Craig H. Moskowitz, MD

Question

Which individuals are at particular risk for developing mantle cell lymphoma (MCL)? Are there signs and symptoms that distinguish MCL from other non-Hodgkin lymphomas?

Answer

There are no risk factors for MCL; it’s an idiosyncratic disease. MCL is unique: it’s the one lymphoma that has so much male propensity. It’s 4:1 male to female, and the median age at diagnosis is 64 to 65 years. Both factors are very important.

It’s also not one disease, really. It’s probably 4 different diseases. There’s a disease where the patient just presented with an elevated white blood cell count, and possibly with a large spleen. Typically these tumors are what’s called SOX11-negative, and usually make up about 10% of patients with MCL. They tend to be able to be monitored.

The second subset of patients, which is also uncommon — making up maybe 5% to 10% of patients with MCL at the most — is gastrointestinal (GI) tract-only MCL. It presents with a number of polyps, and usually it’s thought that the patient has a colon cancer, which turns out to be MCL.

Another category of MCL, which is, thank goodness, highly unusual, is blastic MCL, which is horrific. This is found in about 10% of patients with MCL.

About 70% of patients have “garden variety” MCL, and they tend to present with widespread, non-bulky swollen lymph nodes, bone marrow involvement, and occasionally GI tract involvement. These patients tend to be treated initially, though they can be monitored for a short period of time.

Question

In the era of rituximab and emerging monoclonal antibodies, what role do you foresee cell transplantation playing in the treatment of MCL?

Answer

Recently, nivolumab, a PD-1 checkpoint inhibitor, was approved for patients who failed or were intolerant to sorafenib based on the Checkmate 040 study (ClinicalTrials.gov Identifier: NCT01658878)

Monoclonal antibodies have been around since the 90’s. Everyone who undergoes transplant also gets rituximab — that’s not really an issue.

Depending on the age, some patients are treated extremely aggressively with consolidated transplant. Some patients are just treated with standard chemoimmunotherapy. For blastic MCL, we usually try to transplant patients in remission if at all possible.

For the patients that we monitor, usually they can be monitored for a fairly long period of time. If they need to be treated, I tend to treat those patients depending on age. If their age is such that they should receive more aggressive therapy, then I will do that; if not, I will give them some standard chemoimmunotherapy.

Question

Are Bruton’s tyrosine kinase (BTK) inhibitors likely to replace chemotherapy in MCL treatment?

Answer

They’re not going to replace chemotherapy. They’ll be used combined with chemotherapy as an adjunct. As a single agent, these drugs won’t replace anything; they need to be used in combination.

This is because the duration of response is only 14 months — it’s much better with chemotherapy. Right now, among the patients who get chemotherapy in various different regimens, even a simple one with bendamustine and rituximab, the median time to progression is 40 months.

The big thing people are waiting for is called the SHINE study (ClinicalTrials.gov Identifier: NCT01776840), which is a study of bendamustine and rituximab vs bendamustine, rituximab, and ibrutinib. That study has been done, and the hope is that the addition of ibrutinib will improve progression-free survival.

Question

What are the most important factors when deciding how to best treat relapsed/refractory MCL? Is there a general approach for treating these patients?

Answer

The key things are whether the tumor has blastic pathology and whether it’s p53-positive. Those two things are very critical, and suggest, if they are the case, that trouble is coming.

The third thing is age. Somebody who’s 63 is not someone who’s 78. And also — what was the initial treatment? If the initial treatment was stem cell transplant in first remission, then likely the patient will not get that again.

If they’re still young, they might undergo consolidated allogeneic transplant once they go into remission a second time. Or they’ll just get investigational treatment.

The key thing with MCL: how long was the first remission? There are patients whose first remission can be 7, 8, 9, even 10 years — so if you’re 65 when you start being treated, now you’re 75. So it’s very likely, if your remission duration was long, that the next time you’re treated you’ll have a similarly long remission duration. Then what happens is, these are old men, they have comorbidities aside from MCL — they tend to die with MCL, rather than of MCL. This is different than for patients with blastic pathology, or for patients who are younger. These patients are more likely to die of MCL.

It’s important to remember that MCL is very rare — 3800 patients each year in the United States. The reason that it gets so much press is because it has a specific genetic abnormality (11;14 translocation), which can be monitored.

Question

What is your strategy for treating newly diagnosed patients with MCL with a low number of comorbidities?

Answer

I usually transplant patients in first remission. My current strategy, which is based on the LyMa study (ClinicalTrials.gov Identifier: NCT00921414), is giving 4 cycles of DHAP [dexamethasone, high-dose cytarabine, salt platinum] with rituximab followed by stem cell collection and an auto transplant. That’s followed by rituximab maintenance. Those data are phenomenal — the median time to progression has not been reached at over 6 years. That’s the new standard of treatment, almost worldwide, for patients who are younger than 65 and in good shape.

Question

Do you have a standard strategy for treating relapsed patients more than 80 years old? Do any particular comorbidities affect the strategy you choose?

Answer

Well, of course. For the past 2 months, I’ve been giving acalabrutinib, which I think is less toxic, cardiac-wise, than ibrutinib. It’s now commercially available, so that’s now my choice. Historically I’ve given those patients ibrutinib.

Bleeding and cardiac comorbidities are the 2 that drive treatment decisions.