Nordic MCL3 Study: Zevalin Combined with High-Dose Chemotherapy Followed by Autologous Stem Cell Support As Late Intensification for Mantle Cell Lymphoma (MCL) Patients < 66 Years Not in CR After Induction Chemoimmunotherapy: No Benefit of Zevalin
Authors: Arne Kolstad , Laurell Anna , Jerkeman Mats , Grønbæk Kirsten , Elonen Erkki , Räty Riikka , Pedersen Lone Bredo , Loft Annika , Bogsrud Trond Velde , Nordstrøm Marie , Hansen Per Boye , Fagerli Unn-Merete , Nilsson-Ehle Herman , Lauritzsen Grete Fossum , Lehmann Anne Kristine , Sundstrom Christer , Karjalainen-Lindsberg Marja-Liisa , Ralfkiaer Elisabeth , Ehinger Mats , Delabie Jan , Bentzen Hans , Schildt Jukka , Kostova-Aherdan Kamelia , Frederiksen Henrik , Brown Peter de Nully , Geisler Christian H. 
Published: October 2019

Abstract
Abstract 747
The outcome of mantle cell lympoma (MCL) has improved in recent years. The Nordic Lymphoma Group has since 1996 completed three consecutive phase II trials for front-line treatment of MCL patients < 66 years of age. The first trial (MCL1) showed that quality of response prior to transplant was the most important factor for outcome. Hence, in the second trial (MCL2) induction therapy was intensified by adding cycles of high-dose Ara-C and rituximab to the regimen. Despite significant improvement in overall and progression-free survival, patients who did not achieve CR pretransplant had a shorter time to progression. Therefore, the main objective of the MCL3 study was to improve the time to progression in patients who achieved only CRu or PR pretransplant by adding Zevalin to the high-dose regimen as a late intensification. Results of the – otherwise largely identical - MCL2 trial serve as the historic control.

Methods:
Newly diagnosed stage II-IV MCL patients < 66 years received induction immunochemotherapy with alternating cycles of R- (rituximab) maxi-CHOP and R-Ara-C to a total of 6 cycles. Evaluation of pretransplant response with CT scans and bone marrow was performed after 5 cycles. PET/CT pretransplant was recommended, but would not influence treatment. Responding patients by NCI criteria underwent in-vivo purged stem cell harvest after the 6th cycle (Ara-C + 2 doses of rituximab). Patients in CRu or PR received a standard dose Zevalin (0.4 mCi/kg) one week prior to high-dose therapy with BEAM or BEAC while CR patients received the high-dose chemotherapy without Zevalin. Follow-up included CT-scans, bone marrow and blood sampling for at least 5 years, including PCR for minimal residual disease or molecular relapse. Patients in solely molecular relapse received preemptive therapy with 4 weekly doses of rituximab, as in the MCL2 study.

Results:
161 consecutive patients were included from 2005–2009, with characteristics similar to that of the MCL2 trial with a median age of 57 years (28–65), a male predominance and the majority in stage IV with bone marrow involvement. Only 12 out of 161 patients (7 %) did not receive a transplant, 6 due to stem cell harvest failure, 2 due to toxicity and 4 due to no response to induction treatment. Before transplant 50% were in CR, 17% in CRu, and 30% in PR. Only four out of 161 patients (2 %) did not respond to induction treatment. After a median follow-up of 3.2 years the projected 5-year overall and event free survival, and time to progression were 71, 55 and 65% respectively and the MCL2 and MCL3 curves were superimposable. Of the 69 candidates to Zevalin in CRu/PR according to protocol, 65 (94%) actually received this treatment. There was no significant difference in time to progression for patients in CRu and PR pretransplant between MCL2 and MCL3, indicating no effect of late intensification with Zevalin in MCL3 in this patient group. Interestingly, a positive pretransplant PET scan proved to be a strong negative predictor for outcome. Lack of benefit from addition of Zevalin to the high-dose regimen was shown for both PET-positive and PET-negative patients. In a multivariate analysis of the impact of clinical response, PET positivity and zevalin treatment, only PET positivity pretransplant had independent significance (p=0.0003 HR=3.412 (95% confidence limits 1.744 – 6.673).
The treatment-related mortality was 3 %. Side-effects were similar to that previously reported for MCL2, and we did not find that Zevalin added any toxicity. Of the 3 patients who developed secondary MDS/AML posttransplant, two had received Zevalin and one had not.

Conclusion:
The MCL3 data confirm the good results and tolerability of the Nordic regimen. However, the late intensification with Zevalin, albeit non-toxic, did not prolong the time to progression for patients in only CRu or PR pretransplant. A positive PET prior to transplant was shown to be a strong negative predictor for outcome. The concept of late intensification may be too late in poor responders. In consequence, up-front intensification with increasing use of high-dose AraC for MIPI high-risk patients is used in the subsequent, now ongoing Nordic-British MCL5 study.

Disclosures:
Arne: Bayer Schering Pharma: Research Funding. Geisler:Roche, Schering: Consultancy, Research Funding.