Expert insight on National Comprehensive Cancer Network guidelines with deference to chronic lymphocytic leukemia and mantle cell lymphoma.
Michael A. Kolodziej, MD: The National Comprehensive Cancer Network [NCCN], of course, has panels that are considering the best available evidence. For the purposes of today’s discussion, let’s focus on mantle cell lymphoma and chronic lymphocytic leukemia [CLL]/small lymphocytic lymphoma [SLL]. Mantle cell lymphoma has been a really tough disease to treat for a very long time. If you look back on the history of mantle cell lymphoma, it was thought to be just another subtype of chronic lymphocytic leukemia, except those patients did much poorer than patients with CLL. They relapsed, they died of their lymphoma fairly quickly. And then we started to understand a little bit about the molecular biology of it and a little bit about what makes mantle cell lymphoma different. And so mantle cell lymphoma was distinct in treatment recommendations.
Even within mantle cell lymphoma, there are a couple of subtypes, but when people think about mantle cell lymphoma, they usually think about the aggressive subtype. And the aggressive subtype of mantle cell lymphoma is treated much like, interestingly, aggressive lymphomas like diffuse large B-cell lymphoma. There are conventional aggressive regimens like rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] that are frequently used, especially in the community, to treat these patients. And then there are other regimens like hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone [hyper-CVAD], which was from, I believe, MD Anderson Cancer Center a million years ago. The idea being to get patients into a good remission and then consider them for transplant, transplant at first remission or at first relapse.
Now, given the age at onset of mantle cell lymphoma, that’s not such a wonderful option for most patients. And interestingly, it’s a heterogeneous disease, and there are some patients who actually seem to do pretty well. Until recently, treatment of relapsed and refractory mantle cell lymphoma was really not particularly good. But that changed really, I think, when it became clear that this new class of drugs, the Bruton tyrosine kinase [BTK] inhibitors, were active in this disease. So ibrutinib was the first one on the scene. Acalabrutinib and zanubrutinib came later. These drugs are highly effective in treating relapsed and refractory mantle cell lymphoma, often for a very durable period, often with quite acceptable toxicity.
The NCCN guidelines recommend the efficacy of these agents and offers them as a treatment of choice, if you will. Chemotherapy can be repeated in these patients, particularly those who have a very good first remission duration. But in patients who have the truly aggressive type, we’re seeing the BTK inhibitors becoming the predominant therapy. Interestingly, we’re going to see chimeric antigen receptor T-cell therapy [CAR T] make its way into this space. There’s no reason why CAR T shouldn’t work in these patients, and so we will undoubtedly see that emerge over the next period of time. This is not a particularly common subtype of non-Hodgkin lymphoma. It’s only about 4% or so of all non-Hodgkin lymphoma. So getting big studies done in this patient population is tough.
CLL and small lymphocytic lymphoma are a little bit further along than mantle cell lymphoma. For one thing, it’s a lot more common. Secondly, it’s another disease where we really were stuck in a rut for a very long time. Conventional chemotherapy was used for a very long time. Mind you that not all patients with CLL or SLL actually need treatment. Many of them can be observed for a long period of time. They have a very indolent disease, but in patients who need to be treated, particularly those who are symptomatic, standard chemotherapy was the treatment of choice: bendamustine, rituximab or fludarabine, cyclophosphamide, and rituximab [FCR] were chemotherapy regimens.
The problem is, particularly with fludarabine, cyclophosphamide, and rituximab, it’s tough therapy. Old people do not do well with fludarabine, cyclophosphamide, and rituximab. Now several years ago the BTK inhibitors came out. Ibrutinib has been around for several years now. It is recommended as the treatment of first choice based on very good phase 3 randomized clinical trial data. Again, acalabrutinib and zanubrutinib came out more recently. Again, we’re starting to see data with those agents in CLL and SLL initially now in the relapsed and refractory setting, but they’ll make their way up the chain. That’s just what’s going to happen. We have other classes of drugs interestingly. We’ve got the phosphatidylinositol-3 [PI3] kinase drugs, idelalisib and duvelisib, totally different mechanism of action, very effective therapies. The drug that may wind up doing the best of all of them is venetoclax, which is a BCL2 inhibiting agent. All of those got a lot of press at the recent American Society of Hematology [ASH] meeting.