ALBERT

Description: Adult T-cell leukemia-lymphoma (ATL) is an intractable mature T-cell neoplasm. We performed a nationwide retrospective study of allogeneic hematopoietic stem cell transplantation (HSCT) for ATL in Japan, with special emphasis on the effects of the preconditioning regimen. This is the largest study of ATL patients receiving HSCT. Median overall survival (OS) and 3-year OS of bone marrow or peripheral blood transplantation recipients (n = 586) was 9.9 months (95% confidence interval, 7.4-13.2 months) and 36% (32%-41%), respectively. These values for recipients of myeloablative conditioning (MAC; n = 280) and reduced intensity conditioning (RIC; n = 306) were 9.5 months (6.7-18.0 months) and 39% (33%-45%) and 10.0 months (7.2-14.0 months) and 34% (29%-40%), respectively. Multivariate analysis demonstrated 5 significant variables contributing to poorer OS, namely, older age, male sex, not in complete remission, poor performance status, and transplantation from unrelated donors. Although no significant difference in OS between MAC and RIC was observed, there was a trend indicating that RIC contributed to better OS in older patients. Regarding mortality, RIC was significantly associated with ATL-related mortality compared with MAC. In conclusion, allogeneic HSCT not only with MAC but also with RIC is an effective treatment resulting in long-term survival in selected patients with ATL.

Description: Histone methylation is thought to be important for regulating Ag-driven T-cell responses. However, little is known about the effect of modulating histone methylation on inflammatory T-cell responses. We demonstrate that in vivo administration of the histone methylation inhibitor 3-deazaneplanocin A (DZNep) arrests ongoing GVHD in mice after allogeneic BM transplantation. DZNep caused selective apoptosis in alloantigen-activated T cells mediating host tissue injury. This effect was associated with the ability of DZNep to selectively reduce trimethylation of histone H3 lysine 27, deplete the histone methyltransferase Ezh2 specific to trimethylation of histone H3 lysine 27, and activate proapoptotic gene Bim repressed by Ezh2 in antigenic-activated T cells. In contrast, DZNep did not affect the survival of alloantigen-unresponsive T cells in vivo and naive T cells stimulated by IL-2 or IL-7 in vitro. Importantly, inhibition of histone methylation by DZNep treatment in vivo preserved the antileukemia activity of donor T cells and did not impair the recovery of hematopoiesis and lymphocytes, leading to significantly improved survival of recipients after allogeneic BM transplantation. Our findings indicate that modulation of histone methylation may have significant implications in the development of novel approaches to treat ongoing GVHD and other T cell–mediated inflammatory disorders in a broad context.

Description: Abstract 1506 BACKGROUND: A wide range of neuropsychological sequelae, noted in long-term survivors of ALL, have been in part ascribed to cranial irradiation (CRT), especially in children who are more vulnerable than adults. We had attempted to abandon prophylactic CRT by intensifying systemic chemotherapy and protracted triple IT (TIT) in ALL-02 trial; whereas one third of patients received CRT for CNS directed therapy in the former study (ALL-97). We present here the results of JACLS ALL-02 trials especially about the effect of the CNS-directed therapy. PATIENTS AND METHODS: Between 2002 and 2008, 1139 children with newly diagnosed non-T ALL with 1–18 years of age were enrolled to JACLS ALL-02 trial. Patients with Ph+ALL and T-ALL were registered to independent protocol. The criteria for diagnosis of CNS disease of the JACLS ALL-02 trial were defined as a CSF pleocytosis of 〉 5 cells /microL and the presence of recognizable blast cells on a well-stained cytospin preparation, or the presence of cranial-nerve palsies at a diagnosis of leukemia. Treatment group was divided into 3 groups according to the BFM-style initial prednisolone (PSL) response and the modified National Cancer Institute (NCI) workshop criteria. PSL good responders were divided into standard risk (SR) and high risk (HR) by WBC 10,000 and age 10. BCP-ALL with PSL poor responders and acute mixed lineage leukemia/ acute unclassified leukemias were treated in extremely high risk (ER). The SR patients with unequivocal CNS involvement (CNS3) at diagnosis were treated as an HR group. The patients in M1 marrow at day 33 with M2/M3 at the day 15 bone marrow (BM) were assigned to shift higher risk after induction therapy. Treatment of ALL-02 consists of early phase and maintenance phase. Early phase includes induction, consolidation, sanctuary (2 courses of high-dose MTX at a dose of 3g /m2), and re-induction therapy for 15 to 26 weeks depending on risk group. Prophylactic CRT was replaced by protracted TIT (MTX, CA, HDC) in all except the patients with CNS3 at diagnosis in ALL-02 trial. The patients with CNS3 at diagnosis received CRT at a dose of 12 Gy. Depending on the risk group, protracted TIT was given during induction, intensification and maintenance in ALL-02 (12 doses in SR and 15 in HR/ER). Accumulative doses of DEX were 120 mg/m2 in SR, whereas 170 mg/m2 in HR and 670 mg/m2 in ER. Treatment duration is 24 months for any risk. The patients assigned ER were candidate for allogeneic stem cell transplantation (SCT) by the end of early phase, provided HLA-matched siblings were available. The probability of event-free survival (EFS) and overall survival were constructed using the Kaplan-Meier method. Events in the analysis of EFS included induction failure, death, relapse and secondary malignant neoplasm. All statistical analyses were done according to intent-to treat methods. RESULTS: The numbers of patients at each risk in ALL-02 were 457 (40%) for SR, 543 (48%) for HR, and 139 (12%) for ER. The number of patients with CNS3 at diagnosis was 31 (2.7%). Of 1139 patients, 16 patients (1.4%) had CNS relapses of the leukemia (an isolated CNS relapse: 10 pts, a combined CNS and BM relapse: 6 pts). The 5-year EFS rate ALL-02 was 83.7% (SE=1.1), slightly better than for ALL-97 (79.3%, SE=1.7, p =0.054). The 5-year cumulative risk of an isolated and total CNS relapse was lower in ALL-02 than in ALL-97 (isolated CNS relapse: 0.9% vs 2.7%, p=0.017, total CNS relapse: 4.5% vs 1.4%, p =0.01). The proportion of CRT and SCT were 2%, 8% in ALL-02 respectively, whereas 31%, 11% in ALL-97 respectively. CONCLUSIONS: The ALL-02 trial found that CRT was abolished successfully, in all except those with CNS3 at diagnosis, with substitution of more intensive systemic chemotherapy and protracted TIT. Disclosures: No relevant conflicts of interest to declare.

Description: Ph-like acute lymphoblastic leukemia (also known as BCR-ABL1-like ALL) is a new disease entity of B-cell ALL (B-ALL) that exhibits a mRNA expression profile similar to that of Philadelphia chromosome-positive ALL (Ph+ ALL). Ph-like signature is presumably driven by kinase-activating gene alterations. Thus, both gene expression pattern and DNA mutational status should be assessed to make a definitive diagnosis for Ph-like ALL. A variety of approaches combining multiple methods, including RNA sequencing (RNA-seq), Taqman low-density array (LDA), fluorescence in situ hybridization (FISH) and targeted DNA sequencing, are being tested; however, such multi-omics approaches are available only in limited institutions. Since Ph-like ALL patients generally exhibit poor response to standard chemotherapy, and tyrosine kinase inhibitors (TKIs) may benefit them when used in a timely manner, a fast, accurate and generalizable diagnostic method is critically needed. In the present study, we have developed a nCounter-based diagnostic method for Ph-like ALL and validated it using a cohort of Japanese adult B-ALL cases. To identify genes that are uniquely expressed (or not expressed) in Ph+ B-ALL, we first obtained publicly-available gene expression datasets comprising 1146 B-ALL cases and identified 82 differentially-expressed genes in Ph+ ALL cases. We then assessed expression levels of those genes in an independent cohort using the nCounter, which enables fast, sensitive and accurate RNA detection. We also tested whether nCounter-based methods can detect fusion transcripts relevant for Ph-like ALL pathogenesis using probes targeting ABL1, ABL2, CSF1R, PDGFRB, and JAK2. We analyzed 123 samples (Ph+ = 42, Ph- = 81, age 16 to 67) obtained from newly-diagnosed adult B-ALL patients enrolled in two clinical trials conducted by the Fukuoka Blood and Marrow Transplantation Group (FBMTG) (Nagafuji et al. Eur J Haematol 2019). Unsupervised hierarchical clustering successfully stratified 123 cases into two disease clusters: Ph+ and Ph- subgroups. As expected, Ph+ subgroup included almost all Ph+ ALL cases (40 out of 42 cases), while 18 out of 81 Ph- ALL cases (22%) were categorized into the Ph+ subgroup. We defined these cases as Ph-like ALL. To validate the nCounter-based Ph-like ALL classification, we performed RNA-seq and target-capture DNA sequencing of all Ph- ALL cases. As expected, we detected kinase-activating fusions/rearrangements, including CRLF2 rearrangements (7 cases), PDGFRB fusions (3 cases), JAK2 fusions (2 cases), EPOR rearrangements (2 cases), ABL1 fusion (1 case), and FLT3 internal tandem duplication (1 case) in 16 Ph-like ALL cases, while no genetic alterations were detected in 2 cases. Fusion genes involving PDGFRB were consistently detected by nCounter (3/3); however, detection of those involving JAK2 (1/2) and ABL1 (0/1) were inconsistent. JAK2 and/or RAS mutations were detected in 5 of 7 Ph-like ALL cases harboring CRLF2 rearrangements. Of note, CRLF2 protein expression was detected by FACS in all CRLF2-rearranged cases. We next assessed significance of the Ph-like signature on clinical outcomes using a cohort of 40 Ph- ALL cases, in which minimal/measurable residual disease (MRD) status, assessed by IgH and/or TCR rearrangements, as well as clinical data were available (Nagafuji et al. Eur J Haematol 2019). Ph-like ALL cases exclusively exhibited MRD positivity after induction therapy as compared to non-Ph-like cases (p=0.04), indicative of the chemo-resistant nature of Ph-like ALL as previously reported (Roberts et al. N Engl J Med, 2014 and Roberts et al. J Clin Oncol, 2017). As expected, Ph-like ALL cases exhibited significantly poor disease-free survival compared with non-Ph-like ALL cases (p=0.04); however, no significant difference was evident in overall survival (p=0.62) presumably due to the fact that all MRD-positive cases were subjected to allo-HSCT after induction therapy. These data indicate that MRD-based therapy stratification could overcome chemo-resistant nature of Ph-like ALL. Our data suggest that nCounter-based diagnostic method is fast and accurate to identify Ph-like ALL. Since Ph-like signature generally dictates poor clinical outcomes, and upfront TKI therapy may improve them, our method could facilitate precision medicine in the treatment of Ph- B-ALL. Disclosures Akashi: Sumitomo Dainippon, Kyowa Kirin: Consultancy; Celgene, Kyowa Kirin, Astellas, Shionogi, Asahi Kasei, Chugai, Bristol-Myers Squibb: Research Funding.

Description: Abstract 2444 Poster Board II-421 Alloreactive effector T cells are the central to graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). In GVHD host antigens are never cleared and alloreactive effector T cells are continuously generated over a period of several months or longer, but their suppression and control have proven to be difficult in practice. Using mouse models of GVHD directed against minor histocompatibility antigens (miHAs), we demonstrate that alloreactive effector T cells proliferate and persist upon chronic exposure to alloantigens via reactivation of stem cell transcriptional programs normally expressed in embryonic stem cells and neural stem cells. Many activated stem cell genes in effector T cells were distinct from those in memory T cells and were maintained at high levels upon T cell receptor activation, suggesting a specific role in chronically activated effector T cells. One of these genes, Ezh2, encodes a chromatin modifying enzyme essential to the proliferation, survival and differentiation of stem cells, was upregulated in CD8+ effector T cells upon antigenic stimulation and downregulated when the antigen was withdrawn. Pharmacologically inactivation of EZH2 with 3-Deazaneplanocin A inhibited effector T cell proliferation and survival. Silencing Ezh2 independently validated that Ezh2 was important for regulating effector T cell proliferation and expression of many stem cell genes. To further evaluate whether alloreactive CD8+ effector T cells obtained stem cell-like properties, e.g. the ability to self-renew to continually generate effector cells, we adoptively transferred highly purified miHA H60-specific (H60+) CD8+ effector T cells into secondary allogeneic and congenic recipients, respectively. As compared to congenic recipients, allogeneic recipients had 80-fold more proliferating H60+CD8+ effector T cells. These donor H60+CD8+ effector T cells expressed high levels of CD122, CD69, CXCR3, PD1, IFNγ and Granzyme B, required miHA H60 stimulation to sustain their replication with effector function and expression of stem cell genes, and caused severe GVHD in secondary allogeneic recipients. These results indicate that stem cell transcriptional programs expressed in embryonic and neural stem cells may play important roles in effector T cells. Among these stem cell genes, Ezh2 emerges as an important therapeutic target in modulating alloreactive T cell-mediated GVHD. Disclosures: Zhang: University of Michigan Comprehensive Cancer Center: Research Funding; Damon Runyon Cancer Research Foundation: Research Funding.

Description: Abstract 230 Allogeneic hematopoietic stem cell transplantation (HSCT) provides powerful therapeutic activity through elimination of cancer cells by donor T cells. However, its success is limited by life-threatening graft-versus-host disease (GVHD). Novel immunomodulatory approaches are needed to effectively control GVHD. Notch signaling is a highly conserved cell-cell communication that plays an essential role in T cell development and can influence differentiation and function of mature T cells in a context-dependent fashion. Using several mouse models of allogeneic HSCT, we report that inactivation of Notch signaling in donor T cells inhibits the induction of severe GVHD while preserving significant graft-versus-leukemia (GVL) activity. To block canonical Notch signaling in mature T cells without interfering with T cell development, we used conditional expression of the pan-Notch inhibitor DNMAML (ROSADNMAMLf × Cd4-Cre mice). DNMAML CD4+ T cells derived from donor C57BL/6 (B6) mice had normal initial activation, proliferation and expansion, but failed to differentiate into effector T cells mediating severe GVHD in lethally irradiated major histocompatibility complex-mismatched BALB/c recipient mice. Notably, Notch-deprived alloreactive T cells retained potent GVL activity, leading to improved overall survival of the recipients. Alloreactive DNMAML T cells showed impaired production of IL-2 and multiple inflammatory cytokines (e.g. TNFα, IFNγ and IL-17), as well as defective induction of selected effector molecules (e.g. granzyme B and perforin). The specificity of these findings was independently validated using donor CD4+ T cells with conditional inactivation of Rbpj, encoding CSL/RBP-Jk, a transcription factor that is absolutely required for Notch-mediated transcriptional activation. To further evaluate the effects of Notch signaling in both CD4+ and CD8+ alloreactive T cells, we infused control B6 or DNMAML B6 T cells into unirradiated haploidentical B6xDBA/2 F1 and irradiated minor histocompatibility antigen (miHA)-mismatched BALB/b recipients. Donor DNMAML CD4+ and CD8+ T cells both showed significantly reduced ability to induce severe GVHD in these CD4+ help-dependent CD8+ T cell-mediated GVHD mouse models. These results indicate that Notch is a novel critical signaling pathway regulating CD4+ and CD8+ T cell responses in multiple mouse models of allogeneic HSCT. Given the beneficial immunomodulatory effects of Notch inhibition in alloreactive donor T cells, Notch signaling appears as a promising therapeutic target to limit the harmful effects of GVHD while preserving beneficial GVL activity after allogeneic HSCT. Disclosures: Zhang: University of Michigan Comprehensive Cancer Center: Research Funding; Damon Runyon Cancer Research Foundation: Research Funding. Maillard:University of Michigan Comprehensive Cancer Center: Research Funding; Damon Runyon Cancer Foundation: Research Funding; ASH Scholar Awards : Research Funding.

Description: Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. When we investigated the presence of recurrent molecular lesions in a cohort of 49 children with JMML, neurofibromatosis phenotype (and thereby NF1 mutation) was present in 2 patients (4%), whereas previously described PTPN11, NRAS, and KRAS mutations were found in 53%, 4%, and 2% of cases, respectively. Consequently, a significant proportion of JMML patients without identifiable pathogenesis prompted our search for other molecular defects. When we applied single nucleotide polymorphism arrays to JMML patients, somatic uniparental disomy 11q was detected in 4 of 49 patients; all of these cases harbored RING finger domain c-Cbl mutations. In total, c-Cbl mutations were detected in 5 (10%) of 49 patients. No mutations were identified in Cbl-b and TET2. c-Cbl and RAS pathway mutations were mutually exclusive. Comparison of clinical phenotypes showed earlier presentation and lower hemoglobin F levels in patients with c-Cbl mutations. Our results indicate that mutations in c-Cbl may represent key molecular lesions in JMML patients without RAS/PTPN11 lesions, suggesting analogous pathogenesis to those observed in chronic myelomonocytic leukemia (CMML) patients.

Description: Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for various hematologic malignancies. Infertility associated with ovarian failure is a serious late complication for female survivors of allo-HSCT. While the role of pretransplant conditioning regimen has been well appreciated, it remains to be elucidated whether GVHD could be causally related to female infertility. We have addressed this issue in a mouse model of non-irradiated bone marrow transplantation (BMT) to avoid devastating effects of irradiation on the ovary. Method Female B6D2F1 (H-2b/d) mice (10 week old) were injected with 80 × 106 splenocytes from allogeneic B6 (H-2b) or syngeneic B6D2F1 donors on day 0. To track migration of donor T cells, CAG-EGFP B6 mice were utilized. Morphometric and immunohistochemical assessments were performed on ovarian sections harvested from recipients on day +21 to evaluate the integrity of ovarian architecture and inflammatory changes. To examine ovary functions, recipients were injected with pregnant mare’s serum gonadotropin (PMSG) on day +19 and human chorionic gonadotropin (hCG) on day +21 to induce ovulation and then oocytes were collected. To evaluate fertility of the recipients, recipients were mated with B6D2F1 males after BMT and mating was repeated 6 times until day +150, and newborns were enumerated. Result In this model, GVHD occurred early after BMT at a peak around day +21 particularly in the gut and liver. Histological examination of the ovaries from allogeneic recipients on day +21 demonstrated GFP+ donor T cells infiltrating in the layer of granulosa cells of mature follicles beyond the basement membrane, cleaved-caspase 3+ apoptotic granulose cells surrounded by lymphocytes (satellitosis), and the destruction of PAS+ basal membrane, whereas there was neither donor T cell infiltration nor pathological changes of the ovaries in syngeneic animals (p = 0.002, Table). Majority of T cells infiltrating in the ovary was CD8+ T cells. In experiments of forced ovulation, numbers of oocytes were significantly less in allogeneic animals than in syngeneic animals (p = 0.043, Table), indicating an impairment of ovary functions. When allogeneic recipients were mated to healthy male mice, numbers of both delivery and newborns per litter decreased, whereas syngeneic recipients remain to be fully fertile. As a result, total numbers of newborns delivered by day +150 after BMT were significantly less in allogeneic animals than in syngeneic animals (p〈 0.001, Table). Administration of 10 mg/kg of prednisolone from day 0 to day +20 significantly reduced ovarian GVHD and restored numbers of oocytes in allogeneic animals to the levels of syngeneic animals. Conclusion Our results demonstrate for the first time that GVHD targets ovary and induces impairment of ovary functions and infertility; and therefore, control of GVHD as well as protection of the ovary from the conditioning is important to prevent female fertility after allo-HSCT. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR)-T cell therapy that is approved for adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). In the phase 2 JULIET trial, pts could receive bridging therapy (BT), when needed, to permit flexibility in scheduling and maintain disease control. Lymphodepleting chemotherapy (LDC) was started 5-14 days prior to CAR-T cell infusion. Here we present baseline characteristics, efficacy/safety outcomes, and cellular kinetics by BT and type of LDC used in the JULIET trial. Methods: Pts were categorized based on BT or no BT, as well as LDC (cyclophosphamide/fludarabine [Cy/Flu; 250 and 25 mg/m2 IV daily for 3 doses, respectively] or bendamustine [90 mg/m2 IV daily for 2 days]) or no LDC, received prior to tisagenlecleucel infusion. Cy/Flu was the proposed regimen for LDC, followed by bendamustine (if the pt experienced previous grade [G] 4 hemorrhagic cystitis with Cy or demonstrated resistance to a previous Cy-containing regimen). LDC was not required if white blood cell count was 8 weeks to ≤1 year post-infusion, 〉1 year post-infusion, and any time after infusion were generally consistent across BT and LDC groups for prolonged cytopenias, neurological events (NE), cytokine release syndrome (CRS), and infection (Table). Of note, among pts who did not receive BT, only 1 G3 CRS and 1 G3 NE were reported, and no G4 CRS or NE were reported. Additionally, the rate of cytopenias not resolved by day 28 post-infusion was lowest among pts who did not receive BT (1/11 pts). However, cytopenias resolved to ≤G2 by month 3 or month 6 in the majority of pts. Cmax, Tmax, and exposure (AUC0-28d) were similar between LDC groups (Table). Cmax and AUC0-28d were also similar between pts who received BT and those who did not. Additional analyses of subgroups will be presented at the congress. Conclusions: The majority of pts enrolled in the JULIET trial received BT and LDC, indicating high tumor burden and aggressive disease in this pt population with r/r DLBCL. Although the sample size is small (n=11), pts not requiring BT appeared to have less aggressive disease, achieved high response rates, and had no G4 CRS or NE. Pts who did not receive LDC (n=8) seemed to have low response rates, suggesting either the impact of prior therapy, the importance of LDC, or both. Further evaluation of the impact of BT and LDC on clinical outcomes on larger patient population will be possible with the availability of registry data. Clinical trial information: NCT02445248 Table Disclosures Andreadis: Genentech: Consultancy, Employment; Merck: Research Funding; Roche: Equity Ownership; Novartis: Research Funding; Celgene: Research Funding; Juno: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy; Kite: Consultancy; Jazz Pharmaceuticals: Consultancy. Tam:BeiGene: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie company: Honoraria; AbbVie: Honoraria, Research Funding. Borchmann:Novartis: Honoraria, Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. McGuirk:Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding. Holte:Novartis: Honoraria, Other: Advisory board. Waller:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy. Jaglowski:Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding. Bishop:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foley:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau. Westin:Curis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Unum: Research Funding; Kite: Other: Advisory Board, Research Funding. Fleury:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy. Ho:Novartis: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs. Mielke:DGHO: Other: Travel support; IACH: Other: Travel support; EBMT/EHA: Other: Travel support; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; ISCT: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution). Teshima:Novartis: Honoraria, Research Funding. Salles:Epizyme: Consultancy, Honoraria; Amgen: Honoraria, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Schuster:Novartis: Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors (royalties to Novartis); i3Health, Dava Oncology, Novartis, OncLive, PER Oncology: Speakers Bureau; AbbVie, Acerta, Celgene, DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, TG therapeutics: Research Funding; AbbVie, Celgene, Novartis, Nordic Nanovector, Pfizer: Other: steering committee; Acerta, AstraZeneca, Celgene, Juno, LoxoOncology, Novartis: Other: advisory board; i3Health, Acerta, AstraZeneca, Celgene, Dava Oncology, Juno, LoxoOncology, Novartis, Nordic Nanovector, OncLive, PER Oncology, Pfizer: Honoraria. Bachanova:Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Gamida Cell: Research Funding; GT Biopharma: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Maziarz:Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria; Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees. Van Besien:Miltenyi Biotec: Research Funding. Izutsu:Eisai, Chugai, Zenyaku: Honoraria; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Corradini:Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Gilead: Honoraria, Other: Travel Costs; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs. Tiwari:Novartis: Employment. Awasthi:Novartis: Employment. Lawniczek:Novartis: Employment. Eldjerou:Novartis Pharmaceuticals Corporation: Employment. Kersten:MSD: Other: Travel grants, honorarium, or advisory boards; Janssen/Cilag: Other: Travel grants, honorarium, or advisory boards; Kite: Consultancy, Other: Travel grants, honorarium, or advisory boards; Roche: Consultancy, Research Funding, Travel grants, honorarium, or advisory boards; Bristol Myers Squibb: Other: Travel grants, honorarium, or advisory boards; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel grants, honorarium, or advisory boards; Celgene: Other: Travel grants, honorarium, or advisory boards; Gilead: Other: Travel grants, honorarium, or advisory boards; Amgen: Other: Travel grants, honorarium, or advisory boards; Roche: Other: Travel grants, honorarium, or advisory boards; Celgene: Consultancy, Research Funding.

Description: In Japan, unrelated bone marrow transplantations (U-BMT) for severe aplastic anemia (SAA) were first performed in 1993. Transplant regimens and patient selection have changed substantially since then. We aimed to determine the effect of these changes on transplant outcome. We retrospectively analyzed the outcome in patients with SAA who received U-BMT through the Japan Marrow Donor Program between 1993 and 2005. We selected 302 recipient-donor pairs in which molecular analysis of HLA-A, -B, -C, -DRB1, and DQB1 were performed. Patient ages ranged from 1 to 64 years (median, 17 years). Various preconditioning regimens were used by individual centers. Either tacrolimus with methotrexate or cyclosporine with methotrexate was used for the prophylaxis against graft-versus-host disease (GVHD) in 137 (45%) patients and 127 patients (42%), respectively. Of the 302 pairs, 104 (34%) were found to be matched at HLA-A, -B, -C, -DRB1, and DQB1; 97 (32%) were mismatched at a single HLA allele (23 HLA-A or -B, 42 HLA-C, 32 HLA-DRB1 or HLA-DQB1); 83 (28%) were mismatched at two HLA alleles (35 HLA-A or -B and HLA-C, 8 HLA-A or -B and HLA-DRB1 or -DQB1, 40 HLA-C and HLA-DRB1 or -DQB1); and 18 (6%) were mismatched at three HLA alleles. Currently, 210 of the 302 patients are alive with the median follow-up period of 722 days after transplantation. The incidence of graft failure was 2.2%; that of grade II/IV GVHD was 29.0%; that of III/IV acute GVHD was 13.8%; and that of chronic GVHD was 25.2%. Multivariate analysis revealed the following significant risk factors for survival: patients older than 15 years (RR, 1.98; range 1.17–3.35); HLA-A or -B + HLA-C or HLA-DQB1 or -DRB1 (RR 2.18; range 1.29–3.68); three loci mismatching (RR 3.14; range 1.47–6.69); prophylaxis against GVHD with tacrolimus with methotrexate (RR 0.45; range 0.28–0.73), ABO major mismatch (RR 1.67; range 1.05–2.63), and non-ATG-containing CY+TBI regimen (RR 2.17; range 1.16–4.03). Patients were divided into two cohorts based on years of transplantation and we compared patients transplanted within two time periods: 1993–2000 and 2001–2005. Five-year survival increased 55.9+/−4.6% in the 1993–2000 cohort (n=116) and 72.7+/−3.8% in the 2001–2005 cohort (n=186) (p=0.008). Patients and transplant characteristics that differed significantly between the two periods were patients’ age distribution, GVHD prophylaxis, HLA matching, and conditioning regimens. The percentage of patients older than 15 years was significantly larger in the recent period (p