Elderly Patients with Mantle Cell Lymphoma (MCL) – Efficacy and Feasibility of Prolonged Immunochemotherapy with Rituximab, Cytarabine and Fludarabine Added to CHOP and Followed by Rituximab Maintenance Treatment. A Prospective Study by the Finnish Lymphoma Group

Background: The Nordic Lymphoma Group has shown that adding cytarabine (AraC) and rituximab (R) to high dose CHOP and autologous stem cell transplantation increases response rate, event free survival (EFS), progression free survival (PFS) and overall survival (OS) of patients (pts) with MCL < 65 years (Geisler et al, Blood 2008). About 50% of pts with MCL are older than 65 years. Most of them are not candidates for high dose chemotherapy or transplantations and no satisfactory standard treatment is known for them. In this prospective pilot trial for elderly pts we explored the feasibility and efficacy of a prolonged standard dose induction treatment (10 cycles) with potentially synergistic combinations followed by R maintenance.

Methods: Eligible were pts with histologically confirmed MCL (WHO criteria), CD5+, CD19/20+, cyclinD1+, age > 65 years, with adequate organ functions and performance status < 4. Induction: standard dose R-CHOP (cycles 1, 3, 5), R-AraC (R 375mg/m² x 1, AraC 1g/m² 4 doses with 12 hrs intervals, cycles 2, 4), R-AraC with fludarabine (F) (2 doses of F 25 mg/m², cycles 6 – 8), CHOP (cycles 9–10). Maintenance for pts with CR/PR: R 375 mg/m² bimonthly x 12. Diagnostic workup included physical examination, CT scan, histological lymph node biopsy, bone marrow aspiration and biopsy, and immunohistology or flow cytometry of the diagnostic material. Endoscopies were performed for symptomatic patients. Responses were evaluated according to revised criteria (Cheson et al JCO 2007) after 5^th, 8^th, 10^th cycles and after that every 6 months.

Results: Thirty four pts were recruited. Age median 74 years (67–79 years). Performance status 0 n=12, 1 n=16, 2 n=3, 3 n=3. Stage IIA n=1, IVA n=20, IVB n=13. International prognostic index IPI 2 n=10, 3 n=13, 4 n=9, 5 n=2. Response to induction: CR 23, CRu 6, PR 3, PD 1, not evaluable 1. The response of 7 pts improved with cycles 6 to 8 (R-AraC with F). At diagnosis 32 pts had bone marrow involvement. At best response 24/25 pts with bone marrow involvement studied and CR (n=17), CRu (n=6) or PR (CTscan positive, n=1) were negative in flow cytometry (sensitivity 10⁻³–10⁻⁴). One patient with PR had residual MCL in flow cytometry. Median follow-up time of living patients is 26 months, range 6–43 months. There have been 8 events: progression or relapse 4, secondary AML 1, sudden cardiac death in CR 1, and 2 responding patients withdrew their concents. At 30 months EFS is 72%, PFS 77%, time to progression 85%, and OS 80%. Three pts have discontinued induction after 6,7 or 8 cycles due to toxicity but remain in CR. Infections grade 3 occurred in 8 pts and grade 4 in 1 patient. Eight pts have had transient neutropenia < 0.5 x 10⁹/l during maintenance treatment.

Conclusions: Elderly patients with MCL and with good performance status could be treated relatively intensively with moderate toxicity when supported with G-CSF. In historical comparison to CHOP, R, AraC and F increase response rate and prolong PFS, TTP and OS. Flow cytometry is a powerful tool to study bone marrow involvement at diagnosis and minimal residual disease. A longer follow-up is needed to evaluate the maintenance treatment but several patients have developed transient grade 4 neutropenia during maintenance treatment after this induction schedule.