Ibrutinib, a small molecule inhibitor of Bruton's Tyrosine Kinase (BTK) is approved for use in a variety of lymphomas. Priced at $130,000/year, Ibrutinib imposes a significant financial burden on patients and society. The study serving as the basis for the currently approved dose  demonstrated >95% BTK receptor occupancy at a dose of 2.5 mg/kg. Data suggests that lower doses of Ibrutinib are equally effective and dose reductions[4, 5] do not compromise outcome.
To evaluate patient outcomes and cost savings with clinically indicated low dose (LD) of Ibrutinib in a community practice in hematological malignancies.
All patients treated with standard and LD Ibrutinib between January 2014 and July 2020 were identified. Reason for dose modification and best responses were abstracted. Patients with inadequate follow up or less than a week of treatment were excluded from the analysis. Responses were defined based on the iwCLL response criteria for Chronic Lymphocytic Leukemia (CLL), Lugano criteria for Non-Hodgkin's Lymphoma and International Working Group on Waldenström's Macroglobulinemia (WM), as applicable.
To calculate drug cost at lower doses of Ibrutinib, cumulative number of patient-months on different dose levels of ibrutinib was calculated by adding the number of months each patient had remained at the dose level at the time of data cut-off. Drug cost at LD was calculated by multiplying monthly wholesale acquisition price for different dose levels of ibrutinib by the cumulative number of patient-months at that dose level. Cost differential between actual drug cost and projected drug cost at full dose was calculated.
98 patients were identified. 10 were excluded from the analysis based on drug not started (3), inadequate follow-up (3), other (4). Median length of follow up for all patients was 20 months (4-70 months) and on LD Ibrutinib 12.5 months (1-60 months). 10 and 12 patients received 140 mg and 280 mg of Ibrutinib respectively due to side effects. 61 patients had CLL, 9 WM, 15 mantle cell lymphoma (MCL), and 2 marginal zone lymphoma (MZL). Response rates were similar across diagnoses and dose levels (TABLE 1 and FIGURE 1). Progressive disease (PD) at low dose was seen in 2 CLL patients with complex cytogenetics, deletion 17p and extensive prior therapy. The one WM patient with PD had been extensively pretreated.
Cumulative patient-months at the 140 mg and 280 mg dose levels of Ibrutinib was 177 and 123 months respectively. Drug cost for the 140 mg and 280 mg Ibrutinib cohorts were $712,276 and $989,943 respectively, for a total cost of $1,702,219. Potential drug cost for the 420 or 560 mg dose of Ibrutinib for the same duration of therapy was $3,621,828. Cumulative cost avoidance on LD Ibrutinib was $1,919, 608.
Clinically indicated low dose Ibrutinib was equally effective and produced significant cost savings.
1. Qiushi Chen, N.J., Turgay Ayer, William G. Wierda, Christopher R. Flowers, Susan M. O'Brien, Michael J. Keating, Hagop M. Kantarjian, and Jagpreet Chhatwal, Economic Burden of Chronic Lymphocytic Leukemia in the Era of Oral Targeted Therapies in the United States. Journal of Clinical Oncology, 2017: p. 166-174.
2. Ranjana H. Advani, J.J.B., Jeff P. Sharman , Sonali M. Smith , Thomas E. Boyd , Barbara GrantKathryn S. Kolibaba , Richard R. Furman , Sara Rodriguez , Betty Y. Chang , Juthamas Sukbuntherng , Raquel Izumi , Ahmed Hamdy , Eric Hedrick , Nathan, Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies. Journal of Clinical Oncology, 2013: p. 88-94.
3. Lisa S. Chen, P.B., Nichole D. Cruz , Yongying Jiang , Qi Wu , Philip A. Thompson , Shuju Feng , Michael H. Kroll , Wei Qiao , Xuelin Huang , Nitin Jain , William G. Wierda , Michael J. Keating , Varsha Gandhi, A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia. Blood, 2018: p. 2249-2259.
4. Lad DP, Malhotra P, Khadwal A, Prakash G, Jain A, Varma S. Reduced Dose Ibrutinib Due to Financial Toxicity in CLL. Indian Journal of Hematology and Blood Transfusion, 2018. 35(2): p. 260-264.
5. Othman S. Akhtar, K.A., Ian Lund, Ryan Hare, Francisco J. Hernandez-Ilizaliturri & Pallawi Torka, Dose reductions in ibrutinib therapy are not associated with inferior outcomes in patients with chronic lymphocytic leukemia (CLL). Leukemia & Lymphoma, 2019. 60(7): p. 1650-1655.
No relevant conflicts of interest to declare.
Ibrutinib is approved at a dose of 420 mg orally daily or 560 mg orally daily in different lymphoproliferative disorders.
Asterisk with author names denotes non-ASH members.