How effective is ibrutinib (Imbruvica) in the treatment of Waldenström macroglobulinemia?

Updated: Feb 01, 2021
  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
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In January 2015, ibrutinib (Imbruvica) became the first drug approved by the US Food and Drug Administration (FDA) for treatment of Waldenström macroglobulinemia. [35] Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor; it forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. The approval is based on results of a multicenter phase II study in which 63 patients with previously treated Waldenström macroglobulinemia demonstrated a response rate of 62% (very good partial responses of 11% and partial responses of 51%). These responses were maintained and the median duration of response (DOR) had not been reached, with a range of 2.8+ to 18.8+ months. [36]

Long-term follow-up of patients in that study (median, 59 months) showed overall and major response rates of 90.5% and 79.4%, respectively. MYD88 and CXCR4 mutation status affected response rates: In patients with mutated MYD88, those with wild-type (WT) CXCR4 had a 97.2% major response rate, compared with a 68.2% rate in those with mutated CXCR4 status; in contrast, four patients who had WT MYD88 disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% for those with mutated MYD88and WTCXCR4WT and 38% for those with both MYD88  and CXCR4 mutations. [37]

Single-agent ibrutinib demonstrated high efficacy in an open-label substudy of the larger iNNOVATE trial. In 31 adults with WM that was refractory to rituximab and who had received a median of four previous therapy regimens, 90% of patients had an overall response, of which 71% were major responses, after a median follow-up of 18.1 months. The estimated 18-month progression-free survival rate was 86% (95% confidence interval [CI], 66-94%) and the estimated 18-month overall survival rate was 97% (95% CI, 79-100%). [7]

Response to ibrutinib is highest in patients with the MYD88 L265 mutation and wild-type CXCR4, less in patients with MYD88 L265P and the CXCR4 WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) mutation, and lowest in those with wild-type MYD88. Treon et al have reported major responses to ibrutinib in two patients in two patients with wild-type MYD88, on the basis of allele-specific polymerase chain reaction (AS-PCR) assays, in whom Sanger sequencing in tumor samples identified harbored MYD88 mutations that were not amenable to AS-PCR analysis for MYD88 L265P. [38]  

A  prospective study by Treon et al of ibrutinib as primary therapy in 30 symptomatic patients with untreated Waldenström macroglobulinemia found that ibrutinib monotherapy is highly active, produces durable responses, and is safe. In patients with wild-type CXCR4 versus those with mutated CXCR4, rates of major (94% vs 71%) and very good partial (31% vs 7%) responses were higher and time to major responses more rapid (1.8 vs 7.3 months; P = 0.01). [39]

In August 2018, the FDA approved an expanded indication for ibrutinib in WM beyond its use as a monotherapy to include combination use with rituximab. Approval is based on results from the iNNOVATE study which compared ibrutinib plus rituximab with placebo plus rituximab in 150 patients with either relapsed/refractory disease or previously untreated Waldenström's macroglobulinemia. At 30 months, PFS rate was 82% with ibrutinib-rituximab compared with 28% for placebo-rituximab (hazard ratio for progression or death, 0.20; P< 0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P< 0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P< 0.001). [30]

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