R-DHAP Immunochemotherapy Is An Effective Remission-Induction Treatment For CLL Patients With Fludarabine Refractory Disease With Or Without Deletion 17p, Enabling The Majority To Proceed To Allogeneic Stem Cell Transplantation
Authors: Van Gelder Michel , Ghidey Wendim , Chamuleau Martine ED , Cornelissen Jan , Petersen Eefke J , Daenen Simon M. G. J. , Zachee Pierre , Hoogendoorn Mels , Beker Aart , Timmers Gert Jan , Kater Arnon P. , Van Oers Marinus H.J. 
Published: October 2019

Abstract

Introduction
Allogeneic stem cell transplantation (alloSCT) is the only potentially curative treatment for relapsed CLL patients with fludarabine refractory disease and/or a deletion 17p del(17p). Retrospective analyses identified bulky disease and lack of response to last treatment as predictors for poor survival. There is an unmet need for active salvage regimens for these high-risk patients, but so far prospective data on salvage regimens prior to alloSCT are lacking. Here we report our results with R-DHAP remission-induction studied in a prospective international multicenter phase 2 study. The rationale for R-DHAP is formed by in vitro studies showing that platinum induces p53 independent cell death.
Patients up to the age of 70 years with fludarabine refractory CLL (defined, according to the EBMT consensus, as relapse within 1 year after fludarabine monotherapy or within 2 years after fludarabine plus a monoclonal antibody) and/or with relapsed CLL with a del(17p) , and with an indication for treatment were eligible for inclusion. Patients received at least 3 cycles of R-DHAP salvage therapy (rituximab on day 1 (375mg/m2 1st cycle, 500 mg/m2 later cycles), cisplatinum 100mg/m2 (day 1), cytarabine 2x2000mg/m2 (day 2) and dexamethasone 40mg days 1-4) every 4 weeks. Response to R-DHAP was determined according to 2008 IWCLL guidelines.

Results
Forty patients have been included from February 2009 till April 2012. One patient was ineligible because of Richter’s syndrome at the time of inclusion. The median age was 59 years (range 43-69) and the median number of prior therapies was 2 (range 1-5).
Twenty-four patients completed at least 3 cycles of R-DHAP. Due to long donor search. two of these received 4 cycles, two 5 and 1 six cycles. Nine patients received only one or two cycles of R-DHAP because of toxicity, and two patients never received R-DHAP due to poor performance. Overall response rate (ORR) for all 39 eligible patients was 56%: 6 CR (15%), 16 PR (41%). Five patients had SD (13%) and 2 PD (5%). ORR rates in patients with bulky lymphadenopathy (>5 cm, n=18) and in those having del(17p) (n=17) was 67% and 53% respectively.
In the first 16 patients four infection related deaths occurred (3 septic shock and 1 encephalitis). After an amendment optimizing infection prophylaxis, no additional severe bacterial or fungal infections or infection related deaths were observed.
Twenty-six patients proceeded to alloSCT (67%). With a median follow-up of 16 months (range 6-42 months) 2-years progression-free survival (PFS) and overall survival (OS) after transplantation is 63% and 72% respectively. Sixteen are free from progression and 3 progressed but are still alive. Seven patients died (3 from acute GVHD, 2 due to encephalopathy, 2 other reasons).

Conclusion
R-DHAP is an effective remission-induction regimen for fludarabine-refractory CLL patients even in those having bulky lymphadenopathy and/or del(17p), enabling a high percentage of patients to proceed to alloSCT resulting in a high PFS and OS at 2 years.

Disclosures:
No relevant conflicts of interest to declare.