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 ... -  《-》

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 ... -  《-》

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 ... -  《-》

Treosulfan, fludarabine, and 2-Gy total body irradiation followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome and acute myeloid leukemia.

Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial, we assessed the efficacy and toxicity of treosulfan, fludarabine, and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n = 36: 15 refractory cytopenia with multilineage dysplasia, 10 refractory anemia with excess blasts type 1, 10 refractory anemia with excess blasts type 2, 1 chronic myelomonocytic leukemia type 1) or AML (n = 60: 35 first complete remission [CR], 18 second CR, 3 advanced CR, 4 refractory relapse) were enrolled; median age was 51 (range, 1 to 60) years. Twelve patients had undergone a prior HCT with high-intensity conditioning. Patients received 14 g/m(2)/day treosulfan i.v. on days -6 to -4, 30 mg/m(2)/day fludarabine i.v. on days -6 to -2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n = 27) or unrelated (n = 69) donors. Graft-versus-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30 months, the 2-year overall survival (OS), relapse incidence, and nonrelapse mortality were 73%, 27%, and 8%, respectively. The incidences of grades II to IV (III to IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor-risk and good/intermediate-risk cytogenetics (69% and 85%, respectively) or between AML patients with unfavorable and favorable/intermediate-risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n = 10) at the time of HCT predicted higher relapse incidence (70% versus 18%) and lower OS (41% versus 79%) at 2 years, when compared with patients without MRD. In conclusion, treosulfan, fludarabine, and low-dose TBI provided effective conditioning for allogeneic HCT in patients with MDS or AML and resulted in low relapse incidence, regardless of cytogenetic risk. In patients with AML, MRD at the time of HCT remained a risk factor for post-HCT relapse.

Gyurkocza B ，Gutman J ，Nemecek ER ，Bar M ，Milano F ，Ramakrishnan A ，Scott B ，Fang M ，Wood B ，Pagel JM ，Baumgart J ，Delaney C ，Maziarz RT ，Sandmaier BM ，Estey EH ，Appelbaum FR ，Storer BE ，Deeg HJ ... -  《-》

A Comparison of the Myeloablative Conditioning Regimen Fludarabine/Busulfan with Cyclophosphamide/Total Body Irradiation, for Allogeneic Stem Cell Transplantation in the Modern Era: A Cohort Analysis.

With improvement in transplantation practices in the modern era, nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has improved, while disease relapse rates have remained unchanged. Survival outcomes are therefore driven by NRM in the modern era. Myeloablative conditioning (MAC) regimens are used to maximize disease control and facilitate engraftment; however, their use is often limited by toxicity. The commonly used MAC regimens incorporate either chemotherapy plus total body irradiation (TBI) or combination chemotherapy. Furthermore, reduced-toxicity myeloablative (RTM) regimens, such as fludarabine/busulfan (FluBu), have emerged as alternatives to traditional MAC and their impact on outcomes in the current era have not been fully investigated. In this study, we compare outcomes following HSCT, using the chemotherapy only RTM MAC regimens FluBu with the chemoradiotherapy regimen cyclophosphamide/TBI (CyTBI), for patients with hematologic malignancies who underwent MAC HSCT at the Dana-Farber Cancer Institute. We hypothesized that the chemotherapy-only regimen would fare better, primarily due to improved NRM. A retrospective cohort analysis was performed on 387 patients with myeloid or lymphoid hematologic malignancies who underwent HLA-matched related (8/8), matched unrelated (8/8), or single-antigen mismatched unrelated (7/8) HSCT following myeloablative conditioning. Patients received FluBu (n = 158) or CyTBI (n = 229). The primary outcome was overall survival (OS) and all other outcomes were regarded as secondary. A subset analysis was performed for patients <55 years of age and for acute myelogenous leukemia/myelodysplastic syndrome patients of age <55 years. For the whole cohort, 3-year OS was similar for FluBu compared with CyTBI in unadjusted analysis. However, in multivariable analysis, FluBu resulted in superior OS compared with CyTBI (3-year adjusted estimate: 65% versus 55%, respectively; HR for death, .62; 95% CI, .40 to .97; P = .036). While relapse rates were similar between the 2 regimens, NRM and acute graft-versus-host disease (GVHD) (grade II to IV) were significantly worse with CyTBI compared with FluBu. Rates of chronic GVHD were similar between 2 regimens. These results were consistent in a subset of patients <55 years of age and in acute myelogenous leukemia/myelodysplastic syndrome patients below 55 years of age. The RTM chemotherapy-only regimen FluBu appears to be as effective and more tolerable than the chemoradiotherapy regimen CyTBI, leading to better OS driven by better NRM. The improvement in NRM was attributable chiefly to lower rates of grade II to IV acute GVHD. Relapse rates were not increased with FluBu. In the absence of randomized data, FluBu appears to be the optimal regimen for myeloablative HSCT in patients of all age groups.

Gooptu M ，Kim HT ，Ho VT ，Alyea EP ，Koreth J ，Armand P ，Ritz J ，Nikiforow S ，Glotzbecker BE ，Nageshwar P ，Soiffer RJ ，Antin JH ，Cutler CS ... -  《-》