5.39 Feasibility Analysis of Non-myeloablative Allogeneic Stem Cell Transplantation in Patients with Chronic Lymphocytic Leukemia and 17p Deletion

Abstract

Background: Deletion of 17p (17p–) is the principal predictor of poor outcome in chronic lymphocytic leukemia (CLL) patients after conventional chemotherapy. Several reports have shown better outcomes with non-myeloablative allogeneic stem cell transplantation (NST). However, questions have been raised as to the relevance of NST, in particular, the extent that various selection biases lead to selection of only the ‘best’ patients for this procedure. Purpose: Our primary goal was to update our NST experience with 17p–, and report how often patients underwent transplantation and, within the limits of a retrospective analysis, the reasons for not undergoing transplantation. Methods: We reviewed NST outcomes for 17p– CLL patients transplanted between 2005 (when FISH became routinely performed at our institution) and 2010. Given the poor outcome after conventional fludarabine, cyclophosphamide, and rituximab (FCR) therapy, a diligent effort was started by the leukemia service in 2007 to refer patients to transplant sooner rather than later. Therefore, in a subanalysis, we reviewed the number of 17p– CLL patients who were referred to the transplant consult service from 2007 and assessed the reasons for no transplant. Prognostic factors were evaluated using Cox’s regression model. Multivariate analysis was not possible given sample size limitations. Results: Outcome of NST in 17p– CLL patients: Twenty-six patients were transplanted at our institution between 2005 and 2010. The median age was 56 years (range 37–73 years). At NST, 15 patients (58%) had 2-microglobulin ( 2m) 3; 21/24 patients (87%) had Binet stage B/C disease; 4 patients (15%) had Richter’s syndrome; 16/25 patients (64%) were FDG-avid; the median number of prior chemotherapies was 4 (range 2–14); and 14 patients (54%) had refractory disease. Thirteen patients (50%) had complex cytogenetic abnormalities (in addition to 17p–). IGVH was unmutated in 11/12 patients (92%) tested and 14/15 (93%) were ZAP-70 positive. Prior to their transplantation, 24 patients (92%) were exposed to FCR, 11 (42%) to FCR plus alemtuzumab or oxaliplatin, 7 (27%) to hyper-CVAD, and 17 (65%) to alemtuzumab. With a median follow-up of 18 months (range 3–60 months), 2-year overall survival (OS) and progression-free survival (PFS) rates were 62% and 38%, respectively. On univariate analysis, determinants of outcomes included disease status, 2m at NST, and year of transplant. All but 1 patient with chemosensitive disease had 2m 4, compared with 50% of patients with chemoresistant disease. Chemosensitivity was associated with significantly higher PFS (73% vs 12%, p 0.02; Figure) and a trend toward higher OS (91% vs 45%, p 0.09). PFS was also significantly higher for transplants performed after 2007 (44% vs 20%, p 0.03). 2m 4 was associated with lower 18 month OS (36% vs 71%, p 0.05) in chemoresistant patients, but did not significantly impact PFS (38% vs 14%, p 0.5). Two years’ follow-up was not reached for 2m 4 in this group. Transplant consults and transplantation rate: Between September 2007 and March 2010, 59 patients with 17p– CLL received a transplant service consult. Twenty of these patients (34%) had received a transplant at the time of this analysis, whereas 39 (66%) had not. Reasons for not receiving transplants included: (1) death with salvage pre-transplant chemotherapy (n 14, 36%); (2) patient and/or physician became uninterested after achieving a good response to salvage chemotherapy (n 14, 36%); (3) lost to follow-up after the initial consultation (n 3, 8%); (4) age 75 years (n 2, 5%); (5) insurance denial (n 3, 8%); (6) no donor (n 1, 2%); and (7) other (n 2, 5%). Conclusions: NST is plausibly more effective in 17p– CLL patients when recipients have chemosensitive disease. If, as suggested by our analysis, at most 34% of patients receive this procedure, methods to extend the applicability of transplant are needed. Perhaps the most effective method would be to use NST as consolidation after an initial response to conventional chemotherapy. Such a strategy would allow more patients to have chemosensitive disease at NST, and would decrease the death rate in heavily pre-treated patients during pre-transplant cytoreductive therapy.