Reduction In Bone Marrow Blasts Research Articles

Does IPSS-R downstaging before transplantation improve the prognosis of patients with myelodysplastic neoplasms?

AbstractIn patients with myelodysplastic syndrome (MDS) higher revised International Prognostic Scoring System (IPSS-R) scores at transplant are associated with worse transplant outcome and, thus, lowering IPSS-R scores by therapeutic intervention before transplantation may seem beneficial. However, there is no evidence, to date, to support this approach. In a retrospective analysis, a total of 1482 patients with MDS with sufficient data to calculate IPSS-R score at diagnosis and at time of transplantation were selected from the European Society for Blood and Marrow Transplantation transplant registry and analyzed for transplant outcome in a multivariable Cox model including IPSS-R score at diagnosis, treatment intervention, change in IPSS-R score before transplant, and several patient and transplant variables. Transplant outcome was unaffected by IPSS-R score change in untreated patients and moderately superior in patients treated with chemotherapy with improved IPSS-R score at transplant. Improved IPSS-R score after hypomethylating agents (HMAs) or other therapies showed no beneficial effect. However, when IPSS-R score progressed after chemotherapy, HMAs, or other therapies, transplant outcome was worse than without any prior treatment. Similar results were found when reduction or increase in bone marrow (BM) blasts between diagnosis and transplantation was considered. The results show a limited benefit of IPSS-R score downstaging or reduction of BM blasts after chemotherapy and no benefit for HMAs or other treatments and thus question the role of prior therapy in patients with MDS scheduled for transplantation. The model-based survival estimates should help inform decision-making for both doctors and patients.

Safety and tolerability of AMG 330 in adults with relapsed/refractory AML: a phase 1a dose-escalation study

AMG 330, a bispecific T-cell engager (BiTE®) that binds CD33 and CD3 on T cells facilitates T-cell–mediated cytotoxicity against CD33+ cells. This first-in-human, open-label, dose-escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AMG 330 in adults with relapsed/refractory acute myeloid leukemia (R/R AML). Amongst 77 patients treated with AMG 330 (0.5 µg/day–1.6 mg/day) on 14-day or 28-day cycles, maximum tolerated dose was not reached; median duration of treatment was 29 days. The most frequent treatment-related adverse events were cytokine release syndrome (CRS; 78%) and rash (30%); 10% of patients experienced grade 3/4 CRS. CRS was mitigated with stepwise dosing of AMG 330, prophylactic dexamethasone, and early treatment with tocilizumab. Among 60 evaluable patients, eight achieved complete remission or morphologic leukemia-free state; of the 52 non-responders, 37% had ≥50% reduction in AML bone marrow blasts. AMG 330 is a promising CD33-targeted therapeutic strategy for R/R AML.

Safety, Pharmacodynamic, and Anti-Tumor Activity of SL-172154 As Monotherapy and in Combination with Azacitidine (AZA) in Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) Patients (pts)

Background: CD47 blocking antibodies and SIRPα-Fc fusion proteins have demonstrated activity in combination with azacitidine (AZA) in previously untreated (UnTx) HR-MDS and AML pts. SL-172154 (SIRPα-Fc-CD40L), a hexameric, bi-functional fusion protein consisting of SIRPα domains linked to CD40L domains through an inert Fc linker demonstrated improved anti-tumor activity in comparison to naked CD47 blocking antibodies in pre-clinical studies [de Silva et al. Cancer Immunol Res 2020]. SL-172154, as a CD47 inhibitor, requires combination with AZA to enhance pro-phagocytic signals on leukemic stem cells/blasts thereby potentiating macrophage phagocytosis in AML/HR-MDS. Here we report the results from the Phase 1 Dose Escalation. cohorts for SL-172154 monotherapy [SL-mono] and for SL-172154 + AZA combination [SL-AZA] in pts with HR-MDS or AML. Methods: The objectives of the dose escalation cohorts include evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic effects and efficacy per IWG 2006 for MDS and ELN 2017 for AML. SL-172154 was administered IV weekly of a 28-day cycle as monotherapy or with AZA 75 mg/m 2 for 7 days per cycle. mTPI-2 was used for dose escalation with a DLT threshold of 20%. Pts ≥ 18 years old with R/R HR-MDS or R/R AML were eligible for dose escalation cohorts. In addition, UnTx pts with TP53 mutant (TP53m)-MDS were eligible for SL-AZA cohorts. Results: As of May 25, 2023, 37 pts were enrolled (19 in SL-mono; 18 in SL-AZA cohorts): 14 women; median age 70 years [range 44-81]. 27 pts had R/R AML (16 de novo; 11 secondary), 5 had R/R MDS, and 5 were UnTx TP53m-MDS. 23 (85%) of 27 R/R AML pts had adverse genetic abnormalities per 2017 ELN classification, including 9 (33%) with TP53m or del 17. The median number of prior lines of AML therapy was 2 [range 1-4]; 25 (93%) had received venetoclax (VEN) and 23 (85%) had received a hypomethylating agent (HMA). All 5 pts with R/R MDS had previously received HMA and 2 pts were previously treated with VEN. SL-172154 was dose escalated as monotherapy or with AZA as shown in Table 1. Infusion-related reactions (IRRs) were the most common SL-172154-related treatment-emergent AEs (TEAEs) reported in 13 (68%) and 8 (44%) pts in SL-mono and SL-AZA cohorts, respectively. IRRs (51 events) were Grade (G) 1 or 2 except for 3 G3 events (1 each at 6 mg/kg SL-mono and SL-AZA; 1 at 3 mg/kg SL-mono). Other SL-172154-related TEAEs observed in ≥ 3 pts were AST increased (4; 21%), ALT increased (3; 16%) and nausea (3; 17%) in SL-mono cohorts, and nausea (3; 17%) in SL-AZA cohorts. All events of AST/ALT increased were transient. Only one DLT (G3 IRR in the 6 mg/kg SL-AZA cohort) was reported, which required a dose reduction to 3 mg/kg. As of July 10, 2023, in SL-mono cohorts, 1 pt with R/R AML post 7+3, FLAG and VEN/AZA achieved Morphologic Leukemia-Free State (blast reduction from 19% to <5%) after 1 cycle of 6 mg/kg SL-172154 and proceeded to allogeneic hematopoietic cell transplant (allo-HCT) after cycle 2. In 12 evaluable pts with R/R AML receiving SL-AZA, although no objective responses (OR) were observed, relative reduction in bone marrow (BM) blasts from baseline was reported in 2/5 pts at 1 mg SL-AZA (-50%, -75%) and 5/7 pts at 3 mg SL-AZA (ranging from -35% to -90%). One pt underwent an allo-HCT. In 4 evaluable pts with UnTx TP53m-MDS, the ORs were 1 complete remission (CR), 1 marrow CR, and 2 stable disease. 2 of them proceeded to allo-HCT. SL-172154 induced elevations in serum IL-12p40, IP-10, IL-8, IL-10, MIP3α and MCP1: greater response at 3 mg/kg compared to 1 mg/kg while similar between 3 and 6 mg/kg. In the BM, SL-172154 induced a dose-dependent increase in phagocytic cells (CD11b, HLA-DR, CD16, CD36 and CD64) within mature myeloid immune cell compartments (CD45highCD34-). Reduction in leukemic blasts (CD45lowCD34+) was associated with an increase in mature myeloid and phagocytic cell phenotypes (3 mg/kg SL-AZA > 1 mg/kg SL-AZA). Conclusions: SL-172154 was well tolerated up to 3 mg/kg as monotherapy and in combination with AZA. Preliminary efficacy signals were detected in UnTx TP53m-MDS and R/R AML. A response to SL-172154 monotherapy, dose-dependent increases in serum cytokines and accumulation of mature myeloid cells in BM suggest a potential role for CD40 stimulation. Based on the safety, preliminary efficacy and pharmacodynamic activity, 3 mg/kg SL-172154+ AZA is being evaluated in treatment naïve pts with TP53m AML and HR-MDS.

Phase 1/2 First-in-Human Study of the Menin-MLL Inhibitor DSP-5336 in Patients with Relapsed or Refractory Acute Leukemia

Introduction: Menin inhibitors are an exciting new class of agents in development for patients (pts) with acute leukemia who overexpress HOXA9 and MEIS1 genes. Although there is a growing list of fusion genes in acute leukemia that appear to be dependent on homeobox-related gene activity, menin inhibition has been shown to be particularly active in pts with NPM1 mutations (NPM1c) and KMT2A rearrangements (MLLr). DSP-5336 is an investigational, oral small molecule designed to inhibit the menin and MLL protein interaction. Methods: A Phase 1/2 study of DSP-5336 is being conducted in pts with relapsed or refractory (R/R) acute leukemia. The dose escalation portion of the study consists of two parallel arms (Arm A: without concomitant anti-fungal azole therapy; Arm B: with concomitant azole therapy). Pts were eligible with R/R AML, ALL or acute leukemia of ambiguous lineage without a limit on number of prior therapies, with a focus on those with MLLr and NPM1c. Results: Accrual is ongoing with 24 pts enrolled as of April 2023; 14 pts in Arm A at doses of 40 mg BID (n=2), 80 mg BID (n=4), 100 mg BID (n=2) and 120 mg BID (n=6), and 10 pts in Arm B at doses of 40 mg BID (n=4) and 60 mg BID (n=6). The median age was 67.0 years (range 20 - 85) and 62.5% were male. All pts had AML except for 1 pt with acute leukemia of ambiguous lineage. Pts had received a median of 3 (range 1 to 9) prior treatments, and 6 (25%) had received prior alloSCT. MLLr or NPM1c were present in 6 (25%) and 4 (17%) patients, respectively. No dose-limiting toxicities have been observed thus far. Most treatment-emergent adverse events (TEAEs) were grade 1/2. TEAEs assessed as related to DSP-5336 in ≥ 3 pts were nausea (Grade 1 or 2, n = 3 pts) and vomiting (Grade 1 or 2, n = 4 pts). Grade >3 TEAEs occurring in ≥ 3 pts included anemia (6 pts), pneumonia (5 pts), sepsis (3 pts) and hypokalemia (3 pts), all unrelated to study drug. A possible Grade 4 differentiation syndrome (DS) was observed in 1 pt with a TP53 mutation in Arm A receiving 80 mg BID although concurrent pneumonia and sepsis made a clear attribution difficult. No other DS events of any grade have been reported to date. No cardiac toxicities, and no QTc prolongation of any grade related to DSP-5336 have been observed. Out of the 6 pts enrolled with MLLr, 4 were treated at dose levels projected to be active based on preclinical modeling (≥ 60 mg BID with azoles, or ≥ 120 mg BID without azoles). Of these 4 pts, all had received prior intensive induction chemotherapy as well as a venetoclax-based regimen, and 3 had received prior allo-transplant. Of these 4 pts, 1 achieved CRi with a duration of therapy of 5.1 months, 1 achieved MLFS with a duration of therapy of 6.2 months (ongoing), and 1 achieved SD with clearance of peripheral blasts, recovery of peripheral counts, resolution of leukemic gingival infiltration, and reduction in bone marrow (BM) blasts from 85% to 31%. Of the 4 enrolled pts with NPM1c, 2 were treated at doses projected to be effective. Stable disease with complete clearance of peripheral blasts were observed in both pts, and BM blasts were reduced by 66% and 83% respectively. Preliminary pharmacokinetic (PK) analysis has demonstrated generally higher mean exposures at higher dose levels. Across all the dose levels, plasma t 1/2 ranged from 2-6 hours in Arm A and from 2-10 hours in Arm B, with T max reached within 2 hours. Little to no drug accumulation was observed with repeat dosing in both arms. Data to date suggests that azoles may not have a significant effect on DSP-5336 exposure, but enrollment and comparative analyses are ongoing. Target pharmacodynamic changes have been achieved in pts who have MLLr or NPM1m, including rapid decreases in HOXA9, MEIS1, and PBX3 with treatment and, conversely, increases in CD11b compared to pretreatment. Conclusion: DSP-5336 has been well tolerated with no DLTs to date in heavily pretreated R/R AML patients with NPM1c and MLLr AML. Importantly, no cardiac signals (including no QTcF prolongation) have been observed. PK studies have not identified a significant drug-drug interaction with azoles. Although there are early signs of clinical activity and pharmacodynamic changes during administration of DSP-5336, the study is ongoing to determine a recommended Phase 2 dose for single-agent expansion and potential combination regimens. Updated safety and efficacy data will be presented at the meeting.

Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematologic Malignancies. Results from a Phase I/II Trial

Background: Overexpressionof B-cell lymphoma 2 (BCL-2)-related pro-survival proteins allows cancer cells to evade apoptosis, and targeting these proteins has become important in anticancer therapy. BCL-2 inhibition by venetoclax (VEN) is beneficial in many patients (pts) with acute myeloid leukemia (AML), but resistance is common due to upregulation of other pro-survival proteins such as BCL-extra-large (BCL-xL) and myeloid cell leukemia-1. Dual inhibition of BCL-2/xL has potential for broader activity than agents such as VEN. However, BCL-xL is critical for platelet survival and inhibition can cause dose-limiting thrombocytopenia (Konopleva and Letai. Blood 2018). To broaden therapeutic activity, we developed AZD0466, a drug-dendrimer conjugate in which the BCL-2/xL dual inhibitor AZD4320 is covalently conjugated to a pegylated poly-L-lysine dendrimer and gradually released by hydrolysis. Preclinically, AZD4320 showed greater inhibition of tumor growth than VEN and navitoclax in VEN-resistant xenograft models (Balachander et al. Clin Cancer Res 2020). A first-in-human study (NCT04214093) in pts with advanced solid tumors indicated that AZD0466 is well tolerated with no reported dose-limiting toxicities (DLTs). We present preliminary data from NIMBLE, a Phase I/II trial of AZD0466 in pts with advanced hematologic malignancies (NCT04865419). Methods: Module 1, Part A of NIMBLE is a dose-escalation study of AZD0466 monotherapy investigating its preliminary safety and tolerability, pharmacokinetics (PK), and preliminary efficacy. Dose escalation and de-escalation of AZD0466 follow a modified toxicity probability interval (mTPI-2) design. Eligible pts are ≥18 years old with relapsed/refractory (R/R) AML, acute lymphoblastic leukemia (ALL), or high-risk myelodysplastic syndrome. AZD0466 is administered IV with a dose ramp-up on Days (D) 1, 4, and 8, reaching the target dose on D8 of Cycle 1, with weekly administrations thereafter. Cycle duration is 35 days for Cycle 1 and 28 days for subsequent cycles. Pts remain on study until disease progression, unacceptable toxicity, or withdrawal of consent. Resul ts: As of May 31, 2023, 31 pts (n=25 AML, n=6 ALL; median age 69 years) had received ≥1 dose of AZD0466 at target doses of 300 mg (n=4), 600 mg (n=4), 1200 mg (n=7), 2400 mg (n=5), 3600 mg (n=9), and 5400 mg (n=2). Median treatment duration was 4.1 weeks (range 0.1−29.6). Twenty-two pts (71%) had prior VEN and 11 (35%) had prior hematopoietic stem cell transplantation. Treatment-emergent adverse events (TEAEs) of any grade reported in >10% of pts are displayed in Table 1. One Grade 5 intracranial hemorrhage unrelated to AZD0466 was reported. Four pts experienced a serious adverse event (SAE) possibly related to AZD0466 (alanine aminotransferase [ALT] increase, pneumonia, troponin T increase, and uncoded SAE). Grade ≥3 TEAEs possibly related to AZD0466, reported in 12 pts (39%), included febrile neutropenia (n=3), platelet count decrease (n=2), diarrhea, thrombocytopenia, ALT increase, blood creatinine phosphokinase increase, pneumonia, gamma-glutamyltransferase increase, lipase increased, and troponin T increase (n=1, each). DLTs of asymptomatic troponin increase were observed in two pts (3600 mg [n=1], 5400 mg [n=1]). Evaluation of maximum concentration and area under the concentration-time curve revealed dose-proportional exposure to AZD4320. Released AZD4320 represented 1-5% of total AZD4320 and had a longer half-life than total AZD4320. Preclinical modeling and PK data predicted that 5400 mg may be required to drive efficacy. As a surrogate of BCL-xL on-target activity, transient aggravation of thrombocytopenia post-dosing was observed across all dose cohorts followed by platelet recovery prior to the next dose. Platelet reduction was in line with preclinical models showing a substantial reduction at lower doses with a ceiling effect at higher doses. As of July 6, 2023, no complete responses have been observed. However, preliminary bone marrow (BM) blast reductions of >50% were observed in four pts (1200 mg [n=1], 2400 mg [n=2], 3600 mg [n=1]), indicating antileukemia activity of AZD0466. Conclusions: Given the observed DLTs of asymptomatic increase in troponin levels, and the lack of significant clinical benefit, the study was terminated.

Results of a Phase 1/2 Study of Lower Dose CPX-351 for Patients with Int-2 or High Risk IPSS Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia after Failure to Hypomethylating Agents

INTRODUCTION: Hypomethylating agents (HMAs) are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML). HMA failure (HMA-F) is associated with poor outcomes and median survival of 4 to 6 months. CPX-351 is a drug liposomal encapsulation of cytarabine (araC) and daunorubicin (dauno) at a synergistic 5:1 molar ratio approved for the treatment of pts with therapy-related acute myeloid leukemia (AML) or AML with MDS-related changes. Here we present the results of a phase I-II study of lower dose CPX-351 for HR-MDS and CMML after HMA-F. METHODS: We conducted a phase I/II clinical trial of CPX-351 for pts with MDS or CMML after HMA-F with Int-2 or High risk by IPSS, or Int-1 with >10% bone marrow (BM) blasts. The study included an initial phase I dose-escalation portion, following a 3+3 design, followed by a phase II dose expansion portion. Dose escalation included 4 dose levels of CPX-351: 10 units/m 2 (dauno 4.4mg/m 2 and araC 10mg/m 2), 25 units/m 2 (dauno 11mg/m 2 and araC 25mg/m 2), 50 units/m 2 (dauno 22mg/m 2 and araC 50mg/m 2) and 75 units/m 2 (dauni 33mg/m 2 and araC 75mg/m 2). Therapy was administered intravenously on days 1, 3 and 5 of 28-day cycles during induction and on days 1 and 3 of re-induction or consolidation. Re-induction was allowed in pts not achieving response after induction. The primary end point was to evaluate safety and determine the maximum tolerated dose of CPX-351. Responses were evaluated following 2006 IWG criteria. The Kaplan-Meir product-limit method was used to estimate median survival. RESULTS: Between June 2019 and September 2022, 23 pts have been treated: 15 in the phase I portion, and 8 in the phase II. A total of 17 pts had MDS, and 6 had CMML. Four (17%) pts had intermediate-1 risk IPSS and >10% blasts, 15 (65%) had intermediate-2 and 4 (17%) had high-risk IPSS. Median number of prior therapies was 1 (range 1-4) including 4 (17%) pts with failure to prior venetoclax therapy and 2 (9%) with prior HSCT. In the phase I portion, 3 pts received CPX-351 at dose level 1, 3 at dose level 2, 3 at dose level 3 and six at dose level 4. One pt treated at dose level 4 developed grade 2 congestive heart failure with grade 2 reduction in left-ventricular ejection fraction (LVEF). No additional DLTs were detected during the 28-day DLT evaluation window. The initial two pts treated at the P2RD of 75units/m 2 during phase II experienced cardiac complications: grade 3 congestive heart failure without reduction in LVEF and grade 3 right-sided heart failure, respectively. Study was amended to continue further treatment in phase II at dose level 3 (50units/m 2). Most common adverse events (AEs) were lower extremity edema (n=12, 52%), febrile neutropenia (n=11, 48%), dyspnea (n=10, 44%), mucositis (n=10, 44%), constipation (n=9, 39%), diarrhea (n=9, 39%), and generalized muscle weakness (n=9, 39%). Most common grade 3-4 AEs were febrile neutropenia (n=11, 48%), neutropenia (n=5, 22%), lung infection (n=4, 17%), diarrhea (n=4, 17%) and thrombocytopenia (n=3, 13%). The 4-week and 8-week cumulative incidences of mortality were 0% and 4%, respectively. Median number of days to cycle 2 was 47 days (range 30-83). Dose reductions of CPX-351 occurred in 4 (17%) pts. Median number of cycles was 3 (range 1-9). Median cycles to best response was 1 (range 1-3). Among pts with HR-MDS, the ORR was 71% (n=12): CR in 1 (6%), mCR with HI in 1 (6%) and mCR in 11 (59%) pts (Fig 1A). Among pts with BM blast reduction to <5% by the end of cycle 1, 11 (65%) and 9 (53%) had ANC recovery to >0.5x10 9/L and >1x10 9/L, respectively, and 8 (47%) and 6 (35%) had platelet recovery to >50x10 9/L and >100x10 9/L, respectively. Based on 2023 IWG response criteria, the ORR was 59% (n=10) including CR in 1 (6%), CR bilineage (CRbi) in 4 (24%) and CR unilineage in 5 (29%). Of 11 (65%) pts with baseline cytogenetic abnormalities, 2 (18%) and 2 (18%) achieved complete and partial cytogenetic responses, respectively. Three (13%) pts underwent HSCT at time of best response. Among pts with CMML (n=6), only one (17%) achieved response. Median response duration was 4.5 months (95% CI 0.7-8.2 months) and the median OS was 12.6 months (95% CI 3.6-21.7 months) (Fig 1B). CONCLUSIONS: Lower doses of CPX-351 in HR-MDS after HMA-F can induce clinically meaningful responses and be used as a bridge to allogeneic stem-cell transplant. Therapy is associated with median OS of 12.6 months in this population with expected survival of 4-6 months.

Venetoclax in Combination with Pediatric-Inspired Chemotherapy in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia: Results of a Phase I Trial

Introduction: Young adults with acute lymphoblastic leukemia (ALL) have favorable outcomes compared with historical standards when treated with an asparaginase-containing pediatric regimen (Stock et al., Blood 2019). We have demonstrated the safety and efficacy of pediatric inspired chemotherapy (PIC) for adults up to age 60 (MSK protocol 12-266, Geyer et al., Haematologica 2021). However, cure rates for adults with ALL remain below 60%, prompting the need for novel agents. Venetoclax (ven) is a BCL2 inhibitor being tested in several clinical trials for ALL. Here, we present the first report of ven used in combination with a multiagent, asparaginase-containing chemotherapy regimen for the upfront treatment of ALL. Methods: We conducted a Phase I, single-center, single-arm clinical trial (NCT05386576) to evaluate the safety and efficacy of ven in combination with PIC in adults with newly diagnosed ALL. Adults aged ≤60 years diagnosed with Philadelphia chromosome negative ALL were eligible for the study. The primary objective was to evaluate the safety of ven in combination with asparaginase-based PIC and identify the maximum tolerated dose and recommended phase II dose. The secondary objectives were to assess the rate of complete remission (CR) and measurable residual disease (MRD) negative CR at day 15 and 28 of Induction I, and end of Induction II. The regimen consisted of 6 treatment phases as previously published (12-266). Ven was administered at a final dose of 400mg (with a rapid dose escalation from 100mg over 3 days) during Induction I (days 5-7 dose escalation, days 7-28 full dose), Induction II (days 1-14 and 29-42), Intensification I & II (days 1-22), and Re-Induction I & II (days 1-14 and 29-42). Measurable residual disease (MRD) was assessed by multiparameter flow cytometry with 10 -4 sensitivity. We used historical data from 22 patients (pts) treated on our previous study, who received the same chemotherapy backbone without ven, as a comparator. Median follow up was calculated using the reverse Kaplan Meier indicator. Duration of treatment was compared using the Wilcoxon rank-sum test. Proportions of pts who achieved MRD-CR were compared with the chi squared test. Results: At the time of analysis, 8 pts had enrolled in the study; all 8 pts completed induction I and 6 (75%) pts had completed induction II (Table 1). Median follow up was 171 days. The median age was 38.5 years (min 25, max 60). 50% of pts had B-cell ALL, and 50% T-cell (including 1 patient with early T-cell progenitor). One patient (12.5%) had CNS disease (CNS 3) at diagnosis. Four (50%) pts had intermediate risk cytogenetics by CALGB 19802 classification (Stock et al., Cancer 2013), 2 (25%) had unfavorable, and 1 (12.5%) favorable. Two (40% of B-ALL) had a Philadelphia-like phenotype. During Induction I & II, 4 (50%) pts experienced febrile neutropenia, 6 (75%) grade 4 thrombocytopenia, and all 8 (100%) grade 4 neutropenia. No dose limiting toxicities, as defined per protocol, were observed. The average duration of Induction I on study was 46.6 days compared to 43.6 on 12-266 (p = 0.11). The average duration of Induction II on study for pts who had completed it at the time of analysis was 102 days compared to 74 days on 12-266 (p = 0.02), primarily due to cytopenias. Three (37.5%) of pts achieved an MRD negative CR by the end of Induction I. Of the 6 pts who had completed Induction II by time of analysis, 5 (83%) had achieved an MRD- CR, compared to 81% on 12-266 (p = 0.90) and 1 patient had refractory extramedullary disease. We assessed kinetics and depth of response by plotting the average blast percentage in the bone marrow by flow cytometry across three different timepoints. Pts on the study had numerically lower blast percentages at day 15, end of Induction I and end of Induction II compared to 12-266 (Figure 1). At the time of this analysis, no patient who entered CR had experienced disease relapse. Conclusions: Ven addition to a PIC backbone was overall safe with high MRD negative remission rates in this preliminary report. Compared to historical controls, pts treated with ven had a longer duration of Induction II primarily due to cytopenias, and we are amending the study to shorten ven duration during induction II. Pts treated with ven had a numerically faster reduction in bone marrow blasts compared to historical controls. Longer follow up in a larger patient population in this ongoing study will be required to assess long term toxicity and efficacy of this regimen.

Preliminary Results from a Phase 1 Dose Escalation Study of FHD-286, a Novel BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, Administered As an Oral Monotherapy in Patients with Advanced Hematologic Malignancies

The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its adenosine triphosphate (ATP)-dependent chromatin remodeling activity, BAF complexes regulate the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. FHD-286 is a first-in-class, orally administered compound that potently and selectively inhibits the ATPase components of the BAF complexes, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). In preclinical models, acute myeloid leukemia (AML) cell lines were highly sensitive to BAF inhibition. FHD-286-C-002 (NCT04891757) is a multicenter, open-label, Phase 1 dose escalation study designed to determine the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose and/or the recommended phase 2 dose(s), as well as to evaluate the preliminary clinical activity of FHD-286, in patients with advanced hematologic malignancies. Patients with relapsed or refractory (R/R) AML or myelodysplastic syndrome (MDS) failing all available standard therapies were eligible to receive FHD-286 doses ranging from 2.5 mg once daily (QD) to 10 mg QD on a continuous dosing regimen. Patients had regularly scheduled assessments to evaluate safety, pharmacokinetics (PK), pharmacodynamics, preliminary clinical activity, and exploratory biomarkers. As of 02 Aug 2022, 40 patients with a median age of 65.5 years (range 25 to 84) with R/R AML (36 patients) or MDS (4 patients) had received at least 1 dose of FHD-286. 67.5% of patients had received ≥3 prior lines of therapy for AML/MDS/other antecedent hematologic disorder, with 22.5% having received ≥5 prior lines. 32.5% of patients had prior hematopoietic stem cell transplant. 65% of patients had adverse risk genetics by 2017 ELN recommendations. 85% of patients experienced a treatment-related adverse event (TRAE) of any grade; the most common (≥20% of patients) were dry mouth (27.5%), increased blood bilirubin (22.5%), and alanine aminotransferase (ALT) increased and rash (20% each). 50% of patients experienced a Grade ≥3 TRAE, the most common of which was increased blood bilirubin (12.5%); stomatitis, ALT increased, differentiation syndrome (DS), and hypocalcemia occurred in 7.5% (each). 2 DLTs were reported: Grade 3 hyperbilirubinemia in 1 patient receiving 5 mg QD and Grade 3 muscular weakness in 1 patient receiving 10 mg QD. Treatment-related DS of any grade was investigator-reported in 4 patients (10%). An independent adjudication committee determined that the rate of suspected DS was 15% (6 patients). 16 patients (15 AML; 1 MDS) had a best overall response of stable disease. Markers of myeloid differentiation with neutrophil recovery and reductions in bone marrow and/or peripheral blasts have been observed in a subset of patients in the study who had a broad range of cytogenetic backgrounds, including patients with enhancer-driven leukemias such as MECOM and KMT2A. Preliminary PK analysis indicates that FHD-286 appears to have a long half-life, at a minimum of >24 hours, and that plasma concentrations of FHD-286 increase with increasing dose. Exploratory flow cytometry assessment of markers of differentiation, hematopoietic stem cell identity, and apoptosis suggested dose-dependent target engagement. Additionally, exploratory sequencing analysis on bone marrow blasts revealed comprehensive impacts on AML-specific expression pathways and stemness genes in response to FHD-286. An exposure-response analysis using the percentage of peripheral blasts showed a trend toward lower blast count with higher FHD-286 area-under-the-curve. Enrollment into the single-agent dose escalation phase of the study is complete. Based on nonclinical, translational, and single-agent clinical data, FHD-286 in combination with decitabine or low-dose cytarabine is being evaluated in the combination dose escalation phase of the study.

Preliminary Safety and Efficacy of Emavusertib (CA-4948) in Acute Myeloid Leukemia Patients with FLT3 Mutation

Background Acute myeloid leukemia (AML) is a heterogenous disease and exhibits a dynamic mutational landscape as the disease progresses. Internal tandem duplication (ITD) of FLT3 is considered an acquired late-event mutation and is associated with a poor prognosis in AML. Emavusertib is a potent oral inhibitor of IRAK4 and FLT3, conferring potential efficacy advantages compared to other IRAK4 and FLT3 inhibitors. IRAK4 is upregulated during anti-FLT3- or other cytotoxic therapies, which could drive a resistance pathway of early relapse and progression (Melgar 2019; Li 2019). Presence of spliceosome mutations U2AF1 or SF3B1 results in excessive IRAK4-L and further enhance toll-like receptor pathway activation (Smith 2019). Methods The safety, clinical activity, and potential biomarkers of emavusertib in relapsed/refractory (R/R) AML and higher-risk myelodysplastic syndrome are being investigated in the ongoing open-label, Phase 1/2a TakeAim Leukemia trial (NCT04278768). Here we present preliminary safety and efficacy data in the subset of enrolled AML patients who carried FLT3 mutation (FLT3m) at baseline and were treated with emavusertib monotherapy. Patients' mutational profiles were documented based on local testing results. Results As of 12 June 2023, 10 R/R AML patients with FLT3m have been treated at initial doses of 200, 300, or 400 mg BID. There was 1 patient with FLT3-TKD and 9 patients with FLT3-ITD, of which 2 carry both FLT3-ITD and U2AF1 mutations, and 1 with both FLT3-TKD and SF3B1 mutations. The median number of prior anti-cancer therapies was 3 (range 1-6) and 7 out of 10 patients had prior exposure to gilteritinib. Two patients with prior gilteritinib exposure also received midostaurin therapy. Treatment-emergent adverse events (TEAEs) Grade ≥ 3 were reported in 7/10 (70%) patients, and the majority of Grade ≥ 3 TEAEs were reversible and manageable. No dose-limiting toxicity was reported in these 10 patients. Five of 9 response evaluable patients demonstrated more than 90% bone marrow blast reduction compared to baseline. Enrollment is being expanded in this trial at the Recommended Phase 2 Dose (RP2D) of 300 mg BID for patients with ≤ 2 prior lines of therapy. Preliminary data for the 3 response evaluable patients in this population (for whom baseline and post-treatment marrow assessments were available) include blast count reductions of 99%, 100%, and 100% and include 2 CRs and 1 morphologic leukemia-free state (MLFS), with on-treatment duration of 213 days, 225 days, and 134 days, respectively. FLT3-ITD became undetectable in both patients achieving CR. Conclusion Emavusertib has a favorable safety profile in heavily pretreated AML patients with FLT3m and demonstrated anti-cancer activity in patients with FLT3m, including patients who have progressed on prior FLT3 inhibitor. No dose-limiting myelosuppression was reported. In addition, mutational profiles are suggestive of disease-modifying activity of emavusertib. Enrollment in this trial is continuing at a dose of 300mg BID (phase 2 expansion cohort) for patients with ≤ 2 prior lines of therapy.

Venetoclax Has Potent Efficacy in NPM1 mutated AML with Acquired Resistance Associated with Either Perturbed Pro-Survival Signalling or NPM1 wild-Type Populations

Background We have previously reported outcomes for patients (pts) receiving venetoclax (VEN) combined with intensive chemotherapy in fit older pts ≥65 years with newly diagnosed AML (Chua et al, JCO 2020). In contrast to younger populations, NPM1(mut) does confer favorable prognosis in older AML populations. Our prior studies indicate that VEN-based therapies in older pts have promising efficacy in NPM1(mut) AML (DiNardo et al, Blood 2020). To characterise this further, we performed a posthoc analysis of the efficacy of single agent VEN and in combination with chemotherapy in NPM1(mut) AML in the CAVEAT study and explored mechanisms of treatment failure using a multi-omic approach. Methods NPM1 MRD was performed using RT-qPCR (sensitivity 10 -6). Integrated analysis from bulk sequencing (targeted 42-gene NGS, whole exome/genome sequencing (WES/WGS), RNAseq), single cell (sc) proteogenomic and transcriptomic assessments (scDNA plus surface protein, Tapestri MissioBio; scRNAseq, 10x Genomics) were performed. Flow cytometry included analysis of BCL-2, BCL-XL, MCL1 and BFL1 expression. Results Of 85 pts enrolled on the CAVEAT study, 20 had NPM1(mut). Median age of NPM1(mut) vs (wt) was 71 vs 70 years. At a median follow-up of 38.6 months, CR/CRi rates and median OS for NPM1(mut) vs (wt) was 85% vs 72% (p=0.37), and 43.9 vs 15.1 months (p=0.04), respectively. Pts received a 7-day VEN monotherapy pre-phase prior to CAVEAT induction with paired bone marrow (BM) assessments pre- and at day 8 to evaluate VEN sensitivity. NPM1(mut) pts had a greater median relative blast reduction after 7-day VEN at -66% (range -7 to -98%), compared to -37% (range +51 to -94%) for NPM1(wt) (p=0.03). 18/20 NPM1(mut) sub-group pts completed induction and 17 had serial NPM1 MRD assessments. The NPM1(mut) level fell a median of 4.55-log 10 following induction, with 6 (35%) pts achieving MRD negative (MRDneg) status. After all consolidation, 12/16 (75%) were MRDneg. 12/12 (100%) pts in long-term follow up remain MRDneg. We investigated the mechanisms of resistance in the 5/20 pts with NPM1(mut) whose disease was primary refractory (RD; n=1) or had acquired secondary resistance (Fig). Two patients (CAL-045, CAL-021) had shown BM blast reductions of ≥45% during VEN pre-phase. Subsequently, at the time of clinical treatment failure, both were NPM1(mut) MRD negative indicating eradication of the starting NPM1(mut) clone and early evolution of a new NPM1(wt) population as the mechanism of resistance. Detailed genomic analysis of CAL-045 showed that a TET2/CBL/NPM1(mut) clone was eradicated, with persistence of TET2 and TET2/CBL(mut) clones lacking NPM1(mut) at the time of refractory disease. scRNAseq analysis of these NPM1(wt) clones revealed a pro-inflammatory signature with elevation in BFL1, a pro-survival gene not targeted by VEN (Fig). In patient CAL-021, NPM1(mut) was also absent with the emergence of nonsense/frameshift BAX variants at relapse as previously described (Moujalled et al, Blood 2022). BAX deficiency is associated with resistance to BH3-mimetics. Two other cases (CAL-014, CAL-020) showed BM blast reductions of <45% during VEN pre-phase. In CAL-014, the expansion of an NPM1 subclone was associated with FLT3-ITD. WES revealed evolution of FLT3-ITD loss of heterozygosity at relapse. Flow cytometric analysis demonstrated disproportionate upregulation of intracellular MCL-1 (Fig). In case CAL-020, no obvious genetic determinants of resistance were identified at relapse, with persistence of a DNMT3A/ KIT/ NPM1(mut) clone (VAF~50%). Whole transcriptome analysis revealed skewed expression of a KIT(mut)allele (from 45% to 88%) at relapse, and protein assessment by flow cytometry revealed marked upregulation of BCL-XL (Fig). Conclusion VEN in combination with intensive chemotherapy for NPM1(mut) AML pts ≥65 years resulted in rapid and deep responses ( NPM1(mut) MRD-negativity) that are associated with prolonged remissions and OS. Mechanisms of treatment failure among pts with NPM1(mut) are diverse and may include kinase-linked upregulation of alternative BCL-2 family pro-survival members or disruption of downstream pro-apoptotic BAX.

Spliceosome mutations are associated with clinical response in a phase 1b/2 study of the PLK1 inhibitor onvansertib in combination with decitabine in relapsed or refractory acute myeloid leukemia

PLK1 is overexpressed in acute myeloid leukemia (AML). A phase 1b trial of the PLK1 inhibitor onvansertib (ONV) combined with decitabine (DAC) demonstrated initial safety and efficacy in patients with relapsed/refractory (R/R) AML. The current study aimed to identify molecular predictors of response to ONV + DAC in R/R AML patients. A total of 44 R/R AML patients were treated with ONV + DAC and considered evaluable for efficacy. Bone marrow (BM) samples were collected at baseline for genomic and transcriptomic analysis (n = 32). A 10-gene expression signature, predictive of response to ONV + DAC, was derived from the leading-edge genes of gene set enrichment analyses (GSEA). The gene signature was evaluated in independent datasets and used to identify associated mutated genes. Twenty percent of the patients achieved complete remission, with or without hematologic count recovery (CR/CRi), and 32% exhibited a ≥50% reduction in bone marrow blasts. Patients who responded to treatment had elevated mitochondrial function and OXPHOS. The gene signature was not associated with response to DAC alone in an independent dataset. By applying the signature to the BeatAML cohort (n = 399), we identified a positive association between predicted ONV + DAC response and mutations in splicing factors (SF). In the phase 1b/2 trial, patients with SF mutations (SRSF2, SF3B1) had a higher CR/CRi rate (50%) compared to those without SF mutations (9%). PLK1 inhibition with ONV in combination with DAC could be a potential therapy in R/R AML patients, particularly those with high OXPHOS gene expression and SF mutations.

Palbociclib in Acute Leukemias With KMT2A-rearrangement: Results of AMLSG 23-14 Trial

Palbociclib in Acute Leukemias With KMT2A-rearrangement: Results of AMLSG 23-14 Trial

Abstract 6150: AZD0466, a dual BCL-2/XL targeting nanomedicine, is active in small cell lung cancer models

Abstract Small cell lung cancer (SCLC) is an aggressive malignancy with critical need for new therapies. While currently treated as a single disease, SCLC is heterogenous, comprised of several transcriptional subtypes. Each of these subtypes has distinct drivers and may warrant unique therapeutic targets. Two potential therapeutic targets for SCLC are the pro-survival proteins BCL-2 and BCL-XL. BCL-2 is overexpressed in ASCL1 (A) and POUF3 (P) subtypes of SCLC. We therefore sought to evaluate efficacy of the dual BCL-2/XL inhibitor AZD0466 in SCLC models and to determine whether transcriptional subtype would predict response. AZD0466 is a novel drug-dendrimer conjugate. The active moiety, AZD4320, is a potent dual inhibitor of BCL-2 and BCL-XL. AZD4320 is covalently conjugated to a 5th-generation PEGylated poly-lysine dendrimer through a hydrolytically labile linker to make AZD0466. AZD0466 has been optimized to deliver efficacy while mitigating potential Cmax-driven on-target toxicities of AZD4320. AZD4320 was active (IC50 ≤0.1 µM) in 9/27 SCLC cell lines. AZD4320 in vitro sensitivity was enriched in cell lines that represented A and P subtypes of SCLC compared to NEUROD1 and YAP1 subtypes. We next profiled AZD0466 in a panel of SCLC patient-derived models: 14 patient-derived xenografts and 10 circulating tumor cell-derived xenografts. AZD0466 monotherapy dosed weekly IV was active in 12/24 SCLC xenografts, driving regressions in 8 models. AZD0466 drove efficacy and cleaved caspase-3 induction in a dose-dependent manner. Similar to in vitro, AZD0466 in vivo efficacy was enriched in subtype-A, driving responses in 10/14 ASCL1 models (7 regression, 3 stable disease). AZD0466 response also correlated strongly with BCL-2 mRNA expression (P<0.0001). AZD0466 outperformed the selective BCL-2 inhibitor venetoclax in 6/10 models. Notably, AZD0466 was active in models resistant to platinum/etoposide chemotherapy, the standard-of-care for SCLC. Together, these data suggest BCL-2/XL inhibition has therapeutic potential in SCLC. AZD0466 is in clinical development. The first-in-human study treated 9 patients with advanced solid tumors (NCT04214093) at doses from 50-200mg, all of which were well-tolerated. The BOR was SD observed in 3 patients (100mg) with 1 patient receiving treatment for 5.5 months. AZD0466 is now under evaluation in patients with hematologic malignancies (NCT04865419 and NCT05205161). AZD0466 has been dosed in 33 patients up to 2400mg. No DLTs have been reported to date. Initial clinical activity has been observed through reduction of bone marrow blasts following AZD0466 treatment. AZD0466 exhibits linear PK, consistent across solid tumor and leukemia patients. The doses tested are in line with preclinical studies in SCLC. Citation Format: Courtney L. Andersen, Giulia Fabbri, David Jenkins, Zumla Cader, Shringi Sharma, Areya Tabatabai, Srividya Balachander, Jordan Roebuck, Melanie Galvin, Kathryn Simpson, Caroline Dive, Jordi Rodon Ahnert, Jamal Saeh. AZD0466, a dual BCL-2/XL targeting nanomedicine, is active in small cell lung cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6150.

Safety and efficacy of casein kinase 1α and cyclin dependent kinase 7/9 inhibition in patients with relapsed or refractory AML: A first-in-human study of BTX-A51.

7030 Background: Inactivation of p53 and overexpression of Mcl1 are common mechanisms that cancer cells use to evade apoptosis. BTX-A51 is a novel, oral, direct inhibitor of casein kinase 1α (CK1α) and cyclin dependent kinase 7 and 9 that robustly increases p53 protein levels via CK1α inhibition while preferentially decreasing super-enhancer transcription of Myc and Mcl1, enabling selective apoptosis of leukemia cells. Here, we report the interim results of the first-in-human (FIH) study of BTX-A51 in patients (pts) with R/R AML. Methods: The study utilizes a hybrid accelerated titration with single pt cohorts and a Bayesian optimal interval design in dose escalation. The primary objective is to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of BTX-A51. Secondary objectives include evaluating the antileukemic activity, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 25 January 2022, 30 pts (28 with AML; 2 with HR-MDS) enrolled at dose levels between 1 and 42 mg; 2 pts remain on treatment. Monotherapy doses between 1 and 42 mg were administered orally 3 days/week (wk) (3 wk in a 28-day cycle) and at 21 mg (4 wk in a 28-day cycle). Baseline characteristics include median age 75 years, median number of prior therapies 3, 97% received prior treatment with venetoclax, 97% had prior HMA, and 43% had prior induction failure. The most common treatment-emergent AEs (TEAEs) were hypokalemia, nausea, vomiting, diarrhea, and hypotension. The most common Grade 3 or higher TEAEs were anemia, febrile neutropenia, platelet count decreased, and hypokalemia. DLTs included grade 3 hepatic failure at the 42 mg dose in 1 pt and grade 3 alkaline phosphatase elevation in 1 pt at the 21 mg dose. All events resolved after holding study drug. Plasma PK of BTX-A51 was roughly dose-proportional between 1 and 42 mg with accumulation based on AUC between Day 1 and Day 5. Estimated half-life was between 18 and 55 hours. Among the 30 pts with R/R AML and MDS, CR/CRi rate was 10% (3/30) with 1 pt at the 11 mg and 2 pts at the 21 mg dose levels attaining CRi. Bone marrow (BM) blast reduction > 50% occurred in 4 patients including the 3 responders, all at the 11 and 21 mg dose levels. All 4 pts with > 50% BM blast reduction had RUNX1 mutations; 9 pt with RUNX1 enrolled in the trial. The median duration of response for pts achieving CR/CRi was approximately 1.5 month. Responses were not observed in MDS pts. PD data will be provided in the full presentation. Based on the clinical data from dose escalation, the RP2D is 21 mg administered 3 days/wk for 4 wk of a 28-day cycle. Conclusions: In this FIH study, monotherapy BTX-A51 demonstrated an acceptable safety profile and promising antileukemic activity in pts with heavily pretreated R/R AML. The 21 mg dose administered 3x/wk for 4 wk was identified as the RP2D. RUNX1 mutations were enriched among responders and pts attaining > 50% BM blast reduction. Clinical trial information: NCT04243785.

Venetoclax Plus Hypomethylating Agent for the Salvage Treatment of Myeloid Malignancies Relapsing after Hematopoietic Stem Cell Transplantation: A Multicenter Retrospective Study on Behalf of the Zhejiang Cooperative Group for Blood and Marrow Transplantation

ObjectiveHematopoietic stem cell transplantation (HSCT) is one of the most efficient treatments for hematologic malignancies. However, relapse remains the main cause of transplant failure. In myeloid neoplasia, the long-term survival for patients who relapsed after HSCT ranges from 10% to 20%. Conventional chemotherapy and donor lymphocyte infusion (DLI) exhibit limited effect and are accompanied by high risks of infection and graft versus host disease (GVHD). New, less toxic, and more efficient treatment options are urgently needed. Venetoclax (VEN), a selective inhibitor of anti-apoptotic protein Bcl-2, combined with hypomethylating agents (HMAs) was well-tolerated and showed an impressive response rate in elderly patients with AML, both as frontline therapy and for relapse. While in post-transplant relapsed patients, the efficacy of the combination of VEN and HMA (VEN-HMA) still needs to be explored.MethodsBetween July 2018 and May 2021, forty-two patients who experienced post-transplant relapse were retrospectively analyzed in this study. All these patients received at least one cycle of VEN-HMA. The salvage therapy consisted of VEN for 28 consecutive days (100 mg of VEN for the first day and 200 mg for the second day, then increased to the final dose of 400 mg daily or equivalent with azole co-administration). Thirty-nine patients received azacytidine (100mg/m2, d1-7) while the other 3 patients were given decitabine (10mg/m2, d1-5) in combination with VEN.Disease types included acute myeloid leukemia (AML, n=32), myelodysplastic syndrome (MDS, n=7), chronic myelomonocytic leukemia (CMML, n=2) and chronic myeloid leukemia (CML, n=1). 28 (66.7%) patients achieved complete remission before transplantation and 14 (33.3%) patients were transplanted in a non-remission status. Haploidentical-related donor (HID, n=31) was the most common donor type, followed by matched sibling donor (MSD, n=6) and unrelated donor (URD, n=5). Each patient was analyzed for chromosomal and genetic abnormalities either at diagnosis and at post-transplant relapse. Complex/monosomal karyotype was seen in 10 (23.8%) patients. 9 (21.4%) patients had TP53 mutation or deletion and 7 (17.9%) had IDH1/2 mutation. The median time from transplantation to relapse was 329 (range, 30-1584) days, 27 (64.3%) patients had an early relapse (within 1-year post-HSCT). 16 (38.1%) patients developed acute GVHD and 15 (35.7%) developed chronic GVHD before relapse.24 (57.1%) patients received VEN-HMA as first-line salvage therapy, while the other 18 (42.9%) patients received this combination therapy after failure with chemotherapy or DLI. 22 (52.4%) patients had a higher tumor burden (bone marrow blasts >20%) at the initiation of VEN-HMA. In total, 20 (47.6%) patients responded to the VEN-HMA therapy with a reduction in bone marrow blasts. 14 (33.3%) patients fulfilled the criteria of CR/CRi and all of them achieved the best response in the first cycle of VEN-HMA. However, 4 (9.5%) patients even experienced disease progression after VEN-HMA. After a median follow-up time of 84 (18-535) days, patients who achieved CR/CRi experienced a significantly higher overall survival (OS) than those who did not (85.7% vs 14.3%, p <0.0001). In univariate and multivariate analysis, we found that early relapse (HR=4.000, p=0.046) was the only independent risk factor that influenced the CR/CRi rate.ConclusionVEN-HMA is safe and efficacious for patients with myeloid malignancies relapsing after transplantation. Patients relapsing within 1-year post-transplantation may be more likely to benefit from this combination therapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Phase 1 Results of Novel Combination Therapy: BET Inhibitor PLX51107 with Azacitidine in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Phase 1 Results of Novel Combination Therapy: BET Inhibitor PLX51107 with Azacitidine in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Synergistic Combination Activity of the Novel GSPT1 Degrader CC-90009 in Acute Myeloid Leukemia Models

Introduction: CC-90009 is a novel cereblon E3 ligase modulator (CELMoD ®) agent that is a first-in-class degrader of translation termination factor G1 to S phase transition 1 (GSPT1). CC-90009 has demonstrated antileukemic activity as a single agent and is currently under investigation in patients with acute myeloid leukemia (AML; NCT02848001). Treatment with CC-90009 led to rapid reductions in peripheral and bone marrow blasts, and demonstrated preliminary promising efficacy, including several complete remissions, in patients with relapsed or refractory AML. Here, we describe the identification and preclinical activity of select anti-AML agents as potential combination partners of CC-90009 to further improve its efficacy and therapeutic index. Based on these results, the combination activity of CC-90009 with venetoclax (VEN)/azacitidine (AZA) is being evaluated in a phase 1/2 trial in patients with AML (NCT04336982).Methods: A high-throughput cell viability screen was performed to identify synergistic partners of CC-90009. AML cell lines (HL-60, HNT-34, KG-1, ML-2, NOMO-1, MOLM-13, MV4-11, F-36P, OCI-AML2, OCI-AML3) were treated with CC-90009 in combination with > 70 compounds, including standard anti-AML agents, tyrosine kinase inhibitors (TKIs), unfolded protein response inducers, transcription inhibitors, and epigenetic agents. MOLM-13 and MV4-11 are fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) cell lines. Hits were validated in a colony formation (CF) assay using primary AML cells and bone marrow mononuclear cells (BMMC) from healthy donors. Synergy of the combination partners with CC-90009 was further assessed in AML patient-derived xenograft (PDX) models. Synergy between the isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib and CC-90009 was evaluated in a TF-1 erythroleukemia cell line overexpressing IDH2 R140Q mutant, and an IDH2 R140Q PDX model, AM7577.Results: Our high-throughput combination screen revealed multiple TKIs, epigenetic agents, and pro-apoptotic agents as potential combination partners of CC-90009 in AML cell lines. FLT3 inhibitors, including sunitinib, pexidartinib, midostaurin, lestaurtinib, crenolanib, and gilteritinib, synergized with CC-90009 to reduce viability in FLT3-ITD AML cell lines MV4-11 and MOLM-13. Similarly, the B-cell lymphoma 2 (BCL2) inhibitor VEN potentiated CC-90009-induced apoptosis and accelerated cell-autonomous killing. Reduction in levels of MCL-1, an anti-apoptotic factor, by CC-90009 most likely contributed to the synergy with VEN.We prioritized the evaluation of FLT3, BCL2, and IDH2 inhibitors as partners of CC-90009. In CF assays, midostaurin enhanced the inhibitory effect of CC-90009 in primary AML cells, without augmenting the effect of CC-90009 in CD34+ BMMC from healthy donors. Similarly, VEN enhanced the reduction in CF by CC-90009 in AML patient-derived BMMC without exacerbating the decrease in CF by CC-90009 in BMMC from healthy donors.We characterized FLT3 inhibitor/CC-90009 and BCL2 inhibitor/AZA/CC-90009 combinations in a FLT3-ITD PDX murine model, PDX1. The FLT3 inhibitor quizartinib significantly prolonged survival when combined with CC-90009 compared with either agent alone (P < 0.001). Similarly, VEN/AZA/CC-90009 combination markedly extended survival compared with single agents or VEN/AZA doublets (P < 0.001).The synergy between CC-90009 and epigenetic modulators was validated and further characterized in customized cell differentiation assays. Addition of CC-90009 to enasidenib, a mutant IDH2 inhibitor, enhanced differentiation and killing of CD34+ stem and progenitor cells, and increased differentiated CD235a+ erythroblasts, compared with enasidenib alone in a TF-1 cell line overexpressing IDH2 R140Q. Enasidenib/CC-90009 combination treatment reduced CD45+ malignant populations and increased differentiated CD14+ cells, leading to significantly prolonged animal survival in an IDH2 R140Q PDX model, AM7577, compared with either agent alone (P < 0.0001).Conclusion: Using a high-throughput combination screen, we identified rational combination partners that synergize with CC-90009 in in vitro and in vivo AML models. Collectively, these results support the clinical evaluation of CC-90009 in combination with FLT3, BCL2, and IDH2 inhibitors to further improve treatment outcomes for patients with AML. DisclosuresPierce: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Yao: Bristol Myers Squibb: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months, Research Funding. Pace: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Wang: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Flandin-Blety: Bristol Myers Squibb: Current Employment. Benitez: Bristol Myers Squibb: Current Employment. Guarinos: Bristol Myers Squibb: Current Employment. Hoffmann: Bristol Myers Squibb: Current Employment. Carrancio: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pourdehnad: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

A Phase II Study of Azacitidine, Venetoclax and Trametinib in Relapsed/Refractory AML Harboring a Ras Pathway-Activating Mutation

A Phase II Study of Azacitidine, Venetoclax and Trametinib in Relapsed/Refractory AML Harboring a Ras Pathway-Activating Mutation

MDS-404: Population Pharmacokinetics Modeling and Evaluation of Clinical Efficacy and Safety of Sabatolimab: Dose Selection and Dose-Response Analysis

Context: Sabatolimab is an investigational immuno-myeloid therapy targeting TIM-3. The STIMULUS clinical trial program has been designed to evaluate sabatolimab in multiple phase 1–3 trials in patients with MDS and AML. Here, we report PK and clinical data supporting sabatolimab doses being evaluated in the STIMULUS program. Methods: PK was evaluated in patients with advanced solid tumors (NCT02608268), or high/very-high risk MDS, or AML who were ineligible for intensive chemotherapy (NCT03066648). Main Outcome Measures: Total sabatolimab serum concentration was used in population PK modeling to simulate average (Cavg), maximal (Cmax), and trough (Ctrough) concentrations at steady-state. Total serum soluble TIM-3 was measured, and simulation was used to predict membrane-bound TIM-3 occupancy in the bone marrow (BM). PK exposure-response analysis (data cutoff 27 Nov 2019) and assessment of clinical safety/efficacy by dose (data cutoff 25 Jun 2020) were conducted. Results: Sabatolimab PK was similar for patients with solid tumors (n=252) and higher-risk MDS and AML (n=155); no drug–drug interactions were observed for any combinations. Among sabatolimab+HMA regimens, sabatolimab 400 mg Q2W had the highest Ctrough at steady-state, and 800 mg was predicted to be an equivalent Q4W dosing regimen. Both doses had similar steady-state Cavg and similarly high occupancy rates for membrane-bound TIM-3 in the BM (>95% in ≥95% of patients with higher-risk MDS/AML), suggesting similarly high levels of TIM-3 engagement. There was no relationship between steady-state Cmax or Cavg quartiles and the incidence of treatment-related AEs. Exposure-efficacy analysis showed no clear relationship between steady-state Ctrough or Cavg and percent BM blast reduction or clinical benefit (CR/mCR/CRi/PR). Sabatolimab+HMA was safe and well-tolerated, with a low discontinuation rate due to AEs (3.4% [4/116]). Rates of most common grade ≥3 treatment-emergent AEs did not appear to be dose-dependent. Conclusions: Sabatolimab 400 mg Q2W was predicted to have the highest steady-state Ctrough and TIM-3 occupancy rate when combined with HMA; 800 mg was predicted to be an equivalent dosing regimen. No clear relationship was seen between sabatolimab dose or steady-state exposure and safety/efficacy. These results support the clinical development of the sabatolimab 400 mg Q2W and 800 mg Q4W dosing regimens.

A Phase (ph) 1b/2 Study of TAK-659, an Investigational Dual FLT-3 and SYK Inhibitor, in Patients (Pts) with Relapsed or Refractory Acute Myelogenous Leukemia (R/R AML)

A Phase (ph) 1b/2 Study of TAK-659, an Investigational Dual FLT-3 and SYK Inhibitor, in Patients (Pts) with Relapsed or Refractory Acute Myelogenous Leukemia (R/R AML)