Therapy Considerations for Mantle Cell Lymphoma

Brad S. Kahl, MD:For our patient, I think there are a few reasonable treatment options that one could consider. For older mantle cell patients, my most common induction strategy is a combination of bendamustine and rituximab. One could consider rituximab-CHOP chemotherapy. One could consider a newer regimen called the R-BAC regimen, which uses a slightly reduced dose of bendamustine combined with a relatively low dose of cytarabine. I think one could also consider a combination of lenalidomide and rituximab. So, let me walk through those 4 choices.

Bendamustine/rituximab is starting to accumulate more and more data as a frontline treatment option in mantle cell lymphoma. It’s been compared head-to-head against R-CHOP in a couple of different trials with small numbers of patients. But it was compared against R-CHOP in the StiL trial and in the BRIGHT trial, and in both of those instances BR beat R-CHOP pretty easily for progression-free survival without any significant increase in toxicity. If anything, it seems to be a little less toxic than R-CHOP. So, I like BR better than R-CHOP for a patient like this for an induction strategy.

The R-BAC regimen, which incorporates cytarabine in with bendamustine, has been presented at some meetings and published, but not with very long follow-up at this point. It does produce nice, high complete response rates. The regimen appears to have more cytopenias. There’s more neutropenia, more thrombocytopenia, and I’ve used it a few times and that’s certainly what I see in my practice. There are a lot more cytopenias.

So, is R-BAC better than BR? And if so, by how much? And if so, is it worth the added toxicity? I think all that remains to be seen. The couple of times I’ve used the R-BAC regimen have been for older patients who had really bad biology. They had Ki67 rates that were very high, around 70% to 80%—very proliferative mantle cell lymphoma. I was a little worried BR just wasn’t going to be quite enough. So, that’s the occasional incidence where I’ve gone to R-BAC, but most of the time I go to BR for patients like this.

The lenalidomide/rituximab regimen, or the so-called R2 regimen, has been published in a limited institution phase II trial at a couple of centers. It looks efficacious. The response rates are nice and high—in the 80% range—with CR rates in the 40%, 45% range. Tolerability looks good. Whether it’s better than or comparable to BR, you just can’t tell yet, and I think it’ll take head-to-head trials to really sort that out. I have not gone to the R2 regimen as a frontline go-to regimen, but I’ve certainly used that in the relapse setting at times. So, getting back to our patient, I would choose simple, straightforward bendamustine/rituximab for his induction strategy.

Maintenance therapy has been shown to be beneficial in certain instances of mantle cell lymphoma. For example, in a really large study done by the European Mantle Cell Lymphoma Consortium, patients who received an R-CHOP induction were then randomized to maintenance rituximab or interferon maintenance therapy. And interestingly, the maintenance rituximab was given indefinitely to that group of patients. There was no stop date. That study showed a pretty substantial progression-free survival advantage for maintenance rituximab in that setting, and actually a small overall survival benefit.

There’s also a study that was presented at ASH last year, which looked at maintenance rituximab after autotransplant in younger patients with mantle cell lymphoma. That trial actually showed a progression-free survival benefit and an overall survival benefit. So, 2 pretty strong data sets showing an overall survival benefit—small but measurable—and a big progression-free survival benefit for maintenance rituximab in 2 different settings.

For our patient, the question is maintenance rituximab after BR. And this is a little controversial. There was a study presented at ASCO in 2016 from StiL, which is a German Cooperative Group. It was a small study, but they treated mantle cell patients with BR and then randomized them to maintenance rituximab or observation. That trial showed no benefit for maintenance rituximab after BR therapy. And so, a lot of folks have taken that as definitive evidence that maintenance is not beneficial after BR therapy.

I wasn’t totally convinced by the data. It was a pretty small study with around 60 patients in each arm, and the curve in the maintenance arm was a little odd with a lot of drop-off right at the 6-month mark. Personally, I have still been giving maintenance rituximab after BR, but I will admit that the data there is not conclusive that it’s beneficial, and some data would suggest it’s not. I know a lot of people who do not give maintenance rituximab after BR therapy. So, I would say that’s an area of controversy.

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