Allogeneic Hematopoetic Transplantation for CLL: Results of Combination Chemotherapy as Pre-Transplant Targeted Lymphocyte Depletion on Disease Response, Donor Chimerism, and Transplantation Outcomes.
Authors: Shaffer Brian C , Modric Marko , Liewehr David , Stetler-Stevenson Maryalice , Arthur Diane C , Steinberg Seth , Hakim Frances T , Bryant Kelly , Odom Jeanne , Layton Paula , Salit Rachel B , Rader Christoph , Gress Ronald E , Fowler Daniel H , Bishop Michael R , Pavletic Steven Z 
Published: October 2019

Abstract
Abstract 3476
The development of reduced intensity conditioning (RIC) regimens has increased the use of allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with chronic lymphocytic leukemia (CLL). Despite decreased rates of transplant related mortality, RIC regimens confer slower rates of donor engraftment and increased relapse post-transplant. It has been reported that faster rates of conversion to donor chimerism after RIC alloHSCT result in lower rates of CLL relapse1. We hypothesized that systematic targeted host T-lymphocyte depletion (TLD) to a target level by serial administration of standard chemotherapy prior to RIC alloHSCT will result in more rapid donor engraftment and full donor chimerism, thereby enhancing graft versus leukemia activity. We evaluated the effects of TLD on host CD4 lymphocyte depletion, disease response, and toxicity as well as donor engraftment, non-relapse mortality, and disease control in 27 patients undergoing RIC alloHSCT for CLL from 1999 to 2010. All patients underwent TLD receiving 1–3 cycles of EPOCH-F±R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, fludarabine ± rituximab) prior to RIC (fludarabine/cyclophosphamide) and matched-related (N=17) or unrelated (N=10) donor transplantation followed by calcineurin inhibitor-based GVHD prophylaxis. The number of cycles administered (max of three cycles) was titrated to achieve an absolute CD4 count ≤ 100 cells/μL prior to RIC. The median number of EPOCH-F±R cycles given was 2. The median CD3+, CD4+, and CD8+ lymphocyte counts at baseline were 819, 443, and 269 cells/μL, respectively. The median CD3+, CD4+ and CD8+ lymphocyte counts after TLD were 124, 97, and 52 cells/μL, respectively. The overall response rate to EPOCH-F±R was 50% (9% CR, 41% PR), including 44% of patients who were refractory to their last treatment. The incidence of grade 3 and 4 non-hematologic toxicity with TLD was 72% and 32%, respectively. No patients failed to engraft. The median days to full donor peripheral blood lymphoid and myeloid chimerism were 28 (14-60) and 21 (14-180), respectively. Development of full lymphoid chimerism by day 14 (first evaluation point) versus day 28 or greater trended towards association with development of acute GVHD (90% vs. 35%, P=0.014) but not chronic GVHD (50% vs. 41%, P=0.71). Achievement of full lymphoid chimerism on day 14 as compared to day 28 or greater trended towards association with decreased CLL cells identified in the bone marrow by multicolor flow cytometry at day 100 (median 0% vs. 8.5%, P=0.016) but was not associated with (P=0.077) improved overall survival (OS). There was no association between rates of development of full myeloid chimerism and acute or chronic GVHD or disease control. The rates of acute (grade 2–4) and chronic GVHD were 52% and 44%, respectively. Non-relapse related mortality at one and two years was 21% and 30%, respectively. The rate of complete remission was 54% and the rate of minimal residual disease negativity after transplantation as assessed by multicolor flow cytometry was 55%. The incidence of disease progression after transplant was 33%. The three year event-free and OS probabilities were 56% and 57%, respectively. The median OS was 5.99 years (95% CI, 2.11-NR). In summary, the use of TLD resulted in a high rate of early donor engraftement after RIC alloHSCT in patients with CLL. Rapid donor engraftment was associated with better disease control and occurence of acute GVHD, but it did not appear to alter overall survival. These data suggest that methods resulting in faster donor chimerism may improve CLL control after RIC alloHSCT. Separation of antileukemic effects from severe GVHD remain a challenge.
1. Brown JR et al. Biol Blood Marrow Transplant. 2006 Oct;12(10):1056-64.
Table 1: Patient characteristics at study entry N 27 Median age (range) 56 (37–71) Number male 21 (78%) Rai stage 3/4 16 (59%) Poor risk cytogenetics1 (n=25) 12 (44%) Bulky disease ≥5 cm (n=25) 6 (24%) ≥4 Prior regimens 16 (59%) Refractory to last regimen 14 (52%) Median time from diagnosis to HSCT (range) 58 m (17–205) Sorror comorbidity score2     0-2 20 (74%)     3+ 7 (26%) 1. Defined by deletion of 17p or 11q. 2. Sorror et al. Blood 2005;106:2912-2919.

Disclosures:
No relevant conflicts of interest to declare.