Long-term follow-up of R-CHOP with bevacizumab as initial therapy for mantle cell lymphoma: clinical and correlative results

Clin Lymphoma Myeloma Leuk. 2014 Apr;14(2):107-13. doi: 10.1016/j.clml.2013.10.002. Epub 2013 Nov 18.

Abstract

Background: Emerging evidence indicates that MCL has increased angiogenesis within the tumor microenvironment. We initiated a phase II trial to determine if the addition of bevacizumab to the standard R-CHOP regimen could enhance antitumor effects in patients with previously untreated MCL.

Patients and methods: Eleven patients with previously untreated MCL received bevacizumab at 15 mg/kg on day 1, and standard CHOP-21 (CHOP given every 21 days per cycle) with rituximab (375 mg/m(2) per cycle) on day 3 of each cycle for a total of 6 cycles. Planned study end points included safety and efficacy assessment, and exploratory analysis of angiogenic profiles. The study was suspended in August of 2010 based on safety findings in DLBCL (diffuse large B-cell lymphoma) of increased cardiovascular events with the regimen.

Results: Beyond the standard R-CHOP safety profile, Grade 3 left ventricular dysfunction developed in 2 patients (18%), Grade 1/2 hypertension, proteinuria, and bleeding each developed in 1 patient (9%). The overall response rate was 82% with 36% complete response (CR)/complete response unconfirmed (CRu). The median progression-free survival (n = 11) was 18 months (95% confidence interval, 3-not reached), and 3-year overall survival rate was 82%. Correlative studies showed increased vascular endothelial growth factor receptor 1 expression in tumor cells at baseline, and elevated levels of plasma vascular endothelial growth factor (VEGF) throughout treatment.

Conclusion: The addition of bevacizumab to the standard R-CHOP regimen did not appear to significantly improve efficacy beyond that observed from previous studies using R-CHOP alone. Therapeutic strategies that provide sustained inhibition on VEGF-related and VEGF-independent targets within the tumor microenvironment might further improve antiangiogenic effects and warrant further exploration in MCL.

Keywords: Angiogenesis; Anti-VEGF; Chemotherapy; Mantle cell lymphoma; Tumor microenvironment.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anemia / chemically induced
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab
  • Cell Line, Tumor
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / adverse effects
  • Doxorubicin / administration & dosage
  • Doxorubicin / adverse effects
  • Fatigue / chemically induced
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Kaplan-Meier Estimate
  • Lymphoma, Mantle-Cell / drug therapy*
  • Male
  • Middle Aged
  • Prednisone / administration & dosage
  • Prednisone / adverse effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Treatment Outcome
  • Vascular Endothelial Growth Factor A / blood
  • Vascular Endothelial Growth Factor Receptor-1 / genetics
  • Ventricular Dysfunction, Left / chemically induced
  • Vincristine / administration & dosage
  • Vincristine / adverse effects

Substances

  • Antibodies, Monoclonal, Humanized
  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • Vincristine
  • Doxorubicin
  • Cyclophosphamide
  • Vascular Endothelial Growth Factor Receptor-1
  • Prednisone