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Efficacy and safety outcomes of single-agent ibrutinib therapy in chronic lymphocytic leukemia and relapsed/refractory mantle-cell lymphoma

Year 2023, Volume: 9 Issue: 6 - November 2023, 1483 - 1492, 04.11.2023
https://doi.org/10.18621/eurj.1359362

Abstract

Objectives: We aimed to evaluate patients using ibrutinib for the treatment of chronic lymphocytic leukemia (CLL) and relapsed/refractory mantle-cell lymphoma (MCL), focusing on high-risk subgroups, predictors of efficacy, response levels, and safety profile.

Methods: This retrospective cohort study included adult patients diagnosed with CLL and relapsed/refractory MCL who were started on ibrutinib as a single-agent between May 2015 and December 2021 in Bursa Uludag University, Department of Hematology.

Results: Of the 45 patients (23 CLL, 22 MCL) started on ibrutinib, the median age was 65 (range: 48-86) years, and 66.7% were male. Del(17p) was present in 47.8% of CLL patients; there was no remarkable difference between del(17p) status and the rates of achieving CR. The median follow-up with ibrutinib treatment in CLL patients was 13.3 (range: 0.3-77.8) months. In univariate analysis, progression-free survival (PFS) and overall survival (OS) were associated with the advanced Eastern Cooperative Oncology Group (ECOG) score (p = 0.003 and p = 0.004, respectively), and > 2 lines treatment regimens before ibrutinib (p = 0.016 and p = 0.050, respectively). In multivariate analysis, the ECOG performance status remained significant for OS. The median use of ibrutinib for MCL patients was 6 (range: 1-48) months, and the proportion of patients who achieved CR was 27.3%. In the univariate analysis of MCL patients, the ECOG performance status for PFS and OS was statistically significant (p = 0.045 and p = 0.016, respectively). Patients' most common non-hematological adverse events were pneumonia and urinary tract infection.

Conclusions: Our investigation of patient outcomes treated outside clinical trials confirms ibrutinib's sufficient efficacy and safety profile in CLL and relapsed/refractory MCL.

Ethical Statement

Ethics committee approval was obtained for the conduct of the study (Bursa Uludag University, date, 24 November 2021; no, 2021-17/34). The study was conducted by the 1964 Declaration of Helsinki and subsequent revisions.

References

  • 1. Tam CS, O'Brien S, Plunkett W, Wierda W, Ferrajoli A, Wang X, et al. Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood 2014;124:3059-64.
  • 2. Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 2016;17:928-42.
  • 3. 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.
  • 4. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376:1164-74.
  • 5. Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 2016;127:303-9.
  • 6. Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Döhner K, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 2014;123:3247-54.
  • 7. Rossi D, Terzi-di-Bergamo L, De Paoli L, Cerri M, Ghilardi G, Chiarenza A, et al. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood 2015;126:1921-4.
  • 8. Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2012;30:3209-16.
  • 9. Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 2016;127:208-15.
  • 10. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369:507-16.
  • 11. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, 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. Blood 2008;111:5446-56.
  • 12. US Department of Health and Human Services. National Cancer Institute. Common terminology criteria for adverse events (CTCAE) version 4.0. 2009. US Department of Health and Human Sciences. 2016.
  • 13. Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014;371:213-23.
  • 14. Winqvist M, Asklid A, Andersson PO, Karlsson K, Karlsson C, Lauri B, et al. Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group. Haematologica 2016;101:1573-80.
  • 15. Iskierka-Jażdżewska E, Hus M, Giannopoulos K, Mądro E, Hołojda J, Piotrowska M, et al. Efficacy and toxicity of compassionate ibrutinib use in relapsed/refractory chronic lymphocytic leukemia in Poland: analysis of the Polish Adult Leukemia Group (PALG). Leuk Lymphoma 2017;58:2485-8.
  • 16. Tombak A, Pepedil Tanrıkulu F, Durusoy SS, Dinçyürek HD, Kaya E, Ümit EG, et al. Efficacy and safety of ibrutinib therapy in patients with chronic lymphocytic leukemia: retrospective analysis of real-life data. Turk J Haematol 2021;38:273-85.
  • 17. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32-42.
  • 18. O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood 2018;131:1910-9.
  • 19. Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006;24:4867-74.
  • 20. Goy A, Sinha R, Williams ME, Kalayoglu Besisik S, Drach J, Ramchandren R, et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J Clin Oncol 2013;31:3688-95.
  • 21. Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, et al. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol 2019;94:1353-63.
  • 22. Wang ML, Blum KA, Martin P, Goy A, Auer R, Kahl BS, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood 2015;126:739-45.
  • 23. Göçer M, Kurtoğlu E. Safety and efficacy analysis of ibrutinib in 32 patients with CLL and various B-cell lymphomas: real-world data from a single-center study in Turkey. Blood Res 2020;55:206-12.
  • 24. de Jong J, Skee D, Murphy J, Sukbuntherng J, Hellemans P, Smit J, et al. Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants. Pharmacol Res Perspect 2015;3:e00156.
  • 25. De la Garza-Salazar F, Colunga-Pedraza PR, Gómez-Almaguer D. Cytochrome P450 inhibition to decrease dosage and costs of venetoclax and ibrutinib: a proof-of-concept case study. Br J Clin Pharmacol 2023;89:898-902.
Year 2023, Volume: 9 Issue: 6 - November 2023, 1483 - 1492, 04.11.2023
https://doi.org/10.18621/eurj.1359362

Abstract

References

  • 1. Tam CS, O'Brien S, Plunkett W, Wierda W, Ferrajoli A, Wang X, et al. Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood 2014;124:3059-64.
  • 2. Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 2016;17:928-42.
  • 3. 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.
  • 4. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376:1164-74.
  • 5. Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 2016;127:303-9.
  • 6. Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Döhner K, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 2014;123:3247-54.
  • 7. Rossi D, Terzi-di-Bergamo L, De Paoli L, Cerri M, Ghilardi G, Chiarenza A, et al. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood 2015;126:1921-4.
  • 8. Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2012;30:3209-16.
  • 9. Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 2016;127:208-15.
  • 10. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369:507-16.
  • 11. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, 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. Blood 2008;111:5446-56.
  • 12. US Department of Health and Human Services. National Cancer Institute. Common terminology criteria for adverse events (CTCAE) version 4.0. 2009. US Department of Health and Human Sciences. 2016.
  • 13. Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014;371:213-23.
  • 14. Winqvist M, Asklid A, Andersson PO, Karlsson K, Karlsson C, Lauri B, et al. Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group. Haematologica 2016;101:1573-80.
  • 15. Iskierka-Jażdżewska E, Hus M, Giannopoulos K, Mądro E, Hołojda J, Piotrowska M, et al. Efficacy and toxicity of compassionate ibrutinib use in relapsed/refractory chronic lymphocytic leukemia in Poland: analysis of the Polish Adult Leukemia Group (PALG). Leuk Lymphoma 2017;58:2485-8.
  • 16. Tombak A, Pepedil Tanrıkulu F, Durusoy SS, Dinçyürek HD, Kaya E, Ümit EG, et al. Efficacy and safety of ibrutinib therapy in patients with chronic lymphocytic leukemia: retrospective analysis of real-life data. Turk J Haematol 2021;38:273-85.
  • 17. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32-42.
  • 18. O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood 2018;131:1910-9.
  • 19. Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006;24:4867-74.
  • 20. Goy A, Sinha R, Williams ME, Kalayoglu Besisik S, Drach J, Ramchandren R, et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J Clin Oncol 2013;31:3688-95.
  • 21. Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, et al. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol 2019;94:1353-63.
  • 22. Wang ML, Blum KA, Martin P, Goy A, Auer R, Kahl BS, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood 2015;126:739-45.
  • 23. Göçer M, Kurtoğlu E. Safety and efficacy analysis of ibrutinib in 32 patients with CLL and various B-cell lymphomas: real-world data from a single-center study in Turkey. Blood Res 2020;55:206-12.
  • 24. de Jong J, Skee D, Murphy J, Sukbuntherng J, Hellemans P, Smit J, et al. Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants. Pharmacol Res Perspect 2015;3:e00156.
  • 25. De la Garza-Salazar F, Colunga-Pedraza PR, Gómez-Almaguer D. Cytochrome P450 inhibition to decrease dosage and costs of venetoclax and ibrutinib: a proof-of-concept case study. Br J Clin Pharmacol 2023;89:898-902.
There are 25 citations in total.

Details

Primary Language English
Subjects Haematological Tumours
Journal Section Original Articles
Authors

İbrahim Ethem Pınar 0000-0001-9907-1498

Vildan Ozkocaman 0000-0003-0014-7398

Early Pub Date October 24, 2023
Publication Date November 4, 2023
Submission Date September 12, 2023
Acceptance Date October 19, 2023
Published in Issue Year 2023 Volume: 9 Issue: 6 - November 2023

Cite

AMA Pınar İE, Ozkocaman V. Efficacy and safety outcomes of single-agent ibrutinib therapy in chronic lymphocytic leukemia and relapsed/refractory mantle-cell lymphoma. Eur Res J. November 2023;9(6):1483-1492. doi:10.18621/eurj.1359362

e-ISSN: 2149-3189 


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