Advances in Clinical and Experimental Medicine
2019, vol. 28, nr 8, August, p. 1051–1057
Publication type: original article
Ibrutinib discontinuation in patients with relapsed or refractory chronic lymphocytic leukemia treated in a compassionate use program: A report from the Polish Adult Leukemia Study Group (PALG)
1 Department of Hematology, Copernicus Memorial Hospital, Łódź, Poland
2 Department of Hematology, Institute of Hematology and Transfusion Medicine, Warszawa, Poland
3 Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Poland
4 Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Poland
5 Department of Hematology, Specialist District Hospital, Legnica, Poland
6 Department of Hematology, Copernicus Hospital, Toruń, Poland
7 Department of Hematology, Holycross Cancer Center, Kielce, Poland
8 Department of Hematology, Specialist District Hospital, Olsztyn, Poland
9 Department of Oncological Propaedeutics, Medical University of Gdańsk, Poland
10 Gdynia Oncology Center, Poland
Background. Development of a novel class of drugs, the B-cell receptor-signaling inhibitors, including ibrutinib, has been a major achievement in the therapy of refractory or relapsed chronic lymphocytic leukemia (CLL). However, the CLL patients who have discontinued the ibrutinib treatment in clinical trials have been reported to have poor prognosis.
Objectives. In this retrospective study by the Polish Adult Leukemia Group (PALG), we analyzed the reasons for ibrutinib cessation and outcomes after discontinuing ibrutinib in refractory or relapsed CLL patients treated in a compassionate use program in Poland.
Material and Methods. Polish CLL patients were included if they discontinued ibrutinib for any reason. The clinical data on the course of ibrutinib treatment was collected anonymously using electronic Case Report Forms (CRFs). The causes of discontinuation of ibrutinib as reported by the treating physicians were analyzed.
Results. Thirty-seven patients who discontinued ibrutinib were identified. The median duration of ibrutinib treatment in this group was 4.4 months (range: 0.2–25.2). The main reason for discontinuing ibrutinib was adverse events (n = 20, 54%), while 14 (38%) patients discontinued therapy due to disease progression and 3 (8%) due to other causes. The most common treatment complications that led to ibrutinib cessation were severe respiratory tract infections (9 patients, 24%). In the group discontinuing ibrutinib for progressive disease, 11 patients progressed with untransformed CLL, while in 3 patients, a rare type of Richter transformation to Hodgkin’s lymphoma was diagnosed. Twenty-nine patients (78%) died during the follow-up period, and median overall survival (OS) reached 2.0 months (95% CI = 0.8–5.5 months). Importantly, no significant survival difference was detected between patients who discontinued ibrutinib due to disease progression and due to adverse events.
Conclusion. The results of this analysis indicate that ibrutinib discontinuation in relapsed or refractory CLL is associated with poor prognosis regardless of the reason for ibrutinib cessation.
tyrosine kinase inhibitor, chronic lymphocytic leukemia, ibrutinib
- Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008.
- Pulte D, Redaniel MT, Bird J, Jeffreys M. Survival for patients with chronic leukemias in the US and Britain: Age-related disparities and changes in the early 21st century. Eur J Haematol. 2015;94(6):540–545.
- Eichhorst B, Robak T, Montserrat E, et al; ESMO Guidelines Committee. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):78–84.
- Byrd JC, Brown JR, O’Brien S, et al; for the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–223.
- Burger JA, Chiorazzi N. B cell receptor signaling in chronic lymphocytic leukemia. Trends Immunol. 2013;34(12):592–601.
- Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119(5):1182–1189.
- Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42.
- Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving sin-gle-agent ibrutinib. Blood. 2015;125(16):2497–2506.
- Chanan-Khan A, Cramer P, Demirkan F, et al; HELIOS Investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma [HELIOS]: A randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17(2):200–211.
- Burger JA, Tedeschi A, Barr PM, et al; for the RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–2437.
- Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125(13):2062–2067.
- Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1(1):80–87.
- Iskierka-Jażdżewska E, Hus M, Giannopoulos K, 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(10):2485–2488.
- Hallek M, Cheson BD, Catovsky D, et al; International Workshop on Chronic Lymphocytic Leukemia. 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(12):5446–5456.
- Jamroziak K, Szymczyk A, Hus M, et al. A series of chronic lymphocytic leukemia patients with Hodgkin variant Richter’s transformation during ibrutinib therapy: A report from the Polish Adult Leukemia Group (PALG). Eur J Haematol. 2018. doi: 10.1111/ejh.13016
- Jain P, Thompson PA, Keating M, et al. Long-term outcomes for patients with chronic lymphocytic leukemia who discontinue ibrutinib. Cancer. 2017;123(12):2268–2273.
- Williams AM, Baran AM, Meacham PJ, et al. Analysis of the risk of infection in patients with chronic lymphocytic leukemia in the era of novel therapies. Leuk Lymphoma. 2018;59(3):625–632.
- Winqvist M, Palma M, Heimersson K, et al. Dual targeting of Bruton tyrosine kinase and CD52 induces minimal residual disease-negativity in the bone marrow of poor-prognosis chronic lymphocytic leukaemia patients but is associated with opportunistic infections: Results from a phase I study. Br J Haematol. 2018;182(4):590–594.
- Tillman BF, Pauff JM, Satyanarayana G, Talbott M, Warner JL. Systematic review of infectious events with the Bruton tyrosine kinase inhibitor ibrutinib in the treatment of hematologic malignancies. Eur J Haematol. 2018;100(4):325–334.
- Thorp BC, Badoux X. Atrial fibrillation as a complication of ibrutinib therapy: Clinical features and challenges of management. Leuk Lymphoma. 2018;59(2):311–320.
- Chai KL, Rowan G, Seymour JF, Burbury K, Carney D, Tam CS. Practical recommendations for the choice of anticoagulants in the management of patients with atrial fibrillation on ibrutinib. Leuk Lymphoma. 2017;58(12):2811–2814.
- Furman RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370(24):2352–2354.
- Sharma S, Galanina N, Guo A, et al. Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL. Oncotarget. 2016;7(42):68833–68841.
- Wanquet A, Birsen R, Bonnet C, et al. Management of central nervous system involvement in chronic lymphocytic leukaemia: A retrospective cohort of 30 patients. Br J Haematol. 2017;176(1):37–49.
- Jamroziak K, Tadmor T, Robak T, Polliack A. Richter syndrome in chronic lymphocytic leukemia: Updates on biology, clinical features and therapy. Leuk Lymphoma. 2015;56(7):1949–1958.
- Ahn IE, Underbayev C, Albitar A, et al. Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017;129(11):1469–1479.
- Tsimberidou AM, O’Brien S, Kantarjian HM, et al. Hodgkin transformation of chronic lymphocytic leukemia: The M.D. Anderson Cancer Center experience. Cancer. 2006;107(6):1294–1302.
- Glavey S, Quinn J, McCloy M, et al. Emergence of Bruton’s tyrosine kinase-negative Hodgkin lymphoma during ibrutinib treatment of chronic lymphocytic leukaemia. Eur J Haematol. 2017;99(4):378–380.
- Sachanas S, Pangalis GA, Moschogiannis M, et al. Hodgkin lymphoma transformation of chronic lymphocytic leukemia under ibrutinib therapy: Chance association or therapy-related? Anticancer Res. 2017;37(6):3277–3280.
- Jamroziak K, Grzybowska-Izydorczyk O, Jesionek-Kupnicka D, Gora-Tybor J, Robak T. Poor prognosis of Hodgkin variant of Richter transformation in chronic lymphocytic leukemia treated with cladribine. Br J Haematol. 2012;158(2):286–288.
- Brecher M, Banks PM. Hodgkin’s disease variant of Richter’s syndrome: Report of eight cases. Am J Clin Pathol. 1990;93(3):333–339.
- 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(1):50–66.
- Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: Results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5):1050–1056.
- Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: A multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–778.
- Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: A phase 1b study. Lancet Oncol. 2017;18(2):230–240.
- Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–322.
- Jones JA, Wierda WG, Choi MY, et al. Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib. J Clin Oncol. 2016 34(15 Suppl):7519–7519.