Ibrutinib Therapy in Rituximab-Refractory Patients with Waldenström's Macroglobulinemia: Initial Results from an International, Multicenter, Open-Label Phase 3 Substudy (iNNOVATETM)

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 2^ndInternational 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. 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 agent    Vinca 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)