Single arm NCRI phase II study of CHOP in combination with Ofatumumab in induction and maintenance for patients with newly diagnosed Richter’s syndrome

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• 作者：Toby A Eyre ; Ruth Clifford ; Corran Roberts ; Lucy Boyle ; Anne Francis…
• 关键词：Ofatumumab ; CHOP ; TP53 ; Richter’s syndrome ; Chronic lymphocytic leukaemia ; Diffuse large B cell lymphoma ; Phase II ; Rare cancers
• 刊名：BMC Cancer
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：15
• 期：1
• 全文大小：361 KB
• 参考文献：1. Rossi D, Spina V, Deambrogi C, Rasi S, Laurenti L, Stamatopoulos K, et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood. 2011;117:3391-01. CrossRef
  2. Tsimberidou A-M, O’Brien S, Khouri I, Giles FJ, Kantarjian HM, Champlin R, et al. Clinical outcomes and prognostic factors in patients with Richter’s syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol. 2006;24:2343-1. CrossRef
  3. Rossi D, Cerri M, Capello D, Deambrogi C, Rossi FM, Zucchetto A, et al. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome. Br J Haematol. 2008;142:202-5. CrossRef
  4. Richter MN. Generalized Reticular Cell Sarcoma of Lymph Nodes Associated with Lymphatic Leukemia*. Am J Pathol. 1928;4:285-92.7.
  5. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992-001. Blood. 2006;107:265-6. CrossRef
  6. Bockorny B, Codreanu I, Dasanu CA. Hodgkin lymphoma as Richter transformation in chronic lymphocytic leukaemia: a retrospective analysis of world literature. Br J Haematol. 2012;156:50-6. CrossRef
  7. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma. Volume 346. 2002. p. 235-2.
  8. Parikh SA, Rabe KG, Call TG, Zent CS, Habermann TM, Ding W, et al. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol. 2013;162:774-2. CrossRef
  9. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions. N Engl J Med 2014; 370:1101-10.
  10. Tsimberidou AM, Kantarjian HM, Cortes J, Thomas DA, Faderl S, Garcia-Manero G, et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Rich. Cancer. 2003;97:1711-0. CrossRef
  11. Dabaja BS, O’Brien SM, Kantarjian HM, Cortes JE, Thomas DA, Albitar M, et al. Fractionated Cyclophosphamide, Vincristine, Liposomal Daunorubicin (daunoXome), and Dexamethasone (hyperCVXD) Regimen in Richter’s Syndrome. Volume 42. 2001. p. 329-7.
  12. Tsimberidou AM, O’Brien SM, Cortes JE, Faderl S, Andreeff M, Kantarjian HM, et al. Phase II Study of Fludarabine, Cytarabine (Ara-C), Cyclophosphamide, Cisplatin and GM-CSF (FACPGM) in Patients with Richter’s Syndrome or Refractory Lymphoproliferative Disorders. Volume 43. 2002. p. 767-2.
  13. Tsimberidou AM, Wierda WG, Plunkett W, Kurzrock R, O’Brien S, Wen S, et al. Phase I-II Study of Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy in Patients with Richter’s Syndrome or Fludarabine-Refractory Chronic Lymphocytic Leukemia. Volume 26. 2008. p. 196-03.
  14. Tsimberidou AM, Wierda WG, Wen S, Plunkett W, O’Brien S, Kipps TJ, et al. Phase I-II clinical trial of oxaliplatin, fludarabine, cytarabine, and rituximab therapy in aggressive relapsed/refractory chronic lymphocytic leukemia or Richter syndrome. Clin Lymphoma Myeloma Leuk. 2013;13:568-4. CrossRef
  15. Langerbeins P, Busch R, Anheier N, Dürig J, Bergmann M, Goebeler M-E, et al. Poor efficacy and tolerability of R-CHOP in relapsed/refractory chronic lymphocytic leukemia and Richter transformation. Am J Hematol. 2014;89:239-43.
  16. Barth MJ, Hernandez-Ilizaliturri FJ, Mavis C, Tsai P-C, Gibbs JF, Deeb G, et al. Ofatumumab demonstrates activity against rituximab-sensitive and -resistant cell lines, lymphoma xenografts and primary tumour cells from patients with B-cell lymphoma. Br J Haematol. 2012;
• 作者单位：Toby A Eyre (1)
  Ruth Clifford (2)
  Corran Roberts (3)
  Lucy Boyle (4)
  Anne Francis (4)
  Anna Schuh (2)
  Susan J Dutton (5)
  
  1. Department of Haematology & The Early Phase Clinical Trial Unit, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, OX3 7EJ, UK
  2. NIHR BRC Oxford Molecular Diagnostic Centre, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, OX3 9DU, UK
  3. Centre for Statistics in Medicine (CSM), Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, The Botnar Research Centre, Windmill Road, Oxford, OX3 7LD, UK
  4. CHOP-OR Trial Office, OCTO - Oncology Clinical Trials Office, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
  5. Oxford Clinical Trials Research Unit & Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK
  
• 刊物主题：Cancer Research; Oncology; Stem Cells; Animal Models; Internal Medicine;
• 出版者：BioMed Central
• ISSN：1471-2407

文摘

Background Transformation of B-cell chronic lymphocytic leukaemia (B-CLL) to diffuse large B cell lymphoma (DLBCL) (Richter’s syndrome (RS)) is a rare (2-15% of patients) but catastrophic complication of B-CLL. Dose-intense chemotherapy regimens investigated in small single institution trials, but with the exception of bone marrow transplantation for a minority of patients, little has improved the median overall survival of patients with RS beyond eight months. Patients are often elderly, immunosuppressed, possess co-morbidities and have a deteriorating performance status. TP53 disruption is a common molecular abnormality noted in RS and contributes to the tumour’s chemotherapy resistance. Ofatumumab is a fully human anti-CD20 monoclonal IgG1κ antibody that targets a unique epitope on B lymphocytes. It has displayed increased binding affinity and a longer dissociation time when compared to rituximab resulting in improved complement dependent cellular cytotoxicity (CDCC); a mechanism with the potential to overcome apoptosis-resistance in TP53 disruption. Given the prevalence of TP53 disruption in RS, Ofatumumab was considered a relatively non-toxic agent with a sound rationale to test in a prospective multicentre trial as an adjunct to CHOP induction and subsequent ofatumumab maintenance therapy in responding patients. Methods/Design The CHOP-OR study is a prospective phase II study to evaluate the safety, feasibility and activity of a CHOP chemotherapy in combination with ofatumumab in induction and subsequent maintenance for patients with newly diagnosed RS. The primary objective will be the overall response rate (ORR) in patients with RS after six cycles of CHOP-O. The secondary objectives include feasibility of recruitment, progression free survival (PFS), overall survival (OS) and toxicity. The study will be accompanied by exploratory analysis of the genomic landscape of RS in newly diagnosed patients. Discussion The CHOP-OR trial evaluates the safety, feasibility and activity of CHOP plus Ofatumumab induction and Ofatumumab maintenance in new RS patients. The study is currently recruiting and has met the interim analysis criteria, with more than 7 of the first 25 participants achieving a CR or PR after six cycles of CHOP-O. The study has the potential to identify predictive biomarkers for this treatment modality. Trial registration NCT01171378.