R-DHAP Immuno-Chemotherapy Is An Effective Remission-Induction Treatment for Fludarabine Refractory CLL Patients and Allows the Majority to Proceed to Allogeneic Stem Cell Transplantation. Results of the Planned Interim Analysis of the Dutch-Belgian Prospective Multicenter HOVON88 Trial,
Authors: Van Gelder Michel , Ghidey Wendim , Chamuleau Martine ED , Cornelissen Jan J , Wu Ka Lung , Hoogendoorn Mels , Daenen S. M. G. J. , Petersen Eefke , van Oers Marinus H. J. 
Published: October 2019

Abstract
Abstract 3911

Introduction
Allogeneic stem cell transplantation (alloSCT) is the only potentially curative treatment for relapsed CLL patients with fludarabine refractory disease or a deletion 17p (del 17p). Retrospective analyses identified bulky disease and lack of response to last treatment as predictors for poor survival. The optimal salvage regimen for these patients is not clear, nor is it known what percentage of these patients does respond to salvage therapy before the transplantation. Here we report our results with R-DHAP studied in an international multicenter phase 2 study. The rationale for choosing R-DHAP is that in vitro treatment with platinum and a nucleoside analogue of fludarabine refractory CLL cells with or without dysfunctional p53 in vitro induces cell death independent of p53.1 Patients up to the age op 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) or with relapsed CLL with a del 17p (assessed by FISH), and in need of treatment were eligible for inclusion. Patients were treated with at least 3 cycles of R-DHAP salvage therapy (rituximab 375mg/m2 1st cycle, 500 mg/m2 later cycles, cisplatinum 100mg/m2, cytarabine 2×2000mg/m2 and dexamethasone 4×40mg) once per 4 weeks. A planned interim analysis as to toxicity and efficacy was performed following remisison-induction completion by the 20th patient. According to protocol, the study had to be reconsidered if less than eight out of the first 20 patients actually had received alloSCT, or in case of excessive toxicity.

Results
Twenty patients were included from Feb 16, 2009 till Jan 19, 2011. The median age was 59 years (range 43–68) and the median number of prior therapies was 3 (range 1–5). Fourteen were refractory to fludarabine monotherapy and 16 refractory to fludarabine containing immuno-chemotherapy. Ten of these 20 patients also had del 17p. Six had bulky lymph-adenopathy (>5 cm). Eleven patients completed all 3 R-DHAP cycles on protocol. Responses in these 11 patients were 1xCR, 6xPR and 4x stable disease (SD). Six of these 11 patients also had del 17p and their responses were 1xCR, 3xPR and 2x SD. All 11 patients subsequently proceeded to alloSCT. Three patients received only one or two cycles of R-DHAP as the treatment was considered to toxic and went off-protocol. All three had responsive disease. One patient responded to 1 cycle of R-DHAP but went of protocol due to infectious toxicity and did not proceed to alloSCT. Another patient had disease progression after the 1stR-DHAP and died. All eleven patients treated with 3-R-DHAP cycles and all three responding off-protocol patients received alloSCT immediately following R-DHAP. CTC grade 5 infectious toxicity was noted in 4 patients, including three with fatal septic shock and one with fatal encephalitis in 1. Nine other patients suffered from grade 4 infectious toxicity: febrile neutropenia (n=7), septic shock (n=1), pneumonia (n=3), urinary tract infection (n=1), or catheter-related infection. Despite infections, eight of these 13 patients could proceed to alloSCT. Optimized antibacterial and antifungal prophylaxis was amended to the protocol as from the 16th patient onwards. Since then 13 additional patients were entered in the study and until now none developed severe bacterial or fungal infection or died.

Conclusions
R-DHAP is an effective remission-induction regimen for fludarabine-refractory or early relapsed patients with or without del 17p, allowing a relatively high percentage of patients to proceed to alloSCT (14/20) Despite efficacious, significant infectious toxicity accompanied R-DHAP, necessitating strict adherence to antimicrobial prophylaxis.
1. Tonino SH, van Laar J, van Oers MH, Wang JY, Eldering E, Kater AP. ROS-mediated upregulation of Noxa overcomes chemoresistance in chronic lymphocytic leukemia. Oncogene. 2011;30:701–713.

Disclosures:
No relevant conflicts of interest to declare.