Prognostic Relevance of Dose-Density of DHAP-Reinduction Therapy in Relapsed HL: An Analysis of the German Hodgkin-Study Group (GHSG)
Authors: Sasse Stephanie , Alram Magdalena , Mueller Horst , Smardova Lenka , Metzner Bernd , Döhner Hartmut , Fischer Thomas , Vucinic Vladan , Schmitz Norbert , Schäfer-Eckart Kerstin , Raemaekers John M. , Schmalz Oliver , von Tresckow Bastian , Engert Andreas , Borchmann Peter 
Published: October 2019

Abstract
Abstract 552

Purpose:
Only about 50% of relapsed Hodgkin Lymphoma (HL) patients achieve long-term remission with intensive reinduction therapy followed by high-dose-chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). Response to reinduction treatment indicates chemosensitivity and is predictive for the outcome. An important determinant for the efficacy of reinduction therapy was thought to be dose-density. Based on this hypothesis, we aimed at increasing dose density of DHAP (dexamethasone, high-dose cytarabine, cisplatinum) in the HDR2 trial for patients with relapsed HL by shortening the cycle interval from 21 to 14 days. This was feasible after the introduction of G-CSF and consecutive reduction of neutropenia. However, the prognostic relevance of dose-density of DHAP or any other regimen in relapsed HL has never been proven. Therefore we performed a retrospective analysis of patients treated in the HDR2-trial with regard to time interval of DHAP courses and outcome.

Patients and methods:
In the HDR2 trial, patients with relapsed HL initially received two courses of DHAP. Those patients without disease progression after DHAP were randomized to proceed to HDCT with BEAM and ASCT or to receive additional sequential high-dose reinduction chemotherapy before BEAM and ASCT (Josting et al, JCO 2010). DHAP cycle interval was defined as the time interval between day 1 of the first course and start of the second DHAP course. Kaplan-Meier and Cox regression analysis were used to estimate the prognostic value of the DHAP cycle interval on progression-free survival (PFS) and overall survival (OS) after relapse. Mean differences of DHAP cycle intervals depending on thrombocytopenia were tested using a t-test for independent groups. The level of significance was set to P < 0.05.

Results:
From a total of 284 HL-patients included, 269 patients were evaluable for this analysis. The median age was 36 years, 36% of the patients analyzed were female, 53% had advanced-stage disease at diagnosis of relapse, and 13% had received >1 previous chemotherapy. Median time from initial diagnosis to relapse was 44.3 months. Only 15% of the HL patients received the second DHAP course within the recommended time interval of 14 days; in 39% the DHAP course interval was 21 days or longer.
Cox regression analysis showed a significant association between the length of the DHAP cycle interval and PFS (p= 0.012). This was confirmed (p=0.035) even after adjustment for established prognostic factors including early or multiple relapses, stage III or IV at relapse, and anemia at relapse (Josting et al., 2002). In addition, overall survival was also significant as determined in the multivariate analysis (p=0.003). Patients who received the second DHAP course on day 21 or later had a significantly lower PFS and OS than those patients who proceeded with the second course before day 21 (3-year PFS 58% vs. 73%, p= 0.027; 3-year OS 76% vs. 87%, p = 0.016, respectively). Grade 4 thrombocytopenia occurred frequently (30%, grade 3/4 = 60%) and contributed significantly to the duration of the cycle. The mean DHAP cycle interval was longer for patients with grade 4 thrombocytopenia (20.9 days) than for patients with grade 0–3 thrombocytopenia (19.3 days, p= 0.028). Both PFS and OS were significantly reduced compared to those patients who did not develop thrombocytopenia grade 4 (3-year PFS 58% vs 70%, p= 0.029; 3-year OS 71% vs 88%, p= 0.002).

Conclusion
This is the first analysis showing that dose density of DHAP reinduction therapy is a significant and relevant prognostic factor with regard to PFS and OS of relapsed HL patients. Based on these findings, we recommend minimized cycle duration during reinduction therapy for relapsed HL patients in clinical routine. Furthermore, thrombocytopenia is a frequent and also significant factor which contributes to prolonged DHAP course intervals, and has a negative impact on PFS and OS. These findings support the investigation of thrombopoietin analogues during DHAP reinduction in relapsed HL patients in order to maintain dose density.

Disclosures:
No relevant conflicts of interest to declare.