Aging, Acute Myelogenous Leukemia, and Allogeneic Transplantation: Do They Belong in the Same Sentence?

Comprehensive Review

Aging, Acute Myelogenous Leukemia, and Allogeneic Transplantation: Do They Belong in the Same Sentence? Stefan O. Ciurea,1 Morgani Rodrigues,2 Sergio Giralt,1 Marcos de Lima1 Abstract Acute myelogenous leukemia is a disease of the elderly. Disease biology and functional status of this patient population contribute to poorer treatment outcomes with standard therapy. Allogeneic hematopoietic stem cell transplantation is associated with an immunologic “graft-versus-tumor” effect. However, transplantation was restricted until recently to younger patients because of prohibitive treatment-related mortality. The development of reduced-intensity preparative regimens and improvements in supportive care now allow older patients with myeloid leukemia a greater opportunity for cure with transplantation. Donor availability, graft-versus-host disease, delayed immune recovery, and the high prevalence of relapsed or refractory disease remain important obstacles to be overcome in the future. Herein, we review the current literature on transplantation for older patients with this myeloid malignancy. Clinical Lymphoma & Myeloma, Vol. 9, No. 4, 289-297, 2009; DOI: 10.3816/CLM.2009.n.057 Keywords: Busulfan, FLT3, MDR1, Myelodysplastic syndromes, Reduced-intensity conditioning

Introduction Acute myelogenous leukemia (AML) is the most common malignant myeloid disease in adults. The median age at diagnosis was 67 years as indicated by Surveillance, Epidemiology and End Results data for the years 2001-2005.1 The age-adjusted incidence of AML ranges from 1.7 per 100,000 for subjects aged < 65 years, increasing to 16.4 for those aged > 65 years. The incidence per 100,000 increases from 3.1 in the population aged 50-54 years to 23.1 among those aged > 80 years, versus an incidence of 3.6 per 100,000 in the general population.1 There is compelling evidence demonstrating that unfavorable outcomes in elderly patients with AML are primarily due to differences in genetic and biologic features. Host factors like immunologic senescence, frailty, and clinical comorbidities are also important contributors to the overall poorer outcome of any treatment modality in this age group, whether it is conventional chemotherapy or allogeneic stem cell transplantation (alloSCT). 1Department

of Stem Cell Transplantation and Cellular Therapy, the University of Texas M. D. Anderson Cancer Center, Houston, TX Israelita Albert Einstein, Sao Paulo, Brazil

2Hospital

Submitted: Jul 28, 2008; Revised: Oct 21, 2008; Accepted: Nov 11, 2008 Address for correspondence: Marcos de Lima, MD, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 423, Houston, TX 77033 Fax: 713-794-4902; e-mail: [email protected]

Outcomes of adult patients with AML worsen continuously with increasing age, which makes it difficult to establish a cutoff age that defines “elderly AML.”2 Age has long been found to be associated with unfavorable outcomes in patients with AML, regardless of the presence of poor-prognosis cytogenetics.3 The association of aging and disease refractoriness creates a difficult dilemma for the patient, family, and the treating physician. The controversy surrounding who should receive intensive treatment and what that treatment should be is far from resolved.4-7 It is reasonable to say that the principal cause of treatment failure in older patients with AML is the disease itself.2 Overall, < 10% of patients with AML aged > 55 years are cured with standard chemotherapy, and the median survival is approximately 10 months. Clearly, there is a need for more effective treatment modalities for this age group.3,4,8 Allogeneic stem cell transplantation might offer the chance for cure to a significant minority of patients in this population, but until a decade ago, this procedure was performed mostly in patients aged < 55 years. Reduced-intensity conditioning (RIC) regimens have allowed frailer and older patients to undergo this procedure and benefit from the graft-versus-leukemia (GVL) effect, while ablative regimens are now being offered to selected patients up to the seventh decade of life. We and others have demonstrated the feasibility of allogeneic transplantation for patients in their 60s and even early 70s, but significant obstacles remain before this form of treatment can be offered to the majority of patients in need (Figure 1).9,10

This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.

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AML, AlloHSCT, and Aging Figure 1 Increase in Median Age of Patients With Acute Myelogenous Leukemia and Myelodysplastic Syndrome Who Received an Allogeneic Unrelated Donor Hematopoietic Stem Cell Transplant Over the Past 16 Years at M. D. Anderson Cancer Center (N = 384) 60 55

Mean Age, Years

50 45 40 35 30 Mean ± SE ± 1.96*SE

25 20 1991

1993

1995

1997

1999

2001

2003

2005

2007

Transplantation Year

Herein, we review the literature related to alloSCT in the elderly and discuss trends in this dynamic and rapidly evolving field; because of the large number of studies, not all could be included in this review.

Acute Myelogenous Leukemia of the Elderly Is Intrinsically More Resistant to Therapy The development of myeloid leukemias in humans is characterized by at least 2 types of genetic events, one associated with mutations conferring a proliferative and survival advantage and another characterized by impaired hematopoietic differentiation and cellular apoptosis.11-13 Activating mutations like Fms-like tyrosine kinase 3 (FLT3), c-KIT, or RAS gene mutations are common and confer a poor prognosis.15 AML in the elderly is associated with higher frequencies of such mutations.12-14 Accordingly, the prevalence of unfavorable chromosomal abnormalities is also higher in elderly patients with AML,3 while secondary AML evolving from previous myelodysplastic syndrome (MDS) is more commonly diagnosed in this patient population, paralleling an increased incidence of MDS. Leukemic blasts from older patients with AML have a higher level of expression of multidrug resistance gene-1 (MDR1) than cells from younger patients. Such expression correlates independently with more resistant disease and poorer treatment outcome in several studies.15-17 Cytogenetics is the most important prognostic indicator for AML in the elderly, where a sharp increase in the incidence of unbalanced chromosomal abnormalities is commonly documented.18-20 De novo AML in elderly patients has striking characteristics of alkylating agent–induced secondary AML, with a high frequency of unfavorable cytogenetics, most commonly a complex karyotype or abnormalities of chromosomes 5, 7, and 8 (-5/5q-, -7/7q-, +8). In general, older patients have 2-4 times less favorable cytogenetic abnormalities, twice as much MRD1 expression, and 3-6 times the incidence of secondary AML than younger patients with this disease.3,8,15,20-22

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Secondary AML was found in 24%-56% of elderly patients compared with < 10% in younger patients.6,15,21-23 It is possible that the accumulation of stem cell genetic defects with age, such as changes in telomere length as shown by Rufer et al24 or the negative influence of environmental factors such as smoking as noted by Estey,4 might explain at least in part this association. In addition, the increasing number of patients surviving treatment with alkylating agents and/or topoisomerase inhibitors is contributing to this picture. The MDR1 gene encodes proteins responsible for transmembrane drug and peptide trafficking.25 MDR1 upregulation promotes an efflux of chemotherapeutic drugs like anthracyclines from the tumor cells and might play an important role in resistance to chemotherapy.22 The presence of MDR1 has been reported to be an independent prognostic factor for poor outcome.15,26 Elderly patients with de novo MDR1-negative AML had complete remission rates similar to younger patients with AML, whereas older patients with positive MDR1 disease were much less likely to achieve complete response (CR) in one study.27 Appelbaum and coworkers reported on a cohort of 985 adult patients in which MDR1 expression was present in 57% of patients aged > 75 years compared with 33% of patients aged < 56 years.8 Accumulation of poor risk factors such as secondary disease, unfavorable cytogenetics, and MDR1 expression influence CR rates as noted by Estey.2 In a retrospective analysis, 44% of patients with 1 of these 3 features achieved CR, whereas those with 2 or 3 unfavorable markers had CR rates of 24% and 12%, respectively.2 Stirewalt et al found that approximately 57% of 234 samples from elderly AML patients harbored mutations in FLT3, RAS, or TP53 genes.13 Approximately 10% of all patients had mutations in the TP53 gene, which were associated with abnormalities such as those involving chromosomes 5 and 7 and worse survival.13 The prevalence of FLT3 internal tandem duplication (ITD) in older patients with AML appears to be greater (27%) than previously reported in younger patients.13,28 FLT3 is the single most common mutated gene in this disease, found in approximately 40% of patients with diploid cytogenetics and in up to 30% of all patients with AML. The presence of this genetic abnormality has been associated with a poor outcome, especially in patients aged < 60 years.12,31-34 Approximately 24% of all AML patients have ITD in the juxtamembrane domain of FLT3, and an additional 7% of AML patients have mutations within the activation loop of FLT3.4,28-31 Mutation in FLT3 confers cellular survival advantage and has been correlated with lower CR rates (primary resistant disease).18,35 Beran and colleagues from M. D. Anderson Cancer Center suggested in a large, retrospective study that outcome is poorer also in the FLT3-positive elderly population. Differences in overall survival did not reach statistical significance, however, suggesting that FLT3 mutations alone did not explain the poorer survival in this age group.36

Influence of Clinical Comorbidities As anticipated, performance status is a main predictor of treatment-related death and represents a powerful prognostic indicator not only for patients with AML but also for cancer patients in general. Estey and collaborators at the M. D. Anderson Cancer Center reported in a retrospective analysis that a performance status

Stefan O. Ciurea et al of 3 or 4 at the start of chemotherapy was associated with a median survival of 5 weeks, with only 4 of 95 patients living beyond 1 year (4% 1-year survival).2,8 The prevalence of comorbid conditions increases with age and is very likely to affect the outcomes of transplantation.37 Several indices have been created to measure the influence of comorbidities on the outcome of this treatment and have been proposed as selection and counseling tools. The Charlson Comorbidity Index (CCI) assigns weights to chronic conditions and adds points to each decade of life after the age of 50 years.38 The Seattle group used the CCI to analyze outcomes after related and unrelated allogeneic hematopoietic stem cell transplantations (alloHSCTs). In the related donor study, patients with a variety of hematologic malignancies were prepared with an ablative regimen (busulfan and cyclophosphamide or 12 Gy total body irradiation [TBI] and cyclophosphamide) or a nonablative regimen of 2 Gy TBI with or without fludarabine, which was used for older patients with comorbidities.39 Nonrelapse mortality at 1 year was 56% versus 22% for patients with a CCI score of 1 or greater for recipients of ablative and nonablative transplantations (P = .002). However, for the subgroup of patients with no comorbidities, there was no statistically significant difference in nonrelapse mortality in the 2 cohorts (22% vs. 12%, respectively).39 In the unrelated donor study, recipients of ablative regimens were also younger and had less comorbidities. Differently from the related donor analysis, the incidence of acute graft-versus-host disease (GVHD) was lower after nonmyeloablative conditioning (77% vs. 91%; P = .01), while the incidence of chronic GVHD was approximately the same.40 Ablative transplantations caused significantly higher rates of grade 4 toxicity, with similar rates of day-100 and 1-year nonrelapse mortality.40 Higher CCI scores led to higher rates of treatment-related mortality and severe toxicity in both groups. Nonrelapse mortality at 1 year was 28% for ablative patients with a score of 0 versus 67% for those with a score of 1 or 2.40 Subsequently, Sorror et al proposed the use of the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), which was recently evaluated in a combined report from the Fred Hutchinson Cancer Research Center and the M. D. Anderson Cancer Center on 224 patients with AML in first CR.41,42 Among 3 scores evaluated, the HCT-CI appeared to most accurately predict the outcomes of transplantation. Not unexpectedly, increasing age was associated with poorer comorbidity scores. Only 11% of patients aged > 59 years had a score of 0 as compared with 55% of patients aged < 40 years.42 All of these indices, however, have not been prospectively evaluated.

Intensity of the Preparative Regimen The intensity of the preparative regimen is an important contributor to the outcome of alloHSCT. Thus, “traditional” myeloablative chemoradiation has been mostly restricted to younger patients with good performance status, and prohibitive for many candidates with advanced age or comorbid conditions because of high treatment-related mortality. The European Group for Blood and Marrow Transplantation performed a registry-based retrospective comparison of the outcomes of patients with AML aged > 50 years treated with HLA-identical

sibling HSCT after regimens of reduced or myeloablative intensity. The former consisted mainly of fludarabine with busulfan or lowdose TBI (mostly 2 Gy), while the latter incorporated 10 Gy or greater TBI-based regimens or busulfan-based combinations with more than 8 mg/kg of the drug. Most patients in both groups were in CR (70%), and a minority had high-risk cytogenetics. A tradeoff that is very often seen in the literature was illustrated in this series of patients. Recipients of reduced-intensity transplantations were older but had significantly less grade 2-4 acute GVHD and transplantation-related mortality, with a statistically significant higher rate of relapse. Interestingly, incidence of grade 3-4 acute GVHD and leukemia-free survival was similar.43 As discussed above, several retrospective comparisons indicated higher rates of morbidity and infection after ablative regimens such as high-dose oral busulfan without pharmacokinetic dose adjustment or 12 Gy TBI-based combinations.39,43,44 The experience of the Dana-Farber group with cyclophosphamide and 12 Gy TBI for patients with hematologic malignancies aged > 50 years indicated increased nonrelapse mortality when compared with patients treated with reduced-intensity fludarabine and busulfan (0.8 mg/kg for 4 doses, equivalent to 4 mg of the oral formulation). The study cohort included 152 patients, 43% of the patients with AML or MDS. Early (100-days) treatment-related mortality was 6% versus 30%, while cumulative incidence of transplantation-related deaths was 32% versus 50%, respectively, for nonablative and ablative transplantations. The complex relationship between dose intensity, toxicity, and disease control was again present: relapse rate was higher after nonablative transplantations (46% vs. 30%; P = .052).44 In parallel to the development of RIC, ablative regimens have also become less toxic. Lowering nonrelapse mortality while keeping a higher degree of myeloablation might benefit the most patients with myeloid leukemia, given the relative insensitivity of AML to the GVL effect. The Seattle group reported on 52 patients aged > 60 years (median age, 62.8 years) treated from 1979 to 2002. Preparative regimens were high-dose oral busulfan in combination with cyclophosphamide or fludarabine, cyclophosphamide and high-dose TBI, and cyclophosphamide alone. One hundred–day and 3-year nonrelapse mortality rates were estimated at 27% and 43%, respectively.45 Success rates improved after year 1993. Our experience indicates that the use of intravenous busulfan-based preparative regimens have significantly reduced morbidity and mortality.46 We treated 56 patients aged > 55 years with a median age of 58 years with the diagnosis of MDS (n = 13), AML (n = 33), or chronic myelogenous leukemia/myeloproliferative disorder (n = 10) from 1997 to 2004 on 2 consecutive intravenous busulfan-based protocols.46 This highrisk cohort included mostly patients (60%) not in CR at HSCT. Chemotherapy consisted of fludarabine 40 mg/m2 and once-daily busulfan 130 mg/m2 for 4 days (n = 36) or busulfan 0.8 mg/kg for 16 doses and cyclophosphamide 120 mg/kg (n = 20). GVHD prophylaxis was based on tacrolimus and mini-methotrexate.46 Donors were unrelated in 40% of the transplantations. Treatment-related mortality at 100 days and at 1 year after HSCT was 11% and 29%, respectively. Major causes of treatment failure were GVHD and disease relapse. Currently, patients aged ≤ 65 years with adequate performance status are eligible for our protocol using fludarabine and single daily dosing, high-dose busulfan.47,48

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AML, AlloHSCT, and Aging Table 1A Summary of Studies Reporting Results With Allogeneic Hematopoietic Stem Cell Transplantation for Patients Aged > 50 Years With Acute Myelogenous Leukemia Disease, No. of Patients

Median Age, Years (Range)

Disease Status at Transplantation

Preparative Regimen

Donor

GVHD Prophylaxis

Maris et al (2003)69

MDS: 21 Acute leukemia: 17 Other: 51

53 (5-69)

90% high-risk

NMA FluTBI (2 Gy)

MUD 100%

CsA and MMF

Bertz et al (2003)70

MDS: 3 AML: 15 Other: 1

64 (60-70)

Untreated: 6 pts 1st Relapse: 5 CR1 or CR2: 2 PIF: 5

RIC FluMel and carmustine

MRD = 7 MUD = 12

CsA-based

Wong et al (2003)9

AML:13 MDS: 7 CML: 9

59 (55-69)

AML/MDS: Remission: 20% CML: 1st CP: 11% All others in advanced phase of disease

RIC FluMel (n = 24) BuFlu (n = 5)

MUD 100%

Tacrolimus and mini-MTX

de Lima et al (2004)46

MDS: 26 AML: 68

FAI: 61 (27-74) FluMel: 54 (22-75)

Overall 26% in remission; 74% not in remission Remission: FAI: 44% versus FluMel:16%

RIC FluMel (n = 62) NMA FAI (n = 32)

MRD 54% MUD or mismatched related 46%

Tacrolimus and mini-MTX

Sorror et al (2004)40,a

MDS: 13 Acute leukemia: 12 Other: 35

54 (5-69)

78% high-risk

NMA FluTBI (2Gy)

MUD 100%

CsA and MMF

Martino et al (2005)68

MDS: 20 AML: 31 Other: 11

56 (35-66) Targeted busulfan 59 (22-69) Nontargeted

Early: 51% Advanced: 49%

RIC BuFlu (targeted busulfan versus nontargeted)

MRD (100%)

CsA and MTX

Wallen et al (2005)45

MDS: 35 AML: 6 Other: 11

62.8 (60-68)

AML (CR1 = 1, 1st relapse = 5 pts) MDS (RA = 13, RAEB = 17, RAEBt = 4, CMML = 1)

MA BuCy (67%) CyTBI (21%) BuFlu (10%) Cy (2%)

MRD (n = 48) mismatched related (n = 4)

CsA-based (n = 48) Other: 4

Spyridonidis et al (2005)71

AML: 28 MDS: 6

> 59 Years

Active disease: 91%

RIC Flu, carmustine, Mel, and ATG

MUD 100%

CsA and MMF

Schmid et al (2005)72

AML: 65 MDS: 10

MRD (n = 31) MUD or mismatch related (n = 44)

CsA and MMF

van Besien et al (2005)67

AML: 41 MDS: 11

Oran et al (2007)56

Study

CR1: 8 patients CR2: 8 patients RIC 52.3 (18.5-65.8) 1st or 2nd relapse: 28 patients CyTBI (4 Gy), ATG PIF: 21 patients Prophylactic DLI in 12 patients Untreated: 10 patients 52 (17-71)

CR1: 9 patients CR2: 4 patients AML active disease: 28 patients MDS: 11 patients

RIC FluMel and alemtuzumab

MRD (n = 23) MUD or mismatch related (n = 29)

Tacrolimus

AML: 82 MDS: 30

55 (22-74)

CR: 26.8% Relapsed/ Refractory 38.4% PIF: 28.6%

RIC FluMel ± gemtuzumab

MUD (n = 53) MRD (n = 59)

Tacrolimus and MTX

Majhail et al (2008)58,b

AML: 19 MDS: 10 Other: 12

59 (55-69)

Standard: 28% High: 72%

RIC 2 Gy TBI + Flu/Cy, Flu/Bu or Bu/Cladribine

UCB MRD

CsA and MMF

Uchida et al (2008)59

AML: 28 MDS: 3 Other: 39

61 (55-79)

Standard: 21% High: 79%

RIC 4 Gy TBI + Flu/Mel Flu/Bu

UCB 100%

CsA or Tacrolimus

aResults

of ablative transplants (median age < 50 years) are not summarized here. for UCB only. Abbreviations: AML = acute myelogenous leukemia; ATG = antithymocyte globulin; BuCy = busulfan and cyclophosphamide; BuFlu = busulfan and fludarabine; CML = chronic myelogenous leukemia; CMML = chronic myelomonocytic leukemia; CP = chronic phase; CR1 = first complete remission; CR2 = second complete remission; CsA = cyclosporine; Cy = cyclophosphamide; CyTBI = cyclophosphamide and total-body irradiation; DLI = donor lymphocyte infusion; FAI = fludarabine/cytarabine/idarubicin; FluMel = fludarabine and melphalan; FluTBI = fludarabine and total-body irradiation; MA = myeloablative; MDS = myelodysplastic syndrome; Mel = melphalan; MMF = mycophenolate mofetil; MRD = matched related donor; MTX = methotrexate; MUD = matched unrelated donor; NMA = nonmyeloablative; PIF = primary induction failure; RA = refractory anemia; RAEB = refractory anemia with excess blasts; RAEBt = refractory anemia with excess blasts in transformation; RIC = reduced-intensity conditioning; UCB = umbilical cord blood

bData

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Stefan O. Ciurea et al Table 1B Summary of Studies Reporting Results With Allogeneic Hematopoietic Stem Cell Transplantation for Patients Aged > 50 Years With Acute Myelogenous Leukemia (Continued) Median Follow-up, Months

aGVHD and cGVHD Rates

TRM

PFS/RR

Survival

Maris et al (2003)69

13

Gd II-IV = 52% Gd III-V = 10% cGVHD extensive = 7%

100-Day: 11% 1-year: 16%

1-Year PFS: 38%

1-Year OS: 52%

Bertz et al (2003)70

27.5

Gd II-IV = 59% Gd III-IV = 29% cGVHD = 65%

1-Year: 22%

1-Year: 61%

1-Year: 68%

Wong et al (2003)9

27

Gd II-IV = 41% cGVHD = 63%

1-Year: 55%

1-Year: EFS 37%

1-Year OS: 44%

de Lima et al (2004)46

40

Gd II-IV = 34% Gd III-IV = 16% cGVHD = 34%

100-Day: 21% 3-year: FAI = 15.6% FluMel = 39.2%

3-Year RR: FAI = 53.4% FluMel = 26%

Actuarial 3-year OS: 33%

Sorror et al (2004)40,a

NA

Gd III-IV = 17% cGVHD extensive = 53%

100-Day:12% 1-year: 20%

NA

1-Year OS: 60% (low comorbidity scores) vs. 25% (high comorbidity scores)

Martino et al (2005)68

45

Targeted vs. nontargeted Bu Gd II-IV: 20% vs. 22% cGVHD: 65% vs. 61%

Targeted vs. non targeted Bu 100-day: 5% vs. 3% 2-year: 12% vs. 19%

Targeted vs. nontargeted Bu 2-year: 21% vs. 29% 2-year PFS: 61% vs. 51%

Targeted vs. non targeted 2-year OS: 65% vs. 53%

Wallen et al (2005)45

55

Gd III-IV: 20% cGVHD extensive: 53%

100-day: 27% 3-year: 43%

RR for MDS: 20% AML: 50%

MDS 40% at median of 2.8 years AML: no survivors

Spyridonidis et al (2005)71

30

Gd II-IV: 42% Gd III-IV: 15% cGVHD: 43% (ext 13%)

2-Year: 19.6%

2-Year risk of relapse: 27%

2-Year OS: 63% PFS: 53%

Schmid et al (2005)72

35

Gd II-IV: 49% cGVHD: 45%

MRD: 22.6% MUD or mismatched related: 50%

2-Year LFS: 40%

2-Year OS: 42%

van Besien et al (2005)67

18

Gd II-IV: 33% Gd III-IV: 10% Ext cGVHD: 18%

1-Year: 33%

RR: 27% 1-year PFS: 38%

1-Year OS: 48%

29.4

Gd II-IV: 39% cGVHD: 49%

NRM (patients in CR) day 100: 0 2-year: 20%

Cumulative 2-year RR: 20% (15% pts in CR, 46% not in CR)

2-Year OS: 44% (66% pts in CR, 40% pts with relapse, 23% with circ blasts)

Majhail et al (2008)58,b

27

Gd II-IV: 49% cGVHD: 17%

180-day: 28%

Probability of PFS at 3 years: 34%

3-Year probability of OS: 34%

Uchida et al (2008)59

17

Gd II-IV: 61% Gd III-IV: 43% cGVHD: 40%

NRM 53%

Estimated PFS at 2 years: 23%

2-Year OS: 23%

Study

Oran et al (2007)56

aResults

of ablative transplants (median age < 50 years) are not summarized here. for UCB only. Abbreviations: aGVHD = acute graft-versus-host disease; AML = acute myelogenous leukemia; Bu = busulfan; cGVHD = chronic graft-versus-host disease; CR = complete remission; EFS = event-free survival; ext = extensive; FAI = fludarabine/cytarabine/idarubicin; FluMel = fludarabine and melphalan; Gd = grade; LFS = leukemia-free survival; MDS = myelodysplastic syndrome; MRD = matched related donor; MUD = matched unrelated donor; NA = not available; NRM = nonrelapse mortality; PFS = progression-free survival; RR = relapse rate; TRM = transplantation-related mortality; UCB = umbilical cord blood

bData

Shimoni and collaborators also reported progress in the context of unrelated donor transplantation for patients aged > 55 years using an intravenous busulfan-based regimen. Furthermore, fludarabine and myeloablative doses of intravenous busulfan (0.8 mg/kg for 16 doses) provided better disease control than the same combination given with reduced doses of busulfan (8 doses), without worsening treatment-related mortality.49,50 Supporting evidence for improved disease control with the use of higher dose intensity is available in the ablative and RIC scenarios.51,52 Prospective, randomized support for the choice of a given regimen over other(s) is

not available, however. This therapeutic dilemma is exemplified in a retrospective study conducted at our institution. We compared the outcomes of AML/MDS patients treated with a reduced-intensity regimen consisting of fludarabine and melphalan (FM) versus the nonablative combination of fludarabine, cytarabine, and idarubicin (FAI).51 The more intense regimen, FM, was associated with higher rates of nonrelapse mortality and morbidity, while the nonablative FAI regimen led to poorer disease control and higher relapse rates, despite the higher proportion of lower-risk disease at transplantation in that cohort.51 Disease status and “tempo” have to be taken

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AML, AlloHSCT, and Aging into account: it is possible that patients in first CR are less likely to need higher dose intensity, while those with refractory disease should not receive nonmyeloablative regimens, though this remains to be proven in prospective studies. Commonly used reduced-intensity or nonmyeloablative preparative regimens include combinations of fludarabine with lowdose TBI52; fludarabine with busulfan, as proposed by Slavin et al53; fludarabine with cyclophosphamide54; and fludarabine with melphalan, as reported by Giralt et al.55 Antithymocyte globulin (ATG) or alemtuzumab (Campath®) are frequently added to the conditioning regimen, as a method of in vivo T-cell depletion, most often used for mismatched related or unrelated donor transplantations. Proponents of the use of alemtuzumab highlight the decreased rates of GVHD, while the opponents indicate poor immune recovery, higher rate of mixed chimerism posttransplantation, and increased rates of disease relapse as factors that decrease the enthusiasm for the use of this drug. The influence of disease status at HSCT is represented by our experience with the FM regimen and alloHSCT in 112 patients with AML/MDS (median age, 55 years). With a median follow-up of 29 months, 2-year overall survival was 66%, 40%, and 23% for patients in CR, or with active disease without or with circulating blasts at HSCT, respectively. Disease status was the main determinant of nonrelapse mortality. One hundred–day treatment-related mortality rate was zero versus 32% for patients in CR and for patients with heavily pretreated, relapsed disease, respectively.56 The Seattle group treated AML patients in first CR (median age, 59 years) with a nonmyeloablative low-dose TBI-based regimen and HLA-identical sibling peripheral blood stem cell transplantations. They observed low treatment-related mortality at the expense of a significant relapse rate, leading to a 1-year progression-free survival of 42%.57 Therefore, the preparative regimen of choice remains a matter of institutional and investigator preference. It is unknown whether alkylating agent–containing regimens are better than TBI-based conditioning, as it is unclear whether certain alkylating agents produce better results than others. Given all of these questions, it is recommended that older patients with AML should be treated on clinical trials whenever possible. The Cancer and Leukemia Group B (CALGB) and Blood and Marrow Transplant (BMT) Clinical Trials Network are conducting a single-arm clinical protocol investigating the role of alloHSCT as consolidation for patients with AML aged > 60 years in first remission. Tables 1A and 1B summarizes selected studies that analyzed patients aged > 50 years treated with allogeneic HSCT.

Alternative Donor Transplantation Unrelated umbilical cord blood (UCB) has emerged as a promising source of stem cells for transplantation. Relative ease and speed of procurement and the possibility of using mismatched donors are the major factors that heighten the interest in using UCB. Major obstacles include small stem cell dose that leads to delayed engraftment and slow immunologic recovery after transplantation. Two studies have recently been published indicating the feasibility of this approach to treat patients in the sixth and seventh decade of life.58,59 The University of Minnesota group reported on 43 patients with a median age of 59 years treated with UCB transplantation

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and compared the outcomes of these patients with 47 patients who received a matched related donor (MRD) transplantation. Most patients (67%) had AML/MDS. Three 2-Gy TBI-based RIC regimens were used (combination with fludarabine/cyclophosphamide, fludarabine/busulfan, or busulfan/cladribine). Grafts were 2 UCB units in 88% of the transplantations, which were mismatched at 1 or 2 HLA antigens. Transplantation-related mortality at 180 days was 28%, and the 3-year probability of disease-free survival and overall survival were 34% for recipients of UCB transplantations. Survival was slightly better in the MRD group, but the difference was not statistically significant.58 The only factor influencing survival in this study was the comorbidity index score.58 The cumulative incidence of grade 2-4 acute GVHD was 49%, while Uchida et al reported a 61% GVHD rate.59 This higher incidence of acute GVHD negatively influenced the outcomes in Uchida’s report, which used a higher-intensity preparative regimen without ATG.59 Haploidentical (mismatched, related donor) transplantations also offer the possibility of quick and almost “universal” donor identification. It requires some form of ex vivo or in vivo T-lymphocyte depletion in order to prevent GVHD and is commonly associated with delayed immune recovery and high risk of infections. However, this treatment has been largely restricted to younger patients, though preliminary experience using RIC with in vivo T-cell depletion is promising.60

How Can We Extend Allogeneic Transplantations to a Larger Number of Elderly Patients With Acute Myelogenous Leukemia? The answer to whether we can extend allogeneic transplantation to a larger number of elderly patients with AML is of course multifactorial and complex. The selection process that occurs in this context is illustrated by the following trial performed in our institution. From 2000 to 2003, we evaluated the feasibility of performing an allogeneic RIC HSCT to consolidate first CR in patients aged > 50 years receiving induction chemotherapy for AML or high-risk MDS. Patients were seen in consultation in the hospital during induction chemotherapy by a transplantation physician. The treatment plan was to proceed to transplantation after achievement of first remission should a donor be identified. The CR rate in the cohort of 259 patients was 39% (n = 99), and median age of those achieving remission was 65 years. CR patients included 63 patients with AML and 36 with high-risk MDS. They had a median number of 1 sibling. A transplantation consultation was done in 63% of CR patients, and a donor was identified in 40% of the consulted patients (or 26% of CR patients) while they were in remission. Ultimately, only 14 patients underwent transplantation in first CR after a median of 11 weeks from achieving remission (15% of all patients who entered CR or 56% of those with an identified donor). It is interesting to notice that the proportion of patients with poor-prognosis cytogenetics decreased in the transplantation group, where it was 14%. That proportion was 36% for patients in CR with a donor identified but who did not receive a transplant, 57% in the group without a donor, and 46% in the group that was never consulted. The major reason for not receiving the intended HSCT in first CR was disease relapse, with patient frailty

Stefan O. Ciurea et al Figure 2 Survival of Patients With Acute Myelogenous Leukemia Who Received an Allogeneic Hematopoietic Stem Cell Transplantation From an Unrelated Donor in First Complete Remission

Figure 3 Survival of Patients With Acute Myelogenous Leukemia Who Received an Allogeneic Hematopoietic Stem Cell Transplantation From an Unrelated Donor in Second Complete Remission 100

Cumulative Proportion Surviving, %

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Survival is shown here as a function of recipient age. All transplantations were performed after year 2001 (year in which high-resolution class I HLA typing was prospectively used). Preparative regimens were I.V. busulfan or melphalan based. Donor-recipient pairs were typed with high-resolution HLA typing and were matched for HLA A, B, C; DRB1; and DQB1. Median follow-up is 25 months.

Survival is shown here as a function of recipient age. All transplantations were performed after year 2001. Donor-recipient pairs were typed with high-resolution HLA typing and were matched for HLA A, B, C; DRB1; and DQB1.

as the secondary most important reason. Relapse-free survival of the transplantation patients has not been reached, and it is largely superior to the results of the nontransplantation subgroups, which is presumed to be a consequence of the GVL effect. Therefore, assessment of transplantation efficacy was confounded by the younger age, smaller proportion of high-risk cytogenetics, less comorbidities, lead-time bias, or unknown selection factors. We performed transplantations in only 15% of elderly patients with AML achieving a remission, or 5% of the whole cohort. This study confirmed that disease refractoriness was the major obstacle to taking patients to HSCT, as the majority of the patients never achieved a CR or relapsed before alloHSCT. This also highlights the fact that novel approaches to HSCT for elderly patients with AML are necessary in order to extend the allografting option for this age group.61 This is likely to involve the use of alternative donors, given intrinsic delays associated with unrelated donor bone marrow or peripheral blood stem cell procurement. An interesting untested possibility is the use of “mild” induction therapies with newer, “targeted” medications, buying time for donor procurement and transplantation as soon as possible, not necessarily in CR. It is clear that if alloHSCT is limited to elderly patients in CR, only a very small minority of patients will be eligible. Therefore, treating relapsed and or refractory AML is a key necessity in this field. We are concluding a dose- and schedule-finding study of the hypomethylating agent azacytidine given as maintenance to patients with AML undergoing transplantation with active disease. Eligible patients include those not in first CR. This approach might enable us to capitalize on the high remission rates associated with alloHSCT (which are usually short lived) by treating minimal residual disease. The median age of recipients in the dose-finding study is 60 years, with good tolerance for patients that were in CR 30 days after the transplantation. The dose of 32 mg/m2 given for 5 days will be taken to a randomized, controlled study comparing azacytidine after HSCT maintenance

to standard of care (ie, no AML therapy). Patients aged ≤ 75 years will be eligible. Development of newer and more efficient preparative regimens is likely to follow the incorporation of newer drugs to the existing transplantation “frame.” A good example is clofarabine, an agent with recognized antileukemic efficacy that is under investigation as a replacement for fludarabine in combination with busulfan and is under investigation at the M. D. Anderson Cancer Center and by the University of Michigan group. Patients with AML aged > 65 years in first CR who have a matched donor should undergo transplantation in the context of clinical trials. If one is to extend alloHSCT to older patients, unrelated donors will have to be increasingly used. If available, younger donors are the preferred choice for HSCT62 because aging might affect the homing and engraftment of stem cells.63,64 It is unknown whether a younger unrelated donor is preferable to an elderly sibling. Donor issues are also to be taken into consideration because the donation of bone marrow or peripheral blood is usually better tolerated by younger individuals. Time to engraftment is generally faster and GVHD incidence higher with peripheral blood stem cells. It is unclear whether this source of stem cells is superior to bone marrow in related or unrelated transplantation settings. The determination of the ideal source of hematopoietic stem cells (peripheral blood vs. bone marrow) for unrelated donor transplantation is under investigation in a multicenter BMT Clinical Trials Network. The incidence of GVHD increases with age, though reported rates vary in the published literature. Confounding variables here include donor type and the degree of HLA typing, as well as the regimen intensity. The elderly are more susceptible to GVHDrelated complications, and preventing this complication is a major goal in this context. Donor-recipient allele-level HLA matching is likely to decrease GVHD rates in the realm of unrelated donor HSCT for the elderly, as it has been documented among younger

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AML, AlloHSCT, and Aging patients (Figures 2 and 3). Graft engineering is under intense investigation. Natural killer cells might provide greater GVL effect without GVHD, and enriching the graft with these cells might improve leukemia control. Cytotoxic T-lymphocytes capable of recognizing AML-related antigens may be used with the same purpose, as proposed by Molldrem.65 Alemtuzumab is a humanized immunoglobulin monoclonal antibody against the CD52 antigen that induces profound T-cell depletion, leading to important reduction in acute and chronic GVHD rates. It also induces T-lymphocyte immunity defects that might predispose to infections.66 van Besien et al at the University of Chicago (Tables 1A and 1B) and the group at the King’s College Hospital in London both reported very low rates of acute and chronic GVHD.67 In the British study, 62 patients with AML or MDS received fludarabine, oral busulfan (8 mg/kg), and alemtuzumab 20 mg daily for 5 doses.66 Most recipients of sibling transplantations (67%) and 26% of the recipients of unrelated donor transplantations needed donor lymphocyte infusions to reverse loss of donor chimerism or to treat relapse.68 Cumulative incidence of cytomegalovirus reactivation was 59% for high-risk patients.68 It is unclear, however, whether longer follow-up will show an increased relapse rate with this approach. Similar questions surround the use of ATG in this context. We recommend ATG for unrelated donor transplantations but not for HLA-identical sibling HSCT, as proposed by others.53

Conclusion Allogeneic stem cell transplantation is now feasible in a wide age range that goes up to age 70-75 years for selected individuals. Patients in remission appear to benefit the most, but achievement of CR is a relatively rare event for the elderly AML patient. An inherent selection bias might also exist as more fit elderly patients with AML able to tolerate chemotherapy and with good response to induction therapy are taken to transplantation; however, it is tempting to hypothesize that outcomes are improved with transplantation, and this remains to be definitely proven. Major challenges in the field include transplantation for patients not in CR, and use of alternative donors that will potentially allow quicker transplantations for a larger fraction of those in need of this treatment. The issue of integration of transplantation with newer therapies is largely unsolved, as is the question of how best to incorporate promising anti-AML drugs in the transplantation “package.” GVHD and poor immune recovery remain major causes of transplantation-related mortality and are the subject of multiple ongoing preclinical and clinical studies. Bearing in mind all the controversies that surround the treatment of AML for the elderly, it is clear that age per se is not a contraindication for allogeneic transplantation, and every effort should be made to enroll such patients in prospective clinical trials.

Disclosures The author report no relevant financial conflicts of interest.

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