Identifying Older Patients With Acute Myeloid Leukemia Who May Be Candidates for Reduced-Intensity Hematopoietic Cell Transplantation

Recent studies show that with reduced-intensity and nonmyeloablative conditioning regimens, allogeneic hematopoietic cell transplantation can now be performed with relative safety in patients with acute myeloid leukemia up to 75 years of age, and therefore chronologic age itself should no longer be considered a contraindication for this procedure. Best results are generally seen in patients undergoing transplant during first remission. Results appear superior to what might be expected with conventional chemotherapy but prospective randomized trials have not been completed. If a decision is made to delay transplant until first relapse, a careful monitoring plan should be established.

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at www.medscape.org/journal/jnccn; (4) view/print certificate.

Release date: March 7, 2011; Expiration date: March 7, 2012

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Describe the diagnosis of AML among older adults
  • Evaluate the efficacy of reduced-intensity HCT among older adults with AML
  • Analyze variables associated with worse prognosis of reduced-intensity HCT among older adults with AML
  • Distinguish advantages of reduced-intensity HCT among older adults with AML

The prevalence of acute myeloid leukemia (AML) increases with age, with a median patient age of 67 years at diagnosis, according to SEER statistics (www.seer.cancer.gov). The biology of AML differs between older and younger patients, with an increased incidence of antecedent myelodysplasia, a greater proportion of poor-prognosis cytogenetics, and higher expression of multidrug-resistant glycoprotein MDR1.14 Patients older than 60 years and those with comorbid conditions are usually treated with less-intense regimens because of their presumed inability to tolerate multiple cycles of high-dose chemotherapy. The combination of less-intensive therapy and inherently more resistant disease results in a very poor prognosis.5,6

A recent retrospective analysis including 2444 patients with AML, aged 60 years or older, treated on several SWOG, ECOG, and MD Anderson Cancer Center protocols between 1976 and 2004, reported a 5-year overall survival rate of 7%.7 The application of allogeneic hematopoietic cell transplantation (HCT) to patients with AML in this age group had previously been limited by high rates of transplant-related mortality (TRM) caused by toxicities from high-dose conditioning regimens.8,9 The development of reduced-intensity and nonmyeloablative conditioning regimens now allows for the study of allogeneic HCT in older and medically less-fit patients.1022 These approaches rely on graft-versus-leukemia (GVL) effects for leukemia eradication. Preliminary studies have yielded encouraging results, but inherent selection bias and the lack of prospective randomized trials have caused the true impact of allogeneic HCT for this patient population to be uncertain. This article provides an overview of reduced-intensity and nonmyeloablative conditioning allogeneic HCT in older patients with AML, with particular emphasis on disease- and patient-related factors influencing outcomes.

Biology of AML in Older Adults

The prognosis of AML worsens with increasing age. This is partly because older patients receive less-intense treatment because of their perceived decreased tolerance to intensive therapy. However, disease characteristics of AML also change with patient age. In patients older than 60 years, AML is more often preceded by antecedent hematologic disorders, presents with lower WBC counts and a lower percentage of marrow blasts,23 and is more often associated with the expression of multidrug resistance phenotypes.1,24

Perhaps the most striking difference between younger and older patients is in the distribution of cytogenetic abnormalities. Multiple studies note a high incidence of unfavorable cytogenetic abnormalities among older patients with AML. The United Kingdom Medical Research Council (MRC) observed a marked increase in the incidence of complex aberrant karyotypes and abnormalities of chromosome 5 in older patients,24 whereas Moorman et al.2 reported a marked increase in deletions of all types with increasing age, particularly deletions of chromosomes 5 and 7. Similarly, a report from SWOG showed an increased proportion of patients with unfavorable risk cytogenetics with every 10-year increase in age, and a relative rarity of favorable-risk cytogenetics in older patients with AML.23 Several groups have observed that within each cytogenetic risk group, treatment outcomes deteriorated markedly with age, emphasizing that the poor outcomes observed among older patients with AML are not merely from the increased incidence of unfavorable cytogentics.23,25,26 Delaunay et al.27 reported that among 110 patients with inv(16)/t(16;16) AML, advanced age was associated with a higher risk of relapse and worse disease-free survival.

Nontransplant Treatment of AML in Older Adults: Prognostic Factors and Outcomes

The decision whether to offer allogeneic HCT to a patient with AML should involve, among other considerations, the assessment of outcomes with standard consolidation therapy. Although long-term remission rates with chemotherapy may approach 40% in some groups of adult patients, the standard chemotherapy approach is less successful in patients older than 60 years. With moderate-dose combinations of daunorubicin and cytarabine, only 10% to 15% of patients older than 60 years are expected to be living 5 years after diagnosis. Kantarjian et al.28 reported the outcomes of 998 patients aged 65 years or older (median age, 71 years) who had AML or high-risk myelodysplastic syndromes (MDS; > 10% blasts) treated with intensive chemotherapy between 1980 and 2004. The complete remission rate was 45%, whereas induction mortality was 29%. The median survival was 5.4 months, with 2- and 5-year survival rates of 16% and 7%, respectively. In multivariate analysis, factors predictive of early mortality and shorter overall survival included older age, poor performance status, unfavorable risk cytogenetics, longer duration of antecedent hematologic disorder, abnormal organ functions, and treatment outside laminar airflow room.

The MRC AML 11 trial randomized 1071 patients with newly diagnosed AML aged 60 years or older to receive 2 induction courses containing cytarabine and an anthracycline or anthracenedione, with or without thioguanine or etoposide.29 Patients experiencing complete remission received either 1 or 3 consolidation courses, with or without interferon maintenance, for 1 year. Survival rates at 1 and 3 years were 37% and 15%, respectively. Based on this patient population a prognostic risk index was developed, which was validated using data from the Leukaemia Research Fund AML14 trial. Cytogenetic risk group, age, WBC count, performance status, and AML origin (de novo vs. secondary) were found to have statistically significant impact on overall survival in multivariate analysis.

Earlier studies of AML in patients older than 60 years used attenuated doses of anthracyclines (daunomycin at 45–50 mg/m2 for 3 days with standard-dose cytarabine) because studies from the early 1980s showed increased early mortality with higher doses. However, major improvements in supportive care, including the use of highly effective antiemetics, antibiotics, antifungals, and myeloid growth factors, have changed practice. The weight loss, debility, erosive esophagitis, and aspiration pneumonia once common with induction chemotherapy in older patients are now of low frequency. Thus, more recent studies have explored higher-dose chemotherapy in this population.

For example, Lowenberg et al.30 recently compared standard-dose cytarabine plus daunomycin at either 45 or 90 mg/m2/d for 3 days as induction for patients older than 60 years with AML. The higher dose of anthracycline was associated with a higher complete remission rate (64% vs. 54%; P = .002) and improved survival at 2 years for those aged 60 to 65 years (38% vs. 23%; P < .001).30 A recent analysis by the German Acute Leukemia Cooperative Group included 1284 patients with de novo AML, of whom 764 were older than 60 years.31 Patients were randomly assigned to induction with either a standard-dose (cytarabine, daunorubicin, and 6-thioguanine) or a high-dose (cytarabine and mitoxantrone) combination, or with 2 courses of high-dose combination, which was followed by uniform postremission chemotherapy in both groups. The 4-year overall survival in patients younger and older than 60 years was 37% and 16%, respectively, regardless of the intensity of the induction therapy. The strongest factors with an impact on survival were karyotype, age, and marrow blast percentage at day 16. In addition, patients with normal karyotype were stratified according to NPM1 and FLT3-ITD mutation status. In this large group (n = 670), the most important risk factors predicting improved survival were the sole mutation of NPM1, low day 16 marrow blast count (< 10%), and younger age. Patients older than 60 years had inferior survival compared with younger patients in all prognostic subgroups. However, older patients with normal karyotype and a sole NPM1 mutation (NPM1+/FLT3-ITD–) had an approximately 40% 4-year survival. The recent results from Lowenberg et al.,30 Buchner et al.,31 and others32,33 confirm the fact that the outcome of chemotherapy for older patients is far from satisfactory, but with intensive therapy some subgroups may have a reasonable expectation for survival several years from diagnosis.

Reduced-Intensity and Nonmyeloablative Allogeneic HCT in Older Adults

General Considerations

The observation that patients with graft-versus-host disease (GVHD) after allogeneic HCT had decreased relapse rates led to the recognition that allogeneic hematopoietic cells not only restore hematopoiesis but also impose immunologic GVL effects, resulting in subsequent cure of malignant diseases.3436 The hypothesis that GVL effects alone have the potential to eradicate malignant disorders led to the development of various conditioning regimens of lower intensity over the past 20 years. These studies show that durable engraftment can be attained with appropriate peritransplant immunosuppression. Investigators at MD Anderson Cancer Center used purine nucleoside analogue-based regimens followed by allogeneic HCT for the treatment of hematologic malignancies.37,38 Slavin et al.39 reported a regimen consisting of fludarabine, busulfan, and antithymocyte globulin (ATG) in a group of younger patients with both hematologic malignancies and genetic disorders. Spitzer et al.40 evaluated the use of cyclophosphamide, ATG, and thymic irradiation in patients undergoing bone marrow transplantation from human leukocyte antigen (HLA)-matched donors. Using the canine model of allogeneic HCT, a low-dose total body irradiation (TBI)–based preparative regimen was developed at the Fred Hutchinson Cancer Research Center (FHCRC).41 To prevent graft rejection and increase pretransplantation host T-cell immunosuppression, 30 mg/m2 of fludarabine was added to the conditioning regimen of 2 Gy TBI. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil (MMF).

The spectrum of intensity of some commonly used regimens is shown in Figure 1. Regimens can be placed in 3 general categories: myeloablative, which cause irreversible marrow aplasia if transplantation is not performed; nonmyeloablative, which cause minimal marrow suppression; and reduced-intensity conditioning, which cause cytopenias of intermediate duration.42 Currently, no prospective comparisons of the different reduced-intensity and nonmyeloablative regimens have been published. However, compared with high-dose preparative regimens, nonmyeloablative and reduced-intensity conditioning regimens are associated with shorter inpatient hospital stays, reduced need for transfusions,43 and a shorter duration of neutropenia with fewer bacterial infections.4446 The adoption of less-toxic conditioning regimens has expanded the number of patients eligible to undergo HCT to include those previously excluded because of age or comorbidities. The number of transplants performed in patients older than 50 years increased more than in any other age group between 1999 and 2009 (Figure 2), and currently patients in their mid- to late 70s can be considered for allogeneic HCT.

Figure 1
Figure 1

Spectrum of intensity of commonly used conditioning regimens for hematopoietic stem cell transplant. Abbreviations: ATG, antithymocyte globulin; BU, busulfan; CY, cyclophosphamide; FLU, fludarabine; MP, melphalan; TBI, total body irradiation; TT, thiotepa. Reproduced from Mielcarek M, Storb R. Graft-versus-host disease after non-myeloablative hematopoietic cell transplantation. Leuk Lymphoma 2005;46:1251–1260. Adapted by permission from Informa Healthcare.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 3; 10.6004/jnccn.2011.0028

Outcomes in Patients With AML

Encouraging results of various nonmyeloablative and reduced-intensity conditioning regimens have been reported. McClune et al.47 analyzed Center for International Blood and Marrow Transplant Research (CIBMTR) data on 1080 patients older than age 40 with AML in first complete remission or MDS who underwent reduced-intensity or nonmyeloablative conditioning followed by related or unrelated donor HCT between 1995 and 2005. Four age groups of patients were studied: 40 to 54 years, 55 to 59 years, 60 to 64 years, and older than 64 years. Among the 545 patients with AML, nonrelapse mortality (NRM) at 2 years ranged from 22% to 34%, although 2-year relapse rates for the 4 AML age-groups were 33%, 34%, 37%, and 33%, respectively, resulting in 2-year disease survival rates of 44%, 50%, 34%, and 36% in the 4 respective age groups. The differences among relapse, NRM, and overall survival were not statistically significant among the studied age groups. Obvious selection bias inherent to these retrospective studies may limit the interpretation of results, but the data still imply that allogeneic HCT after reduced-intensity or nonmyeloablative conditioning can result in long-term survival in a substantial number of older patients, in whom nontransplant approaches have historically yielded poor outcomes.

Figure 2
Figure 2

National Marrow Donor Program transplants by year and patient age, 2000–2010. Transplants facilitated by the National Marrow Donor Program (NMDP) for adults older than 50 years increased 14% in 2009 compared with a 9% growth overall. In the past 5 years, annual NMDP-facilitated transplants for patients older than 50 years have more than doubled. NMDP Transplants by Recipient Age, By Year, copyright © 2010 National Marrow Donor Program. Reprinted with permission from National Marrow Donor Program.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 3; 10.6004/jnccn.2011.0028

Mohty et al.12,48 recently updated results of the first prospective trial directly comparing reduced-intensity allogeneic HCT with consolidation chemotherapy in patients with AML using “genetic allocation.” Ninety-five consecutive patients with high-risk AML in first complete remission were enrolled and underwent either reduced-intensity conditioning HCT from an HLA-identical sibling donor if such a donor could be identified, or consolidation therapy if not. In an intention-to-treat analysis, the leukemia-free survival was superior in the donor group (60% vs. 23% at 7 years; P = .003). Few other prospective studies have compared transplantation with chemotherapy in this age group, and virtually no randomized comparisons of preparative regimens are available. Among the published phase II trials, leukemia relapse remained consistently the main cause of treatment failure after reduced-intensity or nonmyeloablative conditioning, with 2- to 4-year relapse rates ranging from 30% to 61%.1013,1521

Influence of Disease-Related Factors on Outcomes

A multicenter study from the FHCRC/Seattle Consortium included 274 patients (median age, 60 years) with de novo or secondary AML who underwent allogeneic HCT from related or unrelated donors after conditioning with 2 Gy TBI with or without fludarabine (90 mg/m2).49 A calcineurin inhibitor and MMF were used for postgrafting immunosuppression. This approach relies almost exclusively on GVL effects in patients with AML, because the conditioning regimen itself has minimal anti-leukemic activity. With a median follow-up of 38 months in surviving patients, the estimated 5-year overall survival, relapse/progression, and nonrelapse mortality rates were 33%, 42%, and 26%, respectively.45,46 Patients in first and second complete remission had better survival rates than those with more advanced leukemia (37% and 34% vs. 18%, respectively; Figure 3A). Unfavorable cytogenetic risk was associated with increased risk of relapse and inferior survival (Figure 3B).

Figure 3
Figure 3Figure 3

Survival of 274 patients with acute myeloid leukemia undergoing nonmyeloablative allogeneic hematopoietic cell transplant (HCT) at the Fred Hutchinson Cancer Research Center/Seattle Consortium between 1998 and 2008, by remission status (A) and cytogenetic risk (B).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 3; 10.6004/jnccn.2011.0028

As seen with other reduced-intensity conditioning regimens, despite an encouraging number of long-term leukemia-free survivors, AML relapse remained the major cause of treatment failure after HCT. Most relapses occurred early, with the median time being 84 days. The 6-month and 1-year relapse rates were 31% and 35%, respectively. Using this dataset, Cox regression was used for multivariate analysis of risk factors for relapse in the subgroup of patients with AML in morphologic leukemia-free state at HCT. Cytogenetic risk status, disease stage (i.e., remission state), and time between diagnosis and HCT were significantly associated with relapse and overall mortality, whereas age, AML origin (de novo vs. secondary), donor type, and the presence of minimal residual disease did not have statistically significant impact on outcomes. In this study, the presence of minimal residual disease was not identified as an independent risk factor, probably because of its close association with unfavorable cytogenetics. In a separate time-dependent analysis, the development of acute GVHD did not influence relapse, whereas the presence of chronic GVHD was associated with decreased relapse rates.

The impact of pretransplant remission status on post-HCT relapse and survival was also observed by other investigators. Shimoni et al.17 reported outcomes of reduced-intensity conditioning with fludarabine and busulfan (in combination with antithymocyte globulin when patients had unrelated or HLA-mismatched donors). The 2-year overall survival was 93% among 15 patients with high-risk AML experiencing first complete remission (median age, 57 years) given reduced-intensity conditioning; none experienced NRM. In contrast, patients with active disease (defined as chemorefractory or previously untreated with > 10% bone marrow blasts at HCT) had poor outcomes with reduced-intensity conditioning because of high post-HCT relapse rates. Similarly, a retrospective study of 113 patients with AML (median age, 51 years) undergoing reduced-intensity conditioning with fludarabine and busulfan (n = 93) or TBI (4–8 Gy; n = 20) followed by HCT from related or unrelated donors, reported by the Cooperative German Transplant Study Group, showed a 2-year event-free survival of 52% for patients in first complete remission.10 Patients in second complete remission had a 40% event-free survival rate at 2 years, whereas fewer than 20% of those with more advanced leukemias were alive at 2 years.

Overall, reports of reduced-intensity and nonmyeloablative conditioning regimens show that this approach is feasible and can result in long-term survival of a substantial number of older patients with AML, with particularly encouraging results in those undergoing HCT in first complete remission.

Influence of Patient-Related Factors on Outcomes

Age: A recent, large retrospective analysis of patients aged 40 to 54 years, 55 to 59 years, 60 to 64 years, or older than 64 years from the CIBMTR did not show statistically significant differences in relapse, NRM, or overall survival in 545 patients with AML undergoing reduced-intensity or nonmyeloablative conditioning followed by HCT from related or unrelated donors. This observation was supported by another retrospective registry study from the European Group for Blood and Marrow Transplantation (EBMT), which included 1333 patients with MDS (median age, 56 years) undergoing related or unrelated donor HCT. Of these patients, 41% had secondary AML (patients previously classified as RAEB-t who fulfill WHO diagnostic criteria for AML); 500 patients (38%) underwent standard high-dose conditioning, whereas 833 patients received reduced-intensity conditioning. Estimated 4-year overall survival was 31% for the whole cohort, whereas it was 34% and 27% for patients aged 50 to 60 years and older than 60 years, respectively (P = .23). As expected, NRM was lower in patients undergoing reduced-intensity conditioning than in those undergoing high-dose conditioning (32% and 44%, respectively; P = .05). In contrast, patients undergoing reduced-intensity conditioning had a higher relapse rate than those receiving high-dose conditioning (41% vs. 33%; P < .01).

In a multivariate analysis, patient age did not show statistically significant association with overall survival, NRM, or relapse. The intrinsic selection bias in these studies is obvious and is acknowledged by the authors; however, important patient characteristics, such as the presence of comorbid conditions, were not captured by the analysis, but likely impact the decision whether to proceed with allogeneic HCT and, if so, what conditioning regimen to use. Nevertheless, the data show that age alone should not be considered a contraindication to allogeneic HCT.

Comorbid Conditions: The development of reduced-intensity and nonmyeloablative conditioning regimens enables older, less fit, and more heavily pretreated patients to undergo allogeneic HCT. Although this procedure has curative potential, its application is limited by treatment-related complications, such as regimen-related toxicities, infections, and GVHD, which can culminate in increased NRM rates, especially in older or less-fit patients. Comorbid conditions can affect patient outcomes, especially in patients with cancer, in whom antitumor interventions generally have a narrow therapeutic window. Therefore, systematically assessing the presence of these conditions is helpful when evaluating the risk–benefit ratio of a particular intervention, such as allogeneic HCT. Integrating the assessment of comorbidities into clinical trials will likely be useful, because comorbid conditions can affect and sometimes independently predict outcomes.

Several comorbidity scales have been developed to rate the impact of different comorbid conditions on outcomes. Because the impact of different comorbid conditions is not the same, they are weighted differently, according to their severity and the magnitude of their impact. The most studied comorbidity index is the Charlson's Comorbidity Index (CCI),50,51 which has been used to predict mortality in various medical conditions, including hematologic malignancies and solid tumors. Sorror et al.52 modified the CCI for use in the context of allogeneic HCT to capture additional parameters more relevant in this setting. This scoring system, the HCT comorbidity index (HCT-CI), seemed to be more sensitive than the standard CCI to assign patients with pretransplant comorbid conditions into risk groups and predict NRM and survival. In the HCT-CI, 17 different categories of comorbidities are considered and each given a weighted score; the sum of the scores is then used to predict outcome (Table 1). Initial studies showed that with increasing HCT-CI scores, NRM increases and survival drops.53,54 The most notable changes appeared once the HCT-CI rose above 3.

The HCT-CI was evaluated among 341 older patients (median age, 54 years) undergoing nonmyeloablative HCT for various hematologic malignancies in conjunction with the Karnofsky performance status score (KPS).54 This retrospective study found that both HCT-CI scores and KPS independently predicted toxicities, NRM, and overall mortality, whereas the 2 measures only weakly correlated with each other, indicating that these tools assessed different aspects of a patient's health status. In addition, no correlation was found between increasing age and either higher comorbidity scores or lower performance status, likely because of selection bias in referring and accepting patients for HCT.

An alternative predictive index of outcome after allogeneic HCT is the Pretransplant Assessment of Mortality (PAM).55 This pre-HCT score incorporates 8 pretransplantation clinical variables: patient age, donor type, disease risk, conditioning regimen, FEV1, carbon monoxide diffusion capacity, serum creatinine level, and serum alanine aminotransferase concentration, and, like the HCT-CI, the PAM score was found to be a very powerful predictor of survival at 2 years after HCT. Although the PAM score includes information about the form of treatment used, the HCT-CI is based solely on comorbidities and therefore might be more appropriate for assigning patients to specific therapies. The PAM might be more useful for informing patients of their risk based on a certain therapy.

Table 1

Weighted Scores of Comorbidities as Summarized by the HCT-CI

Table 1

Donor: Traditionally, the preferred donor for allogeneic HCT has been an HLA-identical sibling, but only 15% to 30% of patients referred for allogeneic HCT have suitable HLA-identical sibling donors. For patients without these donors, HLA-matched unrelated donors may be an alternative. The likelihood of identifying an HLA-matched unrelated donor varies with the patient's specific HLA alleles and ethnicity, which relates to HLA diversity and the number of registered potential donors. A recent retrospective analysis showed that when compared with nonmyeloablative HCT from HLA-identical related donors, transplantation from HLA-matched unrelated donors did not increase the risk of NRM and overall mortality.49 The chronologic age of unrelated donors seems to have little, if any, impact on outcome.

Although unrelated donor registries have undergone substantial growth over the past years, suitable donors are unable to be identified for approximately 30% to 40% of Caucasian recipients and more than 60% of African-American patients. In these cases, HLA-mismatched unrelated donors represent an alternative source of hematopoietic graft. The use of HLA class I–mismatched donors in the nonmyeloablative setting was investigated by Nakamae et al.56 and HCT from these donors were found to be curative, but the observed 69% of grade II to IV acute GVHD and 47% cumulative probability of NRM were higher than those observed in the HLA-matched unrelated donor setting.

For patients lacking suitable HLA-matched unrelated donors, additional alternative stem cell sources are potentially available: umbilical cord blood and HLA-haploidentical family members, both of which are being actively explored in the reduced-intensity and nonmyeloablative setting.

Quality of Life After Allogeneic HCT

Various studies have addressed health-related quality of life (QOL) changes during and after allogeneic HCT after reduced-intensity conditioning in older patients.5759 Although of limited size, these studies consistently showed that physical function returned to pretransplant level in most survivors of reduced-intensity conditioning and nonmyeloablative allogeneic HCT by 1 year. Two of these studies compared recovery after reduced-intensity and high-dose conditioning regimens. Bevans et al.58 found that at 2 years all survivors reported similar or better health-related QOL than at baseline, regardless of conditioning intensity. Similarly, Andersson et al.59 found no significant differences in global QOL at 1 year for patients treated with either reduced-intensity or high-dose preparative regimens; however, the reduced-intensity group regained health and QOL faster than patients undergoing myeloablative conditioning. As expected, most symptoms occurring beyond 1 year after HCT were related to chronic GVHD; however, no significant differences were seen in global QOL between patients with and without GVHD. Further longitudinal and cross-sectional studies are needed to assess QOL as an important outcome after reduced-intensity and nonmyeloablative allogeneic HCT in older patients.

Conclusions

Recent studies show that with reduced-intensity and nonmyeloablative conditioning regimens, allogeneic HCT can now be performed safely in patients up to 75 years of age, and therefore chronologic age itself (< 76 years of age) can no longer be considered a contraindication for this procedure. Best results are generally seen in patients undergoing transplant during first remission. Although randomized trials have not been performed, survival after allogeneic HCT in patients in first complete remission appears superior to what would be expected with chemotherapy for most categories of older patients with AML, although distinct subgroups (e.g., patients with normal karyotype and a single NPM1 mutation) may experience similar outcomes with standard combination chemotherapy. Similar results have been seen with matched related and unrelated donors, and therefore HLA typing should be obtained at diagnosis to determine donor availability. Alternative donor sources, such as cord blood, can be considered in the context of a clinical trial if an HLA-matched related or unrelated donor is not available. Comorbid conditions and performance status should be assessed when counseling patients about risks of treatment-related complications and NRM. Patients and their families should be carefully counseled about the potential development of chronic GVHD and the diminished QOL during the earlier posttransplant period. If the decision is made to delay transplant until first relapse, a careful monitoring plan should be established, but patients must also be informed about the reduced effectiveness of transplantation after first relapse.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, Journal of the National Comprehensive Cancer Network

Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.

CME AUTHOR

Charles P. Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

References

  • 1.

    Leith CP, Chir B, Kopecky KJ. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group Study. Blood 1997;32:33233329.

    • Search Google Scholar
    • Export Citation
  • 2.

    Moorman AV, Roman E, Willett EV. Karyotype and age in acute myeloid leukemia. Are they linked? Cancer Genet Cytogenet 2001;32:155161.

  • 3.

    Leith CP, Kopecky KJ, Chen IM. Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia. a Southwest Oncology Group study. Blood 1999;32:10861099.

    • Search Google Scholar
    • Export Citation
  • 4.

    Rossi G, Pelizzari AM, Bellotti D. Cytogenetic analogy between myelodysplastic syndrome and acute myeloid leukemia of elderly patients. Leukemia 2000;32:636641.

    • Search Google Scholar
    • Export Citation
  • 5.

    Godwin JE, Kopecky KJ, Head DR. A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group Study (9031). Blood 1998;32:36073615.

    • Search Google Scholar
    • Export Citation
  • 6.

    Anderson JE, Kopecky KJ, Willman CL. Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study. Blood 2002;32:38693876.

    • Search Google Scholar
    • Export Citation
  • 7.

    Walter RB, Kantarjian HM, Huang X. Effect of complete remission and responses less than complete remission on survival in acute myeloid leukemia: a combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M.D. Anderson Cancer Center study. J Clin Oncol 2010;32:17661771.

    • Search Google Scholar
    • Export Citation
  • 8.

    Ringdén O, Horowitz MM, Gale RP. Outcome after allogeneic bone marrow transplant for leukemia in older adults. JAMA 1993;32:5760.

  • 9.

    Runde V, de Witte T, Arnold R. Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1998;32:255261.

    • Search Google Scholar
    • Export Citation
  • 10.

    Sayer HG, Kröger M, Beyer J. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor. Bone Marrow Transplant 2003;32:10891095.

    • Search Google Scholar
    • Export Citation
  • 11.

    de Lima M, Anagnostopoulos A, Munsell M. Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood 2004;32:865872.

    • Search Google Scholar
    • Export Citation
  • 12.

    Mohty M, de Lavallade H, Ladaique P. The role of reduced intensity conditioning allogeneic stem cell transplantation in patients with acute myeloid leukemia: a donor vs no donor comparison. Leukemia 2005;32:916920.

    • Search Google Scholar
    • Export Citation
  • 13.

    Tauro S, Craddock C, Peggs K. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005;32:93879393.

    • Search Google Scholar
    • Export Citation
  • 14.

    van Besien K, Artz A, Smith S. Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005;32:57285738.

    • Search Google Scholar
    • Export Citation
  • 15.

    Alyea EP, Kim HT, Ho V. Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant 2006;32:10471055.

    • Search Google Scholar
    • Export Citation
  • 16.

    Gorin NC, Labopin M, Boiron JM. Results of genoidentical hemopoietic stem cell transplantation with reduced intensity conditioning for acute myelocytic leukemia: higher doses of stem cells infused benefit patients receiving transplants in second remission or beyond—the Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol 2006;32:39593966.

    • Search Google Scholar
    • Export Citation
  • 17.

    Shimoni A, Hardan I, Shem-Tov N. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia 2006;32:322328.

    • Search Google Scholar
    • Export Citation
  • 18.

    McClune B, Weisdorf DJ, DiPersio JF. 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) [abstract]. Blood 2008;112:Abstract 346.

    • Search Google Scholar
    • Export Citation
  • 19.

    Mohty M, Labopin M, Milpied NJ. Impact of cytogenetics risk on outcome after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) from an HLA identical sibling for patients with acute myeloid leukemia (AML) in first complete remission (CR1) [abstract]. Blood 2008;112:Abstract 345.

    • Search Google Scholar
    • Export Citation
  • 20.

    Pfeifer T, Schleuning M, Eder M. Improved outcome for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with poor risk cytogenetics - result from an analysis on 172 patients receiving FLAMSA-RIC conditioning for allogeneic stem cell transplantation (SCT) [abstract]. Blood 2008;112:Abstract 1971.

    • Search Google Scholar
    • Export Citation
  • 21.

    Valcarcel D, Martino R, Caballero D. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008;32:577584.

    • Search Google Scholar
    • Export Citation
  • 22.

    Ringdén O, Labopin M, Ehninger G. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol 2009;32:45704577.

    • Search Google Scholar
    • Export Citation
  • 23.

    Appelbaum FR, Gundacker H, Head DR. Age and acute myeloid leukemia. Blood 2006;32:34813485.

  • 24.

    Grimwade D, Walker H, Harrison G. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 10 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001;32:13121320.

    • Search Google Scholar
    • Export Citation
  • 25.

    Schoch C, Kern W, Schnittger S. The influence of age on prognosis of de novo acute myeloid leukemia differs according to cytogenetic subgroups. Haematologica 2004;32:10821090.

    • Search Google Scholar
    • Export Citation
  • 26.

    Buchner T, Berdel WE, Schoch C. Therapeutic outcome in prognostic subgroups of de-novo acute myeloid leukemia (AML) and the role of the age factor: a study in 1834 patients of 16 to 84 years [abstract]. J Clin Oncol 2005;23(Suppl 1):Abstract 6552.

    • Search Google Scholar
    • Export Citation
  • 27.

    Delaunay J, Vey N, Leblanc T. Prognosis of inv(16)/t(16;16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup (Review). Blood 2003;32:462469.

    • Search Google Scholar
    • Export Citation
  • 28.

    Kantarjian H, O'Brien S, Cortes J. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 2006;32:10901098.

    • Search Google Scholar
    • Export Citation
  • 29.

    Wheatley K, Brookes CL, Howman AJ. Prognostic factor analysis of the survival of elderly patients with AML in the MRC AML11 and LRF AML14 trials. Br J Haematol 2009;32:598605.

    • Search Google Scholar
    • Export Citation
  • 30.

    Lowenberg B, Ossenkoppele GJ, van Putten W. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009;32:12351248.

    • Search Google Scholar
    • Export Citation
  • 31.

    Buchner T, Berdel WE, Haferlach C. Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Myeloid Cooperative Group. J Clin Oncol 2009;32:6169.

    • Search Google Scholar
    • Export Citation
  • 32.

    Thiede C, Koch S, Creutzig E. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 2006;32:40114020.

    • Search Google Scholar
    • Export Citation
  • 33.

    Pigneux A, Harousseau JL, Witz F. Addition of lomustine to idarubicin and cytarabine improves the outcome of elderly patients with de novo acute myeloid leukemia: a report from the GOELAMS. J Clin Oncol 2010;32:30283034.

    • Search Google Scholar
    • Export Citation
  • 34.

    Weiden PL, Flournoy N, Thomas ED. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 1979;32:10681073.

    • Search Google Scholar
    • Export Citation
  • 35.

    Weiden PL, Sullivan KM, Flournoy N. Antileukemic effect of chronic graft-versus-host disease. Contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 1981;32:15291533.

    • Search Google Scholar
    • Export Citation
  • 36.

    Sullivan KM, Weiden PL, Storb R. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989;32:17201728.

    • Search Google Scholar
    • Export Citation
  • 37.

    Giralt S, Estey E, Albitar M. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997;32:45314536.

    • Search Google Scholar
    • Export Citation
  • 38.

    Giralt S, Thall PF, Khouri I. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood 2001;32:631637.

    • Search Google Scholar
    • Export Citation
  • 39.

    Slavin S, Nagler A, Naparstek E. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998;32:756763.

    • Search Google Scholar
    • Export Citation
  • 40.

    Spitzer TR, McAfee S, Sackstein R. Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood and Marrow Transplantation 2000;6(3A):309320.

    • Search Google Scholar
    • Export Citation
  • 41.

    McSweeney PA, Niederwieser D, Shizuru JA. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001;32:33903400.

    • Search Google Scholar
    • Export Citation
  • 42.

    Bacigalupo A, Ballen K, Rizzo D. Defining the intensity of conditioning regimens working definitions. Biol Blood Marrow Transplant 2009;32:16281633.

    • Search Google Scholar
    • Export Citation
  • 43.

    Weissinger F, Sandmaier BM, Maloney DG. Decreased transfusion requirements for patients receiving nonmyeloablative compared with conventional peripheral blood stem cell transplants from HLA-identical siblings. Blood 2001;32:35843588.

    • Search Google Scholar
    • Export Citation
  • 44.

    Junghanss C, Marr KA, Carter RA. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 2002;32:512520.

    • Search Google Scholar
    • Export Citation
  • 45.

    Fukuda T, Hackman RC, Guthrie KA. Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative and conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation. Blood 2003;32:27772785.

    • Search Google Scholar
    • Export Citation
  • 46.

    Hogan WJ, Maris M, Storer B. Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients. Blood 2004;32:7884.

    • Search Google Scholar
    • Export Citation
  • 47.

    McClune BL, Weisdorf DJ, Pedersen TL. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol 2010;32:18781887.

    • Search Google Scholar
    • Export Citation
  • 48.

    Mohty M, de Lavallade H, El Cheikh J. Reduced intensity conditioning allogeneic stem cell transplantation for patients with acute myeloid leukemia: long term results of a `donor' versus `no donor' comparison. Leukemia 2009;32:194196.

    • Search Google Scholar
    • Export Citation
  • 49.

    Gyurkocza B, Storb R, Storer BE. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol 2010;32:28592867.

    • Search Google Scholar
    • Export Citation
  • 50.

    Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;32:373383.

    • Search Google Scholar
    • Export Citation
  • 51.

    Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol 1994;32:12451251.

  • 52.

    Sorror ML, Maris MB, Storb R. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;32:29122919.

    • Search Google Scholar
    • Export Citation
  • 53.

    Sorror ML, Giralt S, Sandmaier BM. Hematopoietic cell transplantation-specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood 2007;32:46084613.

    • Search Google Scholar
    • Export Citation
  • 54.

    Sorror M, Storer B, Sandmaier BM. Hematopoietic cell transplantation-comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation. Cancer 2008;32:19922001.

    • Search Google Scholar
    • Export Citation
  • 55.

    Parimon T, Au DH, Martin PJ, Chien JW. A risk score for mortality after allogeneic hematopoietic cell transplantation. Ann Intern Med 2006;32:407414.

    • Search Google Scholar
    • Export Citation
  • 56.

    Nakamae H, Storer BE, Storb R. Low-dose total body irradiation and fludarabine conditioning for HLA class I-mismatched donor stem cell transplantation and immunologic recovery in patients with hematologic malignancies: a multicenter trial. Biol Blood Marrow Transplant 2010;32:384394.

    • Search Google Scholar
    • Export Citation
  • 57.

    Wong R, Giralt SA, Martin T. Reduced-intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years. Blood 2003;32:30523059.

    • Search Google Scholar
    • Export Citation
  • 58.

    Bevans MF, Marden S, Leidy NK. Health-related quality of life in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2006;32:101109.

    • Search Google Scholar
    • Export Citation
  • 59.

    Andersson I, Ahlberg K, Stockelberg D. Health-related quality of life in patients undergoing allogeneic stem cell transplantation after reduced intensity conditioning versus myeloablative conditioning. Cancer Nurs 2009;32:325334.

    • Search Google Scholar
    • Export Citation

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Correspondence: Frederick R. Appelbaum, MD, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D5-310, PO Box 19024, Seattle, WA 98109-1024. E-mail: fappelba@fhcrc.org

Disclosure: Boglarka Gyurkocza, MD, has disclosed no relevant financial relationships.

Disclosure: Frederick R. Appelbaum, MD, has disclosed no relevant financial relationships.

Supplementary Materials

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    Spectrum of intensity of commonly used conditioning regimens for hematopoietic stem cell transplant. Abbreviations: ATG, antithymocyte globulin; BU, busulfan; CY, cyclophosphamide; FLU, fludarabine; MP, melphalan; TBI, total body irradiation; TT, thiotepa. Reproduced from Mielcarek M, Storb R. Graft-versus-host disease after non-myeloablative hematopoietic cell transplantation. Leuk Lymphoma 2005;46:1251–1260. Adapted by permission from Informa Healthcare.

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    National Marrow Donor Program transplants by year and patient age, 2000–2010. Transplants facilitated by the National Marrow Donor Program (NMDP) for adults older than 50 years increased 14% in 2009 compared with a 9% growth overall. In the past 5 years, annual NMDP-facilitated transplants for patients older than 50 years have more than doubled. NMDP Transplants by Recipient Age, By Year, copyright © 2010 National Marrow Donor Program. Reprinted with permission from National Marrow Donor Program.

  • View in gallery View in gallery

    Survival of 274 patients with acute myeloid leukemia undergoing nonmyeloablative allogeneic hematopoietic cell transplant (HCT) at the Fred Hutchinson Cancer Research Center/Seattle Consortium between 1998 and 2008, by remission status (A) and cytogenetic risk (B).

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