Search

7027 Background: TP-0903 is a multi-kinase inhibitor designed to target AXL, a receptor tyrosine kinase, and also inhibits cell cycle regulators such as Chk1/2 and other AML associated kinases. TP-0903 has shown prior anti-tumor activity at a safe dose in solid tumors. In pre-clinical AML studies, TP-0903 shows potent cytotoxicity in TP53 mutant ( TP53m) AML cell lines, an adverse prognostic genomic sub-group of AML. TP-0903 also had synergistic activity with decitabine (dec) in TP53m AML and prolonged survival in xenograft and genetically engineered mouse models. We report here on the initial safety and clinical results from the Leukemia and Lymphoma Society’s ongoing Beat AML phase 1b/2 (Ph1b/2) trial of TP-0903 in combination with dec (ClinicalTrials.gov NCT03013998). Methods: Newly diagnosed AML pts ≥60 years with TP53m and/or complex karyotype (≥3 abnormalities) were selected for a Ph1b/2 dose escalation study of TP-0903 combined with dec. Seven Ph1b pts were given TP-0903 every 28-day cycle from days 1-21 (Dose level (DL) 1 = 37 mg/day) and dec IV days 1-10 (20 mg/m2). A standard 3+3 design was used to evaluate the safety and tolerability. Nine additional patients enrolled onto Ph2 at DL1, but further assessments of safety, pharmacokinetics (PK) and correlative data was used to update the final recommended Ph2 dose (RP2D) of TP-0903 to DL-1 (25 mg/day) with dec. Results: At data cutoff (10Jan2022), 16 total pts were accrued. Ph1b treated 7 pts at DL1, 6 were DLT evaluable, and no DLTs were observed. Ph2 enrolled and treated 9 pts at DL1 before concerns of delayed count recovery led to the reduction of the Ph2 dose of TP-0903 to DL-1 (25 mg/day). For all 16 pts treated at DL1, 1 pt achieved CR, 4 pts CRh, and 1 pt CRi, for a composite CR (CR/CRh/CRi) rate of 37.5% (95% CI, 15.2-64.6), with 4 pts achieving MRD negativity by central flow cytometry. For the remaining 10 pts, 1 pt achieved MLFS (6%), 6 pts had stable disease (37.5%), 1 pt had treatment failure (6%), and 2 pts were not evaluable (12.5%) due to withdrawal of consent and death from early disease progression. Two pts (1 CR and 1 CRh) proceeded to stem cell transplantation. The most common grade 3 and above treatment-related AEs include decreased neutrophil counts (37.5%), platelet counts (31.3%), and anemia (18.8%). Finally, PK and correlative data analysis looking at soluble Axl and Gas6 also supported reduction to DL-1. Conclusions: Initial results with DL1 suggest that TP-0903/dec shows preliminary clinical activity in the prognostically poor TP53m/complex karyotype AML sub-group, with 4 pts achieving MRD negative status out of 6 patients who achieved a CR/CRh/CRi (66%). After further patients were treated on DL1, the toxicity profile and correlative data supported the de-escalation to DL-1 as the RP2D. The Ph2 study is ongoing to determine the clinical activity of this new RP2D (DL-1). Clinical trial information: NCT03013998.

e19026 Background: The USFDA has recently approved several oral targeted therapies for the treatment of acute myeloid leukemia (AML). The relative survival impact of these agents vs standard induction chemotherapy in the frontline setting is unknown, especially in patients who undergo allogeneic hematopoietic cell transplant (HCT). Methods: This is a retrospective, single-institution study of 125 patients with AML diagnosed 2015-2020 who received HCT. Patients were included if induced with high intensity chemotherapy (HiC) or lower intensity targeted therapy (LITT). HiC was defined as cytarabine + anthracycline given on a “7+3” based schedule. LITT was defined as venetoclax, gilteritinib, enasidenib, or ivosidenib alone or combined with hypomethylating agent. Patients receiving liposomal cytarabine-daunorubicin were excluded. Outcomes of interest were overall survival (OS), non-relapse mortality (NRM), and cumulative incidence of relapse (CIR). Between-groups analysis was conducted comparing receipt of any HiC to LITT only. OS was analyzed by Kaplan-Meier method and compared using log-rank test; NRM and CIR was estimated through cumulative incidence function and compared by Fine-Gray test. Results: Of 125 HCT recipients, 108 received any HiC and 17 LITT only. Two patients received HiC after suboptimal response to LITT. Median age at HCT was 61 years, 48% were female, and 90% were in complete remission at HCT. Population characteristics and outcomes as well as between-groups comparison are presented in the table. LITT only group was older with longer time to HCT and exclusively received RIC. With median follow-up of 23 months, median OS had not been reached. There were no statistically significant differences in median OS or one-year NRM or CIR between groups. Conclusions: Despite differences in age, conditioning regimen, and time to HCT in patients receiving any HiC vs LITT only, we have shown similar OS, CIR, and NRM. Difference in age is in contrast to lack of difference in HCT-CI and KPS, but is partially explained by limited access to LITT for younger patients. Longer time to HCT among LITT only recipients represents a major opportunity for pre-HCT optimization of recipient health. Prospective study from time of diagnosis will be important to understanding the appropriate use of LITT in HCT-eligible patients.[Table: see text]

e19004 Background: Acute Myeloid Leukemia (AML) has traditionally been treated frontline with intensive induction chemotherapy in patients fit enough for this treatment. The FDA has approved several oral targeted therapies for AML in recent years. The survival impact of these agents vs induction chemotherapy is unknown. Methods: In this single-center, retrospective study, patients diagnosed with AML from 2015-2020 were included if they received treatment with either high intensity chemotherapy (HiC) or lower intensity targeted therapy (LITT). HiC was defined as a regimen containing cytarabine + anthracycline given on a “7+3” based schedule. Patients treated with liposomal cytarabine-daunorubicin were excluded. LITT was defined as venetoclax, gilteritinib, enasidenib, or ivosidenib alone or in combination with a hypomethylating agent. Patients fell into four groups: HiC only, LITT only, HiC followed by LITT, and LITT followed by HiC with assignment censored at transplant. Overall survival (OS) was estimated using Kaplan-Meier method and patients receiving any HiC vs LITT only were compared using log-rank test. Results: A total of 332 patients were included: 177 received HiC only, 116 LITT only, 32 HiC before LITT, and 7 LITT before HiC. Baseline characteristics and OS data are outlined in the table. The any HiC group had a lower median age and more patients with WBC >10 K/µL at diagnosis, as well as more patients receiving allogeneic hematopoietic cell transplant (HCT). OS was superior in the any HiC group vs LITT only group. Receipt of any HiC remained predictive of OS after adjusting for age (HR 0.65, 95% CI 0.44-0.96, p = 0.03); however, was no longer predictive of OS after adjusting for age and receipt of HCT. Conclusions: While HiC was associated with superior OS compared to LITT only treatment in univariable analysis, the survival benefit was no longer apparent after adjusting for age and receipt of HCT. The results suggest that intensity of AML treatment is less impactful on prognosis than ability to receive HCT. Differences in age were likely confounded by clinical trial eligibility and prescribing information specifically affecting patients receiving LITT. In the era of LITT, prospective randomized studies of intensity of AML therapy, particularly in non-favorable risk disease, are imperative to striking a balance between toxicity and cure for patients of all ages.[Table: see text]

e19510 Background: Over 40% of newly diagnosed acute leukemia patients receiving induction therapy develop acute respiratory failure. Bronchoscopy is a valuable tool for evaluating airway disease, but its diagnostic yield in this setting has not been fully explored. Methods: We performed a retrospective chart review of 75 newly diagnosed acute leukemia patients who had bronchoscopies. Data recorded prior to bronchoscopy included age, diagnosis, induction treatment regimen, chest imaging, assisted ventilation, duration of neutropenia and antibiotic therapy and microbiological studies. Bronchoalveolar lavage (BAL) cultures were sorted by organism, as well as by other pathologic findings. The primary outcome was antibiotic change supported by culture data. Results: The study population is summarized in the table. Induction regimen backbones included 7+3 (51), 7+4+ATRA (2), decitabine (12), hyperCVAD (2), AYA (3), other (1) and none (4); 18 patients were treated on clinical trial. Average days of neutropenia was 10.92 and average days of antibiotic therapy was 10.57. Thirty-eight patients had chest infiltrates, 11 received NIPPV, and 17 were mechanically ventilated. We identified 24 patients with +BAL studies. Of these, 37.5% (9) had + blood, urine or sputum studies before bronchoscopy, but only 3 had cultures positive for the same organism as the BAL. Of 51 patients with –BAL studies, 33.3% (17) had prior negative cultures. Infections were most commonly bacterial (15, 62.5%), followed by viral (5, 20.8%) and fungal (4, 16.7%). The most common organisms were rhinovirus, vancomycin sensitive Enterococcus (4, 16.7% each) followed by VRE, Candida albicans and MRSA (2, 8.3% each). Five patients (6.7%) had alveolar hemorrhage. Of the 24 patients with +BAL cultures, bronchoscopy findings supported changing antibiotics in 18. In contrast, antibiotics were changed in 16 patients without +BAL cultures. Conclusions: We investigated the utility of bronchoscopy on AL patients during their initial admission. BAL cultures were positive in 32% of newly diagnosed AL patients undergoing bronchoscopy. However, +BAL cultures identified a new organism in 87.5% and guided antibiotic therapy in 75% of these patients. Further studies will be needed to establish predictors of bronchoscopy findings in this patient population. [Table: see text]

7515 Background: Therapy-related AML (tAML) is a long-term complication of cytotoxic cancer therapy. It is characterized by adverse genetics and inferior survival outcomes when compared to de novo AML. A proposed mechanism in tAML pathogenesis includes treatment-induced selection of clones harboring pre-existing mutations (i.e. clonal hematopoiesis, CH). We hypothesize that genotoxic therapies used to treat prior malignancy drive leukemogenesis through different mechanisms leading to unique clonal compositions. Methods: AML patients (pts) treated at The Ohio State University between 2015-2018 were included. Genetic profiling was performed using Miseq Illumina platform with a 49-gene targeted sequencing panel at our clinical laboratory. Results: We studied 337 AML pts (Table), of whom 53% had smoking history. Mutations involving ASXL1 were more common in smokers vs non-smokers (14% vs 5.8%, p= .001), while JAK2 mutations were more common in non-smokers (8% vs 1.2%, p= .003). Regarding specific genotoxic therapies and mutations in tAML, we investigated common CH-associated mutations including DNMT3A, TET2, and ASXL1 (DTA mutations). In tAML pts, those exposed to radiotherapy experienced a higher frequency of DTA (52% vs 27%, p= .05), NPM1 (21% vs 0%, p= .002), and SRSF2 (15% vs 0%, p= .01) mutations, and conversely, a lower incidence of TP53 mutations (21% vs 46%, p= .04). Pts with history of cytotoxic chemotherapy had a lower incidence of DTA mutations, including those who received platinum agents (8% vs 49%, p= .005) and taxanes (7% vs 52%, p< .001), but had a higher incidence of TP53 mutations (75% vs 25%, p< .001 for platinum; 53% vs 25%, p= .04 for taxanes). Similarly, alkylators and anthracyclines were associated with lower incidence of DNMT3A (0% vs 20%, p= .009) and ASXL1 (0% vs 12.5%, p= .04) mutations. Conclusions: Different genotoxic agents demonstrate unique effects in leukemia development. Our data suggest that CH clones with DTA mutations may be enriched with smoking and radiotherapy, while cytotoxic chemotherapy may confer a higher incidence of TP53 mutations. Given the adverse prognosis of TP53 mutated AML, identification of pre-existing CH clones might influence treatment selection in solid tumor pts receiving anticancer therapy. [Table: see text]

e18520 Background: Venous thromboembolism (VTE) is common in acute lymphoblastic leukemia (ALL) patients (pts) receiving peg-asparaginase (ASNase) however there is limited data regarding the incidence of VTE and risk factors for VTE in adolescent and young adults (AYA) treated with ASNase. Methods: This is a single institutional retrospective analysis of AYA pts with ALL who received ASNase from January 2013 to December 2018. Time to VTE was calculated from date of starting treatment to onset of VTE or censored at last assessment date, treating death as a competing risk. The cumulative incidence of VTE was estimated and the Fine and Gray regression models accounting for competing risks were used to examine the association between risk factors and VTE. Results: Forty-six AYA ALL patients were included. Pt characteristics are shown in the Table. Twenty pts had a VTE following ASNase with the cumulative incidence rate of 35% (95% CI: 22-48%) at 100 days. The most common VTE sites were cerebral (n=6) and upper extremity (n=6). Nine pts (43%) had at least one recurrent VTE. After initial VTE, ASNase was continued in 13 pts (62%), stopped in 6 pts (29%), and dose reduced in 2 pts (10%). Nine pts (45%) of those who developed VTE received antithrombin. Out of the 6 pts with VTE who had ASNase discontinued or dose reduced, 2 (33%) had progression of ALL. The hazard ratios (HR) for risk of VTE from univariable regression models are listed in Table 1. Male sex was associated with increased VTE risk, with HR=3.33 (95% CI: 1.13-9.77). Conclusions: Our study estimated the incidence of VTE in the AYA cohort. Only male sex was identified as a risk factor for VTE. Additional studies are needed to assess VTE risk factors in AYA pts with ALL. Pt characteristics and hazard ratios for risk of VTE. [Table: see text]

7048Background: Patients (pts) with relapsed or refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. Selinexor (SEL), an oral inhibitor of the nuclear transport protein XPO...

7000Background: IVO is an oral, targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1) that is being evaluated in a phase 1 dose escalation and expansion study of mIDH1 advanced hematologi...

7053 Background: Acute myeloid leukemia (AML) therapy is associated with pancytopenia and a high failure rate due to resistant leukemia stem cells that use CXCL12/CXCR4 to home to marrow niches. Pl...