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Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft (PDX) resource, and perform integrated genomics, transcriptomics, and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized Phase II-like preclinical trial in PDX, imetelstat effectively diminishes AML burden, and preferentially targets subgroups containing mutantNRASand oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing significant disease control in AML.

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Purpose:Inducible caspase 9 (iCasp9) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9-transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies.Patients and Methods:Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5−1.0 × 106/kg donor-derived iCasp9-transduced T cells on day +25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism.Results:Three patients were enrolled. iCasp9-transduced T cells were readily detectable by 4 weeks post-infusion in all patients and remained at high level (114 cells/μL, 11% of T cells) in 1 patient alive at 3.6 years. One patient developed donor-derived Epstein–Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD), which was followed by a marked expansion of iCasp9 T cells and cytokine release syndrome (CRS). These iCasp9-transduced T cells infiltrated the affected lymph nodes and secreted IFNγ and IL-10. They peaked at 1,848 cells/μL and were found to be monoclonal by T-cell receptor (TCR) clonotype and oligoclonal by viral integrant analysis, representing a 6-log in vivo expansion of the dominant T-cell clone. These T cells were not autonomous and contracted with the resolution of EBV-PTLD, which did not recur.Conclusions:iCasp9-transduced T cells could persist long-term. They retained very high in vivo clonotypic proliferative capacity and function, and could cause CRS in response to de novo lymphoma development.

Background: There is limited research on the relationship between side of insertion of central venous catheter (CVAD) and bloodstream infection risk in patients with cancer. Aim: To conduct an exploratory analysis of data from a randomized control trial (RCT) and data from a prospective cohort study to compare infection rates for right- and left-sided insertions. Methods: The study populations were patients aged >14 years with cancer from two tertiary hospitals in Brisbane, Australia. The primary endpoint was catheter-associated bloodstream infection (CABSI) adjudicated by blinded assessors. For the RCT, randomized intention-to-treat comparisons were conducted between left- and right-side allocated insertion for early (≤14 days) and late (>14 days) infection using Cox proportional hazards regression. The RCT data were also combined with cohort study data collected from one of the hospitals prior to the RCT and non-randomized comparisons conducted between left- and right-sided insertions. Findings: In 634 randomly allocated CVADs there were 141 CABSIs. Analysis showed strong evidence of right-side allocated insertions having an increased risk of early infection by 2.5 times (95% confidence interval (CI): 1.3–4.7); however, there was no evidence of increased risk for late infection (hazard ratio: 1.06; 95% CI: 0.71–1.59). Results from analysis of the RCT and cohort study data combined (2786 CVADs and 385 CABSIs) were similar. Conclusion: There appears to be an increased risk of CABSI in patients with cancer for CVAD inserted into the right-side for around two weeks after line insertion. The mechanism underpinning the increased risk is unknown.

PURPOSE Oral mucositis is a common complication in patients undergoing hematopoietic stem cell transplantation. Accurate oral mucositis grading is essential for both clinical practice and oral mucositis research. This study aimed to evaluate the accuracy of daily oral mucositis grading by nurses in a tertiary hospital in Australia. METHODS A retrospective study was undertaken to review the daily patient oral assessment record, including diet, pain, erythema, ulceration and the oral mucositis grade based on World Health Organization (WHO) oral mucositis grading scale. The accuracy of the grade was determined by the observations recorded, and reasons for inaccuracy were documented. Any repetition of the same error in the same patient was noted. RESULTS In total, 6841 oral assessments in 373 patients, conducted between 2017 and 2020, were reviewed. A total of 70% (N = 4781) were graded correctly. Of these, 64% (N = 3043) were grade 0. When the grade 0 scores were excluded, the accuracy of grading was reduced to 46% (N = 1738). Common reasons for incorrect grading included: unable to grade due to diet not specified, no ulceration and no pain was scored grade 1, no ulceration was scored as grade 2-4, oral intake was not taken into account, and pain without ulcer was scored 0. A total of 77% of the errors were repeated in the same patient on consecutive days. CONCLUSIONS Our results suggest there is frequent inaccurate evaluation of oral mucositis and a need for nurse training to accurately assess oral mucositis.

Patients who undergo haematopoietic stem cell transplantation (HSCT) often have multiple health issues following hospital discharge. In many centres, outpatient follow-up is solely conducted by specialist physicians. We aimed to implement and describe the outcomes of a nurse-allied health multidisciplinary clinic. The clinic consisted of six disciplines—nursing, pharmacy, dietetics, physiotherapy, occupational therapy and social work. All allogeneic and high risk autologous HSCT patients were reviewed at 2 weeks after discharge and on day 100 post HSCT, with additional reviews as needed. Occasions of service, interventions, readmission data and physician satisfaction survey were collected prior to and after implementation. Additionally, patient feedback and quality of life survey (FACT-BMT) were collected during the first 6 months. From July to December 2019, 57 patients were reviewed in the clinic (475 reviews, average 8.3 reviews per patient). Common interventions included the following: exercise programs by physiotherapist (n = 111), diet prescription (n = 103), counselling by social worker (n = 53), medication lists provision (n = 51), fatigue management (n = 43) and nurse education (n = 22). The clinic did not reduce patients’ readmission rate; however, positive feedback from patients and physicians were reported. FACT-BMT results demonstrated that there are unmet needs, particularly fatigue management, sexual education and support, body images, back to work support and quality of life improvement. From discharge to day 100, there was no significant improvement in quality of life. This clinic provides an innovative approach to patient-centred care in HSCT. It has been well received by patients who were supported by multidisciplinary interventions.

Australia and New Zealand have achieved excellent community control of COVID‐19 infection. In light of the imminent COVID‐19 vaccination roll out in both countries, representatives of all adult and paediatric allogeneic bone marrow transplant and cellular therapy (TCT) centres as well as representatives from autologous transplant only centres in Australia and New Zealand collaborated with infectious diseases specialists with expertise in TCT on this consensus position statement regarding COVID‐19 vaccination in TCT patients in Australia and New Zealand. It is our recommendation that TCT patients, should have expedited access to high‐efficacy COVID‐19 vaccines given that these patients are at high risk of morbidity and mortality from COVID‐19 infection. We also recommend prioritising vaccination of TCT healthcare workers and household members of TCT patients. Vaccination should not replace other public health measures in TCT patients given the effectiveness of COVID‐19 vaccination in TCT patients is unknown. Furthermore, given the limited available data, prospective collection of safety and efficacy data of COVID‐19 vaccination in this patient group is a priority.

Summary Background A common complication of central venous access devices (CVADs) is catheter-associated bloodstream infection (CABSI). We previously demonstrated that insertion of CVADs on the right side was associated with increased risk of CABSI, and hypothesized that this related to the predominance of right-handedness in the patient population, resulting in greater movement and bacterial contamination. Aim To perform a prospective randomized, controlled, non-blinded study to determine whether the side of CVAD insertion influenced the incidence of CABSI. Methods Adult cancer patients were randomly allocated to either dominant or non-dominant side CVAD insertion. The primary endpoint of the study was the number of line-days until CABSI, determined in a blinded fashion by two assessors. Findings In all, 640 CVADs were randomized to dominant (N = 322) or non-dominant (N = 318) side of insertion, 60% had haematological malignancies, and 40% solid tumours. CVADs were a peripherally inserted central catheter line (67%), tunnelled CVAD (23%), and non-tunnelled CVAD (10%). Twenty-two percent of CVADs were complicated by CABSI. The rate of CABSI per 1000 line-days was 3.49 vs 3.66 in the non-dominant vs dominant group (hazard ratio (HR): 0.91; 95% confidence interval (CI): 0.65–1.28). By multivariable analysis, the rate of CABSI was increased by: use of tunnelled CVADs compared to peripherally inserted central venous catheter lines (HR: 2.05; 95% CI: 1.45–2.91); having a haematological malignancy compared to non-gastrointestinal solid tumours (5.55; 2.47–12.5); but not dominant compared to non-dominant side of CVAD (0.97; 0.69–1.36). Conclusion CABSI in adult patients with cancer was not impacted by whether CVAD insertion was on the dominant or non-dominant side.

PurposeOral mucositis and taste disturbance are common complications during haematopoietic stem cell transplantation (HSCT). This study aimed to review the incidence of severe mucositis and taste disturbance in patients undergoing different HSCT regimens. MethodsThis single-centre retrospective study reviewed daily oral assessment for 467 consecutive patients who underwent different transplant regimens for matched unrelated or related allogeneic HSCT with post-transplant methotrexate, haploidentical or mismatched HSCT with post-transplant cyclophosphamide (PTCy), or autologous HSCT. Oral care and cryotherapy with melphalan were used. Patient demographic data, oral mucositis WHO grade, taste disturbance, use of total parenteral nutrition (TPN) and patient-controlled analgesia (PCA) were collected. ResultsGrade 3-4 oral mucositis was common in myeloablative total body irradiation (TBI) based regimens cyclophosphamide/ TBI (CyTBI) (71%) and fludarabine/ TBI (FluTBI) with PTCy (46%), as well as reduced intensity fludarabine/ melphalan (FluMel) (43%) and carmustine/ etoposide/ cytarabine/ melphalan (BEAM) autologous HSCT (41%). In contrast, Grade 3-4 oral mucositis was less common in reduced intensity haploidentical regimen melphalan/ fludarabine/ TBI with PTCy (19%), all non-myeloablative regimens (0-9%) and high dose melphalan autologous HSCT (26%). TPN and PCA use were correlated to oral mucositis severity. Taste disturbance was common regardless of the regimens (89%, range 71-95%). ConclusionsSevere oral mucositis was associated with myeloablative TBI, methotrexate and melphalan in combination with methotrexate and in BEAM. Use of PTCy was preferable over methotrexate to prevent oral mucositis.

Purpose Oral mucositis is a common complication during haematopoietic stem cell transplantation (HSCT). This study aimed to assess the incidence of severe mucositis in patients undergoing different HSCT regimens. Methods This single-centre retrospective study reviewed daily oral assessment for 467 consecutive patients who underwent different transplant regimens for matched unrelated or related allogeneic HSCT with post-transplant methotrexate, haploidentical or mismatched HSCT with post-transplant cyclophosphamide (PTCy), or autologous HSCT. Oral care and cryotherapy with melphalan were used. Patient demographic data, oral mucositis WHO grade, use of total parenteral nutrition (TPN) and patient-controlled analgesia (PCA) were collected. Results Grade 3–4 oral mucositis was common in myeloablative total body irradiation (TBI)-based regimens cyclophosphamide/ TBI (CyTBI) (71%) and fludarabine/ TBI (FluTBI) with PTCy (46%), as well as reduced-intensity fludarabine/melphalan (FluMel) (43%) and carmustine/etoposide/cytarabine/melphalan (BEAM) autologous HSCT (41%). In contrast, grade 3–4 oral mucositis was less common in reduced-intensity haploidentical regimen melphalan/fludarabine/TBI with PTCy (19%), all non-myeloablative regimens (0–9%) and high-dose melphalan autologous HSCT (26%). TPN and PCA use were correlated to oral mucositis severity. Conclusions Severe oral mucositis was associated with myeloablative TBI, methotrexate and melphalan in combination with methotrexate and in BEAM. Use of PTCy was preferable over methotrexate to prevent oral mucositis.

Introduction Midostaurin is the only approved FLT3 inhibitor for combination with intensive induction and consolidation chemotherapy in newly diagnosed patients with FLT3 mutant AML. The FLT3 inhibitor, sorafenib, was investigated in the randomized SORAML trial (Röllig, Lancet Onc 2015), in combination with intensive chemotherapy (IC) for newly diagnosed adults with AML Methods The Australasian Leukaemia and Lymphoma Group (ALLG) conducted a randomized phase 2 study [ACTRN12611001112954] in 99 adults aged 18-65 years with newly diagnosed FLT3-ITD positive (allelic ratio (AR) ≥0.05) AML to determine whether addition of SOR to IC would improve event-free survival (EFS). The study was powered to identify a 25% increase in 2-year EFS with SOR. Patients 18-55 yrs received induction with IDAC-3 (idarubicin [IDA] 12 mg/m2 D1-3 and ara-C 1.5 g/m2 BD D1,3,5,7); patients 56-65 received 7+3 (IDA 12 mg/m2 D1-3 and ara-C 100 mg/m2 D1-7 IVI). Patients were randomized 2:1 to SOR or PBO 400 mg BD on days 4-10 of induction and each consolidation cycle. Due to the pharmacokinetic interaction between SOR and azoles, antifungal prophylaxis during induction was with AmBisome 5 mg/kg IV twice weekly. For consolidation, patients 18-55 yrs received 2 cycles of IcE (IDA 9 mg/m2 D1-2, ara-C 100 mg/m2 D1-5 IVI and etoposide 75 mg/m2 D1-5), those 56-65 yrs received 2 cycles of IDAC-2 (IDA 12 mg/m2 D1-2 and ara-C 1g/m2 BD D1,3,5). Maintenance was with SOR/PBO 400 mg bd days 1-28 for 12 cycles. Allogeneic HCT (allo-HCT) was at investigator discretion. SOR/PBO was not continued post allo-HCT. The primary endpoint was EFS without censoring for allo-HCT with events defined as failure to achieve complete remission (CR) or CR with incomplete hematologic recovery (CRi), relapse or death. Pre-specified secondary endpoints included overall response rate (ORR) defined as CR and CRi, tolerability, EFS according to FLT3-ITD AR < or ≥ 0.7 and impact of randomization on allograft outcome. Results Between Jan 2013-May 2018, 18 centers randomized 99 patients to induction with either SOR (n=65) or PBO (n=33); one patient later found to be FLT3-ITD negative was excluded. Patient characteristics are shown in Table 1. Treatment arms were balanced apart from fewer patients in the SOR arm with NPM1 mutant AML. Deliverability of therapy was comparable, with commencement of consolidation in 78% and 79% and maintenance therapy in 32% and 27% in the SOR and PBO arms, respectively. The overall response rate (ORR) was high in both arms; 91% in the SOR (CR 80%, CRi 11%) and 94% in the PBO (CR 70%, CRi 24%) arm. In the SOR arm, 5% achieved partial remission, went off study and were deemed treatment failures. With a median overall follow-up of 25 mo, there was no significant difference in EFS (HR 0.87 95% CI 0.50-1.49; P=0.61)(Fig A) or OS (HR 0.70 95% CI 0.38-1.29; P=0.26)(Fig. B), nor in a sensitivity analysis with censoring at HCT. 2 yr EFS was 47.9% (SOR) vs 45.4% (PBO) and 2-year OS 66.8% (SOR) vs 56.4% (PBO). Hematopoietic cell transplant (HCT) in CR1 was performed in 62% and 58% in the SOR and PBO arms, respectively. For patients in CR1, 2 yr OS post-HCT was 78.5% (SOR) vs 54.2% (PBO)(Fig C). Suggestive of an on-target effect against FLT3-ITD, the impact of SOR on OS appeared greater for patients with higher FLT3-ITD AR ≥0.7 (Fig. D) (Table 2). Only one early death (within 30 days) was recorded in each treatment arm. The frequency of grade 3-4 adverse events (AEs) were similar between the two arms, apart from palmar-plantar rash, reported as drug-related in 15.4% and 6.1% pts in the SOR and PBO arms, respectively. Correlative studies will be reported in a companion abstract. Conclusions SOR did not improve EFS when combined with intensive chemotherapy in adults with newly diagnosed FLT3-ITD AML. Although not powered for significance, SOR showed a trend for improved OS among patients with higher FLT3-ITD AR or receiving HCT in CR1. Further exploration of more potent FLT3 inhibitors in the pre- and post-allograft setting are warranted for patients with newly diagnosed FLT3 mutant AML. Acknowledgements: The ALLG AMLM16 trial was funded through an Australian Government NHMRC grant and a research grant from the Leukaemia Foundation of Australia. Bayer supplied sorafenib and Gilead AmBisome. Disclosures Wei: Roche: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; Macrogenics: Honoraria. Enjeti:Novartis: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau; Bayer: Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. D'Rozario:Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS/ Celgene: Membership on an entity's Board of Directors or advisory committees. Marlton:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Verner:Janssen Cilag Pty Ltd.: Research Funding. Hahn:Roche: Honoraria; Astra Zeneca: Honoraria. Hiwase:Novartis Australia: Research Funding. Anstee:Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Levis:FujiFilm: Honoraria, Research Funding; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; Menarini: Honoraria; Astellas: Honoraria, Research Funding. Bajel:Abbvie: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria. Roberts:Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties; Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: Sorafenib for FLT3-ITD AML

Introduction The Australasian Leukaemia and Lymphoma Group (ALLG) conducted a randomized trial (AMLM16) combining the FLT3 inhibitor sorafenib (SOR) or placebo (PBO) with intensive induction and consolidation chemotherapy, followed by 12 months of maintenance therapy in patients with FLT3-ITD mutant AML. The clinical results of the AMLM16 study are detailed in a companion abstract co-submitted to ASH 2020. We hypothesized that the optimal time to administer sorafenib would be d4-10 of induction in order to limit overlap with anthracyclines on d1-3 and to avoid high FLT3 ligand (FLT3L) levels beyond d10, which could abrogate FLT3 on-target activity and diminish the therapeutic index. Key objectives of the correlative studies were to correlate in vivo SOR activity on suppression of FLT3 phosphorylation (P-FLT3) using the plasma inhibitory assay (PIA) with relapse risk and to assess for the presence of FLT3-ITD measurable residual disease (MRD) after therapy. Methods Patients aged 18-65 years with newly diagnosed AML (excluding APML) were enrolled to a National Blood Cancer Registry; those with a FLT3-ITD mutant: wild-type allelic ratio (AR) ≥ 0.05 were eligible for enrolment to the AMLM16 study. Patients were randomized 2:1 to SOR or PBO 400mg orally bd on d4-10 of induction and each consolidation cycle in combination with intensive chemotherapy and for 12 months as maintenance monotherapy. Serum FLT3-L levels were measured by ELISA, SOR and its metabolites by mass spectrometry. SOR mediated inhibition of FLT3 was measured in serum samples using the PIA as previously described (Levis, Blood 2006) in which P-FLT3 inhibition to ≤15% baseline is defined as response. Quantitation of FLT3-ITD levels by NGS was performed at study screening and after each induction and consolidation chemotherapy cycle. Quantitation was by amplicon-based sequencing which detected ITDs >6 bp with a sensitivity of 0.001%: levels below and above this were termed measurable residual disease (MRD) negative and positive respectively. Prepared libraries were sequenced (Illumina) using 150 bp paired-end reads with a minimum coverage of 400,000 reads. Bioinformatics analysis was performed using getITD (Blätte, Leukemia, 2019). Results 98 evaluable patients were randomized to induction with either SOR (n=65) or PBO (n=33) with a FLT3-ITD AR ranging from 0.05 to 8.4. FLT3-ITD AR was ≥ 0.5 or ≥ 0.7 in 48% and 29%, respectively. During induction, FLT3-L levels increased by an average of 150-fold from d4 to d10 and a further 1.6-fold to d15, with a return to baseline by d28. Serial plasma samples to assess PIA were available for 63 patients (Fig A). Response to ≤15% on d10 (relative to d4) was observed in 88% of SOR patients, compared with 4.5% receiving PBO. The relapse risk was 32% and 62% among PIA responders and non-responders, respectively (Fig A). Among patients with PIA response to ≤15% by d10 (the last day of SOR/PBO), only 8.3% had evidence of a sustained PIA response by d15. Reduction of FLT3-ITD to undetectable levels (VAF We compared the relationship between inhibition of P-FLT3 on d10 and bone marrow FLT3-ITD MRD after induction with relapse risk (Fig D, E). In the SOR arm, if P-FLT3 was not reduced to ≤15%, all patients had persistent FLT3-ITD MRD after induction and the relapse risk was 80% (Fig D). In contrast, if P-FLT3 inhibition was ≤15% and FLT3-ITD MRD not detected, the relapse risk was only 20%. In the PBO arm after induction, persistent and undetectable FLT3-ITD MRD (VAF Conclusions These studies demonstrate that in vivo SOR inhibited P-FLT3 to ≤15% during induction in the majority of cases and was associated with reduced relapse risk. Persistent FLT3-ITD MRD post-induction was associated with a high relapse risk in both treatment arms. For patients receiving SOR, failure to reduce P-FLT3 response to ≤15% was associated with a high risk of persistent FLT3-ITD MRD and clinical relapse. Disclosures Anstee: Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Research Funding. Enjeti:Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Bayer: Speakers Bureau; Sanofi: Speakers Bureau. D'Rozario:Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS/ Celgene: Membership on an entity's Board of Directors or advisory committees. Marlton:AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Roberts:Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding; Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties. Wei:Astra Zeneca: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria, Research Funding, Speakers Bureau; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Roche: Honoraria; Macrogenics: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria. OffLabel Disclosure: Sorafenib for FLT3-ITD AML

IntroductionSars-CoV-2 is a novel coronavirus responsible for COVID-19 officially declared pandemic in March 2020. Health systems worldwide responded with swift changes to increase workflow capacity while protecting the vulnerable, including those with cancer. This led to unprecedented and rapid restructuring of health service provision. Published data from the 2003 SARS pandemic focuses on medical and nursing staff, overlooking other departmental employees such as administration officers or food service workers. Our protocol aims to document directives and adjustments communicated to staff in two cancer care departments and correlate this with measures of distress and perceived preparedness across the spectrum of all staff involved in cancer care.Methods and analysisWe use a semiqualitative approach comprising weekly diarising of events and simultaneous staff surveys. Principal investigators will document changes at a metropolitan quaternary cancer centre and a regional cancer centre. Communications, directives and changes will be diarised in real time in four executional domains. Simultaneously, prospective voluntary self-administered online surveys will be conducted at regular intervals by staff. The survey assesses the perceived institutional preparedness and personal well-being, with a combination of Likert scaled and open response questions. A semiquantitative self-assessment of distress adapted from National Comprehensive Cancer Network distress thermometer is incorporated. Additionally, open-text personal reflections on themes including difficult decisions will be invited. Survey participants will be drawn from various work areas of the cancer care departments: administrative staff, health professionals, for example, allied health, ancillary workers, nursing and medical.Ethics and disseminationThe study has been reviewed and approved by the Human Research Ethics Committee (LNR/2020/QRBW/62982). Published literature on domains of distress neglects categories of healthcare worker who form an essential part of the care delivery team. Our study hopes to gather insights about psychosocial impact and adjustment which could direct responses in future emergencies.

Background The COVID‐19 pandemic has forced rapid system‐wide changes to be implemented within cancer care at an alarming pace. Clinical trials are a key element of comprehensive cancer care. Ensuring the continuing safe conduct of cancer clinical trials in the context of a pandemic is challenging. Methods We aimed to describe the COVID‐19 pandemic response of a Cancer Care Clinical Research Unit (CRU) of a tertiary hospital in Queensland, Australia. We used a mixed methods approach for this case study. Emailed directives from CRU managers to all CRU staff sharing were qualitatively analysed and mapped against our unit activities over longitudinal time points. Data from patient recruitment and protocol deviations were analysed using descriptive statistics. Results Mapping activity from 11 March to 30 September 2020 revealed rapid change during the first 2 weeks. Four key strategies to accommodate change were identified: supporting patients and families, introduction of telehealth, accessing investigational product, and social distancing. Early in the pandemic we recognised that our core key stakeholders were integral to our response. When compared to the previous 12 months, our recruitment numbers dropped markedly in early phases of the response but recovered over time, as we accommodated internal and external impacts. Conclusion Our experience of agility as a necessity, adapting to support patients, and managing both clinical research activity and sponsors during the height of the pandemic response is presented here in order to inform future disaster response planning by clinical trial organisations.

Background Piperacillin-tazobactam is commonly used in neutropenic sepsis at standard doses that do not account for inter-individual differences in age, bodyweight and renal function. This study was designed to assess the rate of attainment of pharmacokinetic/pharmacodynamic (PK/PD) targets in patients receiving piperacillin/tazobactam therapy and to evaluate the effect on clinical outcomes. Methods Patients undergoing intensive chemotherapy for aggressive hematological malignancies were enrolled and treated with piperacillin/tazobactam 4 g/0.5 g every 6 h as initial antimicrobial therapy for first fever. Plasma drug concentrations were assayed at 50% and 100% of the dosing interval and compared with target MIC breakpoint of 16 mg/L to calculate the primary endpoints of 50% and 100% time above MIC (fT > MIC), respectively. Secondary endpoints included time to clinical cure, length of hospital stay, duration of antibiotics, and clinical treatment success. Results Fifty-eight percent (14/24) of patients achieved 50% fT > MIC while only 4% (1/24) achieved 100% fT > MIC. Higher creatinine clearance was significantly associated with lower trough drug concentration and appeared to be the dominant reason for the poor PK/PD target attainment. Median time to clinical cure, duration of antibiotic therapy, and hospital length of stay was 3, 13 and 21 days, respectively. There were no statistically significant differences in these outcomes between patients who did and did not achieve 100% fT > MIC. Conclusions A significant majority of febrile neutropenic patients fail to achieve PK/PD targets with 6-hourly piperacillin dosing, although the clinical implications of this finding are unclear. Larger studies are needed to assess any impact on morbidity and mortality. This trial is registered on the ANZCTR (ACTRN12618000110280).

Background In the absence of a method to culture Plasmodium vivax, the only way to source parasites is ex vivo. This hampers many aspects of P. vivax research. This study aimed to assess the safety of apheresis, a method for selective removal of specific components of blood as a means of extracting and concentrating P. vivax parasites. Methods An iterative approach was employed across four non-immune healthy human subjects in single subject cohorts. All four subjects were inoculated with ~ 564 blood stage P. vivax (HMP013-Pv) and subjected to apheresis 10 to 11 days later. Blood samples collected during apheresis (haematocrit layers 0.5% to 11%) were tested for the presence and concentration of P. vivax by microscopy, flow cytometry, 18S rDNA qPCR for total parasites, and pvs25 qRT-PCR for female gametocyte transcripts. Safety was determined by monitoring adverse events. Malaria transmission to mosquitoes was assessed by membrane feeding assays. Results There were no serious adverse events and no significant safety concerns. Apheresis concentrated asexual parasites by up to 4.9-fold (range: 0.9–4.9-fold) and gametocytes by up to 1.45-fold (range: 0.38–1.45-fold) compared to pre-apheresis densities. No single haematocrit layer contained > 40% of all the recovered P. vivax asexual parasites. Ex vivo concentration of parasites by Percoll gradient centrifugation of whole blood achieved greater concentration of gametocytes than apheresis. Mosquito transmission was enhanced by up to fivefold in a single apheresis sample compared to pre-apheresis. Conclusion The modest level of parasite concentration suggests that the use of apheresis may not be an ideal method for harvesting P. vivax. Trial Registration Australia New Zealand Clinical Trials Registry (ANZCTR) Trial ID: ACTRN12617001502325 registered on 19th October 2017. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373812.

Objective Many cancer care services (CCS) provide pragmatic models of emergent care for their patients as part of ‘business as usual’ without understanding the scope of this work. We aimed to describe an Australian CCS-led model of emergent care and quantify and profile emergent care provided over a 6-month period to understand scope and demand. Methods This prospective cohort study was performed at a large tertiary hospital on the eastern coast of Australia in 2016. The study explored emergent care provided during business hour and after-hours, including telephone advice, unplanned care and unplanned admissions. Data were collected via electronic hospital records and clinical nurses regarding who accessed care, why care was accessed, what care was provided and how the episode of care ended. Results Between March and September 2016, 1412 episodes of unplanned care were provided in the CCS-led model of care, including 307 episodes of telephone advice (237 patients; min max 1–4 episodes per patient; 825 episodes of unplanned care (484 patients; min max 1–9 episodes per patient) and 280 unplanned admissions (233 patients; min max 1–6 episodes per patient). During the same time, an additional 459 unplanned admissions (361 patients) occurred via the emergency department (ED), of which 125 (27.2%) occurred during business hours which could have been managed by the CCS. Most people who received care experienced issues associated with disease or treatment and had received systemic anticancer therapy in the past 30 days. Conclusions The data demonstrate that a significant volume of emergent care was provided within the CCS over the study period, in addition to planned cancer treatment. Due to the ever-increasing demands on EDs and the significant need for emergent care for people with cancer, there is need for CCS-led models of care to provide specialist emergent care specifically for people who are receiving systemic anticancer therapy. Such models must be adequately resourced to meet the needs of patients, carers and healthcare professionals. What is known about the topic? There is increasing focus on innovative models of emergent care for people with cancer in the out-patient setting to relieve pressure on EDs and improve patient experiences. Limited literature has focused on such models in the Australian context. What does this paper add? This paper describes, quantifies and profiles care provided in a pragmatic CCS-led model of emergent care in a large tertiary hospital in Australia over 6 months. The data demonstrate significant demand for emergent care within business hours, as well as out of hours, predominantly for people undergoing systemic anticancer therapy. What are the implications for practitioners? The findings of this study highlight the need for CCS to develop pragmatic models of emergent care. Appropriate resources, infrastructure, policies and procedures are required to adequate meet the needs of patients and carers.

Acquired Severe Aplastic Anaemia (SAA) is a rare bone marrow failure syndrome, for which allogeneic haematopoietic stem cell transplant (HSCT) is a proven curative therapy. Despite excellent outcomes for matched sibling SAA recipients in terms of engraftment and survival, HSCT remains highly challenging in older matched-unrelated-donor (MUD) recipients, due to increased non-relapse mortality (NRM) from causes such as graft versus host disease (GVHD), organ failure and infection. We sought to evaluate our local HSCT outcomes for SAA, determine factors that predict for inferior outcomes, and benchmark local outcomes against international cohorts. To define outcomes for sibling and MUD HSCT in adults ≥17 years of age with SAA at a single Australian institution between 2002 and 2018 and compare these outcomes to internationally published cohorts. The primary outcome was 1-year overall survival (OS). Secondary outcomes included the incidences of engraftment, response, secondary graft failure, GVHD, and moderate to severe organ dysfunction. All 21 patients comprising 10 sibling and 11 MUD HSCTs, with a median age of 30 (range 17-64), received bone marrow grafts. At a median follow up of 3.5 years, 17 (81%) of 21 patients remained alive and in remission from SAA. 1-year OS, non-relapse mortality (NRM), and GVHD incidence were 85%, 15%, and 48% respectively. Two patients died prior to engraftment at Day+27 and Day+33. When comparing sibling and MUD HSCT recipients, incidences of survival, engraftment and post-HSCT complications were similar; however, MUD HSCT survivors experienced a higher incidence of chronic GVHD (67% vs. 11%; p=0.04). Age >40 years, AKI by Day+28, infection by Day+100 and deviation from intended GVHD prophylaxis predicted for worse OS. Our outcomes following HSCT for SAA are comparable to international cohorts with age >40 years, early onset infection, AKI and deviation from intended GVHD prophylaxis protocol negatively impacting OS. Further research is warranted to optimise MUD HSCT conditioning and GVHD prophylaxis protocols for SAA, particularly in older patients.

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, treated via a 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.

We determined the efficacy of tocilizumab (TCZ) in preventing grade 2-4 acute graft-versus-host disease (aGVHD) in patients with acute leukemia or myelodysplasia undergoing matched sibling donor (MSD) or volunteer unrelated donor (VUD) allogeneic stem cell transplantation after myeloablative or reduced-intensity conditioning across 5 Australian centers. A total of 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day −1. All patients received T-cell–replete peripheral blood stem cell grafts and graft-versus-host disease (GVHD) prophylaxis with cyclosporin/methotrexate. A planned substudy analyzed the VUD cohort. With a median follow-up of 746 days, the incidence of grade 2-4 aGVHD at day 100 for the entire cohort was 36% for placebo vs 27% for TCZ (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.26; P = .23) and 45% vs 32% (HR, 0.61; 95% CI, 0.31-1.22; P = .16) for the VUD subgroup. The incidence of grade 2-4 aGVHD at day 180 for the entire cohort was 40% for placebo vs 29% for TCZ (HR, 0.68; 95% CI, 0.38-1.22; P = .19) and 48% vs 32% (HR, 0.59; 95% CI, 0.30-1.16; P = .13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade 2 disease. For the entire cohort, transplant-related mortality occurred in 8% vs 11% of placebo-treated vs TCZ-treated patients, respectively (P = .56), and overall survival was 79% vs 71% (P = .27). Median day to neutrophil and platelet engraftment was delayed by 2 to 3 days in TCZ-treated patients, whereas liver toxicity and infectious complications were similar between groups. In this phase 3 randomized double-blind trial, TCZ showed nonsignificant trends toward reduced incidence of grade 2-4 aGVHD in recipients from HLA-matched VUDs but no improvements in long term-survival.

Background Results have been varied regarding the effect of donor age on the outcome of unrelated donor hematopoietic cell transplantation (HCT). Aims This study sought to determine the influence of donor age on adult unrelated donor HCT outcome in Australia. Methods Patients were included in the study if they were aged 16 or above and underwent first allogeneic unrelated donor HCT in Australia for the indications of acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), chronic myelogenous leukaemia (CML) or myelodysplastic syndromes (MDS) between the years of 2001 and 2014 inclusive. The main outcome measure was overall survival (OS), which was tested against independent variables using univariate Kaplan-Meier methods and multivariate Cox regression. Results A total of 1,158 unrelated donor HCT were represented in the data. Cumulative incidences of engraftment, transplant related mortality (TRM), acute graft-versus-host disease (GvHD), chronic GvHD and relapse were not significantly affected by donor age. OS probability at 5 years post-transplant was 48.3%. In multivariate analysis of OS, year of transplant 2001-2007, recipient age 40 years or greater, poor risk disease, HLA match less than 6/6 and poor performance status at transplant (Karnofsky scale) were independently significant adverse OS risk factors. Donor age was not a significant risk factor for OS in univariate or multivariate analysis. Conclusions The conclusion from this study was that donor age (up to 59 years) did not influence post-transplant outcome among adult unrelated donor HCT performed in Australia for hematologic malignancies. This article is protected by copyright. All rights reserved.

Key Points CD34+ cell recovery and viability are variable after thawing cryopreserved hematopoietic progenitor cell products.Reduced CD34+ cell recovery and viability are linked to longer storage time and higher white cell concentration before cryopreservation., Donor registries and transplantation societies recommend cryopreservation of unrelated donor hemopoietic progenitor cell (HPC) products before the recipient commences conditioning therapy to mitigate the donor and travel risks associated with the COVID-19 pandemic. However, little is known regarding the postthaw quality of such allogeneic products or the effect of precryopreservation storage and processing on these characteristics. We investigated the postthaw CD34+ cell recovery and viability of 305 allogeneic HPC products cryopreserved at 9 laboratories across Australia. Median postthaw CD34+ cell recovery was 76% and ranged from 6% to 122%. Longer transit time before cryopreservation, white cell count (WCC) during storage, and complex product manipulation before cryopreservation were independently associated with inferior postthaw CD34+ cell recovery. Longer precryopreservation transit time and WCC were also associated with inferior postthaw CD34+ cell viability. We conclude that although postthaw CD34+ cell recovery and viability of cryopreserved allogeneic HPC is generally acceptable, there is a significant risk of poor postthaw product quality, associated with prolonged storage time, higher WCC, and complex product manipulation precryopreservation. Awareness of expected postthaw recovery and practices that influence it will assist collection, processing, and transplant centers in optimizing outcomes for transplant recipients., Visual Abstract

Objective Comprehensive Geriatric Assessment (CGA) has been proven to assist development of tailored treatment plans for older patients with cancer by identifying health issues affecting their ability to complete systemic therapy or cope with and recover from cancer treatment. Materials and Methods Metro North Hospital and Health Service (MNHHS) has significant older population with cancer. Geriatric Oncology services were commenced in February 2018 at two facilities of MNHHS [North Lakes Cancer Care Services/Caboolture Hospital (NLCCS/CBH) Cancer services and Redcliffe Hospital (RH) Cancer services]. The Geriatric 8 (G8) screening tool was administered to predict patient vulnerability and need for CGA. A bespoke CGA suite comprising of 16 assessments was used. A clinical nurse or Allied Health (AH) practitioner conducted screening, followed by CGA. Proposed care was discussed at multidisciplinary case conference and AH interventions were provided. Results From February’2018 to July’2019, the G8 was administered to 1380 patients between the two facilities (918 patients at NLCCS/CBH and 462 patients at RH), comprising oncology and haematology patients. 825 patients (59%) showed impairment on G8 and were recommended for CGA. Another 50 patients were referred for CGA as per clinical assessment despite normal G8. 65% (572) of recommended CGAs were conducted. The most common impairments identified on CGA leading to AH referrals were timed up & go >13 s, malnutrition, polypharmacy and low mood & depression. Conclusion The nursing/AH practitioner led Geriatric Oncology service is feasible, applicable and beneficial to patients. Further study is planned to assess the impact of the service on patients' health related quality of life and chemotherapy completion rates.

We have previously reported that haematopoietic progenitor cell transplantation recipients with biopsy-negative acute Gastrointestinal Graft versus Host Disease (Discordant GVHD) demonstrate superior survival compared to "True Positive" cases. We aimed to elucidate this discrepancy by examining clinical and laboratory predictors of survival among patients treated for True Positive or Discordant GVHD. Data were obtained by retrospective chart review. At diagnosis, the incidence of severe symptoms, hypoalbuminaemia, hyperbilirubinaemia, and poor performance status were recorded. Following treatment, the incidence of non-response to first-line corticosteroids was assessed. Differences between cohorts were compared using Fisher's exact test. 74 patients were identified, comprising 55 (74%) True Positive and 19 (26%) Discordant GVHD cases. True Positive cases were significantly more likely to have baseline severe symptoms (84% vs. 36%; p = 0.0002) and hypoalbuminaemia (94% vs. 75%; p = 0.023). There was no significant difference between cohorts in terms of hyperbilirubinaemia or performance status. Non-response to corticosteroid therapy was observed significantly more frequently in the True Positive cohort (55% vs. 11%; p = 0.001). In summary, the superior survival observed in Discordant GVHD is explained by a less severe GI-GVHD phenotype at diagnosis and a greater likelihood of response to corticosteroids. Further research is warranted to explain biological mechanisms for these findings.

Acute gastrointestinal graft-versus-host disease (GI-GVHD) after hematopoietic progenitor cell transplantation (HPCT) is a common and life-threatening complication. Endoscopic biopsy of the GI tract (GIT) is required for diagnosis. However, clear evidence to optimize this diagnostic approach is lacking, leading to variation in diagnostic sensitivity between institutions. We aimed to assess the clinical, endoscopic, and histologic findings of endoscopies performed for suspected acute GI-GVHD at our institution to better define the optimal use of this strategy. We performed a retrospective cohort study of adults who had undergone endoscopy for suspected acute GI-GVHD within 180 days after allogeneic HPCT for hematologic malignancy between 2011 and 2016. Details included symptoms at time of referral for endoscopy, type of procedure performed, macroscopic findings on endoscopy, and histologic findings after gut biopsy. Correlation was made with clinical GVHD severity scores. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated and compared for each procedure. Predictors of histologic GVHD and overall survival were also compared. Of the 123 patients included, acute GI-GVHD occurred in 59 (48%). Lower endoscopy demonstrated greater sensitivity than upper endoscopy (50% versus 39%). Single upper endoscopy for upper symptoms alone had the lowest yield of GI-GVHD (14%). Combination upper and lower endoscopy demonstrated strong histologic concordance between upper and lower procedures. The addition of upper endoscopy to lower endoscopy only identified an extra 2 (4%) cases of GVHD. Advanced age and the presence of lower GIT symptoms were the only pre-endoscopy predictors of histologic GVHD on multivariate analysis. Patients with isolated upper histologic GVHD showed similar survival to patients with negative biopsies. Endoscopy and biopsy only identified 74% of those ultimately requiring treatment for acute GI-GVHD. Acute GI-GVHD remains a clinical diagnosis supported by available histologic evidence. Isolated upper GI-GVHD is rare, and in the absence of lower GIT symptoms, routine upper endoscopy does not significantly improve diagnostic yield for histologic GVHD. Overall, endoscopy and biopsy underdiagnoses 26% of clinical GI-GVHD, highlighting a need for research into novel diagnostic strategies.

BACKGROUND/AIMS: We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft-versus-host disease (GVHD) on OSR. METHODS: Data on 386 patients from nine Australian centres with relapsed AML post-alloHSCT were collected retrospectively. OSR was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the log-rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling. RESULTS: On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P

BACKGROUND: Changes to donor availability, collection centre capacity and travel restrictions during the early phase of the COVID-19 pandemic led to routine cryopreservation of most unrelated donor products for haematopoietic transplantation prior to the recipient commencing the conditioning regimen. OBJECTIVE: We investigated the effect of this change on unrelated donor product quality and clinical outcomes. STUDY DESIGN: Product information was requested from transplant centres in Australia and New Zealand, and clinical outcome data from the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR). RESULTS: 191 products were collected between 01 April 2021 and 30 September 2021 and most (74%) were from international collection centres. Median post-thaw CD34 recovery was 78% (range 25%-176%) and median post-thaw CD34 viability was 87% (range 34-112%). Median time to neutrophil recovery was 17 days (inter-quartile range 10 to 24 days) and graft failure occurred in 6 patients (4%). These clinical outcomes were similar to those of 'fresh' unrelated donor transplants reported to the ABMTRR in 2019. However, recipient transplant centres reported problems with 29% of products in the form of damage during transit, low cell dose, inadequate labelling, missing representative samples or missing documentation. These problems were critical in 7 cases (4%). At last follow-up, 22 products (12%) had not been infused. CONCLUSIONS: Routine cryopreservation of unrelated donor HPC products has enabled safe continuation of allogeneic transplant services during the COVID-19 pandemic. However, practices for product tracing, documentation and transportation can be optimised, and measures to reduce the incidence of unused unrelated donor product are required.

Background: Interleukin-6 (IL-6) promotes the differentiation of pathogenic T cells and represents a dominant pathway of cytokine-dysregulation and graft-versus-host disease (GVHD). Cytomegalovirus (CMV) reactivation is a common and life-threatening infectious complication following allogenic bone marrow transplantation (BMT). The role of T cell immunity is long-established, and our group recently demonstrated that CMV strain-specific immunoglobulins (Ig) are critical in preventing CMV reactivation in preclinical models (Martins JP et al, Science 2019). Methods and Results: In a phase I/II clinical trial (Kennedy GA et al, Lancet Onc. 2014), we observed unexpectedly low rates of CMV reactivation following IL-6 receptor (IL-6R) blockade with tocilizumab (TCZ) compared to historical control (8/35 vs 20/43, P < 0.05). We used our preclinical models of murine CMV (MCMV) reactivation to pursue the mechanisms. We transplanted bone marrow (BM) and T cells from naïve B6 donors into CMV-latently infected B6D2F1 recipients and monitored MCMV reactivation. Ablation of IL-6R in donor T cells (using B6 CD4 cre x IL-6R fl/fl transgenic mice; IL-6R -/-) significantly reduced MCMV reactivation 5 weeks after BMT, as measured by plasma viremia and infectious viral loads in the liver (Fig 1A). Next, we examined the contribution of donor T and B cells to the suppression of MCMV reactivation by IL-6R inhibition. At 2 - 3 weeks after BMT and prior to MCMV reactivation, cytokine (IFNɣ/TNF) secretion from CD4 + T cells (in response to MCMV infected DC) was not detectable; MCMV m38 tetramer + CD8 T cells were present at very low frequencies (< 0.1% of CD8 T cells) which were not altered by IL-6R ablation. The frequency of CXCR-5 +PD-1 + T FH cells was comparable or lower in IL-6R -/- vs wild-type (WT) T cells after BMT. Transplant of BM from B6.μMT mice (unable to generate mature B cells and plasma cells) did not increase MCMV viremia (Fig 1B), excluding a role for donor B cells. Thus, early MCMV reactivation in the presence of IL-6 is independent of MCMV-specific T cells and donor B cells. To study the effects of IL-6 on recipient-derived humoral immunity we quantified MCMV-specific IgG in plasma after BMT and found that levels were significantly higher in recipients of IL-6R -/- T cells (Fig 1C). Furthermore, MCMV-IgG levels in plasma correlated with MCMV viremia (r = - 0.72, P < 0.0001) and viral loads in liver (r = - 0.68, P < 0.0001). MCMV-IgG2a, which can only be generated by B6D2F1 recipients, was significantly higher in recipients of IL-6R -/- T cells, confirming that differences in humoral responses were of recipient-origin. To define relevant mechanisms, we examined the kinetics of IgG after BMT by monitoring the loss of murine IgG (transferred on day 0) in plasma (Fig 1D). Recipients of IL-6R -/- T cells showed significantly slower loss of IgG than recipients of WT T cells, with or without GVHD prophylaxis with cyclosporine (CSA). Thus, ablation of IL-6 signaling in donor T cells is associated with reduced loss of recipient IgG and protection from MCMV reactivation, an outcome which seems independent of the effects of IL-6 on GVHD. We correlated our findings with data from a recent randomized, placebo-controlled, double-blind phase III clinical trial of TCZ administration on Day -1 of BMT (Kennedy GA et al, Blood 2021). TCZ reduced CMV reactivation in at risk seropositive BMT recipients of volunteer unrelated donor grafts regardless of acute GVHD (all at risk recipients, TCZ vs. control: 12/26 vs 21/28, P = 0.03; at risk without grade 2-4 GVHD, TCZ vs control: 6/18 vs 9/13, P = 0.03). TCZ did not alter the frequency of B cells or the frequency and function of HCMV-specific CD8 + T cells, quantified by HCMV-pMHC tetramer-staining and HCMV peptide-specific cytokine (IFNγ/TNF) secretion. In contrast, levels of HCMV-specific IgG at day +30 in HCMV-seropositive recipients were significantly higher in the TCZ versus control group (Fig 1E). Consistent with our preclinical studies, the level of HCMV-IgG significantly and inversely correlated with early HCMV reactivation (within 35 days) after transplant. Conclusion: These data confirm the importance of recipient-derived humoral immunity in controlling early CMV reactivation in clinical BMT recipients. Critically, we demonstrate the ability of IL-6R blockade to maintain protective humoral responses until effective donor-derived adaptive immunity can be generated. Figure 1 Figure 1. Disclosures Boeckh: Merck: Consultancy, Research Funding; SymBio Pharmaceuticals: Consultancy; Helocyte: Consultancy; Evrys Bio: Consultancy; Moderna: Consultancy; Gilead: Consultancy, Research Funding; AlloVir: Consultancy; GSK: Consultancy. Hill: Generon corporation: Consultancy; NapaJun Pharma: Consultancy; Compass Therapeutics: Research Funding; Syndax Pharmaceuticals: Research Funding; Applied Molecular Transport: Research Funding; iTeos Therapeutics: Consultancy, Research Funding; Roche: Research Funding; Neoleukin Therapeutics: Consultancy.

Background: Haploidentical Hematopoietic Stem Cell Transplantation (Haplo-HCT) is an established therapy using alternative donors for patients with Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS). There is a limited body of evidence for older patients undergoing Haplo-HCT in AML and MDS. Studies describing Haplo-HCT in older patients have used a high proportion of bone marrow (BM) derived grafts and a variety of conditioning regimens. In this setting, Haplo-HCT demonstrates acceptable Non-Relapse Mortality (NRM) and chronic Graft Versus Host Disease (cGVHD) rates of less than 10% (Ciurea. Biology of Blood and Marrow Transplantation. 2018 Jun 1;24(6):1232-6.). In Australia and New Zealand, Haplo-HCT is predominantly performed using peripheral blood (PB). We performed a retrospective national registry study to examine the outcomes of Haplo-HCT using PB in older patients. Methods: Data was collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients aged 65 or older receiving a PB Haplo-HCT for AML/MDS between January 2010 and July 2020. Cumulative incidence functions were used for engraftment, CMV reactivation, acute GVHD, chronic GVHD, relapse, and NRM. The competing risk for engraftment, CMV reactivation and GVHD was death. Relapse and NRM were competing risks for each other. Overall survival (OS), relapse-free survival (RFS), and composite GVHD and RFS (GRFS) were calculated using Kaplan-Meier analyses. The impact of pre-transplant factors on these endpoints was analyzed using Cox regression. Results: A total of 44 patients were included in the analysis. The median follow-up time was 734 days. The median age was 68 (range 65-74) with a median Karnofsky Performance Status of 90. Thirty patients (68.2%) had AML while 14 (31.8%) had MDS. The median donor age was 40. The most common conditioning regimen was non-myeloablative fludarabine, cyclophosphamide and TBI (73.8%), the remainder of the patients received either melphalan or busulfan based regimens, the majority were reduced intensity with only 2 patients undergoing myeloablative conditioning. All patients received post-transplant cyclophosphamide and mycophenolate mofetil with the majority also receiving tacrolimus (90.5%) and the remainder receiving cyclosporin (9.5%). No patients received anti-thymocyte globulin. Neutrophil engraftment was achieved in 97.6% of patients, at a median of 18 days while platelet engraftment was achieved in 92.7% of patients at a median of 28 days. The cumulative incidences of CMV reactivation and CMV disease were 52.5% and 5.1% at 1 year The incidence of Grade 2-4 aGVHD was 18.2%. The incidence of cGVHD at 2 years was 40.7%, with extensive cGVHD occurring in 17.7% of patients. The incidences of relapse and NRM at 2 years were 8.8%. and 20.7% respectively. The leading causes of death were infection (64.7%) followed by relapse (14.2%). The 2-year OS was 74%. RFS and GRFS at 2 years was 70% and 48% (Figure 1). Recipient age, donor age or disease type (AML vs MDS) had no significant impact on OS or GRFS. Conclusion: These results confirm the safety and effectiveness of Haplo-HCT for AML/MDS in older patients. The rates of cGVHD were higher than expected given the lower rates reported in other studies using PTCy GVHD prophylaxis. Haplo-HCT using a PB graft demonstrates good long-term disease control with reasonable rates of NRM and cGVHD for older patients with AML/MDS. Figure 1 Figure 1. Disclosures Bajel: Abbvie, Amgen, Novartis, Pfizer: Honoraria; Amgen: Speakers Bureau. Perera: Abbvie: Speakers Bureau; BMS: Speakers Bureau. Greenwood: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background: B-cell lineage cancers are a worldwide healthcare burden. Over 500,000 new cases of non-Hodgkin lymphoma (NHL) and 50,000 new cases of acute lymphoblastic leukemia (ALL) are diagnosed world-wide each year (seer.cancer.gov, Smith 2015, Solomon 2017). Despite progress in treatment, many patients diagnosed with this heterogeneous group of cancers still succumb to their disease. Recently approved autologous chimeric antigen receptor (CAR) T cells specific for CD19 have altered the treatment landscape for some patients with relapsed or refractory (R/R) B-cell malignancies, though significant toxicities associated with T-cell expansion and the necessity for bespoke manufacturing have limited their use. Natural killer (NK) cells, part of the innate immune system, efficiently recognize transformed cells and are particularly suited to address limitations of the approved CAR T products (Marcus 2014, Morvan 2016). Lacking a T-cell receptor and the consequent clonal expansion, non-engineered NK cells have been safely administered after lymphodepletion without side effects typically associated with T-cell therapies, such as severe cytokine release syndrome or neurotoxicity (Bachier 2020). Allogeneic NK cell-based therapies allow off-the-shelf use, obviating the necessity to wait for manufacture of autologous T-cell therapies. CD19-directed CAR NK cells have been administered safely, with promising preliminary efficacy (Liu 2020). NKX019 is a cryopreserved product, composed of expanded NK cells engineered to express a humanized CAR against CD19, fused to co-stimulatory (OX40) and signaling (CD3ζ) domains to enhance their intrinsic antitumor activity. NKX019 also expresses a membrane-bound interleukin-15 (IL-15) to serve as an autocrine growth factor and thereby increase NKX019 persistence, with an in vivo half-life of over up to 28 days without systemic IL-2 support. Preclinical characterization has shown that NKX019 cells are 10 times more effective at killing CD19+ target cells than non-engineered NK cells, resulting in greater suppression of xenograft tumor models (Morisot 2020). Further, NKX019, unlike CD19 CAR T cells, retained cytotoxicity even when CD19 antigen density was reduced >50x on target cells. Hence, clinical evaluation of NKX019 is being undertaken in this Phase 1 study in subjects with R/R NHL or ALL. Methods: This is a multicenter, open-label, Phase 1 study of NKX019 (Figure). The study will be conducted in 2 parts: Part 1 (dose finding) to determine the recommended Phase 2 dose (RP2D) of NKX019 separately in adult patients with CAR T naïve R/R NHL or B-ALL, utilizing a "3+3" enrollment schema. Part 2 (dose expansion) will further evaluate safety and tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PDn), and antitumor activity of NKX019 using RP2D with separate expansion cohorts for patients with ALL as well as different subtypes of NHL, including a cohort of CAR T pretreated large B-cell lymphoma. NKX019 is being manufactured from NK cells obtained from healthy adult donors. The study evaluates two dose levels of NKX019: 3 × 10 8 and 1 × 10 9 viable CAR+ NK cells. NKX019 will be administered on Days 0, 7, and 14 of a 28-day cycle following standard fludarabine/cyclophosphamide lymphodepletion (Table). Up to 5 total cycles may be administered based on response and tolerability assessed at the end of each cycle. The primary endpoint is incidence of adverse events, dose-limiting toxicities, clinically significant laboratory abnormalities, and determination of the RP2D. Secondary endpoints include evaluation of standard cellular PK parameters, PDn, immunogenicity, and antitumor responses. Subjects will be assessed for efficacy using disease-specific criteria: Lugano classification with LYRIC refinement for pseudo-progression (NHL), 2018 International Workshop (IW) criteria (CLL), 6th IW criteria (Waldenström macroglobulinemia [WM]), and National Comprehensive Cancer Version 1.2020 (B-ALL) (Cheson 2006, Cheson 2014, Hallek 2018, Owen 2013, Brown 2020). Enrollment across multiple sites in the US and Australia is expected to start in the second half of 2021. Figure 1 Figure 1. Disclosures Dickinson: Celgene: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bryant: Jansen, BMS/Celgene, Skyline Diagnostics: Consultancy; Amgen: Honoraria. Borthakur: Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Shook: Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tan: Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rajangam: Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Liu: SITC: Honoraria; BMS; Karyopharm; Miltenyi: Research Funding; Agios; NGM Biopharmaceuticals; BeiGene: Consultancy. McSweeney: Kite-Gilead: Consultancy; Kite-Gilead, Autolus, Novartis: Research Funding; Kite-Gilead: Honoraria, Speakers Bureau. Hill: Novartis: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; AstraZenica: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.

Human leukocyte antigen (HLA) matched allogeneic stem cell transplant (SCT) is an established curative treatment for various haematologic malignancies1. However, a fully matched HLA-donor may still not be identified in a significant proportion of patients. Those who do not have an available HLA-matched donor can still potentially undertake transplantation utilizing an alternative donor source, including mismatched unrelated donors (MMUD), umbilical cord blood (UCB) or haploidentical donors2. Although MMUD SCT is associated with increased risk of both graft versus host disease (GVHD) and non-relapse mortality (NRM), MMUD have still historically been utilized as alternative donor sources due to ease of donor availability3.

Introduction: Idiopathic pneumonia syndrome (IPS) is a dangerous complication following haematopoietic stem cell transplantation (HSCT). Immunosuppressive therapy (IST) using high-dose methylprednisone and etanercept produces complete response (CR) in the majority of IPS cases. However, exclusion of respiratory pathogens by bronchoscopy prior to IST commencement carries procedural risks that may worsen respiratory failure and IPS severity, with potential negative impact upon IST response and survival. Given this, we perform bronchoscopy post-IST commencement only in those patients with only mild (nasal oxygen) or severe (already intubated) respiratory failure. We commence IST within 24 hours of clinical and radiological suspicion of IPS, and cease IST if alternative aetiologies are subsequently proven. Aim: We aimed to evaluate the safety and efficacy of our local early-intervention IST strategy in patients with new-onset suspected IPS following HSCT. Methods: We performed a retrospective, single-centre descriptive cohort study of patients who received IST for IPS between 2014-2019. Details collected included: patient demographics, IPS diagnostic details/severity, IST response, and survival. The primary study objectives were the incidence of complete response (CR), defined by cessation of supplemental oxygen for at least 48 hours, and overall survival (OS) following IST. IST comprised high-dose corticosteroids (methylprednisolone 2mg/kg/day or equivalent) and etanercept (25mg twice weekly for 4 weeks, then weekly to complete 12 total doses). Results: Of the 480 HSCT performed during the study period, 17 patients developed suspected IPS and received IST. At IPS diagnosis, 10 (59%) required intensive care admission. Non-invasive (NIV) and invasive (IV) ventilation was required in 4 (24%) and 5 (29%) patients, respectively. All patients met clinical and radiological American Thoracic Society (ATS) criteria for IPS. Bronchoscopy was only performed in 9 (53%), comprising all 5 receiving IV and 4 who were only requiring supplemental nasal oxygen. All 4 patients receiving NIV were considered too high-risk for post-bronchoscopy intubation, so did not proceed. Of those who underwent bronchoscopy, none experienced worsening respiratory failure, however 1 received a revised diagnosis of bacterial pneumonia and ceased IST within 3 days of commencement, and survived. In the remaining 16 patients, CR to IST was achieved in 14 (88%) patients, with 1-year OS of 44%. However, at a mean 17 months follow-up, OS for the whole cohort was 31% (Figure 1), reflecting a high incidence of non-relapse mortality (NRM) at 63% (Table 1). There was no significant difference in response or survival between patients who did or did not undergo bronchoscopy. Conclusion: Our early-intervention IST strategy for IPS appears to produce similar response rates and survival as those reported in other prospective and retrospective series, without any obvious safety concerns. Although adherence to ATS diagnostic criteria and exclusion of occult infectious aetiologies is preferred, bronchoscopy may be safely delayed or omitted in a subset of patients. Early intervention may arrest the respiratory failure and ultimately avoid mechanical ventilation. Disclosures No relevant conflicts of interest to declare.

An Australasian Bone Marrow Transplant Registry (ABMTR) Study of the Trends and Outcomes of Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) in Hodgkin Lymphoma between 2009-2019: Relapse remains the most common cause of death post transplantation Introduction: Hodgkin Lymphoma (HL) is an eminently curable disease, with 80% of cases achieving cure with first line therapies. There are a subset of patients who relapse and require salvage therapy including autologous stem cell transplant and more recently novel agents such as brentuximab vedotin (BV) and the PD-1 inhibitors. The latter are less toxic and achieve durable responses but are not considered curative for most (LaCasce et al., 2019). In Australia BV and PD-1 inhibitors were approved in December 2013 and September 2017 respectively. Allogeneic HSCT offers a graft vs lymphoma (GVL) effect that may contribute to long term survival in some patients (Peggs et al., 2005). The introduction of reduced intensity conditioning (RIC) has seen improved outcomes with an OS of 67% (59-74%) and Progression Free Survival (PFS)of 45% (35-56%) (Rashidi et al., 2016) Patients and methods: Data was collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients receiving a first allogeneic transplant for HL between 2009 and 2019. The Kaplan Meier method was used to calculate OS and PFS with log rank test for comparison. Multivariable Cox proportional hazards models were used to identify associations with OS. We divided the patients into 5 year cohorts to compare transplant outcomes over time. Results: A total of 149 patients from 16 sites in Australia and New Zealand were included. The median age at time of transplant was 31 years (range 19-61) and the majority were male (60%). Seventy-five percent of patients had undergone previous autologous HSCT with data missing for 22%. Median follow up was 75 months (range 4.7-137.1). Forty five percent of patients were in complete remission (CR), 34% in partial remission and 15% relapsed/primary refractory (RR) at the time of HSCT with information missing in 4%. The majority of donors were matched unrelated donors (47%) and sibling donors were used for 37% of patients, haploidentical in 11% and umbilical cord blood in 5%. Reduced intensity conditioning was used in 86% of patients and in vivo T cell depletion with ATG or alemtuzumab was used in 27%. Acute GVHD occurred in 53/149 (30%) of which 31% was grade III-IV. In patients who survived beyond 100 days, the incidence of chronic GVHD was 38%, of which 53% was preceded by some form of aGVHD. Non-relapse mortality (NRM) at 100 days was 8% with 5/12 of these patients dying from aGVHD. Two-year OS and PFS were 75% and 49% respectively. A period effect was not detected with no significant difference in OS (p=0.8) nor PFS (0.2) based on transplant year (figure 1a & 1b). Multivariate analysis of factors associated with OS identified age at transplant of >40 (HR 3.24, 95% CI 1.71-6.15, p The numbers of HSCT performed each year are illustrated in figure 1c, with a larger proportion of patients in CR from 2014 onward. Post-transplant relapse occurred in 38% of patients (figure 1d)with a median time to relapse of 8.5 months (range 0.2 -42). Forty-eight percent (27/56) of patients who relapsed post HSCT were in CR at the time of HSCT. Of those who relapsed, 37% died due to progressive disease with no evidence of chronic GVHD. Relapse was the most common cause of death (37%) Conclusion: Although the rates of HSCT for HL in Australia and New Zealand have not varied over the past decade despite the availability of novel agents, there is a larger proportion of patients in CR prior to transplant. Survival outcomes for HL post HSCT are comparable to those reported internationally. Despite a higher percentage of patients transplanted in CR in later years, relapse post HSCT remains the major cause of death. Further studies to examine strategies to prevent or treat relapse of HL post-allograft are needed. Disclosures Sharplin: Novartis: Other: FUnded to attend Australian Haematology Conference . Di Ciaccio:Jansen: Honoraria, Other: travel and accomodation grant. Spencer:AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; Celgene, Janssen and Takeda: Speakers Bureau. Greenwood:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamad:Abbvie: Honoraria; Novartis: Honoraria.

Introduction Mantle cell lymphoma (MCL) is a mature B lymphoproliferative disorder with a frequently aggressive clinical course. Although the response rates in patients eligible for conventional chemoimmunotherapy are high, relapses are virtually inevitable, with a median overall survival (OS) of three to five years. For some patients allogeneic stem haematopoietic cell transplantation (alloHCT) is a potential therapeutic option. AlloHCT for MCL has been associated with long term overall survival (OS) of around 40%, with high rates of non-relapse mortality (NRM) of 20-40% and relapse rates of 20-30% (Urbano-Ispizua et al., Biol Blood Marrow Transplant 2015;21:1746, Robinson et al., Leukemia 2015;29:464). Whilst there is evidence of a graft-versus-lymphoma effect in MCL, it has not been shown to translate into improved OS. We performed a retrospective national registry study to examine alloHCT practice and outcomes for MCL in Australia and New Zealand in the modern era. Methods Data was collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients receiving an alloHCT for MCL between January 2009 and December 2019. This time range was chosen to capture the era of widespread rituximab use. Survival, relapse and toxicities of alloHCT were investigated, as well as transplant trends over time. Survival was analysed using the Kaplan-Meier method, with comparisons between the transplant periods 2009-2014 and 2015-2019 performed using the log-rank test. Cox proportional hazards regression was performed to determine significant risk factors for transplant outcome. The following risk factors were analysed for impact on outcomes: age, transplant before 2015, previous autologous HCT (autoHCT), remission status at transplant, use of myeloablative conditioning (MAC), haploidentical donor and use of T cell depletion (TCD). Results A total of 86 patients were included in the analysis. The median age was 56 (range 39-71). There was a male predominance with only 12% female patients. At the time of transplant, 51% were in complete remission, 26% had a partial response and 20% had stable or progressive disease (data missing in 3%). Sixty-seven percent had undergone previous autoHCT. The majority of donors were HLA-matched siblings (51%), followed by HLA-matched-unrelated (42%) and haploidentical (7%). Myeloablative conditioning was utilised in 14%, and T-cell depletion (TCD) in 24%. The median times to neutrophil engraftment (>0.5x109/L) and platelet engraftment (>20x109/L) were 16 and 20 days respectively. NRM at 1 and 5 years was 23% (95% confidence interval [95%CI] 10-39%) and 30% (95%CI 15-48%) respectively. The 100-day cumulative incidence of grade II to IV acute GVHD was 29%. The 3-year cumulative incidence of chronic GVHD was 27%. The median duration of follow up was 4.17 years (range 0-9.6 years). Median OS was 4.2 years, with an estimated 5-year OS of 47% (95%CI 35-58%) and 10-year OS of 23% (95%CI 8-43%) (figure 1). Five-year relapse free survival (RFS) was 38% (95%CI 26-50%) (figure 2). The cumulative incidence of relapse (CIR) was 20% at 1 year and 33% at 4 years, with a flattening of the curve after this point (figure 3). On multivariate analysis (MVA), the use of myeloablative conditioning (MAC) was associated with inferior RFS (hazard ratio 2.33; 95%CI 1.05-5.17; p=0.038) and OS (hazard ratio 3.11; 95%CI 1.39-7.00; p=0.006) (figure 4). No risk factors on MVA impacted NRM or CIR. Chronic GVHD was not associated with RFS or CIR. An average of nine alloHCTs were performed each year. There was an increase in the proportion of haploidentical transplants between 2009-2014 and 2015-2019 (4% to 10%). There was no significant change over time in OS, RFS or NRM, or in the use of MAC or TCD. Conclusion There has been no significant change in the rates of alloHCT for MCL in Australia and New Zealand over the past decade. Trends show an increasing utilisation of haploidentical donors. Overall outcomes were comparable to those previously published with favourable OS and durable remissions seen in a subset of patients. MAC was associated with inferior OS and RFS, however the cause for this is unclear given the lack of association with NRM or CIR. Ongoing reporting of alloHCT outcomes in MCL is important given the emerging role of novel therapies, such as Bruton tyrosine kinase inhibitors, bispecific T cells and CAR-T cell therapy. Figure 1 Disclosures Di Ciaccio: Jansen: Honoraria, Other: travel and accomodation grant. Greenwood:MSD: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamad:Novartis: Honoraria; Abbvie: Honoraria.

Background The treatment landscape for chronic lymphocytic leukaemia (CLL) has significantly changed over the past decade with the advent of targeted therapies. Subsequent improvement in remission rates has been seen in all patient groups, however patients with high-risk genetic features (del17p, TP53 mutation) continue to have poorer outcomes. In such patients, and in multiply relapsed/refractory standard risk patients, allogeneic stem cell transplantation remains a viable management option despite the associated morbidity and mortality. The aim of this study was to examine trends in allogeneic stem cell transplantation for CLL in Australia and New Zealand over the past decade, and to identify predictive factors for overall survival (OS) and progression free survival (PFS). Methods Data was collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients receiving a first allogeneic stem cell transplantation for CLL, in the absence of Richter's transformation, between January 2009 and December 2018. Transplant outcomes were compared between 2 time periods, 2009-2013 and 2014-2018 using log rank test for survival and Gray's test for cumulative incidence curves. Cox regression analysis was performed to identify factors predictive of survival. Medians are reported with ranges, hazard ratios (HR) and cumulative incidence with 95% confidence intervals (CI). Results A total of 153 patients (75% males) were included. Median age at transplantation was 55 years (range 23-69) with a median time from diagnosis to transplantation of 5.7 years (range 100days - 24.7years). Most patients received reduced intensity or non-myeloablative conditioning (84.3%, n=129) and did not receive T cell depleting therapy (73%, n=94). The median follow up was 5.9 years (range 0.8-11years). Median time to neutrophil engraftment was 16 days (range 6-49) and median time to platelet engraftment was 18 days (range 1-69). At 100 days following transplantation the cumulative incidence of graft failure was 3.9%, CMV reactivation 41% (95% CI 31-50%) and CMV disease 3.2% (95% CI 1-8%). Acute graft versus host disease (aGVHD) grade II-IV occurred in 39% (95% CI 29-49%) of patients and grade III-IV in 17% (95% CI 9-25%). The cumulative incidence of chronic GVHD (cGVHD) was 65% (95% CI 53-76%) at 5 years; extensive cGVHD occurred in 77% of patients with cGVHD. Median OS was 4.3 years (95% CI 3.6-not reached) and PFS was 2.6 years (95% CI 1.7-3.9). The most common contributors to mortality were infection (43%), GVHD (40%) and persistent disease or relapse (24%). In a multivariate analysis active disease at time of transplantation was associated with a worse OS (HR 2.16, 1.01-4.63), however, age, matched sibling donor, myeloablative conditioning and the use of T cell depleting therapies did not have a significant impact. The use of myeloablative conditioning was associated with improved PFS (HR 1.85, 1.1-3.1) in a univariate analysis but lost significance in multivariate analysis. Ninety-seven patients underwent transplantation between 2009-2013 and 56 patients between 2014-2018. There was no statistical difference in patient age, performance status, donor or disease status at transplantation between the groups. Myeloablative conditioning was used in 18.6% and 8.9% (p=0.197), and T cell depleting therapy in 25% and 31% (p=0.58), for the 2009-2013 and 2014-2018 periods respectively. There was a significant improvement in 5-year non-relapse mortality (NRM) from 41.5% (31-52%) to 23.4% (13-29%; p=0.04). Five year OS (46% vs 56%), PFS (36% vs 46%) and relapse rates (21% vs 31%) were not statistically different. Cumulative incidence of both acute and chronic GVHD was reduced in the later cohort; aGVHD 51% (95% CI 34-65%) vs 29% (95% CI 16-43%; p=0.03), cGVHD 76% (95% CI 57-88%) vs 53% (36-66%; p=0.02). Kaplan-meier and cumulative incidence curves for these outcomes are presented in figure 1. Conclusion The number of allogeneic stem cell transplantations performed for CLL has reduced over the past decade in Australasia. There has been an improvement in NRM and incidence of GVHD, however OS and PFS have not significantly changed. This may reflect improved GVHD prophylaxis and management, or advances in supportive care. Further analysis of impact of high-risk genetic factors at transplantation is pending at the time of abstract submission. Figure Disclosures Spencer: Celgene, Janssen and Takeda: Speakers Bureau; AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria. Greenwood:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tam:AbbVie: Honoraria, Research Funding; BeiGene: Honoraria; Janssen: Honoraria, Research Funding. Di Ciaccio:Jansen: Honoraria, Other: travel and accomodation grant. Hamad:Novartis: Honoraria; Abbvie: Honoraria.

e23016 Background: Potential moral hazards from COVID-19 for patient-facing oncology staff include rationalizing treatment, but prior research into staff distress has not included ancillary/administrative staff or compared geographic settings. We sought to document measures of distress and perceived preparedness from diverse oncology staff during the COVID-19 pandemic response, and correlate these with unfolding events. Methods: We utilised a mixed-methods approach comprising weekly diarising of executive communications and events-by investigators, and prospective self-administered online surveys-by staff. Survey domains included perceived institutional preparedness, personal wellbeing, and perceived stress using a distress thermometer (0-10, no-extreme distress). Responses were Likert-scaled or free-text. Quantitative responses were aggregated by role/site and analysed using R. These were correlated with emergent qualitative themes using the Framework Method. The study was conducted at a metropolitan and a regional hospital in Queensland, Australia. Results: 12 surveys across 18 weeks commencing April 3, 2020 (encompassing 1st lockdown, lockdown easing, and 2nd lockdown) had 993 individual responses. 40% respondents were located regionally. Role categories included: nursing (50%), allied health (18%), medical (16%), administrative (15%), ancillary (e.g. cleaner, food service) (1%). Emergent themes were: S trategies for protection- at work and home. Up to 27% respondents reported being able to attend to critical personal needs only sometimes or less, although patients were perceived to be well supported most/all of the time (>90% responses). Navigating rules and keeping up-high levels of perceived institutional preparedness in >75% responders coexisted alongside fluctuating levels of self-reported distress, from median 5 (IQR 3-7) at 1st lockdown outset to 1 (IQR 1-4) after lockdown restriction easing. Tempered optimism-pride in one’s place was reported both as reflecting healthcare worker identity and as Australians in the context of low local infection rates. No significant differences in distress or preparedness perceptions were evident comparing geographic sites. Framing the new normal-although respondents longitudinally reported increasing familiarity with pandemic directives, distress levels increased concurrently with the announcement of 2nd lockdown. Conclusions: In the context of low local COVID-19 infection rates, oncology staff regardless of role and geographic setting reported high perceptions of institutional preparedness. Distress levels increased concurrently with lockdown phases and reports of distress and psychosocial workload fatigue were made by various workers including administrative and ancillary. These should be considered frontline staff for the purpose of workplace psychosocial support in pandemic responses.

Background The role of brentuximab peri-allogeneic transplantation in patients with relapsed and/or refractory CD30 positive lymphomas remains poorly defined. Aim To assess the outcome of use of brentuximab as a bridge to allogeneic stem cell transplantation (SCT) in patient with relapsed/refractory CD30+ classic Hodgkin lymphoma cHL and anaplastic large cell lymphoma (ALCL). Methods Outcomes of consecutive patients with relapsed/refractory cHL/ALCL treated with brentuximab as a bridge to SCT were determined by retrospective review of individual medical records. Survival analysis was measured from start of brentuximab treatment. Results A total of 12 patients (10 cHL, 2 ALCL) had received brentuximab as a planned bridge to allogeneic SCT. Median age was 27 years (range 20-54 years); median prior lines of therapy was 4 (range 3-6) and all except one patient had undergone prior autologous SCT (92%). Patients received at median of 3 brentuximab doses pre-allogeneic SCT (range 1-4), with an overall response rate of 66.7%. At a median follow up of 30 months (range 6-52 months), 2 years progression free survival and overall survival post-allogeneic SCT is 58 and 92% respectively. Incidence of non-relapse mortality, grade 3-4 acute graft versus host disease and extensive stage chronic graft versus host disease is 8, 17 and 18% respectively. Of five patients who subsequently relapsed post-SCT, four remain alive with disease control post manipulation of immune-suppression. Conclusion Our experience suggests that brentuximab use pre-allogeneic SCT is not associated with any significant post-transplant toxicity, and is associated with a rapid response in a majority of patients with relapsed/refractory CD30 positive lymphomas. Brentuximab may thus provide a non-toxic bridge to allogeneic SCT for patients with relapsed/refractory CD30 positive cHL or ALCL.

To describe a nosocomial outbreak of H1N1 influenza A in an inpatient hematology and allogeneic stem cell transplant unit and outcomes of universal oseltamivir prophylaxis. Medical records of all patients admitted to the unit were reviewed to define the nosocomial outbreak, commencing 1 week prior to the index case until 4 weeks following institution of oseltamivir prophylaxis. Timelines for clinical symptoms, viral spread, management, patient outcomes and follow up testing were constructed. All cases of influenza were confirmed on nasopharyngeal swabs and/or bronchoalveolar lavages collected for polymerase chain reaction testing. In addition to the index case, further 11 patients were diagnosed with influenza A during the outbreak. Six patients (50%) had influenza-like-illness, five (42%) had respiratory symptoms only and one (8%) was asymptomatic. In total, five patients died, including four (33%) patients who were admitted to intensive care. A clustering of seven cases led to recognition of the outbreak and subsequent commencement of universal prophylaxis with oseltamivir 75 mg/day in all inpatients within the unit. Strict infection control processes were reinforced concurrently. There were no further cases of influenza A linked to the outbreak after the implementation of universal oseltamivir prophylaxis. Three later cases were linked to H1N1 exposure during the original outbreak. H1N1 influenza infection is associated with significant mortality in hematology patients. Universal prophylaxis with oseltamivir during a nosocomial outbreak appeared to be effective in controlling spread of the virus. We recommend early institution of infection control and universal prophylaxis in any nosocomial outbreak of influenza.