Intensive Induction, Autologous Stem Cell Transplantation and Rituximab Maintenance Has Changed Event Free Survival and Overall Survival in Mantle Cell Lymphoma Patients. Using Gemcitabine and Oxaliplatin in First Line Therapy
Authors: Vorobyev Vladimir I. , Lorie Yuri Yu. , Zvonkov Evgenii' E. , Gemdjian Eduard G. , Magomedova Aminat U. , Melikyan Anait L. , Mangasarova Jana K. , Gribanova Elena O. , Zherebtsova Vera A. , Kravchenko Sergey K. , Savchenko Valeri G. 
Published: October 2019

Abstract
Abstract 2034

Background:
Mantle cell lymphoma (MCL) is aggressive B-cell neoplasm diagnosed predominantly among elderly men. (R)CHOP-like schemes are effective in remission induction, but the progression-free survival is disappointingly short (median 16–20 months) with median overall survival of 3–4 years. Upfront use of high-dose cytarabine (12 g/m2), autoSCT and rituximab at all stages of therapy is the most effective treatment but possible only with patients younger 65 years. Decrease in AraC doses to 4 g/m2 per cycle significantly reduce progression free survival. Prominent efficacy of gemcitabine-oxaliplatin combinations and irinotecan in relapsed and refractory MCL patients allowed including these drugs in first-line treatment in cases when the scheme R-HD-Met-AraC (Romanguera J. 2005) is impossible.

Aim:
Toxicity and efficacy assessment of schemes R-DA-EPOCH/R-GIDIOX and R-DA-EPOCH/ R-HD-Met-AraC in primary MCL patients eligible for autoSCT.

Patients and Methods:
Since May 2008 35 untreated MCL patients (median 55 years (29–63), males/females 68,5%/31,5%, MIPIb: 34% low, 26% intermediate, 40% high risk) were enrolled. After first R-EPOCH course (Wilson W. 2003) patients were stratified according to toxicity they had received either R-DA-EPOCH/R-HD-Met-AraC or R-DA-EPOCH/R-GIDIOX. In the absence of hematological toxicity grade 4 for more than 3 days, severe infection complications and signs of renal failure patients underwent treatment under the scheme R-HD-Met-AraC (rituximab 375 mg/m2 day 0, methotrexate 1000 mg/m2 24 hours CI day 1, cytarabine 3000 mg/m2 q 12 hrs days 2–3). If there was one of these complications patients underwent treatment under the scheme R-GIDIOX (rituximab 375 mg/m2 day 0, gemcitabine 800 mg/m2 days 1 and 4, oxaliplatin 120 mg/m2 day 2, irinotecan 100 mg/m2 day 3, dexamethasone 10 mg/m2 IV days 1–5, ifosfamide 1000 mg/m2 days 1–5). Further these courses are rotated: either R-DA-EPOCH/R-HD-Met-AraC or R-DA-EPOCH/R-GIDIOX. Depending on the terms of response, patients received 6–8 courses (3–4 cycles) of chemotherapy and autoSCT (BEAM-R) with in vivo purging by rituximab before harvest and reinfusion. Patients with residual tumor after autoSCT were consolidated with local radiotherapy. Rituximab maintenance was performed every three months for 3 years. The protocol was approved by the local ethics committee. Patients were analyzed in an intent-to-treat basis. Overall survival (OS) and event-free survival (EFS) rates were estimated (± standard error) by using the Kaplan-Meier method. Efficacy of the therapy was assessed by Cheson's response criteria (2008). Toxicity assessment was performed 93 R-DA-EPOCH, 60 R-HD-Met-AraC and 46 R-GIDIOX courses.

Results:
A median follow-up is 23 months (range 3–54). Toward August 2012 26 patients underwent autoSCT: 14 from R-HD-Met-AraC arm and 12 from R-GIDIOX arm. 1 induction death after first HD-Met-AraC course (acute renal failure and septic shock). Maintenance therapy with rituximab was completed in three patients. All patients achieved CR in R-HD-Met-AraC arm. In R-GIDIOX arm OR was 100%: 11 CR and 1 PR (without progression for 26 months after autoSCT). Main non-hematological toxicity of R-GIDIOX was hepatic, with elevated aminotransferases grades 1–2 and 3–4 in 59,5% and 7,1% of courses respectively, without clinical signs. The sources of stem cells were PB in 23 patients and BM in 3 cases of harvest failure after R-GIDIOX. Hematological toxicity of R-GIDIOX course: leukopenia grade 4 was in 71,4% (medium duration was 5,4 days, range 1–13), thrombocytopenia grade 4 was in 42,9%. The estimated 4-years OS rates for the R-GIDIOX group and the R-HD-Met-AraC group were 100% and 68% ± 17%. The estimated 4-years EFS rates for the R-GIDIOX group and the R-HD-Met-AraC group were 90% ± 10% and 69% ± 14%.

Conclusions:
Our main goal was to incorporate intensive induction, autoSCT and rituximab maintenance in first line therapy MCL patients. However, HD-Met-AraC scheme is highly toxic and its use is possible only in 2/3 of patients younger 65 years. R-GIDIOX scheme is less toxic than R-HD-Met-AraC and equally effective in response induction and mobilizing, so it could be recommended for those in whom high-dose AraC and methotrexate can potentially cause severe adverse consequences. Such an integrated approach might lead to a shift of paradigm of MCL from an incurable to a curable lymphoma.

Disclosures:
No relevant conflicts of interest to declare.