Dr Martin Discusses How to Approach MCL

Peter Martin, MD, Chief of the Lymphoma Program, Weill Cornell Medicine, New York Presbyterian, discusses how to approach mantle cell lymphoma (MCL), including what’s been learned so far and what’s to be expected, at the virtual Great Debates & Updates in Hematologic Malignancies.

Older data in the frontline setting helps set the stage for what is seen in the future, Dr Martin said, referring to long-term follow-up data from the phase 3 open-label YOUNGER trial. The trial included patients 65 years or younger randomized to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and stem cell transplant versus R-CHOP alternating with high-dose cytarabine and stem cell transplant. The cytarabine-containing arm significantly outperformed the R-CHOP arm.

“You can see that those patients who make it to transplant and are successfully transplanted have a median progression-free survival (PFS) of over 10 years from the time of the transplant, when the pre-transplant induction regimen contains high dose cytarabine,” Dr Martin said.

Over the past 10 years, Dr Martin said he’s spoken a lot on aggressive therapies and how they may be failing some of the most aggressive patients with MCL, particularly those with high MIPI scores, high Ki-67, or more proliferative disease in patients with p53 mutations.

“Based on MIPI scores, patients with high Ki-67, blastoid morphology, all appear to do better when they are treated with high-dose cytarabine than not. But it doesn’t necessarily mean they do as well as somebody with low-risk MCL, but it does look as though adding cytarabine does improve their outcomes. The same may be true for a p53 expression, although the numbers are too small to have a lot of confidence around that,” he continued.

These data make the argument that R-CHOP or rituximab, dexamethasone, cytarabine, cisplatin (R-DHAP) followed by a stem cell transplant may be a reasonable option for some patients with high-risk MCL, Dr Martin said.

Focusing on a follow-up of the YOUNGER trial, Dr Martin said the standard arm (R-CHOP/R-DHAP followed by ASCT) includes 3 years of rituximab maintenance added on. The experimental arms include ibrutinib continuously, and the other includes removing the stem cell transplant, but continuing with ibrutinib.

“I think this will be an important trial. Particularly interesting when we look at those risk groups again. Will it be that this benefits in particular lower-risk patients? There's some reason to think that low risk patients might be those who benefit most from some parts of these strategies, and certainly would be attractive if we could remove stem cell transplant from those patients,” Dr Martin said. “It will also be interesting to see what happens with high-risk patients where previously we thought chemotherapy might not be as attractive. It may be that the addition of ibrutinib to chemotherapy works really well, or it may be that we need to consider other strategies and getting rid of chemotherapy altogether in the future.”

Dr Martin said there are several similar studies in the US looking at induction and consolidation, including the OLDER trial. The trial found that in patients 65 years or older, R-CHOP was superior to rituximab, fludarabine, cyclophosphamide (R-FC). In patients treated with R-CHOP, there was a significant PFS and OS benefit in those treated with rituximab maintenance vs interferon maintenance.

That led to the R2Elderly trial, Dr Martin said, a follow up of early data presented at the American Society of Hematology Annual Meeting 2021 (ASH 2021) by Delfau-Larue on the impact of a maintenance arm on the prognostic relevance of minimal residual disease (MRD). Dr Martin said the randomization trial included an induction arm (n = 620) of R-CHOP versus R-CHOP alternating with hydro-cytarabine, and then a maintenance arm (n = 443) of rituximab plus lenalidomide.

“You can see very clearly that there is a significant PFS benefit with the R² arm compared to rituximab maintenance alone, although there was no OS benefit,” Dr Martin said.

Patients who were MRD negative did better than those who were MRD positive. In all, 244 patients were MRD negative with a median survival of 4.7 months, and 157 patients were MRD positive with a median survival of 2.7 months (95% confidence limits [CL]). Dr Martin noted the rituximab arm had no difference based on MRD status. Whereas, in the R² arm, those who were MRD negative did significantly better than those who were not MRD negative.

“This suggests that those patients who are MRD negative clearly still have some lymphoma that's hanging around. Rituximab maintenance by itself doesn't appear to be sufficient to control it. Whereas R² seems to do a better job of controlling that specifically MRD negative population,” Dr Martin said.

R-CHOP is not used as much in North America anymore, Dr Martin said, with most oncology professionals choosing bendamustine and rituximab (BR) based on superiority in the PFS STIL Trial and the PFS BRIGHT Trial. Thus, the E1411 Intergroup trial was designed to treat older patients with previously untreated MCL. The 4-arm trial looked at BR induction plus or minus bortezomib, and then rituximab maintenance plus or minus lenalidomide in the maintenance arm. 

More recent follow-up data presented by Dr Mitch Smith showed that bortezomib added essentially nothing to BR at end of induction. Dr Martin noted this is contrary to most studies where bortezomib has been added to another agent in MCL.

“It always improved outcomes, unfortunately not here. What is interesting is that the median PFS is close to 5 and a half to 6 years in these arms. ... We would have expected closer to 3 years. Whereas here, we're seeing 5 and a half to 6 years. Very good outcomes in an older patient population, but no clear advantage with the addition of bortezomib," Dr Martin said.

This study raises the question on whether the same benefit will come from lenalidomide maintenance that was seen in prior trials, he said.

Dr Martin then overviewed randomized front-line trials for older patients, including the ongoing E1441 trial on lenalidomide maintenance, the SHINE trial on BR plus R maintenance versus BR and R maintenance plus ibrutinib, the ACE-LY-308 trial including acalabrutinib, the ENRICH trial comparing chemotherapy to ibrutinib-rituximab, and the BGB-3111-306 trial on chemotherapy rituximab versus zanubrutinib and rituximab.

“These are all the potential winners that we will see from these trials. There's a very real chance that, despite all of the work that's gone on so far in the past, we're looking at different induction and different maintenance regimens. We may see that replaced by a new strategy that involves a BTK inhibitor. That would be good for patients, but it will raise a whole bunch of other interesting questions,” Dr Martin said.

While those are ongoing, Dr Martin said there’s a bunch of other interesting regimens in development in the frontline setting.

“Over the next 3 or 4 years, we're going to see over a dozen studies published that will considerably change the way we manage MCL,” Dr Martin said.

Transitioning to previously treated MCL, Dr Martin discussed a study presented by Dr Martin Dreyling at ASH on how chemotherapy does not work very well in the relapsed and refractory (R/R) setting with high-dose cytarabine and dexamethasone (R-HAD) plus or minus bortezomib.

“We should move away from chemotherapy in the R/R setting. I think we have all accepted that BTK inhibitors are probably the appropriate second line therapy with ibrutinib, acalabrutinib, and zanubrutinib all presenting very promising data,” Dr Martin said.

For the second line, Dr Martin said, another option is to retreat patients with pirtobrutinib or zilovertimab instead of covalent BTK inhibitors.

A study presented at ASH on pirtobrutinib included 100 patients with MCL and had 50 responses, showing effectiveness of the drug in a post-BTK inhibitor setting. Most patients who had a deep response discontinued the BTK inhibitor for toxicity, or who were BTK inhibitor naive. Patients who had lower responses had discontinued their BTK inhibitor due to progression.

“We're going to have to dig a little bit deeper into that data, as well as the durability of those responses, before we can confidently say that pirtobrutinib should be used in BTK inhibitor refractory patients in the future,” Dr Martin said.

Lastly, Dr Martin overviewed data looking at a multicenter observeratiojnal series of brexucabtagene-autoleucel CAR T-cell approved for MCL. In all, 95 patients were treated.

“Interestingly, the majority (2/3rds) of patients would have been ineligible for treatment on the Zuma 2 trial for a variety of reasons including comorbidities and renal failure, for example. Despite choosing patients who were typically frailer or had other comorbidities, results were very similar to the data presented in Zuma 2, with a 12 month PFS at 51% compared to 61% in Zuma 2. So, CAR T-cells in the BTK inhibitor refractory population are clearly the most effective treatment we have now” Dr Martin said.

In conclusion, Dr Martin said studies like these open the door to combinations with CAR T-cells or new CAR-T cell products in the future.