Leukemia Burden and Outcome of Allogeneic Transplant in Acute Myelogenous Leukemia

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In the January 2006 issue of Biology of Blood and Marrow Transplantation, Blum et al [1] reported the outcomes of 48 patients who underwent unrelated hematopoietic transplantation after myeloablative conditioning at 2 transplant centers over a 12-year period. At a median follow-up of 540 days (range, 145-2716 days), 2-year survival was superior for those with <5000 peripheral blood blasts/mL at the time of transplantation (18% versus 0%; P = .003) and <20% marrow blasts (33% versus 5%; P = .04). Sustained survival occurred only in patients with low disease burden as defined previously [1]. Similar results were reported in 34 patients with active disease for matched related hematopoietic transplantation [2]. Only a few studies have addressed the issue of tumor burden at the time of transplantation [3].

To facilitate patient selection and to define the role of hematopoietic transplantation in patients with active acute myeloid leukemia (AML), we analyzed the significance of residual disease in addition to known prognostic variables (karyotype, age, performance status, availability of related donor, and duration of initial complete remission [CR1]) in 36 patients with refractory AML between 1982 and 2005 at a single institution [4]. We report the long-term follow-up of these patients. After approval by the institutional review board, patient, disease, and transplant characteristics were analyzed. Residual bone marrow disease at time of transplantation was stratified into 2 groups based on percentage of myeloblasts (group I, <20% blasts; group II, ≥20% blasts). Karyotypes were analyzed as good risk versus others [good risk was defined as t(15;17), inv16, t(16/16), or t(8;21)]. Induction failure, untreated first relapse, and refractory first or second relapse defined disease status.

The median age of 17 female and 19 male subjects was 35 years (range, 13-62 years). Primary refractory relapse, refractory relapse, and untreated first relapse were present in 8 (22.2%), 21 (58.3%), and 7 (19.4%) patients, respectively. Twenty-four patients (66.7%) had >20% blasts and 12 (33.3%) had <20% blasts. The conditioning regimen consisted of chemotherapy and total body irradiation in 23 patients (64%) and chemotherapy alone in 13 (36%). Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporine or tacrolimus in all 36 patients. Graft characteristics included matched sibling donors (n = 21, 58.3%), matched unrelated donors (n = 15, 41.7%), bone marrow (n = 26, 72.2%), and mobilized peripheral blood stem cells (n = 7, 19.4%). Three patients (8.3%) received bone marrow and mobilized peripheral blood stem cells. Cytogenetic information was available in 17 patients (47%); 15 patients (89%) had intermediate-risk or poor-risk cytogenetics; good-risk cytogenetics was present in only 2 patients (11%). Grade I-II and III-IV acute GVHDs occurred in 16 (44.4%) and 6 (16.7%) patients, respectively; the overall incidence of grade I-IV acute GVHDs (57.1%) was lower in matched related transplants than in unrelated donor transplants (66.7%). Chronic GVHD (limited = 6, extensive = 3) occurred in 9 patients (25%). Of the 21 patients (63.6%) who previously (before transplantation) achieved remission, median CR1 duration was 6 months (<6 months = 10, 6-12 months = 4, >12 months = 7). CR1 information was not available in 3 patients. Although 27 patients (75%) achieved CR after transplantation, disease relapse at a median of 3 months (range, 1-52 months) accounted for 54.8% of mortality. Nonrelapse mortality accounted for 45.2% of deaths (regimen related toxicity, 19.3%; GVHD and infections, 25.9%). Thirty-one patients (86.1%) died at a median of 4 months (range, 1-52) after transplantation. All 24 patients with >20% marrow blasts (including 6 with peripheral blasts) died at a median of 3 months; of the 12 patients with <20% blasts (no peripheral blast), 7 died at a median of 4 months. Only 5 patients (13.9%) survived long term at a median follow-up of 30 months (range, 13-64 months). All survivors had <20% residual marrow blasts, no peripheral blast, and intermediate risk cytogenetics. No other variable such as age, performance status, donor type, or duration of CR1 correlated with survival.

A higher relapse rate in patients with AML who present with excess myeloblasts at transplantation likely reflects a unique subgroup with intrinsic resistance to treatment. Although CR rates after allografting for residual AML is high (75%), higher relapse rates of approximately 50-60% and 40-40% for nonrelapse mortality result in a dismal 10% in long-term survivors. This observation is important to bear in mind while counseling patients with refractory relapse for allogeneic transplantation or clinical trials.

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1. Blum W , Bolwell BJ , Phillips G , et al.   High disease burden is associated with poor outcomes for patients with acute myeloid leukemia not in remission who undergo unrelated donor cell transplantation . Biol Blood Marrow Transplant . 2006;12:61–67
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2. Kebriaei P , Kline J , Stock W , et al.   Impact of disease burden at time of allogeneic stem cell transplantation in adults with acute myeloid leukemia and myelodysplastic syndromes . Bone Marrow Transplant . 2005;35:965–970
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3. Nemecek ER , Gooley TA , Woolfrey AE , Carpenter PA , Mathews DC , Sanders JE . Outcome of allogeneic bone marrow transplantation for children with advanced acute myeloid leukemia . Bone Marrow Transplant . 2004;34:799–806
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4. Hjortsvang EW , Kamble R , Kharfan-Dabaja MA , Kern W , Ozer H , Selby GB . Residual AML at the time of allograft (outcome analysis based on number of bone marrow blasts) . Biol Blood Marrow Transplant . 2005;11:60
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