Developments in the Treatment of Acute Myeloid Leukemia: Update from ASH 2008

Posted on March 8th, 2009 by

Developments in the Treatment of Acute Myeloid Leukemia: Update from ASH 2008

Several studies presented at the 2008 American Society of Hematology (ASH) meeting focused on improving the outcome of acute myeloid leukemia (AML) in children and adults, with a particular emphasis on elderly patients.

Acute Myeloid Leukemia in Children

Effects of Mylotarg®

Mylotarg® (gemtuzumab ozogamicin) is a monoclonal antibody linked to a toxin called calicheamycin. The monoclonal antibody is directed at CD33, which is present in 80-90% of AML cells but is not present on the normal hematopoietic stem cell. Thus, the antibody-toxin conjugate can selectively kill leukemia cells. The primary toxicity of this agent is veno-occlusive disease (VOD) of the liver, presumably because there are CD33-positive cells in the liver. Mylotarg was approved by the U.S. Food and Drug Administration in 2000 for the treatment of patients with AML over the age of 60 who had failed initial treatment but is not yet approved in children.

A previous study of Mylotarg in 16 children with relapsed AML found that eight had a reduction in bone marrow blasts to less than 5%, but only five of these had complete recovery of platelets.1 Researchers at the Fred Hutchinson Cancer Research Center and six other cancer centers reported a 28% combined partial and complete remission rate in children with relapsed or refractory AML with single-agent Mylotarg.2 Another study from Germany showed single-agent Mylotarg produced responses but no complete remissions in 12 refractory children with AML.3 Mylotarg has also been evaluated as post-transplant treatment in children with AML receiving reduced-intensity allografts.4

At ASH 2008 researchers affiliated with the Children’s Oncology Group reported that addition of a single dose of Mylotarg to standard induction chemotherapy may improve outcomes of children with newly diagnosed AML.5 This study include 340 patients ages one month to 21 years with de novo AML. Patients received two induction courses and three intensification courses. Mylotarg was added to the second intensification course, which also contained mitroxantrone and cytarabine. High-risk patients received only one course of intensification followed by an allogeneic stem cell transplant following a busulfan-cyclophosphamide regimen if a donor was available. Median follow-up was 775 days. The major findings of this study were as follows:

  • After the first induction the complete response (CR) rate was 83%.
  • After the second induction the CR rate was 87%.
  • Three-year event-free survival (EFS) was 49%.
  • Three-year overall survival (OS) was 63%.
  • Treatment-related mortality was 9% after the first and 7% after the second induction regimen.
  • The risk of relapse in patients with a stem cell donor was 12% compared to 39% for those without a donor in an intent-to-treat analysis.
  • The incidence of VOD was 5%.

These authors stated that “Overall, AAMLO3P1 therapy shows a continued historical trend for improved OS and EFS when compared to the previous COG AML trial (CCG-2961).”

Acute Myeloid Leukemia in Younger Adults

Effects of Remission Induction Therapy

Standard remission induction therapy currently consists of three days of an anthracycline and seven days of cytarabine. Most studies have shown that more intensive induction regimens are associated with a higher CR rate. However, the relationship between induction dose intensity and disease-free survival following consolidation therapy is poorly understood.

At ASH 2008 researchers affiliated with the AML-12 Trial of EORTC and BIMEMA Leukemia Groups reported data comparing standard-dose to high-dose cytarabine with daunorubicin and etoposide in 1,700 patients with AML. There were subsequent randomizations for post-induction therapy, but this report focused on the impact of induction therapy.6 Patients receiving high-dose cytarabine in the induction regimen had an approximate 6-10% increase in CR rates, which was observed in patients with no cytogenetics, good cytogenetics, intermediate cytogenetics, and bad cytogenetics. However, there was no improvement of disease-free survival following post-remission therapies. Disease-free survival rates were 40% following standard-dose cytarabine and 43% following high-dose cytarabine in induction.

Effects of Post-remission Therapy

Over the past two decades, intensive consolidation with three to four cycles of cytarabine given in high doses over five days in conjunction with additional chemotherapy drugs such as etoposide, daunomycin, or idarubicin has become standard. In prior studies remission duration has been correlated with the dose of cytarabine and the number of cycles administered. In general, more intensive consolidation is associated with higher disease-free survival rates in younger patients with AML. However, cooperative groups continue to evaluate the impact of dose intensity in consolidation regimens on disease-free survival rates.

Researchers affiliated with the JALSG AML 201 study reported that a less intensive consolidation strategy was as effective as three courses of high-dose cytarabine for consolidation of patient’s ages 15-64 years with less toxicity.7 The following tables summarize five-year outcomes in various patient groups:

Table 1: Effects of High- Versus Conventional-dose Cytarabine Consolidation on Overall Five-year Survival

Group

High-dose Cytarabine

Conventional Cytarabine

All

58%

56%

Good Risk

70%

81%

Intermediate Risk

51%

49%

Poor Risk

13%

17%

Patients <50 years of age

62%

66%

Patients >50 years of age

51%

40%

Table 2: Effects of High- Versus Conventional-dose Cytarabine Consolidation on Five-Year Relapse-free Survival

Group

High-dose Cytarabine

Conventional Cytarabine

All

43%

39%

Good Risk

55%

56%

Intermediate Risk

42%

37%

Poor Risk

13%

16%

Patients <50 years of age

45%

46%

Patients >50 years of age

40%

28%

These data do not support previous observations about the benefit of high-dose cytarabine in younger patients.

Effects of Cladribine

Cladribine (2-CDA) is a purine analog with immunosuppressive properties that is the preferred first-line treatment of hairy cell leukemia. Chemically it mimics nucleoside adenosine and inhibits adenosine deaminase, which interferes with DNA synthesis. Recently, new formulations of this agent have been developed for subcutaneous and oral administration. Cladribine is widely established as first-line standard treatment for hairy cell leukemia. Several clinical trials have demonstrated that cladribine used alone or in combination with other cytotoxic drugs has efficacy and acceptable toxicity profile in the treatment of chronic lymphocytic leukemia, Waldenström macroglobulinemia, low-grade non-Hodgkin’s lymphoma and AML. Previous studies from Poland have shown that a regimen of cladribine, cytarabine, and mitoxantrone produces a complete response rate of 58% in patients with relapsed AML.8

Researchers affiliated with the Polish Adult Leukemia Group reported the outcomes of a randomized Phase III trial comparing induction therapy of AML with standard daunorubicin and cytarabine with or without cladribine.9 This study compared three different induction regimens:

  • Daunorubicin and Cytarabine (DA)
  • Daunorubicin, Cytarabine, and Fludarabine (DAF)
  • Daunorubicin, Cytarabine, and Cladribine (DAC)

Table 3: Standard Daunorubicin and Cytarabine with or Without Cladribine in AML

DA

DAF

DAC

CR after one course

51%

55%

63%

Final CR rate

57%

60%

68%

Overall Survival

39%

36%

51%

Leukemia-free Survival

32%

41%

51%

Early Deaths

10%

10%

10%

These data suggest that cladribine can be added safely to DA with improved results without an increase in toxicity.

Effects of Nexavar

Nexavar® (sorafenib) is an orally active, multi-kinase inhibitor approved by the U.S. FDA for the treatment of advanced renal cell carcinoma and inoperable hepatocellular carcinoma. Nexavar is also being evaluated in patients with other cancers, including non–small cell lung cancer and melanoma. In vitro studies have shown that Nexavar exhibits potent target inhibition and efficacy in FLT3-driven models.10 There is one case report of a complete molecular remission in a patient with extramedullary FLT3-ITD(+) AML following treatment with single-agent Nexavar.11

At ASH 2008 researchers from the M. D. Anderson Cancer Center presented Phase I (n=10) and II (n=30) data on treating patients younger than age 65 years with newly diagnosed AML with the combination of Nexavar, idarubicin, and cytarabine.12 The CR rate for 25 evaluable patients was 88%. In vitro studies suggest greater activity in patients with mutant versus wild type FLT3.

Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation is often used to treat patients with AML who have relapsed after initial therapy and for treatment of intermediate- and high-risk patients in first CR. Allogeneic stem cell transplantation is associated with a lower rate of relapse than alternative therapies, but treatment-related mortality is high.

At ASH 2008 researchers from the M. D. Anderson have reported that a regimen of busulfan and fludarabine followed by allogeneic stem cell transplantation is associated with a low transplant-related mortality.13 They found that regimens other than busulfan and fludarabine were associated with a more than twofold increase in transplant-related mortality. Age was still a significant variable, with patients older than 60 years having a transplant-related mortality of 38% compared with 14% for younger patients.

Researchers affiliated with the Center for International Blood and Marrow Transplantation Research reported that reduced-intensity transplant regimens do not lead to improved overall survival of patients with AML or MDS.14 This study included 3,731 patients who received a marrow ablative regimen and 1,500 who received a reduced-intensity regimen. They reported a lower relapse rate in patients receiving myeloablative regimens; though this group also demonstrated higher treatment-related mortality and no difference in overall survival. However, these and other studies are flawed by the fact that patients are chosen to receive a reduced-intensity regimen because physicians think they will not survive an intensive regimen. The value of comparing the two types of conditioning prior to allogeneic stem cell transplant is limited.

Researchers from Japan reported improved survival of patients up to 64 years of age with average and poor-risk receiving an allogeneic stem cell transplant in first remission.15 Using a matched-pair comparison, patients receiving an allogeneic stem cell transplant in first remission had a five-year relapse-free survival of 63% compared with 28% for those receiving chemotherapy. Overall survival at five years was 63% for transplanted patients compared with 49% for patients receiving chemotherapy. For the group of patients who received a transplant at first relapse, the overall survival at five years was 47%. This latter observation is of major interest as there is the possibility that the combined survival for patients transplanted in first relapse (47%) and for those not relapsing on continued chemotherapy (28%) would equal the survival rate for patients transplanted in first remission. This has for years been the main unresolved question in AML therapy.

Acute Myeloid Leukemia in the Elderly

Effects of Age on Outcome of AML

The median age for patients with AML in the U.S. is 66-67 years and is likely to rise as persons live longer. For elderly patients there has been little, if any, improvement in outcome over the past two to three decades. The current thinking is that older patients fare poorer than younger patients because they have worse disease as characterized by cytogenetics and molecular studies and have more significant co-morbid conditions than younger patients. The mantra has been that age alone should not preclude aggressive successful therapy in elderly patients with AML who do not have significant co-morbidities.

At ASH 2008 researchers from Germany have reported that older age is an independent adverse risk factor for relapse and survival in patients with AML.16 In this study researchers looked at 2734 patients with AML in the present German Multicenter AML Cooperative Group (AMLCG). Patients 60 years of age or older made up 54% of this group; median age was 61 years. Table 4 shows the differences in outcome between younger and older (60 or above) patients:

Table 4: Univariate Analyses of Effects of Age on Outcome of Patients with AML

60 years or older

Younger than 60 years

Five-year survival

13%

40%

Five-year relapse rate

82%

52%

Unfavorable cytogenetics

29%

23%

Favorable cytogenetics

4%

12%

NPM1mut/FLT3-ITneg status

26%

34%

Median WBC

7,360

12,600

In multivariate analyses these researchers found that older patients with good risk features had a worse survival and a higher relapse rate than younger patients with similar risks. In all categories of risk, age was an independent risk factor for increased relapse and lower survival. These researchers suggest that “understanding older age AML requires further genetic and epigenetic work.” These are interesting data. However, even this study underestimates the problem of AML in the elderly. The median age of 61 years for patients entered on this study is probably significantly lower than the median age of all patients with AML in Germany.

Effects of Androgens during Maintenance Therapy

There was considerable interest in the role of androgens in the treatment of AML in the late 1970s and early 1980s. The rationale for this was the possible enhancement and recovery of erythropoiesis and the fact that leukemia cells contain receptors for androgens. However, a randomized EORTC trial published in 1986 found no effect of androgens when compared to chemotherapy or immunotherapy (neuraminidase treated blasts) for maintenance therapy of AML.17 There also appears to be in vitro data suggesting androgens can modulate apoptosis and differentiation of leukemia cells.18

Researchers from France have reported that the “addition of low-dose norethandrolone to maintenance chemotherapy is associated with an improved outcome in elderly patients with AML.”19 Three hundred thirty elderly patients (60 years or older) in the GOELAMS SA-2002 trial received induction with ICL (idarubicin, cytarabine, and lomustine). Patients in partial or complete remission received reinduction and maintenance therapy and were randomly allocated to receive norethandrolone or not. Androgens were continued for the two years of maintenance therapy. The median age of patients in this study was 70 years with the oldest patient being 86 years old. Median follow-up was one year. The 80-day complete remission rate did not differ between the androgen (79%) and the control (83%) groups. The main results of this study are shown in tables 5 and 6.

Table 5: Effect of Androgens on Five-year Relapse, Leukemia-free Survival (LFS), Event-free Survival (EFS), and Overall Survival (OS) from Diagnosis (P-values for these variables ranged from 0.15 to 0.72)

Control

Androgen

Relapse

66%

54%

LFS

23%

33%

EFS

16%

22%

OS

19%

26%

Table 6: Effects of Androgens in Patients Surviving One Year (P-values for these variables ranged from 0.01-0.03)

Control

Androgen

Relapse

55%

33%

LFS

37%

54%

EFS

32%

52%

OS

37%

60%

These data show that patients who were alive in CR at one year from diagnosis had a lower rate of relapse and better LFS, EFS, and OS. These authors also observed that the beneficial effects of androgens were more pronounced in men and in patients with a WBC less than 4,000. These are very interesting observations that will need to be confirmed with other studies and longer follow-up.

Vidaza, Valproic Acid, and ATRA

Vidaza® (azacitadine) is approved by the U.S. FDA for the treatment of myelodysplastic syndromes (MDS). Recently, researchers from the Western Pennsylvania Cancer Institute have reported that Vidaza may provide an effective treatment alternative for elderly patients with AML.20 Recent results from a pilot study evaluating low doses of Vidaza in combination with thalidomide provide promising results in the treatment of MDS and AML.21 Researchers from Loyola University have also reported that the combination of Mylotarg and Vidaza results in a high rate of response in elderly patients with AML or MDS.22

ATRA is primarily use to treat patients with acute promyelocytic leukemia (APL). However, a previous study has shown that ATRA treatment of patients with AML affects leukemic cell morphology, regulation of cell cycle progression and apoptosis, and possibly also microvascular endothelial cell functions.23 At ASH 2008 researchers from Germany reported that etoposide in combination with ATRA was effective for treatment of elderly patients with AML who have the NPM1 mutation without concurrent FLT3-ITD.24 However, a report from researchers affiliated with UK MRC AML12 trial failed to find a significant difference between patients who had the NPM1 mutation and were FLT3-ITD negative and those with normal karyotypes following treatment with ATRA-containing regimens.25 All patients in this study also received daunorubicin, cytarabine, and thioguanine and all were under the age of 68 years with a median of 46 years.

The combination of Vidaza, valproic acid, and ATRA has been previously reported to be effective treatment for patients with AML and MDS. 26 The concept of this regimen is to combine a DNA hypomethylating agent (Vidaza) with a histone deacetylase inhibitor (valproic acid) to restore sensitivity to ATRA. At ASH 2008 researchers from France reported additional data on the combination of Vidaza, valproic acid, and ATRA in older patients, patients deemed unsuitable for intensive chemotherapy, and patients who had relapsed after initial therapy.27 The median age of patients in this study was 73 years (range 50-87) and the median WBC was 2,300. The overall response rate was 31%. The overall response rate was 45% for patients with de novo AML. Cytogenetics but not age was an important prognostic feature for response. Overall median survival was 12 months and the median survival of responding patients had not been reached. These authors suggest further studies with this well tolerated regimen.

Single Agent Dacogen

Dacogen® (decitabine) is a hypomethylating agent with activity in MDS, AML, CML, chronic myelomonocytic leukemia, and sickle cell disease.28 At ASH 2008, researchers from three U.S. medical centers reported outcomes of 55 elderly patients treated initially with Dacogen.29 The median age in this study was 74 years, with the oldest patient being 87. The CR rate was 26%. Sixty-four percent of patients received three or more cycles of therapy. There were three deaths from infection during induction. Responses were seen in de novo AML, transformation of MDS, and AML secondary to prior therapy. Poor- and intermediate-risk patients had similar remission rates. There is currently an ongoing Phase III trial in progress.

Mylotarg in Patients with AML Unfit for Intensive Therapy

Mylotarg is a monoclonal antibody linked to a toxin called calicheamycin. The monoclonal antibody is directed at CD33, which is present in 80-90% of AML cells, but is not present on the normal hematopoietic stem cell. Thus, the antibody-toxin conjugate can selectively kill leukemia cells. The primary toxicity of this agent is veno-occlusive disease (VOD) of the liver, presumably because there are CD33 positive cells in the liver. Mylotarg was approved by the U.S. FDA in 2000 for the treatment of patients with AML over the age of 60 who had failed initial treatment. However, Mylotarg is also active in pediatric AML. Mylotarg is often used in combination with drugs such as fludarabine, cytarabine, and anthracyclines (such as mitoxantrone or idarubicin). Researchers affiliated with the MRC AML 15 trial have reported that the addition of Mylotarg to one of three different induction regimens improves disease-free survival in newly diagnosed younger patients with AML.30

At ASH 2008 researchers affiliated with the EORTC-GIMEMA AML-19 Trial reported that single-agent Mylotarg may provide effective palliation for elderly patients with AML unsuitable for intensive chemotherapy.31 This study essentially established a tolerable dose of Mylotarg for future studies.

Effects of Lomustine (CCNU)

Lomustine is an oral nitrosourea that has activity in a variety of cancers and has the property of penetrating the blood-brain barrier. Researchers from France have previously reported the results of a randomized trial in 364 older patients with AML that showed the addition of oral lomustine to idarubicin and cytarabine increased the CR rate from 58% to 67%.32 Lomustine also increased the median survival from seven months for idarubicin and cytarabine to 12 months with the addition of lomustine. At ASH 2008 researchers affiliated with the GOELAMS Group reported data from three clinical trials of idarubicin and cytarabine (n=339) versus idarubicin, cytarabine, and lomustine (n=508).33 Complete remissions were observed in 57% of patients in the standard induction group and 67% in patients receiving lomustine. Median survival of patient receiving lomustine was increased by four months without a significant increase in toxic deaths.

Effects of Clolar

Clolar® (clofarabine) is a purine nucleoside antimetabolite that is in Phase II testing for acute leukemia. It is approved by the U.S. FDA for the treatment of pediatric patients with ALL who have failed at least two prior treatment regimens. A supplemental New Drug Application has been submitted to the FDA for approval for the use of Clolar as a single agent in patients 60 years or older who have at least one unfavorable prognostic factor with previously untreated AML. Previous studies from the M. D. Anderson Cancer Center showed that the combination of Clolar plus low-dose cytarabine was more effective than Clolar alone for the treatment of patients 50 years of age or older with AML.34 35

At ASH 2008 researchers involved in a U.S. multicenter trial reported outcomes of 112 patients age 60 years or older with AML treated with single-agent Clolar.36 Patients in this study were deemed unsuitable for intensive therapy. The CR rate was 38%, and the PR rate was 8%. Patients with unfavorable cytogenetics had an overall response rate of 42% and patients with prior hematologic disease had a response rate of 50%. The median duration of response had not been reached with a median follow-up of 16 months. Treatment with Clolar was described as well tolerated.

Impact of Post-remission Therapy in Elderly Patients

Optimal post-remission treatment for elderly patients with AML remains unresolved. Previously, researchers from France reported that elderly patients with AML benefit more from prolonged therapy than from intensive consolidation post-remission.37 Researchers from the United Kingdom affiliated with the National Cancer Research Institute AML14 randomized trial have reported that patients with AML over the age of 60 years do not benefit from increasing the dose of daunorubicin or cytarabine or increasing the number of treatment courses.38

French researchers have previously reported the outcome of the Acute Leukemia French Association (ALFA) 9803 trial.39 This trial involved 416 patients aged 65 years or older. The complete remission rate was 57% and the estimated two-year survival was 27%. This trial showed that there were no differences between induction therapy with idarubicin or daunorubicin. One hundred sixty-four CR patients in this study were randomly allocated to receive a non-intensive versus an intensive consolidation regimen for six months. The outpatient ambulatory regimen was found to be superior to the intensive regimen (HR=1.51 for disease-free survival). At ASH 2008 data from the 9803 trial and a previous 9801 ALFA trial involving patients between the ages of 65 and 70 years of age were presented.40 There were a total of 211 patients with de novo AML in this analysis. This analysis compared outcomes of patients receiving an intermediate-dose cytarabine regimen for post-remission therapy with an ambulatory anthracycline-based regimen. These authors reported that more intensive therapy did not significantly improve outcomes. The most unfavorable groups for any type of post-remission therapy were those with adverse cytogenetics.

Allogeneic Stem Cell Transplants in Elderly Patients with AML

Allogeneic stem cell transplants offer the best alternative for preventing relapses in patients with AML but transplant-related mortality has been prohibitively high in elderly patients. However, transplant groups continue to refine the transplant process in the hopes of benefiting older patients.

Researchers affiliated with the Center for International Blood and Marrow Transplant Research (CIBMTR) have reported that older patients receiving a reduced-intensity allogeneic stem cell transplant in first CR have similar outcomes to younger patients.41 This study looked at outcomes of patients with MDS (n=551) and AML (n=565) who received a reduced-intensity allogeneic stem cell transplant in first remission. Results were compared among four age groups: 40-54 years, 54-59 years, 60-64 years, and >65 years. These authors reported that relapse rates (29-39%) and treatment-related mortality rates (31-35%) were similar among age groups. These authors concluded that older patients undergoing reduced-intensity allogeneic stem cell transplants fare as well as younger patients.

Researchers from the M. D. Anderson Cancer Center have reported that patients over the age of 65 years with AML and MDS can benefit from an allogeneic stem cell transplant.42 These authors reported outcomes of 71 patients who were 65 to 69 years of age and 25 patients who were 70 years of age or older receiving reduced-intensity allogeneic stem cell transplants. Two-year overall survival was 35% for the younger group and 13% for the older group. Non-relapse mortality was 24% for the younger group and 44% for the older group. The major predictive factor for outcome was being in remission. These data suggest that older patients in remission can benefit from an allogeneic stem cell transplant but that patients in relapse should receive other novel therapies.

Researchers from several institutions affiliated with a study from the Fred Hutchinson Cancer Research Center have reported the outcomes of 256 patients with AML treated with a reduced-intensity allogeneic stem cell transplant.43 Patients in this study were not considered to be candidates for a myeloablative conditioning regimen. For patients transplanted in first or subsequent remission of de novo AML the five-year survivals were 33% and 38%, respectively. For patients with secondary AML the five-year survival was 20%. Identical results were achieved for HLA-matched related as for HLA matched unrelated donors. However, transplants from HLA mismatched unrelated donors had a 10% lower survival.

Summary

At ASH 2008 there were many papers presented on treating elderly patients with AML, which is reasonable since this disease occurs predominantly in elderly individuals. There appears to be progress in the development of new drugs and new strategies for the treatment of patients with AML, which should be reflected in improved survival in the future.

References:

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27 De Labarthe A, Cras A, Recher C, et al. Epigenetic therapy with 5-azacitidine, valproic acid, and ATRA in patients with high-risk AML or MDS: Results of the French VIVEDEP. Blood. 2008;112:283, abstract 763.

28 Aribi A, Borthakur G, Ravandi F, et al. Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia. Cancer. 2007;109:713-717.

29 Cashen AF, Shiller GJ, O’Donnell MR, et al Preliminary results of a multicenter phase II trial of 5-day decitabine as front-line therapy for elderly patients with acute myeloid leukemia (AML). Blood. 2008;112:210, abstract number 560.

30 Burnett AK, Kell WJ, Goldstone AH, et al. The addition of gemtuzumab ozogamicin to induction chemotherapy for AML improves disease free survival without extra toxicity: Preliminary analysis of 1115 patients in the MRC AML trial. Blood. 2006;108:8a, abstract 13

31 Amadori S, Suciu S, Selleslag D, et al. Phase II-III study of gemtuzumab ozogamicin monotherapy versus best supportive care in older patients with newly diagnosed AML unfit for intensive chemotherapy: First results of the EORTC-GIMEMA AML-19 Trial. Blood. 2008;112:282, abstract number 762.

32 Pignearux A, Perreau V, Jourdan E, et al. Adding lomustine to idarubicin and cytarabine for induction chemotherapy in older patients with acute myeloid leukemia: the BGMT 95 trial results. Haematologica. 2007;92: 1327-1334.

33 Pigneux A, Witz F, Sauvezie M, et al. Improved outcome by addition of lomustine (CCNU) to idarubicin and cytarabine in elderly patients with de novo acute myeloid leukemia. A report of the GOELAMS Group. Blood. 2008;112:282, abstract number 761.

34 Faderi S, Verstovesek S, Cortes J, et al. Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older. Blood. 2006;108:45-51.

35 Faderl S, Ferrajoli A, Wierda W. Clofarabine combinations in acute myeloid leukemia (AML) salvage: a dose-finding phase I study of clofarabine plus idarubicin and clofarabine/idarubicin plus cytarabine (ara-C). Blood. 2005;106:786a, abstract # 2803.

36 Erba HP, Kantarjian H, Claxton DF, et al. Phase II study of single agent clorarabine in previously untreated older adult patients with acute myelogenous leukemia (AML) unlikely to benefit from standard induction chemotherapy. Blood. 2008;112:209, abstract number 558.

37 Gardin C, Turlure P, Fagot T, et al. Post-remission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy – results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007;109:5129-5135.

38 Burnett AK, Milligan DW, Prentice AG, et al. Modification or dose of treatment duration has no impact on outcome of AML older patients: preliminary results of the UK NRCI AML 14 Trial. Blood. 2005;106;162a, abstract # 543.

39 Gardin C, Turlure P, Figot T, et al. Postremission treatment of elderly patients with acute myeloid leukemia at first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) trial. Blood. 2007;109:5129-5135.

40 Gardin C, Pautas C, Thomas Xavier, et al. Impact of post-remission treatments in patients aged 65-70 years with de novo AML: A comparison of two concomitant randomized trials with overlapping age inclusion criteria. Blood. 2008;112:208, abstract number 557.

41 McClune B, Weisdorf DJ, DiPersio JF, et al. Non-myeloablative hematopoietic stem cell transplantation in older patients with AML and MDS: Results from the Center for International Blood and Marrow Transplant Research (CIBMTR). Blood. 2008;112:135, abstract number 346.

42 Girault S, Saliba RM, Rondon G, et al. Outcomes of allogeneic stem cell transplant in patients with myeloid leukemias over 65 years of age. Rationale for aggressive therapy with curative intent. Blood. 2008;112:750, abstract 2153.

43 Gyurkocza B, Storb RF, Storer B, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with de novo and secondary acute myeloid leukemia. Blood. 2008;112:61, abstract 149.

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