ABSTRACT:The purpose of this study was to explore and determine the optimal landmark for defining complete remission after intensive induction therapy that best correlates with long-term survival outcome among patients with newly diagnosed acute myeloid leukemia.

Asciminib, a Myristoyl Pocket BCR::ABL1 inhibitor, recently demonstrated its safety and efficacy in newly diagnosed CP-CML in the Phase III ASC4FIRST (Hochhaus, 2024), and the phase II ALLG CML13 ASCEND studies. Here, we update the ASCEND trial outcomes out to 24 months (mos) including molecular response and outcomes in patients (pts) failing asciminib or with suboptimal responses, and those with BCR::ABL1 mutations. In ASCEND, pts started asciminib (ASC) 40mg twice a day (BID) at diagnosis and switched to 80 mg daily after 12 mos. Pts with treatment failure (BCR::ABL1 >10% at 3 or 6 mos; BCR::ABL1 >1% at 12 or 18 mos) continued ASC, and add either imatinib, dasatinib (DAS) or nilotinib, according to physician preference. Pts without treatment failure, but failed to achieve MMR (BCR::ABL1 ≤0.1%) at 12 mos, or MR4 (BCR::ABL1 ≤0.01%) at 18 mos, could double their ASC dose to 80mg BID. The co-primary end points were Early Molecular Response (EMR, BCR::ABL1 ≤10% at 3 mos) and MMR by 12 mos. ASCEND enrolled 101 pts at 14 Australasian sites. The co-primary endpoints, EMR (BCR::ABL1 ≤10% by 3 mos) and MMR by 12 mos, were achieved in 93% and 79%, respectively. The most common AEs were hypertension (22%) and increased lipase (21%). With a median follow up of 28 mos (range 0-42), 20 pts have discontinued ASC due to: loss to follow up/consent withdrawn N=5; loss of response N=5; lipase elevation N=3; EMR failure N=2. cytopenia N=2; pancreatitis N=1; lymphoid blast crisis N=1 (the only progression event); enrolled but never started N=1. No deaths have been reported. A landmark analysis at 18 mos of 95 pts showed that 25 (26%), 49 (52%) and 77 (81%) achieved MR4.5, MR4 and MMR respectively. At 24 mos (n=76), 24 (32%), 44 (58%) and 62 (82%) were in MR4.5, MR4 and MMR respectively. Only 5 pts had high ELTS risk - 3/5 were in MMR at 12 mos, and 0/5 in MR4 at 18 mos. Three pts were eligible for combination therapy due to treatment failure. Pt 69 had BCR::ABL1 of 24% at 3 mos, on the background of cytopenia from ASC. MR2 (BCR::ABL1 ≤1%) was achieved after switching to dasatinib, maintained at last follow-up (27 mos). Pt 86 had BCR::ABL1 of 210% at 3 mos despite full dose ASC, had grade III headaches with combination ASC/DAS, subsequently failed 3 therapies, then received an allogeneic stem cell transplant (ASCT). Pt 87 had BCR::ABL1 of 1.1% at 12 mos; combination ASC/DAS was interrupted by lipase elevations. MR2 has been achieved at month 18 with DAS monotherapy. Six pts had loss of molecular response - all had MR2 or better at 3 mos, and all but one had low ELTS risk. Pt 26 had BCR::ABL1 of 0.37% at 3 mos, then lymphoid blast crisis with A337T/V & P465S mutations at 6 mos, and has subsequently had ASCT post chemotherapy. Pt 34 achieved a BCR::ABL1 nadir of 0.067% at 6 mos, rose to 0.28% with loss of MMR at 9 mos, without BCR::ABL1 mutations, and has since regained MMR on DAS. Pt 42 was high ELTS, lost MR2 at 6 mos with a V506L mutation, with BCR::ABL1 rising from a nadir of 0.2% to 49%. They switched to DAS and achieved MR4 at 14 mos. Pt 59 had loss of MMR at 6 mos with a A337T mutation without further follow up. Pt 88 achieved MR4.5 at 3 mos, then lost MMR at 12 mos with BCR::ABL1 of 0.16% and T315I (35%) / M224V (70%) mutations in the P-loop domain; ponatinib 45mg for 6 mos has re-established MMR. Pt 101 achieved MR4 at 3 mos, then lost MR4 at 18mo with BCR::ABL1 of 0.066% and A337T; further follow up on DAS is pending. Thirteen pts failed to achieve MMR at 12 mos but with BCR::ABL1 ≤1%: 7 had ASC dose increase to 80mg BID, of whom 5 have subsequently achieved MMR after 3 - 18 mos. Five continued ASC at 40mg QD, of whom 2 subsequently achieved MMR after 6 mos. Thirty-three pts failed to achieve MR4 at 18 mos, (including 3 pts without MMR, with BCR::ABL1 0.12%, 0.28% & 0.31%); 21 of whom had follow up at 24 mos. In this latter cohort, 3 of 12 pts with a dose increase to 80mg BD achieved MR4; one of 9 who remained on 80mg QD achieved MR4. In conclusion, ASC is associated with a high rate of molecular response. Previous studies have suggested EMR achievement significantly protect against the development of secondary resistance, though our results suggest continued vigilance is warranted. Pts without MMR at 12 mos may achieve this milestone with continuing treatment, and numbers are too small to assess the benefit of dose escalation. BCR::ABL1 mutation acquisition rates appears similar to second generation TKIs in the frontline setting; these were mostly myristoyl pocket mutations which have so far responded well to salvage with DAS.

Coronavirus-19 (COVID-19) mortality rates among haemopoietic stem cell transplant (HSCT) patients are high, ranging between 20% and 40%. We prospectively evaluated the mortality outcomes of COVID-19 in Western Australian HSCT patients. A total of 32/492 (6.5%) HSCT recipients contracted COVID-19 during the study, of whom 30/32 (94%) developed mild or asymptomatic disease. Two allogeneic HSCT patients were hospitalised for severe COVID-19; one patient died. Stringent healthcare, social isolation practices, aggressive vaccination programmes and rapid access to COVID-19 antivirals may have promoted mild COVID-19 illness in Western Australian HSCT patients, resulting in one of the lowest COVID-19 mortality rates in HSCT recipients worldwide.

ATP-competitive BCR::ABL1 inhibitors are effective in many patients with CP-CML patients. However, a significant minority experience treatment failure with currently available drugs due to resistance or toxicity. Asciminib, a first-in-class myristoyl site BCR::ABL1 inhibitor, is now indicated in many jurisdictions for CP-CML after ≥2 prior lines of treatment. The Australasian Leukaemia and Lymphoma Group (ALLG) CML13 ASCEND-CML trial assessed its tolerability and efficacy in the frontline setting, where data are scarce. ALLG CML13 is a prospective open-label phase II study that completed enrolment in Dec 2022 at 14 sites. Patients commenced asciminib 40mg twice a day (BID) at time of diagnosis, and were assessed according to optimal 2020 ELN targets ( BCR::ABL1 ≤10%, ≤1% & ≤0.1% at 3, 6, 12 months respectively); and ≤0.01% at 18 months. Patients in Major Molecular Response (MMR; BCR::ABL1 ≤0.1%) at 12 months were switched to 80mg QD for ease of administration. Patients with treatment failure ( BCR::ABL1 >10% at 3 or 6 months; BCR::ABL1 >1% at 12 or 18 months) continued asciminib, with additional imatinib or dasatinib or nilotinib, according to physician preference. Patients with a suboptimal response at 6, 12, or 18 months, but without treatment failure, continued asciminib but with the dose doubled to 80mg BID. This is a pre-specified analysis of the co-primary end points: i) final analysis of Early Molecular Response (EMR, BCR::ABL1 ≤10% at 3 months) and ii) interim analysis of MMR by 12 months. By data cut-off in May 2023, 101 patients had median follow-up of 20 (0-29) months (including 1 patient who enrolled but never started therapy due to elevated lipase at baseline). Grade 3/4 adverse events (AEs) included neutropenia and thrombocytopenia, (reported in 6% and 5% of patients, respectively); increased lipase/amylase reported in 8% (clinical pancreatitis reported in 2%), anaemia (2%), infection (2%) and 1% each of increased AST/ALT, back, abdominal and chest pain from pulmonary embolism. The only treatment emergent vascular event was a stroke, reported in a male patient aged 73 with pre-existing diabetes and hypertension, after 20 months of asciminib. Fifteen patients discontinued asciminib: 6 due to AEs (2 with persistent cytopenia requiring an allograft, 3 with recurrent asymptomatic lipase elevation, 1 with pancreatitis); 3 lost to follow-up; and 6 due to resistant disease (1 confirmed loss of MMR at 9 months, without ABL1 mutation; 1 transformed to lymphoid blast crisis at 6 months with myristoyl site mutations A337T/V and P465S; 1 loss of MMR at 6 months with A337T mutation; 1 loss of MR2 with V506L; and 2 with failure to achieve EMR - below). No other transformation occurred. During the first 3 months of treatment, 85% of patients had an assigned dose density of >90%; 9% of patients dose reduced to <66%. EMR was achieved by 94/101 patients (93.1%; 96% CI 86-97%): 1 patient never started treatment, 1 patient missed this assessment, 3 patients had withdrawn by this timepoint, and 2 had BCR::ABL1 of 24% and 210%, respectively. Neither of the EMR failure patients had myristoyl site mutations; both were subsequently intolerant of combination TKI/asciminib therapy because of cytopenia and headaches, respectively and are now on dasatinib monotherapy. Six patients dose escalated and remain on asciminib 80mg BID: 3 after failing to achieve MMR by 12 months, & 3 failing to achieve MR4 after 18 months; 2 have since achieved their targets. By 3 months, 48/101 (48%) patients achieved MMR and 12 (11.9%) achieved MR4. Considering only patients with >12 months of follow up, the interim rate of MMR by 12 months is 62/75 patients (82.7%; 98% CI 70-92%). With “off-protocol for any reason” as the competing risk, the cumulative incidences of MMR & MR4.5 by 12 months were 81.1% & 32.3% respectively (Figure). ASCEND is one of the first studies using frontline asciminib, with excellent achievement of EMR and MMR, and low transformation rate. Rates of MMR at 12 months are comparable to those reported with second generation TKIs, though achievement of deeper responses appears more rapid with asciminib. Treatment was well tolerated in general: majority of AEs were grade I/II events that did not result in treatment discontinuation, and only one vascular event was observed. Early achievement of MMR and MR4 may accelerate eligibility for, & increased success of, treatment-free remission attempts.

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.

We present an analysis of 98 consecutive patients with peripheral T-cell lymphoma (PTCL) treated over a 10-year period within Western Australia. The most common frontline therapies were CHO(E)P (47%), HyperCVAD (21%), and reduced intensity therapy or supportive care alone (19%). Median and 4-year overall survival (OS) for the whole cohort were 1.59 years and 34%. Amongst CHO(E)P and HyperCVAD-treated patients, elevated LDH, advanced stage, IPI >1, and non-ALK + ALCL histology predicted inferior progression-free survival (PFS). Inferior OS was predicted by elevated LDH, age >60, IPI >1, and non-ALK + ALCL histology. Response rates and PFS were not significantly different between patients treated with CHO(E)P or HyperCVAD. OS was longer in the HyperCVAD group, however this was not significant on multivariable analysis and appears to relate to the younger age and more aggressive therapy at relapse in this group. Our data confirmed the prognostic utility of the IPI in patients with PTCL and do not demonstrate a clear benefit of HyperCVAD.

Abstract Background There has been concern that patients with malignant disease from remote and regional country areas may have adverse outcomes compared with those from cities. Western Australia (WA) with an area of 2,526,786 square kilometers, is one third the size of Australia. It has a population of 2.6 million of which 92% live in the capital city Perth and the southwest corner. In WA, multiple myeloma is managed in tertiary public hospitals and private physician practice located in Perth. While oral based immunomodulators and alkylators are readily delivered in the regional areas, patients travel to Perth for parenteral chemotherapy and stem cell transplantation. The WA state government subsidizes transport and accommodation for patients from regional areas to travel to Perth for treatment and clinical review via the Patient Assisted Travel Scheme (PATS). Telehealth through video conferencing is also used for review of patients on oral-based anti-myeloma treatment or during surveillance periods to avoid expensive and time-consuming travel to Perth. The Royal Flying Doctor Service (RFDS), a non-profit medical organization, provides prompt transfer of unwell patients from regional and remote areas of WA to Perth. Pathology services in remote regions are provided by the publicly funded PathWest organization. Method We retrospectively reviewed the survival outcomes of patients with multiple myeloma in the WA public healthcare system. Patients diagnosed between 2008 to 2017 were included (n=569). Staging information was extracted from the laboratory information system and the cytogenetic database in PathWest. Patient demographics, complications requiring admission, mortality and follow-up data were extracted from the public hospital patient management systems. Patients were segregated into regional or metropolitan by their residential address postcodes. Patients diagnosed and/or followed-up in the private sector were excluded. Survival was analyzed by Kaplan-Meier curves, Log-rank test and Cox proportional hazards model. Result Median age at diagnosis was 67 years old (range 29 to 98), with 56% above 65 years. 56% were males, 44% were females. Overall median survival was 46 months (95%CI:41,52). 1-year, 3-years and 5-years survival rates were 80%, 56% and 30% respectively. 25% (n=143) of patients resided in regional areas. No statistically significant difference in overall survival time between patients from metropolitan and regional areas was identified (p=0.2): 47 months (95% CI:43,54) and 42 months (95% CI: 33,54) respectively. Subgroup analysis also did not find any significant difference in overall survival of each R-ISS staging between metropolitan and regional areas. Discussion This retrospective study provides real-life survival data of of an Australian-based population in a state with a large land mass and low population density outside the capital city. The overall survival of patients living in regional areas was not significantly different from those living in the capital city. This gives credence to the benefit of the WA government supported regional network of travel, accommodation and Telehealth conferencing overcoming the distance barrier in the provision of comprehensive medical care in the management of a hematological malignancy. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Background Peripheral T cell lymphomas (PTCL) are a heterogeneous group of lymphomas that have poor outcomes with current frontline chemotherapeutic strategies. Cyclophosphamide, vincristine, doxorubicin and prednisone, with or without the inclusion of etoposide (CHO(E)P), remains the standard of care, although scarce data exist regarding the benefit of intensive regimens, including hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high dose methotrexate/cytarabine (HyperCVAD). This multicenter study aims to characterize presenting features, prognostic factors and the influence of frontline therapy in patients (pts) with PTCL. Methods We retrospectively analysed presenting features, frontline therapy and outcomes of all pts diagnosed with PTCL at the 3 tertiary referral centers within Western Australia from 2005-2014. Overall survival (OS) and progression free survival (PFS) were calculated by the Kaplan Meier method. Univariate comparisons were made by log rank test and multivariate analysis (MVA) performed using step-wise Cox regression. Comparisons between categorical variables were made using Fisher9s exact tests. Results A total of 98 pts were included in the analysis, with a median follow-up of 4.6 years (range 0.1 - 8.6). Median age was 64 years and 78% presented with advanced stage (III-IV) disease. Complete pt characteristics and histological subtypes are presented in Table 1. Most pts were treated with CHO(E)P (47%) or HyperCVAD (21%), with a smaller proportion receiving reduced intensity chemotherapy (9%), other therapy (12%) or supportive care alone (10%). Four year PFS was 21% (95% CI 12.2 - 29.8%) and 4 year OS was 34% (24.2 - 43.8%). Excluding pts treated with palliative intent, the overall response rate (ORR) was 73%, with a complete response rate (CRR) of 59%. OS was strongly predicted by International Prognostic Index score (IPI) (Figure 1). In MVA, age, elevated LDH and >1 extranodal sites were found to be significantly associated with survival, whereas marrow involvement, B symptoms and stage were not (Table 2). We then restricted the analysis to pts treated initially with either CHO(E)P or HyperCVAD to compare outcomes between these two commonly used regimens at our centers. Response rates were similar with an ORR/CRR to CHO(E)P of 78%/67%, and 76%/61% to HyperCVAD (p=0.90). Likewise, 4yr PFS did not differ significantly between the two regimens - CHO(E)P: 20% (6.9 - 33.1%) vs. HyperCVAD: 33% (12.6 - 53.4%), p = 0.30. On univariate analysis (UVA), 4yr OS was 27% (13.3 - 40.7%) for CHO(E)P and 62% (40.4 - 83.6%) for HyperCVAD, p = 0.042. On MVA adjusted for age, LDH and extranodal sites, there was no significant difference between treatment groups (Table 3). Consolidation stem cell transplantation (SCT) following response to first line chemotherapy was performed in only 6 (10%) pts and occurred more frequently in pts initially treated with HyperCVAD (4/16 [25%] vs. 2/36 [6%], p=0.074). In relapsed or refractory disease, pts treated initially with HyperCVAD were more likely than those treated with CHOP to receive salvage chemotherapy (11/12 [92%] vs. 20/33 [61%], p=0.046) and have SCT incorporated into subsequent lines of therapy (7/12 [58%] vs. 4/33 [12%], p=0.003). Pts treated with reduced intensity chemotherapy had poor outcomes, with median OS of 3 months. Those receiving only supportive care had a median OS of 0.8 months. Conclusion Whilst pts with PTCL presenting with low risk (IPI 0-1) disease have favourable outcomes, the majority present with higher risk disease and have poor long-term survival with current frontline therapy. Survival in our cohort was strongly associated with IPI risk factors including age, elevated LDH and multiple extranodal sites. The use of HyperCVAD did not improve response rate or PFS when compared to CHO(E)P in our pts. The superior OS noted on UVA for this group was lost on MVA, and appears to be explained by selection of younger, fitter pts, more of whom underwent salvage therapy, including autologous or allogeneic SCT, at time of progression. Whilst some expert guidelines support SCT as part of initial therapy (Moskowitz, Blood 2014), this was seldom performed at our centers. Our results do not support the frontline use of HyperCVAD over CHO(E)P in PTCL. Given poor outcomes with current chemotherapeutic options, alternative induction regimens incorporating novel agents are urgently required. Disclosures Cull: Amgen Australia: Other: travel expenses Lugano lymphoma conference 2017; Takeda Australia: Other: travel expenses Highlights of ASH march 2017, Brisbane.

Background: Chronic myelomonocytic leukemia (CMML) is an uncommon and heterogeneous disease with a varying clinical course. Treatment with hypomethylating agents is associated with a low incidence of complete remission and an ongoing risk of transformation to acute leukemia. Treatment strategies for CMML are expanding however allogeneic stem cell transplant (alloSCT) remains the only curative therapy. Transplant outcome data for CMML are limited and often pooled with other myelodysplastic syndromes. This retrospective study aimed at studying the transplant outcomes and identifying prognostic factors for survival and relapse in 57 patients with CMML transplanted in Australia between Jan 2000 and Dec 2013.