TP53 status and impact on AML prognosis within the ELN 2022 risk classification.

This study reports the following: (1) frequency of TP53 comutation within each component of the European LeukemiaNet 2022 acute myeloid leukemia risk classification, (2) relevance of TP53 mutated variant allelic fraction <10%, (3) prognostic impact of -7, -5/del(5q), -17/abn(17p), complex karyotype/monosomal karyotype, or myelodysplasia-related gene mutations with/without mutated TP53.

Phase Ib study of sabatolimab (MBG453), a novel immunotherapy targeting TIM-3 antibody, in combination with decitabine or azacitidine in high- or very high-risk myelodysplastic syndromes.

The safety and efficacy of sabatolimab, a novel immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), was assessed in combination with hypomethylating agents (HMAs) in patients with HMA-naive revised International Prognostic System Score (IPSS-R) high- or very high-risk myelodysplastic syndromes (HR/vHR-MDS) or chronic myelomonocytic leukemia (CMML). Sabatolimab + HMA had a safety profile similar to that reported for HMA alone and demonstrated durable clinical responses in patients with HR/vHR-MDS. These results support the ongoing evaluation of sabatolimab-based combination therapy in MDS, CMML, and acute myeloid leukemia.

ANZTCT practice statement: sinusoidal obstruction syndrome/veno-occlusive disease diagnosis and management.

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.

Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2021.

Antifungal prophylaxis can reduce morbidity and mortality from invasive fungal disease (IFD). However, its use needs to be optimised and appropriately targeted to patients at highest risk to derive the most benefit. In addition to established risks for IFD, considerable recent progress in the treatment of malignancies has resulted in the development of new 'at-risk' groups. The changing epidemiology of IFD and emergence of drug resistance continue to impact choice of prophylaxis, highlighting the importance of active surveillance and knowledge of local epidemiology. These guidelines aim to highlight emerging risk groups and review the evidence and limitations around new formulations of established agents and new antifungal drugs. It provides recommendations around use and choice of antifungal prophylaxis, discusses the potential impact of the changing epidemiology of IFD and emergence of drug resistance, and future directions for risk stratification to assist optimal management of highly vulnerable patients.

Prognostic markers in core-binding factor AML and improved survival with multiple consolidation cycles of intermediate-/high-dose cytarabine.

OBJECTIVES: Core-binding factor acute myeloid leukaemia (CBF AML) defined by t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) has a favourable prognosis; however, 30%-40% of patients still relapse after chemotherapy. We sought to evaluate the risk factors for relapse in a de novo CBF AML cohort. PATIENTS/MATERIALS/METHODS: A retrospective review of patients from four Australian tertiary centres from 2001 to 2012, comprising 40 t(8;21) and 30 inv(16) AMLs. RESULTS: Multivariate analysis identified age (P = .032) and white cell count (WCC)>40 (P = .025) as significant predictors for inferior OS and relapse, respectively. Relapse risk was higher in the inv(16) group vs the t(8;21) group (57% vs 18%, HR 4.31, 95% CI: 1.78-10.42, P = .001). Induction therapy had no bearing on OS or relapse-free survival (RFS); however, consolidation treatment with >3 cycles of intermediate-/high-dose cytarabine improved OS (P = .035) and RFS (P = .063). Five patients demonstrated post-treatment stable q PCR positivity without relapse. CONCLUSIONS: >3 consolidation cycles of intermediate-/high-dose cytarabine improves patient outcomes Age and inv(16) CBF AML subtype are predictors of inferior OS and RFS, respectively. Stable low-level MRD by qPCR does not predict relapse Similar OS in the inv(16) cohort compared to the t(8;21) cohort, despite a higher relapse rate, confirms salvageability of relapsed disease.

Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML.

Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function.

Maintenance lenalidomide in combination with 5-azacitidine as post-remission therapy for acute myeloid leukaemia.

In this Phase 1b study, the safety and tolerability of maintenance therapy, comprising lenalidomide (0-25 mg, days 5-25) in combination with azacitidine (50-75 mg/m(2) , days 1-5) every 28 d, was explored in 40 patients with acute myeloid leukaemia (AML) in complete remission after chemotherapy. Eligibility included AML in first complete remission (CR1) with adverse risk karyotype (n = 8), fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) (n = 5), age ≥60 years (n = 31) or AML in second remission (CR2) (n = 14). Dose-limiting toxicity was not reached. Common toxicities were haematological, infection, injection pain, constipation, fatigue and diarrhoea. In CR1, median relapse-free (RFS) and overall survival (OS) was 12 and 20 months, respectively. In CR2, median RFS was 11 months, with median OS not yet reached. Among 29 patients with intermediate cytogenetic risk, RFS was 50% at 24 months. There were five patients with concomitant FLT3-ITD and nucleophosmin (NPM1) mutation; none have relapsed and all are still alive after 17-39 months. Maintenance lenalidomide/azacitidine augmented the function of cytotoxic T lymphocytes, particularly in patients with NPM1 mutation. The lenalidomide/azacitidine maintenance combination was effective in suppressing residual DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A)-positive disease, resulting in sustained remission in patients with concurrent NPM1 mutation. Azacitidine/lenalidomide as maintenance therapy for high-risk AML warrants further exploration.

Comparison of biosimilar filgrastim with originator filgrastim for peripheral blood stem cell mobilization and engraftment in patients with multiple myeloma undergoing autologous stem cell transplantation.

BACKGROUND: Nivestim is a biosimilar approved for the same indications as Neupogen including the mobilization of autologous peripheral blood stem cells (PBSCs). The clinical efficacy and safety of Nivestim for this use have not been formally assessed in clinical trials. STUDY DESIGN AND METHODS: In our retrospective single-center study we compared variables of PBSC mobilization and engraftment of 60 patients mobilized with Nivestim to that of 38 patients mobilized with Neupogen. RESULTS: We found no difference between Nivestim and Neupogen in peripheral blood CD34+ at first leukapheresis (47 × 10(6) cells/L vs. 60 × 10(6) cells/L, p = 0.48) nor the total CD34+ collected (5.37 × 10(6)/kg vs. 4.59 × 10(6) /kg, p = 0.22). However, a difference in the median number of leukapheresis procedures (one vs. two, p = 0.0007) was observed. Eighty-one patients (51 Nivestim and 30 Neupogen mobilized) went on to transplantation. Median time to neutrophil engraftment (15 days vs. 13.5 days, p = 0.09) and platelet (PLT) engraftment (20 days vs. 18 days, p = 0.01) was longer in the Nivestim group. The significant delay in PLT engraftment did not, however, translate to increased PLT transfusions (two vs. three, p = 0.2) or impact significantly on hospitalization time for admissions within 30 days posttransplant (20 days vs. 18 days, p = .17). CONCLUSION: Nivestim is as effective as Neupogen for PBSC mobilization; however, its use was associated with a delay in PLT recovery. A prospective study should be conducted to confirm our findings.

Laboratory validation and clinical utility of next-generation sequencing-based IGH/TCR clonality testing for the monitoring of measurable residual disease in acute lymphoblastic leukaemia: real-world experience at Austin Pathology.

Measurable residual disease (MRD) testing is an essential aspect of disease prognostication in acute lymphoblastic leukaemia (ALL) and informs clinical decisions. The depth of MRD clearance is highly relevant and requires assays with sufficient sensitivity. Austin Pathology is one of the few laboratories in Australia currently utilising a fully validated and National Association of Testing Authorities (NATA)-accredited ultrasensitive next-generation sequencing (NGS) platform for MRD monitoring in ALL. This technology is based on the detection of clonal rearrangement of immunoglobulin and T cell receptor genes in leukaemic cells, and is capable of achieving a limit of detection at least one to two logs below that of multiparametric flow cytometry (MFC). In this retrospective analysis, we report a clonotype detection rate of up to 85.7% at diagnosis, and a concordance rate of 78.7% in MRD results between NGS and MFC. Of the discordant samples, nearly all were NGS+/MFC-, highlighting the superior sensitivity of NGS. The enhanced sensitivity is clinically relevant, as discordant MRD results often heralded fulminant relapse, and therefore offer clinicians additional lead time and a window of opportunity to initiate pre-emptive therapy. Notwithstanding a small and heterogeneous cohort, our real-world survival data indicate an intermediate relapse risk for NGS+/MFC- patients. In light of recent approval of Medicare rebatable ALL MRD testing, we discuss how NGS can complement other techniques such as MFC in personalising management strategies. We recommend routine clonality testing by NGS at diagnosis and use a multi-modality approach for subsequent MRD monitoring.

CD34 Chimerism Directed Donor Lymphocyte Infusion With or Without Azacitidine Results in Reduced Relapse and Superior Overall Survival When Full Donor Chimerism is Achieved in Allogeneic Stem Cell Transplant Recipients With Acute Myeloid Leukaemia/Myelodysplastic Syndrome.

BACKGROUND: Regular monitoring of CD34 donor chimerism (DC) is a highly sensitive method of predicting relapse in allogeneic stem cell transplant (alloHSCT) recipients with AML/MDS. A fall of CD34 DC below 80% is an indicator of ensuing relapse. There are limited studies assessing the efficacy of donor lymphocyte infusion (DLI) triggered by mixed CD34 DC (MDC), in addressing falling chimerism. PATIENTS AND METHODS: We performed a retrospective analysis of consecutive alloHSCT patients between 2012 to 2023 who received DLI (with or without azacitidine) for CD34 MDC without morphologic relapse at the time of infusion. RESULTS: Of the 21 patients with follow up CD34 DC available, 14 (66.7%) achieved CD34 full donor chimerism (FDC) following DLI with or without azacitidine (dli-FDC), while 7 (33.3%) did not (dli-MDC). The 2-year cumulative incidence of relapse (CIR) was significantly lower in dli-FDC compared to dli-MDC (21.4% vs. 85.7%, P < 0.001), correlating with superior overall survival (OS; median years not reached vs. 0.67 years [95% CI, 0.58-ND], P < .001). Rates of grade II-IV acute GVHD post-DLI were 14.9%, and moderate-severe cGVHD was 42.8% in the dli-FDC group. The 5-year nonrelapse mortality (NRM) of the dli-FDC group was 7.1% following DLI. CONCLUSION: Our study shows the restoration of CD34 FDC post-DLI is associated with reduced relapse and improved overall survival, with low NRM.

Targeting Molecular Measurable Residual Disease and Low-Blast Relapse in AML With Venetoclax and Low-Dose Cytarabine: A Prospective Phase II Study (VALDAC).

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 log10 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 log10 rise in IDH1/2 (12%) were included. By cycle 2 in the MRD relapse cohort, a log10 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.

How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

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.

Animate monitoring is not uniform: implications for the animate monitoring hypothesis.

The animate monitoring hypothesis (AMH) purports that humans evolved specialized mechanisms that prioritize attention to animates over inanimates. Importantly, the hypothesis emphasizes that any animate-an entity that can move on its own-should take priority in attention. While many experiments have found general support for this hypothesis, there have yet been no systematic investigations into whether the type of animate matters for animate monitoring. In the present research we addressed this issue across three experiments. In Experiment 1, participants (N = 53) searched for an animate or inanimate entity in a search task, and the animate was either a mammal or a non-mammal (e.g., bird, reptile, insect). Mammals were found significantly faster than inanimates, replicating the basic AMH finding. However, they were also found significantly faster than non-mammals, who were not found faster than inanimates. Two additional experiments were conducted to probe for differences among types of non-mammals using an inattentional blindness task. Experiment 2 (N = 171) compared detection of mammals, insects, and inanimates, and Experiment 3 (N = 174) compared birds and herpetofauna (reptiles and amphibians). In Experiment 2, mammals were spontaneously detected at significantly higher rates than insects, who were detected at only slightly higher rates than the inanimates. Furthermore, when participants did not consciously identify the target, they nonetheless could correctly guess the higher level category of the target (living vs. nonliving thing) for the mammals and the inanimates, but could not do so for the insects. We also found in Experiment 3 that reptiles and birds were spontaneously detected at rates similar to the mammals, but like insects they were not identified as living things at rates greater than chance when they were not consciously detected. These results do not support a strong claim that all animates are prioritized in attention, but they do call for a more nuanced view. As such, they open a new window into the nature of animate monitoring, which have implications for theories of its origin.

Peripheral Blood CD34 Donor Chimerism has Greater Clinical Utility Than CD3 for Detecting Relapse after Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia or Myelodysplastic Syndrome.

Monitoring of donor chimerism (DC) may detect early relapse following allogeneic hematopoietic stem cell transplantation (allo-SCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Most centers use unfractionated peripheral blood or T-cells to monitor DC, although CD34+ DC may be more predictive. The limited adoption of CD34+ DC may be due to the lack of detailed, comparative studies. To address this knowledge gap, we compared peripheral blood CD34+ and CD3+ DC in 134 patients who underwent allo-SCT for AML or MDS. In July 2011, the Alfred Hospital Bone Marrow Transplantation Service adopted routine monitoring of DC in the lineage-specific CD34+ and CD3+ cell subsets from peripheral blood at 1, 2, 3, 4, 6, 9, and 12 months post-transplantation for AML or MDS. Immunologic interventions, including rapid withdrawal of immunosuppression, azacitidine, and donor lymphocyte infusion, were prespecified for CD34+ DC ≤80%. Overall, CD34+ DC ≤80% detected 32 of 40 relapses (positive predictive value [PPV], 68%; negative predictive value [NPV], 91%), compared with 13 of 40 relapses for CD3+ DC ≤80% (PPV, 52%; NPV, 75%). Receiver operating characteristic analysis showed the superiority of CD34+ DC, with the greatest value at day 120 post-transplantation. CD3+ DC provided additional value in only 3 cases, preceding CD34+ DC ≤80% by 1 month. We further show that the CD34+ DC sample can be used to detect NPM1mut, with the combination of CD34+ DC ≤80% and NPM1mut identifying the highest risk of relapse. Among the 24 patients in morphologic remission at the time of CD34+ DC ≤80%, 15 (62.5%) responded to immunologic interventions (rapid withdrawal of immunosuppression, azacitidine, or donor lymphocyte infusion) with recovery of CD34+ DC >80%, and 11 of these patients remained in complete remission for a median of 34 months (range, 28 to 97 months). In contrast, the other 9 patients did not respond to the clinical intervention and relapsed within a median of 59 days after detecting CD34+ DC ≤80%. The CD34+ DC was significantly higher in responders than in nonresponders (median, 72% versus 56%; P = .015, Mann-Whitney U test). Overall, monitoring of CD34+ DC was considered clinically useful (early diagnosis of relapse enabling preemptive therapy or predicting low risk of relapse) in 107 of 125 evaluable patients (86%). Our findings show that peripheral blood CD34+ DC is feasible and superior to CD3+ DC for predicting relapse. It also provides a source of DNA for measurable residual disease testing, which may further stratify the risk of relapse. If validated by an independent cohort, our results suggest that CD34+ should be used in preference to CD3+ DC for detecting early relapse and guiding immunologic interventions following allo-SCT for AML or MDS.

Response of myeloma to the proteasome inhibitor bortezomib is correlated with the unfolded protein response regulator XBP-1.

BACKGROUND: Multiple myeloma, a malignancy of the antibody-secreting plasma cells, remains incurable by current therapy. However, the proteasome inhibitor bortezomib and other new drugs are revolutionizing its treatment. It remains unclear why myelomas are peculiarly sensitive to bortezomib, or what causes primary or acquired resistance. The 'unfolded protein response' is necessary for folding and assembly of immunoglobulin chains in both normal and malignant plasma cells, as well as for the disposal of incorrectly folded or unpaired chains via the ubiquitin-proteasome pathway. We tested the hypothesis that levels of transcription factor XBP-1, a major regulator of the unfolded protein response, predict response to bortezomib. DESIGN AND METHODS: Expression of XBP-1 and other regulators of the unfolded protein response were measured in myeloma and other cancer cell lines and two cohorts of patients with refractory myeloma and correlated with sensitivity/response to bortezomib. Bortezomib-resistant myeloma cell lines were derived and the effects on expression of unfolded protein response regulators, immunoglobulin secretion, proteasome activity and cross-resistance to cytotoxic drugs and tunicamycin determined. The consequences of manipulation of XBP-1 levels for sensitivity to bortezomib were tested. RESULTS: Low XBP-1 levels predicted poor response to bortezomib, both in vitro and in myeloma patients. Moreover, myeloma cell lines selected for resistance to bortezomib had down-regulated XBP-1 and immunoglobulin secretion. Expression of ATF6, another regulator of the unfolded protein response, also correlated with bortezomib sensitivity. Direct manipulation of XBP-1 levels had only modest effects on sensitivity to bortezomib, suggesting it is a surrogate marker of response to bortezomib rather than a target itself. CONCLUSIONS: The unfolded protein response may be a relevant target pathway for proteasome inhibitors in the treatment of myeloma and its regulator XBP-1 is a potential response marker. (The BIR study was registered with Australian Clinical Trial Registry Number 12605000770662).

The Utility of Euroflow MRD Assessment in Real-World Multiple Myeloma Practice.

Measurable residual disease (MRD) is being recognised as an optimal method for assessing depth of response, identifying higher risk of relapse, and guiding response-based treatment paradigms for multiple myeloma (MM). Although MRD negativity is increasingly replacing complete response as the surrogate endpoint in clinical trials, its role in real-world practice is less established. We retrospectively analyzed EuroFlow MRD results from patients with newly diagnosed MM (NDMM) who underwent bortezomib, cyclophosphamide and dexamethasone (VCD) induction and high dose melphalan conditioned autologous stem cell transplant (ASCT) at the Alfred Hospital between January 2016 and December 2020. Next generation flow MRD evaluation was performed 3 months following ASCT using the standardised EuroFlow platform. 112 patients with available MRD data were identified to have received VCD induction followed by ASCT. Post ASCT MRD was undetectable in 28.6% of patients. Those who achieved MRD negativity had significantly longer progression free survival (PFS) than those with persisting MRD (24-month PFS of 85% [95% CI: 72.4-99.9%] vs 63% [95% CI: 52.9-75.3%], p = 0.022). Maintenance therapy was associated with improved PFS regardless of MRD status (24-month PFS of 100% [95% CI: NA, p = 0.02] vs 73% [95% CI: 53.1-99.6%] in MRD negative, and 75% [95% CI: 64.2-88.6%] vs 36% [95% CI: 20.9-63.2%, p = 0.00015] in MRD positive patients). Results from this retrospective study of real-world practice demonstrate that Euroflow MRD analysis following standard VCD induction and ASCT in NDMM is feasible and allows more accurate prognostication, providing a platform for response adaptive therapies.