PHF6 and JAK3 mutations cooperate to drive T-cell acute lymphoblastic leukemia progression

T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by gene mutations in T-cell progenitors. As an important epigenetic regulator, PHF6 mutations frequently coexist with JAK3 mutations in T-ALL patients. However, the role(s) of PHF6 mutations in JAK3-driven leukemia remain unclear. Here, the cooperation between JAK3 activation and PHF6 inactivation is examined in leukemia patients and in mice models. We found that the average survival time is shorter in patients with JAK/STAT and PHF6 comutation than that in other patients, suggesting a potential role of PHF6 in leukemia progression. We subsequently found that Phf6 deficiency promotes JAK3M511I-induced T-ALL progression in mice by inhibiting the Bai1-Mdm2-P53 signaling pathway, which is independent of the JAK3/STAT5 signaling pathway. Furthermore, combination therapy with a JAK3 inhibitor (tofacitinib) and a MDM2 inhibitor (idasanutlin) reduces the Phf6 KO and JAK3M511I leukemia burden in vivo. Taken together, our study suggests that combined treatment with JAK3 and MDM2 inhibitors may potentially increase the drug benefit for T-ALL patients with PHF6 and JAK3 comutation.

Drugs Associated With Ischemic Stroke: A Review for Clinicians

Certain drugs may increase the risk of ischemic stroke (IS). Our goal was to review associations between frequently used drugs and IS. We created an initial list of frequently used drugs to search Pubmed/MEDLINE from 1966 to 2020 and reviewed phase III and IV data, case series, and drug authorities’ safety warnings to assess a potential association with IS. Drugs were grouped according to the World Health Organization Anatomical Therapeutic Chemical Classification System. Predefined criteria were applied to establish a level of evidence for an association, from A (high level of evidence of association) to E (high level of evidence of absence of association). In addition, we assessed relative risks and reviewed potential mechanisms of IS facilitation. We assessed 81 drugs or drug classes from 11 World Health Organization Anatomical Therapeutic Chemical Groups. We identified a high level of association for erythropoietin, combined contraceptives, oral estrogen replacement therapy, bevacizumab, tamoxifen, and antipsychotics and a moderate level for ponatinib, nilotinib, darunavir, and gonadotropin-releasing hormone agonists. Drug dose and treatment duration may modify the risk. For a substantial number of drugs, we found no association, and for others, there were insufficient data to categorize risk. We identified a high level of association of IS with a limited number of drugs, a potential association with some, and a lack of data for others. The summarized information may help clinicians to estimate the contribution of a drug to an IS, to better assess drug benefit-risk ratios, and to support decisions about using specific drugs.

Novel synthetic lethality (SL) anti-cancer drug target in urothelial bladder cancer (UCB) based on MTAP genomic loss: Incidence and correlations in standard of care (SOC).

485 Background: When UCB presents or progresses to chemorefractory metastatic disease, the search for new therapy targets is paramount. Targeting PRMT5 arginine methyltransferase accumulation in tumors with MTAP (methylthioadenosine Phosphorylase) genomic loss has been proposed as a new SL based anti-tumor strategy and under consideration for development for UCB. We sought to evaluate the incidence of patients with candidate SL and correlate to treatment-guiding biomarkers currently evaluated in SOC. Methods: 2,683 cases of clinically advanced UCB underwent hybrid-capture based comprehensive genomic profiling in a standard of care setting using the F1CDx FDA-approved assay to evaluate all classes of genomic alterations (GA) among 324 genes. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 650 (24%) of UCB feature MTAP loss (MTAP-) (Table). The gene and age distributions were similar MTAP intact (MTAP+) and MTAP- UCB. The GA/tumor was higher in MTAP- UCB likely reflecting the significant GA co-deletions of CDKN2A/ B at the 9p21 locus. Of potential therapeutic targets, FGFR3 and PTEN GA were more frequent in the MTAP- UCB. In contrast, biomarkers of immunotherapy (IO) response included higher frequencies of high TMB and high PD-L1 IHC staining in the MTAP+ UCB. Conclusions: When compared with MATP+ UCB, MTAP- UCB differs in genomic signatures including an increase in potential for targeted therapies but a lower potential for IO drug benefit. Thus, the genomic landscape in MTAP- UCB may play a significant role in the design of clinical trials incorporating SL strategies when targeting PRMT5 in MTAP deficient tumors. [Table: see text]

Costs and Adverse Events Associated with Ibrutinib or Ruxolitinib in Chronic Graft-Versus-Host Disease

Background: Chronic Graft-Versus-Host Disease (cGVHD) is a common and potentially fatal complication after allogeneic hematopoietic stem cell transplantation. Beyond corticosteroids, there are multiple potential treatment options, including ibrutinib and ruxolitinib (off-label). Both ibrutinib and ruxolitinib are associated with adverse events (AEs) that may limit adherence or lead to treatment discontinuation. This retrospective analysis of United States administrative claims data examined ibrutinib and ruxolitinib use in cGVHD patients, including persistence on treatment, cost of care, and healthcare resource utilization (HCRU). Methods: Adult (≥18 years old) patients were identified in IQVIA™ Health Plan Claims Data (1/2014-9/2019) by ≥1 diagnosis claim for cGVHD by ICD-9 (279.51) and ICD-10 (D89.811) codes. The ibrutinib and ruxolitinib cohorts required ≥1 prescription claim (with the first claim as a proxy for treatment initiation = index) for the drug of interest, and no claims for the other drug (i.e., ruxolitinib or ibrutinib) within 12 months post index. Control cohorts required ≥1 prescription or treatment claim (index) for calcineurin inhibitors, mTOR inhibitors, mycophenolate mofetil, imatinib, methotrexate, etanercept, rituximab, or extracorporeal photopheresis, and no ibrutinib or ruxolitinib claim within 12 months post index. Propensity score matching (PSM) analyses required medical and drug benefit continuous enrollment for ≥6 months prior to index and ≥12 months after. Treatment persistence was assessed by Kaplan-Meier methodology, with a 30-day permissible gap between treatments, and AEs reported within 30 days of discontinuation were reported. In addition to individual AEs, composite measures of infections and lung AEs were assembled from ICD diagnosis codes. PSM of the ibrutinib and ruxolitinib cohorts to controls used age, sex, baseline cost, region, comorbidities, and lung involvement. PSM ensured patients will share similar characteristics, and outcome comparisons between these matched cohorts will not be confounded by the covariates used in the matching process. Costs and HCRU were assessed in the 12-month post index period. Results: In discontinuation analyses, 117 ibrutinib and 266 ruxolitinib patients were identified. In the year after index, 58/117 (50%) of ibrutinib and 109/266 (41%) of ruxolitinib patients discontinued (Figure 1). Within 30 days of discontinuation, AEs reported in the ibrutinib cohort in ≥10% of patients included (in decreasing order) the infection composite AE (36%), the lung composite AE (34%), dyspnea (28%), kidney failure (24%), edema (16%), atrial fibrillation (12%), thrombocytopenia (12%), and neutropenia (10%). In the ruxolitinib cohort, AEs reported within 30 days of discontinuation and occurring in ≥10% of patients included (in decreasing order) the infection composite AE (45%), the lung composite AE (37%), dyspnea (34%), thrombocytopenia (31%), edema (27%), kidney failure (27%), hypokalemia (15%), neutropenia (14%), thrombosis (13%), and hemorrhage (11%). In analyses of PSM cohorts, 39 ibrutinib patients matched to 110 control patients, and 81 ruxolitinib patients matched to 187 control patients. Annualized costs for the ibrutinib (median $263,658) and ruxolitinib (median $223,564) cohorts were significantly greater than control cohorts (p<0.001). Costs excluding the treatment of interest were greater for ibrutinib (median $82,989 vs. $64,546; p=0.25) and ruxolitinib (median $66,824 vs. $48,673; p=0.033). Ibrutinib patients showed a greater hospitalization rate versus control patients (24/39, 62% vs. 49/110, 45%; p=0.093). Ruxolitinib patients showed increased mean healthcare visits versus control patients (65.6 vs. 52.6; p=0.034). Conclusions: In this analysis, ibrutinib and ruxolitinib discontinuation and AEs previously reported to be associated with either ibrutinib or ruxolitinib utilization occurred in a similar temporal window. Ibrutinib and ruxolitinib patients also demonstrated higher treatment costs and increased healthcare visits versus control cGVHD patients. Further research is required to better understand the cost of cGVHD treatment with these medications. Sponsorship: Kadmon Corporation, LLC Disclosures Bachier: Sanofi: Speakers Bureau; AlloVir: Honoraria; CRISPR: Honoraria; Juno Therapeutics, a Bristol-Myers Squibb Company: Honoraria. Eiznhamer:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Milgroom:Trinity Life Sciences: Current Employment. Lenco:Trinity Life Sciences: Current Employment. Patel:Trinity Life Sciences: Current Employment. Skaar:Trinity Life Sciences: Current Employment. OffLabel Disclosure: ruxolitinib for chronic graft versus host disease

Better treatment at what cost? A study of myeloma spending.

60 Background: Multiple myeloma represents less than 1.5% of new cancer cases in Canada. Currently, the estimated median overall survival is at least 5-6 years, primarily driven by therapeutic advances over the past decade. As treatment protocols routinely use doublet and triplet combinations, there are increasing concerns about the ability of health systems to afford growing costs of treatment. To inform system planning in Ontario, we examined trends in costs and utilization of myeloma drugs funded by Ontario’s New Drug Funding Program (NDFP) and the Ontario Drug Benefit program (ODB). Methods: NDFP primarily funds IV cancer drugs while ODB funds take-home cancer drugs (THCD). Treatment volumes and government costs, including drug costs and pharmacy fees where applicable, were obtained from ODB and NDFP claims data. Based on the available data, trends were examined from the 2010/11 to the second quarter of the 2019/20 fiscal year. Results: A total of 7 myeloma drugs (3-IV cancer drugs, 4-THCD) were examined. Over 9 years (2010/11 - 2018/19), spending on publicly-funded myeloma drugs increased by 303% while treatment volumes increased by 116%. Between 2014/15 and 2018/19, bortezomib spending decreased by 72%, largely due to generic pricing policies, while lenalidomide spending increased by 158%, likely due to new indications. By 2018/19, these 7 drugs accounted for 17% of the total cancer drug costs under Ontario's publicly funded programs. NDFP spending on IV cancer drugs by the second quarter of 2019/20 has surpassed the annual expenditures in 2018/19 due to the addition of daratumumab. Conclusions: Since 2010/11, growth in Ontario's public expenditures on myeloma drugs has outpaced savings from pricing policies and this growth is mainly driven by the high cost of the novel agents.

Closing the part D coverage gap and out-of-pocket costs for multiple sclerosis drugs

ABSTRACTObjective:To determine whether closing the Part D coverage gap (“donut hole”) between 2010 and 2019 lowered patients’ out-of-pocket costs for disease-modifying therapies (DMTs) for multiple sclerosis (MS).Methods:Using nationwide Medicare Formulary and Drug Pricing Files, we analyzed Part D drug benefit design and DMT prices in 2010, 2016, and 2019. We calculated average monthly list prices for DMTs available in each year (4 DMTs in 2010, 11 DMTs in 2016, and 14 DMTs in 2019). We projected patients’ annual out-of-pocket cost for each DMT alone under a standard Part D plan in that year. We estimated potential savings attributable to closing the coverage gap between 2010 to 2019 (beneficiaries’ cost-sharing dropped from 100% to 25%) under three scenarios; no increase in price, an inflation-indexed price increase (3% annually), and the observed price increase.Results:Median monthly DMT prices rose from $2804, $5987, to $7009 over the years 2010, 2016, and 2019 respectively. Median projected annual out-of-pocket costs rose from $5916, $6229, to $6618. With unchanged or inflation-indexed DMT prices changes, closing the coverage gap would have reduced annual out-of-pocket costs by $2260 (38% reduction) and $1744 (29% reduction) respectively. Despite having the lowest monthly price, generic glatiramer acetate had among the highest out-of-pocket costs ($6731 to $6939 a year) in 2019.Conclusions:Medicare Part D beneficiaries can pay thousands of dollars yearly out-of-pocket for DMTs. Closing the Part D coverage gap did not reduce out-of-pocket costs for patients because of simultaneous increases in DMT prices.