Achieving Complete Remission of MCL

Brad S. Kahl, MD:We know that complete remissions are important in mantle cell lymphoma. Partial remissions tend to not last very long. The one exception may be with chronic daily oral therapies, like ibrutinib, where partial remissions seem to have the ability to be durable. When you look at efficacy data for ibrutinib, the median progression-free survival is about 12 to 14 months. The median response duration is around 18 months. And with longer term follow-up, it looks like about 20% to 25% of patients will still be in remission at 3 years.

So, there is a significant minority of patients who can achieve very durable remissions with ibrutinib therapy. Unfortunately, not the majority, and there is a lot of effort underway to see what can be added to ibrutinib therapy to make the remissions more durable—combining it with rituximab or other anti-CD20s, for example; combining it with other novel agents like venetoclax, which is an investigational BCL-2 inhibitor; or combining it with proteasome inhibitors.

There are lots of clinical trials ongoing right now looking at combining ibrutinib with other therapies to see if we can get remissions to last even longer. And so, I think that’s where the future is for ibrutinib. Ibrutinib is a home-run drug in CLL. It works phenomenally well. It’s not quite as efficacious in mantle cell. The reality is more than half of patients will have broken through their ibrutinib therapy after 2 years, and so we do need to find better ways to keep people in remission with mantle cell lymphoma, and ibrutinib in combination may turn out to be the answer.

When I start patients on ibrutinib therapy, I warn them about the arthralgias and the myalgias. Sometimes we see muscle cramps. This can be quite problematic in the first few months. Occasionally, mouth sores. Most of the time I find those symptoms get better over the first few months if you just hang in there. Sometimes, you need to do mild to moderate dose reductions to get them through those toxicities. Usually, though, once people settle in it becomes pretty manageable.

If I have a patient who’s having bad ongoing muscle cramping, bad ongoing arthralgias, or bad ongoing bruising, which is another potential side effect of ibrutinib, then we’ll try dose reductions. So, 560 mg is 4 pills a day. You can cut it down to 3 pills a day, which is 420 mg, which is the CLL dose. Sometimes, that’s a little better tolerated than the 560-mg dose. That’s a perfectly reasonable thing to do if your patient is having some difficulty with the ibrutinib side effects.

If I have a patient who gets atrial fibrillation on ibrutinib, that can be a bit of a problem. And it’s not so much the atrial fibrillation, because that’s manageable, but patients who get A-fib generally need to go on anticoagulation. Anticoagulation and ibrutinib don’t go that well together. Ibrutinib seems to have some effect on platelets, because of some off-target effect on other kinases besides BTK. So, the bruising and the bleeding can become quite problematic if you have a patient requiring anticoagulation and ibrutinib. In that instance, I might try to find other ways to manage the patient if they develop AFib, and I would stop the ibrutinib and try to find another way to manage their mantle cell lymphoma.

Outcomes in mantle cell lymphoma have improved dramatically over the past 15 years. The progress has been very gratifying to see. Having said that, there is still a lot of room for improvement. We’re doing better with frontline treatment. Intensive therapies seem to be improving outcomes for younger patients. Treatments like bendamustine seem to be improving outcomes for older patients. The development of novel targeted therapies like bortezomib, lenalidomide, and ibrutinib appear to be improving outcomes in the relapse setting in mantle cell lymphoma.

I think a big focus going forward is going to be to try to figure out how to combine these things in the most logical and rational way to improve outcomes even further. For example, there’s a big international trial called the SHINE study, which is taking patients just like ours and randomizing them to bendamustine/rituximab or bendamustine/rituximab plus ibrutinib. And so, we’ll probably see data from this trial and similar trials in about 12 to 18 months’ time, and it’ll be really interesting to see if adding novel targeted agents on to a immunochemotherapy backbone can improve outcomes even further. Those trials are completed, the data are maturing, we’re just waiting for those results. But those studies have the potential to change the standard of care for frontline management of mantle cell lymphoma.

Transcript edited for clarity.

April 2016

• A 72-year-old male presents to his physician complaining of night sweats, intermittent fever (101°-102°) and fatigue lasting 2 months
• PMH: remarkable for hypertension; controlled on a beta-blocker and diuretic
• Physical exam:
  • Right supraclavicular lymph node, markedly enlarged
  • Spleen, palpable
• Laboratory findings:
  • Leukocytes, 6.73 X 10⁹/L
  • LDH, 420 U/L
• Excisional biopsy of the right supraclavicular node:
  • Immunophenotyping: IgD+, CD5+, CD10+, CD19+, CD20+, CD22+, CD23-, cyclin D1+
  • Cytogenetics: t(11;14)(q13;q32)
  • Bone marrow biopsy confirmed the presence of cyclin D1+ lymphoid cells
• PET-CT: diffuse¹⁸F-FDG uptake in lymph nodes and spleen; the largest involved nodes are the right supraclavicular (4.2 cm), right mesenteric (3.8 cm), and splenic hilar (5.7 cm) nodes
• Diagnosis: Mantle-cell lymphoma, Ann Arbor stage IV
• The patient was started on therapy with bendamustine + rituximab

November 2016

• PET/CT findings at 3 months and 6 months showed a partial response to upfront chemoimmunotherapy
• The patient continues to report symptoms of fatigue
• He was started on therapy with ibrutinib