Jonathon Cohen, MD, Talks Treatment Options for MCL

At the Virtual 2021 Great Debates & Updates in Hematologic Malignancies, Jonathon Cohen, MD, Winship Cancer Institute, Emory University, presented standard treatment regiments and novel agents for the treatment of mantle cell lymphoma (MCL).

According to Dr Cohen, most (85%-90%) patients with untreated MCL will require some sort of therapy early on, such as autologous stem cell transplantation. However, there have been several series published which suggest that deferring initial therapy for MCL does not significantly impact overall survival (OS). In fact, in some of the series’, the median time to treatment has been up to 23 months.

“That suggests that a patient who is largely asymptomatic could potentially be observed for up to 2 years before having to do anything and these patients tend to do just as well as those that are started initially on therapy….these are people that you certainly don't need to rush on to treatment,” Dr Cohen said.

There are factors associated with deferred therapy, including leukemic/non-nodal presentation, lack of B symptoms at the time of diagnosis, a normal lactate dehydrogenase and good Eastern Cooperative Oncology Group performance status.

Therapy for MCL can include a number of standard chemotherapy-based induction regimens, including the Nordic regimen; rituximab plus CHOP or DHAP; rituximab plus bendamustine and cytarabine; and more.

“Anyone that tells you that 1 is necessarily better than the other is not telling you the truth,” Dr Cohen said.

With both the Nordic regimen and BR-R-AraC, there’s a significant likelihood of long-term progression-free survival (PFS), 8 to 10 years versus 4 to 5 years, respectively, he added.

In terms of chemotherapy-free MCL approaches, Dr Cohen described a single-arm Phase 2 study which combined rituximab with lenalidomide. He said it was quite effective. The PFS was also “quite good,” he said, with an overall response rate (ORR) of 57%, and a large number of patients remaining in remission. The median duration of response was up to 19 months, and about 25% of patients who received prior ibrutinib responded to this regiment.

Dr Cohen said novel agents for the treatment of MCL include Bruton's tyrosine kinase (BTK) inhibitors and venetoclax. These agents are not currently being incorporated into therapy, but there have been a number of studies looking at utilizing them.

One study focused on a combination of rituximad and ibrutinib, followed by rituximab plus HyperCVAD, and another study looked at the incorporation of venetoclax. In both trials, high- and low-risk patients experienced a high ORR. Also, a large majority of patients achieve a complete remission.

Currently, US Intergroup is evaluating an additional BTK inhibitor, acalabrutinib, for untreated MCL. There are also other ongoing studies looking at the combination of venetoclax with a chemotherapy-based induction. A number of studies have presented data on venetoclax when combined with ibrutinib and found progression free survival at 12 months was 75% and at 18 months was 57%.

“It remains to be seen whether a combination truly makes a difference here versus sequential therapy,” Dr Cohen told listeners

There are a number of FDA approved therapy options for relapsed MCL, including ibrutinib, acalabrutinib, zanubrutinib, bortezomib, and lenalidomide, as well as cellular therapy and CAR-T therapy.

“The truth is that all 3 BTK inhibitors have very comparable efficacy.…It would be impossible to say that one of these (BTK inhibitors) is necessarily better than the other,” Dr Cohen stated.

He noted, however, that there are subtle differences in toxicity with these 3 inhibitors, and that there has been at least 1 trial comparing ibrutinib versus zanubrutinib in Waldenstrom’s macroglobulinemia.

In that study, zanubrutinib monotherapy was compared to ibrutinib and found decreased atrial fibrillation in patients receiving zanubrutinib, as well as a decreased rate of major bleeding. However, there was an increased rate of neutropenia for patients receiving zanubrutinib as opposed to ibrutinib.

Although BTK inhibitor monotherapy typically results in durable remission, Dr Cohen said, outcomes after therapy have been poor. It is not generally curable, especially in MCL, and nearly all patients will relapse, he said.

One such novel BTK inhibitor is LOXO-305, which is effective both in BTK naive patients and in patients who have previously received BTK inhibitors. Among BTK pretreated patients, LOXO-305 had an ORR of 52% and about 25% of patients achieved a complete response. The majority of patients whether or not they achieved a documented response had significant improvement in their overall tumor burden.

CAR T-cells are another therapy approved for patients with relapsed MCL. In a study of 74 patients who had prior BTK inhibitor therapy and/or multiple prior lines of therapy, the ORR was high at about 93%, and 67% of patients achieved a complete response. So far, many of these patients have remained in remission.

Regardless of treatment, one of the most important predictors of a patient’s overall outcome is their time to relapse, Dr Cohen said, referring to a large multicenter cohort study presented at the 2019 ASH Annual Meeting and Exposition. In this study, the OS was significantly different for patients with early relapsing disease compared with those who did not experience relapse.

“I think no matter what you do, the most important thing is to try to do what you can to prolong the initial remission, because the patients who have the prolonged remissions are the ones that tend to have the longest overall survival overtime,” he concluded.—Emily Bader