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A sub-group of patients with Hodgkin Lymphoma (HL) who relapse after autologous stem cell transplant can achieve long-term disease-free-survival after allogeneic stem cell transplant (alloSCT). There is limited information regarding the tolerability and efficacy of double umbilical cord blood transplant (dUCBT) for relapsed/refractory HL. We analyzed 27 consecutive, heavily pre-treated patients receiving dUCBT for relapsed/refractory HL at two centers from 2003–2014. The majority of patients relapsed <6 months after autologous stem cell transplant. A total of 15 patients received myeloablative (most commonly melphalan, fludarabine, thiotepa and anti-thymocyte globulin [ATG]) and 12 non-myeloablative conditioning regimens (fludarabine, cyclophosphamide, 200cGy total body irradiation +/- ATG). All patients engrafted; median time to neutrophil and platelet engraftment was 17 and 37 days, respectively. Overall response rate was 68%; 58% achieved complete remission. Median progression-free survival (PFS) was 12.2 months; median overall survival was 27 months. Cumulative incidences of relapse and of non-relapse mortality at 5 years were 30% and 37.9%, respectively; 5-year PFS was 31.3% (95%CI 10.1–52.5). There was a trend toward inferior PFS in patients with lymph node size ≥2 cm at the time of alloSCT (p = 0.07) and toward inferior survival in patients with chemorefractory disease pre-alloSCT (p = 0.12). dUCBT is feasible in patients with heavily pre-treated HL and can achieve long-term disease-free survival in approximately 30% of patients. [ABSTRACT FROM AUTHOR]

Patients with post‐haemopoietic stem cell transplant or chimeric antigen receptor T ‐cell (CAR‐T) therapy face a significant risk of morbidity and mortality from coronavirus disease 2019 because of their immunosuppressed state. As case numbers in Australia and New Zealand continue to rise, guidance on management in this high‐risk population is needed. Whilst we have learned much from international colleagues who faced high infection rates early in the pandemic, guidance relevant to local health system structures, medication availability and emerging therapies is essential to equip physicians to manage our patients optimally. [ABSTRACT FROM AUTHOR]

Background: Vancomycin-resistant enterococcus (VRE) is an important cause of infection in immunocompromised populations. Few studies have described the characteristics of vanB VRE infection. We sought to describe the epidemiology, treatment and outcomes of VRE bloodstream infections (BSI) in a vanB predominant setting in malignant hematology and oncology patients.Methods: A retrospective review was performed at two large Australian centres and spanning a 6-year period (2008-2014). Evaluable outcomes were intensive care admission (ICU) within 48 h of BSI, all-cause mortality (7 and 30 days) and length of admission.Results: Overall, 106 BSI episodes were observed in 96 patients, predominantly Enterococcus faecium vanB (105/106, 99%). Antibiotics were administered for a median of 17 days prior to BSI, and 76/96 (79%) were neutropenic at BSI onset. Of patients screened before BSI onset, 49/72 (68%) were found to be colonised. Treatment included teicoplanin (59), linezolid (6), daptomycin (2) and sequential/multiple agents (21). Mortality at 30-days was 31%. On multivariable analysis, teicoplanin was not associated with mortality at 30 days.Conclusions: VRE BSI in a vanB endemic setting occurred in the context of substantive prior antibiotic use and was associated with high 30-day mortality. Targeted screening identified 68% to be colonised prior to BSI. Teicoplanin therapy was not associated with poorer outcomes and warrants further study for vanB VRE BSI in cancer populations. [ABSTRACT FROM AUTHOR]

Background Many patients with hematological malignancy develop fever after chemotherapy/conditioning but before chemotherapy-induced neutropenia (preneutropenic fever [PNF]). The proportion of PNF with an infectious etiology is not well established. Methods We conducted a single-center, prospective observational substudy of PNF (neutrophils >0.5 cells/μL, ≥38.0°C) in adults receiving acute myeloid leukemia (AML) chemotherapy, or allogeneic hematopoietic cell transplant (allo-HCT) conditioning enrolled in a neutropenic fever randomized controlled trial between 1 January and 31 October 2018. Eligible patients had anticipated neutropenia ≥10 days and exclusions included concurrent infection and/or neutropenia prior to chemotherapy or conditioning. PNF rates and infections encountered were described. Associations between noninfectious etiologies and fever were explored. Antimicrobial therapy prescription across preneutropenic and neutropenic periods was examined. Results Of 62 consecutive patients included (43 allo-HCT, 19 AML), 27 had PNF (44%) and 5 (19%) had an infective cause. Among allo-HCT, PNF occurred in 14 of 17 (82%) who received thymoglobulin; only 1 of 14 (7%) had infection. During AML chemotherapy, 18 of 19 received cytarabine, of which 8 of 18 (44%) had PNF and 3 of 8 (38%) had infection. Most patients with PNF had antimicrobial therapy continued into the neutropenic period (19/27 [70%]). Those with PNF were more likely to be escalated to broader antimicrobial therapy at onset/during neutropenic fever (5/24 [21%] vs 2/30 [7%]). Conclusions Rates of PNF were high, and documented infection low, leading to prolonged and escalating antimicrobial therapy. In the absence of infection, early cessation of empiric therapy after PNF is recommended as an important stewardship intervention. [ABSTRACT FROM AUTHOR]

Sinusoidal obstruction syndrome/veno‐occlusive disease (SOS/VOD) is a life‐threatening complication which can develop after haemopoietic stem cell transplantation (HSCT) and some antibody–drug conjugates. Several SOS/VOD diagnostic and management guidelines exist, with the most recent and refined being the European Society for Blood and Marrow Transplantation adult and paediatric guidelines. Timely diagnosis and effective management (including the availability of therapeutic options) significantly contribute to improved patient outcomes. In Australia and New Zealand, there is variability in clinical practice and access to SOS/VOD therapies. This review aims to summarise the current evidence for SOS/VOD diagnosis, prevention and treatment and to provide recommendations for SOS/VOD in the context of contemporary Australasian HSCT clinical practice. [ABSTRACT FROM AUTHOR]

High-dose cytarabine (HDAC) is conventionally delivered on days 1, 3 and 5 (HDAC-135) as acute myeloid leukemia (AML) post-remission therapy. Limited data is available on alternative HDAC schedules such as HDAC-123 (given consecutively for 3 days). We retrospectively compared the tolerability and efficacy of HDAC-135 and HDAC-123 delivered in sequential cohorts of adult AML patients. Seventy-three patients were included with 33% aged ≥60 years. HDAC-123 was associated with faster hematological recovery, reduced bacteremia and shorter hospitalization. No differences in safety profile or hematological recovery were seen between patients ≥60 years and <60 years receiving HDAC-123 except a shorter median time to neutrophil count recovery after cycle 1 in the latter group. Three patients (8%) receiving HDAC-123, all aged <60 years, required a change in schedule to HDAC-135 due to transient cytarabine-related side effects. HDAC-123 consolidation was well-tolerated by AML patients, including those ≥60 years, and associated with tangible reductions in resource utilization. [ABSTRACT FROM AUTHOR]

This position paper provides an overview of the assessment and management of both acute and chronic graft‐versus‐host disease (GvHD). There is a focus on the use of ruxolitinib, a selective inhibitor of Janus kinase (JAK)1 and JAK2, for the treatment of corticosteroid‐refractory and corticosteroid‐dependent GvHD. [ABSTRACT FROM AUTHOR]

Cytarabine-containing chemoimmunotherapy followed by autologous transplantation and rituximab maintenance achieves durable remissions for most patients with mantle cell lymphoma (MCL). However, patients with TP53-mutated disease have poor outcomes with standard approaches. We previously reported that allogeneic stem cell transplantation (alloSCT) achieved durable remissions in MCL, however follow-up among patients with TP53-mutated disease was limited. Here we report extended follow-up of the overall cohort (n = 36) and TP53-mutated subset (n = 13) (median follow-up 10.8 and 4.2 years, respectively). Estimated overall survival was 56% at 10 years for the overall cohort and 59% at 4 years for the TP53-mutated subset. Among patients with TP53-mutated disease, no relapses occurred beyond 6 months post-transplant. Survival after post-alloSCT disease relapse was poor (median 2.1 years). These data confirm that alloSCT can be curative in MCL, including patients with TP53-mutated disease, and should be considered for earlier utilization in this subgroup for whom conventional chemoimmunotherapy is ineffective. [ABSTRACT FROM AUTHOR]

Highlights • TBI conditioning for autotransplantation is associated with higher risks of t-MN. • Risks of t-MN after autotransplantation for NHL are increasing. • Autotransplantation increases risks of MDS more than AML. Abstract Background Exposures to DNA-damaging drugs and ionizing radiations increase risks of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods 9028 recipients of hematopoietic cell autotransplants (1995–2010) for Hodgkin lymphoma (HL; n = 916), non-Hodgkin lymphoma (NHL; n = 3546) and plasma cell myeloma (PCM; n = 4566), reported to the CIBMTR, were analyzed for risk of subsequent AML or MDS. Results 335 MDS/AML cases were diagnosed posttransplant (3.7%). Variables associated with an increased risk for AML or MDS in multivariate analyses were: (1) conditioning with total body radiation versus chemotherapy alone for HL (HR = 4.0; 95% confidence interval [1.4, 11.6]) and NHL (HR = 2.5 [1.1, 2.5]); (2) ≥3 versus 1 line of chemotherapy for NHL (HR = 1.9 [1.3, 2.8]); and (3) subjects with NHL transplanted in 2005–2010 versus 1995–1999 (HR = 2.1 [1.5, 3.1]). Using Surveillance, Epidemiology and End Results (SEER) data, we found risks for AML/MDS in HL, NHL and PCM to be 5–10 times the background rate. In contrast, relative risks were 10–50 for AML and approximately 100 for MDS in the autotransplant cohort. Conclusions There are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM. [ABSTRACT FROM AUTHOR]

Momelotinib is a potent inhibitor of JAK1 and JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis. This phase 2, open-label, randomized study evaluated the efficacy and safety of oral once-daily momelotinib (100 mg and 200 mg) for the treatment of polycythemia vera (PV) and essential thrombocythemia (ET). The primary endpoint for PV was overall response rate (ORR), defined as the proportion of patients with hematocrit <45%, white blood cell count <10 × 10 9 /L, platelet count ≤400 × 10 9 /L, and resolution of palpable splenomegaly, each lasting ≥4 weeks. The definition of ORR for ET excluded the hematocrit component. A total of 39 patients (28 PV, 11 ET) were enrolled, with 28 patients receiving ≥12 weeks of treatment. The study was terminated due to limited efficacy. Two patients (ORR 5.1%) met the primary efficacy endpoint (both PV 200 mg). Predose plasma levels of momelotinib were stable over time. A total of 31 (79.5%) patients experienced momelotinib-related adverse events (AEs), the most frequent being headache (23.1%), dizziness (18.0%), somnolence (15.4%), nausea (15.4%), and fatigue (15.4%). Three patients experienced serious AEs (7.7%), with 1 considered related to momelotinib (dyspnea). Peripheral neuropathy occurred in 7 (17.9%) patients (4 PV, 3 ET). [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for patients with chronic myelomonocytic leukemia (CMML); however, few data exist regarding prognostic factors and transplantation outcomes. We performed this retrospective study to identify prognostic factors for post-transplantation outcomes. The CMML-specific prognostic scoring system (CPSS) has been validated in subjects receiving nontransplantation therapy and was included in our study. From 2001 to 2012, 209 adult subjects who received HCT for CMML were reported to the Center for International Blood and Marrow Transplant Research. The median age at transplantation was 57 years (range, 23 to 74). Median follow-up was 51 months (range, 3 to 122). On multivariate analyses, CPSS scores, Karnofsky performance status (KPS), and graft source were significant predictors of survival ( P  = .004, P  = .01, P  = .01, respectively). Higher CPSS scores were not associated with disease-free survival, relapse, or transplantation-related mortality. In a restricted analysis of subjects with relapse after HCT, those with intermediate-2/high risk had a nearly 2-fold increased risk of death after relapse compared to those with low/intermediate-1 CPSS scores. Respective 1-year, 3-year, and 5-year survival rates for low/intermediate-1 risk subjects were 61% (95% confidence interval [CI], 52% to 72%), 48% (95% CI, 37% to 59%), and 44% (95% CI, 33% to 55%), and for intermediate-2/high risk subjects were 38% (95% CI, 28% to 49%), 32% (95% CI, 21% to 42%), and 19% (95% CI, 8% to 29%). We conclude that higher CPSS score at time of transplantation, lower KPS, and a bone marrow graft are associated with inferior survival after HCT. Further investigation of CMML disease–related biology may provide insights into other risk factors predictive of post-transplantation outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Pretransplant detection of KMT2Ar measurable residual disease ≥0.001% by quantitative polymerase chain reaction was associated with significantly inferior posttransplant survival (2-year relapse-free survival 17% vs 59%; P = .001) and increased 2-year cumulative incidence of relapse (75% vs 25%, P = .0004)., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Adoptive T-cell immunotherapy holds great promise for the treatment of viral complications in immunocompromised patients resistant to standard anti-viral strategies. We present a retrospective analysis of 78 patients from 19 hospitals across Australia and New Zealand, treated over the last 15 years with "off-the-shelf" allogeneic T cells directed to a combination of Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKV), John Cunningham virus (JCV) and/or adenovirus (AdV) under the Australian Therapeutic Goods Administration's Special Access Scheme. Most patients had severe post-transplant viral complications, including drug-resistant end-organ CMV disease, BKV-associated haemorrhagic cystitis and EBV-driven post-transplant lymphoproliferative disorder. Adoptive immunotherapy is well tolerated with few adverse effects. Importantly, 46/71 (65%) patients show definitive clinical improvement including reduction in viral load, clinical symptoms and complete resolution of end-organ disease. In addition, seven high-risk patients remain disease free. Based on this long-term encouraging clinical experience, we propose that a dedicated nationally funded centre for anti-viral cellular therapies should be considered to provide T cell therapies for critically ill patients for compassionate use., Competing Interests: Competing interests: R.K. and C.S. are listed as inventors on international patent applications describing virus-specific T cell therapy. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Relapsed/refractory T-cell acute lymphoblastic leukemia (ALL)/lymphoma (LBL) represent a significant unmet medical need. WU-CART-007 is a CD7-targeting, allogeneic, fratricide-resistant chimeric antigen receptor T cell product generated from healthy donor T cells. WU-CART-007 was evaluated in a phase 1/2 study with a 3 + 3 dose-escalation design followed by cohort expansion in relapsed/refractory T-ALL/LBL. Patients received one infusion of WU-CART-007 after standard or enhanced lymphodepleting chemotherapy. The primary objectives, to characterize safety and assess the composite complete remission rate, were met. Of 26 patients enrolled, 13 received the recommended phase 2 dose (RP2D) of 900 million cells of WU-CART-007 with enhanced lymphodepletion. The most common treatment-related adverse event was cytokine release syndrome (88.5%; 19.2% grade 3-4). Biochemical abnormalities consistent with grade 2 hemophagocytic lymphohistiocytosis were seen in one patient (3.8%). Grade 1 immune effector cell-associated neurotoxicity syndrome events (7.7%) and one grade 2 acute graft-vs-host disease event occurred. Grade 5 events (11.5%) were due to fungal infection and multi-organ failure. The composite complete remission rate was 81.8% among 11/13 patients evaluable for response at the RP2D. WU-CART-007 at the RP2D demonstrated a high response rate in patients with relapsed/refractory T-ALL/LBL and has the potential to provide a new treatment option. ClinicalTrials.gov registration: NCT04984356., Competing Interests: Additional Declarations: Yes there is potential Competing Interest. Financial: Armin Ghobadi: Honorarium from Kite, a Gilead company; consultancy provided for Amgen, Atara, Bristol Myers Squibb, CRISPR therapeutics, Kite, Novartis, and Wugen; research funding from Amgen, Genentech, and Kite. Ibrahim Aldoss: Ad Board and consultant fees from Wugen, Amgen, KITE, Abbvie, Takeda; Research support: MacroGenics, Abbvie Shannon L. Maude: Clinical trial support from Novartis and Wugen; advisory and study steering committees for Novartis and Wugen; patent pending and licensed to Novartis Pharmaceuticals without royalty for PCT/US2017/044425: Combination Therapies of Car and PD-1 Inhibitors. Bhagirathbhai Dholaria: Institutional research funding, no direct payment: Janssen, Angiocrine, Pfizer, Poseida, MEI, Orcabio, Wugen, Allovir, NCI, Atara, Gilead, Molecular templates, BMS, AstraZeneca, Adicet. Consultation/Advisory board: Janssen, Pluri Biotech, BOXER CAPITAL, Ellipsis pharma, Lumanity, Autolus, Acrotech, ADC therapeutics, Gilead, Global health research, GSK, Roche Rawan Faramand: Advisory Board: Kite/Gilead; Autolus; Consultancy: Sanofi;Research Funding: Kite/Gilead; Novartis Andre Baruchel: Servier: symposia, travels; Jazz: advisory boards; Amgen: symposia; Servier: funding for academic clinical research protocol; Astra Zeneca: advisory board paid to institution Nicolas Boissel: Consultant for Novartis, Amgen, Bristol Myers Squibb, and Jazz Pharmaceuticals; and receives honoraria from Novartis, Amgen, Incyte, Servier, Bristol Myers Squibb, Jazz Pharmaceuticals, Celgene, Sanofi, and Pfizer. Brent Wood: Dr. Wood’s institution receives funding for contract laboratory testing from a number of biopharma companies including two that have products whose efficacy is being evaluated in T-ALL. However, there is no interaction between the services provided for each company. Dr. Wood also is a paid consultant on MRD testing for clinical trials for Amgen, but does not involve products for T-ALL. Haley Irons: Employment in Wugen Ben Capoccia: Employment in Wugen Deborah Masters: Employment and shares in Wugen Justo Gonzalez: Wugen employment Tony Wu: Employment and shares in Wugen Maria del Rosario: Employment and shares in Wugen Alexander Hamil: Employment and shares in Wugen Ouiam Bakkacha: Employment and shares in Wugen, MacroGenics stock John Muth: Employment and shares in Wugen Brett Ramsey: Employment and shares in Wugen Eileen McNulty: Employment and shares in Wugen Matthew L. Cooper: Equity, ownership, employment in Wugen Jan Baughman: Consultant to Wugen; MacroGenics stock Jan Davidson-Moncada: Employment and shares in Wugen John F. DiPersio: Consulting: Rivervest, Bluebird Bio, Vertex, HcBiosciences, SPARC; Equity-ownership WUGEN and Magenta; Research support: MacroGenics, Bioline, Incyte. Support: NCI R35 CA210084, Leukemia and Lymphoma Society SCOR Non-Financial: Armin Ghobadi: Wugen founders include members of Washington University physicians that are colleagues of Dr. Ghobadi. Ryan J. Mattison:Vice chair of the Acute Lymphoblastic Leukemia committee for the National Comprehensive Cancer Netork (NCCN) C. Michel Zwaan: Chair of Hem-iSMART study for T-cell ALL with support from Abbvie and Novartis

Purpose: A prospective phase II study examined the safety and efficacy of venetoclax combined with low-dose cytarabine (LDAC) in AML at first measurable residual disease (MRD) or oligoblastic relapse., Methods: Patients with either MRD (≥1 log 10 rise) or oligoblastic relapse (blasts 5%-15%) received venetoclax 600 mg once daily D1-28 plus LDAC once daily D1-10 in 28-day cycles. The primary objective was MRD response in the MRD relapse cohort or complete remission (CR/CRh/CRi) in the oligoblastic relapse cohort., Results: Forty-eight adults with either MRD (n = 26) or oligoblastic (n = 22) relapse were enrolled. Median age was 67 years (range, 18-80) and 94% had received previous intensive chemotherapy. Patients received a median of four cycles of therapy; 17% completed ≥12 cycles. Patients with oligoblastic relapse had more grade ≥3 anemia (32% v 4%; P = .02) and infections (36% v 8%; P = .03), whereas grade 4 neutropenia (32 v 23%) or thrombocytopenia (27 v 15%) were comparable with the MRD relapse cohort. Markers of molecular MRD relapse included mutant NPM1 (77%), CBFB::MYH11 (4%), RUNX1::RUNX1T1 (4%), or KMT2A::MLLT3 (4%). Three patients with a log 10 rise in IDH1 / 2 (12%) were included. By cycle 2 in the MRD relapse cohort, a log 10 reduction in MRD was observed in 69%; 46% achieved MRD negative remission. In the oligoblastic relapse cohort, 73% achieved CR/CRh/CRi. Overall, 21 (44%) underwent hematopoietic cell transplantation. Median overall survival (OS) was not reached in either cohort. Estimated 2-year OS rate was 67% (95% CI, 50 to 89) in the MRD and 53% (95% CI, 34 to 84) in the oligoblastic relapse cohorts., Conclusion: For AML in first remission and either MRD or oligoblastic relapse, venetoclax plus LDAC is well tolerated and highly effective.

Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012-2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for., (© 2024. The Author(s).)

There is a limited body of evidence for haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in older patients. Previous studies have used a high proportion of bone marrow-derived grafts and a variety of conditioning regimens. In Australia and New Zealand, haplo-HCST is predominantly performed using peripheral blood (PB) with universal use of post-transplantation cyclophosphamide (PTCy). To characterize the outcomes of older recipients undergoing haplo-HSCT for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Data were collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients aged 65 or older receiving a PB haplo-HSCT for AML/MDS between January 2010 and July 2020. A total of 44 patients were included in the analysis. The median follow-up time was 377 days. The median age was 68 (range 65-74) with a median Karnofsky performance status of 90. Thirty patients (68.2%) had AML, whereas 14 (31.8%) had MDS. The median donor age was 40. The most common conditioning regimen was nonmyeloablative fludarabine, cyclophosphamide, and total body irradiation (75%); the remainder of the patients received either melphalan- or busulfan-based regimens, and the majority were reduced intensity, with only 2 patients undergoing myeloablative conditioning. All patients received post-transplantation cyclophosphamide and mycophenolate mofetil, with the majority also receiving tacrolimus (90.5%) and the remainder receiving cyclosporine (9.5%). No patients received anti-thymocyte globulin. Neutrophil engraftment was achieved in 97.6% of patients at a median of 18 days, whereas platelet engraftment was achieved in 92.7% of patients at a median of 28 days. The cumulative incidences of cytomegalovirus (CMV) reactivation and CMV disease were 52.5% and 5.1% at 1 year. The incidence of grade 2-4 acute Graft Versus Host Disease (GVHD) was 18.2%. The incidence of chronic GVHD at 2 years was 40.7%, with extensive chronic GVHD occurring in 17.7% of patients. The incidences of relapse and non-relapse mortality (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 overall survival was 74%. Relapse free survival and GVHD free, relapse free survival at 2 years was 70% and 48%. Haplo-HSCT using a peripheral blood graft and PTCy GVHD prophylaxis demonstrates long-term disease control with acceptable rates of NRM for older patients with AML/MDS., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background: A recent randomised trial demonstrated [ 18 F]fluorodeoxyglucose positron-emission tomography in combination with low-dose CT (FDG-PET/CT), compared to standard of care computed tomography (CT) imaging, positively impacted antimicrobial management and outcomes of acute leukaemia and haematopoietic stem cell transplant recipients with persistent and recurrent neutropenic fever. We conducted an economic evaluation from a healthcare perspective alongside the clinical trial., Methods: Unit costs in Australian dollars were applied to all resources used (antimicrobials, diagnostic tests, ICU and hospital bed days). Effectiveness was measured as number of patients with antimicrobial rationalisation, 6-month mortality and quality-adjusted life years (QALYs) derived from patient-reported trial-based health-related quality-of-life. Generalised linear models were used to analyse costs and outcomes. Incremental cost-effectiveness ratios (ICERs) for all outcomes and net monetary benefit (NMB) for QALYs were calculated. We performed bootstrapping with 1000 replications using the recycled predictions method., Results: The adjusted healthcare costs were lower for FDG-PET/CT (mean $49,563; 95%CI 36,867, 65,133) compared to CT (mean $57,574; 95% CI 44,837, 73,347). The difference in QALYs between the two groups was small (0.001; 95% CI -0.001, 0.004). When simulated 1000 times, FDG-PET/CT was the dominant strategy as it was cheaper with better outcomes than the standard CT group in 74% of simulations. The estimated NMBs at willingness-to-pay thresholds of $50,000 and $100,000 per QALY were positive, thus FDG-PET/CT remained cost-effective at these thresholds., Conclusions: FDG-PET/CT is cost effective when compared to CT for investigation of persistent/recurrent neutropenic fever in high-risk patients, providing further support for incorporation of FDG-PET/CT into clinical guidelines and funding., Trial Registration: This trial is registered with ClinicalTrials.gov, NCT03429387., (© 2023. The Author(s).)

The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Management of neutropenic fever in high-risk haematology patients is challenging; there are often few localising clinical features, and diagnostic tests have poor sensitivity and specificity. We aimed to compare how [ 18 F]flurodeoxyglucose ([ 18 F]FDG)-PET-CT scans and conventional CT scans affected the guidance of antimicrobial management and the outcomes of patients with persistent or recurrent neutropenic fever., Methods: We did a multicentre, open-label, phase 3, randomised, controlled trial in two tertiary referral hospitals in Australia. We recruited adults aged 18 years or older who were receiving conditioning chemotherapy for haematopoietic stem-cell transplantation or chemotherapy for acute leukaemia and had persistent (>72 h) or recurrent (new fever beyond 72 h of initial onset interspersed with >48 h defervescence) neutropenic fever. Exclusion criteria were pregnancy, allergy to iodinated contrast, or estimated glomerular filtration rate of less than 30 mL/min. Patients were randomly assigned by computer-generated randomisation chart (1:1) to [ 18 F]FDG-PET-CT or conventional CT. Masking was not possible because of the nature of the investigation. Scans were done within 3 days of random assignment. The primary endpoint was a composite of starting, stopping, or changing the spectrum (broadening or narrowing) of antimicrobial therapy-referred to here as antimicrobial rationalisation-within 96 h of the assigned scan, analysed per protocol. This trial is registered with clinicaltrials.gov, NCT03429387, and is complete., Findings: Between Jan 8, 2018, and July 23, 2020, we assessed 316 patients for eligibility. 169 patients were excluded and 147 patients were randomly assigned to either [ 18 F]FDG-PET-CT (n=73) or CT (n=74). Nine patients did not receive a scan per protocol, and two participants in each group were excluded for repeat entry into the study. 65 patients received [ 18 F]FDG-PET-CT (38 [58%] male; 53 [82%] White) and 69 patients received CT (50 [72%] male; 58 [84%] White) per protocol. Median follow up was 6 months (IQR 6-6). Antimicrobial rationalisation occurred in 53 (82%) of 65 patients in the [ 18 F]FDG-PET-CT group and 45 (65%) of 69 patients in the CT group (OR 2·36, 95% CI 1·06-5·24; p=0·033). The most frequent component of antimicrobial rationalisation was narrowing spectrum of therapy, in 28 (43%) of 65 patients in the [ 18 F]FDG-PET-CT group compared with 17 (25%) of 69 patients in the CT group (OR 2·31, 95% CI 1·11-4·83; p=0·024)., Interpretation: [ 18 F]FDG-PET-CT was associated with more frequent antimicrobial rationalisation than conventional CT. [ 18 F]FDG-PET-CT can support decision making regarding antimicrobial cessation or de-escalation and should be considered in the management of patients with haematological diseases and persistent or recurrent high-risk neutropenic fever after chemotherapy or transplant conditioning., Funding: National Health and Medical Research Council Centre of Research Excellence (APP1116876), Melbourne Health foundation, Gilead Research Fellowship grants supported this study., Competing Interests: Declaration of interests SH has received a grant from Janssen, and honoraria from Celgene, Janseen, Novartis, and Kite/Gilead. OB has received honoraria from MSD and Abbvie. BT has received grants from Sanofi Pasteur, MSD, and Seqirus; received honoraria from Pfizer, MSD, and Gilead; and is on the data safety monitoring board (DSMB) of a study with CSL-Behring. SC has received educational grants from F2G and MSD Australia. JS has received honoraria from Alexian Australasia, Sobi Pharmaceuticals, Novartis, and Takeda; is on the DSMB and advisory board from Prevail Therapeutics; and has a leadership role in the Australian Bone Marrow Donor Registry. MY has received grants from the National Health and Medical Research Council (NHMRC) of Australia, MSD Australia, and the Medical Research Futures Fund and consulting fees, honoraria, and Advisory Board involvement for MSD Australia. TS has received speaker fees from Novartis and is on scientific committees for Biogen and Hartmann DE. SYT and AD have received a grant from Gilead. RH is the honorary director of Neuroendocrine Cancer Australia and PreMIT Pty and is the founder and equity holder of PreMIT Pty. MS has been awarded two NHMRC grants as well as grants from Gilead, Merck, and F2G and honoraria from Pfizer, Merck, and Gilead and is on the DSMB and advisory board of Pfizer, F2G, and Roche with all payments to an institution. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are individually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones., (© 2021 by The American Society of Hematology.)