No longer a hand-me-down approach to WM

Investigators have found multiple mutations in the C481 site in individual WM patients, which is where ibrutinib binds. 

These mutations represent a minority of the clone, but they exert almost a fully clonal signature. The few patients with these mutations also have a CXCR4 mutation. 

C481 mutations shift the signaling of cells in the presence of ibrutinib toward ERK, which is a very powerful survival pathway.

So investigators are examining whether an ERK inhibitor combined with ibrutinib can elicit synergistic killing of BTK-resistant cells.

Investigators have also been synthesizing potent HCK inhibitors, which might overcome BTK mutations by shutting down the ability to activate Bruton’s tyrosine kinase. 

Other drugs being developed for WM include:

• Combinations with a proteasome inhibitor, such as ixazomib, dexamethasone, and rituximab
• Agents that target MYD88 signaling, such as the BTK inhibitors acalabrutinib and BGB-3111
  
• Agents that block CXCR4 receptor signaling, such as ulocuplomab
• The BCL2 inhibitor venetoclax
• The CD38-targeted agent daratumumab.

Current treatment strategies

Knowing a patient’s MYD88 and CXCR4 mutation status provides an opportunity to take a rational approach to treating individuals with WM, Dr Treon said.

For patients with mutated MYD88 and no CXCR4 mutation:

• If patients do not have bulky disease or contraindications, ibrutinib may be used if available.
• If patients have bulky disease, a combination of bendamustine and rituximab may be used. 
• If patients have amyloidosis, a combination of bortezomib, dexamethasone, and rituximab is possible.
• If patients have IgM peripheral neuropathy, then rituximab with or without an alkylator is recommended.

For patients with mutated MYD88 and mutated CXCR4, the same treatments can be used as for patients with mutated MYD88 and unmutated CXCR4 with the same restrictions. 

To achieve an immediate response for patients with a CXCR4 mutation, an alternative therapy to ibrutinib—such as the bendamustine, dexamethasone, rituximab combination—may be the best choice, because CXCR4-mutated individuals have a slower response to ibrutinib. 

The problem arises with the MYD88-wild-type patients, because their survival is poorer than the MYD88-mutated patients.

“We still don’t know what’s wrong with these individuals,” Dr Treon said. “We don’t have any idea about what their basic genomic problems are.”

Bendamustine- or bortezomib-based therapy is effective in this population and can be considered. 

In terms of salvage therapy, “the only thing to keep in mind is that if something worked the first time and you got at least a 2-year response with it, you can go back and consider it,” Dr Treon said.