We evaluated the tolerability and efficacy of pegylated interferon alfa-2B (peg-IFNα; PegIntron, MSD) combined with nilotinib in the Australasian Leukaemia and Lymphoma Group CML11 (Pinnacle) study. This phase II study started patients on nilotinib 300 mg twice daily. Subcutaneous peg-IFNα was added at 30-50 50 μg/week from 3 months until 24 months as tolerated. Sixty patients were enrolled with a median age of 48.5 years (range 19-72); 45% were female. With a median follow-up of 60 months, 40 patients (67%) remain on study. The proportion of patients who received ≥50% and ≥85% of their assigned peg-IFNα doses were 58% and 35% respectively. Common reasons for peg-IFNα discontinuation were mood disturbance (5), thyroid disease (4) and myalgia (4). The cumulative incidence of Major Molecular Response (MMR, BCR::ABL1≤0.1%) was 87% by 12 months; Molecular Response 4.5 (MR4.5, BCR::ABL1≤0.0032%) incidence at 24 and 60 months was 55% and 82% respectively. Thirty-seven patients (62%) had MR4.5 for >24 months, 14 of whom attempted treatment-free remission (TFR); 13 remained in TFR at a median follow-up of 32 months. CML11 demonstrated that peg-IFNα with nilotinib leads to high rates of molecular response, with tolerability similar to prior studies. Trial registration ANZCTRN12612000851864.

Despite an increasing desire to use historical cohorts as “synthetic” controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012–2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

Background: Dasatinib treatment leads to excellent molecular responses in chronic phase chronic myeloid leukemia (CP-CML) but at 100mg leads to a substantial risk of pleural effusions, which may be higher in the elderly. Rousselot et al (BJH 2021) suggested this risk may be mitigated through dose modifications as guided by trough levels (Cmin). Aims: The CML12 (DIRECT) study, run by the ALLG, is a single arm phase II study, aiming to minimise dasatinib related toxicity whilst preserving efficacy, through dose adaptation as guided by dasatinib trough levels. We report here the primary end point - cumulative incidence of pleural effusion (PEf) at 24 months (mos) and key efficacy secondary end points. Methods: DIRECT enrolled newly diagnosed CP-CML pts. The first 34 patients (pts) were aged >60 years (yrs), after which the protocol was amended to include pts aged >18 yrs at the recommendation of the trial management committee. All pts started on dasatinib 100mg QD, with Cmin taken at 7, 28, 56 & 90 days, then every 3 mos hence. Pts sequentially dose reduced to 70mg, then to 50mg QD, for Cmin >3nM, within the first 2 mos, prior to assessment of early molecular response at 3 mos. Doses <50mg QD were permitted temporarily only for toxicity management. Chest x-ray and transthoracic echocardiograms were performed at baseline & 24 mos. Results: Eighty pts were enrolled from 14 centres, with a median follow up of 36 mos (range 24-60). Median age was 64 yrs (range 21-86) and 46% were female. The ELTS score was low and intermediate in 54% and 34% respectively, high in 5% and missing in 8%. Cmin and treatment assigned at various timepoints are detailed in Table 1. Older patients had higher Cmin, particularly prior to dose adjustments. The majority of pts were dose reduced to 50mg QD. Fifteen cases of pleural effusion (PEf) occurred, 5 within the first mo, and 12 in total by 24 mos; 3 were asymptomatically detected on chest x-ray. The cumulative incidence of PEf by 24 mos was 15% overall (95% CI 8-25%, Fig 1); with values of 7.6%, 14.3% and 45.5% respectively in patients <60 yrs, 60-75 yrs and ≥75 yrs. The Cmin prior to the PEf was >3nM in 8/15 pts. At 24 mos, 59 (74%) of pts remained on dasatinib. Reasons for discontinuation were intolerance / adverse events (AE) (n=15, 19%); treatment failure (n=4, 5%); death (n=1, 1%) and consent withdrawn (n=1, 1%). AEs leading to discontinuation were PEf (n=6, 7.5%) pulmonary hypertension (n=4, 5%; 2 reported as SAEs), pericardial effusion (n=2, 2.5%) and cardiac failure (n=2, 2.5%). There were no cases of peripheral vascular disease or strokes. An early molecular response (BCR::ABL1 <10% IS at 3 mos) was achieved in 77 pts (96%). Cumulative incidence of MMR (<0.1%) by 12 and 24 mos were 75% (95% CI 66-84%) and 92% (95% CI 86-97%), respectively; MR4.5 by 24 and 48 mos were 48% (95% CI 38-60%) and 76% (95% CI 64-90%), respectively. No patient progressed to AP/BC on or off study. Three pts have died of non CML-related causes (infection n=2; biliary carcinoma n=1). Image:Summary/Conclusion: High rates of MMR/MR4.5 were achieved, despite significant dose reductions, according to target drug levels over the first 2 months. Toxicity profile was also broadly favourable. However, such adaptive approaches had limited capacity to influence early development of PEf. A strategy using lower starting doses, with escalation for failure to achieve molecular targets, may further minimise toxicity, especially in the elderly.

Background Clinical trials investigating novel therapies in relapsed/refractory acute myeloid leukemia (AML) are challenged by rapid disease progression, severe cytopenias and a high frequency of infectious complications, limiting the capacity of such trials to determine efficacy and hematologic tolerance for new drugs and combinations. Guidelines for monitoring measurable residual disease (MRD) and defining MRD relapse have been established (Heuser, Blood 2021), with MRD relapse known to precede clinical relapse by 3-4 months (Ivey, NEJM 2016). A prospective pilot study utilizing low-dose cytarabine (LDAC) plus venetoclax (VEN) for patients with MRD relapse or oligoblastic relapse (5-15% marrow blasts) demonstrated a high response rate and durable outcomes (Tiong, ASH 2021). To extend this concept to include a broader range of targeted drug combinations directed against MRD relapse, we developed the Australasian Leukaemia and Lymphoma Group (ALLG) AMLM26 INTERCEPT study, a multi-domain, multi-arm, platform trial enabling proof-of-concept (POC) efficacy and tolerability to be obtained for multiple therapies in parallel in the setting of MRD relapse. Study Design and Methods Figure 1 summarizes the trial schema. The INTERCEPT trial (ANZCTR: ACTRN12621000439842), due activation in August 2022, is sponsored by the ALLG and conducted in partnership with the ALLG sites and the MD Anderson Cancer Center, U.S. The trial incorporates 2 phases, an MRD Monitoring Phase, and a Treatment Phase. Patients in first or second remission consent to a Master Protocol linked to a coordinated MRD monitoring framework to track FLT3-ITD, RUNX1::RUNX1T1, CBFB::MYH11, NPM1, KMT2A::X and aberrant myeloid immunophenotype. In patients in whom pre-leukemic clonal hematopoiesis is excluded by reduction of variant frequency in remission to <2.5%, IDH1 and IDH2 are also tracked. For molecular markers, MRD relapse is defined according to ELN recommendations (a log10 increase in serial MRD confirmed by repeat testing on concordant tissue). Flow cytometric detected disease for the INTERCEPT study is defined as an aberrant MRD phenotype ≥0.1% confirmed on repeat testing. MRD relapse is confirmed by a central laboratory and eligibility adjudicated by a blinded MRD reference committee. For the Treatment Phase, a clinical Trial Management Committee (TMC) will apply a pre-determined set of clinical decision rules to direct allocation of patients to the most applicable treatment "domain", based on review of prior therapy, baseline molecular profile and MRD relapse characteristics. For example, a patient with rising FLT3-ITD MRD meeting relapse criteria may be allocated to treatment with gilteritinib + VEN, rising IDH1 mutation to ivosidenib + VEN, rising KMT2A::X to SNDX-5613, rising NPM1 to LDAC + VEN or alternatively, to SNDX-5613. Where no specific targeted treatment is available, patients will be randomly allocated to non-targeted therapies, if more than one applicable arm exists, to arms including sabatolimab, sabatolimab + azacitidine, ASTX727 + VEN or LDAC + VEN. Future treatment options can be seamlessly incorporated in the INTERCEPT framework by amendment of the Master Protocol and addition of new Therapy-Specific Protocol Appendices (TSPAs). Each TSPA outlines specific eligibility criteria, dose schedules, study conduct and the statistical plan for each treatment arm. Patients may also be allocated to a morphologic relapse stratum, if MRD relapse was not captured by MRD surveillance. This will enable comparison of treatment tolerance and response at MRD vs morphologic relapse. If progression occurs with one treatment arm (including MRD relapse), the protocol allows the same patient to be transitioned to an alternative treatment arm if eligibility criteria are met. The primary objective is to determine if novel treatment options can produce an MRD response rate of ≥40% as determined by a Bayesian Proof of Concept design in each domain. The primary endpoint is MRD response (≥1 log10 reduction in molecular MRD or flow MRD<0.1%) within 100 days of the first dose of study drug. MRD responses will be determined centrally. Key secondary endpoints will be nadir MRD response, MRD clearance rate, median time to and duration of MRD response, relapse-free survival, overall survival and quality of life measures. Exploratory objectives will include analysis of drug resistance mechanisms and correlates of response. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Two oral hypomethylating agents, oral azacitidine (CC-486) and decitabine/cedazuridine (ASTX727), have recently entered the clinical domain. CC-486 has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia in complete remission, whereas the combination of decitabine with cedazuridine, a cytidine deaminase inhibitor, is indicated for the treatment of adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia with intermediate-1, or higher, International Prognostic Scoring System risk. This article briefly summarizes the clinical development of both drugs, the pivotal studies that led to their approval and some of the issues faced in extending the use of these drugs to other indications.

Abstract 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

We present a retrospective multicenter study of pralatrexate treatment outcomes in an Australian practice setting for patients with relapsed/refractory T-cell lymphoma who had failed 1+ systemic therapies, treatedviaa compassionate access program. Endpoints assessed included response rates, toxicities, and subsequent therapies. Progression-free survival (PFS), time to next treatment (TTNT), event-free survival (EFS), overall survival (OS), and time to best response, were assessed by Kaplan-Meier analysis. The study included 31 patients, with median age 69 years. We demonstrated ORR of 35.5% (n = 11), including 4 complete responses (13%) and 7 partial responses (23%). The predicted median OS was 10 months, with EFS of 9 months, and PFS of 9 months. Median TTNT was 8 months. Mucositis was the most commonly observed toxicity. This study - the second largest real-world cohort reported to date - underscores the importance of pralatrexate in relapsed/refractory T-cell lymphoma, as well as its acceptable toxicity profile.

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 <50% (Fig 1A). There was no difference between patients who had >85% of their assigned dose versus those wwho took <85% with respect to age or sex. The median duration of Pegintron exposure was 15 mths (Range 1-21 months). 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 <1% at 24 mos, 1 transformed to AP after study withdrawal, and 1 was refractory to all TKIs and received an allograft. At 12 mths, MMR (BCR-ABL ≤ 0.1%) and MR4.5 (BCR-ABL ≤ 0.0032%) rates were 78.3% (95% CI 65.3-88.2; Fig 1C) and 43.3% (95% CI 30.1-57.3%; Fig 1D), respectively. At 24 mths, MR4.5 was 50% (95% CI 36.6-63.4%). No BCR-ABL mutations were reported on study. Three pts lost MMR - 2 were transient; the other was associated with non-compliance. Current TKI treatment for pts on study is NIL (n=37; 62%) and IM (n=5; 8%). 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 <50mg/day were permitted temporarily only for toxicity management. 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 <0.0032%; 32%). The cumulative incidence of MMR by 12 months was 88% (80% CI 75-96%). There was no association between dasatinib dose and molecular response. 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.

A 74-year-old man was referred from another hospital with a possible incarcerated hernia after presenting with nausea, vomiting, weight loss and an umbilical protuberance (top left). His past medical history included chronic lymphocytic leukaemia (CLL) treated with fludarabine, cyclophosphamide and rituximab (FCR) chemo-immunotherapy 4 years earlier. Staging computed tomography/positron emission tomography (CT/PET) on arrival at our institution demonstrated extensive, highly 18F-fluorodeoxyglucose (FDG)-avid lymphadenopathy above and below the diaphragm and extranodal disease in the right anterior chest wall, omentum and peritoneal soft tissue as well as a large mesenteric nodal mass in direct communication with a large para-umbilical mass (Sister Mary Joseph nodule)(bottom left). Excisional biopsy of a right inguinal lymph node confirmed diffuse large B-cell lymphoma. Immunohistochemistry showed a germinal centre subtype and a ‘triple expressor’ phenotype (BCL6, BCL2 and MYC positive) with a proliferation fraction (Ki67) of greater than 90%. A diagnosis of Richter syndrome presenting as a Sister Mary Joseph nodule was made. He was treated with dose adjusted rituximab, etoposide, prednisolone, vincristine, cyclophosphamide and doxorubicin (DA-R-EPOCH) resulting in complete resolution of the umbilical nodule clinically and radiologically (top and bottom right). Sister Mary Joseph (peri-umbilical) nodule is a rare clinical sign, most commonly associated with gastrointestinal or genitourinary malignancy where it occurs in 1–3% of cases. When present, it generally reflects advanced malignancy unsuitable for resection and carries a bleak prognosis. Richter syndrome refers to the development of an aggressive B-cell lymphoma in the setting of underlying CLL, this occurring in up to 10% of CLL cases and carrying a poor prognosis. This case highlights the importance of considering lymphoma in the differential diagnosis of umbilical mass lesions.

Deep molecular response in chronic phase chronic myeloid leukaemia (CP-CML) is associated with superior event free survival, provides a platform for treatment free remission and is increasingly being adopted as a goal of therapy. Interferon was a commonly used CML therapy in the pre-imatinib era, exerting direct anti-leukemic activity and immune-stimulatory properties. Combining interferon and tyrosine kinase inhibitors (TKI) may lead to synergistic anti-leukemic effects. We report the interim analysis of the Pinnacle phase II study, combining nilotinib with pegylated interferon alfa-2B (Peg-IFN) in CP-CML, evaluating tolerability of the combination and efficacy as measured by molecular responses.

Internal Medicine JournalVolume 46, Issue 9 p. 1113-1114 Letters to the Editor PET-CT confirmed complete remission and MRD negativity in mantle cell lymphoma patients treated with R-hyper-CVAD results in excellent outcome in the absence of autologous stem cell transplantation: a single-centre case for a transplant-free approach S. Htet, S. Htet orcid.org/0000-0002-4166-7579 Haematology Unit, Cancer Services, University Hospital Geelong, Barwon Health, Geelong, Victoria, AustraliaSearch for more papers by this authorS. Lane, S. Lane Barwon Health Biostatistics Unit, School of Medicine, Deakin University, Geelong, Victoria, AustraliaSearch for more papers by this authorD. Kipp, D. Kipp Haematology Unit, Cancer Services, University Hospital Geelong, Barwon Health, Geelong, Victoria, AustraliaSearch for more papers by this authorH. Rose, H. Rose Haematology Unit, Cancer Services, University Hospital Geelong, Barwon Health, Geelong, Victoria, AustraliaSearch for more papers by this authorP. Campbell, P. Campbell Haematology Unit, Cancer Services, University Hospital Geelong, Barwon Health, Geelong, Victoria, AustraliaSearch for more papers by this author S. Htet, S. Htet orcid.org/0000-0002-4166-7579 Haematology Unit, Cancer Services, University Hospital Geelong, Barwon Health, Geelong, Victoria, AustraliaSearch for more papers by this authorS. Lane, S. Lane Barwon Health Biostatistics Unit, School of Medicine, Deakin University, Geelong, Victoria, AustraliaSearch for more papers by this authorD. Kipp, D. Kipp Haematology Unit, Cancer Services, University Hospital Geelong, Barwon Health, Geelong, Victoria, AustraliaSearch for more papers by this authorH. Rose, H. Rose Haematology Unit, Cancer Services, University Hospital Geelong, Barwon Health, Geelong, Victoria, AustraliaSearch for more papers by this authorP. Campbell, P. Campbell Haematology Unit, Cancer Services, University Hospital Geelong, Barwon Health, Geelong, Victoria, AustraliaSearch for more papers by this author First published: 16 September 2016 https://doi.org/10.1111/imj.13179Citations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume46, Issue9September 2016Pages 1113-1114 RelatedInformation

ObjectivesUsing the prediction of cancer outcome as a model, we have tested the hypothesis that through analysing routinely collected digital data contained in an electronic administrative record (EAR), using machine-learning techniques, we could enhance conventional methods in predicting clinical outcomes.SettingA regional cancer centre in Australia.ParticipantsDisease-specific data from a purpose-built cancer registry (Evaluation of Cancer Outcomes (ECO)) from 869 patients were used to predict survival at 6, 12 and 24 months. The model was validated with data from a further 94 patients, and results compared to the assessment of five specialist oncologists. Machine-learning prediction using ECO data was compared with that using EAR and a model combining ECO and EAR data.Primary and secondary outcome measuresSurvival prediction accuracy in terms of the area under the receiver operating characteristic curve (AUC).ResultsThe ECO model yielded AUCs of 0.87 (95% CI 0.848 to 0.890) at 6 months, 0.796 (95% CI 0.774 to 0.823) at 12 months and 0.764 (95% CI 0.737 to 0.789) at 24 months. Each was slightly better than the performance of the clinician panel. The model performed consistently across a range of cancers, including rare cancers. Combining ECO and EAR data yielded better prediction than the ECO-based model (AUCs ranging from 0.757 to 0.997 for 6 months, AUCs from 0.689 to 0.988 for 12 months and AUCs from 0.713 to 0.973 for 24 months). The best prediction was for genitourinary, head and neck, lung, skin, and upper gastrointestinal tumours.ConclusionsMachine learning applied to information from a disease-specific (cancer) database and the EAR can be used to predict clinical outcomes. Importantly, the approach described made use of digital data that is already routinely collected but underexploited by clinical health systems.

Abstract Background Chimerism analysis is routinely performed following allogeneic haemopoietic stem cell transplantation (allo HSCT) as a means of monitoring donor engraftment and relapse risk, although its role in the management of allografted myeloma patients is controversial. Multiparameter flow cytometry (MFC) assessment of minimal residual disease has been demonstrated to predict outcome following myeloblative autologous stem cell transplantation (ASCT) in multiple myeloma (MM). Relapse and disease progression is the principle cause of allograft failure and the detection of minimal residual disease (MRD) following tandem autologous/non-myeloablative(NMA) allo HSCT may potentially identify patients at risk of early relapse and provide a platform for early post-allograft therapy designed to further cytoreduce or enhance alloreactive T cell function and graft versus myeloma effect. Aim To evaluate the impact of MRD assessment performed at 3 months post-allo HSCT on PFS and OS and document the incidence and kinetics of full donor chimerism (FDC) in a cohort of myeloma patients undergoing tandem ASCT/outpatient non-myeloablative (NMA) allogeneic HSCT for MM. Methods Retrospective analysis of 33 MM patients referred to our centre for tandem ASCT/outpatient NMA HSCT between May 2008 and December 2012. Patients were transplanted as part of their front line management (upfront) (n=18) if they had one or more high risk disease features (poor prognosis cytogenetics/FISH abnormalities, elevated LDH, stage III disease or less than a PR following a novel agent-containing induction regimen) or as a ‘deferred’ procedure (n=15), if relapsing/progressing after an initial ASCT and maintenance/consolidation. Allo HSCT was undertaken as an ambulatory procedure and conditioned with oral fludarabine 48mg/m2 on days -4 to -2 and 2Gy TBI on day 0 followed by donor stem cell infusion, with a target CD34 dose of 2 x 106/kg and T cell dose of 3 x 108/kg. Sequential peripheral blood monitoring of CD3+ and CD33+ donor-specific chimerism was performed on days 30, 60, 90, 180 and 365 following allo HSCT. Bone marrow samples were collected for MRD analysis using MFC incorporating a CD56/CD19/CD45 panel following CD38/CD138 gating on plasma cells. MRD assessment was performed every 3 months during the first 12 months, 6 monthly during the second year and annually thereafter. Results The median age for the entire cohort (M 19, F 14) was 52 years (range 39-65) and the analysis performed after a median follow up of 719 days (50-1733). All patients were transplanted using matched sibling (20/33) or unrelated donors (13/33). Non-relapse mortality was 0% at 1 year and 6% overall. At the time of analysis, 26 (79%) patients were alive including 15 (45%) in CR. The median PFS for all patients was 2.8 years and although the median OS for the entire cohort has not been reached, the estimated probability of overall survival at 4 years is 67% (95% CI: 38-85%). 29/33 (88%) patients had MRD assessments performed at least once post-allo HSCT and 4 patients progressed within 3 months prior to MRD evaluation. At the first 3 month assessment, 11/29 (38%) were MRD +, 12/29 (41%) were MRD – , results were unavailable in 3/29 (10.5%) and 3 (10.5%) patients had morphological evidence of disease. Patients achieving MRD negativity at 3 months had superior PFS in comparison to those who remained MRD positive (median 2.81 years v 1.02 years; p=0.01) but this has yet to translate into an OS advantage. The MRD + patients transplanted as a deferred procedure (n=6) had a median PFS of less than 6 months (0.47 years), suggesting this subset of patients have a particularly poor outcome, although overall numbers are insufficient to directly compare outcome according to MRD status and transplant timing. 30 (91%) patients achieved FDC (16 and 14 in the upfront and deferred groups respectively) with 2 patients not assessed. The median time to FDC for the entire cohort was 180 days (range 30-730) and there was no significant difference according to transplant timing or relationship between FDC and MRD status, GVHD, PFS or PS. Conclusion The majority of patients undergoing outpatient-based tandem ASCT/NMA allo HSCT for myeloma achieve FDC. MRD status as assessed by MFC at 3 months post-allo HSCT appears to predict PFS and may be a useful early trigger for additional post-allograft therapy, particularly in patients with high risk disease or those transplanted later in their disease course. Disclosures: Spencer: Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees.