A 2 Step Approach to Myeloablative Haploidentical Hematopoietic Stem Cell Transplanation (HSCT): Report of a Phase II Trial With 18 Months of Follow-Up for All Patients

Abstract

Haploidentical HSCT using post transplant cyclophosphamide (CY) for elimination of alloreactive lymphocytes has been reported as a safe option for patients lacking an HLA identical donor. We report an alternate approach with the following salient differences: myeloablative vs non-myeloablative conditioning, peripheral blood rather than marrow stem cell source, no exposure vs exposure of HSC to cyclophosphamide, higher fixed number of CD3 cells versus a lower variable number of CD3 cells in each graft. Results are reported now with a followed up of 18-46 months.Table 1Patient Characteristics-2 Step ApproachAge52 (19-67)AML16Remission7Resistant/PIF9Biphenotypic Leukemia (Active Disease)1ALL4CR2 (ph-)3Persistent Disease (PH+)1MDS2NHL Resistant3SAA1HLA MM (GVH Direction)4133112201 Open table in a new tab Patients received 12 Gy of total body irradiation (TBI), followed by a donor lymphocyte product (DLI) containing 2 × 10e8 CD3+ cells/kg (Step 1). This large dose of haploidentical lymphocytes resulted in fever (median temperature 103.8°f), diarrhea and rash. CY 60 mg/kg was given on days -3 and -2 resulting in resolution of symptoms. Tacrolimus and MMF were begun on day-1. A CD 34 selected donor product was infused on day 0 (Step 2). Two of the 27 patients died of toxicity and infection before day 14. Of the remaining 25 patients, 23 had complete engraftment while two with pre-existing anti-donor HLA antibodies failed to engraft. Only 2 of 25 (8%) patients developed severe acute GVHD, 3 of 25 (12%) developed limited chronic GVHD, and no patient died of GVHD. Only two of 25 patients (8%) died of infection. Of 16 disease-free patients surviving 6 months from HSCT, median CD4+ count at day 100 was 105 cells/μl (range 10-403). Eight of 25 (32%) patients relapsed after HSCT. Probability of survival (OS) at 1 and 3 years post transplant is 52% and 48% respectively. All surviving patients are disease-free. OS at 3 years is 75% for patients transplanted in CR, but only 27% for patients transplanted with active disease. KIR mismatching was not correlated with relapse rates. In contrast, child to mother transplants for AML appear to be relapsing at higher rates than other combinations (66% vs 14%). In the context of CY tolerization, a dose of 2 × 10e8/kg T-cells resulted in consistent engraftment, prompt immune reconstitution, little severe GVHD, acceptable toxicity, and encouraging overall survival, particularly in patients transplanted in CR. Using this 2-step platform allows us to explore the use of alternate agents for the elimination of alloreactive lymphocytes, increase the length of time between DLI and CY, and to employ two donor strategies to improve outcomes in high risk patients.