ONE MORE FEATHER IN THE CAP (DECITABINE): YET ANOTHER CASE OF CHEMOTHERAPY-INDUCED LUNG INJURY

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Lung toxicity due to antineoplastic therapy is reported with both cytotoxic and molecularly targeted agents [1]. We present one such case of lung injury induced by capecitabine. CASE PRESENTATION: A 79-year-old female with history of triple negative infiltrating duct carcinoma of the right breast (status post mastectomy and adjuvant chemotherapy with docetaxel and cyclophosphamide 3 years prior) presented to the hospital with dyspnea on exertion following her fourth cycle of capecitabine therapy for breast cancer recurrence. Patient developed nausea, vomiting, and malaise with cycles 1, 2, and 3 of capecitabine therapy with onset of severe dyspnea on exertion, cough, and hypoxia following cycle 4. Computed tomography (CT) scan of the chest on admission showed consolidative opacities in the right upper, right middle, and anterior right lower lobe along with smaller opacities in the left lung apex and small subcentimeter nodules;no pulmonary embolism. Antibiotics were given for a short duration for suspected pneumonia without improvement. Capecitabine was held on discharge. She presented again to the emergency room with worsening shortness of breath, diarrhea, fatigue, and dizziness. COVID test was negative. Chest x-ray redemonstrated patchy airspace disease involving the right apical, lateral, mid lower lung field. Oral steroids were recommended for suspected organizing pneumonia, but the patient refused due to concerns about side effects. Her hospital course was complicated by Clostridium difficile infection (treated with oral vancomycin) and left lower extremity deep venous thrombosis (treated with anticoagulation). Subsequently she followed up with pulmonology outpatient. Repeat imaging showed evolving infiltrates in the same areas with elevated aspergillus IgG level (18.0 mcg/ml) and IgE (178 kU/L) but negative galactomannan and sputum bacterial/fungal/acid fast cultures. Oral steroids were initiated with clinical and symptomatic improvement. DISCUSSION: Capecitabine is a prodrug of fluorouracil (antimetabolite). It is used as a chemotherapy agent in multiple types of cancer including breast cancer. Respiratory side effects include cough (<7%) and bronchitis (<5%). Lung injury/pneumonitis is a rare complication with only a few cases reported to date [2,3]. The timing of symptoms with chemotherapy administration and the negative infectious work-up supports capecitabine as the inciting etiology of lung injury. Withholding chemotherapy and starting systemic steroids were effective treatments in this case of chemotherapy induced lung toxicity. CONCLUSIONS: Capecitabine induced lung injury is a rare but important entity and should always be kept in mind while evaluating dyspnea in cancer patients. Reference #1: Capri G, Chang J, et al. An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer. Ann Oncol. 2010;21(3):474. Epub 2009 Oct 8. DOI: 10.1093/annonc/mdp373 Reference #2: C. J. Benthin, G. Allada. Capecitabine-Induced Lung Injury. American Journal of Respiratory and Critical Care Medicine 2016;193:A1653. Reference #3: Andrew K Chan, Bok A Choo, John Glaholm. Pulmonary toxicity with oxaliplatin and capecitabine/5-Fluorouracil chemotherapy: a case report and review of the literature. Onkologie. 2011;34(8-9):443-6. doi: 10.1159/000331133. Epub 2011 Aug 19. DISCLOSURES: No relevant relationships by William Karkowsky No relevant relationships by Chahat Puri No relevant relationships by Sahib Singh

PROSPECTIVE MULTICENTRIC STUDY ON INFECTIOUS COMPLICATIONS AND CLINICAL OUTCOME IN 230 UNFIT AML PATIENTS TREATED IN FIRST-LINE WITH HYPOMETHYLATING AGENTS ALONE OR IN COMBINATION WITH VENETOCLAX

Background: The hypomethylating agents (HMAs) are an important therapeutic option for older patients (pts) with AML and have become the backbone for combination regimens (eg, with Venetoclax). However, there are very limited real-life prospective studies regarding clinical outcome of these pts, including infectious complications and infection related mortality (IRM) during treatment. Aims: To investigate the infectious complications and clinical outcome in AML patients treated with HMAs± Venetoclax (V) outside of clinical trials. Methods: The recruitment of this prospective multicentric study (CE-Id-study:2908) has been completed on December 31, 2020. We enrolled 230 AML pts with a median age of 75 years (range 25-94);157 pts (68%) had >2 relevant comorbidities. Of the 230 cases, 132 (57%) received a first-line therapy with a combination of HMAs+V while 98 (43%) were treated with HMAs monotherapy (azacitidine or decitabine). A total of 1550 cycles of HMAs have been administered (680/1550 with HMAs+V). Results: The best response achieved, with HMAs treatment, was: CR in 44% of cases (57,6% with HMAs+V and 25,5% with HMAs alone, P=0,0001), PR in 17% and SD in 14% of cases (ORR 61%;72% in HMAS+V and 46% in HMAs alone, P=0,0007). The microbiological or radiological proven infectious complications (almost one) occurred in 160/230 (70%) of pts, mainly pneumonia (in 42% of pts) and/or bacteremia/sepsis (one or more events in 29% of pts). Febrile neutropenia (one or more episodes) occurred in 38% of pts and 14 cases of Covid-19 (6%) were reported. After a median follow-up of 9 months (1-24) from the start of HMAs therapy, 144 (63%) pts died and 86 (37%) were alive. The 1 yr OS probability was 46% with a median OS of 10,3 months (11 months in HMAs+V and 9 months in HMAs alone;P=ns). The primary causes of death were: progression of AML (42%), Infection (26%-37/144), Infection+AML (24%), other causes (8%). The IRM was 26% and 19/144 (13%) pts died of infectious complication while in CR/PR (16 in HMAs+V group and only 3 in HMAs group;P=0,005). Data on antibiotic prophylaxis, hospitalization, drugdoses modulation, are available and analyzed in this study. Summary/Conclusion: The results of this real-life, multicentric, prospective study, confirm a higher CR rate in pts treated with HMAs+V compared to HMAs alone (P=0,0001). However, we found a high rate of infectious complications and IRM (26%) with a higher infection related deaths in patients in CR/PR who were treated with HMAs+V (P=0,005). Findings from this study highlight the critical relevance of infection prevention in reducing infectious mortality, which adversely impacts the OS of this frail AML population.

Anticancer agent 3-deazauridine has the potential to be effective against COVID-19 due to its inhibition of replication of RNA viruses

3-Deazauridine (3DU) is a nucleoside analogue that was investigated for its antineoplastic activity in cancer patients. 3DU after its phosphorylation in cells to its 5'-triphosphate is a potent inhibitor of CTP synthetase. Inhibition of this enzyme results in a reduction in cellular CTP and inhibition of RNA synthesis. This action of 3DU can also inhibit RNA synthesis since the viral RNA polymerase requires CTP for replication of RNA. 3DU was reported to inhibit the in vitro replication of the RNA influenza virus at concentrations in the range of 40 μM (1) and should also have the potential to inhibit the replication of SARS-CoV-2. In a pilot clinical study, we treated a patient with acute lymphoid leukemia with 3DU at doses ranging from 120 to 360 mg/kg using a continuous intravenous infusion ranging from 40 to 72 hr. (2). The objective of the study was to determine if 3DU could enhance the antileukemic action of the inhibitor of DNA methylation, decitabine, and overcome the problem of drug resistance to this deoxycytidine analogue. Partial responses were observed indicating that pharmacological action of 3DU could accomplish this objective. There were minimal signs of toxicity in this clinical study on 3DU which exhibited plasma concentrations of this analogue in the range that inhibit RNA virus replication. This observation suggests that it would be safe to use 3DU in patients with COVID-19. 3DU has a rapid onset of action with a significant sign of antineoplastic action observable after a 4 h in vitro treatment of human leukemic cells. This pharmacological property rapid action of 3DU may be very important in patients with advanced COVID-19 to inhibit the virus is during its rapid replication phase and prevent progression of the disease to acute lung inflammation. It would be interesting to test this hypothesis in advanced COVID-19 patients at high risk for disease progression. For an initial pilot study I recommend a 36 h infusion of 3DU at a total dose of 120 mg/kg. It is possible that therapy with 3DU may have the potential to rescue patients with advance COVID-19.

Curvularia Sinusitis in Leukemic Patients Two Case Reports and Review of the Literature

Curvularia species are dematiaceous filamentous fungi that can cause a variety of infections in both immunocompetent and immunocompromised hosts. We present 2 cases of severely immunosuppressed patients with acute invasive fungal sinusitis due to Curvularia species. Both patients had a history of hematologic malignancy with refractory disease and prolonged neutropenia. They presented with facial and sinus pain, which prompted maxillofacial computed tomography that showed acute sinusitis. Subsequently, they underwent nasal endoscopy with a biopsy that revealed a definitive diagnosis of invasive fungal sinusitis. Dematiaceous fungi are responsible for most fungal sinusitis cases, with Curvularia being one of the most common species isolated. Generally, invasive fungal rhinosinusitis may follow a relatively innocuous and nonspecific course. In addition, fungal infections may complicate chronic allergic sinusitis. Computed tomography scan is the first imaging modality of choice, and magnetic resonance imaging has a role in prognostication in acute invasive fungal rhinosinusitis. Endoscopic sinus surgery with biopsy yields a definitive diagnosis and is therapeutic. Management typically includes a combination of surgery and antifungal agents. Severe neutropenia is a significant risk factor for infection and is associated with poor outcomes. Aggressive surgical debridement, combined with antifungal therapy, should be emphasized in leukemic patients despite their prolonged neutropenia and bleeding tendency.

Efficacy of Oral Decitabine/Cedazuridine (ASTX727) in the CMML Subgroup from the Ascertain Phase 3 Study

text: Background/Introduction: Chronic Myelomonocytic Leukemia (CMML) is an uncommon MDS/MPN overlap syndrome that has historically been included under the umbrella of myelodysplastic syndromes (MDS) for clinical trial and treatment. As a result, DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine have been the established standard of care for the treatment of CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver so treatment has required intravenous infusion or subcutaneous injections daily for 5-7 days every month (m) adding significant burden to older cancer patients due to daily time commitment and travel to treatment centers. In the context of pandemic SARS-CoV-2, parenteral therapy also increases contact with medical settings with increased infection risk. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination of decitabine and the CDA inhibitor cedazuridine that produced equivalent exposure (99%;90% CI 93% to 106%) to IV decitabine 20 mg/m 2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019), and Median overall survival (mOS) for the entire study population in the ASCERTAIN study was approximately 32 months (Savona, 2021). Here, we present outcome data for this study for the enrolled subpopulation of patients with CMML. Methods: We used a randomized cross over design in which patients were randomized in the first 2 cycles 1:1 to either Sequence A: (decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m 2 in Cycle 2), or Sequence B: (IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2). We conducted an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days (unless delays were needed). All patients received oral decitabine/cedazuridine in Cycles 3 and above until disease progression or unacceptable toxicity. Patients were eligible per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: Of the 133 patients enrolled and treated in ASCERTAIN, 16 (12%) had a diagnosis of CMML with demographics and as follows: median age 71.5 years, 69% Male/31% Female, median weight 87kg (range 65-124), 25% ECOG 0, 75% ECOG 1. Population disease characteristics were: 19% poor or intermediate risk cytogenetics, with median baseline hemoglobin 90 g/L, neutrophils 1.27 X 10 9/L, platelets 84 x 10 9/L, bone marrow blasts 5%, with 38% RBC transfusion dependent. Patients received a median of 7 cycles of therapy (range 3-24). Treatment-emergent adverse events of CTCAE Grade 3 or higher in > 10% of patients, independent of relationship to ASTX727, were cytopenias (neutropenia [69%], thrombocytopenia [63%], anemia [56%], leukopenia [19%]), febrile neutropenia (31%), fatigue (13%). Two patients (12.5%) had Complete Responses (CR), 8 (50%) had marrow CR ([mCR], including 3 (19%) with hematologic improvement (HI);Overall Response rate (ORR) [CR + PR+ mCR + HI] was 75%. Of six patients with baseline RBC transfusion dependence 3 (50%) became transfusion independent. Leukemia-free survival was 28.2 months and after a median follow up of more than 33 months, median overall survival had not been reached. Two patients (13%) went on to Hematopoietic Stem Cell Transplant (HCT). Conclusions: In the overall study, oral decitabine/cedazuridine delivered equivalent PK exposure to 5 days of IV decitabine 20mg/m 2 with a resultant clinical activity safety and efficacy profile in CMML patients consistent with the published literature (e.g Zeidan, et a 2017) and the Phase 2 experience. The use of oral decitabine/cedazuridine is a reasonable approach in CMML patients. References: Garcia-Manero, et al ASH 2019 Savona, et al, Int. MDS Symposium, 2021 Zeidan, et al, Cancer 2017: 3754-3762. [Formula presented] Disclosures: Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees;CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees;NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees;Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees;Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;ALX Oncology: Research Funding;Astex: Research Funding;Incyte: Research Funding. McCloskey: Pfizer: Consultancy;Takeda: Consultancy, Speakers Bureau;Incyte: Speakers Bureau;Novartis: Consultancy;COTA: Other: Equity Ownership;BMS: Honoraria, Speakers Bureau;Amgen: Speakers Bureau;Jazz: Consultancy, Speakers Bureau. Griffiths: Boston Biomedical: Consultancy;Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding;Abbvie: Consultancy, Honoraria;Taiho Oncology: Consultancy, Honoraria;Genentech: Research Funding;Astex Pharmaceuticals: Honoraria, Research Funding;Takeda Oncology: Consultancy, Honoraria;Novartis: Honoraria;Apellis Pharmaceuticals: Research Funding;Alexion Pharmaceuticals: Consultancy, Research Funding. Yee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Forma Therapeutics: Research Funding;Geron: Research Funding;Shattuck Labs: Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees;F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie: Honoraria;Janssen: Research Funding;Onconova: Research Funding;Genentech: Research Funding;Otsuka: Membership on an entity's Board of Directors or advisory committees;MedImmune: Research Funding;Jazz: Research Funding;Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding;Tolero: Research Funding;Takeda: Membership on an entity's Board of Directors or advisory committees;TaiHo: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;Paladin: Membership on an entity's Board of Directors or advisory committees. Zeidan: BeyondSpring: Consultancy;Janssen: Consultancy;Boehringer Ingelheim: Consultancy, Research Funding;BioCryst: Other: Clinical Trial Committees;AstraZeneca: Consultancy;Pfizer: Other: Travel support, Research Funding;Kura: Consultancy, Other: Clinical Trial Committees;Incyte: Consultancy, Research Funding;Ionis: Consultancy;Daiichi Sankyo: Consultancy;Epizyme: Consultancy;Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding;Loxo Oncology: Consultancy, Other: Clinical Trial Committees;Genentech: Consultancy;Geron: Other: Clinical Trial Committees;Cardiff Oncology: Consultancy, Other: Travel support, Research Funding;BMS: Consultancy, Other: Clinical Trial Committees, Research Funding;Gilead: Consultancy, Other: Clinical Trial Committees;Aprea: Consultancy, Research Funding;Astellas: Consultancy;Astex: Research Funding;Jazz: Consultancy;Jasper: Consu tancy;Amgen: Consultancy, Research Funding;Agios: Consultancy;ADC Therapeutics: Research Funding;Acceleron: Consultancy, Research Funding;AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Al-Kali: Novartis: Research Funding;Astex: Other: Research support to institution. Patel: Agios: Membership on an entity's Board of Directors or advisory committees;Celgene-BMS: Membership on an entity's Board of Directors or advisory committees;PVI: Honoraria. Sabloff: Takeda: Membership on an entity's Board of Directors or advisory committees;BMS: Membership on an entity's Board of Directors or advisory committees;Astellas: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;TaiHo: Membership on an entity's Board of Directors or advisory committees;Jaxx: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;ROCHE: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Janssen Oncology: Consultancy, Honoraria, Speakers Bureau;Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Gilead Sciences: Consultancy, Honoraria, Speakers Bureau;Novartis: Consultancy, Honoraria, Speakers Bureau;Agios: Consultancy, Honoraria, Speakers Bureau;Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau;Takeda: Consultancy, Honoraria, Speakers Bureau;Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau;AMGEN: Consultancy, Honoraria, Speakers Bureau;Incyte: Consultancy, Honoraria, Speakers Bureau;Jazz Pharmaceuticals:Consultancy, Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau;Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau;Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding;AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Kantarjian: Ipsen Pharmaceuticals: Honoraria;Astra Zeneca: Honoraria;Astellas Health: Honoraria;Aptitude Health: Honoraria;Pfizer: Honoraria, Research Funding;Novartis: Honoraria, Research Funding;Jazz: Research Funding;Immunogen: Research Funding;Daiichi-Sankyo: Research Funding;BMS: Research Funding;Ascentage: Research Funding;Amgen: Honoraria, Research Funding;AbbVie: Honoraria, Research Funding;KAHR Medical Ltd: Honoraria;NOVA Research: Honoraria;Precision Biosciences: Honoraria;Taiho Pharmaceutical Canada: Honoraria. DeZern: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Janssen: Research Funding;AbbVie: Consultancy;Actinium: Consultancy;Agios: Consultancy;Amgen: Consultancy;Astex: Consultancy;Astellas: Consultancy;AstraZeneca: Consultancy;Bayer: Consultancy;Blueprint Medicines: Consultancy;Bristol Myers Squibb: Consultancy;Celgene: Consultancy;Daiichi Sankyo: Consultancy;Glaxo SmithKline: Consultancy;Helsinn: Consultancy;Janssen: Consultancy;Jasper Therapeutics: Consultancy;Jazz: Consultancy;MEI Pharma - IDMC Chair: Consultancy;Mesoblast: Consultancy;Novartis: Consultancy;Otsuka: Consultancy;Pfizer: Consultancy;Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Pfizer: Membership on an entity's Board of Directors or advisory committees, peakers Bureau;BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees.

Oral Decitabine/Cedazuridine in Patients with Lower Risk Myelodysplastic Syndrome: A Longer-Term Follow-up of from the Ascertain Study

[Formula presented] Background/Introduction: Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widely used in this population. Approved intravenous (IV) or subcutaneous (SC) regimens require 5-7 days of treatment every month burdening older cancer pts due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection. Because DNMTis are rapidly degraded by cytidine deaminase (CDA) in the gut and liver, oral availability has only been recently possible. A randomized study with CC-486, an oral formulation of azacitidine, in the Int-1 population showed a median overall survival (mOS) of approximately 17 months for both placebo and treated patients (Garcia-Manero, 2021). Oral DEC 35 mg/cedazuridine 100 mg (ASTX727) or DEC-C, is an oral fixed dose combination (FDC) of DEC and the CDA inhibitor cedazuridine (CED) resulting in equivalent exposure (99%;90% CI 93% to 106%) to standard IV DEC 20 mg/m 2 for 5 days in an intra-patient randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present data on patients with lower risk MDS from that study. Methods: We used a randomized cross over design with pts randomized 1:1 in the first 2 cycles to either Sequence A: (DEC 35 mg/ CED 100 mg in Cycle 1 and IV DEC at 20 mg/m 2 in Cycle 2), or Sequence B (IV DEC in Cycle 1 and oral DEC/CED in Cycle 2). Cycles were repeated every 28 days unless delays were needed, and all patients received oral DEC-C in Cycles 3+ until disease progression or unacceptable toxicity. We conducted an intra-patient comparison of DEC PK (DEC AUC equivalence over 5 days of dosing). Pts were eligible as per the FDA-approved label of IV DEC (MDS pts by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk pts). Clinical endpoints were best response as assessed by an independent expert panel according to IWG 2006 response criteria, transfusion independence (TI), overall survival (OS), and safety. Results: Of the 133 pts treated in ASCERTAIN, 69 had a diagnosis of lower-risk MDS (93% Int-1, 7% LR). Median age was 70.0 years (range 45-87), 65% were male, median weight was 84 kg (range 50-127), median baseline hematologic parameters were: hemoglobin 89 g/L (range 69.8-146.5), WBCs 1.50 X 10 9/L (range 0.11-7.1), platelets (plt) 86 x 10 9/L (range 5-703), bone marrow blasts 4% (range 0-18), cytogenetics: 7 (10.1%) poor-risk, 21 (30.4%) intermediate risk, 37 (53.6%) better-risk, 4 (5.7%) missing or not evaluable. 27(39%) of the pts were RBC transfusion dependent (TD) and 6 (9%) plt TD. 17 (25%) had received prior MDS treatment, 3% prior DNMTi. Pts received a median of 9 cycles of therapy (range 1-28). Treatment-emergent adverse events of CTCAE Gr 3 or higher in >10% of pts, independent of relationship to ASTX727, included cytopenias (neutropenia [59%], thrombocytopenia [58%], anemia [48%], leukopenia [26%]), febrile neutropenia (32%), and pneumonia (19%). Sixteen pts (23%) achieved Complete Response (CR), 18 (26%) had marrow CR (mCR), including 9 (13%) with hematologic improvement (HI). Overall Response rate (ORR;CR + PR+ mCR + HI) was 57%. Of those RBC or plt TD at baseline, 13 (48%) became RBC TI and 4 (67%) became plt TI. With approximately 32 months of median follow up, neither median leukemia-free survival (mLFS) nor mOS had been reached (Figure 1). Twelve pts (17%) went on to allogeneic stem cell transplant. Conclusions: Oral decitabine/cedazuridine given as a FDC in MDS pts produced equivalent PK exposure to 20 mg/m 2 IV DEC;in lower risk MDS pts with treatment indicated, the agent was generally well-tolerated with prolonged treatment and could result in mLFS and mOS which exceeds 32 months. This FDC and other dosing regimens of oral DEC-C should be further studied in this patient population. References: Garcia-Mane o, et al, ASH 2019 Savona, et al, Int. MDS Symp. 2021 Garcia-Manero, et al, Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients with Lower-Risk Myelodysplastic Syndromes. J.Clin.Onc. 2021 39:13, 1426-1436 [Formula presented] Disclosures: McCloskey: Pfizer: Consultancy;Jazz: Consultancy, Speakers Bureau;COTA: Other: Equity Ownership;Incyte: Speakers Bureau;Takeda: Consultancy, Speakers Bureau;Novartis: Consultancy;BMS: Honoraria, Speakers Bureau;Amgen: Speakers Bureau. Griffiths: Alexion Pharmaceuticals: Consultancy, Research Funding;Abbvie: Consultancy, Honoraria;Taiho Oncology: Consultancy, Honoraria;Genentech: Research Funding;Novartis: Honoraria;Takeda Oncology: Consultancy, Honoraria;Astex Pharmaceuticals: Honoraria, Research Funding;Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding;Apellis Pharmaceuticals: Research Funding;Boston Biomedical: Consultancy. Yee: Paladin: Membership on an entity's Board of Directors or advisory committees;TaiHo: Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Genentech: Research Funding;Geron: Research Funding;Janssen: Research Funding;Jazz: Research Funding;MedImmune: Research Funding;Onconova: Research Funding;Tolero: Research Funding;AbbVie: Honoraria;Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees;Otsuka: Membership on an entity's Board of Directors or advisory committees;Shattuck Labs: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;Forma Therapeutics: Research Funding;Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan: Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding;Genentech: Consultancy;Ionis: Consultancy;Astellas: Consultancy;Epizyme: Consultancy;AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding;Jasper: Consultancy;Cardiff Oncology: Consultancy, Other: Travel support, Research Funding;BeyondSpring: Consultancy;Loxo Oncology: Consultancy, Other: Clinical Trial Committees;Janssen: Consultancy;Acceleron: Consultancy, Research Funding;AstraZeneca: Consultancy;Kura: Consultancy, Other: Clinical Trial Committees;Gilead: Consultancy, Other: Clinical Trial Committees;Agios: Consultancy;Daiichi Sankyo: Consultancy;Boehringer Ingelheim: Consultancy, Research Funding;Geron: Other: Clinical Trial Committees;BMS: Consultancy, Other: Clinical Trial Committees, Research Funding;BioCryst: Other: Clinical Trial Committees;Pfizer: Other: Travel support, Research Funding;Aprea: Consultancy, Research Funding;ADC Therapeutics: Research Funding;Jazz: Consultancy;Incyte: Consultancy, Research Funding;Amgen: Consultancy, Research Funding;Astex: Research Funding. Al-Kali: Astex: Other: Research support to institution;Novartis: Research Funding. Patel: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees;PVI: Honoraria;Agios: Membership on an entity's Board of Directors or advisory committees. Sabloff: Pfizer: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Astellas: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;ROCHE: Membership on an entity's Board of Directors or advisory committees;TaiHo: Membership on an entity's Board of Directors or advisory committees;Jaxx: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory ommittees;BMS: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau;Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau;Novartis: Consultancy, Honoraria, Speakers Bureau;Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Janssen Oncology: Consultancy, Honoraria, Speakers Bureau;Incyte: Consultancy, Honoraria, Speakers Bureau;Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau;Gilead Sciences: Consultancy, Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau;AMGEN: Consultancy, Honoraria, Speakers Bureau;Agios: Consultancy, Honoraria, Speakers Bureau;Takeda: Consultancy, Honoraria, Speakers Bureau. Odenike: AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy;Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding. Kantarjian: AbbVie: Honoraria, Research Funding;Novartis: Honoraria, Research Funding;Ascentage: Research Funding;Pfizer: Honoraria, Research Funding;BMS: Research Funding;Daiichi-Sankyo: Research Funding;Amgen: Honoraria, Research Funding;Ipsen Pharmaceuticals: Honoraria;Jazz: Research Funding;Astellas Health: Honoraria;Immunogen: Research Funding;Astra Zeneca: Honoraria;Aptitude Health: Honoraria;KAHR Medical Ltd: Honoraria;NOVA Research: Honoraria;Precision Biosciences: Honoraria;Taiho Pharmaceutical Canada: Honoraria. DeZern: Takeda: Consultancy, Membership on an entity's Board of Directors or advisorycommittees;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Novartis: Consultancy;Mesoblast: Consultancy;Jasper Therapeutics: Consultancy;Jazz: Consultancy;MEI Pharma - IDMC Chair: Consultancy;Daiichi Sankyo: Consultancy;Otsuka: Consultancy;Bristol Myers Squibb: Consultancy;Blueprint Medicines: Consultancy;Bayer: Consultancy;AstraZeneca: Consultancy;Astellas: Consultancy;Astex: Consultancy;Amgen: Consultancy;Agios: Consultancy;Actinium: Consultancy;AbbVie: Consultancy;Janssen: Research Funding;Celgene: Consultancy;Glaxo SmithKline: Consultancy;Helsinn: Consultancy;Janssen: Consultancy;Pfizer: Consultancy;Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees;AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Cons ltancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees;NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees;Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees;Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;ALX Oncology: Research Funding;Astex: Research Funding;Incyte: Research Funding.

Low-Dose Weekly Decitabine and Venetoclax in TP53-Mutated Myeloid Malignancies

Decitabine (Dec) and Azacitidine (Aza) that target DNA methyltransferase 1 (DNMT1) are hypomethylating agents (HMAs) approved to treat acute myeloid leukemia (AML) in combination with Venetoclax (Ven). The combination is also used to treat high-risk myelodysplastic syndromes, especially TP53-mutated (TP53mut) cases in which responses to HMA alone are short-lived. In most patients (pts), however, myelosuppression from treatment leads to frequent Ven duration and/or dose-reductions, and/or cycle delays. An approach to decrease HMA-mediated myelosuppression but maintain S-phase dependent DNMT1-targeting, evaluated in a previous clinical trial (https://doi.org/10.1111/bjh.16281), is to administer noncytotoxic doses/concentrations of Dec (0.2 mg/kg;~5 mg/m 2) by a frequent-distributed schedule of 1X/week. An approach to decrease Ven mediated myelosuppression but maintain cooperation with HMA, shown in pre-clinical studies, is to administer a single-dose prior to HMA. Ven can depolarize mitochondrial membranes;mitochondrial membrane-potential is essential to function of the mitochondrial enzyme DHODH that produces cytidine/deoxycytidine that competes with HMA in cells. Thus, Ven prior to HMA dosing temporarily inhibits de novo pyrimidine synthesis, to counter a major mechanism of resistance to HMA in MDS/AML, without suppressing normal myelopoiesis (https://doi.org/10.1182/blood-2020-143200). We conducted a retrospective analysis of all pts with TP53mut MDS or AML treated with weekly Ven and low-dose subcutaneous Dec at our institution. We analyzed the characteristics of these pts, response to therapy, and outcomes using standard descriptive statistics. Mutational testing was performed using a commercial next-generation sequencing (NGS) panel. Five pts, 3 male and 2 female, with TP53mut MDS or AML were treated with weekly Ven 400 mg on D1 and subcutaneous Dec 0.2 mg/kg on D2, administered weekly in 28 day cycles. Two pts had MDS (1 de novo, 1 treatment related) and 3 pts had AML (1 de novo, 2 secondary from prior MDS). Four pts (80%) received the treatment in frontline, all with poor performance status (PS), and 1 pt (20%) had R/R disease. Median age at diagnosis was 79 years [41-82]. The only young pt had prolonged severe cytopenias after 1 cycle Dec standard dosing during the peak of COVID-19 pandemic so was switched to this regimen. Of the 4 frontline treated pts, 2 pts had high-risk MDS, and 2 pts had adverse risk AML. The R/R pt had high-risk MDS transformed to AML that was refractory to 2 prior lines of therapy: standard Aza/Ven x5 cycles, then standard Vyxeos. Disease cytogenetics were complex in all pts. 60% (3/5) pts had sole TP53mut on NGS, with median variant allelic frequency (VAF) 48% [28-79]. 80% (4/5) pts were transfusion dependent prior to treatment. Median time to initiating therapy was 7 days from initial or refractory diagnosis [3-59] and median follow-up was 7.8 months (mo) [2.9-11.4]. The overall response rate (ORR) was 100%: 4/4 frontline pts had complete remissions (CR), and the 1 R/R pt achieved morphologic leukemia-free state (MLFS). Median time to best response was 2.9 mo. 50% (2/4) pts became transfusion independent. 40% (2/5) pts lost their TP53mut at best response, and another 40% (2/5) pts had significant reductions (83% and 38%) in TP53 mut VAF. The regimen was well tolerated with no pts stopping therapy due to adverse effects (AE). AE included G3/G4 neutropenia (80%), G1 thrombocytopenia (40%), nausea (20%), fatigue (20%), lower extremity edema (20%), pneumonia (60%), and neutropenic fever (20%) with a median of 1 unplanned hospitalization per pt during follow-up. 60% (3/5) pts remain in CR on continued therapy for a median of 7.8 mo [7.2-9.4] thus far. One pt underwent allogeneic stem cell transplantation, however, died 11.4 mo after conditioning due to transplant related mortality. The R/R pt died after being lost to follow-up 2.9 mo after therapy initiation. No pt had measurable relapse during follow-up. Combination weekly Ven with subcutaneous low-dose Dec is well tolerated yielding igh rates of clinical and molecular response in pts with TP53mut MDS/AML. Although small, this case-series extends previous clinical trial proof-of-activity of non-cytotoxic DNMT1-targeting to a high-risk, poor PS, historically chemorefractory patient population. The regimen allowed frequent, sustained exposure to therapy often not possible with standard HMA/Ven regimens. [Formula presented] Disclosures: Shastri: Kymera Therapeutics: Research Funding;Guidepoint: Consultancy;GLC: Consultancy;Onclive: Honoraria. Gritsman: iOnctura: Research Funding. Feldman: Glycomimetics: Current Employment, Current holder of stock options in a privately-held company. Verma: Celgene: Consultancy;Acceleron: Consultancy;Novartis: Consultancy;Stelexis: Consultancy, Current equity holder in publicly-traded company;Eli Lilly: Research Funding;Curis: Research Funding;Medpacto: Research Funding;Incyte: Research Funding;GSK: Research Funding;BMS: Research Funding;Stelexis: Current equity holder in publicly-traded company;Throws Exception: Current equity holder in publicly-traded company. Saunthararajah: EpiDestiny: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

The Impact of COVID-19 on Acute Myeloid Leukemia (AML) Treatment Patterns in the United States: Retrospective Analysis of an Electronic Medical Records (EMR) Database

INTRODUCTION: COVID-19 has disrupted healthcare access for patients (pts) with cancer, which may pose an especially high risk for pts with hematologic malignancies (NCI, 2021). The standard of care for newly diagnosed (ND) AML is induction with intensive chemotherapy (IC;“7+3”) ± consolidation for eligible pts;while during the COVID era, lower-intensity regimens, such as a hypomethylating agent (HMA) plus venetoclax (VEN), may be recommended over 7+3 to eligible pts to minimize transfusions and inpatient hospitalizations. For pts who achieved remission from induction, COVID-19 may have led some practitioners to reduce the number of consolidation cycles and/or lower the cytarabine dose used for consolidation. Transplantation, including hematopoietic stem cell transplantation (HSCT), has been severely impacted (even halted in some areas) during COVID-19 (NasrAllah, 2021). The influence of COVID-19 on AML treatment (Tx) and outcomes has yet to be adequately studied. OBJECTIVE: To assess the impact of COVID-19 on AML Tx patterns and survival in the real-world practice setting. METHODS: The Flatiron™ EMR database was used in this retrospective analysis of US pts aged ≥ 18 years with an AML diagnosis between 1 Jan 2018 and 31 Jan 2021 and who had ≥ 2 months of follow-up. Tx patterns and survival outcomes were compared between a Pre-COVID cohort, defined as pts diagnosed with AML between 1 Jan 2018 and 31 Dec 2019, and a Post-COVID cohort of pts diagnosed between 1 Mar 2020 and 31 Jan 2021. Pt characteristics and Tx patterns were assessed for all pts and in the Pre- and Post-COVID cohorts using summary statistics. Time to event analyses used Kaplan-Meier methods for survival curves and were compared by log-rank tests. RESULTS: In all, 2,133 pts met the selection criteria (mean age was 66.0 years, 57.5% were male, and 75.7% were treated in community practices);1,582 (74.2%) pts were in the Pre-COVID cohort and 551 (25.8%) were in the Post-COVID cohort. Pt characteristics were generally similar between cohorts. In the Post-COVID cohort, use of IC and HMA-only induction decreased significantly, while induction with VEN + an HMA increased (Fig. A): 29.4% of pts (n=132) in the Post-COVID cohort received VEN + azacitidine and 19.8% (n=89) received VEN + decitabine, compared with 16.0% (n=190) and 9.0% (n=107), respectively, in the Pre-Covid cohort (P < 0.001, both comparisons). Time to induction was shorter in the Post-COVID cohort vs the Pre-COVID cohort (median 14 vs 18 days;P < 0.001). In all, 1,056 pts attained remission within 180 days of induction, including 774 Pre-COVID and 282 Post-COVID pts. Among them, 621 pts had a follow-up period of ≥ 180 days (394 pts Pre-COVID, 227 pts Post-COVID) and 41.1% (n=162) vs. 14.1% (n=32) of pts in the Pre- and Post-COVID cohorts, respectively, received consolidation (P < 0.001). Proportions of pts receiving maintenance therapy (MT) were 23.9% (n=94) and 17.6% (n=40) in the Pre- and Post-COVID cohorts, respectively (P = 0.069). Time to HSCT was significantly increased for pts in the Post-COVID cohort (P = 0.035;Fig. B), and rate of HSCT was reduced for Post-COVID pts vs Pre-COVID pts (19.0% vs 13.3%, respectively, at 180 days, and 31.3% vs 22.7% at 360 days). Estimated overall survival (OS) was significantly longer in the Pre-COVID cohort (P = 0.006 vs. Post-COVID);at 360 days of follow-up, estimated survival rates in the Pre- and Post-COVID cohorts were 68.3% vs. 51.3%, respectively. CONCLUSIONS: Induction with IC and HMAs was less frequent for pts diagnosed with AML during COVID-19, while induction with VEN + an HMA increased in these pts. Use of consolidation significantly decreased during COVID-19, and use of MT also decreased. These changes may have been influenced by inpatient resource constraints. Compared with the Pre-COVID cohort, Post-COVID pts were significantly less likely to receive HSCT, and longer HSCT waiting times suggest the pandemic affected access to timely transplantation, potentially due to hospital policies limiting surgeries, lack of available inpatient beds, or donor reluctance to visit a hospital during the pandemic. OS and 1-year survival were compromised in the Post-COVID cohort vs Pre-COVID pts, likely due to COVID-19 infection, but perhaps in part due to constraints on access to healthcare resources. These data suggest a need for oral Tx that can prolong remission while reducing clinic and inpatient visits, and that can bridge the gap until HSCT. [Formula presented] Disclosures: Chen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Rotter: SmartAnalyst Inc.: Current Employment. Potluri: Bristol Myers Squibb: Consultancy.

Genomics-guided targeting of stress granule proteins G3BP1/2 to inhibit SARS-CoV-2 propagation.

SARS-CoV-2 nucleocapsid (N) protein undergoes RNA-induced phase separation (LLPS) and sequesters the host key stress granule (SG) proteins, Ras-GTPase-activating protein SH3-domain-binding protein 1 and 2 (G3BP1 and G3BP2) to inhibit SG formation. This will allow viral packaging and propagation in host cells. Based on a genomic-guided meta-analysis, here we identify upstream regulatory elements modulating the expression of G3BP1 and G3BP2 (collectively called G3BP1/2). Using this strategy, we have identified FOXA1, YY1, SYK, E2F-1, and TGFBR2 as activators and SIN3A, SRF, and AKT-1 as repressors of G3BP1/2 genes. Panels of the activators and repressors were then used to identify drugs that change their gene expression signatures. Two drugs, imatinib, and decitabine have been identified as putative modulators of G3BP1/2 genes and their regulators, suggesting their role as COVID-19 mitigation agents. Molecular docking analysis suggests that both drugs bind to G3BP1/2 with a much higher affinity than the SARS-CoV-2 N protein. This study reports imatinib and decitabine as candidate drugs against N protein and G3BP1/2 protein.