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Long-term follow-up data confirms superior tumor control of more intensive chemoradiationtherapy with early-stage, unfavorable Hodgkin’s lymphoma

The GHSG HD14 trial previously established that more intensive therapy consisting of 2 courses of escalated BEACOPP followed by 2 courses of ABVD (‘2+2’) in combination with 30 Gy radiotherapy (RT) results in a significantly better progression free survival (PFS), compared to 4 courses of ABVD + 30 Gy RT in patients with early-stage unfavorable Hodgkin’s lymphoma (HL). Long-term follow-up data of this trial confirms this finding with a 5.6% absolute difference in PFS rate at 10 years (91.2% in 2+2 vs. 85.6% in ABVD). Moreover, this longer follow-up underscored that the more intensive therapy did not lead to a higher rate of second primary malignancies, nor did it result in more treatment- or HL-related mortality.

Background

In early-stage unfavorable HL, long-term tumor control is approximately 80% with 4x ABVD and 30 Gy involved-field radiation therapy (IFRT). To improve on these results, the GHSG HD14 trial assessed whether an intensified chemotherapy regimen consisting of 2 cycles of escalated BEACOPP plus 2 cycles of ABVD (2+2) would result in a better disease control than 4 cycles of ABVD. All patients in this trial received 30 Gy of IFRT. At the five year mark, the 2+2 regime was found to be associated with a 6.2% absolute benefit in PFS rate compared to 4x ABVD. This formed the basis to adopt 2+2 plus 30 Gy IFRT as the current GHSG standard for patients with early-stage unfavorable HL. The NCCN and ESMO guidelines also denote the 2+2 regime as a first-line treatment option in this setting. However, the fact that the HD14 trial failed to show an overall survival (OS) advantage of 2+2 over ABVD made that this more intensive treatment is not yet widely accepted in clinical practice. Moreover, the potential long-term toxicity of 2+2 is being debated. To address these issues, a long-term follow up analysis of HD14 was performed with a median follow-up time of 104 months.

Study population

From January 2003 to July 2008 a total of 1,550 patients with early-stage unfavorable HL aged 60 years or younger were randomized between the 4xABVD and 2+2 regimes, followed by 30 Gy IFRT in all patients. This randomization was discontinued when the third planned interim analysis of the trial showed a significant advantage for 2+2 in terms of freedom from treatment failure (FFTF). The difference was 7.2% at 5 years and this was the primary endpoint of the trial. From this time forward, patients continued only in the 2+2 arm from July 2008 to December 2009. Moreover, 339 additional qualified patients were treated with 2+2 and 30 Gy. These patients were not reported in the initial report but were added to all analyses of this long-term follow-up.

Results

After a median observation time of 97 months for PFS, 10.2% (79 of 777) and 3.4% (38 of 1112) of patients treated with 4x ABVD and 2+2, respectively, experienced disease progression or relapse. At 10 years, this translated into a PFS rate of 85.6% for 4x ABVD compared to 91.2% for 2+2. This accounts for a statistically significant PFS difference of 5.6% in favor of 2+2 (HR[95%CI]: 0.523[0.387-0.707]; p< 0.0001). Two or more relapses were experienced by 21 of 777 (2.7%) and 10 of 1112 (0.9%) patients who had received 4x ABVD or 2+2 as first-line treatment, respectively. Just like in the primary analysis, this PFS benefit did not translate into a difference in OS between the two groups. Importantly, at the ten year mark, the OS rates in both arms were still very high at 94.1% for 4x ABVD and 94.0% for 2+2. No difference was seen between 2+2 and 4x ABVD regarding late effects. Overall, the HL-related mortality in the trial was low (<1%) as was the rate of treatment-related mortality (approximately 1%). In total, 95 second primary malignancies were reported, corresponding to a 10-year cumulative second malignancy incidence of 4.7% for 4x ABVD and 6.4% for 2+2.

Conclusions

This long-term analysis confirms the superior tumor control of 2+2 as compared to 4x ABVD in patients ≤60 with early-stage, unfavorable HL. However, also with this longer follow-up, this did not translate into a better OS for patients treated with the 2+2 regime. Importantly, no difference was seen between both treatment arms with respect to second primary malignancies.

Reference

Von Tresckow B, et al. Dose-Intensification in Early Unfavorable Hodgkin Lymphoma: Long-Term Follow up of the German Hodgkin Study Group (GHSG) HD14 Trial. Presented at ASH 2019; Abstract 129.

Speaker Bastian von Tresckow

Tresckow1

Bastian von Tresckow, MD, German Hodgkin Study Group (GHSG) and University of Cologne, Germany

 

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