Nonmyeloablative haploidentical peripheral blood stem cell transplantation in congenital anemias

National Heart, Lung, And Blood Institute

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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 a median follow-up exceeding 8 years, the overall survival was 57.1%; 6 died after the return of their sickle cell disease, and 3 following repeat transplant for sickle cell disease. There was no mortality before 100 days post-transplant. 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 SCD. As we reached the stopping rules for the study, we opened a second protocol that added additional immunosuppression in an attempt to improve the success rate while maintaining a low risk of GVHD. 22 patients were transplanted. 21 patients initially 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, fatal in both. One patient died from neurotoxicity related to Epstein-Barr Virus-associated post-transplant lymphoproliferative disorder (PTLD). Two patients developed acute GVHD, one Grade 2 and one Grade 4. 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. Five patients developed PTLD, 2 uncontrolled. Four patients developed autoimmune complications, 2 uncontrolled as described above. Because of the high incidence of unexpected complications, the protocol closed to accrual. A third haploidentical protocol opened to enroll patients with severe SCD, including those with compromised organ function. The protocol includes abatacept to promote tolerance and nongenotoxic conditioning with an anti-c-Kit antibody with the goal of maximizing donor chimerism levels long-term while minimizing toxicity. 3 patients were transplanted; one had falling donor chimerism levels and died just before 6 months post-transplant from SCD-related complications. The other two patients had 100% donor myeloid chimerism, but donor T-cell chimerism <50%. The study drug was withdrawn by the drug company, and a 4th protocol is being prepared. 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. We are participating in a multi-center collaboration with investigators at Vanderbilt University Medical Center, Johns Hopkins Hospital, Emory University, Children's National Hospital, and University of Illinois Chicago to evaluate the long-term health effects of curative therapies in patients with sickle cell disease. We are also performing translational research involving murine models to further explore novel conditioning regimens for the haploidentical setting in sickle cell disease and 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.