Ibrutinib in Waldenstrom macroglobulinemia
- 1 Clinical Question
- 2 Bottom Line
- 3 Major Points
- 4 Guidelines
- 5 Design
- 6 Population
- 7 Interventions
- 8 Outcomes
- 9 Funding
- 10 Further Reading
What is the safety and efficacy of ibrutinib among patients with previously treated Waldenström macroglobulinemia?
Among patients with previously treated Waldenström macroglobulinemia, ibrutinib 420 mg/d is safe and yields an overall response rate of 91%. Patients with MYD88L265P WM had overall response rates of 100% compared to 70-85% in those with MYD88WT disease.
Waldenström macroglobulinemia (lymphoplasmacytic lymphoma, WM) is an indolent B-cell lymphoma marked by adenopathy, splenomegaly, cytopenias, and hyperviscosity due to circulating monoclonal IgM antibodies. Treatment generally targets the lymphoplasmacytic cell, and front-line options include rituximab monotherapy and combination rituximab plus chemotherapy. Identification of the MYD88L265P mutation and its activation of the Bruton tyrosine kinase (BTK) pathway in the majority of WM patients raised the hypothesis that BTK inhibition with ibrutinib would yield favorable responses.
This phase 2 study published by Treon and colleagues prospectively evaluated the safety and efficacy of ibrutinib 420 mg/d in symptomatic patients with previously treated WM. A total of 63 patients with an indication to treat were enrolled from 3 academic centers in the US. All patients underwent MYD88 and CXCR molecular studies with responses stratified by genotype. Responses were defined using standard IWWM consensus criteria and independently reviewed. At 2 years, estimated progression-free survival (PFS) was 69% and overall survival (OS) was 95%. High IPSS score, >3 prior lines of therapy, and MYD88WT/CXCRWT status were associated with inferior PFS and OS. Side effects were relatively moderate and included cytopenias, atrial fibrillation, GI upset, and bleeding. IgM flares, well described with rituximab therapy, were not observed in patients receiving ibrutinib.
The strengths of this study include that it was investigator initiated, employed standardized response criteria, and utilized independent review. As with most phase 2 studies, this trial lacked a comparator, was open-label, and had significant industry sponsorship, all of which are sources of bias. Nevertheless, this important trial provided the safety and efficacy data on which the FDA granted expanded approval for ibrutinib as a single agent in WM in January 2015. In 2018, the INNOVATE trial demonstrated improved depth of response and progression-free survival with combination ibrutinib/rituximab compared to ibrutinib monotherapy; this came at the expense of expected increase in toxicity, and combination therapy was not associated with improved overall survival.
NCCN Guidelines on Waldenström macroglobulinemia, Version 2.2016
- Consider ibrutinib for untreated disease (Category 2A)
- Consider ibrutinib for previously treated disease (Category 2A)
- Investigator-initiated, industry-sponsored, prospective, single-arm, open-label phase 2 trial
- N=63 patients with symptomatic WM
- Setting: 3 academic centers in the US
- Enrollment: 2012-2013
- Follow-up: 2 years
- Analysis: Intention-to-treat
- Primary outcome: Overall response rate
- Age ≥18 years
- Previously treated Waldenström macroglobulinemia by independent, central pathology review
- ECOG performance status ≤2
- Need for treatment based upon consensus guidelines
- Adequate bone marrow function (ANC ≥1,000/mm3, Hgb ≥8 g/dL, Plts ≥50,000/mm3)
- Adequate renal and liver function (Cr ≤2 mg/dL, bilirubin ≤1.5 mg/dL, AST/ALT ≤2.5x ULN)
- CNS involvement
- Clinically significant cardiovascular disease
- Concomitant cancer (except non-melanoma skin cancers and insitu cervical or breast cancer)
- HIV, HBV, or HCV infections
- Concomitant medications that prolong the QT interval, or other investigational medications
- Concomitant warfarin (likely because prior studies demonstrated spontaneous hemorrhage in some patients taking warfarin and ibrutinib concurrently.)
- Age, median: 63 years
- Females: 24%
- Time since WM diagnosis, median: 6.3 years
- Prior regimens, median: 2
- Refractory to most recent regimen: 40%
- IPSS score: low 22%, intermediate 43%, high 35%
- Serum IgM, median: 3,520 mg/dL
- Hgb, median: 10.5 g/dL
- Plt, median: 214,000/mm3
- Serum β2-microglobulin, median: 3.9 mg/L
- Adenopathy: 59%
- Splenomegaly: 11%
- Bone marrow involvement, median: 60%
- In this single-arm trial, all patients received ibrutinib 420 mg/d orally for 26 cycles, each lasting 4 weeks, until disease progression or unacceptable toxicity.
- Patients without disease progression could re-consent to receive therapy beyond the initial 26 cycles.
- Ibrutinib was withheld and/or dose-reduced for cytopenias.
- G-CSF was permitted.
- Ibrutinib was held 3-7 days before and 1-3 days after invasive procedures.
- MYD88L265P and CXCR4WHIM status was determined in 62 of 63 patients.
The primary outcome was overall response rate, determined by a reduction in serum IgM: Additional response categories included minor response (≥25% reduction), partial response (≥50% reduction), very good partial response (VGPR; ≥90% reduction), and complete response (normalization of IgM and absence of M-spike on serum immunofixation).
- Overall response rate
- 90.5% (95% CI 80.4-96.4%)
- Partial response
- Minor response
- Complete response
- Median time to at least minor response
- 4 weeks
- 2-year progression-free survival
- 69.1% (95% CI 53.2-80.5%)
- 2-year overall survival
- 95.2% (95% CI 86.0-98.4%)
Overall Response by Genotype
Listed are selected grade ≥2 toxicities deemed at least possibly attributable to ibrutinib.
Funded by the makers of ibrutinib (Pharmacyclics, Janssen), along with public and private foundations.
- Treon SP, et al. Paradoxical increases in serum IgM and viscosity levels following rituximab in Waldenstrom's macroglobulinemia. Ann Oncol. 2004 Oct;15(10):1481-3.
- Ibrutinib package insert, Janssen Pharmaceuticals
- Dimopoulos MA et al. Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. N. Engl. J. Med. 2018. 378:2399-2410.
- NCCN Guidelines on Waldenström's Macroglobulinemia, Version 2.2016