Phase II Study of Modified Hyper-CVAD with Rituximab Maintenance for Previously Untreated Mantle Cell Lymphoma: A Wisconsin Oncology Network Study.
Authors: Kahl Brad S. , McGovern James , Blank Jules , Jaslowski Anthony , Bayer Gerald , Bottner Wayne A. , Rezazadeh Hamied , McFarland Thomas , Hei David , Smith Jamie , Stevens Emily A. , Eickhoff Jens C. , Longo Walter L. 
Published: April 2020

Introduction: Mantle cell lymphoma has the poorest 5-year survival of all the non-Hodgkin’s lymphoma subtypes and appears incurable with standard therapies. High response rates are seen with CHOP plus rituximab (R), but the progression free survival (PFS) is disappointingly short (median 16–20 months). Favorable results have been reported for hyper-CVAD + R with midcycle high dose methotrexate and cytarabine, but this regimen can be prohibitively toxic for some patients. We hypothesized that eliminating methotrexate and cytarabine while adding R to the induction hyper-CVAD would produce high response rates with acceptable toxicity. We further hypothesized that adding R maintenance would prolong the PFS.

Methods: Eligible patients had histologically confirmed CD20+ mantle cell lymphoma and could not have received more than 1 cycle of CHOP-like therapy for their disease prior to study entry. PS 0-2 was allowed. The treatment plan included rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1–3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1–2, vincristine 2 mg IV day 3, dexamethasone 40 mg po days 1–4, and G-CSF 5mg/kg/day starting after therapy until ANC ≥ 4000/mm3. Cycles were repeated every 28 days, up to 6 cycles. Patients achieving at least a PR received R maintenance therapy (375 mg/m2 IV weekly X 4 doses) every 6 months for 2 years. The accrual goal was 20 patients evaluable for response.

Results: Enrollment is completed. All 22 patients are evaluable for toxicity, PFS, and OS and 20 patients evaluable for response rate (2 patients died before any restaging). Patient characteristics include 20/22 male, median age 63 (40–81), median IPI 3 (1–5), and 19/22 stage IV. All patients have completed the induction chemotherapy. Six patients have completed the R maintenance, 10 remain on R maintenance, and 6 patients came off study due to progressive disease (4) or death (2). The ORR is 85% (17/20) with 3 PR, 14 CR/CRu. With a median follow up of 22.5 months (range 4–45), the median PFS and OS have not been reached. The 2-year PFS is 73% (95% CI 50–89%) and the 2-year OS is 82% (95% CI 60–95%). Responses are ongoing in 16 patients, with response duration ranging from 2+ to 39+ months. The most common grade 3–4 toxicities in the 22 patients included neutropenia (10), anemia (5), thrombocytopenia (5), and infection (4). To date, five patients who participated in this study have died (1 treatment-related neutropenic fever, 1 post-surgical infection, 3 progressive disease). The major toxicity of this treatment regimen is expected hematologic toxicity.

Conclusion: Modified hyper-CVAD with rituximab maintenance demonstrates ORR comparable to conventional hyper-CVAD (85% vs. 93%) and is less toxic, especially in patients over 60. Compared with published reports for R-CHOP, we observed higher CR rates (70% vs 34–48%) and considerably longer median PFS (not yet reached vs. 16–20 months). Longer follow up will better define the effectiveness of this regimen, but the encouraging results of this pilot study provide the basis for additional study in a larger setting.