ALBERT

Description: Allogeneic hematopoietic cell transplantation (HCT) is the only treatment modality that can either cure or prolong life of patients with primary myelofibrosis (PMF). However, the issues of the choice of stem cell source, the choice of conditioning regimen, and the timing of HCT are currently under debate. To determine whether a difference in stem cell source affects the outcome of HCT for PMF patients, a retrospective study was conducted using the national registry data on 224 patients who received first allogeneic HCT in Japan with bone marrow (BM), peripheral blood stem cells (PBSC) or umbilical cord blood (UCB). This study was approved by the Data Management Committee of the Japan Society for Hematopoietic Cell Transplantation and by the ethics committee of the Nagoya University School of Medicine. One hundred fifty-two male and 72 female, with a median age of 55 years (range, 21-79 years), were treated with a myeloablative (48%) or non-myeloablative (52%) preconditioning and GVHD prophylaxis such as calcineurin inhibitor with methotrexate (78%) between 1993 and 2016. Stem cell sources were HLA-A, -B and -DR 6/6 matched related BM (Rtd-BM) (n = 22), HLA-A, -B and -DR 6/6 matched related PBSC (Rtd-PBSC) (n = 48), HLA-A, -B, -C and -DRB1 alleles 8/8 or 7/8 matched unrelated BM (UR-BM) (n = 91), unrelated UCB (UR-UCB) (n = 29) and others (n = 34) including HLA 5/6 or 4/6 matched related BM and PBSC, HLA-haploidentical related BM and PBSC, HLA alleles 6/8 or 5/8 matched unrelated BM, and HLA alleles 8/8 or 7/8 matched unrelated PBSC. All UR-UCB transplantation was performed with a single unit. The median follow-up term for living patients was 48 (0.3-202) months. Cumulative incidences of neutrophil recovery (≥0.5 × 109/L) on day 60 were 100% in Rtd-BM (median days to recovery, 21 days), 94% in Rtd-PBSC (16 days), 86% in UR-BM (21 days), 79% in UR-UCB (25 days) and 91% in other transplantation (23 days). Cumulative incidences of grade II-IV and III-IV acute GVHD on day 100 were 23% and 5% in Rtd-BM, 27% and 19% in Rtd-PBSC, 27% and 10% in UR-BM, 31% and 10% in UR-UCB, and 26% and 15% in other transplantation, respectively. Cumulative incidences of chronic GVHD at 2 years after HCT were 35% in Rtd-BM, 41% in Rtd-PBSC, 34% in UR-BM, 19% in UR-UCB and 13% in other transplantation. Non-relapse mortality (NRM) at 2 years after HCT were 22% in Rtd-BM, 41% in Rtd-PBSC, 39% in UR-BM, 47% in UR-UCB and 48% in other transplantation. Multivariate analysis demonstrated that RBC transfusion ≥20 times before HCT (HR, 2.05; 95% CI, 1.06-3.98), PLT transfusion 10-19 times before HCT (3.56, 1.57-8.05), UR-UCB transplantation (4.70, 1.13-19.6) and other transplantation (4.38, 1.05-18.3) were predictive factors for higher NRM. Although performance status ≥2 at HCT was significant for higher NRM in univariate analysis, it was not significant in multivariate analysis. Relapse rates at 2 years after HCT were 14% in Rtd-BM, 17% in Rtd-PBSC, 13% in UR-BM, 24% in UR-UCB and 15% in other transplantation. Multivariate analysis demonstrated that no factor was associated with the incidence of relapse, although high-risk group of chromosome karyotype was significant for higher relapse rate in univariate analysis. Neither stem cell source groups nor DIPSS was not significant in univariate analysis. Overall survival (OS) rates at 2 and 5 years after HCT were 71% and 71% in Rtd-BM, 52% and 52% in Rtd-PBSC, 54% and 46% in UR-BM, 43% and 27% in UR-UCB, and 48% and 33% in other transplantation, respectively. Multivariate analysis demonstrated that age of 46-55 years (HR, 2.14; 95% CI, 1.00-4.56) and ≥56 years (2.69, 1.32-5.48), RBC transfusion ≥20 times before HCT (1.91, 1.13-3.25) and PLT transfusion 10-19 times before HCT (3.51, 1.64-7.52) predicted lower OS rate. Although performance status ≥2 at HCT, DIPSS intermediate-2 or high at HCT, high-risk group of chromosome karyotype, UR-UCB transplantation and other transplantation were significant for lower OS in univariate analysis, they were not significant in multivariate analysis. The present study could not find an advantage of use of JAK1/2 inhibitor before HCT, use of anti-thymoglobulin as a preconditioning, and non-myeloablative preconditioning regimen in terms of decreasing NRM or increasing OS rate. Our results suggest that allogeneic HCT provide a curative treatment for PMF patients, however careful management is required in HCT with other than Rtd-BM, Rtd-PB and UR-BM. Further analysis in a large cohort is required. Disclosures No relevant conflicts of interest to declare.

Description: [Background] We previously demonstrated that allogeneic hematopoietic stem cell transplantation (HSCT) in the first complete remission (CR1) was recommended for adult patients wih Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) who have a human leukocyte antigen (HLA)-matched related (Leukemia 2011;25:259-265) or unrelated donor (Bone Marrow Transplant 2013;48:1077-1083). However, pediatric-inspired high-intensity chemotherapy dramatically improved the prognosis of adult patients with Ph-negative ALL. Therefore, the optimal treatment strategy for Ph-negative ALL in CR1 has not been established in the era of high-intensity chemotherapy. [Methods] Outcomes of patients with Ph-negative ALL who underwent HSCT from HLA-matched related or unrelated donor in CR1 performed between 2002 and 2011 (HSCT-MRD group and HSCT-MUD group, respectively) were obtained from the Transplant Registry Unified Management Program (TRUMP), which is the registry database of the Japanese Society for Hematopoietic Cell Transplantation (JSHCT). Patients aged between 16 and 24 and between 25 and 65 were analyzed separately, and their outcomes were compared with those of patients who did not receive HSCT in CR1 in clinical studies by Japan Adult Leukemia Study Group (JALSG), ALL-202U study in which patients received chemotherapy designed for pediatric patients (Blood Cancer J 2014;4:e252)(202U group) and ALL-202O study in which patients were randomly assigned to receive adult-type chemotherapy with high-dose or intermediate-dose methotrexate (MTX) therapy (Leukemia 2018;32:626-632)(202O group), respectively. Median durations between diagnosis to HSCT were obtained from the TRUMP data, and only patients who were disease-free more than each median duration were included from the JALSG studies. Risk stratifications were performed based on the white blood cell (WBC) count and cytogenetics. [Results] In patients aged less than 25 who underwent HSCT from related donor, the median duration between diagnosis to HSCT was 188 days. Overall survival (OS) in 202U group (N = 93) was significantly superior compared with OS in HSCT-MRD group (N = 102) (OS at 5 years: 81.8% vs 67.8%, P = 0.016) (Figure 1(A)), and which was attributed to the higher non-relapse mortality in HSCT-MRD group (NRM at 5 years: 1.4% vs 9.5%, P = 0.015). Disease-free survival (DFS) and relapse rate (RR) were similar between two groups (DFS at 5 years: 70.2% vs 62.5%, P = 0.115, and RR at 5 years: 28.4% vs 28.4%, P = 0.689). Higher OS was preserved in younger (

Description: For patients with malignant hematological diseases that relapse after allogeneic hematopoietic stem cell transplantation (HSCT), a second HSCT is thought to be a curative option. A second donor is usually searched for due to HLA discrepancy between the graft and the host. However, it is unclear whether HLA discrepancy between the graft and the first donor has an impact on the outcome of second HSCT. To address this issue, we focused on second HSCT patients who had received first HSCT from an HLA-mismatched (MM) donor and compared the effects of HLA discrepancy between graft and first donor with those between graft and host. We retrospectively analyzed 646 patients receiving second HSCT between 1994 and 2016 after an initial HLA-MM transplantation. With regard to the graft versus host results, the one-allele mismatch (1 MM) group (relative risk [RR], 1.88; 95% confidence interval [CI], 0.79-4.45; p=0.163) and more than one-allele mismatch group (≥ 2 MM) (RR, 1.84; 95% CI, 0.75-4.51; p=0.182) had higher risks of grade III-IV acute GVHD compared to the HLA-matched (0 MM) group, although the results were not significant. In contrast, almost no difference in risk of acute GVHD was found among the 0, 1, and ≥ 2 MM group with respect to graft vs. first donor. Furthermore, with regard to graft vs. host, the ≥ 2 MM group showed a significantly higher risk of treatment-related mortality (TRM) (RR, 1.90; 95% CI, 1.04-3.50; p=0.038) compared to the 0 MM group. In contrast, the risk of relapse was slightly lower in the ≥ 2 MM group (RR, 068; 95% CI, 0.44-1.06; p=0.086). Consequently, no significant difference in OS was found among the three groups. In the analysis of each HLA allele MM, B allele MM between graft and host was associated with an increased risk of grade III-IV acute GVHD (RR 2.87; 95% CI, 1.42-5.79; p=0.003) and DR allele MM between graft and host was associated with a lower risk of relapse (RR, 0.75; 95% CI, 0.58-0.95; p=0.018) and higher risk of TRM (RR, 1.44; 95% CI, 1.03-2.00; p=0.033). In contrast, with regard to graft vs. first donor, there were no significant differences in relapse, TRM, or OS among the three groups, and also analysis of each HLA allele MM indicated no associations with relapse, TRM, or OS. These findings suggested that HLA discrepancy between graft and host, rather than between graft and first donor may induce transplant-related immunological responses in second HSCT leading to an increase in TRM. In conclusion, HLA-MM donor is an option after initial HLA-MM transplantation, however, TRM remains a challenge, particularly with a ≥ 2 MM donor regarding to graft versus host. In this study, the biological effects of HLA discrepancy between the graft and the first donor on the outcome appeared negligible, and our findings shed light on the role of nonhematopoietic APCs on transplant-related immunological responses. Figure. Figure. Disclosures Nakamae: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding. Ichinohe:Mundipharma: Honoraria; Eisai Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Zenyaku Kogyo Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; CSL Behring: Research Funding; Novartis.: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Astellas Pharma: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding. Kanda:Ono: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Pfizer: Research Funding; Taisho-Toyama: Research Funding; MSD: Research Funding; Novartis: Research Funding; Tanabe-Mitsubishi: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; CSL Behring: Research Funding; Asahi-Kasei: Research Funding; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria.

Description: Introduction: Philadelphia chromosome-positive acute myeloid leukemia (Ph+AML) is a rare form of AML and confers a dismal prognosis when treated with chemotherapy, with limited data available on the outcome when treated with allogeneic transplantation (allo-HCT). Methods: Patients were selected from the Japanese nationwide transplantation registry database based on the following criteria: AML patients aged ≥16 years; first allo-HCT conducted between 1995 and 2016; complete remission at transplantation; and intermediate- or poor-risk cytogenetics. Patients with secondary AML or chronic myeloid leukemia in blast phase were not included. Ph+AML was defined as AML, including mixed phenotype acute leukemia (MPAL), that presented with t(9;22)(q34.1;q11.2) or BCR-ABL1 fusion transcripts at diagnosis. The primary endpoint was overall survival (OS) and secondary endpoints were relapse and non-relapse mortality (NRM). The probability of OS was estimated based on the Kaplan-Meier method and compared between the groups with log-rank test. The incidences of relapse and NRM were estimated using cumulative incidence analysis and compared between the groups with Gray's test. Multivariate analysis was performed using the Cox proportional hazards model. A matched-pair analysis was also performed based on the propensity score to minimize the confounding effect of baseline patient characteristics. Sex, age at HCT (20,000/µL), GVHD prophylaxis (cyclosporine- or tacrolimus-based), disease status at HCT (CR1/CR2 or CR〉2), conditioning regimen (RIC or MAC), donor type (HLA-matched related/unrelated donor or alternative donor), MPAL or not, and performance status at HCT (0-1 or 2-4) were used to calculate the propensity score. Results: Of 5,304 eligible patients, 4,372 (82.4%), 882 (16.6%), and 50 (1.0%) were classified into cytogenetically intermediate-risk AML, cytogenetically poor-risk AML (excluding Ph+AML), and Ph+AML groups, respectively. Their median age was 47, 47, and 43.5 (range: 16-76, 16-74, and 16-85) years, respectively. The median follow-up for surviving patients was 2.3 (range, 0.0-22.4) years. MPAL accounted for 1.7% of the whole cohort, and its distribution was different among groups: 1.3%, intermediate-risk AML; 2.4%, poor-risk AML; and 26.0%, Ph+AML (p 〈 0.001). No significant difference was noted in OS between patients with and without MPAL (p = 0.22). OS at 3 years after allo-HCT was 62.8% for intermediate-risk AML, 51.1% for poor-risk AML, and 70.2% for Ph+AML (p 〈 0.001) (Fig 1A). The 3-year incidences of relapse and NRM were 19.6% and 22.2% for intermediate-risk AML, 32.6% and 21.7% for poor-risk AML, and 6.3% and 27.9% for Ph+AML, respectively (Fig 1B and 1C). Multivariate analysis revealed that the Ph+AML and intermediate-risk AML groups had comparable risk in terms of OS [hazard ratio (HR), 0.75; 95% confidence interval (CI), 0.45-1.28; p = 0.29]; for these groups, the risk of Ph+AML was significantly lower than the poor-risk AML (HR, 0.54; 95% CI, 0.31-0.91; p 〈 0.001). Ph+AML had significantly lower risk of relapse than poor-risk AML (HR, 0.16; 95% CI, 0.05-0.51; p 〈 0.001) and intermediate-risk AML (HR, 0.31; 95% CI, 0.10-0.94; p = 0.04). There was no significant difference in the risk of NRM (HR, 1.45; 95% CI, 0.86-2.45; p = 0.17 for Ph+AML vs. intermediate-risk AML; HR, 1.50; 95% CI, 0.87-2.57; p = 0.14 for Ph+AML vs. poor-risk AML). The matched-pair analysis extracted 39 and 38 patients from each group based on the propensity score using optimum matching (intermediate-risk AML vs. Ph+AML and poor-risk AML vs. Ph+AML). OS in the Ph+AML group was comparable with that in the intermediate-risk AML group (p = 0.81), whereas it was significantly better than that in the poor-risk AML group (p = 0.012). Conclusion: Our data show that post-transplant outcomes were better for Ph+AML patients than those with other poor-risk cytogenetics and were comparable with those for patients with intermediate-risk cytogenetics, suggesting that allo-HCT overcomes the poor prognosis of Ph+AML. Although our registry did not secure information on the use of tyrosine kinase inhibitors, their use may partly contribute to improvements in post-transplant outcomes. Disclosures Mizuno: Celgene Corporation: Honoraria; Bristol-Myers Squibb Corporation: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Kanda:Eisai: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Tanabe Mitsubishi: Research Funding; Otsuka: Research Funding; Celgene: Consultancy, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Alexion: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Nippon-Shinyaku: Research Funding; Alexion: Consultancy, Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Mochida: Consultancy, Honoraria; Sanofi: Research Funding; Takara-bio: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Nippon-Shinyaku: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Tanabe Mitsubishi: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; CSL Behring: Research Funding; Pfizer: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Novartis: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; CSL Behring: Research Funding; MSD: Research Funding; Taiho: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria; Taisho-Toyama: Research Funding; Taiho: Research Funding. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria.

Description: Purpose It is difficult to decide whether children with leukemia who could not achieve complete remission (CR) after relapse or primary induction failure should undergo transplantation. Nonetheless, allogeneic hematopoietic stem cell transplantation (HSCT) is a possible approach for refractory acute myeloid leukemia (AML). Despite being refractory to conventional chemotherapy, a graft versus leukemia (GVL) effect could be expected to some extent. This approach is considered to be experimental because the mortality rate of HSCT is extremely high. A previously conducted large-scale study demonstrated that age less than 10 years was a factor of good prognosis; however, the details in children remain unclear. The purpose of this retrospective analysis was to describe the outcomes and risk factors of HSCT for children with refractory AML. Patients and Methods The data was collected through the Transplant Registry Unified Management Program (TRUMP) system, the registry of The Japan Society for Hematopoietic Cell Transplantation. A total of 417 patients with AML younger than 21 years old at the time of HSCT between January 2001 and December 2015 who had blasts in peripheral blood and/or bone marrow were analyzed. Both myeloablative and reduced-intensity conditioning regimens were analyzed. Patients with AML were classified according to a previous report, which was based on the Eastern Cooperative Oncology Group/Southwest Oncology Group classification as good (inv16, t[8;21], t[15;17]), poor (5/del[5q], 7/del[7q], inv[3q], abn11q, 20q or 21q, del[9q], t[6;9], t[9;22], abn17p, and complex karyotype defined as 3 or more abnormalities), or intermediate (other and normal karyotypes) risk. Myeloablative conditioning was defined as total body irradiation (TBI) of 〉8 Gy and the administration of 8 mg/kg of busulfan (BU), 〉140 mg/m2 of melphalan, or 〉10 mg/kg of thiotepa. All other regimens were analyzed as reduced-intensity conditioning HSCT, including low-dose TBI (≤8 Gy) and low-dose BU (≤8 mg/kg). The graft included bone marrow, peripheral blood stem cells, or cord blood. Overall survival (OS) was used as a primary outcome because for HSCT during relapse, post-HSCT CR was not always achieved or reliably documented. Results The median follow-up time of survivors was 1052 days (range 60-4399). The median age was 13 years. Twenty-three percent of patients had a pre-HSCT performance status (PS) of 0, which corresponds to a Karnofsky PS ≥90. The rate of pre-HSCT fungal infection was 12%. Fifty-two percent of patients had more than 25% marrow blasts at the time of HSCT. At the time of HSCT, 36%, 47%, and 17% of patients exhibited primary induction failure, first relapse, and second or additional relapse, respectively. Eighty-nine percent of patients had neutrophils and 70% exhibited platelet recovery by day 100. Three hundred and fourteen patients died. The causes of death were leukemia progression (58%), followed by graft-versus-host disease (GVHD) (11%) and graft failure (10%). The 3-year OS rate was 23% (95% confidence interval (CI) 19-28). Grade ≥2 acute GVHD did not affect OS. Patients with chronic GVHD had better 3-year OS (47%, 95% CI 36-57%) compared to that in patients without chronic GVHD (22%, 95% CI 16-28%) (p = 0.001) (Figure 1). Low PS, greater than 25% marrow blasts, the presence of blasts in blood at the time of transplantation, French-American-British subgroup other than M1 or M2, transplant from a male donor, and a history of transplantation were adverse pre-HSCT variables (Table 1). Patients with 0 (n = 24), 1-2 (n = 175), 3-4 (n = 188), and 5-6 (n = 30) variables had 52% (95% CI 30-71%), 30% (95% CI 23-37%), 17% (95% CI 12-23%), and 0% 3-year OS, respectively (p 〈 0.001) (Figure 2). Discussion Some patients with refractory pediatric AML achieved relatively long survival following HSCT in the relapsed period, especially when a GVL effect was obtained. A scoring system using pre-HSCT variables should help decide whether HSCT should be performed or not. HSCT is worth considering for children who have undergone ≤2 pre-HSCTs. Disclosures No relevant conflicts of interest to declare.