Nonmyeloablative haploidentical peripheral blood stem cell transplantation in congenital anemias

National Heart, Lung, And Blood Institute

Investigators

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Abstract

Based on our murine data, we developed a phase 1 and 2 protocol employing alemtuzumab, 400cGy total body irradiation (TBI) and escalating doses of post-transplant cyclophosphamide (PT-Cy) ranging from 0mg/kg in cohort 1 and 50mg/kg in cohort 2 to 100mg/kg in cohort 3. A total of 21 patients with sickle cell disease and 2 patients with beta thalassemia were transplanted and had baseline complications including cirrhosis, pulmonary hypertension, heart failure, and end-stage renal disease. The engraftment rate improved from 1/3 (33%) in the first cohort, to 5/8 (63%) in the second cohort to 10/12 (83%) in the third cohort. Percentage of donor myeloid and CD3 chimerism also improved with subsequent cohorts. With median follow-up exceeding 6 years, overall survival is 73.9%; all 6 died after return of their sickle cell disease and 2 following repeat transplant. There was no mortality before 100 days post-transplant. At present, 0% in the first cohort, 12.5% in the second cohort, and 50% in the third cohort remain free of their disease. There was no Grade 2-4 acute or moderate to severe chronic graft-versus-host disease (GVHD). Therefore, we have shown that PT-Cy improves engraftment in patients with SCD who are at high risk for early mortality. 3 patients were re-transplanted with myeloablative conditioning and the same donor and are free of sickle cell disease with 100% donor myeloid chimerism. As we reached stopping rules for the study, we opened a new protocol which adds additional immunosuppression in an attempt to improve the success rate while maintaining a low risk of GVHD. Since June 2017, 19 patients have been transplanted. 18 patients achieved high donor chimerism levels. One patient with history of stroke and chronic thromboembolic pulmonary hypertension on anticoagulation died 60 days after her second transplant. One of the 12 developed Grade 2 acute GVHD which responded well to steroids. One patient rejected his graft and required infusion of his backup autologous cells. One patient with slowly falling donor myeloid chimerism levels experienced return of his sickle cell disease at 2.5 years post-transplant. Two patients developed refractory Evans syndrome followed by an unexpected severe hyperinflammatory reaction that led to multi-organ failure in both patients, fatal in one. The protocol is currently being adjusted in an attempt to decrease toxicity and improve long-term graft function. Our clonal hematopoiesis protocol in patients with sickle cell disease and deep phenotyping of major organs in patients with sickle cell disease are currently under review and are expected to open soon. We will also continue our search for early biomarkers associated with graft rejection in an attempt to identify graft rejection at an early and potentially more reversible state and explore mechanisms of engraftment and tolerance induction. We also seek to identify whether patients are indeed tolerant of their grafts so that unnecessary immunosuppression can be discontinued. Lastly, we will explore non-genotoxic conditioning in a mismatched murine model and the murine model of sickle cell disease in an attempt to decrease long-term toxicity while maintaining good efficacy in patients with sickle cell disease who undergo curative therapies.