ALBERT

Description: Chromatin remodeling is fundamental for B-cell differentiation. In the present study, we explored the role of KAP1, the cofactor of KRAB-ZFP transcriptional repressors, in this process. B-lymphoid–specific Kap1-KO mice displayed reduced numbers of mature B cells, lower steady-state levels of Abs, and accelerated rates of decay of neutralizing Abs after viral immunization. Transcriptome analyses of Kap1-deleted B splenocytes revealed an up-regulation of PTEN, the enzymatic counteractor of PIK3 signaling, and of genes encoding DNA-damage response factors, cell-cycle regulators, and chemokine receptors. ChIP/seq studies established that KAP1 bound at or close to several of these genes and controlled chromatin status at their promoters. Genome wide, KAP1 binding sites lacked active B cell–specific enhancers and were enriched in repressive histone marks, further supporting a role for this molecule in gene silencing in vivo. Likely responsible for tethering KAP1 to at least some of these targets, a discrete subset of KRAB-ZFPs is enriched in B lymphocytes. Our results therefore reveal the role of KRAB/KAP1–mediated epigenetic regulation in B-cell development and homeostasis.

Description: Key Points Maturation, homeostasis, and function of peripheral B lymphoid cells require Rictor, an essential mTOR complex 2 component. Rictor regulates survival of B cells and their balance of proapoptotic vs antiapoptotic gene expression.

Description: Background: Projected costs of cancer care are expected to reach $172.8 billion dollars by 2020[1]. Cost of oncology drugs have outpaced other areas[2] with novel drugs priced at a median of $115,981/year between 2009 and 2013[3], making cost control an important priority. Rounding drug doses to the nearest vial size, as long as the difference is smaller than an accepted percentage, has been shown to reduce the cost of care[4]. This also allows workflow efficiency by simplifying compounding and decreasing waste documentation[5] and reduces the potential for medication errors[6]. Dose rounding has been recommended by the Hematology/Oncology Pharmacy Association (HOPA)[5] and the HOPA position paper was endorsed by NCCN[7]. Methods In accordance with HOPA position statement, an integrated community-based healthcare system comprised of 13 providers across 8 infusion centers implemented dose rounding to the nearest vial if within 10% based on actual calculated dose for biological and cytotoxic agents. Performed manually by oncology pharmacists at the time of initial introduction in January 2020, this was transitioned to automated dose rounding by the oncology chemotherapy software (Epic Beacon, Epic Systems, Verona, WI) in June 2020. To facilitate provider adoption and maximize cost-savings, we compiled a list of 31 biological and chemotherapy agents that provided the greatest therapeutic margin and potential for cost savings. Dose rounding parameters for each agent was developed to standardize and facilitate automated dose rounding. Lower and upper bounds were set so that the vial size was within 10% of the actual calculated dose (e.g. doses between 91 mg and 111 mg to a 100 mg vial, Table 1). Cost avoidance was calculated based on the acquisition price of the lowest vial size available and necessary to make the pre-rounded dose. Results Total cost avoidance between January 2020 and July 2020 by dose rounding 31 different chemotherapy and biological agents was $679,780.02. Automated dose rounding drugs introduced in June 2020 high value drugs resulted in cost savings of $ 112,994.12 over a seven week period. Dose rounding of biological drugs accounted for 89.4% of the total cost savings. Rounding of cytotoxic drugs resulted in a cost saving of $71,588.35. Trastuzumab dose rounding was associated with the greatest amount of cost avoidance of $147,194.44, accounting for 21.65% of total cost avoidance. Dose rounding up to the nearest vial ranged between 0.13%-9.75% (median 3.52%). Dose rounding down to the nearest vial ranged between -0.10% -9.93% (median -3.36%). Conclusions: We demonstrate feasibility of implementing an automated EHR based dose rounding protocol in an integrated delivery network, widespread adoption across multiple centers and significant cost avoidance accrued from the intervention. Similar dose rounding protocols should prioritize biologics agents due to their high utilization and costs. References: 1. Mariotto A B, K.Y.R., Shao Y, Feuer E J, Brown M L, Projections of the Cost of Cancer Care in the United States: 2010-2020. Journal of the National Cancer Institute, 2011. 103(2): p. 117-128. W2. Medicines Use and Spending in the US: a Review of 2016 and Outlook to 2021.https://www.iqvia.com/institute/reports/medicines-use-and-spending-in-the-us-a-review-of-2016. 2016, IQVIA. W3. Mailankody S, P.V., Five Years of Cancer Drug Approvals: Innovation, Efficacy, and Costs. JAMA Oncology, 2015. 15(4): p. 539-540. W4. Vandyke TH, A.P., Ballmer CM, Kintzel PE., Cost avoidance from dose rounding biologic and cytotoxic antineoplastics. Journal of oncology pharmacy practice, 2017. 23(5): p. 379-383. W5. Fahrenbruch, R., Kintzel, P., Bott, A. M., Gilmore, S., Markham, R, Dose Rounding of Biologic and Cytotoxic Anticancer Agents: A Position Statement of the Hematology/Oncology Pharmacy Association. Journal of oncology practice, 2018. 14(3): p. e130-e136. W6. Goldspiel, B., Hoffman, J. M., Griffith, N. L., Goodin, S., DeChristoforo, R., Montello, C. M., Chase, J. L., Bartel, S., Patel, J. T, ASHP guidelines on preventing medication errors with chemotherapy and biotherapy. American journal of health-system pharmacy, 2015. 72(8): p. e6-e35. W7. National Comprehensive Cancer Network. NCCN Chemotherapy Order Templates (NCCN Templates®). https://www.nccn.org/professionals/OrderTemplates/PDF/HOPA.pdf. Accessed July 30, 2020. 2020, NCCN: Plymouth Meeting, PA 19462. Disclosures No relevant conflicts of interest to declare.

Description: 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.