New treatments are in clinical development for Waldenström macroglobulinemia (WM), a disease for which better treatments are needed, and these agents were recently described in a review article in Leukemia.

One group of agents in particular are combination therapies featuring the Bruton tyrosine kinase (BTK) inhibitor ibrutinib. For example, ibrutinib plus rituximab was shown in the INNOVATE study to be superior to placebo plus rituximab, supporting the idea that ibrutinib adds efficacy to rituximab — but without an ibrutinib alone comparator arm, it’s unclear whether the better efficacy seen is a result of the addition of rituximab.

Other ibrutinib combinations being studied include ibrutinib plus the anti-CXCR4 monoclonal antibody ulocuplumab (ClinicalTrials.gov Identifier: NCT03225716) and ibrutinib plus the oral proteasome inhibitor ixazomib (ClinicalTrials.gov Identifier: NCT03506373). Although they are not yet recruiting, trials to assess ibrutinib plus (subcutaneously administered) bortezomib and rituximab (ClinicalTrials.gov Identifier: NCT03620903); ibrutinib with the anti-CD38 monoclonal antibody daratumumab (ClinicalTrials.gov Identifier: NCT03679624); and ibrutinib in combination with the investigational extracellular signal-related kinase (ERK) 1/2 inhibitor LY3214996 (ClinicalTrials.gov Identifier: NCT04043845) are planned.

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In addition, there are new BTK inhibitors in clinical development that may offer more specificity than ibrutinib, and so far these 2 agents, acalabrutinib and zanubrutinib, have each shown high response rates in single-arm, early-phase trials. As a result, zanubrutinib is also being evaluated head-to-head with ibrutinib in the phase 3 ASPEN trial (ClinicalTrials.gov Identifier: NCT03053440).

Another new proteasome inhibitor, oprozomib, is also in clinical development (ClinicalTrials.gov Identifier: NCT01416428); single-arm, early-phase clinical trials examining this treatment have already concluded. 

Another agent in development is the BCL-2 inhibitor venetoclax, which is currently being evaluated in a multicenter phase 2 trial (ClinicalTrials.gov Identifier: NCT02677324). A phase 2 trial to assess venetoclax in combination with ibrutinib is being planned.

Phosphoinositide 3-kinase (PI3K) inhibitors are yet another group of potential agents that could have potential in WM. Specifically, PI3K gamma inhibitor idelalisib was shown to have clinical activity in a phase 2 trial, but the trial was stopped early due to toxicity (ClinicalTrials.gov Identifier: NCT02439138). Currently, idelalisib is being evaluated in combination with obinutuzumab by the French Innovative Leukemia Organization in a trial dubbed RemodelWM3 (ClinicalTrials.gov Identifier: NCT02962401). Also, umbralisib is being evaluated in a phase 2 trial (ClinicalTrials.gov identifier: NCT03364231).

“It is safe to conclude that it is an exciting time for the development of novel therapies for WM patients,” the review authors wrote.

Disclosure: Author Jorge J. Castillo of the Dana-Farber Cancer Institute is the principal investigator on some of the clinical trials mentioned in the original review. Dr Castillo received honoraria and/or research funds from AbbVie, BeiGene, Janssen, Millennium, Pharmacyclics, and TG Therapeutics. Dr Treon received honoraria and/or research funds from Bristol-Myers Squibb and Pharmacyclics.

Reference

Castillo JJ and Treon SP. What is new in the treatment of Waldenstrom macroglobulinemia [published online October 7, 2019]. Leukemia. doi: 10.1038/s41375-019-0592-8