Rituximab Maintenance Bimonthly for Two Years after Prolonged Immunochemotherapy in Elderly Patients with Mantle Cell Lymphoma (MCL) Results in Long Remissions: Update with Six-Year Follow-up of a Prospective Study By the Finnish Lymphoma Group

Background Rituximab (R) maintenance therapy bimonthly until progression has been shown in a recent randomized study to prolong duration of remission (with median follow-up of 37 months) and overall survival in elderly patients (pts) with MCL after R-CHOP, but not after R-FC, induction therapy (Kluin-Nelemans et al, N Engl J Med 2012; 367:520-31). We have previously reported initial results of 60 elderly pts with MCL treated with induction therapy consisting of 10 cycles of alternating standard CHOP and intermediate-dose AraC (combining fludarabine in 3 cycles) with 8 doses of R, followed by bimonthly R maintenance for 2 years (yrs) (Räty et al. Leuk Lymphoma 2012; 53:1920-8). High response rate to induction therapy with ORR of 95% (CR/CRu 87%) was seen. PFS was 70% and OS 72% at 4 yrs with the median follow-up of 40 months. Herein, we update our results of this prospective study with completed maintenance therapy in all pts with a median follow-up time of 6 yrs for surviving pts.

Methods The pts were recruited at 10 Finnish centres during Dec 2004 and Aug 2010. Eligible pts were > 65 yrs old with histologically confirmed newly diagnosed (WHO criteria, CD5+, CD19/20+, Cyclin D1+) and previously untreated stage II-IV MCL with adequate organ functions and performance status (WHO) <4. Induction: standard dose R-CHOP (cycles 1, 3, 5), R-AraC (R 375 mg/m² x1, AraC 1 g/ m² 4 doses with 12 hrs intervals; cycles 2, 4), R-AraC with fludarabine (F) (F 25 mg/m² 2 doses, cycles 6-8), CHOP (cycles 9, 10). Maintenance for pts in CR/PR: R 375 mg/m² bimonthly x 12. Response was evaluated according to Cheson’s criteria after 5^th, 8^th and 10^th cycle, every 6 months during maintenance and 1 year follow-up, and clinically for later follow-up every 6 months. Median follow-up time at the time of this analysis was 70 months (range 41 – 113 months) for living pts.

Results At the time of diagnosis the median age of 60 recruited pts was 74 yrs (range 65-83), 62% were males, 97% had advanced disease (stage III-IV), 77% had good performance status (PS 0-1). Most (87%) had a history of some other notable illness, most typically cardiovascular disease. Another cancer had been diagnosed earlier in 9 pts (prostate n=3, breast n=3, other n=3). The MIPI risk was low in 2%, intermediate in 45% and high in 53% of the pts, respectively. ORR was 95% (CR/CRu n= 52, PR n=5, PD n=2). One patient could not be evaluated for response due to withdrawal of consent after the first cycle. Seven pts did not receive R maintenance (died/progressed/relapsed during induction n=5, withdrawal of consents n= 2). All 12 doses were given to 34 of 53 pts (64%, CR/CRu n=32, PR n=2). Four pts discontinued maintenance due to recurrent infections / neutropenia,10 pts due to relapse and 5 due to other reasons (secondary MDS n=1, general fatigue n=2, unknown n=2). A transient grade 4 neutropenia was seen in 20 pts during maintenance with no serious infections. HZV or VZV infections were recorded in 9 pts. Altogether 22 of responding pts have progressed/relapsed (during induction n=2, during maintenance n=10, during follow-up n=10), 6 of them with isolated CNS relapse. Twenty-one pts have died (sudden cardiac death during induction n=1, progressive MCL n=17, secondary MDS/AML n=1, unknown n=2). At 6 yrs (intention to treat) PFS was 64% (median 97 months, 95% CI 75 – 120 months), EFS 59% (median 95 months, 95% CI 75 – 114 months) and OS 62% (median not reached), respectively. DFS was 72% at 6 yrs (median 91 months, 95% CI 89 – 93 months) for 52 pts in CR/CRu. Two pts have developed secondary MDS (at 27 and 67 months). Eight new cancers (prostate n=3, breast n=1 and skin n=4) have been recorded in 6 patients during maintenance or follow-up.

Conclusions Long PFS and OS over 60% at 6 yrs with median DFS of more than 7 yrs can be achieved with prolonged cytarabine-containing immunochemotherapy followed by 2 yrs R maintenance in elderly pts with MCL. Maintenance therapy was well tolerated in general. Transient neutropenia during maintenance was not uncommon, but serious infections were not seen and only 4 pts discontinued maintenance therapy because of recurrent neutropenia or infections. Attention for second malignancies is requested as 9 pts had cancer before MCL diagnosis, MDS/AML was developed in 2 pts and 6 pts showed carcinomas during follow-up in this elderly patient population.