IMPACT OF DOSE DENSITY AND HEMATOTOXICITY OF DHAP-REINDUCTION THERAPY ON THE OUTCOME IN RELAPSED HODGKIN LYMPHOMA (HL): AN ANALYSIS OF THE GERMAN HODGKIN-STUDY GROUP (GHSG)

Background:

Despite of an intensive reinduction therapy followed by highdose- chemotherapy (HDCT) and autologous stem cell transplantation (ASCT), only 50% of patients with relapsed Hodgkin Lymphoma (HL) achieve long-term remission. Response to reinduction treatment is predictive for the outcome. In order to optimize the reinduction therapy in relapsed HL, we aimed at increasing dose density of DHAP (dexamethasone, high-dose cytarabine, cisplatinum) in the HDR2 trial by shortening the cycle interval from 21 to 14 days.

Aims:

In this retrospective analysis of the HDR2 trial, the clinical impact of dose density of DHAP was evaluated. In addition, we assessed the impact of DHAPassociated hematotoxicity on dose density and treatment outcome.

Methods:

In the HDR2 trial, patients with relapsed HL without disease progression after two courses of DHAP were randomized to receive additional sequential HDCT or to directly proceed to HDCT with BEAM followed by ASCT. 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 analyses were used to estimate the prognostic value of the DHAP cycle interval and of hematotoxicity on progression free survival (PFS) and overall survival (OS) after relapse. The impact of different variables on the length of DHAP cycle interval was examined with linear regression analysis. The level of significance was set to P<0.05.

Results:

Data of 269 patients were evaluable for this analysis. The median age was 36 years; 36% of the patients analyzed were female, 53% had advancedstage 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 analyzed 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. 232 patients were randomized after two courses of DHAP. A significant association between the length of the DHAP cycle interval and the outcome was shown in univariate (PFS: P=0.017; OS: P= 0.012) as well as in multivariate cox regression analysis including early or multiple relapses, stage IV disease and anemia at relapse as established prognostic factors (PFS: P=0.035; OS: P=0.003). Patients who received the second DHAP course on day 21 or later had a significantly poorer PFS and OS when compared to those patients who proceeded before day 21 (3-year PFS 58% vs. 73%, P= 0.027; 3-year OS 76% vs. 87%, P=0.016, respectively). DHAP-associated grade 4 hematotoxicity had a significant impact on the length of DHAP course intervals (P=0.022 in multivariate linear regression analysis). Those patients who developed thrombocytopenia or leukocytopenia grade 4 had significantly longer course intervals. In addition to the prognostic factors of the Josting score and the length of the DHAP course interval (> 21/≤21 days), severe hematotoxicity was associated with a significantly shorter PFS (HR 1.36: P= 0.036) and OS (HR 1.79; P= 0.012) in multivariate analysis.

Summary / Conclusion:

Dose density of DHAP reinduction therapy is an independent prognostic factor with regard to PFS and OS in relapsed HL patients. Additionally, hematotoxicity grade 4 is a significant factor contributing to prolonged DHAP course intervals and has a negative impact on PFS and OS. These results support the mandatory use of G-CSF in this setting as well as an investigation of thrombopoietin analogues during DHAP reinduction therapy in order to maintain dose density.

Abstrakta v časopise Haematologica 2013, Suppl1

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