ALBERT

Description: Objective: With the routine use of next generation sequencing (NGS) for diagnosis and prognosis, a growing number of pathogenic mutations have been discovered in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). TP53 is the most frequently mutated gene in human cancer. Mutations in TP53 are found in approximately 8% of de novo AML, but occur more frequently, up to 30% in secondary-AML (s-AML) and therapy-related AML (t-AML), as well as 5-20% of patients with MDS. They are associated with older age, chemotherapy resistance, and worse overall survival. Previous studies have shown potent carcinogens in tobacco smoke can induce transversion mutations along the p53 gene in patients with lung cancers, laryngeal cancers, and head and neck cancers. The association between cigarette smoking and TP53 mutations and its prognostic implications in AML and MDS have not been characterized before. Methods: We performed a retrospective review of AML and MDS patients with or without TP53 mutations at Thomas Jefferson University Hospital between April 2016 and December 2018. Data on patient age, gender, smoking status (current or past history of smoking), disease type, induction regimen, cytogenetics, and genetic mutations via NGS from bone marrow or peripheral blood were collected. Overall response rate (ORR) defined as complete remission and partial response and overall survival (OS) were analyzed. Kaplan-Meier method was used to estimate OS and compared using the log-rank test. Chi-square test was used where appropriate in comparison. P

Description: Introduction Disparities in age, socioeconomic status, insurance status and race/ethnicity have all been shown to impact the treatment and survival outcomes in patients with acute myeloid leukemia (AML). Database studies have highlighted that elderly patients with AML have worse survival outcomes. There is also evidence that Black and Hispanic patients with AML have an increased risk of death compared with Caucasian patients despite a higher prevalence of favorable cytogenetics and a younger age at diagnosis in those minority groups. We sought to assess the impact of age, race/ethnicity, socioeconomic and insurance status on treatment and survival outcomes in AML patients treated at our institution. Methods We performed a retrospective analysis of adult patients with newly diagnosed AML treated between April 2017 and August 2019 at Thomas Jefferson University Hospital. Patient specific variables included demographics, diagnosis, insurance coverage, treatment characteristics and survival outcomes. Socioeconomic status was assessed by matching the patient's residential address to the United States Area-Deprivation Index (ADI). Treatment characteristics included initial treatment type and time to treatment initiation (TTI). Initial treatment type included standard chemoimmunotherapy, clinical trial or novel therapy as defined by the Center for Medicare and Medicaid Services. The primary outcome of initial treatment type and secondary outcomes of TTI, progression free survival (PFS) and overall survival (OS) were analyzed using multivariable bias-reduced logistic regression and multivariable Cox proportional hazards models. Results Ninety-six patients were included in the analysis (median age 62; male, n = 48, female, n=48). 46% of patients were in the lower socioeconomic group (ADI = 6-10). 74% of patients were Caucasian, 17% were Black, 9% were Hispanic, and 9% were Asian or other. 44% of patients had private insurance, 44% had Medicare, 7% had Medicaid and 5% were uninsured. 58% of patients received standard chemoimmunotherapy, 35% received novel therapy, and 7% went on clinical trial. Patients who received novel therapy and clinical trial were older (p

Description: INTRODUCTION: With the FDA approval of CPX-351 (Vyxeos; Jazz Pharmaceuticals, Inc.; Palo Alto, CA), the prospect of inducing select patients with acute myeloid leukemia (AML) with a regimen that does not require continuous intravenous in the outpatient (OP) setting became a reality. With the recognition that an OP-induction strategy has the potential benefits of reduced healthcare resource utilization (HRU),1,2 improved quality of life3 and decreased risk of nosocomial infections, some centers have opted to administer Vyxeos in the OP setting and to admit patients only if complications which necessitate inpatient (IP) management occur. The safety and decreased HRU of this approach during consolidation has been demonstrated4 in the study population treated on the pivotal phase III trial (NCT01696084).5 We present the first real-world experience of OP AML induction with Vyxeos without planned hospital admission. METHODS: We performed a retrospective analysis of all patients at our institution treated with OP-Vyxeos without planned admission (OP-Vyxeos) between August, 2017 and June, 2020. Patients were deemed safe for OP induction if they met the criteria outlined in Table 1 at diagnosis or could be stabilized in the hospital and discharged when these criteria were met. Primary and secondary objectives were to evaluate the safety and HRU, respectively, of this approach. The primary endpoint was 30-day mortality. Secondary endpoints included 60-day mortality, rate of adverse effects (AEs), number of hospitalizations, number of hospital days, number of intensive care (ICU) days, and number of days receiving intravenous (IV) antibiotics. When possible, primary and secondary endpoints were compared to patients who received Vyxeos induction in the inpatient setting (IP-Vyxeos) on the phase III trial.5,6 RESULTS: Twenty-five patients received OP-Vyxeos at our institution between August, 2017 and June, 2020 and all were evaluable for the primary endpoint. Baseline characteristics of the OP- and IP-Vyxeos populations are presented in Table 2. The mean age of OP-Vyxeos patients was less than IP-Vyxeos patients (65.4 years vs. 67.7 years) and a higher proportion of OP-Vyxeos patients were

Description: Background: The combination of a hypomethylating agent (HMA) and the Bcl-2 inhibitor venetoclax (VEN) has revolutionized the treatment of elderly patients with newly diagnosed acute myeloid leukemia (AML). However, patients treated with this regimen inevitably relapse and subsequent treatment options are limited. Furthermore, the success of this combination in the relapsed/refractory setting has been less impressive. Mechanisms of resistance to HMA/VEN are of great interest, and alterations in leukemic cell metabolism have been implicated. It is hypothesized that drugs that target oxidative phosphorylation (OXPHOS), fatty acid metabolism, and /or amino acid metabolism may be successful in overcoming HMA/VEN resistance. OPB-111077 is a novel, oral, low-molecular-weight compound that was shown in preclinical models to inhibit mitochondrial electron transport and have an inhibitory effect on the growth of AML cells. When given in combination with decitabine, OPB-111077 showed a more potent antitumor effect in a KG-1 tumor-bearing mouse model, thus providing support for conducting clinical trials of this combination. AML cells treated with OPB-111077 and venetoclax have also been shown to have decreased proliferation and increased apoptosis. The effects on proliferation and apoptosis of the combination of OPB-111077 and venetoclax were more pronounced in AML cells that were genetically engineered to increase OXPHOS. These data formed the basis for the development of a clinical trial utilizing the triplet of OPB-111077, decitabine, and venetoclax for the treatment of newly diagnosed or relapsed/refractory AML. Herein, we report results from the Phase Ib dose escalation study. Methods: In this phase Ib single center study (NCT03063944), OPB-111077 is administered daily starting on day 1 and continuing throughout the treatment cycle. Decitabine 20mg/m2 is given for 5 days starting on day 4 of cycle 1. Venetoclax 70mg daily (if receiving posaconazole prophylaxis) or 100mg daily (if receiving voriconazole) is started on day 4 and given continuously until day 28. If a response is seen within 2 cycles, treatment continues until toxicity, disease progression, or availability of an alternative therapy. Patients were enrolled in cohorts of escalating dose levels of OPB-111077 using a traditional 3+3 design. The primary objectives were to determine preliminary safety and tolerability as well as maximum tolerated dose (MTD) of OPB-111077. The secondary objective was to measure preliminary efficacy. Correlative studies including metabolomics, ATP measurement, apoptosis, and proliferative assays were performed on samples of blasts and non-cancerous cells that were collected from blood or marrow. Results: As of July 15, 2020, 2 patients with newly diagnosed AML and 7 patients with relapsed/refractory AML were treated with the triplet. Patients received OPB-111077 at 150mg (n=3), 200mg (n=3), and 250mg (n=3). Median age was 73 years (range, 23-79) and 7 patients (78%) were male. The median number of prior systemic anticancer regimens for patients with relapsed/refractory disease was 2 (range, 1-5); no patients had undergone prior stem cell transplant. The median treatment duration has not yet been reached; 3 patients are receiving ongoing treatment. No patients experienced a dose limiting toxicity. The most common Grade ≥3 adverse event (AE) was febrile neutropenia (56%). No patients discontinued due to AEs. No pts experienced tumor lysis syndrome. Three patients died after completing their study treatment, all due to progressive AML. The best overall response to therapy was a complete remission in 2 (22%) patients (1 with newly diagnosed AML and 1 with relapsed/refractory disease). Metabolomics using liquid chromatography/mass spectrometry was performed on paired pre- and post-treatment samples and intracellular metabolic changes in glycolysis and the tricarboxylic acid (TCA) cycle were observed consistent with on-target effects. Conclusion: The triplet of OPB-111077, decitabine, and venetoclax for the treatment of newly diagnosed or relapsed/refractory AML was safe and well tolerated, and showed preliminary anti-leukemic efficacy. A planned expansion phase is underway utilizing the 250mg daily dose of OPB-111077. Disclosures Martinez-Outschoorn: Otsuka Pharmaceutical: Research Funding. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding. Kasner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka Pharmaceutical: Research Funding.

Description: Introduction :The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and subsequent coronavirus-19 (COVID-19) pandemic has impacted hematologic malignancies (HM) care worldwide. Reported risk factors for severe COVID-19 presentation include older age, medical comorbidities, and cardiac disease - many of which apply to patients with HM (Guan et al., 2020; Zhou et al., 2020). Additionally, patients with HM may be at even higher risk of infections with or complications from SARS-CoV-2 due to immune dysfunction from their underlying disease or treatment (He et al., 2020). However, data regarding rates of infection and outcomes in this population are limited. Here we describe the demographic characteristics, coexisting conditions, presenting symptoms, treatment, and outcomes of a cohort of patients with HM and COVID-19 infection at network sites across the Sidney Kimmel Cancer Center- Jefferson Health. Methods : We created an HM-specific COVID-19 database within our health system. Patients were identified for inclusion in the database by physician referral and query of the electronic medical record. Epidemiological, clinical, and laboratory data, therapy details, and outcomes on patients were obtained by accessing electronic medical records. A retrospective study of patients with a diagnosis of a HM- within 5 years of COVID-19 diagnosis-and a confirmed diagnosis of COVID-19 were was conducted using this database. A confirmed diagnosis of COVID-19 was defined as a positive result on a real-time RT-PCR assay of a specimen collected by nasopharyngeal swab. Results: More than 3,000 telehealth or in-person patient visits were conducted for patients with HM in the Jefferson Health Network between March 9, 2020 and July 15, 2020. During that period, 21 patients with HM had a confirmed diagnosis of COVID-19. Median age was 67 years (range 21-89). The majority of patients (86%) had at least 1 comorbid medical condition, and 76% had a history of tobacco use. The most common HM was multiple myeloma (7/21, 33%), followed by diffuse large B-cell lymphoma (3/21, 14%). 12/21 (52%) patients were on active cancer treatment at the time of COVID-19 diagnosis, and patients had received a median of 2 lines of cancer therapy (range 0-6). All 12 patients who were on active therapy at the time of COVID-19 diagnosis experienced a treatment interruption. Two patients had undergone prior autologous stem cell transplant (SCT) and 1 had undergone prior allogeneic SCT. Details on HM diagnosis and treatment are presented in Table 1. Twenty patients required hospital admission at the time of COVID-19 diagnosis, 7/21 were admitted to the ICU, and 6/21 required intubation. The most common presenting symptoms were fever (48%), cough (43%), and shortness of breath (43%), and lymphopenia (absolute lymphocyte count (ALC)

Description: Introduction The hypomethylating agents (HMA) decitabine (dec) and azacytidine (aza) are used in acute myeloid leukemia (AML) for induction therapy in patients with either newly diagnosed or relapsed disease and who are above the age of 60 or for those who would not tolerate intensive induction chemotherapy. As a result, HMA have been widely used at our institution, on both inpatient (IP) and outpatient (OP) services. The decision to administer IP-HMA vs OP-HMA is complex, but IP-HMA is recommended at our institution for neutropenic infections, debility, or risk of tumor lysis. The prognostic significance of this decision, if any, has not been widely explored. We hypothesized that because patients who receive their first cycle of HMA as an IP were at higher risk for complications, they would have a worse 100-day survival than their OP counterparts. Methods This was a retrospective observational study of patients treated at Thomas Jefferson University Hospital from January 2016-January 2020. Inclusion criteria were patients who had a diagnosis of AML, were above the age of 18 when treated, were treated with an HMA during the course of their disease, and were treated at our institution where electronic medical records (EMR) were complete and readily accessible. Exclusion criteria were patients who had died as a direct result of their hematopoietic stem cell transplant (HSCT) and whose records were incomplete or who had been treated at an outside institution. Logistic regression models were used to analyze data. Survival was calculated from day one of the first cycle of HMA received. Results A total of 68 patients were evaluated. Twenty-nine patients received IP-HMA while 39 received OP-HMA. Mean overall survival from HMA initiation was 252 days (95% CI 164-340) in the IP-HMA group and 430 days (95% CI 269-591) in the OP-HMA group. Mean 100-day survival in the IP-HMA group was 78 days (95% CI 65-91) and 93 days (95% CI 87-99) in the OP-HMA group. The average age at HMA initiation in the IP group was 69 (95% CI 64-74) and was 66 (95% CI 62-70) in the OP group. Average Charlson co-morbidity index was 5.5 (95% CI 5.0-6.0) in the IP group and 5.6 (95% CI 5.0-6.2) in the OP group. In the IP group, there were 1 low risk, 7 intermediate risk, and 21 high risk patients according to the European LeukemiaNet (ELN) risk stratification scale. In the OP group, there were 3 low risk, 8 intermediate risk, and 28 high risk patients. Nineteen of the 29 patients in the IP group and 11 of the 39 patients in the OP group received venetoclax in addition to an HMA as part of their therapy. Using a logistic regression model, location of HMA induction was found to have a significant effect on 100-day survival with IP induction being associated with worse survival (odds ratio=3.94; p=0.028) (see figure 1). Co-variates for this model included age at HMA initiation as this was the only confounder found in Wilcoxon rank sum testing to be significant. Other confounders which were tested but not included in logistic regression due to non-significance included race, gender, ELN risk, and Charlson co-morbidity indices. Discussion In this retrospective study, we found that IP-HMA induction was associated with a worse 100 day and overall survival than its OP counterpart. Though we found that co-morbidity indices and ELN risk scores were similar between the two groups, we postulate the reason the IP group had a significantly worse 100 day survival was that being admitted for neutropenic fever, risk of tumor lysis, etc. inherently put them at higher risk for complications like septic shock and hypoxic respiratory failure. Additionally, we found that patients who received HMA as an IP were far more likely to die shortly after their induction, within 100 days and often within 20 days. This would indicate they were potentially poor candidates for chemotherapy and that a palliative approach may have been more appropriate.. This study describes the survival differences seen in patients receiving IP-HMA versus OP-HMA. Knowledge of these results could spawn a more palliative approach for future patients requiring IP-HMA induction. Figure Disclosures Kasner: Otsuka Pharmaceutical: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding.