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48 Treatment of Relapsed/Refractory Waldenström Macroglobulinemia Patients: Final Clinical and Molecular Results of the Phase II Brb (Bendamustine, Rituximab and Bortezomib) Trial of the Fondazione Italiana Linfomi (FIL)

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Mantle Cell, Follicular, and Other B-Cell Lymphomas: Clinical and Epidemiological: Targeted Therapy in Low Grade Lymphoma
Hematology Disease Topics & Pathways:
Clinical Trials, Clinical Research
Saturday, December 11, 2021: 10:45 AM

Giulia Benevolo, MD1*, Simone Ferrero, MD2,3, Nicoletta Villivà, MD4*, Anna Castiglione, MSC5*, Federico Monaco, MD6*, Carola Boccomini, MD1*, Maria Giuseppina Cabras, MD7*, Catello Califano, MD8*, Paolo Casula, MD9*, Federica Cavallo, MD, PhD10,11*, Annarita Conconi, MD12*, Daniela Drandi, PhD13*, Gianluca Gaidano, MD14, Anna Ines Gregorini, MD15*, Stefano Felici, MD4*, Martina Ferrante3*, Donato Mannina, MD16*, Anna Lia Molinari, MD17*, Pellegrino Musto, MD18, Gerardo Musuraca19*, Michele Merli20*, Roberto Sartori, MD21*, Monica Tani, MD22*, Marzia Varettoni23*, Umberto Vitolo, MD24 and Lorella Orsucci25*

1Division of Haematology, Città della Salute e della Scienza, Turin, Italy
2Ematologia Universitaria, University of Torino/AOU Città della Salute e della Scienza di Torino, Torino, TO, Italy
3Department of Molecular Biotechnologies and Health Sciences, University of Torino, Torino, Italy
4UOSD di Ematologia, ASL Roma 1, Rome, Italy
5SSD Epidemiologia Clinica e Valutativa, A.O.U. Città della Salute e della Scienza di Torino e CPO, Torino, Italy
6AOSS Antonio e Biagio e Cesare Arrigo - SC Ematologia, Alessandria, Italy
7Struttura Complessa di Ematologia e CTMO, Ospedale Oncologico Businco, Cagliari, Italy
8U.O. Medicina-Oncoematologia, Presidio Ospedaliero A. Tortora, Nocera Inferiore, Italy
9PO San Martino - Ematologia, Oristano, Italy
10Ematologia Universitaria, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy
11Department of Molecular Biotechnologies and Health Sciences, Division of Hematology, University of Torino, Torino, Italy
12SSD Ematologia, Ospedale degli Infermi di Biella, Biella, Italy
13Hematology Division I, Department of Molecular Biotechnologies and Health Sciences, University of Turin, Turin, Italy
14Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
15UOC Ematologia - Fondazione IRCCS Cà Granda OM Policlinico, Vimodrone, Italy
16Department of Hematology, Azienda Ospedaliera Papardo, Messina, Italy
17Hematology Unit, Ospedale degli Infermi, Rimini, Italy
18Department of Emergency and Organ Transplantation, "Aldo Moro" University School of Medicine, Hematology and Stem Cell Transplantation Unit, AOUC Policlinico, Bari, Italy
19Hematology Unit, IRCCS - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola (FC), Italy
20Division of Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi-Azienda Socio-Sanitaria Territoriale Sette Laghi, University of Insubria, Varese, Italy
21Ospedale di Castelfranco Veneto - Ematologia, Castelfranco Veneto, ITA
22Hematology Unit, Ospedale Santa Maria delle Croci, Ravenna, Italy
23Division of Hematology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
24Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
25Division of Hematology, Azienda Ospedaliera e Universitaria Città della Salute e della Scienza, Torino, Italy

Introduction

Symptomatic patients with relapsed/refractory Waldenström Macroglobulinemia (RR-WM) treated with standard rituximab plus chemotherapy as second-line salvage therapy, generally show a 18-months progression free survival (PFS) of about 50%. On behalf of the Fondazione Italiana Linfomi, a multicenter phase II study was designed to assess whether a combination of bendamustine, rituximab and bortezomib (BRB) (EudraCT Number:2013-005129-22) could be considered a promising new treatment in this setting.

Patients and Methods

This single-arm phase II study tested the hypothesis that 18-months PFS is at least 65%. The required sample size was 38 patients (alpha=0.10; beta=0.25; minimum follow up=24 months). Treatment plan provided: rituximab 375 mg/m2 intravenously on day 1 followed by intravenously bendamustine 90 mg/m2 on day 1 and 2 and subcutaneous bortezomib 1.3 mg/m2 on day 1, 8, 15 and 22, every 28 days for 6 months (6 cycles).

MYD88L265P and CXCR4S338X mutations were tested by ddPCR in bone marrow (BM), plasma and peripheral blood (PB) samples, both at baseline (as mutational screening) and at the end of treatment (for minimal residual disease purposes, MRD).

Results

Median age was 66.8 years (8 patients were older than 75 years). Many patients had features of advanced disease such as cytopenia (anemia 71%, thrombocytopenia 20%), systemic symptoms (40%) and symptomatic splenomegaly (24%). Sixteen (42%) patients had at least one comorbidity, mostly cardiovascular disease (21%) or metabolic disorders (16%), such as diabetes mellitus.

Thirty patients completed six cycles, 7 patients stopped therapy for toxicity and 1 for progressive disease. Overall response rate at the end of therapy was 82%, including 4 (11%) complete, 15 (39%) very good partial, 12 (32%) partial responses according to IWM response criteria.

At 18, 24, and 30 months PFS was 84% (95% CI 68-92%), 81% (95%CI 65-91) and 79% (95%CI 62-89) respectively. At 18 months OS was 92% (95%CI 77-97%) and no deaths were observed between 18 and 30 months. Nineteen patients (50%) experienced grade ≥3 hematological toxicity, mainly thrombocytopenia, 12 patients (31.5%) developed grade ≥3 extra-hematological toxicity of which only one cutaneous toxicity related to bendamustine. Bortezomib-related nervous system disorders were observed in 6 patients (5 of grade 1-2 and 1 of grade 3), with no discontinuations.

Mutational data were available for 21 patients: all patients scored MYD88L265P in BM, 18/19 (95%) in plasma and only 18/21 (86%) in PB, prospectively confirming the risk of false negative results when only PB of rituximab pre-treated patients is analyzed. CXCR4S338X was detected only in one patient at baseline. MRD negativization rates after treatment differed across investigated tissues: in detail, 5/17 (29%) in BM, 6/14 (43%) in plasma and 12/16 (75%) in PB. Overall, a good concordance was observed between BM and plasma (Cohen’s kappa= 0.714), suggesting the possibility of avoiding BM aspiration for mutational screening and MRD analysis.

Conclusion

The final results of FIL BRB phase II trial showed that BRB regimen, used as second-line therapy, is an effective and well-tolerated salvage treatment for RR-WM patients. The deep anti-tumor activity of the novel combination is highlighted by an absolute increase of PFS rate in comparison to historical controls (30-months PFS of 79%), as well as by high rates of clinical response, with an ORR (CR+VGPR+PR) of 82% (95%CI 66-92). Moreover, MRD monitoring showed promising efficacy of BRB regimen in clearing the residual disease.

Disclosures: Benevolo: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau. Ferrero: Morphosys: Research Funding; Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Clinigen: Membership on an entity's Board of Directors or advisory committees. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Gilead: Speakers Bureau. Gaidano: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Musuraca: janssen: Consultancy, 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; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Varettoni: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; beigene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; roche: Membership on an entity's Board of Directors or advisory committees. Vitolo: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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