Paediatric-inspired acute lymphoblastic leukaemia (ALL) regimens have led to improved leukaemic outcomes in adults. However, avascular necrosis (AVN) has emerged as a debilitating orthopaedic complication. AVN is likely multifactorial, with corticosteroids and asparaginase therapy playing key roles in its pathogenesis. We assessed the incidence and potential risk factors for AVN, in older adolescent and adult patients with ALL treated with the FRALLE-93 protocol across three Australian tertiary centres. AVN occurred in 24% of 59 patients, primarily affecting hip and knee joints. Diagnosis occurred at a median of 11.7 months from commencement of chemotherapy. No association was identified between AVN risk and sex, age, BMI, smoking status and vitamin D level. The majority of patients required orthopaedic intervention (64%). Approximately two thirds had chronic pain or impaired mobility. AVN risk in adult patients with ALL receiving FRALLE protocols appears at least comparable to rates reported in paediatric cohorts.

BACKGROUND:Immune responses may determine natural history and optimal management of cytomegalovirus (CMV) reactivation following allogeneic hematopoietic cell transplantation (alloHCT). To assess this, we performed serial QuantiFERON-CMV (QFCMV, Qiagen) and QuantiFERON-Monitor (QF-monitor, Qiagen) tests, measuring CMV-specific T cell interferon-γ responses (IFNγ), and stimulators of innate (TLR7) and adaptive immunity (CD3), respectively. METHODS:In a prospective multicenter study of adult CMV-seropositive alloHCT recipients, QFCMV and QF-monitor tests were collected serially. Association with CMV outcomes was analyzed using multivariable Cox and mixed effects regression analysis. RESULTS:Overall, 119 patients had 385 QFCMV tests (median [IQR]:3 [3-4] per patient). csCMVi occurred in 45.4% patients. QFCMV reactivity was achieved in 16% of patients at 6 weeks, 38.3% at 12 weeks, and 40.2% any time during the study. Reactivity was predictive of lower peak CMV viral load in the 6 weeks following testing (-0.41 × log10 [95% CI -0.77 to -0. 04 × log10], p = 0.02), but did not impact csCMVi. Analysis of mitogen-stimulated IFNγ responses within QFCMV testing showed reduced risk of csCMVi in the following 6 weeks (adjusted HR 0.92 [95% CI 0.85-0.99], p = 0.025) and each 1 IU/mL IFNγ increase was associated with decreased peak viral load (-0.02 × log10 [95% CI -0.03 to 0.00 × log10], p = 0.02). QF-monitor was not associated with any CMV outcomes. CONCLUSION:QFCMV reactivity was associated with lower peak CMV viral load but not csCMVi. Mitogen-stimulated IFNγ response correlated with csCMVi, suggesting a role for broader assessment of cellular immunity post-transplant. Despite incorporating adaptive immunity measures, QF-monitor was limited in assessing CMV risk. QFCMV reactivity was infrequently achieved in the early post-allogeneic stem cell transplant period. Qualitative QFCMV result was associated with peak CMV viral load but not clinically significant infection, while magnitude of the mitogen response predicted reduction in clinically significant CMV infection.

For patients with chronic myeloid leukemia in chronic phase (CML-CP), disease management, treatment experiences, and decisions around switching therapies due to resistance or intolerance can have significant impacts on their lives. Experiences and perspectives regarding the roles of patients and treating physicians in shared decision-making are poorly understood. The CML Survey on Unmet Needs (CML SUN), the largest CML survey to date, was initiated to gather insights from patients with CML-CP and physicians on disease management, including treatment goals, decision-making, satisfaction, tolerability and the impact of CML on daily life. The survey was deployed in 11 countries with 361 patient and 198 physician participants and comprised separate questionnaires for each group. Results indicated that nearly three-quarters of physicians saw themselves as the ultimate initial treatment decision-makers; only a quarter of patients reported that these decisions were discussed and decided together with their physician. Nearly half of physicians reported making treatment decisions across all lines of therapy with little to no input from the patient. Disparities between patient and physician opinions were observed regarding treatment goals, especially the balance between efficacy and tolerability. The CML SUN highlights the need for improvements in communication about treatment options and the importance of shared treatment decisionmaking to unify treatment goals.

Asciminib is a novel allosteric STAMP (specifically targets the ABL myristoyl pocket) inhibitor of the BCR::ABL1 oncogene. Real-world clinical outcomes of patients with tyrosine kinase inhibitor (TKI)-resistant/intolerant chronic myeloid leukaemia (CML) in Australia on the Managed Access Programme for asciminib showed higher molecular responses for those with intolerance versus resistance ± intolerance to their last TKI. There remains a clinical need to improve outcomes in patients with CML who have resistance to multiple TKIs, especially in the ponatinib-pretreated cohort.

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.

Abstract Asciminib is a myristoyl site BCR::ABL1 inhibitor approved for patients with chronic-phase chronic myeloid leukemia (CP-CML) failing ≥2 prior lines of therapy. The Australasian Leukaemia and Lymphoma Group conducted the Asciminib Evaluation in Newly Diagnosed CML study to assess efficacy of asciminib for newly diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily. Patients with treatment failure, defined as BCR::ABL1 of >10% at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib, or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1% to 10% at 6 months, >0.1% to 1% at 12 months, or >0.01% to 1% at 18 months, the asciminib dose was increased to 80 mg twice daily. With a median follow-up of 21 months (range, 0-36), 82 of 101 patients continue asciminib. Most common reasons for treatment discontinuation were adverse events (6%), loss of response (4%), and withdrawn consent (5%). There were no deaths; 1 patient developed lymphoid blast crisis. The coprimary end points were early molecular response (BCR::ABL1 of ≤10% at 3 months), achieved in 93% (96% confidence interval [CI], 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI, 70-87%), respectively. Cumulative incidence of molecular response 4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline CP-CML therapy leads to high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. This trial was registered at https://www.anzctr.org.au/ as #ACTRN12620000851965.

Arsenic trioxide is an essential component of therapy for acute promyelocytic leukaemia (APL) and is currently dosed on actual body weight with no upper limit. Arsenic-induced neurotoxicity is a well-recognised complication; however, there is uncertainty about its relationship to arsenic dose and obesity. We conducted a large multicentre retrospective study of 487 patients with APL treated with arsenic-based therapy across 23 sites in Australia from 2008 to 2023. The primary outcome was incidence of neurotoxicity, and secondary outcomes included relationship of neurotoxicity to obesity and cumulative arsenic dose. Any-grade neurotoxicity occurred in 113 (23%) patients, predominantly peripheral neuropathy (91%). Most events were grade 1-2 severity (85%), with grade 3 events in 12% and grade 4-5 in 3%. The incidence of neurotoxicity increased with BMI (non-obese: 16%, obesity class I: 25%, obesity class II-III: 41%; p < 0.001). On univariable analysis, obesity class I (OR 1.81, p = 0.036), obesity class II-III (OR 3.93, p < 0.001), weight >100 kg (OR 2.72, p < 0.001), daily arsenic trioxide dose >15 mg (OR 5.05, p < 0.001) and cumulative induction dose >500 mg (OR 3.95, p < 0.001) were all significantly associated with neurotoxicity. Obesity class II-III and induction dose >500 mg remained significant on multivariable analysis. Our study highlights the strong association between BMI, arsenic trioxide dose and neurotoxicity. Pre-emptive dose reductions should be considered for obese patients receiving high doses of arsenic.

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

Infection and lymphopenia are established bendamustine-related complications. The relationship between lymphopenia severity and infection risk, and the role of antimicrobial prophylaxis, is not well described. This multicentre retrospective study analysed infection characteristics and antimicrobial prophylaxis in 302 bendamustine-treated indolent non-Hodgkin lymphoma patients. Lymphopenia (<1 × 109/L) was near universal and time to lymphocyte recovery correlated with cumulative bendamustine dose. No association between lymphopenia severity and duration with infection was observed. Infections occurred in 44% of patients (50% bacterial) with 27% hospitalised; 32% of infections occurred ≥3 months post bendamustine completion. Infection was associated with obinutuzumab and/or maintenance anti-CD20 therapy, prior therapy and advanced stage. Twenty-four opportunistic infections occurred in 21 patients: ten varicella zoster virus (VZV), seven herpes simplex virus (HSV), one cytomegalovirus, one progressive multifocal leucoencephalopathy, one nocardiosis, one Pneumocystis jiroveci pneumonia (PJP) and three other fungal infections. VZV/HSV and PJP prophylaxis were prescribed to 42% and 54% respectively. Fewer VZV/HSV infections occurred in patients receiving prophylaxis (HR 0.14, p = 0.061) while PJP prophylaxis was associated with reduced risk of bacterial infection (HR 0.48, p = 0.004). Our study demonstrates a significant infection risk regardless of lymphopenia severity and supports prophylaxis to mitigate the risk of early and delayed infections.

Acute lymphoblastic leukaemia (ALL) in 20%-30% of adult patients contains the Philadelphia (Ph+) chromosome. Historically, Ph+ ALL denoted a markedly inferior outcome and long-term survival in the absence of an allograft was uncommon. However, the advent of targeted therapy directed against the BCR::ABL1 fusion protein with various tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis, resulting in a number of treatment controversies in allograft-eligible patients. Which is the best TKI to use in induction? What is the clinical relevance of the subdivision of Ph+ ALL into multilineage vs lymphoid types? Do all patients in first morphological complete remission (CR1) after induction and consolidation with chemotherapy/TKI require an allograft? If not, what risk factors predict a poor outcome without an allograft? Can chemotherapy-free approaches, such as blinatumomab in conjunction with more potent TKIs, obviate the need for an allograft in high-risk patients? What is the best strategy to deal with persistent or emerging minimal residual disease both pre- and post-transplant? Is maintenance TKI indicated in all patients post allograft? Can salvage therapy and a subsequent allograft cure patients who relapse after not being transplanted in CR1? This manuscript reviews the latest data influencing contemporary management and discusses these controversies.

The Philadelphia-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of overlapping bone marrow disorders defined by characteristic peripheral blood counts and bone marrow morphological findings in conjunction with recurrent somatic mutations. The accurate diagnosis and subclassification of MPN relies upon careful reporting of bone marrow morphology combined with ancillary information in an integrated pathology report. This co-operative trial group study ALLG MPN01 (ANZCTR:12613000138785), led by the Australasian Leukaemia & Lymphoma Group (ALLG), aimed to describe the current approach to diagnosis of MPN in routine practice. Specifically, we assessed the frequency with which bone marrow biopsies were performed, and the adherence of reporting pathologists to recommendations contained in the revised 2016 WHO classification pertaining to MPN. We reviewed the diagnosis of 152 patients from eight institutions who were enrolled in a national MPN registry of the ALLG between 2010 and 2016. The ALLG MPN01 registry is now closed to recruitment. Key features were extracted from pathology reports provided to the registry. Bone marrow biopsies were performed in 112/152 cases (74%). The pathological information entered was concordant with the stated clinical diagnosis in 75/112 cases (67%). The main reasons for discordant results were incomplete descriptions of megakaryocyte topography and morphology, inconsistent grading of reticulin fibrosis, and failure to integrate the available morphological and ancillary clinicopathological information. In this retrospective audit, 26% of MPN patients did not undergo a diagnostic bone marrow biopsy. In those who did, the specific MPN subtype may not have been reported correctly in 33% of cases, as evidenced by inconsistent features reported or insufficient information to assess. A more standardised approach to bone marrow reporting is required to ensure accuracy of MPN diagnoses and consistent reporting to cancer registries and clinical trials.

Budesonide is a 'non-absorbable' corticosteroid often used for gut graft versus host disease. Systemic exposure is usually minimal because of metabolism by cytochrome (CYP) 3A4 in enterocytes and the liver. However, concomitant use of posaconazole and voriconazole, inhibitors of CYP3A4 commonly used as antifungal prophylaxis in allograft patients receiving immunosuppression, can lead to substantial systemic steroid exposure. This paper describes a case of severe iatrogenic Cushing syndrome and tertiary adrenal insufficiency because of this interaction, highlighting the necessity for improved awareness of this phenomenon.

The phase III GALLIUM trial assessed the safety and efficacy of obinutuzumab-based versus rituximab-based immunochemotherapy in patients with previously untreated follicular lymphoma (FL) or marginal zone lymphoma (MZL). At the primary analysis, the trial met its primary end point, demonstrating improvement in investigator-assessed progression-free survival (PFS) with obinutuzumab-based versus rituximab-based immunochemotherapy in patients with FL. We report the results of the final analysis in the FL population, with an additional exploratory analysis in the MZL subgroup. Overall, 1202 patients with FL were randomized 1:1 to obinutuzumab- or rituximab-based immunochemotherapy followed by maintenance with the same antibody for up to 2 years. After a median 7.9 (range, 0.0-9.8) years of follow-up, PFS remained improved with obinutuzumab- versus rituximab-based immunochemotherapy, with 7-year PFS rates of 63.4% versus 55.7% (P = 0.006). Time-to-next antilymphoma treatment was also improved (74.1% versus 65.4% of patients had not started their next antilymphoma treatment at 7 y; P = 0.001). Overall survival was similar between the arms (88.5% versus 87.2%; P = 0.36). Irrespective of the treatment received, PFS and OS were higher in patients with a complete molecular response (CMR) versus those with no CMR (P < 0.001). Serious adverse events were reported in 48.9% and 43.4% of patients in the obinutuzumab and rituximab arms, respectively; there was no difference in the rate of fatal adverse events (4.4% and 4.5%, respectively). No new safety signals were reported. These data demonstrate the long-term benefit of obinutuzumab-based immunochemotherapy and confirm its role as a standard-of-care for the first-line treatment of advanced-stage FL, taking into account patient characteristics and safety considerations.

Supplementary Figure 3. Effects of kinase inhibitor treatment on expression of the pro-apoptotic molecule BIM.