Improved PFS seen in the G-B arm of the GADOLIN study did not result in poorer patient HRQoL

In February 2017, Bruce Cheson from the Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington DC, and colleagues published in the Annals of Hematology the results of a Health-Related Quality Of Life (HRQoL) assessment of patients who were treated as part of the GADOLIN phase III study. The phase III GADOLIN study compared bendamustine therapy (B) with combination therapy of obinutuzumab in addition to bendamustine (G-B). The study was conducted in patients who had CD20+ rituximab-refractory indolent Non-Hodgkin Lymphoma (iNHL) and found that the group who received G-B had a significantly longer PFS (G-B PFS = 25.8 months, B PFS = 14.0 months, HR = 0.57 (P<0.0001)), although with a higher incidence of ≥ grade 3 AEs. Full details of the GADOLIN study were presented by Bruce Cheson at the 58^th American Society of Hematology (ASH) Annual Meeting 2016 and reported by the Lymphoma Hub. Bruce Cheson also gave his comments on the GADOLIN trial in a video interview during ASH 2016.

HRQoL was quantified through the Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) questionnaire which was composed of two parts: FACT-General (FACT-G) which featured general questions, and FACT-Lym Lymphoma-specific Subscale (FACT-Lym LYMS). The reported results were grouped into three main summary measures: FACT-Lym trial outcome index (FACT-Lym TOI), FACT-G score, and FACT-Lym Total Score (FACT-Lym TOT). 

Key Highlights:

• 396 pts were recruited and randomized
• Treatment:
  • B group = B at 120mg/m²/day D1+D2 of each 28D cycle, max six cycles
  • G-B group = B at 90mg/m²/day D1+D2 of each 28D cycle: G at 1,000mg D1, D8, D15 of the first 28D cycle, then D1 of cycles 2–6, max six cycles
  • Pts without CR, PR, or SD by end of cycle 6 received 1,000mg G maintenance every two months, up to two years
• HRQoL questionnaire given at D1 of cycles 1, 3 and 5, at end of cycle 6, annually until PD
  • Pts undergoing G-maintenance were additionally given HRQoL every two months for two years or until PD
• HRQoL completion rates G-B vs B: baseline = 89.7% vs. 88.6%, end of induction = 77.7% vs. 76.1%, lowest completion rate at 18 months after end of induction = 76.1% vs. 58.1%
• Findings:
• Time to deterioration (FACT-Lym TOI)
  • Median time to deterioration: G-B = 8.0 months, B = 4.6 months
  • Divergence of FACT-Lym TOI scores occurred at Cycle 3
  • FL pts alone median time to deterioration: G-B = 7.8 months, B = 5.6 months
• Clinically meaningful improvement
  • More patients reported meaningful improvement in G-B group than B group reported through FACT-Lym TOI, FACT-Lym LYMS, and FACT-Lym TOT scores

In conclusion, the authors state that this study shows that the improved PFS seen in the G-B arm of the GADOLIN study did not result in poorer HRQoL due to treatment-related toxicities and adverse events, however the study was limited by the decay in successful complete of the FACT-Lym questionnaires.

Abstract:

We present health-related quality of life (HRQoL) data from GADOLIN, comparing bendamustine (B) alone or combined with obinutuzumab (G-B) in rituximab-refractory indolent non-Hodgkin lymphoma patients. The Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) questionnaire was administered on day 1 of cycles 1, 3, and 5 during treatment, at end of induction (EOI), bi-monthly for 2 years during maintenance/follow-up, and annually during extended follow-up until progression/death. Time to first ≥6-point worsening from baseline in the FACT-Lym trial outcome index (TOI) was estimated. Minimally important differences at individual subscale and total score level were used to define the proportion of patients reporting improvement on the FACT-Lym lymphoma-specific subscale (≥3 points), FACT-Lym TOI (≥6 points), and FACT-Lym total score (≥7 points). Overall, 396 patients were randomized. Analysis was conducted when 175 Independent Review Committee-assessed progression-free survival (PFS) events were observed. Questionnaire completion rates were generally balanced between arms at baseline, EOI, and final follow-up. Median time to ≥6-point worsening from baseline on the FACT-Lym TOI was 8.0 months in the G-B arm and 4.6 months in the B arm (HR 0.74; 95% CI 0.56–0.98). More G-B patients reported meaningful improvements on the FACT-Lym questionnaire subscales. Results were similar when follicular lymphoma patients were analyzed separately. The delayed time to worsening and greater proportion of patients reporting meaningful improvement in HRQoL in the G-B arm suggest that benefit in PFS is not at the expense of an increase in treatment-related toxicity that could lead to reduced HRQoL.