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Introduction Despite the advent of targeted therapy for FLT3-mutated AML, unmet need still exists for patients unfit for intensive chemotherapy, with no evidence that overall survival (OS) can be improved by combining either venetoclax (Konopleva et al., ASH 2020) or gilteritinib (Astellas press release, December 2020) with azacitidine. Although gilteritinib has been shown to improve median OS from 5.5 to 9.8 months, the majority will relapse (Perl et al., 2019). Adaptive on-target gilteritinib resistance may be due to the FLT3-F691L gatekeeper mutation, whereas off-target resistance may be due to loss-of-function variants in CBL, which encodes an E3 ubiquitin-protein ligase that negatively regulates FLT3 (McMahon et al, 2019). Ponatinib is a type-1 FLT3 inhibitor that is active in vitro against FLT3 F691L (Smith et al., 2013) and had an overall response rate (ORR) of 43% in a small pilot phase-I study (Talpaz et al., 2011). Combination of a FLT3 inhibitor with azacitidine may antagonize the synergistic hypermethylation reported for FLT3-ITD in association with epigenetic mutations (Shih et al., 2015). CBL loss-of-function mutations may also enhance responsiveness to FLT3 inhibitors (Taylor et al, 2015). We thus hypothesize that the combination of ponatinib and azacitidine could mitigate the rapid evolution of drug resistance typical of more selective FLT3 inhibitors used as single agents. Methods A phase-Ib study was conducted with the primary objective safety and key secondary objective preliminary efficacy of azacitidine in combination with ponatinib in patients with FLT3-ITD AML failing prior therapy or unfit for intensive chemotherapy. Exploratory objectives included mechanisms of ponatinib resistance and responsiveness of CBL-mutant AML to FLT3 inhibition. At dose level 1 (DL1), patients received azacitidine 60 mg/m 2 on days 1-5 and 8-9 and ponatinib 30 mg daily on days 5-25 of each cycle. In patients not achieving CR or CRi after cycle 1, the ponatinib dose was increased to 45 mg during cycle 2. For dose level 2 (DL2), the dose of azacitidine was increased to 75 mg/m 2. Results Thirty-one patients were evaluable for response. Median age was 67 years (range, 26-87). Frequency of prior lines of therapy was 0 (15%), 1 (46%), 2 (23%) or 3 (8%). Four patients had a history of prior allogeneic hematopoietic cell transplant and one had previously received a FLT3 inhibitor. FLT3-ITD was present in 28 patients (median VAF 0.33; range, 0.009-17.95) and 3 had inactivating CBL mutations. A total of 20 patients were treated at DL1 and 12 patients at DL2. There were two grade-4 DLTs (raised AST/ALT [DL1] and tubulointerstitial nephritis [DL2]). Three grade-2 thromboembolic events were observed (two cannula-related DVTs and a distal lower-limb DVT). There were two grade-5 AEs (infection and cardiac failure), which were not considered drug related. The most common grade-3-4 AEs were febrile neutropenia (57%), neutropenia (47%), infections (47%), thrombocytopenia (40%) and anaemia (27%). Cardiac arrhythmias (atrial fibrillation/flutter, bradycardia, sinus tachycardia and ventricular tachycardia [1 patient]) were observed in 30% of patients. Of these, 80% were grade 1 or 2 and only one was considered by the investigator to be related to study treatment. Response was evaluable in 23 of 31 patients. Nine patients (39%) achieved CR or CRi, 3 (13%) achieved a PR and 8 (35%) achieved SD (ORR 52%). ORR at DL1 and DL2 was 43% and 66%, respectively. Median time to best response was 1.4 months (range 1.0-11.9). Median duration of best response was 12.9 months at both dose levels. Median OS for DL1 was 6.5 months and not reached for DL2. Despite shorter follow-up, DL2 patients experienced better OS than DL1 patients (p = 0.015). Responses were seen in 2 of 4 patients with post-allograft relapse. Two of three patients with a CBL mutation responded (1 CR and 1 CRi). Eradication of the CBL mutation was seen in one patient, who remains on therapy after 15 cycles. Molecular studies to investigate dynamic changes in molecular architecture are ongoing. Conclusions The recommended phase-II dose of ponatinib is 30 mg on days 5-25 and that of azacitidine is 75 mg/m 2 for seven doses each cycle. The ORR was 52% and durable disease control was observed, especially in patients receiving DL2. Preliminary efficacy was observed in CBL-mutated patients. Further clinical investigation of this regimen is warranted in patients with FLT3- or CBL-mutant AML. Figure 1 Figure 1. Disclosures Kipp: Novartis: Honoraria. Perkins: Celgene: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau. Lane: Novartis: Consultancy; Geron: Consultancy; BMS: Consultancy, Research Funding; Abbvie: Honoraria; Astellas: Membership on an entity's Board of Directors or advisory committees. Enjeti: Sanofi: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria; Roche: Speakers Bureau; Astra Zeneca: Honoraria. Bajel: Abbvie, Amgen, Novartis, Pfizer: Honoraria; Amgen: Speakers Bureau. Reynolds: Novartis AG: Current equity holder in publicly-traded company; Abbvie: Research Funding; Alcon: Current equity holder in publicly-traded company. Wei: Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Novartis, Abbvie, Celgene/BMS: Speakers Bureau; Former employee of Walter and Eliza Hall Institute: Patents & Royalties: Prof. Andrew Wei is a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Honoraria; Servier: Consultancy; Abbvie, Amgen, AstraZeneca, Celgene/BMS, Novartis, Servier and F. Hoffmann-La Roche: Research Funding. OffLabel Disclosure: Ponatinib - used as an experimental therapy for AML in combination with azacitidine

Pegylated interferon (Peg-IFN) increases molecular response rates when used in combination with imatinib (IM) and dasatinib compared with tyrosine kinase inhibitor (TKI) monotherapy in de novo chronic phase chronic myeloid leukemia (CP-CML). (Preudhomme NEJM 2010, Hjorth-Hansen Leukemia 2016). The phase II Pinnacle (ALLG CML 11) study evaluated the tolerability and molecular response rate of nilotinib (NIL) with Peg-IFN alfa-2B (PegIntron, MSD) in CP-CML patients. Co-primary end points were MMR (BCR-ABL1 ≤ 0.1%) at 12 mths and MR4.5 (BCR-ABL1 ≤ 0.0032%) at 24 mths. Key secondary end points were survival and overall molecular response. Patients were screened for cardiac / vascular disease and associated risk factors at baseline (EKG, left ventricular ejection fraction, arterial duplex of carotids and lower limbs, blood HbA1c and lipid profiles). Those with uncontrolled vascular risk factors (diabetes, hypertension, dyslipidemia) or a history of vascular events were excluded. Eligible pts received NIL 300mg BID alone for the first 3 months (mths). PegIntron was then added at 30mcg/week in pts without persistent hematological toxicities, increasing to 50mcg/week as tolerated over the following mth. Combination therapy continued until 24 mths, when pts reverted to TKI monotherapy. Switching to IM 400-600mg QD was allowed for pts with persistent grade II or any grade III/IV toxicity from NIL. Sixty pts were enrolled from 12 Australian centres. Median age was 48.5 years (range 19-72); 45% were female. Sokal risk was low in 43% and high in 18%. Median follow up (FU) was 34 mths (24-60). Data is presented on an intention to treat basis. Eight pts (13%) did not commence Pegintron (2 due to persistent haem toxicities, 4 from GI disturbance, liver/pancreatic enzyme derangements, and 2 from pt preference). Considering Pegintron as a product of protocol assigned dose and duration, adjusted for time from study entry, 21 pts (35%) received >85% of their assigned dose, 13 (22%) received between 50-84% and 18 pts (30%) received 85% of their assigned dose versus those wwho took Adverse events (AE) are reported at a similar frequency compared to the interim analysis. Grade III/IV AEs attributed to NIL were increased lipase and neutropenia (each 12%), pancreatitis (6%), thrombocytopenia and rash (each 5%). Grade III/IV AEs attributed to Pegintron were neutropenia (10%), atrial fibrillation (6%), and myalgia, depression and rash (4% each). Three vascular revents occurred: one case each of ischaemic colitis, femoral artery occlusion, coronary artery disease. The former occurred on imaitnib and the latter 2 occurred after 2.5 and 4 years of niloitnib respectively; both patient have since switched to imatinib. Eighteen pts (30%) have withdrawn from study: 2 withdrew consent, 6 due to intolerance (diarrhoea, pancreatitis, GI upset, rash, high amylase and LFT derangements), 4 for failing to consistently achieve BCR-ABL MMR, 2 for loss of response; 4 pts withdrew for other reasons. Fig 1B shows BCR-ABL1 transcript levels over time. At 3 mths, 22 (37%) have achieved MMR, 23 (38%) had BCR-ABL between 0.1-1%, and 6 (10%) had BCR-ABL between 1-10%; 3 have already withdrawn. Six pts (10%) had BCR-ABL1 ≥10%; 3 subsequently achieved and maintained MMR, 1 has BCR-ABL Combination therapy with NIL and Peg-IFN leads to favourable rates of molecular responses that may be superior to NIL monotherapy (Table). While the majority of patients did not durably tolerate full dose Pegintron, there was minimal interference with TKI dose intensity. Such strategies may maximise achievement of deep molecular response, allowing a trial of TKI cessation and the benefit of treatment free remission to an increased number of patients. Disclosures Yeung: BMS: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria; Novartis: Honoraria, Research Funding. Shanmuganathan:Gilead: Other: Travel Support; Janssen: Other: Travel Support; Amgen: Other: Travel Support; Bristol-Myers Squibb: Honoraria, Other: Travel Support; Novartis: Honoraria, Other: Travel Support. Grigg:Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Reynolds:AUSTRALASIAN LEUKAEMIA & LYMPHOMA GROUP (ALLG): Consultancy; Novartis AG: Equity Ownership; Novartis Australia: Honoraria; Alfred Health: Employment, Other: Biostatistician for trials funded by the Australian government and Abbvie, Amgen, Celgene, GSK, Janssen-Cilag, Merck, Novartis, Takeda, but sponsored by Alfred Health.. Harrup:Cooperative Trial Group for NeuroOncolog: Other: Collaborative Clinical Trials Group; Cancer Council of Tasmania: Membership on an entity's Board of Directors or advisory committees. Ross:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mills:Novartis: Other: Speaker Fees; Specialised Therapeutics: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Conference Sponsorship; MSD: Membership on an entity's Board of Directors or advisory committees. Yong:BMS: Honoraria, Research Funding; Celgene: Research Funding; Novartis: Honoraria, Research Funding. White:BMS: Honoraria, Research Funding; AMGEN: Honoraria, Speakers Bureau. Branford:Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cepheid: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hughes:Novartis, Bristol-Myers Squibb, Celgene: Research Funding; Novartis, Bristol-Myers Squibb: Consultancy, Other: Travel. OffLabel Disclosure: Pegylated interferon is not registered for use in chronic phase CML

Dasatinib treatment leads to excellent molecular responses in chronic phase chronic myeloid leukemia (CP-CML). Pleural effusions, an adverse event related dasatinib treatment, may lead to intolerance and drug discontinuations. Strategies aimed at minimising this may improve outcomes. In the Phase III Dasision study, pleural effusion affected ~22% of patients after 4 years of dasatinib treatment at 100mg/d (Cortes et al, 2016 JCO 34(20) 2333-40). The elderly are at particular risk (Latagliata et al 2013 Hem Onc 31(2) 103-9), and there is suggestion that higher dasatinib trough (Cmin) levels may increase the risk of pleural effusions. The randomised OPTIM study (EHA 2014 abstract 5678) has previously reported that patients with Cmin >3nM benefited from dose reductions with preservation of molecular responses. The CML12 (DIRECT) study, run by the Australasian Leukaemia & Lymphoma Group (ALLG) with financial support from BMS, is a single arm phase II study with the aim of minimizing dasatinib related toxicity whilst preserving efficacy using a similar treatment schema to the OPTIM study. Here, we report results of a per-protocol interim analysis based on early molecular response (EMR; BCR-ABL1 ≤10% at 3 months) and MMR (BCR-ABL1 ≤0.1%) at 12 months, both key secondary endpoints of the study. The primary endpoint of the study- the cumulative incidence of pleural effusion at 24 months - is not yet evaluable. DIRECT initially only enrolled patients >60 years old, predicted to derive the greatest potential benefit from a reduction in toxicity. The protocol was amended after 34 pts were accrued to include patients >18 years old at the recommendation of the trial management committee. All patients started treatment with dasatinib 100mg/day. Dasatinib Cmin was taken at 7, 28 and 56 days after treatment commencement. All Cmin directed dose adjustments were made prior to assessment of BCR-ABL1 at 3 months. Patients sequentially dose reduced to 70mg/day, then to 50mg/day, for Cmin results >3nM. Doses As of June 2019, 71 patients (of 80 planned) from 14 centres have been enrolled, with a median follow up of 7 months (range 0-31). Median age was 64 years (range 21-86) and 48% were female. Sokal risk was low in 40% and high in 9.2%. The median dasatinib Cmin at days 7, 28, 56 and 90 were 4.9, 3.5, 3.5 and 2.7nM respectively (Table). At these time points, 83%, 59%, 73% and 44% of patients had Cmin ≥3nM. There was a trend to lower Cmin after protocol directed dose reduction. The number of patients remaining on 100mg/day after 1, 2 and 3 months of therapy were 11/69 (16%), 5/63 (8%) & 5/55 (9%) respectively. Molecular response data were available for 48 patients at 3 months and 22 patients at 12 months. At 3 months, BCR-ABL1 ≤ 10% was achieved by 46 of 48 patients (96%), of whom 13 (27%) had achieved MMR (27%). At 12 months, MMR was achieved by 20/22 patients (91%), of whom 7 have achieved MR4.5 (BCR-ABL1 Adverse events occurred in 91.5% of patients at all grades - the majority of which were mild. Grade III/IV events occurred in 36.6% and 1.4% of patients respectively. Six of the 71 patients have discontinued dasatinib treatment early, all due to adverse events / dasatinib intolerance. Detailed adverse event data is embargoed until primary endpoint analysis. No patient has progressed to accelerated or blast phase CML. The DIRECT study demonstrated the feasibility of using dasatinib Cmin levels to optimise dosing. Early molecular response rates are encouraging and predict for excellent achievement of long-term molecular response. Long term efficacy and safety data are awaited. Table Disclosures Yeung: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria. Grigg:Abbvie: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel. Shanmuganathan:Novartis: Honoraria, Other: Travel Support; Bristol-Myers Squibb: Honoraria, Other: Travel Support; Amgen: Other: Travel Support; Janssen: Other: Travel Support; Gilead: Other: Travel Support. White:BMS: Honoraria, Research Funding; AMGEN: Honoraria, Speakers Bureau. Branford:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Qiagen: Consultancy, Honoraria; Cepheid: Consultancy, Honoraria. Mills:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Speaker Fees; Amgen: Other: Conference Sponsorship; Specialised Therapeutics: Honoraria; MSD: Membership on an entity's Board of Directors or advisory committees. Shortt:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astex: Research Funding; Amgen: Research Funding; Gilead: Speakers Bureau; Takeda: Speakers Bureau. Ross:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Harrup:Cancer Council of Tasmania: Membership on an entity's Board of Directors or advisory committees; Cooperative Trial Group for NeuroOncolog: Other: Collaborative Clinical Trials Group. Hughes:Novartis, Bristol-Myers Squibb, Celgene: Research Funding; Novartis, Bristol-Myers Squibb: Consultancy, Other: Travel.

Alfa Interferon, commonly used in chronic phase chronic myeloid leukemia (CML-CP) in the pre-imatinib era, was able to induce a cytogenetic response in a minority of patients (pts). Pegylated interferon (Peg-IFN) is better tolerated than IFN, and increases molecular response rates when used in combination with imatinib (IM) compared with IM monotherapy (Preudhomme NEJM 2010). The phase II Pinnacle (ALLG CML 11) study evaluated the tolerability and molecular response rate of nilotinib (NIL) with Peg-IFN alfa-2B (PegIntron, MSD) in de novo CML-CP. Pts were screened for cardiac / vascular disease and associated risk factors at baseline (EKG, left ventricular ejection fraction, arterial duplex of carotids and lower limbs, blood HbA1c and lipid profiles). Those with uncontrolled vascular risk factors (diabetes, hypertension, dyslipidemia) or a history of vascular events were excluded. Eligible pts received NIL 300mg BID alone for the first 3 months (mths). PegIntron was then added at 30mcg/week in pts without persistent hematological toxicities, increasing to 50mcg/week as tolerated over the following mth. Combination therapy continued until 24 mths, when pts reverted to TKI monotherapy. Switching to IM 400-600mg QD was allowed for pts with persistent grade II or any grade III/IV toxicity from NIL.. Sixty pts were enrolled from 12 Australian centres. Median age was 48.5 years (range 19-72); 45% were female. Sokal risk was low in 43% and high in 18%. Median follow up (FU) was 28 mths (16-51). Data is presented on an intention to treat basis. Figure 1a shows BCR-ABL1 transcript levels over time. The co-primary end points are MMR (BCR-ABL1 ≤0.1% IS) AT 12 mths and MR4.5 (BCR-ABL1 ≤0.0032% IS) at 24 mths. At 12 mths, MMR and MR4.5 rates were 76.7% (95% CI 63.4-87%). and 43.4% (95% CI 30.1-57.3%), respectively. In 40 evaluable pts at 24 mths, MR4.5 was 50% (95% CI 29.9-70.1%). The median time to MMR and MR4.5 was 5.8 mths and 18 mths respectively for pts achieving these responses (Figs 1B & C). Six pts (10%) had BCR-ABL1 ≥10% at 3 mths - 2 of whom had multiple dose interruptions due to toxicity; 3/6 have since achieved MMR, 1 has BCR-ABL Dose intensities of NIL were assessed in 3 mth blocks. Median and lower quartile NIL dose intensity was 600mg/d for all 3 mth blocks up to mth 24, except for the lower quartile NIL dose of 567mg for the first 3 mths. Eight pts (13%) did not commence Pegintron (2 due to persistent haem toxicities, 4 from GI disturbance, liver/pancreatic enzyme derangements, and 2 from pt preference). Considering Pegintron as a product of protocol assigned dose and duration, adjusted for time from study entry, 22 pts (37%) received >90% of their assigned dose, 13 (22%) received between 50-90% and 25 pts (41%) received Grade III/IV adverse events (AE) attributed to NIL were increased lipase and neutropenia (each 12%), pancreatitis (6%), thrombocytopenia and rash (each 5%). Three thrombotic events occurred: ischemic colitis in a patient on IM monotherapy, femoral artery thrombosis in a 56yo man after 2.5 yrs of NIL, and coronary disease in a 51yo man after 4 yrs of NIL. Grade III/IV AEs attributed to Pegintron were neutropenia (10%), and myalgia, depression and rash (4% each); other common AEs included fatigue (35%), myalgia (23%), flu-like symptoms (21%) and depression (17%). Ten pts (13%) have withdrawn from study: 2 withdrew consent, 5 due to toxicity (pancreatitis, GI upset, rash, high amylase and fatigue), and 3 for failing to consistently achieve BCR-ABL 90% of assigned NIL/IM and Pegintron doses. This interim analysis suggests that combination therapy with NIL and Peg-IFN leads to favourable rates of molecular responses when compared with with NIL monotherapy (Table 1). While the majority of patients did not durably tolerate full dose Pegintron, there was minimal interference with TKI dose intensity. Longer term results, and impact upon treatment free remission outcome of this combination is awaited. Disclosures Yeung: Pfizer: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Specialised Therapeutics Australia: Honoraria; Amgen: Honoraria. Grigg:Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Shanmuganathan:Janssen: Honoraria; Royal Adelaide Hospital Research Fund: Other: Scholarship; Novartis: Honoraria, Other: Travel sponsorship; Bristol-Myers Squibb: Honoraria, Other: Travel sponsorship. Reynolds:Novartis: Equity Ownership, Other: former employee of Novartis AG and holds stock in the company. . Ross:BMS: Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding. Yong:Celgene: Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. White:Novartis: Honoraria, Research Funding; BMS: Research Funding. Branford:Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cepheid: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hughes:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: 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.