EMN 2021 | Long-term follow-up of ibrutinib in Waldenström’s macroglobulinemia

In symptomatic previously treated Waldenström patients, we recently published the update of the pivotal trial. This was a trial that actually supported the approval of ibrutinib monotherapy in patients with Waldenström’s both in North America, as well as in Europe and across many, many other countries. In this report we now had 59 months of median follow-up, which was considerably more than the two-year follow-up that we originally had when the study was published in the New England Journal of Medicine in 2015.

And what we learned with this is that the depth of response, particularly VGPR attainment, did go up over time with ibrutinib. We did once again see differences based on both MYD88 and CXCR4 mutation status. Those patients that had a MYD88 mutation showed high levels of activity versus those patients that were MYD88 wild-type. And among the individuals that were MYD88 mutated, CXCR4 also impacted response. There were less VGPRs in the patients that were double mutated versus MYD88 alone. In fact, if you look at the VGPR rate, it was five times greater if the patients only had the MYD88 mutation and not the two mutations together. And even the time to attainment of a major response was much shorter, by about three months, in fact, for those patients that were MYD88 mutated alone. And this may be clinically significant because if you keep in mind getting responses and getting them quick is very important in our pharmacotherapy of this disease.

Now what we also learned was that progression-free survival was actually the median was not reached at five years, which was wonderful news. At five years, in fact, it was 54% of the patients were still progression-free. 87% were alive. This is important when you think about the median prior therapies was two, and 40% of the patients were refractory to their previous therapy.

But here too MYD88 and CXCR4 mutation status impacted progression-free survival. We saw in fact that 70% of patients were still progression-free at five years if they only have the MYD88 mutation. If they have both mutations, the median PFS had been reached in 42 months, which is still, if you think about it, very, very exciting given the heavily pretreated nature of this population. And those that were MYD88 wild-type most progressed very, very early along in the trial.

So a lot to actually digest from this trial, but I think the take home here is that genomics do impact response to BTK inhibitors, in particular ibrutinib from this study, and that ibrutinib is actually very, very active in this population of previously treated Waldenström patients.