Danish researchers claim possible 'cure' of MCL

ATLANTA—Use of intensive immunochemotherapy plus purged stem-cell support can result in long-term survival in patients with mantle cell lymphoma, suggesting that MCL could be considered as curable. Christian Geisler, MD, PhD, of Rigshospitalet, Copenhagen, Denmark, presented this provocative idea, based on final results of the MCL2 study, at ASH 2007 (abstract LB1), speaking on behalf of the Nordic Lymphoma Group.

"We believe that this is the beginning of a new era for the treatment of mantle cell lymphoma," Dr. Geisler said.

In small studies of patients with advanced-stage MCL in first remission, myeloablative induction chemotherapy using CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) followed by stem-cell transplantation significantly improved outcomes, compared with interferon maintenance therapy. This approach did not result in effective long-term control, however.

Since high-dose cytarabine and rituximab (Rituxan) have also been found effective in MCL, these agents were incorporated into a Nordic protocol (MCL1) that evaluated intensive induction immunochemotherapy prior to transplant.

The phase II nonrandomized MCL2 study involved 159 untreated MCL patients: 84% had stage IV disease; all were under age 66. Treatment consisted of one cycle of augmented CHOP (maxi-CHOP) alone, then six cycles of rituximab plus maxi-CHOP alternating with rituximab plus high-dose cytarabine. Responders underwent stem-cell harvest followed by BEAM/BEAC with in vivo purged (rituximab) stem cell transplant. Patients were evaluated for survival after a median follow-up of 3 years from study entry.

Of 159 patients, 153 (96%) responded to induction chemotherapy (55% CR, 41% PR). Intent-to-treat analysis showed 5-year event-free survival (EFS) of 63% and 5-year overall survival (OS) of 74% (see Figure). Of the 144 (91%) responders who completed treatment, 72% were alive and disease free at 5 years.

Compared with MCL1, the MCL2 regimen resulted in significant increases in both EFS (P < .0001) and OS (P < .001). Response duration was also significantly increased. Treatment on the MCL2 study was well tolerated, Dr. Geisler said, with six (3.8%) treatment-related deaths.

Molecular studies of the 77 patients with available stem cell primers showed that 90% converted to PCR-negative status within 2 months post-transplant. Those who remained PCR negative for at least 1 year had a significantly longer response duration vs those who did not (P < .0001). Analysis of 42 available stem-cell products indicated 88% were PCR negative vs 12% in the MCL1 study.

In multivariate analysis, only IPI and Ki-67 status were independent predictors of EFS and response duration, respectively, while IPI and cytological variant predicted for overall survival.

Dr. Vose comments

"The MCL2 results are excellent and mirror the results with R-HyperCVAD/alternating with methotrexate/cytarabine and then followed by BEAM/BEAC and autologous stem cell transplant," said Julie Vose, MD, of the University of Nebraska. "In previous studies, patients receiving R-HyperCVAD plus transplant had 3-year EFS of 78% and 3-year OS of 97% [Vose et al: ASCO 2006, abstract 7511]." These intense combinations can only be used in a subset of MCL patients, Dr. Vose said, "but should be considered when medically possible. Only a large randomized trial would be able to detect a difference between the intense therapy and alternative treatments."