolidation dueto failure to achieve a remission or decline of func-tional status as a consequence of induction therapy.

The decision to proceed to either autologous or allo-geneic HCT is strongly influenced by the followingfactors: expectations of outcome with the prevailingnon-HCT conventional therapy, the effectiveness of sal-vage options for disease relapse, the toxicities of trans-plant including long-term complication of infertilityand second malignancy, and the individual patient’s co-morbid conditions. The patient’s cytogenetic risk groupand time to achieve remission are currently the majordisease-specific factors to be considered in opting forHCT as consolidation therapy, whereas donor availabilityand the impact of recipient performance status on theability to tolerate the rigors of even a reduced-intensityHCT are important factors to consider at relapse. Whilethere are several studies with long-term outcome datacomparing myeloablative conditioning regimens fol-lowed by either autologous or allogeneic HCT, the fol-low-up data on reduced intensity HCT is much shorterand the patient populations are not comparable.

Comparisons of Autologous Transplantation,Allogeneic and Reduced-Intensity HCT

Autologous transplantation has been used primarily asa component of consolidation following initial remis-sion; less commonly, it can be used as a component of

salvage therapy for patients in second remission. Tominimize both the total body leukemic burden and thecontamination of the PBSC product, current practice isto administer one to two cycles of a high-dosecytarabine-based consolidation to achieve “in vivo purg-ing” prior to collection of G-CSF–mobilized PBSC.To assure that an adequate hematopoietic progenitorcell product of at least 5 × 106 CD34+ cells/kg recipientbody weight can be collected, it is recommended thatno more than 2 cycles of consolidation occur beforePBSC collection. While the nonhematologic toxicitiesof the conditioning regimens used for autologous HCTare significantly greater than those seen with high-dosecytarabine consolidation, the hematologic recovery isquite rapid (8–11 days) following infusion of autolo-gous G-CSF–mobilized PBSC. The combined treat-ment-related mortality (TRM) for one cycle of high-dose cytarabine-based consolidation followed by 1200cGy fractionated total body irradiation (FTBI), etopo-side and cyclophosphamide (Cy) and autologous HCTat our institution ranged between 3% and 6% in threesequential trials inclusive of patients up to age 60. At-trition between consolidation and autologous transplantranged from 18% to 24% due to relapse, inadequateHPC collection or treatment-related toxicities such asinvasive fungal infection and cytarabine-induced neuro-toxicity, making this a reasonable consolidation optionfor most patients up to age 60.7

Over the last 15 years, the upper age limit consid-ered to be acceptable for a fully ablative allogeneic HCThas advanced from 40 to “robust” 60 year olds (perhapsin response to the maturing age of the transplanters them-selves as much as to improvements in supportive careand GVHD prophylaxis).8 If an HLA-matched donorhas been identified while the patient was receiving in-duction therapy, there is no advantage to administeringpostremission chemotherapy prior to allogeneic HCT.9

GVHD and transplant-related toxicity remain the ma-jor obstacles to successful outcome with allogeneic HCT.The introduction of two new immunomodulatory drugsfor GVHD prophylaxis may have an important impacton both these problems. Investigators from the Dana-Farber recently reported a Phase II trial in whichsirolimus was substituted for methotrexate (MTX) in atacrolimus-based GVHD prophylaxis regimen for PBSCHCT utilizing a fully myeloablative conditioning regi-men.5 Engraftment was prompt and only 3/30 (10%)patients developed acute GVHD (all Grade II) com-pared to the expected incidence of 35%–40% acuteGVHD in sibling-donor HCT with tacrolimus/MTX.TRM was only 6% at 1 year compared to 25%–30% inmost traditional allogeneic studies. Chronic GVHD de-veloped in 40% of the study patients. Toxicities in-


cluded significant hyperlipidemia, thrombotic micro-angiopathy and a 10% incidence of veno-occlusive dis-ease primarily in patients with recent exposure togemtuzumab ozogamicin. Other studies of the substitu-tion of mycophenolate mofetil (MMF) for MTX inGVHD prophylaxis regimens have demonstrated de-creased regimen-related toxicities of severe mucositis andinterstitial pneumonias, as well as more rapid engraft-ment compared to a MTX-containing regimen (14–16days versus 19–22 days for neutrophil engraftment).10,11

Improvements in molecular matching for unrelateddonor-recipient pairs have significantly improved out-comes for this group, although there continues to be anapproximately 10% higher incidence of TRM when sib-ling allogeneic HCT is compared to allogeneic HCTfrom molecularly matched unrelated donors for patientsin CR1. Because of the perception of higher TRM, theprofile of patients who undergo unrelated donor HCTin CR1 is skewed toward those with poorer risk cytoge-netics, prolonged time to achieve a remission, or a his-tory of antecedent myelodysplasia or therapy-relatedAML. The majority of unrelated donor transplants are

still being performed for AML patients beyond CR1.The foremost advantage of the nonmyeloablative

or reduced-intensity HCT is the reduction of TRM. Mu-cositis in the immediate post-HCT period is much re-duced due to the low antiproliferative activity of theconditioning regimen and the substitution of MMF forMTX in the GVHD prophylaxis regimen. The reduc-tion in mucosal disruption led to a decreased incidenceof acute (12%) and chronic (19%) GVHD for reduced-intensity fludarabine/melphalan versus 36% acute and40% chronic GVHD for patients receiving ablative sib-ling HCT in an MD Anderson Cancer Center study.11

Infectious complications are also reduced, with a 9%incidence of bacteremia at day 100 for nonmyeloablativeconditioning versus 27% for standard HCT and a dif-ference in day 100 survivals of 93% versus 81%, re-spectively, in a case-matched control series from Se-attle.12 However, other investigators have reported higherrates of CMV reactivation before day 100 and persis-tent risk of bacteremia and fungal infections late post-HCT with nonmyeloablative regimens because of theprolonged immunosuppressive effects of fludarabine

Table 4. Treatment outcomes and toxicity for autologous and allogeneic hematopoietic cell transplantation (HCT) forconsolidation or salvage therapy.

Reduced-IntensityAutologous HCT Allo HCT (Sib) AlloHCT/MUD AlloHCT + MUD

CONSOLIDATION (CR1)

Cytogenetic risk

t(15;17) No role No role No role No role

t(8;21)inv(16) DFS 60%–80%* DFS 65%TRM 4%–8% TRM 18% = No Role No role No role

Intermediate DFS 42%–55% DFS 48%–62% Insufficient data forTRM 4%–6% TRM 16%–20% nonmyeloablative

Poor DFS 18%–25% DFS 35%–45% 5-yr DFS 30%–40% Reduced intensity DFS 50%TRM 4%–8% TRM 18%–20% TRM 30% for older AML CR1 at 2 yr

SALVAGE

CR2 DFS 30% overall DFS 40% Pediatric 40% 2-yr DFS 40%–50%reducedDFS 60%–80% Adult 5-yr DFS 30% intensityfor t(15;17) TRM 30%

Relapse Not an option unless DFS 20%–30% Pediatric DFS 20% 2-yr DFS 10%–30%“back-up” product from Adult 5-yr DFS depending on the volumeCR1 available 10%–15% of residual disease

Induction Failure No Role DFS 30%–40% (3 yrs) DFS 20%–30%** 1-yr DFS 15%–30% (sibling)(20% for untreatedsecondary AML)

* Because of high salvage rate and long-term sequelae, many would reserve autologous HCT for relapse for patients withfavorable cytogenetics.

** Most of these patients represent patients with high grade myelodysplastic syndrome (MDS) in which an unrelated donor searchwas initiated prior to leukemic evolution.

*** DFS interval will be 5 years unless otherwise noted

Abbreviations: AML, acute myeloid leukemia; DFS, disease-free survival; TRM, treatment-related mortality; HCT, hematopoietic celltransplantation; MUD, matched unrelated donor; allo, allogeneic; CR, complete response

Hematology 2004 107

even in the absence of GVHD.Table 4 provides a schematic of current thinking

on the role of the various types of HCT in the therapyof AML. A caveat for interpretation of all consolida-tion trials in which HCT is a component is the exist-ence of selection bias. There have been several largenational or co-operative group trials conducted between1986 and 1995 that tried to answer the question of therole of transplantation in consolidation in younger pa-tients with AML.13-15 Patients with sibling donors wereassigned to the allogeneic marrow transplantation andthe remainder were randomized, between a variety ofconsolidation (2–4 cycles) chemotherapy versus autolo-gous marrow transplant after 1–4 cycles of consolida-tion. The conclusions ranged from no survival advan-tage to either form of HCT compared with consolida-tion chemotherapy in the initial analysis of the US Na-tional Trial involving the Eastern Cooperative Oncol-ogy Group (ECOG), Southwest Oncology Group(SWOG) and CALGB to a significant difference in dis-ease-free survival for both allogeneic (55%) and au-tologous HCT (48%) compared to chemotherapy (30%)in the European Organisation for Research and Treat-ment of Cancer (EORTC) trial (albeit with no overallsurvival advantage as a high percentage [58%] of che-motherapy relapses were salvaged with transplant).When the US National Trial was reanalyzed usingcytogentic risk groupings there were clear differencesin favor of HCT (allo and auto) for favorable risk andfor allogeneic in patients with poor risk cytogenetics.15

In all these trials as well as the MRC10 trial, there wasconsiderable patient attrition from achieving remissionto initiating any form of consolidation.16 Fully one thirdof younger (< 55 yr) patients received no documentedform of consolidation; 50%–80% of patients actuallyreceived the designated HCT treatment. While it is ap-propriate to compare treatment strategies on an intent-to-treat basis from the time CR is achieved, the inter-position of multiple nontransplant therapies before HCTmay cause high attrition rates that provide a negativebias, while analyses that start only at time of transplantmay give an overly optimistic prediction of outcome.

Consolidation

Good-risk cytogeneticsGiven the high curability of acute promyelocytic leu-kemia (APL) with conventional chemotherapy, there isno role for autologous or allogeneic HCT for patientsin CR1 who achieve a molecular remission by thecompletion of consolidation. Several series have dem-onstrated that autologous HCT can produce durable sec-ond remissions in 75%–100% of the patients in whom

a molecularly negative product can be collected.17 How-ever, for patients with persistence of the PML/RAR geneproduct, allogeneic transplantation should be consid-ered since the relapse rate following infusion of a mo-lecularly positive product exceeds 85%.

Relapse free-survivals of 60%–83% have been re-ported for patients with t(8;21) or inv(16) using intent-to-treat analysis from the start of high-dose cytarabineconsolidation through autologous HCT with relapse ratesof 15%–20% post-HCT and TRM of 4%–8% over-all.18,19 While these disease-free survival (DFS) ratesare higher than the DFS seen with multiple cycles ofhigh-dose cytarabine-based consolidation and the timeto completion of treatment may be shorter, long-termtoxicities associated with autologous HCT need to befactored into the decision to pursue autologous HCT inindividual patients. Many with expertise in AML wouldreserve autologous HCT for relapse in patients withgood risk cytogenetics. In patients who opt for conven-tional chemotherapy, one should consider cryopreservingautologous PBSC as a “back-up” for salvage therapy inthe event of relapse in patients who lack a histocompat-ible sibling. Autologous HCT can provide long-termsalvage for 40% of patients who achieve a second re-mission overall; factors that correlate with better out-come include cytogenetics and duration of first remis-sion.20 Sibling allogeneic HCT in CR1 in the group withfavorable cytogenetics had only 62% DFS with a 17%TRM in the EORTC/GIMEMA (Gruppo ItalianoMalattie Ematologiche dell’ Adulto) trial based on in-tent-to-treat from time of remission that compared au-tologous to allogeneic transplant during the time pe-riod of 1993–1999 (Figure 1A). The high TRM asso-ciated with allogeneic HCT indicates that allogeneicHCT has no advantage over conventional chemotherapyor autologous HCT until the toxicity profile improves.19

Intermediate cytogeneticsThe European Bone Marrow Transplant (EBMT) groupreported an overall 2-year leukemia-free survival of49% for 1040 patients who received autologousunpurged marrow transplant during the period of 1986–1994.21 The TRM was 11%, with a median time togranulocyte and platelet recovery of 29 days and 42days, respectively. Factors that influenced outcomeswere time to achieve remission (1 vs 2 inductions) forleukemia-free survival and older age (> 35 years) forTRM. Karyotypic analysis was not included in that study.In the EORTC/GIMEMA study, patients with normalkaryotype who underwent autologous HCT had a 48%DFS with a 5% TRM compared to 45% DFS and 20%TRM in patients transplanted from a sibling donor.14 Ina consortium study that included 128 patients up to age


65 receiving autologous HCT in CR1, Linker et al re-ported a 51% DFS for patients with intermediate riskcytogenetics, with a combined TRM of 3% for bothconsolidation and transplant.18 Since TRM in alloge-neic recipients increases significantly with age, autolo-gous transplant may offer equivalent DFS with less mor-bidity for older patients (≥ 50 years) than standardmyeloablative allogeneic transplant. Younger (≤ 40years) patients with a sibling donor can expect a betterrelapse-free survival of 62% with a 15% relapse rateand TRM of 15%–20%. Since TRM is 10%–18% higherfor unrelated-donor HCT using myeloablative condi-tioning, a donor search is rarely initiated during CR1for intermediate-risk patients in the absence of otherrisk factors such as antecedent MDS.

Poor-risk cytogeneticsA donor search for a related or unrelated donor shouldbe initiated as soon as the patient is identified as havingpoor-risk cytogenetics as this group may not achieveremission and may require allogeneic HCT for earlysalvage. Patients with poor-risk cytogenetics are pro-portionally underrepresented in autologous transplantseries, accounting for less than 10% of patients becauseremissions are more difficult to achieve and the recov-ering marrow may have underlying myelodysplasia,which impairs the ability to collect adequate numbersof stem cells with normal proliferative capacity. In mostseries, the results of autologous HCT for patients inthis group are poor, with DFS of 20% or less.21 In con-trast, sibling allogeneic transplant for this group results

Figure 1. Disease-free survival (DFS) from complete response (CR) for four prognostic cytogenetic risk groups—EORTC/GIMEMA trial comparing sibling allogeneic versus autologous HCT for consolidation.

The cytogenetic risk groups are good risk (1A), normal (1B) and bad/very bad risk (1C). 1D captures the data for patients in whomcytogenetics were unknown. Reprinted with permission from Blood. 2003;102,1237.

Hematology 2004 109

in a 40%–45% DFS for patients ≤ 45 years of age19

(Figure 1C). Most unrelated donor transplants in CR1are performed in patients with poor-risk cytogenetics.Data from the NMDP demonstrated an overall 40% 5-year relapse-free survival for all AML patients in CR1transplanted between 1987 and 2001, which is compa-rable to the 44% reported by the EORTC for siblingHCT of patients with poor-risk karyotypes.

Reported outcomes for reduced intensity transplantsin patients with AML in CR1 are based on smallsamples. The group from the University of Michigantreated 21 patients over age 55 (median 61 years) withMDS or AML who had HLA-matched sibling donorswith the reduced intensity regimen of fludarabine (Flu)and busulfan (Bu) with tacrolimus and MMF for GVHDprophylaxis.22 Seven of 12 patients who were in CR attime of transplant remain in remission with a medianfollow-up of 1 year (range 210–733 days). There were3 relapses and 2 treatment-related deaths. All the pa-tients with active disease died (5 relapse and 4 TRM)with a median survival of 108 days. Overall, the inci-dence of acute GVHD was 38% with a maximum se-verity of grade 2. TRM at day 100 for the whole groupwas 19% and was only 8% in the patients who did nothave active disease at transplant.

The German Cooperative Transplant Study Groupreported on 113 AML patients treated with Bu/Flu (93patients) or Flu/TBI (20 patients) with a radiation doseof either 400 or 800 cGy. The reduced intensity regi-mens were chosen for these patients because of age > 50,co-morbid condition or prior HCT; the median age was51 and more than half the patients received unrelateddonor allografts.23 The minority of patients (22%) werein CR1, and half the patients were in relapse at HCT.Five patients with relapse did not clear their diseaseand 1 did not engraft. Acute GVHD (Grade 2–4) oc-curred in 42% of patients and chronic GVHD occurredin 35% of patients at risk after day 100 with the major-ity of these cases being of limited extent. The 2-yearDFS was 50% for those in CR1, 40% for those in CR2or 3, and 15% for those with relapsed disease. Causesof death were evenly divided between relapse and treat-ment-related toxicity (29 patients each). In addition toremission status, performance status (≤ 70%) and do-nor type (sibling versus unrelated donor) were predic-tive factors for event-free survival.

SalvageThe majority of allogeneic transplants are performedas salvage for patients who have relapsed after conven-tional chemotherapy or autologous HCT. The decisionregarding reinduction prior to salvage transplant is in-fluenced by (1) the availability of an identified donor

and (2) the likeliness of achieving a remission, whichin turn is based on cytogenetic risk group, duration ofCR

1 and comorbid conditions. Data from EBMT,

IBMTR and the NMDP show DFS of 44% with siblingallografts and 30% with matched unrelated donor al-lografts at 5 years for patients transplanted in secondremission and DFS of 35%–40% in sibling transplantsand 10% in unrelated donor transplants for patients withinduction failures or HCT in relapse.24 It should be notedthat the majority of these patients received marrow ratherthan PBSC. In the Seattle study comparing sibling mar-row versus PBSC in patients with more advanced dis-ease, there was a significant difference in DFS (57% vs33%) using PBSC compared to marrow.1 Additionaldata from the IBMTR also showed an advantage forPBSC compared to marrow for patients transplanted insecond remission.3 The reduced intensity regimens havehad a tremendous impact on TRM in the setting of sec-ond transplants or secondary MDS/AML following priorautologous HCT, increasing the DFS from 16% withstandard Bu plus Cy conditioning to 40% with Flu/Buor Flu/Melphalan conditioning.25 The recent formationof the Blood and Marrow Transplant Clinical TrialsNetwork (CTN) to facilitate the conduct of large scalecomparative transplant trials should enable the trans-plant community to expeditiously define the role ofnewer reduced-intensity conditioning regimens andGVHD prophylaxis regimens in exploiting the antileu-kemic effect of donor alloreactivity, minimizing trans-plant-related toxicities and broadening the applicabil-ity of HCT as a curative treatment strategy for patientswith AML.

III. AML IN OLDER ADULTS: ARE WE LISTENING?

Mikkael A. Sekeres, MD, MS*

AML is a disease of older adults. In the US, the medianage is 68 years and the age-adjusted population inci-dence is 17.6 per 100,000 for people 65 years of age orolder, compared with an incidence of 1.8 per 100,000for people under the age of 65 years.1 Therefore, of theestimated 11,900 new AML diagnoses in the US in2004, over half will affect patients 60 years of age orolder, a population considered “elderly” in the leuke-mia literature.2-5 This number will only increase as thepopulation of US citizens 65 years or older, estimatedto be approximately 35 million in the year 2000, is

* The Cleveland Clinic Foundation, Hematology and MedicalOncology, Desk R35, 9500 Euclid Avenue, Cleveland OH44195


expected to double by the year 2030.Older adults with AML, when compared to

younger patients with the same disease, have a poorprognosis and represent a discrete population in termsof disease biology, treatment-related complications, andoverall outcome. As a result, older patients require dis-tinctive management approaches to determine whetherstandard treatment, investigational treatment, or low-dose therapy or palliative care is most appropriate. Par-ticularly in this population, the tradeoff between po-tential for cure or survival prolongation and quality oflife must be weighed carefully.

Disease Biology

CytogeneticsOlder adults with AML have a lower incidence of fa-vorable chromosomal abnormalities [including the corebinding factor abnormalities, such as t(8;21) or abnor-malities of chromosome 16, or the t(15;17) associatedwith APL] and a higher incidence of unfavorable ab-normalities (including complex cytogenetics or abnor-malities of chromosomes 5, 7, or 8) compared toyounger adults with AML (Table 5).6-8 The rare olderpatient fortunate enough to have good-risk cytogeneticabnormalities may have a survival advantage over other

older patients,8,9 though it is not clear that this findingholds for patients older than 65 years.

Bone marrow biologyIn older adults, AML is more likely to arise from aproximal bone marrow stem cell disorder, such asmyelodysplastic syndrome (MDS), and with leukemia-specific abnormalities in more than one hematopoieticcell lineage. This may explain the different disease be-havior in this group, as well as prolonged neutropeniafollowing chemotherapy.3 Older adults with AML alsoare more likely to have reduced proliferative capacitiesin normal hematopoietic stem cells, which may affectblood count recovery following intensive chemotherapy.

Drug-resistance genesThe expression of genes that mediate drug resistanceoccurs with increased frequency in this age cohort.MDR1, the so-called P-glycoprotein (gp170) chemo-therapy efflux pump, was found in 71% of leukemicblasts in subjects in a SWOG study of AML patientsover the age of 55 years, compared to a prevalence of35% in younger AML patients.10 MDR1/P-glycopro-tein expression is associated with lower complete re-mission (CR) rates and more chemo-resistant disease.

Prior stem cell insultOlder adults with AML are more likely to have a sec-ondary leukemia arising from an antecedent MDS orfrom prior treatment with chemotherapy or radiationtherapy for another cancer. Patients with this type ofAML are predisposed to having abnormalities in chro-mosome 5 and/or 7.7 Secondary AML (AML that aroseafter MDS, myeloproliferative disorders, and therapiesof malignancy) comprises 24%–56% of AML diagno-sis in older patients,10,11 compared to a prevalence ofapproximately 8% in younger AML patients in theMedical Research Council (MRC) AML 10 trial.7 AMLarising from prior bone marrow stem cell disorders orantecedent hematologic disorders, particularly when theprocess is greater than 10 months in duration prior tothe development of AML, is less responsive to chemo-therapy, resulting in shorter event-free survival, a lowerCR rate, and conferring a worse prognosis.12

Response to TherapyOlder adults are not as tolerant of or responsive to re-mission induction and consolidation chemotherapy com-pared to their younger counterparts. High mortality rateslikely result from inherent disease biology, an increasedprevalence of comorbid disease, and a differential me-tabolism of induction regimen drugs, particularlycytarabine, resulting in supratherapeutic drug levels.4

Table 5. Characteristics of older and younger adults withacute myeloid leukemia (AML).

Older AML Younger AMLCharacteristic Patients A Patients A

Population incidenceB 17.6 1.8

Favorable cytogeneticsC

t(8;21) 2% 9%inv 16 or t(16;16) 1–3% 10%t(15;17) 4% 6–12%

Unfavorable cytogeneticsC

-7 8–9% 3%+8 6–10% 4%Complex 18% 7%

MDR1 expression 71% 35%

Secondary AML 24–56% 8%

Treatment-related mortalityD 25–30% 5–10%

Complete remissionD 38–62% 65–73%

Long-term survivalC 5–15% 30%

A In general, Older AML Patients are defined as ≥ 60 years ofage; Younger AML Patients as < 60 years of age.B New diagnoses, per 100,000 US citizens per year. Older/younger division occurs at 65 years.C Percentages rounded to nearest whole numberD Rates following remission-induction therapy with ananthracycline- or anthracenedione-based regimen.

Hematology 2004 111

Concern over potential treatment-related toxicities mayresult in undertreatment of disease. Paradoxically, ad-ministration of full-dose daunorubicin, for example,may result in a reduction in early deaths by effecting amore rapid CR.

The outcome of older adults with AML is alsoworse. Adults under the age of 60 years treated with aninduction regimen consisting of an anthracycline com-bined with cytarabine have a 65%–73% chance of at-taining a complete remission (CR), while those over 60years of age have a 38%–62% chance of a CR.2-4,13-15

Patients who fall into the “very elderly” category (80years or older) can attain a CR with intensive therapy,but their chance of doing so is 30%, and only 7% oftreated patients are alive at one year. Similar numbershold for patients 70 years of age or older.9 Moreover,long-term survival occurs in approximately 30% ofyounger adults (or 45% of those entering a CR), com-pared to only 5%–15% long-term DFS in adults overthe age of 60 years.2-4,15

Indications for TreatmentFor 85%–95% of older AML patients, any therapy ul-timately will be purely palliative. Treatment optionsrange from supportive care (blood and platelet transfu-sions when needed, antibiotics to treat infections, andgrowth factor support) to low-dose chemotherapy (e.g.,hydroxyurea or low-dose cytarabine) or investigationalagents as part of clinical trials, and high-dose chemo-therapy (anthracycline- or anthracenedione-based re-mission induction therapy). Two trials have random-ized older patients to receive either immediate remis-sion induction chemotherapy with an anthracycline-based regimen versus a less aggressive or palliative ap-proach.16,17 Only one of these studies16 demonstrated asurvival advantage for patients receiving induction che-motherapy (21 vs 11 weeks, P = 0.015), for a mediansurvival time only 16 days longer than the median amountof time they spent hospitalized to receive therapy. Thus,the decision of whether or not to offer remission induc-tion therapy (on the part of physicians) or to receive it(on the part of patients) is not straightforward.

In making this decision, older patients overesti-mate the potential benefit they may derive from in-tensive chemotherapy and may not recall all treat-ment options. One study18 found that 74% of olderpatients estimated their chance to be cured by re-mission induction therapy to be ≥ 50%, and almost90% estimated their chance of being alive in oneyear to be ≥ 50%. In contradistinction, physicianscaring for these patients estimated the chance of cureto be ≤ 10% almost 89% of the time. Nearly two-thirds of patients did not recall being offered treat-

ments other than the one they chose, despite physi-cian documentation of alternatives in all cases. Pa-tients choosing to receive remission induction therapyspent 79% of their days during the first 6 weeks ofthe study period either hospitalized or being seen inclinic, compared to 14% of days for patients choos-ing less aggressive therapy or best supportive care.Thus, treatment decisions should be based on indi-vidual patient preferences after an informed discus-sion has taken place that incorporates risk estimatesmodified to a patient’s performance status, comorbid-ities, and leukemia-specific risk factors, without us-ing absolute cutoffs for prognostic factors or chrono-logical age. For example, an active, “younger” olderadult with de novo AML and favorable cytogeneticsshould be presented with different prognostic informa-tion than a bed-bound septuagenarian with secondarydisease and complex cytogenetics. Ideally, this discus-sion should include specifics about prognosis and treat-ment-related complications, and the potential impacttherapy will have on a patient’s quality of life. Whenavailable and clinically appropriate, older patientsshould always be offered the opportunity to partici-pate in clinical trials for up-front therapy.

Treatment Options

Remission induction therapyAs with younger AML patients, the backbone of remis-sion induction in older adults consists of an anthracycline(daunorubicin or idarubicin) or anthracenedione(mitoxantrone) and cytosine arabinoside (Ara-C), a regi-men that has not changed in over two decades. Typi-cally, daunorubicin is given at a dose of 45 mg/m2/d × 3days, or mitoxantrone or idarubicin are given at dosesof 12 mg/m2/d × 3 days, in combination with Ara-C,which is administered as a continuous infusion at 100or 200 mg/m2/d × 7 days (frequently referred to as 7+3chemotherapy). While studies have compared differentanthracyclines and anthracenediones, varied doses andschedules, and added additional agents with some im-provement in CR rates, they have not demonstrated animprovement in overall survival (OS) rates (Table6).2,5,13,15,19-21 For example, a recent study from the ECOGrandomized older AML patients to remission inductiontherapy with either daunorubicin, idarubicin, ormitoxantrone along with a standard dose of Ara-C.9

The outcome was not significantly different, with CRrates of 40%, 43%, and 46% and median survivals of7.7, 7.5, and 7.2 months, respectively. Once a decisionhas been made to initiate intensive chemotherapy, itshould not be delayed, as this may impact outcome.9,22


Table 6. Selected randomized studies defining remission induction therapy in older adults.

Remission CompleteGoal Induction Agents Remission Overall Survival CommentsCompare Anthracyclines and Anthracenediones

Lowenberg, 19982 M (8 mg/m2/d) + 47% 39 weeks (median) Early and post-induction death ratesA (100 mg/m2/d) 9% (5 years) were similar for both arms. Patientsvs. vs. vs. receiving mitoxantrone had a significantlyD (30 mg/m2/d) + 38% 36 weeks (median) higher rate of severe infections (25.1%A (100 mg/m2/d) P = 0.07 6% (5 years) vs 18.6%) and a trend toward a longer

P = 0.23 duration of aplasia (22 vs 19 days).

AML Collaborative I (8-20 mg/m2/d) + 51% 33.6 weeks (median) Early induction failure tended to be higherGroup, 199819 A (100-200 mg/m2/d) with idarubicin, while late induction failure

vs. vs. vs. was lower. Myelosuppression wasD (45-50 mg/m2/d) + 46% 29.9 weeks (median) greater in patients receiving idarubicin.A (100-200 mg/m2/d) P = ND P = 0.58

Archimbaud, 199920 I (8 mg/m2/d) + 45% 7 months (median) No difference between groups in degreeA (100 mg/m2/d) + 21% (2 years) of myelosuppression or in early deathE (100 mg/m2/d) rates.vs. vs. vs.M (7 mg/m2/d) + 50% 7 months (median)A (100-200 mg/m2/d)+ P = 0.52 21% (2 years)E (100 mg/m2/d) P = ND

Vary 7+3 Dose

Buchner, 199721 D (60 mg/m2/d) + 54% 16% (5 years) The 30 mg daunorubicin arm was closedA (100 mg/m2/d) prematurely due to higher response ratesvs. vs. vs. in the 60 mg arm, resulting in 42 patientsD (30 mg/m2/d) + 42% 10% (5 years) receiving lower dose daunorubicin, andA (100 mg/m2/d) P = 0.038 P = 0.11 130 patients receiving the higher dose.

Dillman, 199113 D (45 mg/m2/d) + 44% 11.0 weeks (median) This study has short overall survival timesA (100 mg/m2/d) compared to other studies in this patientvs. vs. vs. population.D (45 mg/m2/d) + 38% 9.6 weeks (median)A (200 mg/m2/d) P = 0.68 P = 0.23

Add Agents

Goldstone, 200115 D (50 mg/m2/d) + 62% 12% (5 years) There were no significant differences inA (100 mg/m2 q 12 hours)+ myelosuppression or other toxicities,T (100 mg/m2 q 12 hours) neutrophils were slower to recover in thevs. vs. vs. mitoxantrone arm. Patients receiving ADED (50 mg/m2/d) + 50% 8% (5 years) had higher rates of induction death (26%A (100 mg/m2 q 12 hours) + P = 0.0021 P = 0.021 compared to 16% for DAT and 17% forE (100 mg/m2/d) MAC)vs. vs. vs.M (12 mg/m2/d) + 55% 10% (5 years)A (100 mg/m2/d P = 0.042 P = 0.1,2 0.23

Baer, 20025 D (60 mg/m2/d) + 46% 7 months (median) Because of concern about excessiveA (100 mg/m2/d)+ mortality on the ADEP arm (25 deaths vsE (100 mg/m2/d) 12 on the ADE arm), it was closed early tovs. vs. vs. to further accrual. Survival between theD (40 mg/m2/d) + 39% 2 months (median) two arms was similar at one year.A (100 mg/m2/d) +E (60 mg/m2/d) + P = 0.008 P = 0.48P (10 mg/kg/d)

Use Hematopoietic Growth Factors

Stone, 19953 D (45 mg/m2/d) + 54% 10.8 months Median duration of neutropenia was 15A (200 mg/m2/d) (median) days in the GM-CSF arm and 17 days invs. vs. vs. placebo arm (P = 0.02). The duration ofD (45 mg/m2/d) + 51% 8.4 months hospitalization did not differ between theA (200 mg/m2/d) + (median) arms; nor did the rates of life-threateningGM-CSF (5 µg/kg/d) P = 0.61 P = 0.10 infection, or persistent leukemia.

Godwin, 199814 D (45 mg/m2/d) + 50% 9 months The duration of neutropenia was 15%A (200 mg/m2/d) (median) shorter in the G-CSF arm compared to thevs. vs. vs. placebo arm (P = 0.14). The duration ofD (45 mg/m2/d) + 41% 6 months hospitalization did not differ between theA (200 mg/m2/d) + (median) arms; nor did the rates of life-threateningG-CSF P = 0.89 P = 0.71 infection, or persistent leukemia.

Abbreviations: M, mitoxantrone; A, Ara-C (cytosine arabinoside); D, daunorubicin; I, idarubicin; E, etoposide; T, thioguanine; P, PSC-833;GM-CSF, granulocyte macrophage colony stimulating factor; G-CSF, granulocyte colony stimulating factor; ND, not done1 For comparison of DAT to ADE 2 For comparison of DAT to MAC 3 For comparison of ADE to MAC

Hematology 2004 113

Hematopoietic growth factorsIn the majority of AML patients, death results frombleeding or infectious complications. This is particu-larly true in older adults with AML. The utility of he-matopoietic growth factors (HGF) for ameliorating themyelosuppressive complications of AML therapy inolder adults has been studied extensively.3,14 These tri-als were also designed to determine whether or not HGFhad detrimental effects due to inappropriate stimula-tion of leukemic cell proliferation and thus resistance,or whether they had beneficial effects in “priming” leu-kemic cells to proliferate prior to the administration ofS-phase specific chemotherapy agents such as Ara-C.9,23

With the exception of one ECOG study that demon-strated a CR rate and overall survival benefit in patientsrandomized to the GM-CSF arm (compared to patientsreceiving no growth factor support), these trials foundthat while HGF are safe, reduce the duration of neutro-penia (by a range of 2–6 days), and do not supportleukemia cell proliferation, they also do not reliablyimprove the CR rate, the length of hospitalization, orthe induction death rate or prolong survival.

Post-remission chemotherapyNo randomized trial has ever demonstrated that anyamount of post-remission therapy in older AML pa-tients provides better outcomes than no post-remissiontherapy. That being said, the only studies demonstrat-ing that long-term DFS is possible in older AML pa-tients have included remission induction and post-re-mission therapy. It is reasonable, then, to administerpost-remission therapy consisting of a repeat of remis-sion induction therapy, single-agent Ara-C, or 2 daysof an anthracycline or anthracenedione (the same typeof drug given at the same doses as with remission in-duction therapy) combined with 5 days of Ara-C, againgiven at the same dose as with remission inductiontherapy (frequently referred to as post-remissiontherapy). There does not appear to be any additionalsurvival benefit attained from administering more than1–2 cycles of post-remission therapy or in treating olderAML patients with maintenance therapy. In the Medi-cal Research Council (MRC) AML 11 trial, 371 pa-tients who entered a complete remission followinganthracycline- or anthracenedione-based remission in-duction therapy were randomized to receive either 1cycle of daunorubicin, Ara-C, and thioguanine (DAT) con-solidation therapy, or DAT along with 3 additional cyclesof Ara-C–based consolidation therapy (for a total of 4cycles of post-remission therapy).15 Of those randomizedto the long consolidation course, 61% were able to com-plete all 4 cycles. Survival was similar at 5 years for pa-tients randomized to the short and long consolidation arms.

Postremission bone marrow transplantationAn even more aggressive approach than inductiontherapy followed by consolidation consists of bonemarrow transplantation. Nonmyeloablative allogeneicbone marrow transplants take advantage of a graft-ver-sus-leukemia effect using a less-intensive preparativeregimen with lower up-front mortality. The reducedTRM and ability to perform these transplants in theoutpatient setting make them an appealing option forthe older AML patient with few comorbidities and anadequate performance status. Preliminary studies thatinclude older AML patients have demonstrated that du-rable complete remissions are attainable with this treat-ment, though with limited follow-up. One study of 19patients with myeloid malignancies (17 of whom hadadvanced MDS or AML) and a median age of 64 years(range, 60–70 years) demonstrated a 68% survival at amedian follow-up of 825 days following nonmyeloab-lative transplantation.24 These early data have promptedcooperative groups to explore the role of bone marrowtransplantation in older AML patients in first CR.

Newer approachesRemission induction therapy for older adults with AMLis no panacea, with median and 5-year survival ratesresembling those of patients with advanced lung can-cer.1 It is thus reasonable to consider investigationalagents for older AML patients as initial therapy, par-ticularly those that may be associated with less TRM.Potential targets for antileukemia therapy include spe-cific signaling molecules required for the maintenanceof the leukemic state, such as tyrosine kinases;overexpression of bcl-2, an anti-apoptosis signal; DNAmethylation, associated with suppression of regulatorygenes and with disease progression; indirect pathwaysthat maintain leukemogenesis, including angiogenesisand drug resistance; and investigational agents withmechanisms of action that differ from anthracyclines,anthracenediones, and Ara-C, such as nucleoside ana-logs, farnesyl transferase inhibitors (FTIs), and MDRmodulators, alone or in combination with standard thera-pies.25-29 These approaches are discussed in more detailin Section I. The efficacy of the FTI Zarnestra will beexamined in newly diagnosed AML patients over theage of 70 years in the US cooperative group setting(SWOG 0432). One recent trial from the Dutch-Bel-gian Hemato-Onocology Cooperative Group (HOVON)randomized predominantly older patients, most of whomhad a diagnosis of advanced MDS or AML, to Ara-Cand G-CSF or the same regimen plus fludarabine for 2cycles followed by Ara-C and daunorubicin for 1 cycle.30

This study is typical of many novel combination trialsin older AML patients in that, while the CR rate was


improved in AML patients receiving fludarabine (95%vs 71%, P = 0.046), survival was not impacted.

Supportive/palliative careIntensive chemotherapy provides only marginal, if any,survival benefit to older AML patients, so non-inten-sive (or non-chemotherapy-based) approaches are rea-sonable. We use the phrase aggressive supportive careto emphasize that symptoms will be treated vigorouslyand to distinguish this modality from hospice. Bloodand platelet transfusions should be administered to al-leviate symptoms stemming from anemia and thromb-ocytopenia, and antibiotics started when appropriate.Low-dose chemotherapy should only be used in the set-ting of leukocytosis and/or associated symptoms. Anyrecommendations for the institution of neutropenic pre-cautions (i.e., avoiding crowds, refraining fromingestions of raw foods) must be balanced with the lackof evidence supporting the benefit of these maneuversand the impact such restrictions will have on a patient’squality of life. Hospice services should be institutedwithin 6 months of anticipated demise. While somehospice organizations prohibit blood product transfu-sions, we consider these to be palliative in this popula-tion as they may result in improved quality of life interminal cancer patient populations.

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23. Lancet JE, Gojo I, Gotlib J, et al. Tipifarnib (ZARNESTRA)in previously untreated poor-risk AML and MDS: interimresults of a phase 2 trial [abstract]. Blood. 2003;102:176a.

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II. The Role of Autologous and Allogeneic (“Full”and “Mini”) Stem Cell Transplantation in AML

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acute myeloid leukemia

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