No longer a hand-me-down approach to WM

They enrolled 63 patients in the multicenter study. Patients had a median of 2 prior therapies (range, 1–9), and 60% had bone marrow involvement.

Patients received single-agent ibrutinib at a dose of 420 mg orally each day until disease progression or the development of unacceptable toxic side effects.

“By the time they came back 4 weeks later to be evaluated, many of them were already in a response,” Dr Treon said. “And what we saw, in fact, was almost immediate improvement in hemoglobin, something that we didn’t see with many of our trials before that.” 

The best IgM response reduced levels from 3520 to 880 mg/dL (P<0.001) for the entire cohort. 

The best hemoglobin response increased hemoglobin levels 3 points, from 10.5 to 13.8 g/dL (P<0.001).

The progression-free survival at 2 years was 69% and overall survival was 95%. 

At 37 months, most patients who achieve a response experience a durable, ongoing response, according to an update presented at the IX International Workshop on Waldenstrom’s Macroglobulinemia. 

And toxicities were “very much in line with what our colleagues have seen in other disease groups,” Dr Treon stated. 

Response to ibrutinib by mutation status

The overall response rate was 90% for all patients, but there were differences according to mutation status. 

Patients with no MYD88 mutation and no CXCR4 mutation had absolutely no major response.

Patients with a MYD88 mutation responded at an overall rate of 100% and had a major response rate of 91.7% if they did not have a CXCR4 mutation as well. 

If they also had a CXCR4^WHIM mutation, the overall response rate was lower, at 85.7%, and the major response rate was 61.9%. 

“It’s still something to be incredibly excited about—61.9% single-agent activity,” Dr Treon said.

Patients with a CXCR4 mutation also respond more slowly than those without the mutation.

This investigator-sponsored study led to the approval of ibrutinib in WM in the US as well as in Europe and Canada.

“And the point to make about this is that investigators can bring their data to the FDA, the EMA, even Canada, and it can make a difference,” Dr Treon said. 

“We don’t always have to have company-sponsored registration studies to be able to make these kinds of advances.” 

Ibrutinib in rituximab-refractory patients

A multicenter, phase 3 study of ibrutinib in rituximab-refractory patients was “almost a photocopy of our study,” Dr Treon said.

The main difference was that the patients were even sicker, having failed a median of 4 prior therapies.

Patients experienced rapid improvements in hemoglobin and IgM levels and had an overall response rate of 90%.

Patients with a CXCR4 mutation also tended to lag in terms of pace of hemoglobin improvement and reduction in IgM.

The study was just accepted for publication in Lancet Oncology.

IRAK inhibition

Investigators were puzzled by the paucity of complete responses with ibrutinib, and they found the IRAK pathway remained turned on in patients treated with ibrutinib.

So they took cells of patients treated for 6 months with ibrutinib and co-cultured them with ibrutinib and an IRAK inhibitor. They observed the induction of apoptosis.

Based on this finding, the investigators are manufacturing a very potent IRAK1 inhibitor (JH-X-119), which, when combined with ibrutinib, synergistically increases tumor-cell killing.

“And so one of the strategies we have going forward,” Dr Treon said, “is the ability to advance ibrutinib therapy in MYD88-mutated tumors by the addition of the IRAK inhibitor.”  

Resistance to ibrutinib