BTK Inhibitors in MCL: Long-Term Safety & Efficacy Data

Jonathon Cohen, MD, MS: Traditionally, we have thought that ibrutinib, although it’s incredibly effective in mantle cell lymphoma, has not been associated with true long-term progression-free survival. It’s been thought that it’s unlikely that we’re curing patients who have relapsed mantle cell lymphoma. For most patients, unfortunately this is the case. They tend to respond well, but will most likely ultimately progress and require additional therapy. There have been, however, recent studies, including 1 presented at ASH [American Society of Hematology Annual Meeting] this past year, that have pooled several clinical trials and looked at the outcomes for patients who received ibrutinib for relapsed/refractory mantle cell lymphoma on those studies. There have been a few key findings. The first is that it does appear that taking ibrutinib earlier on in the course of therapy—typically after your first line of therapy as opposed to later on—has been associated with an improvement in progression-free survival compared with taking ibrutinib later in the course—as a third or fourth line of therapy or beyond.

It’s important to interpret these data with a bit of a grain of salt. Certainly, any treatment is likely to be more effective if you take it earlier on in the disease course as opposed to if you take it later in a disease course. But the findings for ibrutinib have been particularly striking. The other thing we’ve started to see is that there is a small percentage of patients who have stayed on ibrutinib for several years who remain in remission. If you actually look at the Kaplan-Meier curve, you can see that by the time you get that far out, only a handful of patients are still being evaluated. Some patients have been censored, and many patients have unfortunately progressed or died either of their disease or from other causes. But it does suggest that there’s probably at least a small number of patients who will enjoy a prolonged remission on ibrutinib. Certainly, administering it earlier in the course of therapy does appear to increase the likelihood of achieving this long-term remission.

In the case that we reviewed today, the patient had received bendamustine-rituximab, which is a very commonly utilized frontline regimen. However, the fact that the patient then progressed within 9 months of treatment would certainly suggest to me that a chemotherapy-based approach is unlikely to be the most effective option in this case. In addition, this particular patient did not receive a stem cell transplant. Whether this was because maybe they had some other findings, or maybe they weren’t interested in such an aggressive course, it would suggest that therapy that we offer in the second-line setting and beyond is unlikely going to be highly aggressive or highly intensive.

Ibrutinib really makes a lot of sense in this case. This is a patient who doesn’t have any comorbidities that would prohibit them from receiving ibrutinib and can be expected to respond well. The fact that he has responded so quickly and with a complete remission makes me hopeful that he will be 1 of the long-term responders. Certainly, he’ll need continued observation, and we’ll want to be prepared to move forward with an alternative therapy if and when he progresses or develops some toxicity. But in the current scenario, it makes a lot of sense to use a therapy like ibrutinib, given the inferior response that he had previously to chemotherapy.

Transcript edited for clarity.

Case: A 68-Year-Old Male with Mantle Cell Lymphoma

Initial presentation

• A 68-year-old man presented with generalized lymphadenopathy, fatigue and an unintentional 8-lb weight loss
• PMH: HTN, medically controlled
• PE: abdominal distention, splenomegaly
  
  

Clinical workup

• LDH 345 U/I, ANC 3500/mm3, beta-2-microglobulin 4.4 µg/L, leukocytes, 5.98 X 109/L, hemoglobin 9.6 gm/dL
• FISH: t (11;14)
• Immunocytochemistry: cyclin D1+, CD5+, CD20++
• BMB positive for lymphoid cells with cyclin D1
• PET/CT scan showed widespread lymphadenopathy in numerous nodal regions including left mesenteric (3.4 cm), bilateral axillary (3.9 cm, 5.3 cm), and cervical (5.1 cm)
• Ann Arbor stage IV; MIPI score 6.3; ECOG PS 1
  
  

Treatment

• Patient was started on bendamustine + rituximab
  • Achieved PR
  • Continued on maintenance rituximab q8W
• At 9 months the patient had clinical disease relapse
  • He was started on ibrutinib 560 mg PO qDay
  • Imaging at 12-week follow-up showed no evidence of disease