Mantle cell lymphoma (MCL) is a rare disease that is seldom encountered by the average community oncologist and infrequently studied independently of other B cell lymphomas. Especially lacking have been studies of treatment for newly diagnosed MCL patients, many of whom develop resistance to or cannot tolerate cytotoxic first-line treatments. The University of Texas MD Anderson Cancer Center, however, is now evaluating a noncytotoxic combination of targeted and immunotherapy agents for first-line treatment of MCL in clinical trials.
As a tertiary care center, MD Anderson sees more patients with MCL than does any other hospital in the country, and researchers saw this as an opportunity. “We have attracted a critical mass of patients with MCL, and this enabled us to design clinical trials that are purely for MCL; so we are now regarded as the authority in this disease,” said Michael Wang, M.D., a professor in the Department of Lymphoma and Myeloma and the co-leader of MD Anderson’s B Cell Lymphoma Moon Shot Program.
Most MCL trials test novel interventions in patients with relapsed disease, but two ongoing trials from MD Anderson are focusing on previously untreated patients. “For MCL, the first therapy is the most important,” Dr. Wang said. “If you do well with the first-line therapy, you can eliminate almost all of the MCL cells. They won’t have the opportunity to develop resistance, and the remission can last longer.”
Standard first-line therapy
Standard first-line treatments for MCL include high-dose chemotherapy regimens such as hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) with or without stem cell transplant. Such intensive therapies given up front lead to low rates of recurrence and to overall survival times of several years.
However, these intensive regimens can be too toxic for many patients, especially older patients. Thus, the standard first-line therapy for elderly MCL patients is bendamustine plus rituximab. This combination is less toxic than intensive therapies, but the response rate is lower and the responses less durable than those from more intensive regimens.
Even young patients, who often can tolerate intensive therapies, experience acute or long-term adverse effects from cytotoxic therapies. “For every 10 patients we treat with standard intensive therapy, we lose one patient to toxicity. That is not acceptable,” Dr. Wang said.
Also, remissions in MCL patients are not always durable. One reason for this may be that the cytotoxic drugs given intravenously as standard first-line therapy sometimes cannot eliminate the many MCL cells that reside in the bone marrow and lymphatic tissues.
Ibrutinib plus rituximab
The surviving MCL cells could potentially be eliminated by exploiting a phenomenon called compartmental shift, in which a drug induces a transient migration of cancer cells to the peripheral blood from other parts of the body, such as the bone marrow or lymph nodes. Once in the peripheral blood, the cancer cells are more vulnerable to intravenous anticancer drugs.
The oral targeted agent ibrutinib, which inhibits B cell receptor signaling by targeting Bruton tyrosine kinase, has been observed to induce compartmental shift in MCL. Furthermore, Dr. Wang and his colleagues have shown that combining ibrutinib with intravenous rituximab, which destroys B cells by binding to CD20 on the cells’ surface, improves the activity of both drugs in patients with relapsed or refractory MCL. On the basis of these findings, Dr. Wang’s group hypothesized that the drug combination would be effective against newly diagnosed MCL. This targeted–immunotherapy drug combination also represents a less toxic alternative to standard treatment regimens for MCL.
Trial for younger patients
To exploit the potential of ibrutinib plus rituximab as a first-line therapy that can allow patients to undergo fewer cycles of cytotoxic drugs, Dr. Wang and his colleagues are currently enrolling patients aged 65 years or younger with newly diagnosed MCL in a single-center phase II clinical trial (No. 2014-0559). Most patients treated thus far have had advanced disease, and all had good performance status and organ function.
The patients are treated in two steps: first, during a chemotherapy-free “window,” they receive oral ibrutinib and intravenous rituximab; then, they receive consolidation chemotherapy comprising rituximab plus hyper-CVAD alternating with rituximab, methotrexate, and cytarabine. The ibrutinib and rituximab are given for two to 12 cycles, depending on response; and consolidation chemotherapy is given for four to eight cycles, depending on whether complete remission is achieved at the end of the chemotherapy-free step.
“If we take advantage of the window of time before the start of cytotoxic chemotherapy to administer targeted, biological therapy, then less chemotherapy will be needed. This could both decrease the toxicity of treatment and increase survival time,” said Dr. Wang, the trial’s principal investigator.
The preliminary results have affirmed expectations. Among patients treated thus far with ibrutinib and rituximab, the overall response rate (complete plus partial responses) has been 100%, and the complete response rate has been 73% and is still rising, allowing most of the patients to undergo only four cycles of consolidation chemotherapy. The most common adverse events due to the targeted therapy have been fatigue, myalgia, diarrhea, and oral mucositis, all at low grades; and common adverse events due to the chemotherapy have included anemia, lymphocytopenia, thrombocytopenia, and leukopenia. Further follow-up is needed to determine survival outcomes, but after a median follow-up of 9 months, no patient has died or had disease progression or recurrence.
“This has been the first time a first-line chemotherapy-free regimen has had an overall response rate of 100% in young patients with MCL,” Dr. Wang said. The early success of the trial led to the addition of another 50 patients to the trial’s projected recruitment.
Trial for older patients
Older patients with MCL typically receive less intensive—and thus less effective—therapy than younger patients. As a result, survival times in these older patients are usually shorter, only 3–5 years. To prolong survival without compromising safety in this older group, Dr. Wang and colleagues designed an international randomized controlled phase III trial for 550 patients 65 years or older with newly diagnosed MCL (No. 2013-0056). Jorge Romaguera, M.D., a professor in the Department of Lymphoma and Myeloma, said, “Because of its low toxicity and high efficacy profile, ibrutinib is the perfect drug to add to the established first-line therapy for elderly patients with newly diagnosed MCL.”
The patients in the double-blind trial received six cycles of a standard regimen of bendamustine and rituximab plus either ibrutinib or placebo. The objective of the trial was to prolong progression-free survival and, potentially, overall survival.
Results of the trial, which has completed enrollment, could lead to the approval of ibrutinib as a first-line treatment for MCL. Dr. Wang said, “If the primary objective is achieved, this will be the new standard for elderly MCL patients around the world.”
Although the trial of ibrutinib and rituximab in younger patients has achieved excellent responses, even the patients who received only four cycles of consolidation chemotherapy experienced some significant adverse effects. Another trial aimed at reducing this remaining toxicity is being planned. Also, laboratory studies are planned to identify molecular correlates of the outcomes in the trial of ibrutinib plus rituximab in younger patients, and long-term follow-up is needed to ensure that the patients’ responses are durable.
The use of ibrutinib plus rituximab will, Dr. Wang expects, change practices in MCL treatment. “This approach reduces the use of first-line cytotoxic chemotherapy while improving efficacy and greatly reducing toxicity,” he said. And in the longer term, he anticipates that the impact of these MCL trials on cure rates and survival outcomes will contribute to MD Anderson’s goal of dramatically increasing the cure rate for B cell lymphomas.
For more information, contact Dr. Jorge Romaguera at 713-745-4247 or Dr. Michael Wang at 713-792-2860. For more information about clinical trials for patients with lymphoma, visit www.clinicaltrials.org.
OncoLog, April 2017, Volume 62, Issue 4