Ibrutinib Therapy in Rituximab-Refractory Patients with Waldenström's Macroglobulinemia: Initial Results from an International, Multicenter, Open-Label Phase 3 Substudy (iNNOVATETM)
Authors: Dimopoulos Meletios A. , Trotman Judith , Tedeschi Alessandra , Matous Jeffrey V. , Macdonald David , Tam Constantine , Tournilhac Oliver , Ma Shuo , Oriol Albert , Heffner Leonard T. , Shustik Chaim , García-Sanz Ramón , Cornell Robert F. , Fernández de Larrea Carlos , Castillo Jorge J. , Granell Miquel , Kyrtsonis Marie-Christine , Leblond Veronique , Symeonidis Argiris , Singh Priyanka , Li Jianling , Graef Thorsten , Bilotti Elizabeth , Treon Steven , Buske Christian 
Published: October 2019

Abstract
Background: Current treatments for Waldenström's macroglobulinemia (WM) are not curative, and a standard of care does not exist. MYD88 L265P, a mutation identified in patients (pts) with WM, signals through interleukin-1 receptor-associated kinase 1 and Bruton's tyrosine kinase (BTK), leading to the constitutive activation of the NF-κB pathway (Yang, 2013). Ibrutinib (ibr), an oral inhibitor of BTK, attenuates the interaction between MYD88 and BTK and blocks BTK-dependent downstream signaling, inducing apoptosis of WM cells (Treon, 2012). In a phase 2 trial of ibr in previously treated WM, durable responses were seen (overall response rate [ORR] of 90.5% and an estimated 24-month PFS of 69.1%; Treon, 2015) leading to FDA and EU approval of ibr in pts with WM. Single-agent ibr indicated favorable responses in pts with WM failing prior monoclonal antibody therapy (Treon, 2015). Here, we report on the efficacy and safety of single-agent ibr in pts with WM refractory to the last rituximab-containing therapy.
Methods: Pts with centrally confirmed diagnosis of WM and symptomatic disease requiring treatment per 2nd International Workshop on WM criteria were enrolled in this open-label, international, multicenter, phase 3 substudy (PCYC-1127 Arm C). Other key inclusion criteria included disease refractory to the last rituximab-containing therapy defined as either relapse after <12 months or failure to achieve at least a minor response. Pts received oral ibr 420 mg daily continuously until progressive disease (PD) or unacceptable toxicity. Main objectives include progression-free survival, ORR, improvement of hemoglobin, and overall survival.
Results: Among the 31 pts treated, the median age was 67 years (range, 47-90); 19% had an ECOG performance status of 2, and 42% had a high International Prognostic Score System for WM (IPSSWM). The median number of prior therapies was 4 (range, 1-8; 68% with ≥3 prior therapies). In addition to rituximab, the most common prior treatments included corticosteroids and alkylating agents (Table). The initial ORR at a median follow-up of 7.7 months was 84%, with a major response rate (≥PR) of 65%. Five pts required plasmapheresis, with no additional need beyond Cycle 1 in 4 pts. Baseline median hemoglobin of 10.3 g/dL increased to 11.4 g/dL after one cycle and baseline median IgM of 3830 mg/dL declined by >50% by end of Cycle 1 (Figure), with continued improvement over time. Any-grade adverse events (AEs) occurred in 29 pts (94%), and grade ≥3 AEs in 16 pts (52%). Most common any-grade AEs (>15%) included diarrhea (39%); hypertension (23%); neutropenia and upper respiratory tract infections (URTIs; 19% each); pyrexia; thrombocytopenia; and increased tendency to bruise (16% each). Common grade ≥3 AEs included neutropenia (13%); anemia, diarrhea, hypertension, and thrombocytopenia (6% each). Overall, 16 pts (52%) developed infections (10% grade ≥3). Serious AEs occurred in 6 pts (19%). All patients remain alive at data cut, with no events of IgM flare, atrial fibrillation or major bleeding. Dose reductions occurred in 4 pts (13%), with no dose reductions for hematologic toxicity. Two pts discontinued ibr-1 pt due to early PD (MYD88 wild-type), and 1 pt discontinued after 8 days of treatment due to an AE of gastrointestinal AL amyloidosis. Overall, 29 pts (94%) continue on ibr therapy. Additional data will be provided.
Conclusions: Single-agent ibr is highly active in this heavily pretreated rituximab-refractory WM population, with a high ORR. No new or unexpected AEs were observed, with a manageable safety profile consistent with previous studies of single-agent ibr.
Table 1. Baseline characteristics N=31 Median age, years (range) Age ≥ 65 years, n (%) 67 (47-90) 17 (55) ECOG, n (%) 0-1 2 25 (81) 6 (19) IPSSWM, n (%) Low Intermediate High 7 (23) 11 (35) 13 (42) Median serum IgM, mg/dL (range) 3830 (740-10700) Median b2-microglobulin, mg/L (range) 3.6 (1.7-24) Median hemoglobin levels, g/dL (range) 10.3 (6.4-14.6) Median platelet count (109/L) (range) 218 (51-896) Median absolute neutrophil count (109/L) (range) 2.9 (0.7-15.4) Median number of prior therapies (range) 4 (1-8) Types of prior therapies, n (%) Rituximab Corticosteroids Alkylating agentVinca alkaloids Proteasome inhibitor Purine analog Anthracyclines Immunomodulating agent Nucleoside analog Other 31 (100) 25 (81) 25 (81) 14 (45) 14 (45) 13 (42) 8 (26) 2 (6) 2 (6) 4 (13) Prior autologous stem cell transplantation, n (%) 2 (6)
Figure 1. Figure 1.

Disclosures
Dimopoulos: Genesis Pharma: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Trotman:Janssen: Research Funding. Macdonald:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Lundbeck Canada: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding. Tam:Janssen: Consultancy, Honoraria, Research Funding. Tournilhac:Roche: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Janssen: Honoraria; GSK: Other: Travel Expenses, Research Funding; Amgen: Other: Travel Expenses, Research Funding. Ma:Abbvie: Research Funding; Xeme: Research Funding; Novartis: Research Funding; Idera: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Speakers Bureau; Giliead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding. Heffner:Amgen: Consultancy. Shustik:Amgen: Honoraria; Roche: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy; Novartis: Consultancy. García-Sanz:Janssen: Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Honoraria, Other: Travel, Accommodations, Expenses; Novartis: Research Funding. Fernández de Larrea:Celgene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Castillo:Otsuka: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Biogen IDEC: Consultancy; Millennium: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding. Kyrtsonis:Amgen: Research Funding; Lilly: Research Funding; Genesis: Honoraria; Millenium: Research Funding. Leblond:Janssen: Consultancy, Honoraria, Speakers Bureau; Mundipharma: Honoraria; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau. Symeonidis:Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Pfizer: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; MSD: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Research Funding; Actellion: Research Funding; Proton-Pharma: Research Funding; Astellas: Other: Travel, Accommodations, Expenses, Research Funding; Teva: Other: Travel, Accommodations, Expenses, Research Funding; ApoPharma: Research Funding; Genzyme: Other: Travel, Accommodations, Expenses, Research Funding; Alexion: Other: Travel, Accommodations, Expenses, Research Funding; GenesisPharma: Consultancy; Glaxo: Consultancy. Singh:Pharmacyclics LLC, an AbbVie Company: Employment. Li:Pharmacyclics LLC, an AbbVie Company: Employment. Graef:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Membership on an entity's Board of Directors or advisory committees. Bilotti:Pharmacyclics LLC, an AbbVie Company: Employment. Treon:Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Onyx: Consultancy, Research Funding. Buske:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy.