Study of Low Dose Ibrutinib Use in a Community-Based Oncology Practice

Background: 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[1]. The study serving as the basis for the currently approved dose [2] demonstrated >95% BTK receptor occupancy at a dose of 2.5 mg/kg. Data suggests that lower doses of Ibrutinib are equally effective[3] and dose reductions[4, 5] do not compromise outcome. Objective: To evaluate patient outcomes and cost savings with clinically indicated low dose (LD) of Ibrutinib in a community practice in hematological malignancies. Method: 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. Results: 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. Conclusions: Clinically indicated low dose Ibrutinib was equally effective and produced significant cost savings. References: 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. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Ibrutinib is approved at a dose of 420 mg orally daily or 560 mg orally daily in different lymphoproliferative disorders.

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Low Dose Oral Fludarabine Plus Cyclophosphamide in Elderly Patients with Untreated and Refractory Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v110.11.2055.2055 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2055-2055

Author(s):

Francesco Forconi ◽

F. Toraldo ◽

E. Sozzi ◽

M. Lenoci ◽

A. Fabbri ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Elderly Patients ◽

Total Dose ◽

Idiopathic Thrombocytopenic Purpura ◽

Low Dose ◽

Lymphocytic Leukemia ◽

Thrombocytopenic Purpura ◽

Highly Effective ◽

Dose Oral

Abstract The intravenous regimen of fludarabine plus cyclophosphamide (FC) at conventional doses is highly effective in Chronic lymphocytic leukemia (CLL), where it is currently indicated in first line therapy, and low-grade non Hodgkin lymphomas (LG-NHL). We have shown that intravenous or oral FC regimens at reduced doses remain highly effective in elderly patients with LG-NHL other than CLL. We tested tolerability and efficacy of oral FC at reduced doses in elderly patients with previously untreated (UT-CLL) or relapsed/refractory CLL (R-CLL). Twenty-five patients (>60 years) with UT-CLL (n=13) or R-CLL (n=12) were given oral F (25mg/m2/day, 40 mg total dose) and C (150mg/m2/day, 200 mg total dose) in an outpatient regimen for 4 consecutive days every 4 weeks for a maximum of 4 cycles. Patients were evaluated after every cycle for toxicity and hematological response. Toxicity was defined according to NCI criteria. Responses were defined as Complete (CR) when a normalization of blood count and misurable masses (lymph nodes and spleen) was documented, partial (PR) when at least a 50% reduction of lymphocytosis or nodes/splenomegaly occured, no response (NR) when disease was stable (less than PR) or progressed (>25% increment of tumor manifestations). Progression, new treatment or death was defined as “event”. Median age of the whole population was 70 years (range 61–80), 70 (61–80) in the UT-CLL, 71 (62–79) in the R-CLL. M:F distribution was 14:11 (7:6 in UT-CLL, 7:5 in R-CLL). Performance status was ≥1 in 80% patients. Of 25 patients, 16 (64%) were diagnosed CLL in stage A, 8 (32%) in stage B, 1 (4%) in stage C. Tumor IGHV gene was unmutated in 90% cases (in 85% UT-CLL, in 100% R-CLL). CD38 was positive in 68% (77% UT-CLL, 55% R-CLL) and ZAP-70 in 68% (82%, 67%). Chromosomal deletions of 11q or 17p regions were documented in 25.5% patients (27% UT-CLL, 25% R-CLL). The R-CLL had received 1–4 (median 2) treatment lines prior to FC. Median time from diagnosis or from prior treatment to FC was 24 months (range 1–77), 37 (1–77) in the UT-CLL, 12 (3–48) in the R-CLL. Overall, biological risk and clinical characteristics were indicative of an aggressive behavior of the investigated cohort. Patients received median 3 cycles (4 in UT-CLL, 3 in R-CLL). Nine-of-25 (36%) reduced the number of cycles because of fatigue (1 patient), heart failure (1), idiopathic thrombocytopenic purpura (1) in the UT-CLL (3/13) or infection (2), femur fracture (1), prolonged isolated thrombocytopenia or pancitopenia (2) and idiopathic thrombocytopenic purpura (1) in the R-CLL (6/12). Overall, 23/25 patients (92%) obtained a response (11/25 CR, 44%; 12/25 PR, 48%). Among UT-CLL, all responded to treatment (8/13 CR, 61.5%; 5/13 PR, 38.5%). Among R-CLL, 10/12 (83.5%) responded (3/12 CR, 25%; 7/12 PR, 58.5%; 2/12 NR, 16.5%). With a median follow-up of 23 months, 14/25 patients (56%) were event-free and 23/25 (92%) were alive. Among UT-CLL (median follow-up 12 months), 9/13 (69%) were event-free and all were alive. Among R-CLL (median follow-up 25 months), 5/12 (42%) were event-free and 10/12 (83%) were alive. Deaths occurred in the 2 R-CLL that had not responded to treatment, after 2 and 4 years, respectively. Despite the poor risk of the investigated population, this low-dose oral FC treatment showed good efficacy both in untreated and refractory/relapsed CLL. The treatment may be useful in elderly patients who cannot benefit of more aggressive or eradicating strategies and is easy to administer on an outpatient basis.

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Results of a Phase II of Low-Dose Fludarabine and Cyclophosphamide Combined with Standard Dose Rituximab (FCR-LITE) in Elderly, Untreated Patients with Chronic Lymphocytic Leukemia (CLL): The Israeli CLL Study Group Experience

Blood ◽

10.1182/blood-2018-99-111681 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5566-5566

Author(s):

Tamar Tadmor ◽

Yair Herishanu ◽

Andrei Braester ◽

Osnat Bairey ◽

Ariel Aviv ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Elderly Patients ◽

Phase Ii ◽

Research Funding ◽

Low Dose ◽

Lymphocytic Leukemia ◽

Novel Agents ◽

Categorical Variables ◽

Positive Direct

Abstract Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. Despite the development of novel agents and new monoclonal antibodies, FCR still remains the combination chemoimmunotherapy of choice for fit patients with CLL, yielding the longest durations of remission. When this study was first started, no established chemo-immunotherapy regimen was unanimously regarded as standard therapy for less fit elderly patients with CLL; this category of patients had clearly been underrepresented in clinical trials utilizing chemo - or chemo-immunotherapy. Patients and Methods We conducted a single arm, phase II trial to assess the efficacy and toxicity of low dose fludarabine and cyclophosphamide in combination with a regular dose of rituximab (FCR-LITE) in elderly patients with therapy naïve CLL. Our intention was to deliver 6 courses of Fludarabine which was given intravenously (IV) at 12.5 mg/m2/day together with IV cyclophosphamide 150 mg/m2/day for 3 consecutive days. IV rituximab was administered on day 0 of cycle 1 at a dose of 375 mg/m2, and at 500 mg/m2 on day 1 of cycles 2-6. Categorical variables were compared in patients with and without CR using chi-square test or Fisher's exact test and continuous variables were also compared using Mann Whitney test. Duration of follow-up was recorded using reverse censoring method. Kaplan Meier curve was used to establish PFS during clinical follow-up. All statistical tests were two sided. P<0.05 was considered as statistically significant. Results Forty patients treated with FCR-LITE were included in the efficacy analysis. The median age of the entire cohort was 72.7 years (range, 65.0 to 85.0), and 69% were male. The mean number of treatment cycles was 5.1 (range 1-6). The overall response rate was 67.5% (95% CI, 50.9%-81.4%); 17 patients (42.5%) achieved CR and 10 (25.0%) PR. Median PFS was 35.5 months (95% CI, 29.27-41.67). Two patients (4.8%) died during the study period. Reduced cumulative doses of FCR and fewer courses of treatment were both associated with lower CR rate. Hematological toxicities were the most common side effects encountered; grade-3/4 neutropenia occurred in twenty (47.6%) patients, only six (14.3%) developed neutropenic fever. Positive direct antiglobulin test (DAT), was seen in 11 patients but none of them developed autoimmune hemolytic anemia (AIHA) during treatment; two patients (4.8%) progressed to Richter's transformation and two (4.8%) had second malignancies (lung and metastatic colon carcinoma). Conclusion FCR-LITE is effective and safe for treating elderly patients with therapy-naïve CLL. It has the advantage of being both time and cost effective. In an era of novel agents, it can still be considered as suitable frontline treatment for fit elderly patients with CLL. This research was supported by roche pharmaceuticals Table. Table. Disclosures Tadmor: ABBVIE: Consultancy; ROCHE: Research Funding; NOVARTIS: Consultancy; JNJ: Consultancy; PFIEZER: Consultancy. Herishanu:JNJ: Consultancy; ABBVIE: Consultancy; ROCHE: Research Funding. Bairey:ROCHE: Research Funding; AbbVie: Consultancy; Jansen: Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Rahimi-Levene:ABBVIE: Consultancy. Fineman:ABBVIE: Consultancy; JNJ: Consultancy. Ruchlemer:JNJ: Consultancy; ABBVIE: Consultancy. Shvidel:JNJ: Consultancy; ROCHE: Consultancy, Research Funding; ABBVIE: Consultancy, Research Funding. Polliack:ABBVIE: Consultancy; ROCHE: Research Funding.

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Ibrutinib Dose Reductions and Discontinuations Patterns Among Patients with Chronic Lymphocytic Leukemia from a Large Community Medical Oncology Practice

Blood ◽

10.1182/blood-2020-137151 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-35

Author(s):

Senxi Du ◽

Bruno S. Fang ◽

Percy Yeung ◽

Eileen Peng ◽

Marisa Keck

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Dose Reduction ◽

Median Time ◽

Real World ◽

Medical Oncology ◽

Lymphocytic Leukemia ◽

Disease Characteristics ◽

Oncology Practice ◽

Dose Reductions

Introduction: Ibrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of first-line (1L) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Original approval of ibrutinib was based, in part, on results from the RESONATE and RESONATE-2 studies demonstrating improved efficacy of ibrutinib among R/R CLL patients. Data from the trial reported as few as 4% of participants required dose reduction and 4% discontinued treatment because of adverse events (AEs). Real-world studies have demonstrated that the rates of dose reductions and discontinuations of ibrutinib because of AEs are significantly higher (as high as 25%). The aim of this study was to analyze baseline characteristics of patients with CLL who were treated with ibrutinib in the community setting, as well as the subsequent rates of and reasons for dose reductions and discontinuations. Methods: We conducted a retrospective chart review of 50 randomly selected patients of RCCA, a large medical oncology group in New Jersey with 13 practices over 30 sites that services approximately 1200 patients with CLL annually. Patients with a diagnosis of CLL were included if ibrutinib therapy was started between March 2014 and June 2019, and they had a minimum of 6 months of follow-up on therapy and were 18 years of age or older. Exclusion criteria were participation in a trial involving ibrutinib, active treatment for another malignancy, and pregnancy. The index date was defined as the date of novel agent initiation. De-identified data collected for descriptive analysis were used to summarize patient and disease characteristics, as well as to identify reasons for dose reduction and discontinuation. Result: 50 Patients with CLL were included in this analysis; 21 (42%) received ibrutinib as 1L therapy and 29 (58%) for R/R disease. Patient and disease characteristics at baseline are shown in Table 1. 17 Patients (34%) underwent at least 1 dose reduction. Most dose reductions were due to AEs, and 1 reduction was due to a drug-drug interaction. The most common category of AE that led to dose reduction was gastrointestinal disorders (n=4 [24%]) (Table 2). In our study, 15 patients (30%) discontinued treatment. Of these discontinuations, 10 (66%) were due to AEs, 2 (13%) were due to deaths, and 2 (13%) were due to progression of disease. The most common AE for drug discontinuation was atrial fibrillation (n=3 [20%]) (Table 2). The median follow-up time for all patients was 21.5 months. For those who underwent dose reduction (n=17), median time to dose reduction was 1.9 months. Median time to discontinuation of treatment was 6.9 months overall (n=15), whereas median time to discontinuation specifically due to AEs (n=10) was 3.4 months. Conclusion: Patients with CLL who were treated with ibrutinib in the real-world setting frequently experienced dose reductions and treatment discontinuations. In our medical oncology practice, about one-third had their treatment dose reduced and about one-third had treatment discontinued. We found much higher rates than those originally reported in the RESONATE and -2 studies, with rates closer to those found in other real-world analyses. This is probably because patients with preexisting conditions and concurrent medication use may be excluded from clinical trials, resulting in a healthier participant population. For example, based on the RESONATE trial's exclusion of patients taking warfarin or strong CYP3A4/5 inhibitors, about one-fifth of our patients would have been excluded from that study. Further research is still needed to gather population characteristics and responses to therapy that may help guide clinicians in the optimal management of patients with multiple comorbid conditions and concurrent medications who are receiving ibrutinib for CLL. Disclosures Du: AstraZeneca: Other: Grant. Fang:AstraZeneca: Other: Grant. Yeung:AstraZeneca: Research Funding. Peng:AstraZeneca: Other: Grant. Keck:AstraZeneca: Other: Grant.

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