Treatment decisions in primary myelofibrosis (PMF) are guided by numerous prognostic systems. Patient specific comorbidities have influence on treatment related survival, and are considered in clinical contexts, but have not been routinely incorporated into current prognostic models. We hypothesized that patient specific comorbidities would inform prognosis and could be incorporated into a quantitative score. All patients with PMF or secondary MF (sMF) with available DNA and comprehensive electronic health record (EHR) data treated at Vanderbilt University Medical Center between 1995-2016 were identified within Vanderbilt's Synthetic Derivative and BioVU Biobank. We recapitulated established PMF risk scores (e.g., DIPSS, DIPSS plus, GPSS, MIPSS 70+) and comorbidities through EHR chart extraction and next generation sequencing (NGS) on biobanked peripheral blood DNA. The impact of comorbidities was assessed via DIPSS-adjusted overall survival using Bonferroni correction. Comorbidities associated with inferior survival include renal failure/dysfunction (hazard ratio [HR] 4.3; 95% CI 2.1-8.9; p = 0.0001), intracranial hemorrhage (HR 28.7; 95% CI 7.0-116.8; p=2.83e-06), invasive fungal infection (HR 41.2; 95% CI 7.2-235.2; p=2.90e-05), chronic encephalopathy (HR 15.1; 95% CI 3.8-59.4; p=0.0001). The extended DIPSS model including all four significant comorbidities showed a significantly higher discriminating power (C-index 0.81; 95% CI 0.78-0.84) than the original DIPSS model (C-index 0.73; 95% CI 0.70-0.77). In summary, we repurposed an institutional biobank to identify and risk-classify an uncommon hematologic malignancy by established (e.g., DIPSS) and other clinical and pathologic factors (e.g., comorbidities) in an unbiased fashion. The inclusion of comorbidities into risk evaluation may augment prognostic capability of future genetics-based scoring systems.

Purpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (PMF), or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F mutant cell lines. Patients and Methods: In a phase I dose-escalation and expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor umbralisib in combination with ruxolitinib in MF patients who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that maximally tolerated dose at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. Results: Thirty-seven MF patients with prior exposure to ruxolitinib were enrolled. 2 patients treated with 800mg umbralisib experienced reversible Grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved complete response (CR), and 12 patients (32%) met the IWG-MRT response criteria of clinical improvement (CI). With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. Conclusions: Adding umbralisib to ruxolitinib in patients was well-tolerated and may re-sensitize MF patients to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors.

We aim to identify predictors of therapy-related myeloid neoplasms (t-MN) in patients with breast cancer (BC) and cytopenias to determine the timing of bone marrow biopsy (BMBx). Patients with BC and cytopenias who were referred for BMBx between 2002-2018 were identified using the Memorial Sloan Kettering Cancer Center institutional database. Characteristics associated with the risk of t-MN were evaluated by multivariable logistic regression and included in a predictive model. The average area under the receiver operating characteristic curve (AUC) was estimated by 5-fold cross-validation. Of the 206 BC patients who underwent BMBx included in our study, 107 had t-MN. By multivariable analysis, white blood cell count 4-11 K/mcL, absolute neutrophil count (ANC) /1.5 K/mcL, hemoglobin h12.2 g/dL, red cell distribution width 11.5-14.5%, the presence of bone metastasis and a time from BC diagnosis to BMBx

TPS7064 Background: Menin, a protein involved in transcriptional regulation, impacting cell cycle control, apoptosis, and DNA damage repair, plays a direct role in oncogenic signaling in multiple cancers. Inhibition of menin is therefore a novel approach to cancer treatment. Preclinical data of BMF-219, a highly selective, orally bioavailable, small-molecule irreversible inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling in vitro and in vivo. BMF-219 exhibited a strong anti-proliferative effect on various menin-dependent acute myeloid leukemia (AML) cell lines, DLBCL lines representing Double/Triple Hit Lymphoma (DHL/THL) and Double Expressor Lymphoma (DEL), and MM cell lines with diverse mutational backgrounds. BMF-219 also showed high potency ex vivo in patient samples from MLL-rearranged and NPM1-mutant AML, THL and MYC-amplified DLBCL, and bone marrow mononuclear cells from treatment-naive and R/R MM. Methods: COVALENT-101 (NCT05153330) is an open-label, multi-cohort, non-randomized, multicenter Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of once daily oral BMF-219 in patients with R/R AL, DLBCL and MM who have received standard therapy. Utilizing an accelerated titration design, doses of BMF-219 will be escalated in single-subject cohorts independently for each indication until 1 subject experiences either a ≥ Grade 2 related-adverse event or dose limiting toxicity (DLT). At that point, the cohort will switch to a classical “3 + 3” design. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts for each indication will enroll patients to obtain further safety and efficacy data. Patients with R/R AL, R/R DLBCL ≥ 2 but ≤ 5 therapies, and R/R MM who received ≥ 3 therapies and failed or are ineligible for any standard therapies are eligible. Patients must have ECOG PS ≤ 2, and adequate organ function. Key exclusion criteria include known CNS disease involvement, prior menin inhibitor therapy, and clinically significant cardiovascular disease. The primary objective is to determine independently for each cohort/indication the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-219 oral monotherapy. Key secondary objectives include further evaluation of safety and tolerability, characterization of the pharmacodynamics and pharmacokinetics of BMF-219, and assessment of its antitumor activity based on best overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and time to progression (TTP) per disease-specific response criteria as assessed by the investigator. Food-effect studies will be performed in DLBCL and MM patients at certain dose levels. The enrollment commenced in January 2022. Clinical trial information: NCT05153330.

<p>Supplemental Tables S1-S9Supplemental Figures S1-S2</p>