Improved Outcome in Unrelated Donor Recipients After Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Advanced Relapse / Refractory Chronic Lymphocytic Leukemia

Abstract 4474

Chronic lymphocytic leukemia (CLL) remains incurable with standard therapies and a large number of patients become refractory to treatment or develop toxicities that prevent further treatment and contribute to their mortality. Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only known curative treatment for CLL. However, management and prevention of toxicities as well as patient / donor selection remain as the most significant challenges that limit the success of this treatment.

In this observational study we evaluated the efficacy and tolerability of Allo-HSCT in relapse / refractory patients with CLL and correlated the clinical outcome with prognostic markers as well as the donor type.

All patients were enrolled at the University of California, San Diego - Moores Cancer Center between November 1998 and July 2009. Eighteen patients with progressive relapse / refractory CLL were included (9 males [8 Caucasian, 1 Hispanic], 9 females [8 Caucasian, 1 Hispanic]), nine patients received stem cells from related donors and the other nine from unrelated donors. The median age was 50 years (age range, 26–71), median interval between diagnosis and Allo-HSCT was 83 months, and the median number of regimens prior to transplant was 5.3 (range, 2–11).

Five out of eighteen patients were fludarabine-refractory and one was not evaluable (NE). All patients had a high-risk disease at the time of transplantation, with advanced stages according to Rai classification, and high prevalence of IgV_H unmutated state, as well a high expression of CD38 and ZAP-70. Six patients had cytogenetic abnormalities, ten were normal and two were not evaluated. The most common pre-transplantation cytogenetic alteration was deletion 17p (33.3%), followed by deletion 13q (22.2%) and deletion 11q (22.2%). Prior to Allo-HSCT, three were in CR, ten patients were in PR and five had PD. CMV serologic reactivity was present in 67% of patients. Seventeen patients received non-myeloablative conditioning regimens and one patient was treated with a myeloablative regimen.

Disease status was assessed 30 and 100 days, 1, 2 and 3 years post Allo-HSCT. 13 out of 18 patients showed response to Allo-HSCT (6 PR and 7 CR) with the remaining patients having PD. Two patients had acute GVHD and 3 patients had extensive chronic GVHD. We observed no differences in the rate of GVHD in unrelated vs. related donor recipients (p=0.1). Five patients died, three due to progression of the disease, one due to post-transplant organ failure and one for acute GVHD. Survival analysis showed a median OS of 60.1 ± 3.9 months. We observed a significant difference in terms of OS in patients who had unrelated vs. related transplants (HR=3.1 [95% CI 1.5–18.7]). We observed no difference in survival of patients discriminated by the IgV_H mutational status (HR =1.8 [95% CI 0.2–17.5]) or ZAP-70 expression (HR =1.0 [95% CI 0.9–1.1]). The median progression free survival was 56 months.

Five of the 18 patients were retreated with donor lymphocyte infusions or a second Allo-HSCT after relapse or lost of chimerism. Three of these patients died of PD while the other two are still alive.

In conclusion, Allo-HSCT induces long-term remission and survival in high-risk relapse / refractory CLL patients including patients with multiple previous treatments and progressive disease status at the time of transplantation. The response to Allo-HSCT is independent of prognostic markers such as IgV_H and ZAP-70 expression. Patients that received stem cells from unrelated donors have a better clinical outcome including OS with no evidence of increased GVHD.