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Background Mold-active primary antifungal prophylaxis (PAP) is routinely recommended in neutropenic patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing remission-induction chemotherapy (RIC). Isavuconazole (ISAV) is an extended spectrum mold-active triazole and has superior tolerability and fewer significant drug–drug interactions compared with other triazoles. Methods In our investigator-initiated, phase 2 trial, treatment-naive adult patients with AML or MDS starting RIC received ISAV per the dosing recommendations in the US label until neutrophil recovery (absolute neutrophil count [ANC] ≥ 0.5 × 109/L) and attainment of complete remission, occurrence of invasive fungal infection (IFI), or for a maximum of 12 weeks. The primary endpoint was the incidence of proven/probable IFI during ISAV PAP and up to 30 days after the last dose. Results Sixty-five of 75 enrolled patients received ISAV PAP (median age, 67 years, median ANC at enrollment, 0.72 × 109/L). Thirty-two patients (49%) received oral targeted leukemia treatments (venetoclax, FTL3 inhibitors). Including the 30-day follow-up period, probable/proven and possible IFIs were encountered in 4 (6%) and 8 patients (12%), respectively. ISAV trough serum concentrations were consistently > 1 µg/mL, showed low intraindividual variation, and were not significantly influenced by chemotherapy regimen. Tolerability of ISAV was excellent, with only 3 cases (5%) of mild to moderate elevations of liver function tests and no QTc prolongations. Conclusions ISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC in the era of recently approved or emerging small-molecule antileukemia therapies. Clinical Trials Registration NCT03019939.

Background: Philadelphia chromosome-positive (Ph+) advanced leukemias, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) in myeloid blast phase (MBP), have poor outcomes. Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKI) in preclinical studies. However, clinical activity of venetoclax and TKI-based regimens is unknown. Methods: We conducted a retrospective study on patients with Ph+ AML (n = 7) and CML-MBP (n = 9) who received venetoclax combined with TKI-based regimens at our institution. Results: Median patient age was 42 years, and the median number of prior therapy cycles was 5 (range 2–8). Nine patients received decitabine-based, and 7 received intensive chemotherapy-based regimens. Ten patients (63%) received ponatinib. The overall response rate (ORR) in 15 evaluable patients was 60% (1 complete remission [CR], 6 CR with incomplete hematologic recovery [CRi], 1 morphologic leukemia-free state, and 1 partial response). The ORR was 43% in Ph+ AML and 75% in CML-MBP. The median overall survival (OS) for all patients was 3.6 months, for AML OS was 2.0 months, and for CML-MBP OS was 10.9 months. The median relapse-free survival for AML and CML-MBP was 3.6 and 3.9 months, respectively. Compared to nonresponders, patients achieving CR/CRi had higher baseline Ph+ metaphases and BCR-ABL1 PCR. Conclusions: Combination therapy of venetoclax with TKI-based regimens shows encouraging activity in very heavily pretreated, advanced Ph+ leukemias, particularly CML-MBP.

Background Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has become the standard of care for patients aged >75 years and for those not eligible for intensive chemotherapy who have newly diagnosed acute myeloid leukemia (AML). The benefit of VEN-based therapy in patients who have newly diagnosed AML with mutations in the TP53 gene (TP53mut ) over standard therapy is undefined. Methods In this single-institutional, retrospective analysis, the authors assessed the clinical outcomes of 238 patients with newly diagnosed TP53mut AML and compared the clinical characteristics, response to different therapies, and outcomes of those who received VEN-based (n = 58) and non-VEN-based (n = 180) regimens. Results Patients who received VEN-based regimens were older (aged >65 years: 81% vs 65%; P = .02) and had higher response rates (complete remission, 43% vs 32%; P = .06) than those who received non-VEN-based regimens. Compared with patients who received non-VEN-based regimens, no difference in overall survival (median, 6.6 vs 5.7 months; P = .4) or relapse-free survival (median, 4.7 vs 3.5 months; P = .43) was observed in those who received VEN-based regimens, regardless of age or intensity of treatment. Conclusions The addition of VEN to standard treatment regimens did not improve outcomes in younger or older patients who had TP53mut AML. These data highlight the need for novel therapies beyond VEN to improve the outcome of patients with TP53mut AML.

Background E. faecalis (Efc) isolates are usually susceptible to ampicillin (AMP). AMP-based regimens are the standard of care for enterococcal infections, although other antibiotics are often used as definitive treatment. We thus compared outcomes of patients with cancer and Efc bacteremia treated with AMP-containing (ACR) and non-AMP-containing antibiotic regimens (NACR). Methods A multicenter, prospective, observational cohort study conducted at MD Anderson Cancer Center, Henry Ford Hospital, and Memorial Hermann Health System. Eligible patients were ≥ 18 years old, diagnosed with cancer, and had at least one Efc bloodstream isolate collected from 12/2015 to 12/2018. Patients with polymicrobial infections were excluded. Patients were divided into two groups: i) ACR and ii) NACR. ACR included patients who received AMP at any time during treatment; other antimicrobials were permitted. NACR patients did not receive AMP at any time. The primary outcome compared desirability of outcome ranking (DOOR) between ACR and NACR at day 14. The DOOR consisted of six hierarchical levels: 1 - death; 2 - inpatient without microbiological cure (MC) and with acute kidney injury (AKI); 3 - inpatient without MC and without AKI; 4 - inpatient admitted with MC and with AKI; 5 - inpatient with MC and without AKI; 6 - alive and discharged. Comparison of DOORs between ACR and NACR was performed using inverse probability of treatment weighted (IPTW) ordered logistic regression. Results Seventy-one patients were included (ACR, n = 35; NACR, n = 36). No difference was seen in DOORs at day 14 between ACR and NACR (odds ratio [OR] 1.14, 95% Confidence Interval [CI] 0.45 – 2.92, p=0.78). No difference was observed for all-cause mortality at day 14 (OR 0.6, 95% CI 0.09 – 3.77, p=0.58) or day 30 (OR 0.42, 95% CI 0.09 – 1.94, p=0.27). Patients treated with ACR received a lower median duration of other antibiotics at any point during treatment compared to NACR: daptomycin (2 v 4 days) vancomycin (2 v 4 days), and linezolid (1 v 2 days). Conclusion Patients with cancer and Efc bloodstream infections had similar outcomes when treated with ACR and NACR. ACR were associated with less use of broad-spectrum antimicrobials. Future research should focus on the ecologic impact of use of NACR. Disclosures Marcus Zervos, MD, Melinta Therapeutics (Grant/Research Support) Cesar A. Arias, MD, MSc, PhD, FIDSA, Entasis Therapeutics (Scientific Research Study Investigator)MeMed (Scientific Research Study Investigator)Merck (Grant/Research Support)

Introduction: A first-in-class anticancer quinolone derivative with topoisomerase II activity, mechanistically, vosaroxin is similar to the anthracycline class. However, vosaroxin displays advantageous pharmacokinetic properties such as minimal metabolism, a lack of free radical production, is not a substrate for the P glycoprotein efflux pump, and can exert its antineoplastic activity independently of P53 function. Vosaroxin has shown encouraging results when combined with cytarabine in older patients with relapsed or refractory acute myeloid leukemia (AML) while balancing early toxicity and mortality, making it a compelling novel therapy for acute myelogenous leukemia.Areas covered: Herein, we review the clinical data from published and internationally presented clinical trials utilizing vosaroxin for AML in the elderly, and relapsed and refractory population. Pivotal trials reviewed include the multicenter, phase II, REVEAL-1 study of single-agent vosaroxin in untreated elderly patients and the...

Background Coagulase-negative staphylococci, including Staphylococcus epidermidis, are the most common cause of bloodstream infection in cancer patients. Linezolid resistance is increasingly identified in S. epidermidis, but whether such resistance alters the clinical course of S. epidermidis infections is unknown. The purpose of this study was to assess the clinical impact of linezolid resistance in leukemia patients with S. epidermidis bloodstream infection. Methods This was a retrospective, single-center cohort study of all adult leukemia patients with S. epidermidis bacteremia treated with empiric linezolid between 2012 and 2015. The primary end point was adverse clinical outcome on day 3, defined as a composite of persistent bacteremia, fever, intensive care unit admission, or death. Fourteen- and 30-day mortality were also assessed. Results Eighty-two unique leukemia patients with S. epidermidis were identified. Linezolid resistance was identified in 33/82 (40%). Patients with linezolid-resistant S. epidermidis were significantly more likely to have persistent bacteremia (41% vs 7%; adjusted relative risk [aRR], 5.15; 95% confidence interval [CI], 1.63–16.30; P = .005); however, adverse short-term clinical outcomes overall were not more common among patients with linezolid-resistant S. epidermidis (61% vs 33%; aRR, 1.46; 95% CI, 0.92–2.32; P = .108). No differences were observed in 14- or 30-day mortality. Conclusions Leukemia patients with linezolid-resistant S. epidermidis bacteremia who were treated with linezolid were significantly more likely to have persistent bacteremia compared with those with linezolid-sensitive isolates. Interventions to limit the clinical impact of linezolid-resistant S. epidermidis are warranted.

Introduction Venetoclax (VEN), a selective BCL2 inhibitor, has single-agent activity in relapsed and refractory (R/R) acute myeloid leukemia (AML), and efficacy in lower intensity combinations for treatment-naive elderly AML patients. VEN treatment combinations in R/R AML have not been previously reported. Methods All R/R myeloid patients (including AML, myelodysplastic syndrome (MDS), and blastic plasmacytoid dendritic cell neoplasm (BPDCN)) treated with VEN combinations in the salvage setting were reviewed. Results Forty-three patients with median age 68 (range, 25-83) were treated for AML (91%), MDS (5%), or BPDCN (5%). Most (n = 36, 84%) were ≥ salvage-2 treatment status, including prior hypomethylating agent (HMA) in 77%. In combination with VEN, most patients received HMA therapy (n = 31, 72%); eight (19%) received low-dose cytarabine (LDAC). Patients received a median of 2 treatment cycles (range, 1-4). Objective response was observed in 9 (21%) patients, including 2 complete responses (CR), 3 CRi, and 4 morphologic leukemia-free state (MLFS). Median survival was 3.0 months (range, 0.5-8.0), and estimated 6-month survival was 24%. Responses were observed in five (24%) of 21 patients with intermediate-risk cytogenetics, 3 (27%) of 11 IDH1/2-mutant, and 4 (50%) of 8 RUNX1-mutated patients. Two (20%) of 10 TP53-mutated patients responded; both had concurrent RUNX1 mutations. Of the 3 (15%) responding patients with adverse cytogenetics, all had concurrent RUNX1 mutations. Conclusion Low-intensity chemotherapy, including HMAs or LDAC, in combination with VEN is a viable salvage option, even in multiply relapsed/refractory patients with AML, MDS, and BPDCN. Notable responses were identified in patients with diploid/intermediate cytogenetics, RUNX1, and/or IDH1/2 mutations.

Introduction: Venetoclax (VEN) is approved for the treatment of acute myeloid leukemia (AML) in combination with hypomethylating agents (HMAs) or low-dose cytarabine and commonly used for patients (pts) unfit for intensive chemotherapy. Prophylaxis with triazole antifungals (azoles) during induction treatment in pts with AML has decreased mortality and is the standard of care for pts receiving treatment regimens associated with prolonged myelosuppression (Cornely et al, 2007). Azoles inhibit CYP3A4 (CYP3A4i), the enzyme responsible for the metabolism of VEN, and p-glycoprotein to varying degrees, which VEN is a substrate. Based on this interaction and the results of a small pharmacokinetic study, significant VEN dosage reductions are recommended (Agarwal et al, 2017). Little real-world data exists to demonstrate the tolerability of VEN in combination with azoles during induction treatment with VEN and HMAs. Methods: All pts with newly diagnosed AML treated at our institution with VEN and HMAs from 11/2014-1/2019 were retrospectively reviewed. Pts were treated as standard of care or as part of clinical trial in combination with azacitidine (NCT02203773) or decitabine (NCT03404193; NCT02203773). Pts who received concomitant antifungal for >5 days while also receiving VEN for >7 days were included. VEN 100mg daily with posaconazole or voriconazole (strong CYP3A4i) and VEN 200mg daily with isavuconazole or fluconazole (moderate CYP3A4i) were considered 400mg equivalent dosages. Higher doses of VEN in these combinations were considered >VEN 400mg equivalent. To determine the clinical impact of concomitant azoles, time to absolute neutrophil count (ANC) and platelet (PLT) recovery after induction was analyzed, in addition to response rates, episodes of febrile neutropenia (FN) and documented infections. Results:One-hundred twenty-one pts treated with HMA and VEN were identified (Table 1). The median age was 72 years (48-86) and 35% were > 75 years. Forty pts (33%) had secondary AML, and 10% had therapy-related AML. Most were treated with decitabine 20mg/m2 administered for 10 days (67%) or 5 (22%). VEN was administered for a median of 23 days (7-30) at a 400mg daily dose equivalent in 74 pts (62%) and >400mg dose equivalent in 40 pts (33%). Eighty-nine (74%) received a concomitant azole with VEN including posaconazole (38%), isavuconazole (21%), voriconazole (13%), or fluconazole (2%). Following induction therapy with VEN and HMA, 37% achieved a complete response (CR) and 22% achieved a CR with incomplete blood count recovery (CRi). An additional 10% achieved a morphologic leukemia free state (MLFS) (Table 2). Prior to cycle 2, 55% of pts achieved ANC>500 cells/mm3 and 64% achieved PLT>50,000 cells/mm3 after a median of 34 days and 24 days, respectively. No difference in response was observed based on VEN dosage or duration (Table 3). Pts achieving CR/CRi received VEN for a median of 22 days (7-29), and 38% at the 400mg equivalent VEN dosage with an azole. When analyzing VEN dosage by the use of an azole, duration of neutropenia (ANC0.05) (Table 4). Number of pts achieving PLT>50,000 cells/mm3 was not affected by concomitant antifungal or VEN dosage, but duration of thrombocytopenia was. Time to PLT>50,000 cells/mm3 was significantly longer for pts receiving VEN 400mg equivalent with an azole (25 vs 20 days, p=0.01) as well as time to PLT>100,000 cells/mm3 (27 vs 22 days, p=0.03). Despite prolonged cytopenias, all pts receiving the VEN 400mg equivalent dosage had similar rates of FN, documented infections, and hospital duration regardless of the use of an azole (Table 4). Those receiving >400mg VEN equivalent had numerically higher rates of FN, infections, and duration of hospitalization. Conclusion: The combination of VEN with HMA is an effective treatment option in pts with newly diagnosed AML. VEN is associated with significant myelosuppression which can be enhanced by concomitant CYP3A4i, such as the azoles. The combination of VEN and azoles resulted in prolonged cytopenias, namely thrombocytopenia, compared to the use of VEN without an azole. This did not result in higher rates of FN, infections, or duration of hospitalization, therefore the concomitant use of VEN and azole appear to provide a clinically safe and effective therapeutic regimen. Higher doses of VEN do not appear to be advantageous in this setting. Disclosures DiNardo: daiichi sankyo: Honoraria; jazz: Honoraria; syros: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria. Maiti:Celgene: Other: research funding. Kadia:Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Borthakur:Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Novartis: Research Funding; Cantargia AB: Research Funding; Arvinas: Research Funding; Oncoceutics: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Agensys: Research Funding. Pemmaraju:affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; incyte: Consultancy, Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding. Kantarjian:Astex: Research Funding; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding. Konopleva:Astra Zeneca: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Agios: Research Funding; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding.

Introduction: The addition of tyrosine kinase inhibitors to hyperfractionated cyclophosphamide, dexamethasone, vincristine, and doxorubicin alternating with high-dose methotrexate and cytarabine (HCVAD) for the treatment of Ph-positive ALL has significantly improved outcomes. However, with the increased median survival, an increased incidence of CNS relapses were documented over time, thus suggesting an increased risk among pts with Ph-positive disease (Ravandi et al, Cancer 2015).In order to reduce this incidence, treatment protocols for Ph-positive ALL were amended in 2012 to increase prophylactic IT chemotherapy from 8 to 12 at our institution. The aim of this study is to compare the incidence of CNS relapses in pts with Ph-positive ALL treated with 8 versus 12 ITs. Methods: We conducted a retrospective chart review of 156 pts with newly diagnosed Ph-positive ALL treated with Rituximab (R)± HCVAD plus imatinib (n=35), dasatinib (n=68), or ponatinib (n=53) between July 2001 and January 2019. Pts with CNS disease at initial diagnosis were excluded. Complete molecular response (CMR) at 3 months was defined as absence of a quantifiable BCR-ABL1 transcript. CNS relapse was identified by detection of blasts or rare atypical cells in the cerebrospinal fluid (CSF) in at least 2 successive evaluations and/or findings of leptomeningeal disease on imaging. Landmark analysis was performed at 6 months at the approximate time of completion of both systemic and IT therapy. Poor risk cytogenetic abnormality was defined as the presence of +der(22)t(9;22) and/or −9/9p in the absence of high hyperdiploidy (51‐65 chromosomes). CNS relapse-free survival (RFS) was defined from the start of therapy to the time of CNS relapse. Patients who died or relapsed in bone marrow were censored at the time of death and systemic relapse, respectively. Survival was assessed with and without the censoring of allogeneic stem cell transplantation (ASCT). Results: Pt characteristics are summarized in Figure A. One hundred and twelve pts (72%) received a median of 8 ITs (range, 2-8) and 44 pts (28%) received a median of 12 (range, 9-15). There were no statistically significant differences between groups in regards to baseline characteristics with the exception that more patients in the > 8 ITs cohort received ponatinib (66% vs 21%) and thus achieved a higher rate of 3-month CMR (70% vs 52%; p=0.04). CNS relapses were identified in 11 pts overall (7%, 4 treated with imatinib and 7 with dasatinib) and all of them received 8 or less prophylactic ITs (IT ≤8, 10% vs IT >8, 0%; p=0.023). The median follow-up of the entire population was 81 months, and 97 and 43 months for pts who received ≤8 and >8 ITs, respectively. The 3 and 6-year CNS RFS was 89% and 88% in pts with ≤8 ITs and 100% in pts with >8 Its, respectively (overall P=0.041; 3-yr CNS RFS P=0.049; 6-yr CNS RFS P=0.045) (Figure B). The outcomes remained statistically significant even after censoring for ASCT (P=0.048) (Figure C). In a multivariate analysis and after adjusting for the follow-up time, a median of 12 prophylactic IT chemotherapies was a prognostic factor significantly associated with a decrease rate of CNS relapses (P=0.03; HR=0.64 95%, CI: 0.43-0.96) (Figure D). Conclusion: In pts with newly diagnosed Ph-positive ALL, incorporation of 12 prophylactic IT chemotherapy in addition to systemic therapy is a very effective strategy to reduce the long-term incidence of CNS relapses. Figure Disclosures Paul: Pfizer: Consultancy; Agios: Consultancy. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Kadia:BMS: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Kantarjian:BMS: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding.

e18515 Background: Ph+ AML and CML MBP have poor outcomes. VEN synergizes with BCR-ABL TKIs in vitro and may eradicate Ph+ leukemic stem cells. However, the clinical activity of VEN+TKI regimens is unknown. Methods: We conducted a retrospective study on patients (pts) with Ph+ AML and CML MBP who received regimens with VEN+TKI at our institution. Results: We identified 6 pts with relapsed/refractory (R/R) Ph+ AML and 7 with CML MBP (2 transformed from chronic phase, 5 R/R). 10 pts (77%) were refractory to prior therapy and 3 (23%) had relapsed disease. Pt characteristics are shown in the Table. 5 AML pts (83%) had complex cytogenetics. Pts with CML MBP had received a median of 2 prior TKIs (range 1-3). 7 pts received decitabine-based combinations and 6 pts received intensive chemotherapy in combination with VEN+TKI. TKIs included ponatinib (n=7), dasatinib (n=4), bosutinib (n=1) and nilotinib (n=1). Among 12 evaluable pts, the overall response rate (CR + CRi + MLFS) was 50% (Table). In addition, 1 pt with AML developed aplastic marrow, underwent stem cell transplantation, and is still alive. Pts with CR/CRi vs. those without CR/CRi had higher median number of Ph+ metaphases (100% vs. 32%, p

Over 90% of leukemic blasts in patients with acute lymphoblastic leukemia express the marker CD22. Inotuzumab ozogamicin (INO) is a CD22-directed humanized monoclonal antibody conjugated to the potent cytotoxin, calicheamicin, via an acid labile linker. INO has shown high rates of response in the treatment of relapsed and refractory (R/R) ALL in single-agent studies, with fewer adverse effects than traditional cytotoxic chemotherapy. Given this experience, studies are now being done to evaluate INO in combination with low-intensity chemotherapy as frontline treatment for older adults with ALL and patients with R/R disease. Herein we will discuss the use of INO in the treatment of acute lymphoblastic leukemia.

Introduction: Invasive fungal infections (IFIs) are important causes of morbidity and mortality among patients (pts) with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), and consensus guidelines recommend the use of mold-active antifungal prophylaxis (ppx), e.g., voriconazole (vori) or posaconazole (posa). Isavuconazole (ISAV), the most recently introduced triazole antifungal, is currently approved for the treatment of invasive aspergillosis and invasive mucormycosis. ISAV is an appealing option for ppx against IFIs in neutropenic pts with AML/MDS because of its extended spectrum, superior tolerability (over vori), fewer drug-drug interactions (than posa), absence of need for therapeutic drug monitoring (TDM) and lack of prolongation of the QT interval (enabling easier administration in pts receiving certain anti-leukemic targeted therapies, 5-HT3 antagonists, quinolones, etc). NCT03019939 is an investigator-initiated, phase 2, single-arm, open-label trial of primary antifungal ppx with ISAV in pts with AML/MDS. Methods: Previously untreated adult pts with AML or MDS who are or are anticipated to become neutropenic as a result of their first therapy for AML/MDS are eligible to participate in this ongoing trial. Accrual of 100 pts is planned. Stopping rules exist for both futility and toxicity, assuming equivalence between ISAV and the current standard of care, posa, in preventing breakthrough IFIs (expected rate, 5%). In pts who have begun definitive anti-leukemic treatment, ISAV must be initiated within 4 days. Use of systemic antifungal therapy for >72 hours during the week prior to ISAV initiation is not allowed. ISAV is administered orally as the pro-drug, isavuconazonium sulfate, and dosed per the US label. ISAV ppx is administered until recovery from neutropenia (absolute neutrophil count (ANC) ≥0.5 x 109/L and attainment of complete remission (CR), with or without complete count recovery, occurrence of a proven or probable IFI (per 2008 EORTC/MSG criteria), development of unacceptable toxicity, pt withdrawal or death, or for a maximum of 12 weeks. The primary endpoint is the incidence of proven/probable IFI during the study period (up to 30 days from the last dose of ISAV). ISAV plasma concentrations are determined immediately pre-dose on days 8 and 15 using a validated assay. Results: A total of 50 pts were enrolled between April 28, 2017 and July 10, 2018. Four pts did not begin ppx with ISAV (1 each could not complete caspofungin washout and screening tests in time, 2 insurance denials). Of the remaining 46 pts (Table 1), 2 remain on study. Reasons for going off study (n = 44) included achievement of CR with neutrophil recovery (n = 26), completion of 12 weeks of therapy (n = 7), possible IFI (n = 5), investigator decision (n = 2), death (n = 2, 1 disease progression, 1 cardiac arrest), probable IFI (n = 1) and transaminitis (n = 1). In these 44 pts, the median duration of ISAV ppx was 30 (10-86) days. Only 1 case of proven breakthrough IFI occurred: a gluteal abscess that later grew Candida glabrata in a pt who had come off study upon achievement of CR. One case of probable IFI (focal mass-like opacity with ground-glass halo on CT; elevated Aspergillus antigen in broncho-alveolar lavage (BAL) fluid) occurred. All 5 cases of possible IFI were based on pulmonary radiologic findings alone: lower respiratory fungal cultures remained negative at 4 weeks in all 5 pts, and galactomannan was not detected in serum or BAL fluid in any pt. Tolerability of ISAV was excellent, with mild transaminitis attributed to ISAV reported in 1 pt (2%). No pt experienced QTc prolongation while on ISAV. Plasma ISAV levels were measured in 62 blood samples from 34 individual pts, including 28 paired samples. Median (range) ISAV concentrations were 3.74 (2.03-7.65) and 4.1 (2.17-9.25) mcg/ml on days 8 and 15, respectively. There was no correlation between plasma ISAV concentrations (available in 4 of the 7 pts) and the occurrence of confirmed, probable or possible IFI. Conclusions: These results demonstrate ISAV to be a safe and effective alternative for antifungal ppx in treatment-naïve pts with AML/MDS undergoing induction therapy with a variety of different regimens. ISAV's weak inhibition of P-glycoprotein and lack of risk of QT prolongation may make ISAV particularly attractive for antifungal ppx in the era of recently approved or emerging AML therapies such as enasidenib, ivosidenib, midostaurin and quizartinib. Disclosures Bose: CTI BioPharma: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Research Funding; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding. Wiederhold:Astellas Pharmaceuticals: Research Funding. Kadia:Celgene: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Takeda: Consultancy; Jazz: Consultancy, Research Funding. Ravandi:Abbvie: Research Funding; Xencor: Research Funding; Xencor: Research Funding; Jazz: Honoraria; Orsenix: Honoraria; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria. Thompson:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; abbvie: Research Funding; SagerStrong Foundation: Research Funding; cellectis: Research Funding; samus: Research Funding; stemline: Consultancy, Honoraria, Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; plexxikon: Research Funding; Affymetrix: Research Funding. Daver:Sunesis: Consultancy; Otsuka: Consultancy; Incyte: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Daiichi-Sankyo: Research Funding; Kiromic: Research Funding; ARIAD: Research Funding; Incyte: Consultancy; Karyopharm: Consultancy; Pfizer: Research Funding; Sunesis: Research Funding; ImmunoGen: Consultancy; Novartis: Consultancy; Alexion: Consultancy; Novartis: Research Funding; Pfizer: Consultancy. Cortes:Arog: Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Jain:Verastem: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Celgene: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologioes: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Cellectis: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Adaptive Biotechnologioes: Research Funding; Infinity: Research Funding; BMS: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Abbvie: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. DiNardo:Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Sasaki:Otsuka Pharmaceutical: Honoraria. Kontoyiannis:Astellas Pharmaceuticals: Research Funding.

Coinciding with the continually increasing population of immunocompromised patients worldwide, the incidence of invasive fungal infections has grown over the past 4 decades. Unfortunately, infections caused by both yeasts such as Candida and molds such as Aspergillus or Mucorales remain associated with unacceptably high morbidity and mortality. In addition, the available antifungals with proven efficacy in the treatment of these infections remain severely limited. Although previously available second-generation triazole antifungals have significantly expanded the spectrum of the triazole antifungal class, these agents are laden with shortcomings in their safety profiles as well as formulation and pharmacokinetic challenges. Isavuconazole, administered as the prodrug isavuconazonium, is the latest second-generation triazole antifungal to receive U.S. Food and Drug Administration approval. Approved for the treatment of both invasive aspergillosis and invasive mucormycosis, and currently under investigation for the treatment of candidemia and invasive candidiasis, isavuconazole may have therapeutic advantages over its predecessors. With clinically relevant antifungal potency against a broad range of yeasts, dimorphic fungi, and molds, isavuconazole has a spectrum of activity reminiscent of the polyene amphotericin B. Moreover, clinical experience thus far has revealed isavuconazole to be associated with fewer toxicities than voriconazole, even when administered without therapeutic drug monitoring. These characteristics, in an agent available in both a highly bioavailable oral and a β-cyclodextrin-free intravenous formulation, will likely make isavuconazole a welcome addition to the triazole class of antifungals.

Antimicrobial resistance among gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) continues to limit therapeutic options. The oxazolidinones are a synthetic class of agents now commonly relied on for the treatment of serious MRSA and VRE infections. With increasing utilization of linezolid, resistant pathogens have once again begun to emerge. Tedizolid, a next-generation oxazolidinone, possesses a spectrum of activity including MRSA and VRE, with significantly enhanced potency also against linezolid-resistant strains. Preclinical and early clinical studies have reported positive results, demonstrating a favorable pharmacokinetic profile in combination with key potential safety advantages. In two phase III clinical trials, tedizolid was found noninferior to linezolid in the treatment of acute bacterial skin and skin structure infections. Investigations for treatment of ventilator-acquired and health care-associated pneumonia are currently underway. Tedizolid has been subjected to pharmacodynamics studies throughout its development that have highlighted properties unique to this agent. Considerable accumulations in epithelial lining fluid and antimicrobial activity greatly augmented by the presence of granulocytes suggest that slow but bactericidal activity may be possible in some clinical scenarios. Structural distinctions between tedizolid and linezolid suggest that tedizolid has decreased vulnerability to oxazolidinone resistance mechanisms. Tedizolid minimum inhibitory concentrations are essentially unchanged in organisms possessing the chloramphenicol-florfenicol resistance gene, a horizontally transferable linezolid resistance mechanism. Although the clinical experience with tedizolid remains limited, early data suggest a potential role in the treatment of serious infections due to multidrug-resistant gram-positive pathogens.