Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma

N Engl J Med. 2018 Mar 29;378(13):1211-1223. doi: 10.1056/NEJMoa1715519.

Abstract

Background: Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination.

Methods: We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood.

Results: The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%).

Conclusions: In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).

Publication types

  • Clinical Trial, Phase II
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Agammaglobulinaemia Tyrosine Kinase
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bone Marrow Examination
  • Bridged Bicyclo Compounds, Heterocyclic / administration & dosage*
  • Bridged Bicyclo Compounds, Heterocyclic / adverse effects
  • Disease-Free Survival
  • Female
  • Historically Controlled Study
  • Humans
  • Intention to Treat Analysis
  • Lymph Nodes / pathology
  • Lymphoma, Mantle-Cell / drug therapy*
  • Lymphoma, Mantle-Cell / genetics
  • Lymphoma, Mantle-Cell / mortality
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm, Residual
  • Prognosis
  • Protein Kinase Inhibitors / administration & dosage
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Pyrazoles / administration & dosage*
  • Pyrazoles / adverse effects
  • Pyrimidines / administration & dosage*
  • Pyrimidines / adverse effects
  • Sulfonamides / administration & dosage*
  • Sulfonamides / adverse effects
  • Survival Rate

Substances

  • BCL2 protein, human
  • Bridged Bicyclo Compounds, Heterocyclic
  • PCI 32765
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrazoles
  • Pyrimidines
  • Sulfonamides
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • venetoclax

Associated data

  • ClinicalTrials.gov/NCT02471391