Conversion of Low Donor Chimerism Following Nonmyeloablative Conditioning for Hematopoietic Cell Transplantation (HCT) Using Pentostatin and Donor Lymphocyte Infusion (DLI).
Authors: Sandmaier Brenda M. , Maloney David G. , Maris Michael B. , Chauncey Thomas R. , Pulsipher Michael , Bethge Wolfgang , Little Marie-Terese , Storb Rainer 
Published: October 2019

Abstract
Nonmyeloablative allogeneic HCT from both related or unrelated HLA-matched donors after pretransplant conditioning with 2 Gy TBI with or without fludarabine and with posttransplantation CSP/MMF has resulted in initial mixed donor/host chimerism in the majority of recipients. While the risk of rejection of HLA-matched related or unrelated donor grafts was <5% with the regimen, low donor CD3 chimerism appeared to predict rejection. We previously analyzed the outcomes in patients given DLI for either persistent/recurrent disease or low donor chimerism (Blood. 2004; 103:790). Among patients given DLI for low or falling donor CD3 chimerism, success was seen only with pre-DLI CD3 chimerism levels >40%. Among patients receiving DLI for disease, those with disease responses had chimerism levels >90% after DLI, supporting the concept that full chimerism was necessary to eradicate malignant cells and exert graft-vs-tumor effects. Therefore, a protocol was developed to evaluate safety and efficacy of the immunosuppressive drug pentostatin given before DLI to reverse pending graft rejection. Patients considered at risk for rejection had low (<50%) or declining (>20%) donor CD3 chimerism and persistent or stable (including CR) malignant disease; they had no ongoing acute grades II-IV GVHD nor chronic extensive GVHD. Eight patients have been treated a median of 100 (range 54–339) days after HCT. They were originally conditioned for HCT with 2 Gy TBI with (n=7) or without (n=1) fludarabine (30 mg/m2 per day x 3 days) and given both donor and host immunosuppression with MMF and CSP after HCT. Donors were HLA-matched related (n=6) or unrelated (n=2). Diagnoses included NHL (n=2), CLL (n=2), AML (n=1), CML (n=1), and multiple myeloma (n=1); median patient age was 54.5 (range 44–66) years. The patients received pentostatin (4 mg/m2) 2 days before DLI (107 CD3 cells/kg); no post-DLI immunosuppression was given. The median donor CD3 chimerism level before pentostatin and DLI was 29.5 (range 5–34)%. Five patients developed neutropenia and the median number of days of ANC <500 was 11 (0–36) days. Four of 8 patients showed increases of donor CD3 chimerism levels ranging from 63–100%. All 4 patients developed acute GVHD (Grades II n=2; III n=2), and two, chronic extensive GVHD. Currently all 4 patients are alive (CR=3; PR=1) a median of 218 (66–293) days after DLI and 305 (127–377) days after HCT. In the remaining 4 patients, donor CD3 chimerism remained at 5–25% following DLI; two patients received second HCT from the original donors for persistent low chimerism and aplasia, one patient died in CR from infectious complications, and the second is alive in CR with persistent low donor chimerism day 141 following the second HCT. The remaining two patients with low donor chimerism are alive in relapse 157 and 395 days after DLI and 255 and 734 days, respectively, after HCT. In summary, preliminary findings suggest that immunosuppression with pentostatin followed by DLI may be more effective for conversion to full donor chimerism then DLI alone for patients at risk for graft rejection after a nonmyeloablative HCT.