Phase II Trial In Advanced Waldenstrom Macroglobulinemia (WM) Patients With Bortezomib: Interest Of Addition Of Dexamethasone To Bortezomib On Behalf Of The French CLL/WM Intergroup (NCT 00777738)

Bortezomib (B) is an effective drug alone or in combination in naive and pretreated WM patients. The interest of high dose of dexamethasone (D) with bortezomib (B) has not been evaluated in WM patients and D is systematically added to bortezomib combination with or without Rituximab (R) (BD, BDR). However, D is responsible for side effects in elderly population. We tested in a phase II trial the efficacy and safety of the addition of D to B after 2 B cycles in patients with a stable or progressive disease (SD, PD).

Bortezomib was used at 1.3mg/m2 IV D1, 4, 8 and 11 every 21 days for 6 cycles. In no responding patients, D (20mg) was added at D1,2, 4, 5, 8, 9, 11 and 12 at Cycles 3 to 6. The main endpoint was the overall response rate (ORR) at two months before D adjunction; secondary outcomes were ORR at 4 and 6 months, response duration, overall survival (OS) and progression-free survival (PFS). Two interim analyses were scheduled and performed after the inclusion of 17 and 27 patients, respectively, using Bayesian estimation of ORR with stopping rules.

Interim analyses did not allow stopping the trial, with probability of ORR above 35% below 0.9. Thus, a total of 34 patients (pts) were enrolled in the study in two years (2009-2011) in 17 centers. The median age was 70.2 (64.2-79.6).ECOG was ≥1 in 53% of the pts. The median of previous lines, hemoglobin, beta 2 microglobulin, IgM, and albumin was 1, 9.8g/dL, 4.35mg/L, 29g/L, 35 g/L respectively. At 2 cycles, there were 6 partial responses and 10 minor responses(group I), with estimated ORR at 44.1% (95%CI: 27.6-61.9%). D was added in 16/18 pts with stable or progressive disease (group 2). At 4 and 6 cycles, 22/28 and 20/26 pts were in response (12 and 8 in group 1, 10 and 12 in group 2), with resulting 4 and 6 cycles ORR estimated at 75% (95%CI: 47.4-91.7) and 50% (95%CI: 28.0-72.0) in group I and 62.5% (95%CI: 35.9-83.7) and 75% (95%CI: 47.4-91.7) in group 2. A total of 62 adverse events grade > 2 (first course: 11, second course: 18, subsequent courses: group 1: 14, group 2: 19) were observed in 38 courses. Of these 62 events (49 grade 3 and 13 grade 4), 52 (84%) consisted in hematological adverse events (18: platelets, 15: hemoglobin, 8: leucocytes, 1 lymphocytes, and 10 neutrophils); 3 neurological toxicities grade >2 were observed, 1 after the second course and 2 after the third course in group 1. Otherwise, there were 26 peripheral neurological toxicities grade ≤2, namely 5 for the first 2 courses, 11 in group 1 and 10 in group 2. With a median follow up of 36 months, 23 pts experienced disease progression or died (18 had disease progression and 5 died in response). For patients who achieved at least a minor response, the 18-month progression rates were 31.9% in group 1 and 52.1% in group 2 (p=0.43) and WM unrelated death rates were 6.3% in group I and 16.7% in group 2 (p=0.79). The 2-year survival rate was 79.8% [IC95%: 64.7; 98.3]. The median progression free survival time was 16.8 months [IC95%: 13.0-23.6].

We showed that addition of D to B in the elderly population was well tolerated and allowed reaching 6-month response in patients who did not respond to two courses of isolated B. Dexamethasone must be associated to bortezomib-based regimen.

Leblond:Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Bortezomib in Waldenstrom macroglobulinemi. Dilhuydy:Roche: Honoraria. Leleu:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; LeoPharma: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Amgen: Honoraria; Novartis: Honoraria. Tournilhac:MUNDIPHARMA: Consultancy, travel funding Other; GSK: Consultancy, travel funding, travel funding Other; Celgene: Consultancy, teaching, teaching Other.