| | Allogeneic Hematopoietic Stem Cell Transplantation for the Treatment of High-Risk Acute Myelogenous Leukemia and Myelodysplastic Syndrome Using Reduced-Intensity Conditioning with Fludarabine and MelphalanReceived 20 September 2006; accepted 27 November 2006. published online 12 February 2007. 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 = 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. 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 associated with a relatively high rate of graft-versus-host 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, 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, 4, 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 acyclovir or valacyclovir. Filgrastim 5 μg/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 fragment-length polymorphisms at the AY-29 or YNH24 loci [12], conventional cytogenetic analysis by G-banding, or fluorescent in situ hybridization studies in sex-mismatched 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 abnormalities. 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 chemotherapy-refractory 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 unrelated donor transplants. Median duration of CR1 for 10 patients receiving allogeneic HSCT in second or third CR was 10.8 months (range, 2-58.5 months). Patients with relapsed/refractory disease at HSCT had a median CR1 duration of 9 months (range, 1.3-46.7 months). The median time interval between first relapse and transplantation was 2.5 and 5.1 months for related and unrelated donor transplants, respectively. Melphalan Dose There was no difference in survival and risk of progression between subgroups of patients treated with FM140 versus FM180. Patients were therefore grouped and analyzed together. FM100 was used mostly for patients in CR1, and any effect of melphalan dose in that subgroup could not be investigated given the small numbers of patients in CR1 treated with FM140 and FM180. Figure 1A and B shows the comparable results of FM100, 140, and 180 in patients in CR at HSCT and FM140 and FM180 in patients with active disease at HSCT. Overall, patient and disease characteristics were similar in the melphalan subgroups, except for the association of CR1 with FM100 (10 of 13 patients in CR1), and the older median age (59 versus 53 years) in the FM100 subgroup compared to FM140 or FM180 subgroups. The proportion of patients in remission at HSCT was 77% (FM100) versus 19% (FM140 and 180). Gemtuzumab ozogamicin was added to FM140 under a phase I/II study, without inducing excessive toxicity. All recipients of the drug (n = 16) had relapsed disease at study entry. Engraftment and Chimerism Neutrophil recovery was documented in 105 (94%) of the patients, while 7 patients died without evidence of engraftment. Median time to a neutrophil count >0.5 × 109/l was 13 days (range, 8-28 days). Four patients had primary graft failure (all recipients of unrelated donor HSCT), and 3 had secondary graft loss. Platelet recovery to >20 × 109/l occurred in 90 cases (86%), at a median time of 20 days (range, 7-139 days). A month after transplantation, median donor chimerism was 100%, and 8 of 99 evaluable patients had mixed chimerism (8%). Two of the mixed chimeras subsequently lost their graft, and 3 had disease progression within the first 100 days post-transplantation; these patients received donor lymphocyte infusion or second allogeneic HSCT, 1 converted to complete donor chimera, and 2 remained mixed chimeras in CR on day 100. Response, Relapse, and Overall Survival Ninety-seven patients (87%) were in CR 30 days post-transplantation. Early death occurred in 8 cases, and 7 did not respond and had persistent disease. The CR rate was 84% and 78%, respectively, for patients with relapsed/refractory disease and primary induction failure. Disease progression occurred in 19 of 67 (29%) patients that achieved a CR after HSCT, at a median of 4.2 months. Among patients transplanted in CR, disease progression occurred in 6 of 30 patients (20%) at a median of 6.8 months after transplant. Most relapses occurred during the first 6 months post-treatment, and all but 3 patients relapsed within a year after transplantation. Only 1 subject relapsed more than 2 years after treatment. The 2-year cumulative incidence of disease progression for the whole cohort was 25%. The 2-year cumulative incidence of relapse was 20%; 15%, and 46%, respectively, for patients in CR at transplantation, and for patients with active disease with and without circulating blasts (Figure 2). In univariate analysis, presence of circulating blasts was the only significant risk factor for disease progression (Table 2, Table 3), with a hazard ratio (HR) of 3.7 compared to patients in CR at transplantation (95% confidence interval [CI], 1.4-9.8; P = 0.01). No significant difference for progression of disease was observed between patients in CR versus those with active disease at transplantation without circulating blasts (HR = 1.1, 95% CI = 0.4-3.2, P = 0.9). Development of acute or chronic GVHD did not prevent relapse. | 1 1st CR and untreated cases were excluded; 2time dependent variable; 3outcome from day 100; cGVHD, chronic graft-versus-host disease. |
| 1 1st CR and untreated cases were excluded; 2time dependent variable; 3outcome from day 100; cGVHD, chronic graft-versus-host disease. |
The median follow-up of 43 surviving patients is 29.4 months (range, 13.1-87.7 months), while the median survival of 69 patients (62%) that have died was 11.3 months. The 2-year overall survival for the whole cohort is 44%. One patient was lost to follow-up. Most deaths (90%) occurred within the first 2 years after transplantation. Estimates of 2-year overall survival were 66% for those in CR, 40% for patients not in CR but without circulating blasts, and 23% for those with active disease and circulating blasts (Figure 3). In univariate analysis, the following variables were found to be significantly associated with improved survival: less extensive disease at HSCT, intermediate risk karyotype, and absence of grade II-IV acute GVHD (Table 3). Only disease status and absence of grade II-IV acute GVHD remained statistically significant in the multivariate analysis. Compared to patients in CR, patients with active disease at HSCT had worse survival (HR 2.8; 95%CI = 1.4-5.3; P = .002, for patients with circulating blasts, and HR 1.8; 95% CI = 0.9-3.5, P = .06, for patients without circulating blasts). Among patients with active disease, presence of peripheral blood blasts was associated with worse survival (HR = 1.7, 95% CI = 0.99-2.8, P = .06). Development of grade II-IV acute GVHD was associated with significantly shorter survival (5.3 months versus 43.8 months for patients without grade II-IV acute GVHD; HR = 2.8 as a time-dependent variable, 95% CI = 1.8-4.6, IP < .001). GVHD and Causes of Death The cumulative incidence of grade II-IV acute GVHD was 39% (n = 46), with a median time to onset of 29 days (range, 7-97 days). Chronic GVHD was documented in 51 of 81 patients surviving beyond 100 days, with a cumulative incidence of 49%. Seventy-one percent of the cases had extensive disease. The presentation was de novo in 22 (43.1%), relapsed in 18 (35.3%) and progressive in 11 (21.6%) patients. Median time to development of chronic GVHD was 6.1 months (range, 3.3-33.2 months). The most common causes of death were GVHD (n = 28), relapse (n = 21), infection (n = 10) and others including severe hemorrhage, veno-occlusive disease and multiorgan failure (n = 10). Acute or chronic GVHD was the cause of death of 36% of the recipients of unrelated donor transplant, while 17% died of relapse, 10% of infections, and 6% of other causes. Among recipients of related donor transplants, these proportions were 15%, 20%, 7%, and 12%, respectively. In the group of 46 patients that developed acute grade II-IV GVHD, acute GVHD was the cause of death in 11, while 14 patients died subsequently of chronic GVHD. There were 15 deaths beyond the first year post-transplant, due to disease progression (n = 5), chronic GVHD (n = 5), and infection (n = 3). Cause of death was unknown in 2 cases. Late deaths due to relapse occurred only among patients transplanted with active disease at HSCT. Patients in CR at transplant died of infection (n = 2), GVHD (n = 1) and other complications (n = 2). Late deaths (occurring after 3 years from transplantation) were due to GVHD and infection (n = 4), relapse (n = 1), and unknown cause (n = 1). Nonrelapse Mortality Cumulative incidence of NRM in this cohort was 54% at last follow-up. Cumulative incidence of day 100 and 2-year NRM was 0% and 20%, respectively, for patients in CR at HSCT. These numbers were 20% and 30% for patients receiving a related donor transplant with active disease, and 35% and 56% for patients treated with a matched unrelated donor without CR at transplantation. Patients with active disease at transplantation had a significantly higher risk of nonrelapse mortality compared to patients in CR at transplantation (HR = 3, P = .02) (Figures 1A, 1B and 4). The impact of donor type on nonrelapse mortality was correlated to disease status, as described above. The use of unrelated donors did not increase the risk of treatment-related mortality among patients in CR, but it did so among patients with active disease at transplantation. Age, karyotype, and use of FM140 versus FM180 did not affect the probability of nonrelapse mortality. Discussion AML and MDS are diseases of the elderly, characterized by being refractory to therapy and high rates of morbidity and mortality with current available chemotherapy [16]. Allogeneic hematopoietic transplantation produces significantly higher remission rates than chemotherapy, but only a small fraction of all patients with these diseases receive a transplant, primarily because of concerns regarding the toxicity of the preparative regimen and treatment related morbidity and mortality. Therefore, a major goal is to increase the applicability of the transplantation to older or medically infirm patients. With the use of nonablative preparative regimens, the median age of patients treated with related or unrelated donor HSCT is increasing, and several groups have reported series of patients in the 6th decade of life [6, 7, 17, 18]. Since 1996, when the first reports of RIC regimens were being presented in the meetings of the American Society of Hematology, the use of this therapeutic modality has increased dramatically with now almost 30% of allografts being done after a reduced intensity regimen primarily being used in older patients [19]. Initial reports all demonstrated the feasibility and short-term efficacy of RIC allografting in patients with AML/MDS. This report demonstrates that long-term disease control can be achieved with this therapeutic modality. The patient population in this series had many unfavorable patient and disease characteristics. The majority had refractory disease with intermediate or high-risk karyotype. Median age was 55 years, with 25% of patients older than 60 years of age. More than 70% of patients had active disease, consistent with the low complete remission rate in this age range [3, 4]. In this report we confirm the safety and efficacy of the combination of the FM combination. Given the 0% 100-day and 20% 2-year NRM rate in patients with a median age of 59 years transplanted in remission, FM would appear to compare favorably to other RIC regimens keeping in mind the lack of direct comparisons among the available preparative regimens. However, nonrelapse mortality was high in subsets of patients, such as those with active disease in which NRM was 20%-35% at 100 days and 35%-56% at 2 years. Disease status at the time of transplant was the single most important prognostic factor for survival and disease progression. Development of moderate to severe acute GVHD had a strong deleterious effect on survival, but we failed to detect a protective effect of cGVHD on disease progression or overall survival as recently reported in a study with conditioning regimen of 2 Gy TBI and F [20]. However, another study using 8 Gy TBI and F showed results similar to ours [21]. Although this difference may be partially explained by the different conditioning regimens administered, the protective effect of cGVHD may be more difficult to detect in a cohort of AML and MDS only patients, because these diseases are less sensitive to the GVL phenomenon. In addition, older patients are less likely to tolerate GVHD-related complications such as steroid side effects, infections, and delayed immune recovery, which may negate the potential benefit of a maximized GVL effect. Similar outcomes were observed after FM140 and FM180. Nonlethal toxicity, however, was higher with FM180, and we do not recommend that regimen currently given the lack of evidence indicating improved efficacy. More caution is recommended when analyzing the use of FM100, given that 77% of the small number of patients in that subgroup was in first CR in contrast to 19% of the remaining patients. Bearing in mind these considerations, 2-year survival of FM100 recipients is greater than 60%. We continue to investigate the use of FM100 for older patients in first CR, while patients with more advanced stages of disease are treated with FM140-based regimens. The issue of optimal intensity of preparative regimens for advanced age patients is far from resolved. Considerations must be made for functional status and the presence of comorbidities. It is possible that the use of comorbidity indices may help identify patients in the late 50’s and early 60’s that could be treated with higher intensity regimens [22]. Extent of prior treatment, donor type, and disease status must be considered. Improvements in GVHD prevention and treatment are clearly needed, especially for recipients of unrelated donor transplants. Use of high-resolution allele level matching for class I and II loci is likely to decrease GVHD rates and improve nonrelapse mortality. Our data would suggest that older age cannot be the sole reason for denying allogeneic HSCT to a patient with myeloid leukemia. Major causes of mortality remain GVHD and relapse, and every effort should be made to enroll older patients in clinical trials investigating novel strategies to address these problems. Patients with active disease at transplantation should be considered for novel post-transplant interventions designed to prevent relapse. References 1. 1Litzow MR, Perez WS, Klein JP, et al. 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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.
PII: S1083-8791(06)00779-8 doi:10.1016/j.bbmt.2006.11.024 © 2007 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. | |
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