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, 50mg/kg in cohort 2, and 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. The percentage of donor myeloid and CD3 chimerism also improved with subsequent cohorts. With median follow-up exceeding 8 years, the overall survival is 60.9%; 6 died after the return of their sickle cell disease, and 2 following repeat transplant for sickle cell disease. 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 2 are alive and free of sickle cell disease. As we reached the stopping rules for the study, we opened a new protocol that added additional immunosuppression in an attempt to improve the success rate while maintaining a low risk of GVHD. Since June 2017, 21 patients have been transplanted. 20 patients achieved high donor chimerism levels. One patient with a history of stroke and chronic thromboembolic pulmonary hypertension on anticoagulation died 60 days after her second 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 both. One of the patients developed Grade 2 acute GVHD, which responded well to steroids. One patient rejected his graft and required infusion of his backup autologous cells. Two patients with slowly falling donor myeloid chimerism levels experienced the return of their sickle cell disease at 2.5 years post-transplant. The protocol has been 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 enrolling patients to help us identify clinical and genetic risk factors of heart, lung, and kidney disease and myeloid malignancy development after curative therapies for sickle cell disease. We have published two manuscripts that have identified proteins, cytokines, and immunoregulatory cell populations that were associated with a successful transplant outcome. 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.