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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
JAMA. Author manuscript; available in PMC May 2, 2012.
Published in final edited form as:
PMCID: PMC3217787
NIHMSID: NIHMS330607
Long-Term Outcomes Among Older Patients Following Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation for Advanced Hematologic Malignancies
Mohamed L. Sorror, MD, MSC,1,2 Brenda M. Sandmaier, MD,1,2 Barry E. Storer, PhD,3,4 Georg N. Franke, MD,7 Ginna G. Laport, MD,8 Thomas R. Chauncey, MD,1,5,6 Edward Agura, MD,9 Richard T. Maziarz, MD,10,11 Amelia Langston, MD,12,13 Parameswaran Hari, MD,14 Michael A. Pulsipher, MD,15,16 Wolfgang Bethge, MD,17 Firoozeh Sahebi, MD,18 Benedetto Bruno, MD,19 Michael B. Maris, MD,20 Andrew Yeager, MD,21 Finn Bo Petersen, MD,22,23 Lars Vindeløv, MD, DMsc,24 Peter A. McSweeney, MD,20,25 Kai Hübel, MD,26 Marco Mielcarek, MD,1,2 George E. Georges, MD,1,2 Dietger Niederwieser, MD,7 Karl G. Blume, MD,8 David G. Maloney, MD, PhD,1,2 and Rainer Storb, MD1,2
1Transplantation Biology Department, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
2Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA
3Clinical Statistics Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
4Department of Biostatistics, University of Washington School of Public Health, Seattle, WA
5Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
6Marrow Transplant Unit, VA Puget Sound Health Care System, Seattle, WA
7Division of Hematology, Oncology and Hemostaseology, Department of Medicine, University of Leipzig; Leipzig, Germany
8Division of Blood and Marrow Transplantation, Department of Medicine, Stanford School of Medicine, Stanford, CA
9Hematopoietic Stem Cell Program, Baylor University School of Medicine, Dallas, TX
10Hematopoietic Stem Cell Transplant Program & Center for Hematologic Malignancies, OHSU Knight Cancer Institute, Portland, OR
11Stem Cell Transplantation, Division of Hematology and Medical Oncology, Oregon Health & Science University School of Medicine, Portland, OR
12Division of hematology-Oncology, Emory University School of Medicine, Atlanta, GA
13Bone Marrow & Stem Cell Transplant Center Winship Cancer Institute of Emory University, Atlanta, GA
14Division of Hematology and Oncology, Medical College Wisconsin School of Medicine, Milwaukee, WI
15Division of Hematology/Blood and Marrow Transplantation, University of Utah School of Medicine, Salt Lake City, UT
16Pediatric Blood and Marrow Transplant Program, Primary Children’s Medical Center, Huntsman Cancer Institute, Salt Lake City, UT
17University of Tübingen School of Medicine, Tübingen, Germany
18City of Hope School of Medicine, Duarte, California
19University of Torino School of Medicine, Torino, Italy
20Colorado Blood Cancer Institute, Denver, Colorado
21Department of Medicine and Pediatrics, University of Arizona School of Medicine, Tucson, Arizona
22Intermountain Blood and Marrow Transplant/Acute Leukemia Program, Intermountain Health Care, Salt Lake City, UT
23University of Aarhus Medical School, Aarhus, Denmark
24Hematopoietic Cell Transplantation Program, Department of Hematology, The Rigshospitalet, Copenhagen, Denmark
25University of Colorado School of Medicine, Boulder, CO
26Stem Cell Transplant Program, Department I of Internal Medicine, University of Cologne School of Medicine, Cologne, Germany
Correspondence to: Mohamed L. Sorror, M.D. Clinical Research Division (D1-100), Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024, Telephone: 206-667-2765, Fax 206-667-6124, msorror/at/fhcrc.org
Context
A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbidities.
Objective
To describe outcomes of patients ≥ 60 years.
Design, Setting, and Participants
From 1998 to 2008, 372 patients, 60–75 years old were enrolled in prospective clinical HCT trials at 18 collaborating institutions using conditioning with low-dose total body irradiation alone or combined with fludarabine 90 mg/m2 before related (n=184) or unrelated (n=188) donor transplants. Post-grafting immunosuppression included mycophenolate mofetil and a calcineurin inhibitor.
Main Outcome Measures
Overall and progression-free survivals were estimated by Kaplan-Meier method. Cumulative incidence estimates were calculated for acute and chronic GVHD, toxicities, achievement of full donor chimerism, complete remission, relapse, and non-relapse mortality. Hazard ratios (HR) were estimated from Cox regression models.
Results
Overall, 5-year cumulative incidences of non-relapse mortality and relapse were 27% (95% CI, 22%–32%) and 41% (95% CI, 36%–46%), respectively, leading to overall and progression-free 5-year survivals of 35% (95% CI, 30%–40%) and 32% (95% CI, 27%–37%), respectively. These outcomes were not statistically significantly different when stratified by age groups. Furthermore, increasing age was not associated with increases in acute or chronic graft-versus-host disease (GVHD) or organ toxicities. In multivariate models, HCT-CI scores of 1–2 [HR, 1.58 (95% CI,1.08–2.31)] and ≥3 [HR, 1.97 (95% CI,1.38–2.80)] were associated with worse survival compared to HCT-CI score of 0 (overall P = 0.003). Similarly, standard relapse risk [HR, 1.67 (95% CI, 1.10–2.54)] and high relapse risk [HR, 2.22 (95% CI, 1.43–3.43)] were associated with worse survival compared to low relapse risk (overall P = 0.0008).
Conclusion
Among patients aged 60–75 years and treated with nonmyeloablative allogeneic HCT, 5-year overall and progression-free survivals were 35% (95% CI, 30%–40%) and 32% (95% CI, 27%–37%), respectively.
Keywords: Marrow transplantation, hematopoietic cell transplantation, age, comorbidities, toxicities, infections, performance status, graft-versus-host disease, withdrawal of immunosuppression, mortality, survival, comparative outcomes research
Increasing age has been historically implicated in higher mortality after high-dose allogeneic hematopoietic cell transplantation (HCT) for patients with hematologic malignancies.1 These transplants are preceded by intense, cytotoxic conditioning regimens that are aimed at reducing tumor burden. The risk of organ toxicities has limited the use of high-dose regimens to younger patients in good medical condition. Therefore, age cut-offs of 55–60 years have been in place for decades for high-dose HCT. This excluded the vast majority of patients from allogeneic HCT given that median ages of patients at diagnoses of most hematologic malignancies range from 65–70 years.2,3
To circumvent this limitation, a nonmyeloablative conditioning regimen for allogeneic HCT was developed. The regimen relies on graft-versus-tumor (GVT) effects to cure cancer and consists of fludarabine and a low dose of total body irradiation (TBI) before and a course of immunosuppression with mycophenolate mofetil and a calcineurin inhibitor after HCT.4,5 This regimen has allowed extension of allogeneic HCT to a previously unserved population of older or medically infirm patients. Use of this regimen has contributed to improving allogeneic HCT outcomes over the past decade.6 Here, we describe outcomes among 372 patients with advanced hematologic malignancies who were ≥ 60 years old and underwent allogeneic HCT on prospective clinical trials.
Patients
Between March 4th 1998 and December 24th 2008, 372 patients who were 60–75 years old underwent allogeneic HCT for advanced hematologic malignancies after nonmyeloablative conditioning on multi-institutional protocols executed at 18 centers coordinated through the Fred Hutchinson Cancer Research Center (FHCRC; Seattle, WA). The primary differences between protocols were the addition of fludarabine to 2 Gy TBI, the use of HLA-matched related or unrelated or HLA-mismatched grafts, variations in the duration and intensity of post-transplantation immunosuppressive medications, and disease-specific protocols (Supplemental Table 1). These changes were aimed at reducing both the risks of graft-versus-host disease (GVHD) and graft rejection.
All protocols were approved by the Institutional Review Boards (IRB) of the FHCRC and the collaborating sites. All patients signed consent forms approved by the local IRB’s. Inclusion criteria included: (a) diagnoses of hematologic malignancy with disease-specific high-risk features favoring allogeneic HCT; (b) >55–60 years of age; (c) <55–60 years of age but at high risk for NRM due to failed prior high-dose HCT or pre-existing comorbidities; (d) failure of one or more frontline therapies for B-cell malignancies; and (e) morphologic remission (<5% bone marrow blasts) for acute myeloid leukemia (AML) or MDS. Exclusion criteria included: (a) >75 years of age; (b) pregnancy; (c) cardiac ejection fraction of <40% for related recipients and of <35% for unrelated recipients; (d) pulmonary diffusion capacity <35%; (e) decompensated liver disease: fulminant hepatic failure, liver cirrhosis with portal hypertension; (f) Karnofsky performance status <50–<70; and (g) serologic evidence of infection with the human immunodeficiency virus.
HCT
Two hundred fifty-two patients were conditioned with 2 Gy TBI with (n=211) or without (n=40) fludarabine, 30 mg/m2/day on days -4, -3, and -2 before HCT (Supplemental Table 1). Twenty-one patients received 3 Gy or 4 Gy TBI in addition to fludarabine. Postgrafting immunosuppression included mycophenolate mofetil plus a calcineurin inhibitor (cyclosporine or tacrolimus) in different schedules (Supplemental Table 1). Patients and their donors were matched for HLA-A, -B, and -C by at least intermediate resolution DNA typing, and -DRB1 and -DQB1 by high-resolution techniques.7 All but 3 patients, who had marrow grafts, received peripheral blood mononuclear cells.5 Infection prophylaxis and treatment were done according to each institution’s standard practice guidelines.
Definition of Terms and Risk Assessment Instruments
Complete remission (CR) was defined as complete disappearance of disease. Progression was defined as ≥50% increase in disease burden compared to pre-transplant status, while relapse was defined as emergence of minimal residual disease after achievement of complete remission,
Pre-transplant comorbidities were evaluated and scored by a single investigator (MLS) per the HCT-CI(Supplementary Material).8 Physical functions before and after HCT (at last contact) were assessed prospectively by clinicians using the Karnofsky performance status scale (KPS). Relapse-risk scores were classified retrospectively according to the published categorization for nonmyeloablative patients (Supplementary Material).9
GVHD
The peak severity of acute GVHD were graded by protocol PIs.10 Chronic GVHD was diagnosed and staged according to published criteria,11 and was labeled as extensive if treated with systemic steroids in addition to continuation of the study immunosuppressive medications. The time point of 30 days after last use of any immunosuppressive medication was designated as date of resolution of chronic GVHD.
Statistical Analyses
Outcome data were determined as of June 23, 2010. OS and PFS were estimated by the Kaplan-Meier method. Cumulative incidence estimates were calculated for acute and chronic GVHD, graft rejection, toxicity, complete remission, relapse/progression, NRM, and discontinuation of immunosuppression.12 Prevalence of chronic GVHD was estimated by methods previously described.13 Hazard ratios were estimated from Cox regression models. Rate ratios for infection were estimated from Poisson regression models. Deaths were treated as competing events in analyses of graft rejection, GVHD, complete remission, toxicity, discontinuation of immunosuppression, and disease progression. Progression and NRM were the components of PFS and were treated as competing events. The association of age with time-to-event outcomes was based on a Cox regression analysis using age as a continuous variable. Comparisons of infection rates were performed similarly using Poisson regression. Comparison of rates of hospitalization was based on the chi-squared test. Comparison of CD3 and CD34 chimerism was based on the Kruskal-Wallis test. Factors tested in univariate models prior to inclusion in the multivariate model included recipient age, donor age, recipient/donor gender combinations, recipient/donor ABO matching degree, recipient/donor CMV sero-status, donor type, HCT-CI scores,8 pre-transplant KPS percentages, interval between diagnosis and HCT, number of prior regimens, prior radiation treatment, prior HCT, relapse-risk,9 graft CD3 cell dose, graft CD34 cell dose, and dose of TBI. The multivariate models included all factors associated with a given outcome at the 0.10 level of significance. Multivariate p-values for a variable were based on adjustment for all other variables in the model. All p-values were derived from likelihood ratio statistics and were two-sided. Statistical analysis was performed using SAS Version 8 (Sas Institute, Cary, NC). Expected population mortality rates were based on sex-specific 2001 US life table data from the National Center for Health Statistics.
Patient Characteristics
The median age of patients was 64.1 (range, 60.1–75.1) years. Table 1 shows demographic, disease, and transplant characteristics for all patients, as stratified by age groups. Older patients were more frequently transplanted for acute leukemia and myelodysplastic syndromes (MDS)/myeloproliferative diseases (MPD) and less frequently for multiple myeloma (MM)/lymphoma. Older patient age was associated with older donor age, shorter times between diagnosis and HCT, and fewer preceding chemotherapy regimens or prior HCT. Differences between age groups did not reach statistical significance for other variables (Table 1). Median pre-transplant KPS percentage was 90% (50%–100%), while median HCT-CI score was 2 (0–11).
Table 1
Table 1
Patient Characteristics
Overall Outcome Measures
As of June 23, 2010, 133 of the 372 patients were alive with a median follow-up of 55 (range, 12–133) months. By 120 days, cumulative incidences of grades II–IV and grades III–IV acute GVHD were 52% (95% CI, 47%–57%) and 13% (95% CI, 10%–17%), respectively. The cumulative incidence of extensive chronic GVHD at 2 years was 42% (95% CI, 37%–47%). Cumulative incidences of non-relapse mortality (NRM) at 100-days, 1-year, and 5-years post-HCT were 7% (95% CI, 4%–10%), 20% (95% CI, 16%–24%), and 27% (95% CI, 22%–32%), respectively (Figure 1A). Relapse rates at 1-year and 5-years post-HCT were 33% (95% CI, 29%–37%) and 41% (95% CI, 36%–46%), respectively (Figure 2A). Five-year rates of overall (OS, Figure 3A) and progression-free survivals (PFS, Supplementary Figure 1A) were 35% (95% CI, 30%–40%) and 32% (95% CI, 27%–37%), respectively. Among 3-year survivors (n=121), the subsequent 5-year survival was 61% (95% CI, 49%–72%), compared to 88% expected for an age- and gender-matched general population.
Figure 1
Figure 1
(A) Cumulative incidence of non-relapse mortality of 27% among 372 patients aged 60 years or older, who were treated with nonmyeloablative conditioning and HCT. (B) No statistically significant difference (p=0.81, likelihood ratio statistics from Cox (more ...)
Figure 2
Figure 2
(A) Rate of disease progression or relapse of 41% among 372 patients aged 60 years or older, who were treated with nonmyeloablative conditioning and HCT. (B) No statistically significant difference (p=0.38, likelihood ratio statistics from Cox regression (more ...)
Figure 3
Figure 3
(A) Kaplan-Meier estimate of overall survival of 35% among 372 patients aged 60 years or older, who were treated with nonmyeloablative conditioning and HCT. (B) No statistically significant difference (p=0.18, likelihood ratio statistics from Cox regression (more ...)
Overall, disease progression/relapse has been the most common cause of death (n=135). Non-relapse deaths occurred among 104 patients, mainly due to infections, GVHD, and multi-organ failure (Supplemental Table 2). In aggregate, the time point order of causes of death, per median onset, was organ failure followed by GVHD, infections, cerebro-vascular accidents and, finally, second cancers.
Outcome Measures by Age Groups
Cumulative incidences for NRM at 5 years (Figure 1B) were comparable among patients aged 60–64, 65–69, and ≥ 70 years old (27% [95% CI, 21%–33%] vs. 26% [95% CI, 18%–34%] vs. 31% [95% CI, 14%–47%], respectively). The HR for NRM per 5 years of age was 1.04 (95% CI, 0.78–1.38, P=0.78). Likewise, the 5-year rates of relapse (38% [95% CI, 32%–45%] vs. 45% [36%–54%] vs. 42% [26%–59%], respectively) were similar (Figure 2B). The HR for relapse per 5 years of age was 1.19 (95% CI, 0.95–1.49, P=0.15). Complete remission rates at 5 years were 40% (95% CI, 31%–49%), 40% (95% CI, 28%–52%), and 63% (95% CI, 39%–86%), respectively. The HR for remission per 5 years of age was 1.30 (95% CI, 0.96–1.76, P=0.10). Five-year rates of OS were 38% (95% CI, 31%–45%), 33% (95% CI, 24%–41%), and 25% (95% CI, 9%–41%), respectively (Figure 3B). The HR for mortality per 5 years of age was 1.16 (95% CI, 0.97–1.38, P=0.12). The 5-year rates of PFS were 34% (95% CI, 28%–41%), 29% (95% CI, 20%–38%), and 27% (95% CI, 11%–44%), respectively (Supplementary Figure 1B). The HR for PFS per 5 years of age was 1.13 (95% CI, 0.94–1.34, P=0.20).
HCT Complications as Stratified by Age Groups
GVHD
Patients aged 60–64, 65–69, and ≥ 70 years old had comparable incidences of grades II–IV (54% [95% CI, 47%–60%] vs. 50% [95% CI, 41%–59%] vs. 52% [34%–69%], respectively) or grades III–IV (15% [95% CI, 10%–20%] vs. 12% [95% CI, 6%–17%] vs. 9% [95% CI, 1%–17%], respectively) acute GVHD at 120 days. The HR for grade II–IV acute GVHD per 5 years of age was 0.86 (95% CI, 0.70–1.05, P=0.14), and for grade III–IV GVHD was 0.70 (95% CI, 0.46–1.05, P=0.07). Chronic GVHD rates at 2 years were also comparable (42% [95% CI, 36%–49%] vs. 41% [95% CI, 32%–50%] vs. 49% [95% CI, 31%–66%], respectively). The HR for extensive chronic GVHD per 5 years of age was 1.14 (95% CI, 0.91–1.42, P=0.27).
Organ Toxicities
Grades III and IV organ (non-hematologic) toxicities within the first 100 days were comparable among patients aged 60–64, 65–69, and ≥ 70 years old (Grade III: 24% [95% CI, 18%–29%] vs. 30% [95% CI, 22%–39%]vs. 32% [95% CI, 16%–49%], respectively; Grade IV: 12% [95% CI, 8%–17%] vs. 16% [95% CI, 9%–22%] vs. 6% [1%–14%], respectively). The HR for grade III toxicity per 5 years of age was 1.12 (95% CI, 0.84–1.48, P=0.45), and for grade IV toxicity was 1.03 (95% CI, 0.68–1.55, P=0.90).
Infections
Rates of bacterial infection episodes per 100 patients days of at risk within the first 100 days varied among patients aged 60–64, 65–69, and ≥ 70 years old (0.75 [95% CI, 0.63–0.87] vs. 1.12 [95% CI, 0.92–1.32] vs. 0.98 [95% CI, 0.62–1.35], respectively). The rate ratio for bacterial infection per 5 years of age was 1.19 (95% CI, 1.01–1.40, P=0.04). The rates of viral infection episodes (0.67 [95% CI, 0.55–0.78] vs. 0.77 [95% CI, 0.61–0.94] vs. 0.63 [95% CI, 0.34–0.92], respectively) or fungal infection episodes (0.17 [95% CI, 0.11–0.22] vs. 0.18 [95% CI, 0.10–0.26] vs. 0.14 [95% CI, 0.01–0.28], respectively) were similar among the three groups. The rate ratio for viral infection per 5 years of age was 1.00 (95% CI, 0.83–1.22, P=0.96), and for fungal infection was 1.05 (95% CI, 0.71–1.54, P=0.80).
Hospitalization
Overall, 54% (95% CI, 47%–60%), 36% (95% CI, 28%–45%), and 55% (95% CI, 38%–72%) (P=0.007) of patients who were aged 60–64, 65–69, and ≥ 70 years old, respectively, were either never hospitalized or hospitalized only overnight for unrelated donor stem cell infusion within the first 100 days after HCT.
Chimerism and Graft Rejection
Median percentages of CD33 donor chimerism at day 28 were 98% (range, 0%–100%), 99% (range, 0%–100%), and 97% (range, 10%–100%) (P=0.36), respectively, for age groups 60–64 vs. 65–69 vs. ≥ 70 years, and all reached 100% at day 180. Median percentages of CD3 donor chimerism at day 28 were 82% (range, 0%–100%), 84% (range, 0%–100%), and 73% (range, 34%–97%) (P=0.27), respectively, and all reached 99% at day 180. Rates of graft rejection were similar among patients aged 60–64, 65–69, and ≥ 70 years old (4% [95% CI, 1%–7%] vs. 4% [95% CI, 1%–8%] vs. 3% [95% CI, 1%–9%], respectively). The HR for rejection per 5 years of age was 0.96 (95% CI, 0.45–1.03, P=0.91).
Resolution of Chronic GVHD and Duration of Immunosuppressive Therapy, and Last-Contact Physical Condition
Overall, at 5 years after HCT, an estimated 14% of patients (approximately 39% of surviving patients) continued to require immunosuppressive medications, while 21% of patients (61% of surviving patients) had all immunosuppressive medications discontinued, in a median of 30 (5.5–119) months, indicating resolution of chronic GVHD. Among the 158 patients who developed extensive chronic GVHD, the rates of discontinuation of immunosuppressive drugs within 5 years after onset of chronic GVHD among patients aged 60–64, 65–69, and ≥ 70 years old were (43% [95% CI, 29%–54%] vs. 33% [95% CI, 18%–47%] vs. 20% [95% CI, 1%–41%], respectively). The HR for discontinuation of immunosuppression per 5 years of age was 0.80 (95% CI, 0.52–1.22, P=0.28). Among 133 patients alive at last contact, 115 (86%) were assessed by physicians for physical function using KPS with a median of 90% (range, 60–100%) for patients both with or without chronic GVHD.
Associations Between Pretransplant Factors and HCT Outcomes
Multiple risk factors were analyzed for their associations with NRM, relapse, OS, and PFS using univariate analyses. Patient age, patient/donor gender combinations, CD34+ cell dose, CD3+ cell dose, pre-HCT KPS, number of preceding chemotherapy regimens, prior radiation, and TBI dose (2 vs. 3–4 Gy) were not significantly associated with any of the 4 outcomes at the 0.10 level of significance. The remaining factors which were associated with each outcome in univariate analyses at the 0.10 level of significance were entered in multivariate analyses (Table 2). Increasing HCT-CI scores and major ABO-mismatch were associated with higher hazard ratios for NRM, while the relapse-risk score9 was the only factor associated with increased progression/relapse. As a result, the same three factors were independently associated with OS and PFS.
Table 2
Table 2
Cox regression models for assessment of risk factors for NRM, Progression/relapse, OS and PFS among 372 patients 60 years and older who were treated with nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation*.
Overall, patients aged 60–75 years old who had HCT-CI scores of 0 vs. 1–2 vs. ≥ 3 experienced 5-year OS of 48% (95% CI, 37%–60%) vs. 38% (95% CI, 29%–47%) vs. 27% (95% CI, 20%–35%), respectively (P=0.0002, Supplementary Figure 2A). Patients with low vs. standard vs. high relapse risk had 5-year OS of 55% (95% CI, 42%–69%) vs. 35% (95% CI, 28%–42%) vs. 25% (95% CI, 16%–33%), respectively (P=0.0001, Supplementary Figure 2B). Grafts from HLA-matched related, HLA-matched unrelated, and HLA-mismatched donors resulted in 5-year OS of 36% (95% CI, 29%–44%) vs. 37% (95% CI, 29%–46%) vs. 17% (95% CI, 1%–34%), respectively (P=0.22). Patients diagnosed with acute myeloid leukemia (AML), MDS/MPD, and chronic myeloid leukemia (CML) had 5-year OS of 40% (95% CI, 30%–49%) vs. 28% (95% CI, 19%–38%) vs. 31% (95% CI, 9%–53%), respectively (P=0.40, Supplementary Figure 2C), while those diagnosed with lymphoma, chronic lymphocytic leukemia (CLL), and MM had 5-year OS of 53% (95% CI, 38%–68%) vs. 33% (95% CI, 16%–50%) vs. 30% (95% CI, 15%–44%), respectively (P=0.41, Supplementary Figure 2D).
Given that comorbidity and disease risk were the most influential factors for OS, we stratified outcomes of all patients based on these two risk factors (Supplemental Table 3). Patients with low comorbidity burden and low relapse risk had 5-year OS of 69% (95% CI, 44%–95%) compared to 23% (95% CI, 11%–35%) for patients with high comorbidity burden and high relapse-risk.
This study reports on long-term outcomes among 372 patients with advanced hematologic malignancies, who were ≥ 60 years and enrolled in multi-center, prospective clinical trials of allogeneic HCT after a uniform nonmyeloablative conditioning regimen. Regardless of age, 5-year survivals ranged from 23% in patients with high comorbidity scores and high disease-risk to 69% in patients with low comorbidity score and low disease-risk with the majority of patients having discontinued all immunosuppressive medications. While there is much room for improvement, particularly with regards to relapse, these results are encouraging given the poor outcomes with non-transplantation treatments especially for patients with high-risk AML,14 fludarabine-refractory CLL,15 or progressive lymphoma.16 The older population is expanding; demographic changes in the USA suggest that 20% of the population will be ≥ 65 years old by 2030. Further, increases of up to 77% in the number of newly diagnosed hematologic malignancies among the older population are expected to occur in the next 20 years.17 Greater age is also associated with increased medical comorbidities.18,19 Thus, establishing treatment options with curative outcomes and near-normal long-term physical function have become an important future goal for older patients with hematologic malignancies.
Two registry studies reported allogeneic HCT outcomes among older patients with AML or MDS who were given various reduced-intensity regimens. In a study from the European Group of Blood and Marrow Transplantation (EBMT),20 449 patients >60 years old had 4-year NRM of 39% and OS of 27%. In a study from the Center of International Blood and Marrow Transplantation Research (CIBMTR),21 376 patients >60 years had 2-year NRM between 34%–39% and OS of 34%–36% among patients with AML and MDS, respectively. A relatively large group of 154 patients aged >65 years are included in the current study compared to 118 patients in the CIBMTR and an unknown number in the EBMT studies. Our study is distinguished from the two registry studies at least three ways. First, the current study includes consecutive patients entered on prospective, registered clinical trials with a uniform conditioning regimen versus retrospective analyses registry data from patients given multiple regimens. Secondly, we introduce a comorbidity/relapse risk-based stratification model which provides guidance for future patient counseling and enrollment on trials. Finally, we report details on organ toxicities, infections, hospitalization, and the course of chronic GVHD including its resolution among older patients.
Also, while the number of patients is small (n=33), to our knowledge this study is the first to report on allogeneic HCT among patients >70 years, 82% of whom had AML/MDS with otherwise predictably poor outcomes on conventional chemotherapy (predicted 5-year OS is <10%).22 Thus, the 24% 5-year OS is encouraging. In the current study, no differences could be detected in NRM, relapse, or survival when age was tested as categorical or continuous variable. Therefore, severe organ malfunctions but not age should be used as protocol exclusion criterion.
Greater age was associated with increased bacterial infections and subsequently increased rate of hospitalization. This might have been in part due to age-related decline of the host immune system,23 which provides infection control early after HCT while the donor immune system is attempting to establish itself. Also, approximately half of the older patients received grafts from older sibling donors, whose immune system might have similarly regressed. Finally, thymic neo-generation of T-cells remains low for patients ≥ 60 years of age,24 resulting in low circulating naïve T cells required for immune responses.25 However, rates of fungal and viral infections were similar between age groups and, importantly, the increase in bacterial infections with age did not translate into increased NRM, consistent with successful antibiotic intervention policies.
Chronic GVHD is a complication of allogeneic HCT which requires extended immunosuppressive therapy and has associated morbidity, which is particularly concerning for older and medically frail patients. There are no published data on the course of chronic GVHD among older patients, even though they are increasingly important for adequate risk-benefit ratio assessment.26 Our study shows that approximately two-thirds of living patients at 5 years who were affected by chronic GVHD had complete resolution of their symptoms and discontinued immunosuppressive medications after a median of 2.5 years from diagnosis of chronic GVHD. Both the incidence of chronic GVHD and its resolution among older patients were comparable to those among younger patients treated with high-dose HCT.2729 These findings, together with the normal to near-normal performance status of surviving patients, should help allaying reluctance in entering older patients with hematologic cancers on nonmyeloablative HCT protocols. Finally, lack of an HLA-identical sibling should no longer be a limitation given that HLA-matched unrelated grafts give comparable outcomes.
Current efforts are focused on reducing morbidity and mortality rates by addressing the principal problems: acute GVHD and relapse. Chronic GVHD conveys definite, powerful GVT effects,30 while acute GVHD does not appear to have such GVT effects but contributed significantly to mortality.30 Biomarkers for severe acute GVHD might enable prompt and more powerful therapy.31 Also, preliminary retrospective data suggest that grafts from donors who are on statins might not cause grades III–IV acute GVHD, thereby averting their associated mortality.32 Therefore, statins might become part of future GVHD prevention strategies. As for recurrent malignancies, most relapses occur during the first year after transplantation when GVT effects have as yet not been fully developed. These early relapses are being addressed by reducing tumor burden through tandem autologous followed by allogeneic HCT for MM and advanced lymphoma33 or the addition of disease-specific agents. These disease-specific manipulations, while not curative on their own, are meant to help bridge the immuno-compromised post-HCT period until GVT effects develop. Further, minimal residual disease monitoring using multi-parameter flow cytometry and molecular techniques34,35 combined with pre-emptive therapies36 with or without subsequent donor lymphocyte infusion will be useful to avert disease progression.
Hematologic malignancies are mainly diseases of the elderly. For example, while the average general annual incidence of AML is approximately 3.43 per 100,000, it increases progressively with age, to a peak of 55.1 per 100,000 at age ≥ 65.3 Yet, only 12% of patients treated with HCT between years 2004–2008 were >60 years old,37 and only 26% of AML patients who were seen in consultation for HCT ended up receiving it.38 This clearly highlights the reluctance of providers in offering allogeneic HCT to the elderly. To our knowledge, there is no literature on the reasons behind low referral rate of older patients to transplant or how nonmyeloablative HCT outcomes compare to those after conventional therapies. We are initiating multi-center longitudinal observational study designed to follow patients from the time of diagnosis in order to answer both questions.
In summary, treatment of patients aged 60–75 years and diagnosed with advanced hematologic malignancies with nonmyeloablative conditioning followed by allogeneic HCT resulted in 5-year OS and PFS of 35% and 32%, respectively. Moreover, half of those older patients were never hospitalized and two thirds of survivors experienced eventual resolution of their chronic GVHD with return to normal or near-normal physical function. Comorbidities and disease relapse-risks but not increasing age were associated with worse outcomes.
Supplementary Material
Supplementary Data
Acknowledgments
Funding/Support: Our research has been supported by grants from the National Institutes of Health (P01HL036444 [R.S.], P01CA078902 [R.S.], P01CA018029 [R.S.], P30CA015704 [L. Hartwell], and R00HL088021 [M.S.]) and from the Leukemia/Lymphoma Society (7008-08). Both funding organizations had absolutely no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health nor its subsidiary Institutes and Centers.
Role of the Sponsor: The funding source had no role in the design or conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.
 
AuthorLevel of ParticipationContributions made to the intellectual content of the paper as described below*
PartWhole12345678910
SorrorXXXXXXX
SandmaierXXXXXXX
StorerXXXX
FrankeXXXX
LaportXXX
ChaunceyXXXX
AguraXXXX
MaziarzXXXX
LangstonXXXX
HariXXXXX
PulsipherXXXXX
BethgeXXXX
SahebiXXXXX
BrunoXXXX
MarisXXXXXX
YeagerXXXXX
PetersenXXXX
VindelovXXXX
McSweeneyXXXX
HuebelXXXXX
MielcarekXXXXXX
GeorgesXXXXX
NiederwieserXXXX
BlumeXXXXXXX
MaloneyXXXXXX
StorbXXXXXXXX
*Codes for Contributions
  • Conception and design
  • Acquisition of data
  • Analysis and interpretation of data
  • Drafting of the manuscript
  • Critical revision of the manuscript for important intellectual content
  • Statistical analysis
  • Obtaining funding
  • Administrative, technical, or material support
  • Supervision
  • No additional contributions
Footnotes
Author Contributions: Drs Sorror and Storer had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflict of Interests and none were reported.
Additional Contributions: We are grateful to all research nurses and data coordinators for implementation of protocols. We also thank our and administrative staff for their assistance with manuscript preparation. We are grateful to the many physicians, nurses, physician assistants, nurse practitioners, pharmacists, and support staff who cared for our patients, and to the patients who allowed us to care for them and who participated in our ongoing clinical research.
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