Biology of Blood and Marrow Transplantation 13:454-462 (2007) 䊚 2007 American Society for Blood and Marrow Transplantation 1083-8791/07/1304-0001$32.00/0 doi:10.1016/j.bbmt.2006.11.024
Allogeneic Hematopoietic Stem Cell Transplantation for the Treatment of High-Risk Acute Myelogenous Leukemia and Myelodysplastic Syndrome Using Reduced-Intensity Conditioning with Fludarabine and Melphalan Betul Oran, Sergio Giralt, Rima Saliba, Chitra Hosing, Uday Popat, Issa Khouri, Daniel Couriel, Muzaffar Qazilbash, Paolo Anderlini, Partow Kebriaei, Shubhra Ghosh, Antonio Carrasco-Yalan, Ernesto de Meis, Athanasios Anagnostopoulos, Michele Donato, Richard E. Champlin, and Marcos de Lima M.D. Anderson Cancer Center, Houston, Texas Correspondence and reprint requests: Marcos de Lima, MD, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 423, Houston, TX 77030-4009 (e-mail:
[email protected]). Received September 20, 2006; accepted November 27, 2006
ABSTRACT Reduced-intensity conditioning has extended the use of allogeneic hematopoietic stem cell transplantation (HSCT) to patients otherwise not eligible for this treatment due to older age or frailty. One hundred twelve acute myelogenous leukemia/myelodysplastic syndromes patients received fludarabine and melphalan (FM) conditioning with allogeneic HSCT. Most patients (73%) were not in remission. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate. Median age was 55 years (range, 22-74). Donors were related (53%) and unrelated (47%). Median follow-up of surviving patients (n ⴝ 43) was 29.4 months (range, 13.1-87.7). The complete remission (CR) rate was 82%. Estimates of 2-year survival were 66%, 40%, and 23% for patients in CR, with active disease without and with circulating blasts at HSCT, respectively. In multivariate analysis, survival was negatively influenced by active disease at HSCT and development of grade II-IV acute GVHD. Presence of circulating blasts at HSCT negatively influenced freedom from disease progression. Incidence of nonrelapse mortality (NRM) was significantly higher for patients with active disease, but was not influenced by patient age. Patients in CR had a day-100 and 2-year NRM of 0% and 20%, respectively. Use of unrelated donors increased the risk of NRM only among patients with active disease. FM and HSCT elicited long-term disease control in a significant fraction of this high-risk cohort. © 2007 American Society for Blood and Marrow Transplantation
KEY WORDS Leukemia
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Myelodysplastic syndrome
INTRODUCTION Chemotherapy- or radiation-based preparative regimens used prior to allogeneic hematopoietic stem cell transplantation (HSCT) deliver different degrees of direct antileukemic activity and host immunosuppression. The graft provides an immune-mediated graft-versus-leukemia (GVL) effect. Use of myeloablative conditioning regimens has traditionally been limited to younger patients without major comorbidities, given the high rates of treatment-related morbidity and mortality. In addition, ablative regimens are 454
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Transplant
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Aging
associated with a relatively high rate of graft-versushost disease (GVHD), a complication that is to some extent precipitated by toxicity, inflammation, and organ damage inflicted by the chemo or radiation therapy [1,2]. Acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) are diseases of the elderly, with the median age at diagnosis in the 7th decade of life. The age-specific incidence rate per 100,000 goes from 1.8 to 16.3, for subjects under and above age 65, respectively. Unfortunately, results of chemotherapy are dramatically worse in the elderly,
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compared to younger patients. Five-year survival rates are typically 15%-20% for patients older than 55 years [3,4]. Aging is associated with multiple biologic changes that decrease the tolerance to chemotherapy leading to high rates of toxicity. Furthermore, myeloid leukemias in the elderly are morel likely to have unfavorable cytogenetic and molecular abnormalities, and are intrinsically less sensitive to current available therapies [3-5]. Allogeneic transplantation offers higher cure rates for AML and MDS, but the applicability of the procedure to the majority of patients in need is severely limited by high rates of toxicity. Over the last 10 years, the development of reduced intensity regimens has allowed extending the use of allogeneic transplantation to older and frailer patients not considered eligible for ablative conditioning. Given the lower cytoreduction produced by a reduced intensity regimen, this strategy relies on the GVL effect to eradicate the malignancy [6,7]. Furthermore, hematologic malignancies have different sensitivities to GVL effects, and AML and MDS are considered to be of intermediate sensitivity [8,9]. Therefore, some degree of cytoreduction is an important part of treatment of these diseases. We previously reported that increasing myelosuppressive intensity of nonablative regimens improves leukemia control in a select population of patients [10]. Our group has investigated the use of the combination of melphalan (M) and the purine analog fludarabine (F) for the treatment of AML and high-risk MDS over the last decade. The rationale for the drug association relies on F-mediated inhibition of DNA repair, triggered by exposure to the alkylating agent. In addition, the purine analog is a potent immunosupressive drug [11]. Here, we report long-term results of the reduced intensity regimen FM followed by allogeneic HSCT for treatment of AML.
PATIENTS AND METHODS Eligibility Criteria
Patients with AML or high-risk MDS treated with the combination of F and M 100, 140, or 180 mg/m2 (FM100, FM140, or FM180) and allogeneic HSCT using bone marrow or peripheral blood progenitor cells were included in this study. Transplants occurred between April 1998 and December 2003. Patients received transplants from human leukocyte antigen (HLA)-compatible related donors or unrelated donors, serologically matched for HLA-A and -B and matched for HLA-DRB1 by high-resolution molecular methods. Grafts were depleted of erythrocytes as indicated for ABO incompatibility, but no patient received a T cell-depleted transplant.
Patients were prospectively accrued to 1 of 4 protocols utilizing the FM preparative regimen within the study period. The first study was designed to determine the toxicity and feasibility of FM180. The second protocol compared FM180 to FM140, with the major goal of reducing toxicity associated with FM180. A third study investigated the addition of gemtuzumab ozogamicin to FM140. For these studies, patients were required to be older than 50 years of age or have comorbidities rendering them ineligible for myeloablative conditioning regimens. The 4th study evaluated FM100 with allogeneic HSCT for patients older than 55 years in first remission (CR1). Patients who received a prior allogeneic hematopoietic transplant were not included in this analysis. Fifty percent of the patients in this cohort were previously reported, with shorter follow-up [10]. All patients were treated on protocols approved by the institutional review board (IRB) or with IRB approval under the compassionate IND mechanism. All patients provided written informed consent. The IRB granted permission for this analysis. Preparative Regimen
The conditioning regimen consisted of fludarabine 25 to 30 mg/m2 for 4 to 5 days (transplant days ⫺6 or ⫺5 to ⫺2) with melphalan 100 mg/m2 (n ⫽ 13; 11.7%), 140 mg/m2 (n ⫽ 46; 41.1%) or 180 mg/m2 (n ⫽ 53; 47.3%). Melphalan was given on day ⫺2. Gemtuzumab ozogamicin 2 or 4 mg/m2 was added in 16 cases (day ⫺12). Antithymocyte globulin was given to 31 patients receiving an unrelated donor. GVHD prophylaxis consisted of tacrolimus and methotrexate 5 mg/m2 intravenously on days 1, 3, 6, and 11 after transplantation in all but 1 patient who received cyclosporine. Tacrolimus doses were adjusted to maintain blood levels of 5 to 15 ng/dL during the first 100 days and then tapered as indicated depending on donor type, presence or absence of GVHD, and degree of donor cell chimerism. Bone Marrow and Peripheral Blood Stem Cell Procurement
Donor bone marrow or G-CSF primed peripheral blood progenitor cells were procured using standard mobilization protocols and apheresis techniques. All donors provided written informed consent. Bone marrow procured from unrelated donors was obtained through the National Marrow Donor Program according to applicable guidelines. As required by the National Marrow Donor Program, donors provided informed consent at the donor center. Supportive Care
Infection prophylaxis during the peritransplantation period consisted of levofloxocin, fluconazole, and
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acyclovir or valacyclovir. Filgrastim 5 g/kg was administered subcutaneously daily from transplant day 7 until recovery of the granulocyte count to ⬎1.5 ⫻ 109/L for 3 days. Patients were screened biweekly for cytomegalovirus antigenemia with preemptive use of ganciclovir in the event of a positive assay. Blood product transfusions were irradiated and filtered to remove leukocytes. After recovery of the neutrophil count to ⬎1.0 ⫻ 109/L blood, patients received prophylaxis against Pneumocystis carinii infection using trimethoprim-sulfamethoxazole given orally twice weekly or pentamidine intravenously every 3 weeks. Engraftment and Chimerism
Engraftment was defined as the first of 3 consecutive days with an absolute neutrophil count ⬎0.5 ⫻ 109/L. Failure to engraft by day 30 was considered primary graft failure. Platelet engraftment was defined as the first of 7 consecutive days that the platelet count exceeded 20 ⫻ 109/L without transfusion support. Chimerism analysis was performed on days 30 and 100 post-transplantation, and every 3 months thereafter. Chimerism was monitored using restriction fragmentlength polymorphisms at the AY-29 or YNH24 loci [12], conventional cytogenetic analysis by G-banding, or fluorescent in situ hybridization studies in sexmismatched cases for Y chromosome, and by DNA microsatellite polymorphisms by polymerase chain reaction with D6S264, D3S1282, D18S62, and D3S1300 fluorescence-labeled primers. Definitions
CR prior to HSCT was defined as a normocellular bone marrow containing ⬍5% blasts, with evidence of normal maturation of other marrow elements, absence of peripheral blood blasts, and a platelet count greater than 100 ⫻ 109/L. CR after transplantation was defined using the same criteria except for platelet count, with donor cell engraftment. Response evaluation was performed on day 30 after HSCT, and every 3 months during the first 2 years. For patients not in CR, disease status was categorized as relapsed/refractory, primary induction failure and untreated disease (eg, chemotherapy naïve MDS). In addition, patients with active disease were categorized in 2 subgroups: those with and without circulating blasts. AML cytogenetic abnormalities were grouped according to published criteria adopted by the SWOG [13] and defined as follows: “favorable risk” was inv(16)/t(16;16)/del(16q) or t(15;17) with any additional abnormalities, or t(8;21); “intermediate risk” was ⫹8, ⫺Y, ⫹6, del(12p), or normal karyotype; and “poor risk” was ⫺5/del(5q), 7/del(7q), inv(3q), abn 11q, 20q, or 21q, del(9q), t(6;9), t(9;22), abn 17p, and complex karyotype defined as 3 or more abnormali-
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ties. Cytogenetic subgroups for MDS were defined as follows: “favorable risk” group was normal, ⫺Y alone, del(5q) alone, del(20q) alone; “poor risk” group was complex (ie, 3 abnormalities) or chromosome 7 anomalies; and “intermediate risk” group was other abnormalities [14]. Mixed chimerism was defined as the presence of any detectable (1% or greater) recipient DNA or cells in addition to donor-derived DNA or cells. Statistical Methods
Overall survival was measured from the day of allogeneic stem cell infusion (day 0) until death from any cause, with censoring performed at the date of last contact. Actuarial survival was estimated using the method of Kaplan Meier. Time to disease progression was measured from day 30 until relapse for patients that were in CR 1 month after transplantation. Death of any cause other than relapse or disease progression was scored as nonrelapse mortality. Deaths occurring during the first 30 days prior to disease reassessment were scored as “early deaths”, and considered as nonrelapse mortality. The incidence of disease progression, nonrelapse mortality, acute and chronic GVHD was estimated using the cumulative incidence method accounting for competing risks. Cox proportional hazards model was used to evaluate prognostic factors for survival and disease progression in univariate and multivariate analysis. Statistical significance was determined at the 0.05 level. Analysis was performed using STATA (StataCorp. 2001; Stata Statistical Software: Release 7.0. College Station, TX: Stata Corporation).
RESULTS Patient and Disease Characteristics
Patient, disease, and treatment characteristics are summarized in Table 1. There were 112 patients that met the inclusion criteria for this review. Median age at HSCT was 55 years (range, 22-74 years). Disease status was CR in 30 (26.8%), relapsed/refractory in 43 (38.4%), and primary induction failure in 32 (28.6%) patients. Seven patients with MDS (6.3%) were chemotherapy-naïve prior to HSCT. Karyotype was poor, intermediate, and favorable prognosis in 42.9%, 51.8%, and 2.7% of the cases, respectively. Karyotype was unknown in 3 patients. Thirty patients had MDS with high-risk karyotype or intermediate to poor risk disease based on the International Prognostic Scoring System [15]. Most MDS patients had chemotherapyrefractory disease (n ⫽ 16, 53.3%). Median time from diagnosis of MDS or AML to allogeneic HSCT was 11 months (range, 0.9-176 months). Patients in CR1 underwent allogeneic HSCT after a median of 4.7 and 7.2 months after diagnosis, respectively, for recipients of related or un-
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Table 1. Patient, Disease and Donor Characteristics Variable Age >55 years
