Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group

Abstract

Mantle cell lymphoma (MCL) is considered incurable. Intensive immunochemotherapy with stem cell support has not been tested in large, prospective series. In the 2nd Nordic MCL trial, we treated 160 consecutive, untreated patients younger than 66 years in a phase 2 protocol with dose-intensified induction immunochemotherapy with rituximab (R) ؉ cyclophosphamide, vincristine, doxorubicin, prednisone (maxi-CHOP), alternating with R ؉ highdose cytarabine. Responders received highdose chemotherapy with BEAM or BEAC (carmustine, etoposide, cytarabine, and melphalan/cyclophosphamide) with R-in vivo purged autologous stem cell support. Overall and complete response was achieved in 96% and 54%, respectively. The 6-year overall, event-free, and progressionfree survival were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years. Multivariate analysis showed Ki-67 to be the sole independent predictor of event-free survival. The nonrelapse mortality was 5%. The majority of stem cell products and patients assessed with polymerase chain reaction (PCR) after transplantation were negative. Compared with our historical control, the Nordic MCL-1 trial, the event-free, overall, and progression-free survival, the duration of molecular remission, and the proportion of PCR-negative stem cell products were significantly increased (P < .001). Intensive immunochemotherapy with in vivo purged stem cell support can lead to long-term progression-free survival of MCL and perhaps cure. Registered at www.isrctn.org as #ISRCTN 87866680.

ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

“…The effectiveness of combining ABT-737 with compounds that inactivate Mcl-1 firmly establishes the validity of such a therapeutic approach in the treatment of MCL (12,(35)(36)(37). A similar synergistic effect is measured when ABT-737 is combined with ara-C, which is a heavily prescribed drug in the treatment of MCL (24,38,39). As reported with flavopiridol, ara-C induces Mcl-1 downregulation at the mRNA level (40).…”

High-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting in mantle cell lymphoma: a 10-year update of the R-HDS regimen

“…In particular, our data (10-year OS, 68% for intermediate/ high-risk group, 76% for low-risk group; EFS, 34 and 57%, respectively) compare favorably with long-term reports from other groups who have used immunotherapy in association with dose-intense chemotherapy 6 (hyper-CVAD; 5-year OS, 65%; EFS, 48%), even though a stratification based on MIPI score would have helped in the comparison of the results; in addition, they are in agreement with data obtained after a shorter (6-year) follow-up with a similar chemoimmunotherapy strategy. 7 A direct comparison with data obtained in conventionally treated patients, as those reported recently by Determan et al, 8 is impossible for the short follow-up of these patients.…”

Changing therapeutic landscape – The last decade

“…First, the role of autografting in first remission after rituximab-containing chemotherapy was established by large trials [24]. Second, new drugs, the immunomodulators, thalidomide and lenalidomide, the proteasome inhibitor bortezomib and the mTOR inhibitor temsirolimus have improved the bleak outlook of failing patients [25][26][27][28].…”

“…These improvements have resulted in an increase in survival rates of 50% and above at five years [24]! Opposite from what one would have guessed earlier, the superiority of highdose cytarabine containing regimens over standard R-CHOP has not been established yet, results of a large European trial designed to prove this are still unknown.…”