Comparison of a fludarabine and melphalan combination-based reduced toxicity conditioning with myeloablative conditioning by radiation and/or busulfan in acute myeloid leukemia in Japanese children and adolescents.

The relative efficacy of allogeneic hematopoietic cell transplantation (allo-HCT) after reduced toxicity conditioning (RTC) compared with standard myeloablative conditioning (MAC) in pediatric patients with acute myeloid leukemia (AML) has not been studied extensively. To address whether RTC is a feasible approach for pediatric patients with AML in remission, we performed a retrospective investigation of the outcomes of the first transplant in patients who had received an allo-HCT after RTC or standard MAC, using nationwide registration data collected between 2000 and 2011 in Japan. We compared a fludarabine (Flu) and melphalan (Mel)-based regimen (RTC; n = 34) with total body irradiation (TBI) and/or busulfan (Bu)-based conditioning (MAC; n = 102) in demographic- and disease-criteria-matched childhood and adolescent patients with AML in first or second complete remission (CR1/CR2). The incidence of engraftment, early complications, grade II-IV acute graft-versus-host disease (GVHD), and chronic GVHD were similar in each conditioning group. The risk of relapse (25% vs. 26%) and non-relapse mortality (13% vs. 11%) after 3 years did not differ between these groups, and univariate and multivariate analyses demonstrated that the 3-year overall survival (OS) rates after Flu/Mel-RTC and MAC were comparable (mean, 72% [range, 51-85%] and 68% [range, 58-77%], respectively). The results suggest that the Flu/Mel-RTC regimen is a clinically acceptable conditioning strategy for childhood and adolescent patients with AML in remission. Although this retrospective, registry-based analysis has several limitations, RTC deserves to be further investigated in prospective trials.

Ishida H ，Adachi S ，Hasegawa D ，Okamoto Y ，Goto H ，Inagaki J ，Inoue M ，Koh K ，Yabe H ，Kawa K ，Kato K ，Atsuta Y ，Kudo K ... -  《-》

Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are 2 widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (allo-SCT). The current survey compared transplantation outcomes for a cohort of 394 acute myeloid leukemia (AML) patients given bone marrow or peripheral blood stem cells from human leukocyte antigen-identical siblings after FB (n = 218) or FM (n = 176). Patients given manipulated grafts and those given T-cell-depleting agents (anti-thymocyte globulins or alemtuzumab) were not included. At the time of transplantation, 266 patients (68%) were experiencing their first complete remission (CR), 69 (18%) were experiencing a later CR, and 59 (15%) had advanced disease. The incidences of acute and chronic graft-versus-host disease were similar in the 2 groups of patients. The 2-year relapse incidence (RI), nonrelapse mortality (NRM) rate, leukemia-free survival (LFS) rate, and overall survival (OS) rate were 31% ± 3%, 18% ± 3%, 51% ± 4%, and 54% ± 4%, respectively, for FB patients and 20% ± 3% (P = .007), 20% ± 3% (P = .4), 60% ± 4% (P = .08), and 62% ± 4% (P = .2), respectively, for FM patients. Among FB patients given intravenous busulfan (n = 81), the 2-year RI, NRM, LFS, and OS rates were 26% ± 5% (P = .43 vs FM patients), 25% ± 6% (P = .18), 49% ± 7% (P = .07), and 54% ± 7% (P = .13), respectively. In multivariate analyses, FM was associated with a lower RI (hazard ratio [HR], 0.5; P = .01) and a trend toward higher NRM (HR, 1.6; P = .1) with similar LFS (HR, 0.8; P = .2) and OS (HR, 0.9; P = .6). These results suggest that although FM provides better AML control than FB as an RIC regimen for allo-SCT, the 2 regimens provide similar survival. Multicenter randomized studies are needed to confirm these findings.

Baron F ，Labopin M ，Peniket A ，Jindra P ，Afanasyev B ，Sanz MA ，Deconinck E ，Nagler A ，Mohty M ... -  《-》

Fludarabine, cytarabine, granulocyte colony-stimulating factor and melphalan (FALG with L-PAM) as a reduced toxicity conditioning regimen in children with acute leukemia.

The conventional conditioning regimen for patients with leukemia prior to allogeneic stem cell transplantation is myeloablation to eradicate residual leukemic cells and host immunocompetent cells. This helps prevent leukemic relapse as well as rejection after transplantation. A myeloablative conditioning regimen with busulfan (BU) or total body irradiation (TBI) is effective for eradication of leukemic cells but is also associated with significant toxicities in the acute or late phase in pediatric patients. In an effort to minimize these adverse effects, we conducted bone marrow transplantation (BMT) from unrelated volunteer donors using a conditioning regimen without BU or TBI. Ten patients with acute leukemia in first or second remission were given a "non-BU, non-TBI conditioning regimen," which consisted of fludarabine (FLU), cytarabine (CA), and melphalan (L-PAM) after FLAG combined with L-PAM. Engraftment was obtained in all patients, and two patients died of relapse. Eight of 10 patients have been disease-free for a median of 126 months (116-142) after transplantation. The overall survival, event-free survival, relapse rate, and treatment-related mortality were 80.0%, 80.0%, 20.0% and 0.0%, respectively. In female patients, spontaneous menstruation with normal luteinizing hormone (LH), follicle stimulating hormone (FSH), and estradiol (E2) levels was observed in all four patients at post-pubertal age. This conditioning regimen of FLAG combined with L-PAM (which did not contain BU and TBI) was associated with good outcomes and minimal late adverse effects in children with acute leukemia who have undergone allogeneic BMT from unrelated volunteer donors.

Kato K ，Yoshida N ，Matsumoto K ，Matsuyama T ... -  《-》

Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen--a report from the acute leukemia worki

Nagler A ，Rocha V ，Labopin M ，Unal A ，Ben Othman T ，Campos A ，Volin L ，Poire X ，Aljurf M ，Masszi T ，Socie G ，Sengelov H ，Michallet M ，Passweg J ，Veelken H ，Yakoub-Agha I ，Shimoni A ，Mohty M ... -  《-》

Comparison of Outcomes for Pediatric Patients With Acute Myeloid Leukemia in Remission and Undergoing Allogeneic Hematopoietic Cell Transplantation With Myeloablative Conditioning Regimens Based on Either Intravenous Busulfan or Total Body Irradiation: A

Pediatric patients with acute myeloid leukemia (AML) mainly receive myeloablative conditioning regimens based on busulfan (BU) or total body irradiation (TBI) before allogeneic hematopoietic cell transplantation (allo-HCT); however, the optimal conditioning regimen remains unclear. To identify which of these regimens is better for pediatric patients, we performed a retrospective analysis of nationwide registration data collected in Japan between 2006 and 2011 to assess the outcomes of patients receiving these regimens before a first allo-HCT. Myeloablative conditioning regimens based on i.v. BU (i.v. BU-MAC) (n = 69) or TBI (TBI-MAC) (n = 151) were compared in pediatric AML patients in first or second complete remission (CR1/CR2). The incidences of sinusoid obstruction syndrome, acute and chronic graft-versus-host disease, and early nonrelapse mortality (NRM) before day 100 were similar for both conditioning groups; however, the incidence of bacterial infection during the acute period was higher in the TBI-MAC group (P = .008). Both groups showed a similar incidence of NRM, and there was no significant difference in the incidence of relapse between the groups. Univariate and multivariate analyses revealed no significant differences in the 2-year relapse-free survival rates for the i.v. BU-MAC and TBI-MAC groups in the CR1/CR2 setting (71% versus 67%, P = .36; hazard ratio, .73; 95% CI, .43 to 1.24, respectively). TBI-MAC was no better than i.v. BU-MAC for pediatric AML patients in remission. Although this retrospective registry-based analysis has several limitations, i.v. BU-MAC warrants further evaluation in a prospective trial.

Ishida H ，Kato M ，Kudo K ，Taga T ，Tomizawa D ，Miyamura T ，Goto H ，Inagaki J ，Koh K ，Terui K ，Ogawa A ，Kawano Y ，Inoue M ，Sawada A ，Kato K ，Atsuta Y ，Yamashita T ，Adachi S ... -  《-》