ALBERT

Description: Background: Hydroxyurea (HU) is an effective and common therapy for high-risk Polycythemia Vera (PV). Some patients may demonstrate resistance or intolerance to HU, but the consequences of these warrant further studies. Objective: Evaluate the clinical and economic implications of HU resistance/intolerance, in routine clinical practice in Israel. Methods: A retrospective analysis of Maccabi Health Services' (MHS) database was performed. MHS is a Non-for-Profit healthcare insurer and provider in Israel, with over 2.2 million members. Patients were included in the study if they had a recorded PV diagnosis or complete blood count indicative of PV, and had purchased HU for at least 3 months between 2000-2015. Enrolled patients were divided into 3 groups: A) Resistant to HU (patients prescribed 2g/day of HU); B) Intolerant of HU (patients who stopped HU, transitioned to another line of therapy or who developed HU related cytopenias); C) Stable on HU. A mid-time point was added to "Stable" to compensate for the time required for transition in the "Intolerant" group. Only patients who developed Intolerance within 5 years were included. Collected data pertained to demographics, clinical outcomes, resource utilization and expenditure data. Results: A total of 830 patients were identified. Only 3 met criteria for Resistance and were disregarded for further analysis, while 318 (38%) were defined as "Intolerant" and 509 (61%) as "Stable". At baseline, there were no significant differences between "Intolerant" and "Stable" groups, apart from platelet counts (431 vs. 495, respectively) and red cell distribution width (RDW) (18.4 vs. 17.6, respectively). Intolerance was determined based on HU-related cytopenias (n=144, 45% of Intolerant), transition to other treatment line (n=52, 16%) or stopping HU (n=122, 38%). These results indicate some patients continue HU treatment despite lack of disease control. "Intolerant" patients who had transitioned by 5 years from first HU purchase (N=173) and "Stable" patients who met the mid-point of time to transition (N=487) were eligible for comparison. Median follow up time was 4.9 and 5.5 years for "Intolerant" and "Stable" groups, respectively. Thrombotic events occurred in 8% of the "Intolerant" group compared with 3% of "Stable" (p=0.003) and event rate per 100 patient-years was 1.6 versus 0.5 (p

Description: Background and Aims Venous thromboembolism (VTE) is considered as a preventable cause of death for hospitalized patients. Current guidelines recommend pharmacologic prophylaxis for medical patients considered high risk for VTE, despite failure of studies to show reduction in mortality. We aimed to assess the benefit and safety of VTE prophylaxis in acutely ill medical patients hospitalized in internal medicine wards. Methods Retrospective cohort study of all patients admitted to the internal medicine and acute geriatric departments, with an admission lasting more than 48 hours, during 2012-2018. Patients who received pharmacologic prophylaxis were compared to those who did not. The primary outcome was 30-day mortality. Secondary outcomes were the 90 day incidence of pulmonary embolism (PE), symptomatic deep vein thrombosis (DVT), and major bleeding. Propensity-weighted logistic multivariable analysis was performed. Results A total of 18890 patient-unique episodes were included in the analysis. Of them 3206 (17%) received prophylaxis. A total of 1309 (6.9%) died. 540/1309 (41.3%) of those who received VTE prophylaxis died and 769/1309 (58.7%) of those who did not receive prophylaxis died. VTE Prophylaxis was not associated with a reduction in mortality, multivariate-adjusted OR 0.99 (95% CI 0.84-1.14). One hundred and forty two patients (0.7%) developed VTE. The frequency of VTE among patients who received VTE prophylaxis was 31% (44/142) compared with 69% (98/142) in patients who did not receive prophylaxis. The frequency of VTE in patients who had a Padua score ≥4 and received VTE prophylaxis, was 1.9% (30/1573) compared with 1.6% (44/2797) in those with a Padua score ≥4 who did not receive prophylaxis. 74/142 (52.1%) of patients with VTE had a Padua score ≥4, 44/1309 (1.4%) of those who received VTE prophylaxis and 98/15864 (0.6%) of those who did not. VTE Prophylaxis was not associated with reduction in VTE in the whole cohort, multivariable-adjusted OR 1.09 (95% CI 0.52-2.29). VTE prophylaxis was associated with an increase in major bleeding (multivariable-adjusted OR 1.24, 95% CI 1.04-1.48) Conclusion The current practice of routinely administering VTE prophylaxis to medically ill patients considered at high risk for VTE, resulted in a high risk for bleeding a without clear clinical benefit, and should be reassessed. Disclosures No relevant conflicts of interest to declare.

Description: Background: In addition to a drug's anti-tumor efficacy and tissue toxicity, it is now apparent that affordability is a pivotal factor determining the net therapeutic value of an anti-cancer compound. Cost-Effectiveness Analyses (CEA) are therefore key to appreciating the overall balance between the clinical and economical repercussions of a pharmaceutical agent. We aimed to investigate the cost-effectiveness data of newly approved drugs in cancer care. Methods: The FDA website was reviewed for all drugs approved for any cancer indication between the years 2015-2017. A systematic search of Pubmed and Google Scholar was conducted for Cost-Effectiveness Analyses (CEA) of each of these medications. Average Wholesale Prices were collected from Uptodate.com. Results: 30 drugs were approved for cancer indications in 2015-2017. Each of the approved drugs had an average of 1.27 CEA studies (range 0-6). 4 of the 38 (10.5%) available CEAs were done before approval of an index drug. 18 (60%) of the approved medications had an available published CEA at the time of our search (March, 2018). Partition survival modelling (31.5%) and Markov modelling (26.3%) were the most common methods of analysis. 47.3% (18/38) of the CEAs were thought to reflect a favorable ICER per the analysis's investigators. The nature of the malignancy (solid versus hematologic) did not distinguish between the mean number of a drug's CEAs (1.25; 1.2) but drugs for solid cancer indications were less likely to be associated with a favorable CE assessment compared with hematological cancers (47.8% versus 58.3%). "Expensive" drugs (defined as monthly cost greater than 8,618 dollars) had a lower mean number of CEA studies than "less expensive" drugs (1.09 versus 1.36) and were less likely to be associated with a favorable cost-effectiveness profile (27.2% versus 73.6%). 47.3% (18/38) of the economic evaluations were published as conference proceeding/abstract, 36.8% (14/38) were in the form of a full-text article, and the remainder as journal letters or conference posters (6/38; 15.7%). Conclusion: Insufficient data on the cost-effectiveness profile of novel anti-cancer medications jeopardises our ability to determine their real value. Although these drugs are being routinely used in a large-scale fashion, gaps persist as to their financial harm relative to the associated (potential) clinical benefit. Our study shows that recently-approved anti-cancer drugs have a very small number of CEAs to back their clinical-societal merit. Paradoxically, more costly drugs have fewer CEAs compared with cheaper drugs. Also of note, the majority of the analyses followed the approval of the drug, were published in a non full-text format, and were associated with non-sustainable ICER values. We argue that publication of rigorous, peer-reviewed CEAs should be a mandatory pre-approval step for academia/industry and serve as a pre-requisite to the routine distribution and usage of new cancer-directed medications. Disclosures No relevant conflicts of interest to declare.

Description: The introduction of several tyrosine kinase inhibitors (TKIs) into the armamentarium of chronic myeloid leukemia (CML) treatment has revolutionized the prognosis of this disease, changing it from a fatal one into a potentially curable disease. Five TKIs are now in clinical use: imatinib, nilotinib, dasatinib, bosutinib and ponatinib. This allows the clinician the privilege to personalize treatment based on the toxicity profile of the various TKIs, taking into account patients' comorbidities and lifestyle. Although side effects are common to all TKIs, each one has its unique safety profile. Consequently, one of the main challenges in the contemporary management and research of CML is the understanding and control of TKI-associated adverse events. TKI-associated vascular disease is amongst the most perturbing and poorly understood of these adverse events. Nilotinib is probably associated with an increased risk of arterial vascular events, especially peripheral artery occlusive disease (PAOD) compared with imatinib. Conversely, the notorious effect of nilotinib on PAOD, manifested in comparative clinical trials, might be attributed to a protective effect of imatinib. Similar data has started to emerge regarding ponatinib, including fatal cerebrovascular events, ranging from 20-42% of patients. These side effects of ponatinib occur after as little as 8 months of treatment. The mechanism of this increased tendency for vascular events associated with specific TKIs, remains incompletely understood, and there has been only limited research exploring the possible pathophysiological mechanisms involved. We therefore initiated a preclinical in vitro study in order to ascertain a potential molecular mechanism responsible for these adverse vascular events. Specifically, we studied the effect of nilotinib and ponatinib on human umbilical vein endothelial cells (HUVEC) in comparison to that of imatinib. When examining pharmacologically relevant concentrations (5.3µM imatinib, 4.3µM nilotinib and 0.11µM or 0.17µM ponatinib), annexin/PI staining showed that following a 24 hour exposure period, imatinib, nilotinib and ponatinib did not lead to an increase in apoptosis (DMSO (control): 8.8%±2.4; imatinib: 13.2%±1.2; nilotinib: 9.6%±0.6; ponatinib 11.1%±1.8, p-value not statistically significant). However, under these same conditions, ponatinib dramatically inhibited angiogenesis of HUVECs in a tube-formation assay. This inhibition was evident even when exposing the cells to the lower physiological concentrations of the drug (0.11µM). Relative average tube area (calculated relative to control) was as follows: DMSO (control): 1; imatinib: 0.86±0.3; nilotinib: 1±0.5; 0.11µM ponatinib (equivalent to 30mg/day): 0.4±0.1 p-value

Description: Introduction: The significance of viral respiratory infections (VRI) and efficacy of anti-flu vaccine in patients (pts) with lymphoproliferative malignancies (LPM) have not been fully elucidated. The current large comprehensive study was designed to evaluate the incidence of respiratory infections in LPM pts, define clinical significance of VRI and assess the impact of anti-flu vaccine on RI prevention in this population. Methods: All consecutive pts, diagnosed either with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), followed at the Rambam Hematology Outpatient Unit between 01/2011 and 03/2012 (during or after anti-cancer therapy or untreated) were evaluated. Data regarding anti-lymphoma/MM therapy used, respiratory infections occurring during the study period, tests performed to assess these infections (focusing on viral ones), administration of anti-flu vaccine and infection-related outcome were recorded. Samples of nasopharyngeal aspirate (NPA) or bronchoalveolar lavage (BAL) were evaluated for VRI pathogens using both immunofluorescence and polymerase chain reaction (PCR) methods. Results: Five hundred and sixty two respiratory infection episodes were reported in 369 pts. In 224 (40%) episodes, VRI investigation was performed using either NPA (n=180) or BAL (n=44) samples. The decision regarding the sample source was taken based on the respiratory infection severity. The cohort screened for VRI included a larger proportion of pts receiving anti-cancer therapy during the study period than the non-screened cohort (70% vs 30%, respectively, p

Description: Introduction - Salvage chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) is the standard-of-care for relapsed and refractory (R/R) diffuse large B cell lymphoma (DLBCL) patients. Eligibility is based on the presence of chemo-sensitive disease as defined by complete remission (CR) or partial remission (PR) according to FDG PET/CT study post salvage therapy. Patients achieving CR prior to auto-HCT have better prognosis than those undergoing it in PR. However, to this date, it is not clear whether one should struggle to achieve CR prior to auto-HCT or is PR after first salvage therapy good enough. Aim - To evaluate the role of additional salvage regimen prior to autologous HCT in R/R DLBCL patients who achieved PR per FDG PET/CT following first salvage regimen. Methods - We retrospectively reviewed the medical records of all patients who underwent auto-HCT for R/R DLBCL at three Israeli stem cell transplant centers between 2008 and 2018. Patients were identified based on the reports to the EBMT registry or according to the center's surveillance data. We recorded and compared outcomes between patients who achieved PR after first salvage therapy and proceeded immediately to auto-HCT vs. patients who continued with additional salvage treatment (either the same or a different regimen) before auto-HCT. Outcomes were compared between these groups and between patients who achieved CR after first salvage and patients with chemo-refractory disease who proceeded to transplant. Continuous variables were described as the mean, median, standard deviation and range of n observations. Categorical data were described with contingency tables including frequency and percent. Differences between the two groups of patients were examined by the Mann-Whitney test for continuous variables, and the two-tailed Fisher's exact test for categorical variables. Progression Free Survival (PFS) was defined as the time from autologous HCT to post transplant disease progression or to death from any cause, whichever occurred earlier. Overall survival (OS) was defined as the time from HCT until the date of subject death from any cause. The Kaplan-Meier method was used to estimate the distribution and median PFS and OS. Disease response and disease progression were assessed according to the Lugano criteria. Results - Between the years 2008 - 2018 149 patients underwent auto-HCT for R/R DLBCL. After first salvage chemotherapy 81 patients (54%) achieved CR, 50 patients (33%) achieved PR and 18 (12%) had progressive disease (PD). Among the 50 patients achieving PR after first salvage, 30 patients (60%) proceeded immediately to transplant and 20 patients (40%) were treated with additional salvage treatment. There were no differences between the two groups in the characteristics of the patients, the disease and regimens being given (Table). Median PFS was better for patients proceeding to HCT in PR compared to those who continued with additional salvage therapy in order to achieve CR (not reached vs. 12.5 months, p=.089). This was also true, with respect to OS (105 months vs. 35 months, p=.019). Interestingly, OS was comparable between patients who proceeded to transplant in CR or in PR after first salvage (Median not reached, vs. 105 months, p=0.245). Among patients who received further salvage chemotherapy (either the same or a different regimen) and obtained CR before HCT (n=8), overall survival was comparable to those who achieved CR after first salvage (mean 84 months vs. 99 months, p=.35). Patients who were still in PR after second salvage had a dismal prognosis which was comparable to that of patients proceeding to HCT in progressive disease after first salvage (mean OS of 11 vs. 22 months, p=.24). Conclusions - Albeit the small number of patients, our results do not support the administration of further salvage treatments in R/R DLBCL patients achieving PR after first salvage treatment in order to achieve pre-transplant CR. Table Disclosures Gurion: Roche: Consultancy.

Description: Background Umbilical cord blood (UCB) is an important alternative graft source for allogeneic hematopoietic cell transplantation (HCT) for patients without a HLA - matched donor. However, platelet recovery is significantly hampered following UCB transplantation, and patients remain platelet transfusion-dependent for prolonged periods of time. In the largest registry study to date, median time to platelet recovery over 20K/µL was over 70 days, and at 6 months only 50% of the patients had platelet engraftment. We hypothesized that eltrombopag (Revolade, GSK/Novartis), a thrombopoietin-receptor agonist, would enhance platelet engraftment after UCB transplantation. Methods This was a pilot multicenter open label single arm phase 2a study, in both adults and children (NCT01757145, NCT01940562). Oral eltrombopag was given from day +1 until platelet count exceeded 50K/µL for 14 consecutive days without platelet transfusion. Starting dose was 100 mg/d for adults and children weighing 〉40 kg and 50 mg/d for children weighing 20-40 kg. Based upon platelet response dosage was modified, with a maximal dose of 300mg/d for adults and 200mg/d for children. Study endpoints included safety, time to non-transfused platelet counts 〉20K/µL and 〉50K/µL, and platelet engraftment rate by day +50. Results Between February 2013 and July 2016, 12 patients with hematological malignancies in complete remission were enrolled. The study cohort included 10 adults and 2 children, with a median age at transplantation of 50 (range 6-74) years (Table 1). Conditioning regimen was reduced-intensity in 7 patients and myeloablative in the remainder. Four patients received a single UCB unit, and 8 patients were given 2 units. The median total collected total nucleated cells (TNCs) *10^7/kg was 5.9 (range 2.7-8.6), and the median total collected CD34+ cells *10^5/kg was 3.1 (range 1.7-7.8). Patients received eltrombopag for a median of 76 days (range 15-175). Overall, eltrombopag was well tolerated even at maximal doses, and there was no need for dose reduction due to toxicity. No clinically significant side effects related to the study drug were reported. Of note, two patients developed mild, asymptomatic and transient indirect hyperbilirubinemia. No patient developed sinusoidal obstructive syndrome. No patient developed a thrombotic event while receiving eltrombopag. There was one case of lower extremity deep vein thrombosis, 6 months post-transplant (#03). No significant bone marrow fibrosis was documented even after prolonged eltrombopag administration. One patient (#07) died due to fungal respiratory infection on day +15 prior to engraftment. One patient (#01) had primary graft failure and autologous reconstitution, and is still alive in complete remission (CR) 5 years post-transplant. Among the 10 evaluable patients, median time to neutrophil engraftment was 23 (range 16-40) days. Median time to platelets〉20K/µL and platelets〉50K/µL was 55 (range 25-199) and 66 (range 31-230) days, respectively. Median time to RBC transfusion independence was 39 (range 13-157) days. Overall, 4 patients developed grade 2 (n=2) or grade 3 (n=2) acute graft versus host disease (GVHD), and 4 patients developed chronic GVHD (mild, n=3; moderate, n=1). There was no death attributable to GVHD. The median follow up time was 20 months (range 15 days - 61 months). At last follow up, 7 patients were alive, all still in CR at a median of 3.5 years post-transplant (range 1-5 years). Two patients died of relapse of their primary disease (#05, 7 months after transplant; #02, 29 months after transplant), for both these patients the UCB transplantation was the second transplant. Three patients died of infectious complications (#07, early death due to fungal respiratory infection on day +15; #08, pneumonia on day +157; #06 sepsis on day +153). Conclusions In the present study, eltrombopag was safe in the context of UCB transplantation. With the limitation of our small sample size, the use of eltrombopag was associated with enhanced platelet recovery time compared to published data. Further prospective studies are warranted to confirm these results. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: The KIT D816V oncogene is a key driver in 90-95% of patients with systemic mastocytosis (SM), a group of mast cell (MC) neoplasms including indolent SM (ISM), smoldering SM (SSM) and AdvSM. Debilitating symptoms related to MC proliferation and degranulation characterize ISM and SSM and are also prominent in AdvSM, which is further complicated by SM-related organ damage and decreased survival. Currently, there are no approved agents that selectively target KIT D816V, and there are limited tools to assess symptom improvement in SM. Avapritinib, a highly potent and selective inhibitor of the KIT D816V mutant, showed substantial clinical activity in AdvSM (83% overall response rate (ORR) per modified IWG-MRT-ECNM criteria) in the Phase 1 EXPLORER study [Deininger, et al, EHA, 2018]. We present results using a novel PRO questionnaire, the AdvSM-SAF, developed in accordance with FDA guidance, to assess changes in symptoms in the Part 2 dose expansion phase of EXPLORER. Methods: Patients (pts) received avapritinib at the recommended Phase 2 dose (300 mg once daily [QD]) in continuous 28-day (d) cycles. Pts completed the AdvSM-SAF and 2 additional PROs used in other cancers, the Patient Global Impression of Symptom Severity (PGIS) and the European Organization for Research and Treatment of Cancer Quality of Life (QLQ). PROs and KIT D816V mutant allele fraction (MAF) in blood were assessed serially as follows: AdvSM-SAF daily, from 7 d before first avapritinib dose, ie, baseline (BL: Cycle [C]1 Day [D]1) and through C12, using an electronic diary; PGIS and QLQ at BL (C1D1) and on D1 of each cycle through C12; and KIT D816V mutant allele fraction (MAF) at BL and on D1 of C3, 7, 11, and then every 6 cycles. The AdvSM-SAF assesses severity of 8 symptoms (pruritus, flushing, spots, nausea, vomiting, diarrhea, abdominal pain, fatigue) on a 0-10 scale, and 2 items assess frequency of diarrhea and vomiting. Results are analyzed as a Total Symptom Score (TSS), combining all 8 severity items (maximum symptom score=80), and as a GI domain (combining 4 symptoms: nausea, vomiting, diarrhea, abdominal pain; maximum score 40) and Skin domain (combining 3 symptoms: pruritus, flushing, spots; maximum score 30). Analyses were based on 7 d average scores. AdvSM-SAF data were summarized at BL (C1D-7 to C1D-1), and over the 7-d interval prior to C3D1 and C7D1, and correlated with QLQ, PGIS and KIT D816V MAF. Results: As of 22 June 2018, 25 pts were treated in Part 2 of the study; 24 are ongoing, and enrollment and follow-up continues. The median duration of avapritinib treatment was 5.7 mo (range, 1.7+ to 10.3+ mo). AdvSM-SAF scores for 24 pts with data are shown the Table. Mean BL TSS, GI and Skin scores were 22.6, 9.1, and 7.1. The most severe BL symptom was fatigue (mean score of 6.4). Among 21 pts with scores at C3D1 and 12 pts with scores at C7D1, mean reductions from BL TSS, GI and Skin scores were 6.4, 3.9, and 1.5 points, and 11.1, 5.7, and 4.4 points, respectively, indicating further improvement with continued treatment. Symptom reductions were seen for all 8 items at C3D1. Further symptom improvement was observed for 6 of 8 items from C3D1 to C7D1. Reductions in AdvSM-SAF TSS, GI and Skin scores significantly correlated with improvement in QLQ Emotional (EF) and Cognitive functioning (CF) scales (p values for Pearson Correlation Coefficients