Secondary MDS/AML In Hodgkin Lymphoma Patients Treated within German Hodgkin Study Group (GHSG) Clinical Trials After Introduction of the BEACOPP Protocol

With modern multi-agent chemotherapy regimens optionally combined with radiotherapy, even patients with advanced Hodgkin lymphoma (HL) are cured in over 80% of cases. Since there is only little room for further therapeutic improvements, one major focus of current clinical research in HL consists in reducing treatment-related late effects such as secondary malignancies. Secondary MDS/AML represents a relevant problem since it was reported to be associated with a very poor prognosis. To shed some more light on incidence, course and outcome of patients with secondary MDS/AML after HL treatment, we performed an analysis addressing this issue. Patients treated within German Hodgkin Study Group (GHSG) clinical trials after introduction of the BEACOPP protocol were included.

11891 HL patients of all stages aged 16 to 75 and treated within the third (HD7-HD9, 1993–1998), fourth (HD10-HD12, 1998–2003) and fifth (HD13-HD15, 2003–2009) GHSG trial generation, the BEACOPP14 pilot study (1997-2000) and a phase II trial evaluating the role of GnRH analogues and oral contraceptives in female patients receiving BEACOPPescalated were retrospectively analyzed. Treatment consisted of radiotherapy alone, chemotherapy alone or combined-modality approaches.

With a median follow-up of 70 months, overall secondary MDS/AML rate was 0.8% (99 patients). However, 13 patients had a concurrent event (i.e. progress/relapse of HL or another secondary malignancy requiring salvage treatment) prior to MDS/AML diagnosis so that 86 patients were included in the present analyses. Median time from HL treatment to MDS/AML diagnosis was 28.3 months. The median age of patients developing secondary MDS/AML was significantly higher than the median age in the whole patient group (41 vs 34 years, p=.0002). To determine the impact of treatment intensity on the risk to develop secondary MDS/AML, patients were assigned into three groups. Groups consisted of patients who had received no BEACOPP-containing treatment, less than four cycles of BEACOPPescalated and four or more cycles of BEACOPPesclated, respectively. As a result, patients receiving four or more cycles of BEACOPPescalated had a significantly increased risk to develop secondary MDS/AML when compared to the other groups (5-year cumulative incidence 1.5% vs 0.5% and 0.3%, respectively, log-rank p<.0001). In 36 patients included in this analysis, allogeneic stem cell transplantation (aSCT) was applied to treat secondary MDS/AML. Patients who received aSCT had a significantly lower median age than those treated with conventional chemotherapy or supportive care only (35 vs 50 years, p=.0016) and showed an improved outcome. However, median overall survival (OS) after MDS/AML diagnosis was only 7.2 months.

Secondary MDS/AML is a relevant problem after HL therapy particularly in patients diagnosed with advanced stages treated with intensive first-line protocols. However, the clinical benefit achieved by the use of these more intensive protocols clearly outweighs the risk of developing secondary MDS/AML. To reduce the risk of developing secondary MDS/AML, novel treatment strategies should include risk-adapted early treatment stratification based on modern tools such as positron emission tomography (PET) to prevent overtreatment whenever possible.

No relevant conflicts of interest to declare.