Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma.
BACKGROUND
Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results with the rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide (RT-PEPC) regimen in patients with recurrent mantle cell lymphoma (MCL).


METHODS
RT-PEPC included induction (Months 1-3) of rituximab 4 times weekly, daily thalidomide (50 mg), and PEPC followed by maintenance thalidomide (100 mg), oral PEPC titrated to the neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies, including tumor angiogenic phenotyping, plasma vascular endothelial growth factor (VEGF), and circulating endothelial cells.


RESULTS
Twenty-five patients were enrolled, and 22 were evaluable. The median age was 68 years (range, 52-81 years), 24 patients (96%) had stage III or IV disease, 18 patients (72%) had an International Prognostic Index (IPI) score of 3 to 5, and 20 patients (80%) had high-risk Mantle Cell International Prognostic Index (MIPI) scores. Patients had received a median of 2 previous therapies (range, 1-7 previous therapies), and 15 patients (60%) had progressed on bortezomib. At a median follow-up of 38 months, the overall response rate was 73% (complete response [CR]/unconfirmed CR rate, 32%; partial response [PR] rate, 41%; n = 22 patients), and the median progression-free survival was 10 months. Four CRs were ongoing (> or =6 months, > or =31 months, > or =48 months, and > or =50 months). Toxicities included grade 1 and 2 fatigue, rash, neuropathy, and cytopenias, including grade 1 and 2 thrombocytopenia (64%) and grade 3 and 4 neutropenia (64%). Two thromboses and 5 episodes of grade 3 or 4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGF A and VEGF receptor 1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF levels and circulating endothelial cells trended down with treatment.


CONCLUSIONS
RT-PEPC had significant and durable activity in MCL with manageable toxicity and maintained QoL. Novel, low-intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients.
Division of Hematology-Oncology, Center for Lymphoma and Myeloma, Weill Cornell Medical College, New York, New York, USA.
Jia
J
Ruan
Peter
P
Martin
Morton
M
Coleman
Richard R
RR
Furman
Ken
K
Cheung
Adam
A
Faye
Rebecca
R
Elstrom
Mark
M
Lachs
Katherine A
KA
Hajjar
John P
JP
Leonard
D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000523:psychology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D011241:Prednisone / Q000008:administration & dosage; D011344:Procarbazine / Q000008:administration & dosage; D011788:Quality of Life; D012008:Recurrence; D000069283:Rituximab; D013792:Thalidomide / Q000008:administration & dosage; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D011344:Procarbazine; D000069283:Rituximab; D013792:Thalidomide; D005047:Etoposide; D003520:Cyclophosphamide; D011241:Prednisone