Brad S. Kahl, MD, sheds light on the distinctive clinical features of MCL.
Brad S. Kahl, MD
When it comes to managing mantle cell lymphoma (MCL), Brad S. Kahl, MD, suggests taking the long view. “My overarching treatment considerations are to assume the disease is incurable, so I need a strategy for long-term disease management,” said Kahl, a professor of medicine and oncology at Washington University in St. Louis. “I think, in advance, about how to sequence my therapies, and I remind myself that it’s OK to do watch-and-wait in MCL.”
Kahl, who discussed the issue during a "How I Treat" session at the 2016 Annual ASH Meeting on Hematologic Malignancies, shed light on the distinctive clinical features of MCL. These include a 3:1 male predominance and a median patient age of 65 years. He noted that 85% to 90% of patients have stage III/IV disease at diagnosis. Areas of involvement include the blood (lymphocytosis), bone marrow, and gastrointestinal (GI) tract (lymphomatous polyposis). Central nervous system involvement is rare, he adds, occurring in less than 5% of patients. MCL is generally regarded as “aggressive and incurable,” yet about 15% to 20% of patients present with indolent disease.
In an interview withTargeted Oncology, Kahl elaborated on this seeming discrepancy. “Because mantle cell is a moderately aggressive lymphoma, there can be a knee-jerk reaction to treat it aggressively immediately, as we would with a truly aggressive, but curable, lymphoma,” he said. “Since mantle cell is incurable, it requires a different approach. We need to leave the patient in good enough shape for subsequent treatments.”
Oncologists should also be aware of 2 important prognostic factors in MCL, Kahl said: the proliferation rate and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score. “A Ki67 rate greater than 30% has repeatedly been shown to be prognostic,” he said. As for the MIPI, Kahl reminded colleagues that it aggregates 4 key factors: patient age, ECOG performance status, lactate dehydrogenase, and white blood cell count.
Regarding key diagnostic and staging considerations, Kahl adds that if nodal tissue is available, he recommends nuclear cyclin D1 staining because it is sensitive and specific. Additionally, a lymph node biopsy is not necessary, he said. “You can reliably diagnose from marrow or blood with FISH (fluorescence in situ hybridization) for t(11;14) and use flow cytometry to obtain a typical immunophenotype.”
PET imaging, he finds, is very useful for staging, and he typically orders a bone marrow biopsy. “But I do not perform EGD [esophagogastroduodenoscopy] and colonoscopy because I assume the GI tract is involved,” he said. “I do not screen for central nervous system [CNS] involvement unless there is some obvious symptom. I can’t recall a case with CNS involvement at diagnosis, although I have seen rare cases in the relapsed/refractory setting.”
Treatment approaches may vary for patients aged 65 and older. “I find bendamustine/rituximab [BR] to be a highly effective and very tolerable regimen,” he said. “I do not see much of a role for R-CHOP or its derivations, nor do I see much of a role for intensive therapies in older patients due to their substantial toxicities and disappointing efficacy.”
He noted one area of controversy: should oncologists give maintenance rituximab after BR induction? “I will continue to do so,” he said. “The Rummel et al ASCO 2016 study, although ‘negative,’ was far from definitive.”1
When it comes to patients with MCL under age 65, Kahl reiterates that watchful waiting is an acceptable strategy, as well as intensive initial treatment, which includes autologous stem cell transplantation (ASCT) as consolidation therapy or intensive chemotherapy, such as conventional R-hyperCVAD with alternating R-M/A (rituximab-methotrexate/cytarabine).
In younger patients, Kahl recommends a more intensive strategy, with the goal of maximizing the length of the patient’s first remission, as the median is now more than 7 years. “This would give your patient 6 years free of any treatment and you 6 years to find better ways to treat relapsed/refractory MCL,” he said. “It allows you to preserve all other treatment options, whereas had you saved your intensive option for later, your patient would be older and less fit at the time of application.”
Considerations for relapsed/refractory patients include age, comorbidities, prior therapies, and treatment goals. Kahl reminded colleagues they have a menu of options at that point that includes salvage chemotherapy with or without ASCT, palliative radiation therapy, novel therapies and/or clinical trials, and allogeneic stem cell transplantation (SCT).
As far as treatment sequencing in relapsed/refractory MCL, Kahl suggests enrolling patients on an appropriate clinical trial. If none is available, his preferred commercial agents, in order of preference are, ibrutinib (Imbruvica), rituximab/lenalidomide (Revlimid), and bortezomib (Velcade). Novel agents may be best utilized before resorting to allogeneic SCT.
“Some patients get lucky with targeted agents and achieve good disease control with excellent quality of life,” he said, noting that there is a 30% nonrelapse mortality rate at 2 years with reduced-intensity conditioning (RIC) allogeneic SCT. “Up to 50% of RIC allo SCT patients can suffer from chronic, extensive GVHD [graft versus host disease], and this does not necessarily show up on a Kaplan-Meier curve. The difference in outcomes for early versus late RIC allo SCT is not large enough to justify taking on these risks prematurely.”
There are a number of treatment strategies on the horizon in MCL. The SHINE trial is exploring BR in combination with ibrutinib in newly diagnosed patients who are over the age of 65 (NCT01776840). Additionally, in this patient population, the ongoing E1411 study is exploring BR plus bortezomib followed by rituximab maintenance therapy with lenalidomide (NCT01415752).
Therapies for younger patients with MCL are being investigated in TRIANGLE (2014-001363-12), a randomized, open-label, international study looking at the efficacy of 6 courses of CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT versus alternating courses of 3 doses of CHOP and 3 doses of DHAP (dexamethasone, high- dose cytarabine, and cisplatin) plus rituximab, followed by a high-dose cytarabinecontaining myeloablative regimen and ASCT.
In relapsed/refractory disease, the BCL-2 inhibitor venetoclax (Venclexta) is being looked at in combination with ibrutinib in an open-label phase II study (NCT02471391). Ibrutinib is also being tested in combination with palbociclib (NCT02159755) in a phase I study of relapsed/refractory patients.
Kahl concluded by encouraging colleagues to start a donor search early for younger patients who may need an allogeneic SCT. Moreover, for those patients who are between 60 and 65 years of age or slightly less fit but not infirm, he suggested using both their MIPI scores and their Ki-67 status to guide the intensity of initial treatment.
Rummel MJ, Knauf W, Goerner M, et al. Two years rituximab maintenance vs. observation after first-line treatment with bendamustine plus rituximab (B-R) in patients with mantle cell lymphoma: First results of a prospective, randomized, multicenter phase II study (a subgroup study of the StiL NHL7-2008 MAINTAIN trial).J Clin Oncol. 2016;34(suppl;abstr 7503).