A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL

Key Points • Patients with DLBCL Richter transformation of CLL have a poor prognosis, especially if they have had prior BTKi exposure.• Nivolumab and ibrutinib combination therapy is a safe and potential treatment option in patients with DLBCL Richter transformation.

[1]  C. Cheah,et al.  Emerging Therapies for the Management of Richter Transformation. , 2022, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  M. Kesavan,et al.  Cellular Therapy in High-Risk Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter Syndrome , 2022, Frontiers in Oncology.

[3]  Douglas B. Johnson,et al.  Immune-checkpoint inhibitors: long-term implications of toxicity , 2022, Nature Reviews Clinical Oncology.

[4]  A. Schuh,et al.  Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the Richter transformation cohort of an open-label, single-arm, phase 1-2 study. , 2021, The Lancet. Haematology.

[5]  M. Hallek,et al.  Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures , 2021, American journal of hematology.

[6]  I. Levy,et al.  Richter Transformation in Chronic Lymphocytic Leukemia: Update in the Era of Novel Agents , 2021, Cancers.

[7]  W. Wierda,et al.  PIRTOBRUTINIB (LOXO‐305), A NEXT GENERATION HIGHLY SELECTIVE NON‐COVALENT BTK INHIBITOR IN PREVIOUSLY TREATED RICHTER TRANSFORMATION: RESULTS FROM THE PHASE 1/2 BRUIN STUDY , 2021, Hematological Oncology.

[8]  S. Slager,et al.  Distinct immune signatures in chronic lymphocytic leukemia and Richter syndrome , 2021, Blood Cancer Journal.

[9]  P. Feugier,et al.  Microenvironment Remodeling and Subsequent Clinical Implications in Diffuse Large B-Cell Histologic Variant of Richter Syndrome , 2020, Frontiers in Immunology.

[10]  A. Nagler,et al.  Safety and Efficacy of CD19-CAR T Cells in Richter's Transformation after Targeted Therapy for Chronic Lymphocytic Leukemia , 2020 .

[11]  J. Byrd,et al.  Clinical activity of axicabtagene ciloleucel in adult patients with Richter syndrome. , 2020, Blood advances.

[12]  A. Stathis,et al.  Pembrolizumab in relapsed or refractory Richter syndrome , 2020, British journal of haematology.

[13]  S. Slager,et al.  Clinical characteristics and outcomes of Richter transformation: experience of 204 patients from a single center , 2019, Haematologica.

[14]  A. López-Guillermo,et al.  Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study. , 2019, The Lancet. Haematology.

[15]  W. Faridi,et al.  Significant Risk of Graft-versus-Host Disease with Exposure to Checkpoint Inhibitors before and after Allogeneic Transplantation. , 2019, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[16]  A. Behdad,et al.  PD‐1 is highly expressed by neoplastic B‐cells in Richter transformation , 2018, British journal of haematology.

[17]  J. Byrd,et al.  Use of PD‐1 (PDCD1) inhibitors for the treatment of Richter syndrome: experience at a single academic centre , 2018, British journal of haematology.

[18]  T. Shanafelt,et al.  PD-1 Expression in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and Large B-cell Richter Transformation (DLBCL-RT): A Characteristic Feature of DLBCL-RT and Potential Surrogate Marker for Clonal Relatedness , 2018, The American journal of surgical pathology.

[19]  D. Rossi,et al.  Biology and treatment of Richter syndrome. , 2018, Blood.

[20]  Jeffrey A Jones,et al.  A single‐institution retrospective cohort study of first‐line R‐EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor , 2018, British journal of haematology.

[21]  A. Tojo,et al.  Association between GvHD and nivolumab in the FDA adverse event reporting system , 2017, Bone Marrow Transplantation.

[22]  Deborah A. Bowen,et al.  Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. , 2017, Blood.

[23]  R. V. Van Heertum,et al.  Lugano 2014 criteria for assessing FDG-PET/CT in lymphoma: an operational approach for clinical trials , 2017, Drug design, development and therapy.

[24]  R. Houot,et al.  Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma. , 2017, Blood.

[25]  T. Kipps,et al.  Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  Jeffrey A Jones,et al.  Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. , 2016, The Lancet. Oncology.

[27]  J. Gribben,et al.  NCRI phase II study of CHOP in combination with ofatumumab in induction and maintenance in newly diagnosed Richter syndrome , 2016, British journal of haematology.

[28]  M. Keating,et al.  Richter transformation of CLL , 2016, Expert review of hematology.

[29]  H. Döhner,et al.  Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. , 2016, Blood.

[30]  S. Leprêtre,et al.  Platinum and high‐dose cytarabine‐based regimens are efficient in ultra high/high‐risk chronic lymphocytic leukemia and Richter's syndrome: results of a French retrospective multicenter study , 2015, European journal of haematology.

[31]  J. Gribben,et al.  Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model. , 2015, Blood.

[32]  J. Gribben,et al.  PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia. , 2015, Blood.

[33]  Deborah A. Bowen,et al.  The efficacy of ibrutinib in the treatment of Richter syndrome. , 2015, Blood.

[34]  H. Kohrt,et al.  Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK , 2015, Proceedings of the National Academy of Sciences.

[35]  H. Döhner,et al.  Poor efficacy and tolerability of R‐CHOP in relapsed/refractory chronic lymphocytic leukemia and Richter transformation , 2014, American journal of hematology.

[36]  J. Gribben,et al.  Immunomodulation and immune reconstitution in chronic lymphocytic leukemia. , 2014, Seminars in hematology.

[37]  Jeffrey A Jones,et al.  Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. , 2013, Blood.

[38]  Jeffrey A Jones,et al.  Phase I-II clinical trial of oxaliplatin, fludarabine, cytarabine, and rituximab therapy in aggressive relapsed/refractory chronic lymphocytic leukemia or Richter syndrome. , 2013, Clinical lymphoma, myeloma & leukemia.

[39]  J. Gribben,et al.  Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. , 2012, Blood.

[40]  J. Byrd,et al.  Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. , 2008, The Journal of clinical investigation.

[41]  Michael Hallek,et al.  Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. , 2008, Blood.

[42]  K. Do,et al.  Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  R. Simon,et al.  Optimal two-stage designs for phase II clinical trials. , 1989, Controlled clinical trials.

[44]  B. Hoerni,et al.  [Treatment of chronic lymphocytic leukemia]. , 1971, Bordeaux medical.