1.
Myeloablative haploidentical BMT with posttransplant cyclophosphamide for hematologic malignancies in children and adults
Symons, H. J., Zahurak, M., Cao, Y., Chen, A., Cooke, K., Gamper, C., Klein, O., Llosa, N., Zambidis, E. T., Ambinder, R., et al
Blood advances. 2020;4(16):3913-3925
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Abstract
Promising results have been reported for patients with high-risk hematologic malignancies undergoing HLA-haploidentical bone marrow transplantation (haploBMT) with posttransplantation cyclophosphamide (PTCy), but there are few data on outcomes with myeloablative conditioning in this context. We report the results of a single-institution, prospective phase 2 trial of myeloablative haploBMT using busulfan-based or total body irradiation-based conditioning in 96 children or adults (median age, 42 years; range, 1-65 years) with high-risk hematologic malignancies. Recovery of neutrophils and platelets occurred at a median of 24 and 29 days. Engraftment of donor cells with chimerism >95% was achieved in 91%. The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and grades III to IV at day 100 was 11% and 4%, and of chronic GVHD at 6 and 12 months was 4% and 15%, with 6% moderate to severe. The cumulative incidence of nonrelapse mortality was 6% at 100 days and 11% at 1 year (19% in those aged >55 years). The cumulative incidence of relapse at 1 year was 35%; at 3 years, it was 43%. In multivariable analysis, relapse was associated with increased age (P = .02 for age 20-55 years and P = .02 for age >55 years) and with minimal residual disease before transplantation (P = .05). The overall survival at 1 and 3 years is 73% and 54%, and event-free survival at 1 and 3 years is 57% and 49%. We show that haploBMT with PTCy after myeloablative conditioning is safe and efficacious for adult and pediatric patients with hematologic malignancies. Careful consideration must be given to using myeloablative conditioning in patients age >55 years. This trial was registered at www.clinicaltrials.gov as #NCT00796562.
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A prospective study of peri-transplant sorafenib for FLT3-ITD AML patients undergoing allogeneic transplantation
Pratz, K. W., Rudek, M. A., Smith, B. D., Karp, J., Gojo, I., Dezern, A., Jones, R. J., Greer, J., Gocke, C., Baer, M. R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
FLT3-ITD mutated acute myeloid leukemia (AML) remains a therapeutic challenge. FLT3 inhibition in the setting of minimal residual disease and a new immune system via allogeneic transplantation offers a promise of improved survival for these patients. We performed a prospective study of patients with FLT3-ITD AML undergoing allogeneic transplant was conducted to evaluate the safety, tolerability, and outcome of sorafenib administered peri-transplant. Sorafenib dosing was individualized, starting at 200 mg BID, and titrated based on tolerability or toxicities until a tolerable dose was identified. Forty-four patients, with a median age of 52, undergoing allogeneic transplant were started on sorafenib in the peri-transplant period (21 pre-transplant). The median duration of post-transplant follow up is 27.6 months (range, 5.2-60.4). Overall survival was 76% at both 24 and 36 months. Event-free survival at 24 and 36 months was 74% and 64%, respectively. Ten patients died in the post-transplant period, with six deaths due to relapsed leukemia and four from transplant-associated toxicity. Tolerable doses ranged from 200 mg QOD to 400 mg BID with similar exposure. Correlative studies evaluating FLT3 inhibition via a plasma inhibitory activity assay showed consistent inhibition of FLT3 at all tolerability-determined dosing levels. Sorafenib is well tolerated in the peri-transplant setting irrespective of the conditioning intensity or the donor source. Our findings indicate that sorafenib dosing can be individualized in the post-transplantation setting according to patient tolerability. This approach results in effective in vivo FLT3 inhibition and yields encouraging survival results.