Efficacy and safety of bendamustine, rituximab and bortezomib treatment in relapsed/refractory Waldenstrom Macroglobulinaemia: results of phase 2 single-arm FIL-BRB trial
Summary
This multicentre phase II study Fondazione Italiana Linfomi (FIL)-bortezomib plus rituximab plus bendamustine (BRB) tested a combination of bendamustine (90 mg/m2 on days 1–2), rituximab (375 mg/m2 intravenously on day 1) and bortezomib (1.3 mg/m2 sc on days 1, 8, 15, 22) every 28 days for six cycles in 38 symptomatic patients with relapsed/refractory Waldenstrom macroglobulinaemia (RR-WM). Moreover, MYD88L265P and CXCR4S338X mutations were tested by droplet digital polymerase chain reaction (ddPCR) both at baseline and at the end of treatment in 21 patients. Overall response rate at the end of therapy was 84.6%, including 4 (11%) complete remission, 15 (39%) very good partial response, 12 (32%) partial responses according to IWWM response criteria. At 18, 24 and 30 months, progression-free survival was 84.2% (95% CI 68.2%–92.6%), 81.5% (95%CI 65.1–90.7) and 78.8% (95%CI 62.0–88.8) respectively. At 18 months, the Overall survival was 92.1% (95%CI 77.5%–97.4%). Overall, 19 patients (50%) experienced grade 3–4 haematological toxicity, mainly thrombocytopenia, and grade 1–3 neuropathy rate was about 10% and required bortezomib dose reduction but did not result in treatment interruption. Moreover, BRB treatment induced the high rates of undetectable molecular minimal residual disease (MRD) at the end of the therapy. BRB regimen used as second line is an effective and well-tolerated salvage treatment for relapsed refractory Waldenstrom macroglobulinaemia patients. MRD monitoring showed promising efficacy in clearing the residual disease.
Graphical Abstract
Bortezomib plus rituximab plus bendamustine regimen is a short-time, low-cost and well-tolerated salvage treatment for relapsed refractory Waldenstrom macroglobulinaemia (RR-WM) patients after the first line of therapy. The deep anti-tumour activity is highlighted by an absolute increase of progression-free survival (PFS) rate in comparison to historical controls (30-month PFS of 79%), as well as by high rates of clinical response, with 30% of minimal residual disease (MRD) negativity at the end of the therapy. As expected, toxicity was mainly haematological, gastrointestinal and neurological, but required discontinuation of therapy only in few cases. MYD88 is a valid marker for WM diagnosis at baseline and can be used as marker for MRD at the end of the therapy MYD88 mutation detection in circulating cell-free DNA from plasma shows a good concordance with bone marrow. By using droplet digital polymerase chain reaction (ddPCR), molecular analysis in unsorted blood white cells is a new feasible and inexpensive assay.
CONFLICT OF INTEREST STATEMENT
GB: speaker's bureau and advisory board: Janssen, BMS, GSK, Novartis, Menarini. SF: research funding: Janssen, Morphosys, Gilead, Beigene; consultancy: EusaPharma, Janssen, Sandoz, Abbvie; advisory Board: EusaPharma, Janssen, Clinigen, Incyte, Italfarmaco; speakers Honoraria: Janssen, EusaPharma, Servier, Gentili; research funding: Janssen, Beigene. CB: advisory board: ABBVie; speaker grant: Janssen. GG: advisory boards and speaker's bureau: Abbvie, Astra-Zeneca, BeiGene, Incyte, Hikma, Janssen, Lilly. FGR: advisory board: Janssen, Incyte, Takeda. GM: advisory and honoria: Janssen, Takeda, Incyte, Abbvie. RF: consultant: Kite, Incyte, Sobi, Novartis. MV: advisory board and speaker honoraria: ABBVie, Astrazeneca, Beigene: advisory board: Janssen. NV, AC, FM, DD, CC, LC, FC, AC, DD, TCdT, MF, DM, PT, GP, MM, RS, MT: no CO.
Open Research
DATA AVAILABILITY STATEMENT
For clinical original data, please contact: [email protected]. For biological original data, please contact: [email protected].
