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Ablative Allogeneic Hematopoietic Cell Transplantation in Adults 60 Years of Age and Older
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     the Clinical Research Division, Fred Hutchinson Cancer Research Center, and the Departments of Medicine, Division of Medical Oncology, and Biostatistics, University of Washington, Seattle, WA

    ABSTRACT

    PURPOSE: To evaluate outcomes of ablative allogeneic hematopoietic cell transplantation (HCT) in older patients with hematologic malignancies.

    PATIENTS AND METHODS: We treated 52 patients from 1979 to 2002 with a median age of 62.8 years (range, 60.1 to 67.8 years) using ablative preparative regimens followed by allogeneic HCT from sibling donors. Diagnoses included myelodysplastic syndrome (MDS; n = 35), chronic myeloid leukemia (CML; n = 8), acute myeloid leukemia (AML; n = 6), and other (n = 3). Conditioning regimens included cyclophosphamide (CY) and busulfan (BU) (67%), total-body irradiation and CY (21%), BU-fludarabine (10%), and CY (2%).

    RESULTS: Eighteen (35%) of 52 patients are alive at a median of 4.6 years (range, 0.8 to 9.1 years) after transplantation. Median overall survival (OS) and progression-free survival were 300 and 218 days, respectively. Three-year OS and relapse rates are estimated to be 34% and 24%, respectively. Nonrelapse mortality (NRM) rates at 100 days and 3 years are estimated to be 27% and 43%, respectively. Grade 3 to 4 acute graft-versus-host disease (GVHD) occurred in 20% of patients, and chronic extensive GVHD was described in 53% of patients. Fourteen (40%) of 35 patients with MDS are alive at a median of 2.8 years (range, 0.8 to 8.2 years). Four of six patients with CML in chronic or accelerated phase are alive at a median of 6.9 years (range, 4.1 to 9.1 years) after transplantation. None of the patients with AML, CML in blast crisis, or other diagnoses have survived. Patients who underwent transplantation after 1993 had improved survival.

    CONCLUSION: These data suggest that allogeneic HCT is feasible in selected patients 60 years of age, although novel methods to reduce NRM while maintaining efficacy are needed.

    INTRODUCTION

    Allogeneic hematopoietic cell transplantation (HCT) offers the only curative potential for many patients with hematologic malignancies. However, older adults are often denied this option because of concerns regarding the toxicities of myeloablative regimens. Increasing age has been implicated as a risk factor for transplantation-related mortality, and complications, such as graft-versus-host disease (GVHD), have, in effect, limited this therapy to patients under 50 to 60 years of age.1-3 However, such an approach would exclude most patients with chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), myeloproliferative syndromes, and non-Hodgkin's lymphoma (NHL) from this potentially curative therapy because the median age for these diseases is in the seventh decade of life.4 This age restriction will be even more relevant as the proportion of people who are 65 years of age and older grows to an estimated 21% of the total US population by 2030.5

    Despite the hypothesized concern, information is scarce regarding the safety and efficacy of conventional transplantation in patients over 60 years of age. This study addresses this issue by describing our experience in 52 patients over 60 years of age who underwent myeloablative conditioning followed by allogeneic transplantation with related donor HCT, representing the largest reported series in this population.

    PATIENTS AND METHODS

    Patients and Institutional Approval

    All patients who had reached their 60th birthday by the time they received allogeneic HCT were identified from the Fred Hutchinson Cancer Research Center (Seattle, WA) computerized database. Clinical and research records of the identified patients were reviewed from transplantation dated from April 2, 1979 through August 30, 2002. All patients provided informed consent for treatment on transplantation protocols approved by the appropriate institutional review boards. In addition, separate institutional approval was obtained to retrospectively gather data from patient records and databases. Baseline patient characteristics are listed in Table 1. Fifty-two patients had reached the age of 60 years before undergoing allogeneic HCT after a myeloablative conditioning regimen at our center between 1979 and 2002. Time of transplantation was divided into three eras as the standard of care evolved. The first six patients underwent transplantation from 1979 to 1991, before the advent of routine use of both ganciclovir and fluconazole. The next 22 patients underwent transplantation between 1993 and 1997. Only four of these 22 patients received stem cells from granulocyte colony-stimulating factor–mobilized peripheral blood (PBSC); the rest of the patients received stem cells from bone marrow sources. The most recent cohort of 24 patients who underwent transplantation from 1998 to 2002 received primarily PBSC as a source of stem cells (22 of 24 patients).

    Study Variables

    The specific baseline variables evaluated included year of transplantation, diagnosis, previous chemotherapy, sex, conditioning regimen, international prognostic scoring system6 (IPSS) score, recipient cytomegalovirus (CMV) serostatus, and source of stem cells. Outcome variables included overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), cause of death, engraftment times, and acute and chronic GVHD.

    Definition of End Points

    OS and PFS were computed from the date of transplantation. NRM was defined as death in the absence of disease progression. Deaths occurring after disease progression were categorized as relapse regardless of the remote cause of death. Infection was considered the cause of death when bacterial, viral, or fungal infection was determined to be the proximate cause of death in patients who had not relapsed. Deaths from direct hepatic and pulmonary injury were only attributed to their respective organ systems if there was no evidence of infection by bronchoalveolar lavage, biopsy, or autopsy. All cases of bronchiolotis-obliterans with organizing pneumonia were confirmed by tissue analysis. Patients underwent routine bone marrow surveillance at day 28, 84, and 365 after transplantation or if clinically indicated. Relapse for AML, CML, or MDS was determined by flow cytometric, morphologic, or cytogenetic evidence of malignant or dysplastic cells with clonal markers similar to those observed before transplantation. Relapse for NHL was defined as progressive adenopathy or bone marrow involvement. An IPSS score was generated retrospectively for all patients with MDS based on the percentage of blasts, cytogenetic abnormalities, and number of hematopoietic lines affected at the time of transplantation.6 Acute and chronic GVHD were defined and graded by standard criteria.7

    Statistical Methods

    Kaplan-Meier estimates were used to summarize the probability of OS and PFS.8 The probabilities of GVHD, relapse, and NRM were summarized using cumulative incidence estimates.9 Death without GVHD and death without relapse were considered competing risks for the end points of GVHD and relapse, respectively, and relapse was considered a competing risk for NRM. Cox regression models were fit to assess the association of various pretransplantation factors with the hazard of overall mortality. The Wald test was used to estimate two-sided P values from regression models, and no adjustments were made for multiple comparisons. The data analyzed were current through August 15, 2003.

    Conditioning Regimens

    Thirty-five patients were conditioned with 16 consecutive doses of busulfan (BU) at 1 mg/kg every 6 hours for 4 days followed by a total of 120 mg/kg of cyclophosphamide (CY; 60 mg/kg for 2 days). Twenty-five of the patients conditioned with BU-CY received BU adjusted for targeted steady-state plasma levels of 600 to 900 ng/mL. Eleven patients underwent total-body irradiation (three patients with liver and lung shielding) for total doses of 10 to 12 Gy, followed by 120 mg/kg of CY. Five patients were administered fludarabine 120 mg/m2 (30 mg/m2 for 4 days) with BU at the previously mentioned doses targeted to 800 to 900 ng/mL. One patient received exclusively CY at 200 mg/kg. Phenytoin was administered to all patients who received BU.

    Hematopoietic Progenitor Cell Source

    All patients received HCT from related donors. Forty-eight of the patients received stem cells matched for HLA-A, HLA-B, and HLA-DR loci; three patients received cells mismatched at a single locus, and one patient received a dual antigen/allele mismatched transplantation. There were no syngeneic donors. Hematopoietic cells were derived from bone marrow in 26 patients and peripheral blood mobilized with granulocyte colony-stimulating factor (PBSC) in the remaining 26 patients. Of the latter, five patients from the PBSC group underwent further Baxter Isolex column (Baxter, Munich, Germany) enrichment for CD34+ cells.10

    GVHD Prophylaxis and Therapy

    Prophylaxis for acute GVHD consisted of cyclosporine (CSA) and methotrexate for 42 patients. CSA was administered at 3 to 5 mg/kg/d intravenously, transitioning to an oral regimen of 12.5 mg/kg/d in divided doses when tolerable, and tapering beginning at day 50 with discontinuation at day 180 when possible (in the absence of GVHD). Methotrexate was dosed intravenously at 10 to 15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11. Three other patients received CSA as described previously in combination with mycophenolate mofetil at 45 mg/kg/d intravenously in three divided doses and converted to an equivalent oral formulation after day 27. The first two patients (received transplantation in 1979 and 1981) received methotrexate exclusively on days 1, 3, 6, and 11 in doses described earlier, and a third patient received methotrexate on these days and weekly thereafter until day 90. Three more patients were intended to receive CSA and methotrexate, but because of liver function abnormalities, they received prophylaxis with CSA alone. Finally, one patient received tacrolimus in combination with methotrexate. Acute GVHD was treated with methylprednisolone, antithymocyte globulin, tacrolimus, CSA, mycophenolate mofetil, or oral beclomethasone per specific protocol or at the discretion of the attending physician. Conditioning regimens and GVHD prophylaxis are listed in Table 2.

    Supportive Care

    Prophylactic antibiotics, including fluconazole and acyclovir, were used routinely after 1991 (excludes the four patients enrolled before 1991). Patients who underwent transplantation after 1992 received additional standard supportive care, including ganciclovir or foscarnet, for any sign of CMV reactivation. All CMV-negative patients received CMV-negative or filtered blood products. Pneumocystis carinii prophylaxis included trimethoprim-sulfamethoxazole as first-line therapy or dapsone in sulfa-intolerant patients.

    RESULTS

    Engraftment

    Three patients died on days 11, 14, and 24, with no signs of engraftment by the day of death. Three other patients experienced delayed neutrophil engraftment (on days 30, 30, and 31). As presented in Table 3, the median time to reach a neutrophil count of 0.5 x 109/L for at least 2 consecutive days was 22 days (range, 17 to 31 days) for bone marrow allografts versus 17 days (range, 13 to 30 days) for PBSC grafts. Platelet recovery, defined as the time to recover a platelet count greater than 50 x 109/L for 2 consecutive days, occurred at a median of 28 days (range, 17 to 114 days) for marrow grafts and 16 days (range, 10 days to platelet transfusion dependent) for PBSC grafts.

    GVHD

    As presented in Table 4, 50 patients (96%) were assessable for acute GVHD. Thirty-six (72%) of these 50 patients developed acute GVHD of grade 2 or greater, including 10 patients (20%) who developed grades 3 or 4 acute GVHD. Among the 36 patients who survived past day 100, limited chronic GVHD was observed in 11 patients (31%), and 19 patients (53%) experienced extensive chronic GVHD requiring immunosuppressive therapy.

    Disease Progression

    Twelve patients (23%) showed progression of the underlying disease at a median of 141 days (range, 28 to 718 days) after transplantation, and 11 of these patients died of malignancy. One patient with refractory anemia with excess blasts in transformation was induced into a remission with a donor lymphocyte infusion after relapsing at day 658 and is surviving without disease recurrence at 2,718 days. The estimated probability of disease progression was 24% at 3 years. Relapse occurred in three (50%) of six AML patients, seven (20%) of 35 MDS patients, one (13%) of eight CML patients, and in the single NHL patient. The patient who relapsed with CML was in blast crisis at the time of transplantation.

    OS

    Eighteen of 52 patients are surviving at the time of analysis at a median of 4.6 years (range, 0.8 to 9.1 years) after transplantation. The Kaplan-Meier estimates of OS and PFS at 3 years were 34% and 35%, respectively (Fig 1). Kaplan-Meier curves for OS and PFS were similar because only one patient who relapsed has survived. The median OS time was 300 days (range, 0.8 to 9.1 years), and the median PFS time was 218 days. As shown in Table 5, 14 of the 35 patients with MDS were alive at 0.8 to 8.2 years, with an estimated 3-year survival probability of 36%. Four of six patients with CML who underwent transplantation in chronic or accelerated phase have survived. All other patients died, including six patients with AML (74 to 285 days after transplantation), two patients with CML in blast phase (days 24 and 165), two patients with agnogenic metaplasia with myelofibrosis (AMM) (days 107 and 425), and one patient with NHL (day 115). Comparative survival curves between patients with MDS or less advanced CML and other diagnoses are depicted in Figure 2.

    Causes of Death

    As shown in Table 6, 34 patients died; 11 died with disease progression, and 23 died from nonrelapse causes. Of the nonrelapse deaths, 12 were caused by infection (five fungal, two viral, and five bacterial infections), six were caused by hepatic toxicity (four from veno-occlusive disease and two from GVHD), four were caused by pulmonary toxicity (all related to bronchiolotis-obliterans with organizing pneumonia), and one was caused by gastrointestinal hemorrhage. Six patients died as a direct result of complications of GVHD. NRM rate at day 100 was estimated to be 27%, with a 3-year NRM rate estimated at 43% (Fig 3). To estimate the NRM of ablative preparations in patients of this age group absent of any influence of GVHD, we also analyzed the outcome of 14 patients more than 60 years of age receiving syngeneic transplantations for hematologic malignancies. NRM rates at day 100 and 1 year were estimated at 37%, which is not statistically different from the allogeneic group (data not shown).

    Factors Correlating With OS

    Table 7 lists the results from univariate analyses of the association of various baseline factors with the hazard of overall mortality. Two variables, the year of transplantation and diagnosis, demonstrate statistically significant associations with mortality. Each of the six patients who underwent transplantation between 1979 and 1991 has died (on days 23, 41, 60, 115, 126, and 291). Four of these patients underwent transplantation for MDS (two with RA and two with RAEB), one underwent transplantation for NHL, and one underwent transplantation for AML in first relapse.

    Patients who underwent transplantation for CML in chronic or accelerated phase or MDS fared much better than patients who underwent transplantation for other diagnoses. The hazard of mortality among patients with other diagnoses was 2.82 times that among patients with MDS or less-advanced CML. Source of stem cells was suggestively associated with mortality (hazard ratio = 1.70 for bone marrow v PBSC; P = .13), but after restricting analysis to the patients who underwent transplantation during the 1993 to 2002 timeframe (fluconazole and ganciclovir era), this association was less prominent (hazard ratio = 1.34; P = .44). No other factors were statistically significantly or suggestively associated with OS, either among all patients or among those who underwent transplantation in 1993 or later. When analyses were restricted to patients who underwent transplantation for MDS during the modern era from 1993 or later, no factors were statistically significantly associated with outcome, although some were suggestive (Table 7). In particular, patients who received bone marrow as a source of stem cells had a higher hazard of mortality than patients who received PBSC (hazard ratio = 2.24; P = .10), and patients with a higher IPSS had an increased hazard of mortality (P = .16 when IPSS was treated as a continuous linear variable). There was also no statistically significant superior conditioning regimen in terms of NRM (Table 8) or OS (Table 7). Five patients underwent T-cell depletion through CD34 selection. These five patients offer no suggestion that outcomes are different from grafts that are non–T-cell depleted. Three (60%) of five patients undergoing CD34 selection died compared with 66% of T-cell–replete patients. Engraftment times and GVHD also did not differ (data not shown).

    DISCUSSION

    Myeloablative allogeneic HCT has traditionally been the only curative treatment for many patients with hematologic malignancies, although there have been few investigations assessing whether this treatment can be applied safely to a population 60 years of age. Our retrospective analysis suggests that this approach offers the possibility of long-term disease-free survival among selected patients in this age group.

    In this and other retrospective analyses, however, nonrelapse morbidity and mortality were considerable. Studies of elderly cohorts have generally been limited to patients 40 to 59 years of age. de la Camara et al11 described favorable outcomes in 32 patients 50 to 59 years of age, with an impressive OS rate of 51% and an NRM rate of 22% at 3 years. However, half of this cohort had CML, a population that historically has fared well and that also fared well in our study. Du et al12 described an additional 59 patients aged 50 to 59 years and demonstrated an OS rate of 48% at 2 years and an NRM rate of 36% at 1 year. Most, but not all, series suggest that age is not a significant factor for morbidity or mortality, but most of those studies included only patients less than 60 years of age.3,11-15 Studies in patients aged 50 to 59 years undergoing conventional allogeneic transplantation found no significant differences in GVHD, relapse, or survival between this group and younger patients.3,11,12,14 In contrast, a prospective study of 145 patients in Spain, who were treated with a reduced-intensity conditioning (RIC) regimen followed by transplantation from HLA-identical related donors, suggests that age more than 60 years is a risk factor for NRM and survival.15

    Several recent series have been dedicated to patients in their seventh decade. Bertz et al16 described 19 patients with active or poor prognosis myeloid malignancies (median age, 64 years) treated with RIC regimen of high-dose fludarabine, carmustine, and melphalan followed by HCT from unrelated or related donors. One-year survival and NRM rates were 68% and 22%, respectively, with a median follow-up of 2.3 years. Shapira et al17 studied 17 elderly patients (median age, 62.5 years) diagnosed primarily with AML and conditioned with a fludarabine-BU–based RIC regimen. They reported NRM and survival rates of 33% and 29%, respectively, at a median of 11 months of follow-up, which are encouraging results in this high-risk population.

    In our study, survival favored patients who underwent transplantation for a diagnosis of MDS or CML in chronic or accelerated phase. None of the 11 patients diagnosed with AML, CML in blast phase, AMM, or NHL have survived. Ten of these 11 patients underwent transplantation either in leukemic relapse (n = 7) or after prolonged periods of pancytopenia (n = 3). Seven patients died of NRM, and four patients died from progressive disease. It is unlikely that these patients would have been candidates for other less intensive alternatives, such as nonmyeloablative transplantation, because of active leukemia or lack of known efficacy (as in the case of AMM). In contrast, four of six patients who underwent transplantation for CML in chronic or accelerated phase have survived, with follow-up ranging from 4.1 to 9.1 years after transplantation. These results are similar to the results in patients with CML who are 50 to 59 years of age.11,18 Our center reported results in 33 patients with CML who were aged 50 to 59 years (10 patients between 56 and 60 years), with an OS rate of 80% at 3 years.18 Such patients may fare better because of less prior treatment-related immunosuppression and organ toxicity as well increased sensitivity of the disease to the conditioning regimen or a graft-versus-leukemia effect.

    Among patients with MDS, 14 of 35 patients are currently surviving at 0.8 to 8.2 years after transplantation, for a 3-year OS estimate of 36%. Although there was no statistically significant association between survival and French-American-British classification or IPSS, the statistical power to detect such a difference was limited by the small number of events. These results are comparable with another study of conventional transplantations for MDS involving 50 younger patients with MDS (median age, 58.8 years). Their estimated survival rate at 3 years was 46%, with a 2-year NRM rate of 39%.19

    No patients who underwent transplantation in the earliest time period (1979 to 1991) survived past 1 year. Subsequent patients, who underwent transplantation in the "modern" post-1992 era, may have had a survival advantage related to improvements in supportive care, including routine use of antifungal and antiviral agents. In 1998, PBSC became the dominant source of stem cells. Although there were no statistically appreciable differences in survival between the 1993 to 1997 and 1998 to 2002 eras, there is a suggestion that PBSC may be superior to bone marrow for the MDS subset of patients who underwent transplantation after 1992. PBSCs are being used increasingly for a number of reasons, including ease of harvest, faster engraftment times, higher T-cell donor chimerism, potentially greater graft-versus-tumor effect, and improved survival.20-23

    Our data suggest that conventional allogeneic HCT in patients greater than 60 years of age carries significant risks of morbidity and mortality yet offers curative potential for a clinically significant subset of patients with favorable-risk diseases (less advanced CML and MDS). Although ablative allogeneic HCT should not necessarily be withheld based solely on age, novel methods to reduce treatment-related mortality are urgently needed. The advent of nonmyeloablative regimens is an exciting option for patients who are not deemed conventional transplantation candidates. A recent comparison of NRM and toxicities of nonmyeloablative HCT (median age, 54 years) versus an ablative approach (median age, 48 years) showed reduced 1-year NRM rates (16% v 30%, respectively).24 However, longer follow-up is needed to determine the OS and PFS of patients participating in nonablative regimens in various disease settings. Although it may be feasible to treat patients with minimal disease burden with a nonmyeloablative preparative regimen, patients with active, rapidly progressive disease or significant tumor burden likely need a more intensive approach. For example, Maris et al23 observed poor PFS for patients with hematologic malignancies with greater than 5% blasts in the marrow when treated with a nonmyeloablative regimen. Such patients are currently excluded from most nonmyeloablative regimens and require prior successful cytoreductive therapy or traditional ablative approaches. Studies using radiolabeled monoclonal antibodies to provide an enhanced antileukemia or antilymphoma effect while minimizing toxicity to normal organs are also being evaluated in this challenging patient group.25 Until transplantation conditioning regimens are further optimized, conventional myeloablative approaches remain a viable option for selected older patients with hematopoietic malignancies.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    NOTES

    Supported by A Specialized Center for Research Grant from the Leukemia and Lymphoma Society (grant No. 7040-03); grant Nos. NIH PO1 CA1802, CA15704, CA78902, and HL 36444 from the National Institutes of Health; The Veteran's Administration PRIME program National Institutes of Health/National Cancer Institute Training grant No. T32 CA009515-20; The Westlund Foundation; and a gift from Frank and Betty Vandermeer.

    Authors' disclosures of potential conflicts of interest are found at the end of this article.

    REFERENCES

    Sutton L, Chastag C, Ribausd P, et al: Factors influencing outcome in de novo myelodysplastic syndromes treated by allogeneic bone marrow transplantation: A long-term study of 71 patients—Societe Francaise de Greffe de Moelle. Blood 88:358-365, 1996

    Zikos P, Van Lint MT, Franssoni F, et al: Low transplant mortality in allogeneic bone marrow transplantation for acute myeloid leukemia: A randomized study of low-dose cyclosporin versus low-dose cyclosporin and low-dose methotrexate. Blood 91:3503-3508, 1998

    Cahn JY, Labopin M, Schattenerg A, et al: Allogeneic bone marrow transplantation for acute leukemia in patients over the age of 40 years: Acute Leukemia Working Party of the European Group for Bone Marrow Transplantation (EBMT). Leukemia 11:416-419, 1997

    Molina AJ, Storb RF: Hematopoietic stem cell transplantation in older adults, in Rowe JM, Lazarus HM, Carella AM (eds): Handbook of Bone Marrow Transplantation. London, United Kingdom, Martin Dunitz Ltd, 2000, pp 111-137

    Frank-Stromborg M: Changing demographics in the United States: Implications for health professionals. Cancer 67:S1772-S1778, 1991 (suppl 6)

    Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079-2088, 1997

    Sullivan KM: Graft-versus-host-disease, in Tomas ED, Blume KG, Foman SJ (eds): Hematopoietic Cell Transplantation (ed 4). Boston, MA, Blackwell Science, 1999, pp 515-536

    Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958

    Gooley TA, Leisenring W, Crowley J, et al: Estimation of failure probabilities in the presence of competing risks: New representations of old estimators. Stat Med 18:695-706, 1999

    Rowley SD, Loken M, Radich J, et al: Isolation of CD34+ cells from blood stem cell components using the Baxter Isolex system. Bone Marrow Transplant 21:1253-1262, 1998

    de la Camara R, Alonso A, Steegmann J, et al: Allogeneic hematopoietic stem cell transplantation in patients 50 years of age and older. Haematologica 87:965-972, 2002

    Du W, Dansey R, Abella EM, et al: Successful allogeneic bone marrow transplantation in selected patients over 50 years of age: A single institution's experience. Bone Marrow Transplant 21:1043-1047, 1998

    Ringden O, Horowitz MM, Gale R, et al: Outcome after allogeneic bone marrow transplant for leukemia in older adults. JAMA 270:57-60, 1993

    Rapaport AP, Dipersio JF, Martin A, et al: Patients > or = age 40 years undergoing autologous or allogeneic BMT have regimen-related mortality rates and event-free survivals comparable to patients < age 40 years. Bone Marrow Transplant 15:523-530, 1995

    Gomez-Nunez M, Martino R, Caballero MD, et al: Elderly age and prior autologous transplantation have a deleterious effect on survival following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: Results from the Spanish multicenter prospective trial. Bone Marrow Transplant 33:477-482, 2004

    Bertz H, Potthoff K, Finke J: Allogeneic stem-cell transplantation from related and unrelated donors in older patients with myeloid leukemia. J Clin Oncol 21:1480-1484, 2003

    Shapira MY, Resnick IB, Bitan M, et al: Low transplant-related mortality with allogeneic stem cell transplantation in elderly patients. Bone Marrow Transplant 34:155-159, 2004

    Clift RA, Appelbaum FR, Thomas ED: Treatment of chronic myeloid leukemia by marrow transplantation. Blood 82:1954-1956, 1993

    Deeg HJ, Shulman HM, Anderson JE, et al: Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood 95:1188-1194, 2000

    Bensinger WI, Martin PJ, Storer B, et al: Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 344:175-181, 2001

    Couban S, Simpson DR, Barnett MJ, et al: A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood 100:1525-1531, 2002

    Cutler C, Giri S, Jeyapalan S, et al: Acute and chronic graft-versus host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: A meta-analysis. J Clin Oncol 19:3685-3691, 2001

    Maris M, Niederwieser D, Sandmaier BM, et al: HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 102:2021-2030, 2003

    Diaconescu R, Flowers CR, Storer B, et al: Morbidity and mortality with nonmyeloablative compared to myeloablative conditioning before hematopoietic cell transplantation from HLA matched related donors. Blood 104:1550-1558, 2004

    Pagel J, Matthews D, Appelbaum F, et al: The use of radioimmunoconjugates in stem cell transplantation. Bone Marrow Transplant 29:807-816, 2002(Herschel Wallen, Theodore)