Pentostatin Low-Dose TBI Is an Effective Conditioning Regimen That Permits Donor Engraftment in Patients with High Co-Morbidities Undergoing the First Transplant or Prior to a Second Transplant

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for malignant and nonmalignant hematological disease patients. Despite initial engraftment in the great majority of patients, the ability to transplant patients with high co-morbidities or re-transplant patients following early post-transplant relapse or graft rejection remains challenging. We used an immuno suppressive regimen consisting of 3 doses (1^st transplant) or 2 doses (2^nd /3^rd transplant) of 4 mg/m2 pentostatin and total body irradiation with 2 daily fractions of 200 cGY (Pento/TBI) as primary therapy for patients too ill to tolerate a standard reduced-intensity conditioning regimen, or for patients who rejected or relapsed after their first or second transplant.

Methods: We conducted an IRB-approved retrospective analysis of 10 patients who received Pento/TBI between 2016 to 2024. GvHD prophylaxis was reduced-dose post-transplant cyclophosphamide on days +3 and +4 (25 mg/m2, rPTCy) with 6 months of therapeutic levels of either sirolimus or tacrolimus and twice daily mycophenolate to day 35. The primary endpoints of interest were hematopoietic engraftment, lineage-specific donor chimerism, overall survival (OS), and rates of acute GvHD (aGvHD) and chronic GvHD (cGvHD). Clinical outcomes were compared to similar patients receiving a Fludarabine and Melphalan (140 mg/m2) reduced intensity conditioning regimen who received full-dose PTCy (50 mg/m2 x 2 doses). Comorbidities were assessed with the Hematopoietic cell transplantation-specific comorbidity index (HTC-CI).

Results: Four patients received Pento/TBI before the first allo-HCT, and 6 patients received reconditioning before their 2^nd or 3^rd allo-HSCT following graft rejection or relapse. Five patients had a primary diagnosis of myeloid malignancy, three with T cell lymphoma, and one each with marrow failure and sickle cell disease. The median HCT-CI was 3 (range 1-6). In the four patients undergoing initial transplants, three received a graft from a mismatched unrelated donor (MMUD), and one patient was transplanted with a haploidentical related donor. In the second group of six patients undergoing a 2^nd or 3^rd transplant, two donors were MMUD, three were MUD, and one was haploidentical. The median cell doses for all transplants were 8.0 x 10E6/kg CD34+cells/kg (range 2.6-28.6 x 10E6/kg) and 270 x 10E6 CD3+ cells/kg (range 25-530 x10E6/kg). Blood chimerism obtained at a median of day 31 post-transplant showed a median of 100% donor CD3 T cell chimerism (range 92-100%) and 100% donor myeloid chimerism (range 97-100%). Median times for platelet and neutrophil engraftment for all patients were 20 and 16 days, respectively, with day 60 neutrophil and platelet engraftment rates of 100% and 90%, respectively. One first-transplant patient with myelofibrosis failed to achieve sustained platelet engraftment; all 2^nd /3^rd transplant patients engrafted after Pento/TBI. Overall survival at one year was 100% for the 1st allo-HCT and 33% for the 2^nd allo-HCT, with death in 4 patients from relapsed disease(n=3) and complications of acute GvHD (n=1). Two of 10 patients developed grade 2 aGvHD, with no severe aGvHD. Four of ten patients developed cGvHD: two mild and two moderate cGvHD. When comparing the Pento/TBI/rPTCy group to similar patients who received FluMel conditioning with full-dose PTCy GvHD prophylaxis, the hazard ratio (HR) for developing aGvHD was 1.11 (0.32-3.83 CI 95 %). Similarly, the HR for developing cGvHD in the Pento/TBI group was 0.42 (0.11-1.65: CI 95 %).

Conclusion: Pento/TBI conditioning with rPTCy was well tolerated in a poor-risk group of patients undergoing first or subsequent allogeneic transplant and permitted rapid and full donor stem cell engraftment and full donor T cell chimerism. Furthermore, in a group of patients receiving HLA mismatched related and unrelated donor blood stem grafts, rates of aGvHD and cGvHD are similar to a control group of patients who received Flu-Mel conditioning and full-dose PTCy. Pento/TBI conditioning with rPTCy is a promising approach appropriate for patients with significant co-morbidities undergoing first allogeneic transplant or patients who require a second or third transplant following primary graft failure/rejection or relapse. The kinetics of immune reconstitution based on serial blood mononuclear cells collected post-transplant will be presented.

Rimando:Merck: Current holder of stock options in a privately-held company. Hall:Sanofi: Consultancy; CSL-Behring: Consultancy. Waller:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biolinerx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forte Bioscience: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cambium Medical Technologies: Current equity holder in private company; Cambium Oncology: Current equity holder in private company; Doximity: Current equity holder in private company.