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

The widespread application of allogeneic hematopoietic stem cell transplantation (HSCT) to cure patients with clinically aggressive sickle cell disease (SCD) has been limited by a lack of HLA-matched sibling donors. HSCT from a haploidentical donor represents a feasible option to increase transplant availability to a majority of the patients. However, current published studies using haploidentical donors in adults with SCD have resulted in long-term event-free survival rates of only 50-57%.

Here we describe 10 consecutive haploidentical HSCT (haplo-HSCT) performed in adult patients with clinically aggressive SCD lacking an HLA-matched sibling donor. The median age of recipients was 27 years (range, 20-52 years) and all 10 patients met at least two standard SCD eligibility criteria for HSCT (Table 1). Based on our successful experience in matched related peripheral blood stem cell (PBSC) HSCT using a nonmyeloablative conditioning regimen with alemtuzumab 1mg/kg and 3 Gy total body irradiation (TBI), we initially performed two haplo-HSCT using the same conditioning regimen followed by high dose post-transplant cyclophosphamide (PT-Cy) at 50mg/kg on day+3 and +4. Both SCD patients failed to engraft donor cells and recovered autologous neutrophils on day +39 and day +34, respectively.

In the following 8 patients, transplanted between September 2015 and March 2017, we utilized a modified version of the Hopkins protocol with: fludarabine 30mg/m², Cy 14.5mg/kg, 3 Gy TBI (increased from the original 2 Gy dose), antithymocyte globulin 0.5mg/kg, PT-Cy 50mg/kg, and infusing mobilized PBSC instead of marrow cells (Table 1). G-CSF at 5µg/kg was administered starting on day +12 post-HSCT in neutropenic patients with HbS <30% and the median time to neutrophil engraftment was 22 days (range, 18-23 days). All 8 patients initially engrafted donor cells and only 1 (12%) subsequently developed secondary graft failure. The remaining 7 (88%) currently maintain a stable donor cell engraftment. Transplant related toxicities included: neutropenic fever resolving after antibiotic therapy (n=8/8), ≥ grade II mucositis (n=3/8), CMV reactivation (n=2/8), and small intracranial hemorrhages (n=2/8) on (i) day +10 in a patient refractory to platelet transfusions that resolved after cross-matched platelets became available, and, (ii) on day +12 in a patient with prior stroke history that resolved after increasing the platelet threshold from 50 to 100 x10³/µL. Acute GVHD ≥ grade 2 was seen in 2/8 patients (one non-compliant with immunosuppressive treatment), with complete resolution after steroid therapy in one case, and transformation into chronic GVHD (skin, eye and liver) in the other. No other cases of chronic GVHD have been observed to date. With a median follow up of 9 months (range, 5-22 months), all 8 patients are alive and 7 (88%) maintain >90% donor cell chimerism with an improved median hemoglobin concentration from 8.8g/dL (range, 6.4-12.8g/dL) to 13.3g/dL (range, 9.9-15.3g/dL).

Our study demonstrates that modifying the Hopkins conditioning regimen by increasing the TBI dose from 2Gy to 3Gy and using PBSC instead of bone marrow grafts allows 88% of SCD patients to achieve stable donor engraftment without severe toxicity. We also demonstrate that G-CSF can be safely administered to adult patients with SCD after HSCT. Haploidentical HSCT is the only curative option for many adult patients with clinically advanced SCD and our study suggests a basis for larger, multicenter clinical studies.

View largeDownload slide

View largeDownload slide

Close modal