Evaluating treatment strategies in advanced Waldenstrom macroglobulinemia:: use of quality-adjusted survival analysis

A randomized phase II multicenter clinical trial comparing the efficacy of fludarabine (FAMP) to that of the association of cyclophosphamide, doxorubicin and prednisone (CAP) in 92 patients with Waldenstrom's macroglobulinemia in first relapse or with primarily resistant disease, was conducted on the behalf of the 'Groupe Cooperatif Macroglobulinemie'. The main analysis of this study failed to demonstrate a clear cut benefit of FAMP in terms of overall survival (OS), although a significant benefit in terms of time to disease progression and event-free survival (EFS) was noted. In this rare disorder, where few randomized trials have been conducted, we took advantage of this trial to assess treatment differences while integrating quality of life considerations. We thus performed a quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWIST) approach. Four health states differing in terms of quality of life (QoL) were defined, namely treatment-related toxicity, treatment free of toxicity, no treatment or symptoms, and relapse. The average time spent in these health states (TOX, CT, TWIST and REL, respectively) were then weighted by utility coefficients reflecting relative QoL value according to that of TWIST and summed up giving the so-called Q-TWiST. No difference was found between randomized groups in terms of mean CT. Mean TOX in the two groups were similarly close except when considering alopecia as a relevant toxic event. By contrast, mean TWIST was 5.9 months longer in the FAMP group than in the CAP group (P=0.006). Unsurprisingly, given the absence of difference in OS but the difference in EFS in favor of the FAMP group, mean REL was increased by 6.8 months in the CAP group (P=0.047). As a result, benefit of FAMP in terms of average Q-TWiST only relied on the value of the utility coefficient attributed to REL (U-REL), with a significant benefit when UREL ranged from 0 to 0.28, ie in patients undergoing poor QoL after relapse, which is likely.