Abstract: Background: Contemporary trials in adult Ph+ ALL patients with TKIs continue to show improved outcomes with allogeneic blood or marrow transplantation (alloBMT) in first remission (CR1) (Chalandon. Blood. 2015 AND Ravandi. Blood Adv. 2016). These studies have relied on myeloablative conditioning (MAC) and largely required an HLA-matched donor. Post-transplant survival in Ph+ ALL has been shown to be similar between patients transplanted with reduced-intensity conditioning (RIC) and MAC, but the incidence of relapse after RIC is higher (Bachanova. Leukemia. 2014). Post-transplant TKI maintenance reduces the incidence of relapse (Brissot. Haematologica. 2015), but this strategy has not specifically been investigated after RIC. Additionally, HLA-haploidentical donor transplants using post-transplant cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis have comparable outcomes to HLA-matched transplants (McCurdy. Haematologica. 2017). We analyzed outcomes among patients who universally received PTCy and attempted post-transplant TKI prophylaxis to determine the importance of remission status (CR1 vs. later), conditioning regimen, donor type, and TKI choice. Methods: The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using PTCy between January 2008 and August 2018. Characteristics of patients were summarized and compared using the student's T test for continuous variables and Fisher's exact test for categorical variables. Estimators of OS and RFS were reported using the Kaplan-Meier method. Differences in time-to-event outcomes were estimated using Cox proportional hazards model. Results: A total of 81 transplants for Ph+ ALL were performed: 69 (85%) in CR1 and 12 (15%) in second or greater remission (CR2+). The demographics are presented in Table 1 and separated by conditioning regimen [MAC vs. nonmyeloablative (NMAC)] for transplants in CR1. The cumulative incidences of grade 2-4 and grade 3-4 aGVHD at 1 year were 33% (95% CI, 23% to 44%) and 9% (95% CI, 3% to 15%), respectively. The incidence of moderate or severe cGVHD at 2 years was 8% (95% CI, 2% to 13%). Nearly all patients (91.4%) initiated a post-transplant TKI at a median of 56 days. Overall, 44.4% of patients were able to take a TKI on ≥85% of nonrelapse days from day 31-395 post-transplant. AlloBMT in CR1 (compared to CR2+) improved RFS (HR=0.25, p=0.0002) and pre-transplant minimal residual disease (MRD) by flow cytometry (MFC) was associated with decreased RFS (HR=2.57, p=0.039). The presence of pre-transplant MRD by PCR did not confer an increased risk of relapse (HR 1.12, p=0.84). Among the 69 patients transplanted in CR1, the 5-year OS was 77.6% (95% CI, 64.8% to 86.2%) and RFS was 67% (95% CI, 52.4-76.5%). As shown in Figure 1, the use of NMAC versus MAC (HR 0.37, p=0.02) and dasatinib versus imatinib at diagnosis (HR 0.21, p=0.007) led to improved relapse-free survival (RFS) in univariate analyses. Neither donor type (with the majority being haploidentical) nor recipient age ≥60 affected RFS. Post-transplant TKI prophylaxis was discontinued prior to relapse in 20 patients among whom 12 remain in an MRD-negative remission, 4 died of non-relapse causes, 3 relapsed, and 1 developed recurrent MRD controlled by a TKI. The median duration of post-transplant TKI prophylaxis prior to discontinuation was 46.5 months in those who remain in treatment-free remission versus 15.6 months in those who relapsed (p=0.01). Eighteen relapses occurred on maintenance therapy, and 90% of tested cases were positive for a kinase domain mutation conferring resistance to the TKI in use at relapse. No significant difference in the median time to TKI initiation post-transplant was noted between those who relapsed on maintenance and those who did not (70 days vs. 55 days, p=0.6). All patients in ongoing remission were MRD-negative by PCR at their most recent evaluation. Conclusions: AlloBMT with PTCy in Ph+ ALL was most effective when performed in CR1 with negative MFC for MRD. The initiation of post-transplant TKI prophylaxis was nearly universal. Among patients transplanted in CR1, the best results were achieved in patients treated with dasatinib at diagnosis (5-year RFS 83%) and NMAC (5-year RFS 73.1%). Thus post-transplant TKI prophylaxis appeared to overcome any relapse control advantage for MAC, yielding better outcomes with NMAC. Disclosures Webster: Amgen: Consultancy; Pfizer: Consultancy. Luznik:WindMil Therapeutics: Patents & Royalties: Patent holder; Genentech: Research Funding; Merck: Research Funding, Speakers Bureau; AbbVie: Consultancy. DeZern:Abbvie: Consultancy; Astex: Research Funding; MEI: Consultancy; Celgene: Consultancy, Honoraria. Pratz:Jazz Pharmaceutical: Consultancy; Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Celgene: Other: Scientific Advisory Board; Boston BioMedical: Consultancy; Astellas: Other: Scientific Advisory Board, Research Funding; AbbVie: Other: Scientific Advisory Board, Research Funding. Levis:Astellas: Honoraria, Research Funding; Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria. Gojo:Amgen: Research Funding; Merck: Research Funding; Genentech: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Amphivena: Research Funding. Bolanos-Meade:Incyte: Other: DSMB Fees. Dalton:Eli Lilly: Research Funding; AbbVie: Research Funding. Jain:Takeda: Consultancy, Honoraria; Bristol Myer Squibb: Other: for advisory board participation; CareDx: Other: Advisory Board. Ali:Celgene: Membership on an entity's Board of Directors or advisory committees. Borrello:Celgene: Research Funding; Aduro: Patents & Royalties; WindMIL Therapeutics: Other: Founder , Research Funding. Wagner-Johnston:ADC Therapeutics, Regeneron, CALIB-R, Verastem: Membership on an entity's Board of Directors or advisory committees. Smith:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: 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; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract: Background: Reduced-intensity induction (RII) with imatinib yields comparable outcomes to HyperCVAD with imatinib with fewer induction deaths and an improved CR rate in Ph+ ALL (Chalandon. Blood. 2015). Dasatinib with steroids also produces excellent responses with little toxicity (Foa. Blood. 2011). Allogeneic bone marrow transplant (AlloBMT) remains the goal of therapy in Ph+ ALL based on contemporary trials with TKIs demonstrating improved survival in patients transplanted in CR1, and we have shown that transplant following induction with dasatinib yields better outcomes than with imatinib. Thus we implemented RII with dasatinib for the treatment of Ph+ ALL and compared to patients who received HyperCVAD with a 2nd generation TKI. Methods: Patients with newly diagnosed Ph+ ALL admitted to Johns Hopkins Hospital from September 2017-June 2020 underwent a 4-week RII with: vincristine 2 mg/d weekly, dexamethasone 40 mg PO weekly on days 1 and 2, and dasatinib 100 mg PO daily. CNS prophylaxis with IT MTX was given on day 8. Dexamethasone and vincristine were reduced by 50% for patients over age 70. Filgrastim was started on day 15 for patients without ANC recovery. Patients who received HyperCVAD with dose adjustments for age (Rausch et al. Cancer. 2020) from July 2011-June 2020 were included for comparison. Dasatinib 100 mg PO daily or nilotinib 400 mg PO BID were given with HyperCVAD at the discretion of the treating physician. Rituximab 375 mg/m^2 on days 1 and 8 was given based on CD20 status. Subsequent therapy after induction was not specifically mandated. Results: 21 patients received RII and 24 received HyperCVAD. The cohorts were comparable in terms of gender (38.1% female vs. 50%, p=0.55), age (median 49.8 vs. 50.3, p=0.33), age & gt;60 (33.3% vs. 29.2%, p & gt;0.99), median WBC at diagnosis (19 vs. 23.5, p=0.56), and the presence of decompensated DIC (fibrinogen & lt;150) prior to treatment initiation (4.8% vs. 8.3%, p & gt;0.99). Among the patients treated with HyperCVAD, 15 received dasatinib (62.5%) and 9 received nilotinib (37.5%). Rituximab use was balanced between the cohorts (61.9% vs. 58.3%, p & gt;0.99). Table 1 compares the time to ANC recovery & gt;500, transfusion requirements within 30 days of chemotherapy initiation, rates of decompensated DIC following treatment initiation, and the duration of inpatient hospitalization for induction. While the rates of decompensated DIC were similar in each cohort, patients treated with RII required fewer platelet and pRBC transfusions. ANC recovery was faster following RII, and only 5 patients (23.8%) received growth factor support. All patients achieved a hematologic response. There was one induction death with HyperCVAD (4.2%). Most patients received a subsequent cycle of high-dose (HD) MTX and Ara-C with TKI (76.2% following RII and 91.7% following HyperCVAD). The remaining patients treated with RII subsequently received HD MTX (14.2%) or blinatumomab (9.5%) with TKI due to co-morbidities. Among those patients treated with HD MTX and Ara-C, blinatumomab was given with TKI to 6 patients (37.5%) who initially received RII and 1 patient (4.5%) after HyperCVAD (p=0.03) due to persistent MRD. As shown in Figure 1, the incidence of MRD-negativity by multi-color flow cytometry (MFC) with a sensitivity of 10-4 at day 120 after treatment initiation was similar for RII (85.4%, 95% CI 64.8-97.1) versus HyperCVAD (86.7%, 95% CI 69.8-96.6). Among patients subsequently treated with HD MTX and Ara-C, 62.5% proceeded to alloBMT after RII with an additional 12.5% currently undergoing transplant evaluation, while 86.4% proceeded to alloBMT after HyperCVAD. The 1-year RFS and OS following RII were 87.9% (95% CI 59.6-96.8) and 100% compared to 87.5% (95% CI 66.1-95.8) and 95.8% (95% CI 73.9-99.4) following HyperCVAD. Conclusion: RII with dasatinib results in fewer transfusions and less myelosuppression compared to HyperCVAD with a 2nd generation TKI. More patients treated with RII received blinatumomab following high-dose MTX and Ara-C, but the rates of MRD-negativity were comparable between the two regimens. Thus RII with dasatinib followed by MRD-guided follow-up therapy facilitates MRD negative remissions with less toxicity than HyperCVAD. The vast majority of fit patients were able to proceed to alloBMT following either regimen. Transplant outcomes following dasatinib with induction are presented in our concurrent abstract demonstrating a 5-year RFS of 83% (95% CI 59.8-93.5). Disclosures Webster: Amgen: Consultancy; Pfizer: Consultancy. Jain:Bristol Myer Squibb: Other: for advisory board participation; CareDx: Other: Advisory Board; Takeda: Consultancy, Honoraria. Dalton:AbbVie: Research Funding; Eli Lilly: Research Funding. DeZern:Abbvie: Consultancy; Astex: Research Funding; Celgene: Consultancy, Honoraria; MEI: Consultancy. Gojo:Genentech: Research Funding; Amphivena: Research Funding; Merck: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Bolanos-Meade:Incyte: Other: DSMB Fees. Luznik:WindMil Therapeutics: Patents & Royalties: Patent holder; AbbVie: Consultancy; Merck: Research Funding, Speakers Bureau; Genentech: Research Funding. Ali:Celgene: Membership on an entity's Board of Directors or advisory committees. Borrello:Celgene: Research Funding; Aduro: Patents & Royalties; WindMIL Therapeutics: Other: Founder , Research Funding. Wagner-Johnston:ADC Therapeutics, Regeneron, CALIB-R, Verastem: Membership on an entity's Board of Directors or advisory committees. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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. Levis:Menarini: Honoraria; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding.

Abstract: Posttransplantation cyclophosphamide is effective as sole GVHD prophylaxis for myeloablative HLA-matched–related or –unrelated BMT. Despite low chronic GVHD with PTCy, relapse and survival are comparable with outcomes reported using other GVHD prophylactic approaches.

Abstract: Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.

Abstract: Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder that can be treated with bone marrow transplantation, immunosuppressive therapy, and high-dose cyclophosphamide. Here, we report long-term follow-up on 67 SAA patients (44 treatment-naive and 23 refractory) treated with high-dose cyclophosphamide. At 10 years, the overall actuarial survival was 88%, the response rate was 71% with the majority being complete, and the actuarial event-free survival was 58% in 44 treatment-naive SAA patients. Patients with refractory SAA fared less well after high-dose cyclophosphamide therapy; at 10 years, overall actuarial survival, response, and actuarial event-free survival rates were 62%, 48%, and 27%, respectively. High-dose cyclophosphamide is highly effective therapy for severe aplastic anemia. Large randomized controlled trials will be necessary to establish how results of high-dose cyclophosphamide compare with either bone marrow transplantation or standard immunosuppressive regimens, such as antithymocyte globulin and cyclosporine.

Abstract: Because of its potent immunosuppressive yet stem cell–sparing activity, high-dose cyclophosphamide was tested as sole prophylaxis of graft-versus-host disease (GVHD) after myeloablative allogeneic bone marrow transplantation (alloBMT). We treated 117 patients (median age, 50 years; range, 21-66 years) with advanced hematologic malignancies; 78 had human leukocyte antigen (HLA)–matched related donors and 39 had HLA-matched unrelated donors. All patients received conventional myeloablation with busulfan/cyclophosphamide (BuCy) and T cell–replete bone marrow followed by 50 mg/kg/d of cyclophosphamide on days 3 and 4 after transplantation. The incidences of acute grades II through IV and grades III through IV GVHD for all patients were 43% and 10%, respectively. The nonrelapse mortality at day 100 and 2 years after transplantation were 9% and 17%, respectively. The actuarial overall survival and event-free survivals at 2 years after transplantation were 55% and 39%, respectively, for all patients and 63% and 54%, respectively, for patients who underwent transplantation while in remission. With a median follow-up of 26.3 months among surviving patients, the cumulative incidence of chronic GVHD is 10%. These results suggest that high-dose posttransplantation cyclophosphamide is an effective single-agent prophylaxis of acute and chronic GVHD after BuCy conditioning and HLA-matched BMT (clinicaltrials.gov no. NCT00134017).

Abstract: Nonmyeloablative, related HLA-haploidentical BMT utilizing high-dose posttransplantation cyclophosphamide has a favorable safety profile. Risk-stratified relapse and survival outcomes with this approach are comparable to those of HLA-matched BMT.

Abstract: After PTCy, ∼50% of MRD alloBMT patients and ∼30% of MUD alloBMT patients required no additional systemic immunosuppression. By 1-year posttransplant, the vast majority of patients had permanently discontinued all systemic immunosuppression.