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Evidence that Mantle Cell Lymphoma Can Be Cured by Intensive Immunochemotherapy, Stem-Cell Support

Fuerst, Mark

doi: 10.1097/01.COT.0000312311.08843.32
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ATLANTA—Intensive immunochemotherapy with high-dose cytarabine and the anti-B-cell antibody rituximab along with autologous stem-cell support may cure mantle cell lymphoma, according to data presented here at the ASH Annual Meeting in a late-breaking session (Abstract LB1).

That cancer, a rare form of lymphoma, is recognized as a subtype with a poor prognosis and has been considered to be incurable. Speaking here at a news conference that featured the study, Christian Geisler, MD, principal investigator of the Nordic Lymphoma Group at Rigshospitalet in Copenhagen, Denmark, estimated that 6% to 10% of lymphoma patients have the mantle cell type, approximately 50% of whom die three to four years after diagnosis.

In the 1990s, researchers attempted to improve upon standard chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) by using high-dose chemotherapy plus stem-cell support. This regimen increased survival slightly, but was no better for disease control, Dr. Geisler noted. “CHOP is simply not sufficient for induction.”

Combined intensive immunochemotherapy and stem-cell support has appeared promising in small patient cohorts, but has not been tested in a large, consecutive series. Dr. Geisler reported the final results of the second trial from the Nordic MCL (Mantle Cell Lymphoma) Project after a median of three years of follow-up from study entry.

This unrandomized, Phase II trial included 160 untreated patients younger than 66 (median age 52), 81% with classical cytology and 19% with blastoid/pleomorphic cytology. Most of the patients (85%) had Stage IV disease, about half (45%) had splenomegaly, and about one third (31%) had more than one extranodal site.

Patients received six cycles of intensive induction immunochemotherapy with alternating cycles of rituximab plus “maxi-CHOP,” which is dose-intensified CHOP (cyclophosphamide at 1,200 mg/m2, doxorubicin at 75 mg/m2, vincristine at 2 mg, and prednisone at 100 mg on Days 1 to 5) and rituximab plus high-dose cytarabine.

Responders received BEAM (BCNU, etoposide, cytarabine, and melphalan) or BEAC (BCNU, etoposide, cytarabine, and cyclophosphamide) with in vivo purged stem-cell support.

Almost all (96%) of the patients responded to induction therapy, with 55% having a complete response and 41% having a partial response. The five-year event-free survival (EFS) rate was 63%, progression-free survival (PFS) rate was 77%, and the overall survival rate was 74% for all patients enrolled in the trial.

Of the 144 (91%) responders who completed treatment, 72% were without disease at five years, with plateaus emerging in all three survival curves at these levels.

“Compared to historical controls with five-year EFS of 15%, PFS of 22%, and overall survival of 41%, I believe this allows us to say that a cure is in sight,” Dr. Geisler said. “For younger patients up to age 65 who can tolerate this new combination, it seems to be a cure.”

Even patients in the worst CHOP groups did fairly well, he said, with a 50% overall survival rate. “All CHOP groups do well,” noted Dr. Geisler.

In an interview after the news conference, he said that the combination of high-dose cytarabine (Ara C) and rituximab was the main reason for the success of the regimen. “Previously, small studies of 20 to 25 patients had reported responses, but this is the first large, mature, prospective study that shows that high-dose Ara C and rituximab is an effective regimen for MCL,” he said. “It looks like a bona fide cure in two thirds of patients.”

Christian Geisler, MD: “Compared to historical controls with five-year event-free survival of 15 percent, progression-free survival of 22 percent, and overall survival of 41 percent, I believe this allows us to say that a cure is in sight. For younger patients up to age 65 who can tolerate this new combination, it seems to be a cure.”

Toxicity Mild

The toxicity was quite mild, he said, including 20 patients who developed septicemia. There were six treatment-related deaths (3.8%), which is about the standard in the setting of high-dose chemotherapy with stem-cell support, he noted.

Three patients died of infection, two patients from vascular involvement, and one from graft failure. Overall, 32 deaths were recorded, including 26 from lymphoma. “We have shown that eight cycles of maxi-CHOP plus rituximab is safe,” he said.

Of 77 patients with available primers, 90% had become polymerase chain reaction (PCR)-negative two months post-transplant, compared with 38% of patients in the first MCL Project study, in which patients received four cycles of maxi-CHOP without rituximab before BEAM or BEAC plus stem-cell support.

Those in the second MCL Project study who remained PCR-negative more than one year post-transplant had significantly longer clinical response duration than patients who did not.

Of 42 stem-cell products assessed, 85% were PCR-negative as compared with only 12% in the first MCL Project study. “We can see, looking at both patients and stem-cell products, that the majority do not house any tumor cells after treatment,” Dr. Geisler said. Rituximab is a preemptive treatment for solely molecular relapse. The availability of a molecular marker did not affect progression-free survival, he noted.

“The addition of high-dose Ara C and rituximab to CHOP and BEAM/BEAC with stem-cell support increased the rates of EFS and overall survival, molecular remission, and the proportion of minimal residual disease-negative stem-cell products.

“The results were surprising, with a 63 percent disease-free survival at five years. After three years, we see a plateau in the survival curve, indicating that this is the first time the disease may be cured. This is the beginning of a new era of treatment for MCL.”

He added: “Of course, the median observation time is only three years. We will follow up and report this cohort consistently in the years to come. I believe the results will hold up. It would be strange that one half of the patients would have a different response than the other half. The curves might look like those for diffuse large B-cell lymphoma, which is a curable disease.”

Also interviewed after the news conference, moderator Jane Winter, MD, Professor in the Division of Hematology/Oncology at Northwestern University, said, “We see a plateau in the survival curves, which is very exciting. As Dr. Geisler said, for MCL, there is no other therapy that provides us with that kind of response. This is dramatic when we see a plateau that may mean a cure.”

Previously, the other best data in MCL had been with rituximab and hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), which has been applied only to younger patients, Dr. Winter noted. “This is provocative data, but we need to see longer follow-up.”

Other drugs, including 90Y-ibritumomab tiuxetan (Zevalin) and bendamustine, alsobendamustine, also may be possibilities for the treatment of MCL, said Dr. Winter.

Dr. Geisler noted that bendamustine and related combinations with cyclophosphamide “are too toxic, even more than CHOP.” In the next step in his research, he plans to provide Zevalin plus BEAM with stem-cell support to those patients who are only partial responders to induction chemotherapy before recommending a transplant. “We believe we can heighten the stem-cell response and get some partial responders to turn into complete responders,” he said.

At the question-and-answer session after his presentation, in a response to a question of whether rituximab could be added upfront, Dr. Geisler noted that rituximab could be started as early as the second cycle with the same results as starting it in the fourth cycle.

“Rituximab has shown to be valuable in inducing remissions,” he said. “It has a great role to play in MCL.”

© 2008 Lippincott Williams & Wilkins, Inc.
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