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Mantle Cell LymphomaBy Stephanie P. Deming
Until about 20 years ago, most patients with the disease now known as mantle cell lymphoma (MCL) were classified as having either poor-prognosis lymphocytic lymphoma or poor-prognosis follicular lymphoma. Then, in 1990, a breakthrough occurred: molecular, genetic, and immunohistochemical testing revealed that these patients, about 6%–10% of all patients with non-Hodgkin’s lymphoma, actually had a distinct subtype of lymphoma affecting B cells in the lymph-node mantle zone. Investigators at The University of Texas M. D. Anderson Cancer Center were among the first to take advantage of this breakthrough and begin searching for the treatment strategies that would be most successful for patients with MCL. “When MCL was first identified, nobody really focused on it as a separate disease. It was just treated like other forms of lymphoma,” said Issa Khouri, M.D., a professor in the Department of Stem Cell Transplantation and Cellular Therapy at M. D. Anderson. “Then we started focusing on it back in the early ’90s. And by focusing on MCL, conducting clinical protocols, carefully studying what does and doesn’t work, and trying to understand the biology, we have made important progress.” Despite this progress, MCL is one of the more difficult-to-treat subtypes of lymphoma—it tends to highly resist chemotherapy and to recur after treatment. In the early 1990s, the median survival time for newly diagnosed patients was only 3–4 years. Since then, this median survival time has increased, but only to about 5–6 years. Investigators at M. D. Anderson and other institutions continue to test new treatment strategies and new agents and combinations to try to prolong patient survival. However, no single approach has yet proven to be clearly superior to the others, and today there is still no standard therapy for MCL. Treating new MCL with intensive chemotherapy A tiny fraction of patients with MCL have stage I or II disease at initial diagnosis—i.e., the disease is limited to lymph nodes on one side of the diaphragm. At M. D. Anderson, these patients are generally treated with either a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab and radiation therapy or, if they are 65 years old or younger, an intensive regimen of alternating chemotherapy combinations (described below). In contrast, for the vast majority of patients who have stage III or IV disease at initial diagnosis, treatment generally consists of intensive cytotoxic immunochemotherapy, followed by high-dose chemotherapy and stem cell transplantation (SCT) in patients who do not achieve a complete remission after the first six cycles of therapy. In the mid-1990s, physicians at M. D. Anderson were looking for an aggressive treatment to improve the survival of patients with advanced MCL. They turned to a chemotherapy regimen that had been developed for children with acute lymphoblastic leukemia at St. Jude Children’s Research Hospital and then modified by Hagop Kantarjian, M.D., chairman of the Department of Leukemia at M. D. Anderson, for use in adult patients with leukemia and other hematologic malignancies. “This experimental regimen consisted of two chemotherapy combinations given in an alternating fashion: hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and high-dose methotrexate,” said Jorge Romaguera, M.D., a professor in the Department of Lymphoma and Myeloma. “We really had nothing else for newly diagnosed, advanced mantle cell lymphoma that we thought would work, so we decided to try a clinical trial with the experimental regimen.” The regimen was followed by additional high-dose chemotherapy and either autologous SCT (using a patient’s own stem cells) or allogeneic SCT (using donor stem cells), depending on the patient’s age and whether a suitable stem cell donor was available. Results were promising: the response rate was 93%, and at a median follow-up time of 49 months, the estimated 5-year overall and disease-free survival rates were 77% and 43%, respectively, better than rates in a historical control group treated with CHOP. Rituximab improves outcomes
In 1997, rituximab—a monoclonal antibody against CD20, which is overexpressed in MCL—was approved by the U.S. Food and Drug Administration for lymphoma treatment. Evidence of rituximab’s positive effect on outcomes of patients with MCL soon began to emerge. In 1998, on the basis of preliminary observations in a small number of patients, Dr. Romaguera and colleagues at M. D. Anderson designed another clinical trial for MCL in which they added rituximab to an alternating hyper-CVAD and methotrexate-cytarabine regimen. If after six cycles of this regimen (rituximab-hyper-CVAD was considered one cycle and rituximab-methotrexate-cytarabine was another cycle) patients were in complete remission, as established by intensive testing, they skipped high-dose chemotherapy and SCT. The complete response rate was 86%, and in 2005, at a median follow-up time of 40 months, the 3-year estimated overall and failure-free survival rates were 82% and 62%, respectively, for the entire cohort of patients age 41–80 years. The survival rates were even better for patients age 65 years or younger, who previously would have been offered consolidation with autologous SCT. As a result of the study, this rituximab-containing chemotherapy regimen is now widely used in patients with newly diagnosed MCL. A recent update of the study showed that patients age 65 years or younger who received the regimen had a 52% failure-free survival rate at a median follow-up of 7 years, and only one failure in this age group occurred in the past 3 years. In an effort to further improve failure-free survival, particularly for patients older than age 65 years, Dr. Romaguera and collaborator Andre Goy, M.D., from Hackensack University Medical Center, recently conducted a phase I clinical trial in which the proteasome inhibitor bortezomib was added to this regimen. Bortezomib, a newer drug, has activity in relapsed MCL and was shown to have additive or synergistic effects when added to rituximab-hyper-CVAD and rituximab-methotrexate-cytarabine. The addition of bortezomib did not increase the risk of toxicity of the regimen. A phase II study is planned. As expected with such an intense regimen as rituximab-hyper-CVAD alternating with rituximab-methotrexate-cytarabine, hematologic toxicity can be significant. About 4% of patients treated with this regimen experience fatal myelodysplasia while their MCL is in remission. And during therapy, intensive supportive care is necessary. Patients are always admitted to the hospital for the rituximab-methotrexate-cytarabine portion of therapy, and for the rituximab-hyper-CVAD regimen, physicians prefer to admit patients older than 65 years and those with certain comorbid conditions. Autologous SCT: needed for new MCL? One of the most important questions that remain to be resolved in the treatment of MCL is whether patients with newly diagnosed disease who have a complete remission or good response with intensive immunochemotherapy—for example, rituximab-hyper-CVAD alternating with rituximab-methotrexate-cytarabine—benefit from undergoing autologous SCT once this chemotherapy is finished. According to Dr. Khouri, M. D. Anderson’s results to date and results presented by the Nordic Lymphoma Group at the December 2007 American Society of Hematology meeting suggest that intensive rituximab-containing chemotherapy followed by autologous SCT may actually be able to cure MCL. The Nordic Lymphoma Group showed that in a large set of patients with newly diagnosed disease, a significant proportion of patients experienced long-term disease-free survival when treated with an intensive rituximab-containing chemotherapy regimen (similar to the one used at M. D. Anderson) followed by SCT. “We are now having the courage to say that some patients may be cured with intensive immunochemotherapy with stem cell support,” said Dr. Khouri. However, there has been no randomized trial to compare outcomes in patients in first remission who do and do not undergo autologous SCT after intensive immunochemotherapy. For his part, Dr. Romaguera believes further study is warranted, since the Nordic study had a relatively short follow-up period (3.8 years) and because participants who developed molecular recurrence were treated with rituximab preemptively and were not counted as treatment failures. Allogeneic SCT helps control recurrent MCL For patients with recurrent MCL, the goal is to use chemotherapy to shrink disease—to the point of complete remission if possible—and then do allogeneic SCT. Autologous SCT is not used in patients with relapsed disease because studies at M. D. Anderson and elsewhere have shown that autologous SCT in this setting does not confer a benefit. Whereas autologous SCT is done as supportive therapy to allow patients to survive high-dose chemotherapy, allogeneic SCT actually has a direct effect against the lymphoma, known as a graft-versus-lymphoma effect. “In the 1990s,” said Dr. Khouri, “we used to give patients getting a donor transplant high-dose chemotherapy, as we do with the autologous transplant. But one third of the patients died within 30 days. Then, we realized that it was the high-dose chemotherapy that was causing these deaths. And also we realized that it is actually the donor cells inducing the cure, not the high-dose chemotherapy.” Dr. Khouri, Dr. Romaguera, and colleagues began offering patients with recurrent MCL nonmyeloablative chemotherapy (chemotherapy that does not completely destroy the bone marrow) followed by allogeneic SCT. The chemotherapy facilitates engraftment of the donor stem cells, which, once they are taken into the patient’s bone marrow, attack the lymphoma. “The donor stem cells recognize the lymphoma cells through a certain mechanism that we don’t understand fully,” Dr. Khouri said. “The biological activity of the donor stem cells is probably the most potent activity against the disease—and an activity that we’re not able to reproduce with any form of chemotherapy.” Nonmyeloablative conditioning regimens are now widely used in patients receiving allogeneic SCT, and this change in therapy represents one of the major advances to date in the treatment of MCL. If allogeneic SCT is so powerful, why is it not used in all patients undergoing transplant? Dr. Khouri points out that allogeneic SCT is associated with a significant risk of graft-versus-host disease or death—about 10%–15% of patients die even with the nonmyeloablative conditioning regimens. Thus, allogeneic transplantation is generally reserved for patients with relapsed disease or newly diagnosed disease with high-risk features such as blastic histology. Another factor that influences treatment planning is that patients who have no suitable related donor and who are from a racial or ethnic group underrepresented in donor registries may never be able to undergo allogeneic transplantation. Such patients may be more likely to be offered autologous SCT at the time of initial diagnosis. What does the future hold? Efforts are ongoing to elucidate the molecular features of MCL, which will provide clues about which agents and treatment strategies may be most effective against this disease. Also, in the future, molecular testing may be done for each patient so that treatment can be individualized on the basis of each patient’s disease features. Among the many new agents being tested are inhibitors of mammalian target of rapamycin inhibitors, Bcl-2 inhibitors, vaccines, siRNAs, and histone deacetylase inhibitors. There is also great interest in identifying prognostic factors for MCL. Mutations in the p53 gene and blastoid cytology have been confirmed to predict poor prognosis. Other predictors of poor prognosis include high Ki-67 expression, high beta-2-microglobulin level, and the presence of minimal residual disease on molecular testing after high-dose chemotherapy and autologous SCT.For more information, contact Dr. Romaguera at 713-792-2860 or Dr. Khouri at 713-745-3219. Other articles in OncoLog, December 2008 issue:
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