HLA-Matched Unrelated Donor HCT after Nonmyeloablative Conditioning for Patients with Chronic Myeloid Leukemia.
Authors: Baron Frederic , Maris M. , Sandmaier B. , Storer B. , Stuart M. , McSweeney P. , Radich J. , Pulsipher M. , Agura E. , Petersdorf E. , Heimfeld S. , Chauncey T. , Little M.T. , Maloney D. , Blume K. , Storb R. 
Published: April 2020

We retrospectively analyzed the efficacy of unrelated HCT after nonmyeloablative conditioning with fludarabine 3 x 30 mg/m2 and 2 Gy total body irradiation as treatment for CML. Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine. Data from 21 CML pts in CP1 (n=12), AP (n=5), CP2 (n=3), or BC (n=1) were analyzed. Median pt age was 54 (range, 33–66) years. Median time from diagnosis to HCT was 26 (range, 5–121) months. Two pts (in BC and in AP) had previously failed myeloablative allogeneic HCT. Four pts received marrow as stem cell source, and 17 G-PBMC. Two pts each had single HLA class 1-allele mismatches with their donor, the remaining were matched for 10/10 HLA antigens. One pt died before donor engraftment was evaluable. Donor engraftment at day 28 (defined as ≥ 5% donor T-cell chimerism) was observed in 18 of the 20 evaluable pts (90%), and was sustained in 11 of those (55%). All graft rejections were nonfatal and followed by autologous hematopoietic reconstitution. Day 28 T-cell chimerism was assessed in 19 pts. Eight of 9 pts with day 28 donor T-cell chimerism levels ≤ 40 rejected their grafts, compared with 1 of 10 pts with day 28 T-cell chimerism levels &gt; 40%. The two marrow recipients who had not received chemotherapy prior to the HCT rejected their grafts. Eight of 11 (70%) patients with sustained engraftment (including 4 of 5 pts in CP1, 3 of 4 pts in AP, 1 of 2 pts CP2) achieved sustained complete cytogenetic remissions (CCR) (Table 1). In addition, another patient who had progressed to blast crisis after HCT achieved CCR and BCR/ABL molecular negativity by Q-PCR, following a short course of farnestyl transferase inhibitor and development of chronic GVHD. Analysis of minimal residual disease by Q-PCR in 6 pts with sustained CCR showed disappearance of BCR/ABL transcripts 84 to 524 days after HCT, consistent with graft-versus-tumor effects. Grade II-IV acute GVHD was seen in 11 pts and extensive chronic GVHD in 8. One pt transplanted in CP2 died of progressive disease (PD), and two pts transplanted in CP2 (n=1) and in AP (n=1) died of nonrelapse mortality (NRM), while in CCR. Three of 9 pts with graft rejection died of progressive disease, 5 were alive in CP, and 1 in AP at the time of the analysis. One hundred-day and two-year nonrelapse mortalities for all pts were 0% and 12%, respectively. Two year probability of overall survivals were 100% for pts transplanted in CP1, and 0% for those transplanted in more advanced stage. In summary, unrelated donor HCT following nonmyeloablative conditioning with fludarabine and low-dose TBI was feasible with low nonrelapse mortality. Sustained CCR were achieved in patients with stable engraftment, but graft rejection occurred in 45% of pts. Further efforts are being directed at reducing the risk of graft rejection by exclusive use of G-PBMC and increasing the intensity of pretransplant immunosuppression.

Outcome

Status at HCT Graft rejection Outcome (days after HCT) CP1 (n=12) No (n=5) Alive in CCR (1205+, 1126+, 1123+, 867*+, 89+) Yes (n=7) Alive in CP (1188+, 960+, 946+, 698+, 533+) Alive in AP (356+) Death of PD (806) AP (n=5) No (n=4) Alive in CCR (267+, 115+) Death of NRM (478) Death of PD (241) Yes (n=1) Death of PD (271) CP2 (n=3) No (n=2) Death of NRM (164) Death of PD (233) Yes (n=1) Death of PD (540) BC (n=1) NE Died of PD (21)