乌鸦传媒

Patients who present with indolent mantle cell lymphoma (MCL) have a better prognosis and can often defer treatment for months or sometimes years, but evidence on the best approach for this subgroup is sparse.

"Mantle cell lymphoma is increasingly recognized as a heterogeneous lymphoma," Peter Martin, MD, Chief of the Lymphoma Program at Weill Cornell Medicine and NewYork-Presbyterian Hospital in New York City, told 乌鸦传媒. "Not only are there recognized biological variants in terms of how they arise, there are also variants in terms of how the same subtype of mantle cell lymphoma might behave from person to person [and] variations in how it changes over time."

There are two major recognized subgroups of MCL, the most common of which is nodal and typically more aggressive. The leukemic, non-nodal variant is responsible for up to 20% of cases, grows mostly in the bone marrow and spleen, and is associated with a more indolent disease course. Patients with non-nodal MCL are often asymptomatic when diagnosed during routine blood tests, though symptoms may include fatigue, bloating or discomfort of the abdomen, and early satiety as the enlarged spleen pushes against the stomach.

"They took a different path toward becoming mantle cell lymphoma, and as they get worse and as they lose more and more control of the cell cycle, they start to converge again and become more similar," said Martin. "You see people who start out with nodal mantle cell lymphoma who later on have a lot of lymphoma spilling over into their bloodstream. And you see people with leukemic, non-nodal mantle cell lymphoma eventually develop big lymph nodes everywhere."

Often, indolent cases of MCL can first be managed with a watch-and-wait strategy. One from Canada with outcomes on 75 patients who initially deferred treatment (including 16 with non-nodal disease) showed that 80% were able to continue observation for beyond a year, including 10 patients observed for more than 5 years.

But Martin explained that fundamentally, problems related to control of the cell cycle still underlie indolent cases of MCL, as well as other issues, including metabolic changes and evasion of immune surveillance.

"Ultimately those things eventually result in a lymphoma that becomes more aggressive," said Martin. "But it's nice that for these people, there's a period of time that can sometimes last many years where it's not problematic and can either be observed or can be controlled with less intensive therapies."

When patients do require therapy, there are no agreed upon standards for every potential scenario, he said, and historically indolent cases would eventually receive the same type of treatment as someone needing immediate treatment at the time of initial diagnosis.

Standard upfront options typically include chemotherapy plus rituximab (Rituxan), and can include autologous stem cell transplant and rituximab maintenance as well. But chemotherapy regimens are associated with high rates of toxicity, and treatment-related secondary malignancies remain a concern.

"Many of us now wonder if these people with very indolently behaving mantle cell lymphomas might do well with non-chemotherapy approaches like rituximab by itself or combinations of rituximab with targeted drugs," said Martin.

"There are emerging data that that may be true," he continued. "And that may be true broadly, it may be that ... many people with mantle cell lymphoma could do fine with non-chemotherapy approaches."

Though not specific to indolent disease, one of the first non-chemotherapy trials for the initial treatment of MCL demonstrated that -- so-called R-squared -- yielded a high overall response rate (92%), with nearly two-thirds achieving complete remissions. Median duration of response had not been reached with a follow-up of 64 months. Estimated 5-year progression-free survival (PFS) and overall survival rates were 63.9% and 77.4%, respectively.

"It showed that chemotherapy is not necessarily the only approach in everybody with mantle cell lymphoma, and that other approaches are reasonable," said Martin.

Other frontline trials involving Bruton tyrosine kinase (BTK) inhibitors, which are approved in the relapsed or refractory setting, have shown promise. For example, results from a phase Ib study of 38 patients showed that adding acalabrutinib (Calquence) to bendamustine (Bendeka, Treanda) and rituximab led to responses in 94% of previously untreated patients, with complete remissions in 72%.

"A lot of us believe that we'll eventually evolve toward seeing BTK inhibitors in the frontline setting, and maybe lenalidomide in the frontline setting, maybe some version of rituximab combined with them," said Martin. "We'll see."

The first trial exclusively in indolent disease, , was presented at last year's American Society of Hematology annual meeting. The phase II trial, which included both nodal and leukemic non-nodal forms of the disease, showed that ibrutinib in combination with rituximab was highly effective, with 27 of 40 patients (82%) responding to treatment and three-fourths achieving complete remissions. Only one patient progressed within a year, and the estimated PFS at 15 months was 96%.

"My guess is that further iterations will be further exploring a similar [non-chemotherapy] strategy," said Martin. "Hopefully we'll have more and more evidence as we go forward that not everybody with mantle cell lymphoma needs to be treated with a chemotherapy right away, or maybe we'll find that chemotherapy really is the standard of care, but the only way to do that is to do the clinical trials."

But he also noted the challenges in conducting large randomized trials in MCL, which would likely require the support of a company.

"It's not an easy cancer to do phase III clinical trials in for a variety of reasons, including the relative rarity of the disease, the relative rarity of the subtypes, the fact that right now in the frontline setting, only chemotherapy is approved," said Martin.

"It would be a big clinical trial that would probably take years and years, maybe a decade. And that's a pretty big commitment," he said. "I think that may be where we're all headed or where we'd like to head, but those clinical trials are not going to be straight forward."

Comment