Haploidentical Peripheral Blood Stem Cell Transplantation in 20 Adult Patients with Sickle Cell Disease

Allogeneic hematopoietic stem cell transplantation (HSCT) cures patients with clinically aggressive sickle cell disease (SCD), although its application has been limited by < 15% of eligible patients having an HLA-matched sibling donors. HSCT from a haploidentical donor has the potential to increase transplant availability to a majority of patients.

Here we describe 20 consecutive haploidentical HSCT (haplo-HSCT) performed in adults between 9/2015 and 5/2021 with clinically aggressive SCD lacking an HLA-matched sibling donor. All 20 patients received the following conditioning regimen: red blood cell exchange with Rh and Kell matched leukoreduced units on day -10 (goal hemoglobin S < 30%), antithymocyte globulin 2.5mg/kg (days -9 to -7) fludarabine 30mg/m²/day (days -6 to -2), cyclophosphamide 14.5mg/kg/day (days -6 & -5), 3 Gy total body irradiation (day -1), post-HSCT-cyclophosphamide 50mg/kg (days +3 & +4), and infusing G-CSF mobilized peripheral blood stem cells. Patients received oral mycophenolate mofetil (15 mg/kg/day) until day + 35 and sirolimus (target trough 5 - 15 ng/mL) for 1 year followed by a taper. Platelet transfusions were administered to maintain platelet counts > 50 x10⁹ cells/L and patients received standard antimicrobial prophylaxis.

The median age of recipients was 28 years (range, 20-39 years), 11 were female recipients, 12 received HSCT from a donor with sickle cell trait, and 3 had a history of red blood cell antibodies (none to the donor's red blood cell antigens). The indication for haplo-HSCT in this cohort included ≥ 3 vaso-occlusive episodes per year despite hydroxyurea use (n = 19), ≥ 2 severe lifetime episodes of acute chest syndrome (n = 14), and stroke (n = 5). The median CD34+ dose was 8.5 x 10⁶ cell/kg (range, 4.2 - 15.9 8.5 x 10⁶ cell/kg. G-CSF (5µg/kg) was administered starting on day +7 post-HSCT in neutropenic patients with HbS <30% and the median time to neutrophil engraftment was 20 days (range, 15-25 days).

All 20 patients initially engrafted donor cells and 2 (10%) subsequently developed secondary graft failure. The median CD3 and CD33 donor chimerisms at 1 and 2 years post-HSCT in those with stable engraftment are 100%. Transplant related toxicities included neutropenic fever resolving after antibiotic therapy (n=20/20), ≥ grade II mucositis (n=3/20), CMV reactivation (n=7/20), and an intracranial aneurysm rupture leading to hemorrhagic stroke (n=1/20). Acute GVHD ≥ grade 2 was seen in 2 patients; one in a patient at day+83 involving the skin, liver and eyes and another at day +50 involving the gut. Moderate to severe chronic GVHD was observed in 3 patients; 2 of 3 have had clinical improvement with ruxolitinib therapy while the 3^rd with intermittent compliance passed away at home from unclear causes at day +407. With a median follow up of 4.4 years (range, 1 - 8.6 years), 19 of 20 (95%) patients are alive and 18 (90%) maintain stable donor cell chimerism with an improvement in hemoglobin concentration from a median of 7.8 g/dL (range, 6.6 - 12.8 g/dL) pre-HSCT to 13.2 g/dL (range, 10.2 - 15.8g/dL) and 13.7 g/dL (range, 12.0 - 16.5 g/dL) at 1 and 2 years post-HSCT, respectively.

Our study demonstrates that modifying the Hopkins haplo-HSCT conditioning regimen by increasing the TBI dose from 2Gy to 3Gy and using peripheral blood stem cells instead of bone marrow grafts allows 90% of SCD patients to achieve stable donor engraftment without severe toxicity. Haploidentical HSCT is the only curative option for many adult patients with clinically advanced SCD and our study suggests this approach can provide cure to those without an HLA-matched sibling donor or where gene therapy is inaccessible.

Rondelli:Vertex Pharmaceuticals: Honoraria. Saraf:Chiesi: Consultancy; GBT/Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Forma/Novo Nordisk: Consultancy, Research Funding; BEAM Therapeutics: Consultancy; Agios: Consultancy, Research Funding; Fulcrum: Membership on an entity's Board of Directors or advisory committees.