Richter transformation (RT) is an aggressive lymphoma that arises in patients with chronic lymphocytic leukemia (CLL), most commonly diffuse large B-cell lymphoma (DLBCL-RT). Outcomes remain poor with conventional chemoimmunotherapy, reflecting the role of increased genomic instability and impaired DNA repair in the pathogenesis of RT.. Targeted therapies used in CLL (BTK or BCL2 inhibition) have shown efficacy in RT; however, durable disease control remains elusive, highlighting the need for immunological approaches. This review discusses the clinical evidence supporting immunologic approaches in RT, focusing on allogeneic stem cell transplantation, chimeric antigen T-cell (CAR T-cell) therapy, bispecific T-cell directing antibodies, and checkpoint inhibition. Allogeneic stem cell transplantation can provide long-term remission in selected patients; however, there are considerable barriers, such as the requirement for adequate patient fitness and pre-transplant disease control. Post-approval observational studies have provided evidence of the efficacy and safety of CAR T-cell therapy, as well as the risk of immunologic toxicity. Early phase studies on bispecific antibodies and checkpoint inhibition have demonstrated disease activity, and multiple studies on combination strategies are ongoing. Future priorities include optimizing disease control prior to immunologic therapy, testing novel combination approaches and conducting correlative studies to optimize future therapeutic strategies.

Chimeric antigen receptor T (CAR T) cell therapy has improved outcomes in several hematological malignancies but is associated with immune and hematologic toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hematotoxicity (ICAHT), and immune effector cell-associated hemophagocytosis-like syndrome (IEC-HS). Although diagnostic and grading criteria have been established, there is no consensus on the optimal use of prediction tools. This review describes the incidence of these toxicities and highlights the utility of available tools for predicting and risk-stratifying patients. These studies focus on clinical scores, immunoassays by analyzing CAR T-cell expansion and imaging biomarkers of tumor burden. Among the former, the EASIX score and its derivatives have been validated for predicting severe CRS and ICANS, whereas the CAR-HEMATOTOX score has been validated for predicting prolonged cytopenia. Emerging prediction models aim to integrate these domains to allow early intervention or de-escalation of immunosuppression therapy.

In this retrospective analysis of 584 patients who received CAR T-cell therapy for LBCL at six Australian centres we found no association between time of infusion and outcome, accounting for confounders, suggesting minimal clinical impact of chronobiology in this setting.

Long-term allergies can exhibit persistent concentrations of circulating immunoglobulin E (IgE). Here, we examined the lifespan of IgE antibody-secreting cells (ASCs) to determine whether the IgE that sustains allergies receives contributions from long-lived cells or relies more heavily on constant ASC production. In mouse aeroallergy, IgE ASCs localized to the lungs, mediastinal lymph nodes, spleen, and bone marrow (BM). IgE ASC production continued for months after allergen exposure ceased. We identified long-lived IgE ASCs residing predominantly outside the BM, with a half-life exceeding 49 days; in contrast, most IgE ASCs had a 3-day half-life. Long-lived IgE ASCs matured phenotypically, became quiescent, retained their surface B cell receptors, but showed low expression of the BM homing receptor CXCR4. They were hierarchically more reliant on the navitoclax-sensitive anti-apoptotic molecules BCL2, BCLXL, and BCLW than MCL1. Thus, continual production of short-lived IgE ASCs and retention of long-lived IgE ASCs outside the BM together drive IgE persistence, perpetuating allergic disease.

The bone marrow microenvironment is intimately linked to the biology that underpins the development and progression of multiple myeloma. However, the complex cellular and molecular features that form bone marrow niches are poorly defined. Here, we used subcellular spatial transcriptomics to profile the expression of 5001 genes in human bone marrow in the context of multiple myeloma. Using this approach, we explored the plasma cell and stroma ecosystem in bone marrow trephine biopsy specimens (herein referred to as trephines) from 21 individuals, including 7 with premalignant disease and 10 with newly diagnosed multiple myeloma. Using spatial transcriptomics in conjunction with an optimized trephine biobanking methodology, we could resolve major components of the human bone marrow microenvironment and reliably characterize distinct plasma cell populations in samples from healthy, premalignant disease and active myeloma. When plasma cells were visualized in the context of location, we detected spatially restricted subpopulations of plasma cells in 5 of 10 newly diagnosed myeloma trephines. Surprisingly, the composition of hematopoietic and stromal microenvironments varied significantly between newly diagnosed myeloma trephines. Furthermore, these differences in microenvironments were also observed within trephines that had spatially restricted plasma cell subpopulations. Thus, these data are not consistent with the hypothesis that a universal bone marrow microenvironment supports the expansion of malignant plasma cells in myeloma. Instead, we propose that myeloma subpopulations form distinct microenvironments and can vary both between patients and spatial locations.

Aim: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy has demonstrated outstanding response rates and durability in heavily pre-treated (³3) myeloma patients (CARTITUDE-1), and superiority compared to standard-of-care in lenalidomide-refractory myeloma patients after 1-3 prior lines of therapy (CARTITUDE-4). Patients with extramedullary myeloma appear to have a reduced progression-free survival as compared to their respective counterparts in subgroup analyses. We aimed to study the early biodistribution of cilta-cel using a novel nanoparticle-based tracking technology, combined with immunological correlative studies on blood, bone marrow and plasmacytoma biopsies, in order to elucidate the biology of resistance in extramedullary myeloma and identify opportunities for novel interventions to improve outcomes. Method: Copper-64 (Cu-64) super paramagnetic iron oxide nanoparticles (SPION) is a dual PET-CT PET-MRI cell tracking technology that is suited for studying early in vivo trafficking after adoptive cellular therapies. We performed pre-clinical studies to assess the effect of Cu-64-SPION labelling on in vitro CAR T-cell function. We then initiated CAR-T cell therapy in Advanced Myeloma with Extramedullary disease - an in vivo imaging and molecular monitoring study (CARAMEL). Myeloma patients with measurable extramedullary disease and ³2 prior lines of therapy (including a proteasome inhibitor and an immunomodulatory imide drug (IMiD) are eligible. Patients receive 70% unmanipulated cilta-cel, followed by 30% Cu-64 SPION-loaded cilta-cel. Dual Cu-64 PET-CT and PET-MRI imaging is performed over the first 4 days, followed by MRI alone at later time points. Results: Pre-clinical studies demonstrated no deleterious effect of Cu-64 SPION labelling on cilta-cel viability, phenotype, killing or cytokine release in vitro. To date, three Caucasian, male patients, ranging in age from 55 to 59, have been enrolled and treated on CARAMEL. Preliminary imaging analysis demonstrates dynamic biodistribution initially within lung with trapping in the pulmonary vasculature, and migration of cells into the systemic circulation over time, including liver, spleen and bone marrow. In patient 1 the distribution of radioisotope at 12 hrs was 21% to liver, 47% to spleen, 3% to bone marrow. On the pre-infusion FDG-PET a distinct lesion was visible in the right pelvis, indicative of a bone-based plasmacytoma. On day 1 and day 3 post infusion, a rim of activity was seen on the Cu-64 PET, suggesting Cu64-SPION labelled cilta-cel tracking. The patient also had a soft-tissue plasmacytoma in the left axilla, with no tracking observed over the first four days, despite achieving a partial response on the D+28 FDG-PET. Patient 2 had numerous nodal as well as soft-tissue sites of myeloma involvement. The distribution of radioisotope at 12 hrs was 51% to liver, 14% to spleen, and 2.5% to bone marrow. Patient 3 had numerous subcutaneous and soft-tissue lesions in his pancreas and nasopharynx. The distribution of radioisotope at 12 hrs was 53% to liver, 16% to spleen, and 3% to bone marrow. Specific uptake at the soft-tissue plasmacytomas was not observed over the first 4 days. Analysis of longer-term tracking on MRI by the SPION component of the nanoparticles and correlative immunological studies on blood, marrow and plasmacytoma biopsies is ongoing. Conclusion: First results from CARAMEL confirm the ability of Cu-64 SPION tracking technology to visualise the dynamic biodistribution of Cu-64 SPION-loaded cilta-cel. Enrolment in CARAMEL is ongoing and further research is needed to ascertain the sensitivity for detecting migration to bone-based or soft-tissue plasmacytomas. (NCT05666700).

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. Adoptive T-cell immunotherapy offers promise to patients who are resistant to standard anti-viral strategies. Here the authors describe clinical observations in patients with viral complications treated with adoptive immunotherapy over the last 15 years.

Aim: Autologous anti-CD19 CAR T-cell therapy is an established standard-of-care (SOC) for relapsed/refractory (R/R) LBCL, but successful delivery requires disease control through the manufacturing period. The effects of bridging radiotherapy (RT) on outcome are unclear and impacted by disease factors such as bulk and distribution. We sought to compare outcomes of patients receiving RT-alone versus systemic-based bridging therapies (BT) delivered after apheresis and prior to axi-cel infusion. Method: Data were collected retrospectively for all patients with R/R LBCL treated with SOC axi-cel between 2020-2024 with ≥3 months of follow-up post CAR T-cell infusion. Patients were included in the RT-alone group if they received radiotherapy and no systemic therapy (apart from corticosteroids) as their BT. All other patients were included in the systemic-based bridging (ST) group. The primary endpoints were complete response (CR) rate and progression-free survival (PFS) measured from date of axi-cel infusion. We performed univariable and multivariable Cox proportional hazards (CoxPH) modelling of candidate predictive factors at two time points: (1) apheresis, and (2) pre-LD chemotherapy. Results: 98 patients received axi-cel with a median follow-up of 12.9 months. 35 patients received RT-alone and 63 patients received ST (including 22 patients in the ST group who received systemic and RT to a dominant mass as BT). Baseline characteristics were similar between RT-alone and ST groups at both the pre-apheresis and pre-LD timepoint. Median age pre-LD was 63 (range 22-81), RT median age 62 (range 42-80); ST median age 64 (range 22-81)), pre-LD ECOG ≥1 n=38, 39% (RT n=12, 34%; ST n=26, 41%), 54% had elevated LDH pre-apheresis (RT n=21, 62%; ST n=31, 49%), 42% had elevated LDH pre-LD (RT n=15, 43%; ST n=26, 41%), median total metabolic tumour volume (TMTV, ml) pre-apheresis was 48 (range 0 - 2809, RT median 46 (range 1 -1562); ST median 48.5 (range 0 - 2809)), median TMTV pre-LD was 21.5 (range 0 - 2777, RT median 22 (range 0 - 948); ST median 21 (range 0 - 2777)), 64% had stage 3-4 disease pre-apheresis (RT n=16, 46%; ST n=45, 75%) and 56% of patients had stage 3-4 disease pre-LD (RT n=19, 54%; ST n=36, 57%). Within the RT group, the median dosage was 30 (range 8-40) Gy delivered in a median of 10 fractions (range 1-20), with volumetric modulated arc therapy (VMAT) utilised in the 14/17 patients with assessable data. The CR rate post axi-cel infusion was 76%: 85% in the RT and 71% in the ST group (p=0.21). PFS at 12 months was 58% (95% CI: 0.49 - 0.69) for all patients: 75% (95%CI: 0.61 - 0.92) in the RT and 49% (95% CI: 0.38 - 0.64) in the ST group (p=0.02, log-rank test). Within the ST group, those who received concurrent RT (n=22) had near identical 12-month PFS when compared to the remaining patients in the ST group (n=41) - 12-month PFS 53% (95% CI: 0.35 - 0.79) versus 53% (95% CI: 0.37 - 0.75). On univariable CoxPH modelling, elevated LDH (Hazard Ratio (HR) 2.29, 95% CI 1.22 - 4.29) and TMTV continuous per 100ml (HR 1.10, 95% CI 1.05 - 1.15) were negatively associated with PFS at the pre-LD time point. This association was not seen at apheresis (elevated LDH HR 1.15 (95% CI 0.61 - 2.14) and TMTV HR 1.03 (95% C1 0.97 - 1.08)) suggesting that the impact of these risk factors is modifiable with BT. On multivariable CoxPH modelling of PFS adjusted for pre-LD ECOG, LDH, TMTV, and stage, RT alone in comparison to ST was associated with improved PFS (HR 0.41, 95% CI 0.19 - 0.88). Rates of grade 3 or above CAR T-cell associated toxicity were similar between groups, namely cytokine release syndrome n=2, 2% (RT n=1, 3%; ST n=1, 2%), immune effector cell associated neurotoxicity syndrome n=15, 15% (RT n=6, 17%; ST n=9, 14%), month 3 neutropenia n=13, 17% (RT n=7, 21%; ST n=6, 13%) and thrombocytopenia n=7, 9% (RT n=1, 3%; ST n=6, 15%). Conclusion: Bridging with radiotherapy-alone to axi-cel was associated with improved CR rates and PFS for LBCL in third-line and beyond, over systemic therapy-based BT. Multivariable analysis, adjusted for predictors of poor PFS, suggests the effect is not simply explained by better disease control at infusion. In this retrospective analysis it was not possible to separate the impact of disease distribution that is amenable to radiotherapy from the impact of radiotherapy itself. However, given the favourable outcomes seen, radiotherapy should be considered as part of the bridging strategy wherever feasible.

Background: Allogeneic stem cell transplantation (alloSCT) remains the only curative therapy for myelodysplastic syndromes (MDS). Outcomes in alloSCT for MDS are often pooled with AML, making the interpretation of risk factors and application to clinical practice challenging. Prior studies have demonstrated impact of adverse cytogenetics, molecular mutations, and high-risk subgroups on survival post alloSCT in MDS. Aims: A retrospective study was conducted to describe current transplant practice in Australian centres and analyse outcomes of MDS patients undergoing alloSCT to identify factors predicting survival following transplant. Methods: Consecutive patients with MDS who received alloSCT across five Australian transplant centres from 2013-2020 were included. Survival analysis with Kaplan-Meier and Cox proportional hazards was used and linear regression was implemented for variable selection prior to multivariate analysis. Analysis was performed using R (2024.04.2+764) and p value < 0.05 was considered statistically significant. Results: 289 patients (pts) who received their first alloSCT for MDS from 2013 to 2020 were included. Median age of the cohort was 55 years (19-75 yrs) with 38.4% female patients. MDS subtype at diagnosis (WHO 2016) included 65 (23.5%) MDS-EB1, 93 (33.6%) MDS-EB2, 76 (27.4%) MDS-MLD, 6 (2.2%) MDS-RS-SLD, 11 (3.9%) MDS-RS-MLD, 3 (1.1%) MDS-Del(5q) and 16 (5.8%) MDS-U. At diagnosis 55 (22.2%), 47 (18.9%) and 35 (14.1%) pts had intermediate, poor and very poor cytogenetics. IPSS-R risk stratification at diagnosis revealed 7 (2.6%) very low, 62 (23.3%) low, 73 (27.4%) intermediate, 82 (30.8%) high and 42 (15.78%) very high-risk pts. 140 (48.4%) patients had received azacitidine therapy prior to alloSCT, with a median of 6.8 cycles (1-35). A further 23 (7.9%) pts received chemotherapy, and 16 (5.5%) received other treatment (including lenalidomide) prior to alloSCT. 81 pts (43.08%) were transfusion dependant (WPSS criteria) at transplant. Median time to transplant from diagnosis was 8.8 months (1.7-241.4). 31 pts (14.7%) had ≥10% BM blasts pre-SCT and 83 (37.2%) had an HCI-CI of ≥ 3. Majority 173 pts (59.9%) had matched unrelated donor transplants, with 11 (3.8%) mismatched unrelated donor, 88 (30.4%) matched sibling donor and 17 (5.9%) haploidentical donor transplants. 208 (79%) received reduced intensity conditioning, 179 (61.9%) pts received fludarabine and melphalan and 79 (27.3%) pts received in-vivo T cell depletion with ATG/thymoglobulin. At a median follow up was 30 months, 151 patients were alive without progression/relapse, 83 died without progression/relapse and median overall survival was 83.9 months (62.3-105.7mnths). At 2-year post transplant overall survival was 62.4% (56.4-67.7), relapse-free survival was 58.9% (52.9-64.5), cumulative relapse/ progression rate was 21.1% (16.3-27.1), and non-relapse mortality was 29% (24.3-35.7), Notably, univariate analysis of pre-transplant therapy demonstrated inferior survival in patients who received azacitidine (HR = 0.66 p = 0.016). This association was preserved when analysis was restricted to intermediate and higher IPSS-R groups (HR = 0.47 p = 0.002). Patients attaining < 5% blasts with azacitidine prior to alloSCT showed a non-significant superior survival (HR = 1.77 p = 0.055). Ongoing transfusion dependence at transplant was associated with a non-significant trend towards inferior survival (HR = 0.68 p = 0.082). Multivariate analysis with Cox proportional hazards was performed to evaluate whether adjustments to account for disease resolved the influence of prior azacitidine and transfusion dependence. This demonstrated inferior post alloSCT survival amongst patients who received prior azacitidine (HR = 0.25, p = 0.009) and patients who had transfusion dependence (HR = 0.33, p = 0.028) when adjusted for established disease- and patient-risk factors. Further unrelated donor type (HR = 0.37 p = 0.034), very poor cytogenetic (HR = 0.43 p = 0.002) and very high IPSS-R (HR = 0.52 p = 0.023) were significantly associated with inferior survival post-transplant in multivariate analysis. Further analysis will be undertaken to understand the association of azacitidine with inferior survival Conclusion: Our multisite study identifies prior azacitidine therapy and ongoing transfusion dependence as associated with inferior post-transplant survival.

Introduction: Multiple myeloma is haematological malignancy that remains difficult to cure despite recent therapeutic advances. Novel T cell redirecting therapies such as CAR-T cells and bispecific antibodies have shown promising efficacy in the relapse setting However, durable responses have yet to be achieved. Mechanisms of resistance and the dynamics of immune cell interactions within the bone marrow remain poorly defined. Here, we used in situ imaging of the bone marrow in living mice (intravital imaging) to characterise immune cell interactions with myeloma in the context of murine BCMA bispecific antibody therapy. Methods: We used a traceable myeloma cell line derived from the spontaneous Vk*MYC mouse model (Vk14451-GFP) that recapitulates human disease. To visualise the cytotoxic immune response, Vk14451 cells were transplanted into recipient mice where CD8 T cells were labelled with fluorescent tomato protein (E8I-Cre tomato). >Five weeks post-transplant, multi-day intravital imaging of the calvarium bone marrow was performed using 2-photon microscopy. This imaging approach was performed in the absence or presence of murine BCMA bispecific antibody. Mice were treated with 1 to 4 doses of the bispecifc antibody to visualise immune and myeloma responses. Results: Direct visualisation of T cells in situ in the absence of therapeutic intervention revealed CD8 T cells were excluded from areas of myeloma infiltration. Furthermore, CD8 T cells that gained entry to tumour had significantly altered cell interactions compared to T cells in healthy bone marrow. Following administration of a dose of bispecific antibody, we observed drastic changes in the biology and spatial distribution of CD8 T cells within the bone marrow. Surprisingly, following activation the immunosuppressive myeloma microenvironment had no effect on the ability of CD8 T cells to engage with myeloma cells within tumour foci and undergo rapid expansion. However, we observed significant changes in the persistence of T cells within the myeloma foci. In addition, in cohorts of mice that received repeated dosing of bispecific antibody, we observed loss of tumour control. In these mice, we still observed access of T cells to the tumour foci and active proliferation. However, we did not observe sustained interactions and active killing of MM cells suggesting development of a tumour agnostic state of T cells. Conclusion: This dynamic analysis of immune cell interactions with myeloma within the bone marrow microenvironment suggests that targeting persistence of activated T cells may play a key role in the therapeutic efficacy of T cell redirecting therapies. Declaration: This research was supported by Bristol Myers Squibb. The company had no role in analysing the data or preparing the abstract

Allogeneic transplant (HSCT) is standard consolidation therapy for patients (pts) with newly diagnosed acute myeloid leukemia (AML) with adverse risk (AR) cytogenetics induced with intensive chemotherapy (IC), but whether this occurs commonly in routine practice is uncertain. The Australasian Leukaemia and Lymphoma Group (ALLG) National Blood Cancer Registry (NBCR) (ANZCTR 12612000337875) prospectively collects longitudinal data from diagnosis on treatment and outcomes for patients with AML from participating centres in Australia and New Zealand. The Australia and New Zealand Transplant and Cellular Therapy (ANZTCT) Registry holds outcome data on all transplants in ANZ. We established data linkage between the ALLG NBCR and the ANZTCT Registry to describe the outcomes and patterns of treatment particularly HSCT in first response for fit pts with newly diagnosed AML bearing non-favourable cytogenetics across ANZ. Methods: NBCR AML participants treated with IC were matched to the ANZTCT registry using the date of birth, sex, date of diagnosis (DOD), and diagnosis. Survival analysis was performed using the Kaplan-Meier method from the time of diagnosis or as a landmark from the time of first composite complete response (CRc = CR+CRi+MLFS). The impact of baseline variables, including MRC 2010 cytogenetic risk stratification, on survival was assessed using univariable and multivariable Cox proportional hazards (CoxPH) models, with transplant status treated as a time-dependent variable. Results: Of the cohort of 600 newly diagnosed AML participants obtained from NBCR between 2013 and 2018, 102 were excluded due to non-intensive treatment, other diagnoses, favourable /no cytogenetics or incomplete data. Of the final analysis cohort of 498 AML pts treated with IC, 386 (78%) had intermediate risk (IR) and 112 (22%) had adverse risk (AR) cytogenetics. 151 (30%) and 71(14%) had NPM1 and FLT3-ITD mutations at diagnosis, respectively. The median age was 58 years (17-78y). 48% of participants were females. A total of 334 (67%) pts received a standard dose of cytarabine and idarubicin. The remainder received intermediate/high-dose cytarabine-based induction. A total of 368 (74%) patients achieved a composite complete response (CR/CRi/MLFS), with 4% induction death. Major proportion 250 (50%) received a single consolidation chemotherapy post-response and 87 (18%) received 2 or more consolidations. 125 (25%) pts underwent HSCT in the first response (transplant cohort (TC)), whereas 373 pts were treated with IC without HSCT in the first response (No Transplant Cohort (NTC)). Pts in the TC were younger (median age, 50 vs. 60 years, P<0.0001). 82 (66%) TC and 168 (45%) NTC pts received a single cycle of consolidation chemotherapy while 19 (15%) TC and 68 (17%) NTC received two or more consolidations respectively. 80 (23%) and 40 (51%) pts in the IR and AR groups, respectively, received HSCT after the first CRc. Median time to matched sibling and unrelated donor HSCT from CRc was 2.1 (0.7-5.3) and 3.7 (0.7-11.5) months respectively. Seventy-eight (62%) and 42 (34%) pts underwent matched unrelated and sibling donor transplantation, respectively. Sixty-two (50%) received reduced-intensity conditioning. Peripheral blood stem cells were the graft source in 113 pts (90%) and double cords in 5 (4%). In vivo T-cell depletion for GVHD prophylaxis was used in 52 (42%). At a median follow-up of 64.3 months, the median overall survival (OS) from diagnosis in IR and AR AML pts was 47.6 (33.5-78.7) and 9.4 (7.4-13.7) months, respectively. The median OS landmarked from the first CRc was superior in the TC vs NTC in both the IR (not reached vs 46.6 months, P<0.0001) and AR groups (14.5 vs 9.6 months, P<0.0001). There was no impact of time to HSCT from CRc. In multivariable Cox PH modelling, the hazard ratio (HR) for AR vs. IR was 3.36 (95% C.I. 2.55-4.42), and the HR for TC vs. NTC (as a time-dependent variable) was 0.18 (95% C.I. 0.13-0.26). Analysis of factors influencing whether HSCT was performed is ongoing. Conclusions This first AML and HSCT registry data linkage analysis conducted in Australia and New Zealand means we can now reliably track pts undergoing HSCT from diagnosis. Our data represent the first report of the treatment patterns in non-favourable risk AML in ANZ and confirm the superior outcomes with HSCT in both IR and AR AML. Further work is required to improve utilization of HSCT in AML patients to improve survival outcomes.

Introduction Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common side-effect of chimeric antigen receptor T-cell (CAR-T) therapy, with symptoms ranging from mild to occasionally life-threatening. The neurological, cognitive, psychiatric and psychosocial sequelae of ICANS are diverse and not well defined, posing a challenge for diagnosis and management. The recovery trajectory of the syndrome is uncertain. Patients are rarely examined in this population pretherapy, adding a layer of complexity to specifying symptoms pertinent solely to CAR-T treatment. We present a protocol of a prospective longitudinal research study of adult patients in a single Australian haematology service undergoing CAR-T therapy. The study will describe neurocognitive features specific to ICANS, characterise the underlying syndrome, capture recovery, identify predictors of differential postinfusion outcomes and determine a set of cognitive instruments necessary to monitor patients acutely.Methods and analysis This is a prospective longitudinal study that comprises neuropsychological and neurological examinations occurring prior to CAR-T, during the acute post-treatment period, 28 days, 6 months and 12 months post infusion. Data will be sourced from objective psychometric measures, clinical examinations, self-report questionnaires of psychopathology and accounts of subjective cognitive complaint.Ethics and dissemination This study aims to guide diagnosis, management and monitoring of neurocognitive features of CAR-T cell therapy. Results of this study will be disseminated through publication in peer-reviewed journals and presentations at scientific conferences. All procedures involving human subjects/patients were approved by the Peter MacCallum Cancer Centre Human Research Ethics Committee (21/145).