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Dysregulation of immune-checkpoint receptors has been reported at diagnosis of chronic myeloid leukemia (CML), however, their role in the maintenance of remission after tyrosine kinase inhibitor (TKI) cessation is unclear. We assessed programmed cell death-1 (PD-1), T-cell immunoglobulin, and mucin-domain containing protein-3 (TIM-3), cytotoxic T-lymphocyte–associated protein-4 (CTLA-4), lymphocyte-activation gene-3 (LAG-3), and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) expression on T-cell subsets, regulatory T cells (T-regs), and natural killer (NK) cells at the time of TKI cessation in 44 patients (22 patients sustained treatment-free remission [TFR] and 22 experienced molecular relapse [MolR]). We confirmed our previous finding that absolute numbers of T-regs are increased in patients who experienced MolR compared with those who sustained TFR. The immune-checkpoint receptors PD-1, CTLA-4, LAG-3, and TIGIT on T or NK cells were not differentially expressed between the MolR and TFR groups. However, TIM-3 was consistently upregulated on bulk T cells (CD3+) and T-cell subsets including, CD4+ T cells, CD8+ T cells, and T-regs, in patients who relapsed in comparison with those who maintained TFR after discontinuation. Furthermore, gene expression analysis from publicly available data sets showed increased TIM-3 expression on CML stem cells compared with normal hematopoietic stem cells. These findings suggest that among the targetable immune-checkpoint molecules, TIM-3 blockade may potentially improve effector immune response in patients with CML stopping TKI, while concomitantly targeting leukemic stem cells and could be a promising therapeutic strategy for preventing relapse after cessation of TKI in patients with CML.

Introduction While exposure to sulfur mustard (SM) is commonly associated with the production of vesicating dermal, ocular, and respiratory injuries, systemic damage to bone marrow and lymphatic tissue can decrease critical immune cell populations leading to higher susceptibility to life-threatening infection and septicemia. There are currently no approved medical countermeasures for SM-induced myelosuppression. An intravenous SM challenge model was developed in adult rats as a preliminary proof-of-principle platform to evaluate the efficacy of candidate immunostimulants. Materials and Methods Adult male and female Sprague Dawley rats were exposed to SM through tail vein injection. Toxicity progression was monitored through clinical observations, body weights, body temperatures, hematology, serum clinical chemistry, and flow cytometry of blood and bone marrow samples. Results Following SM exposure, overt toxicity progression was characterized by weight loss, changes in body temperature, and manifestation of toxic clinical signs (diarrhea, lethargy, hunched posture, rough hair coat, respiratory distress, and death). Drastic alterations in complete blood cell profiles included an early-onset lymphopenia followed by a delayed-onset neutropenia and thrombocytopenia. Only transient changes in serum clinical chemistry parameters were observed. Flow cytometry analysis of circulating blood revealed that B-cells were more predominantly affected by SM exposure than T-cells. Challenge with SM resulted in loss of hematopoietic and mesenchymal stem cell populations in the bone marrow. Conclusions The small animal model developed in this study replicates many key aspects of human SM exposures and should serve as a relevant, rapid, and cost-effective platform to screen candidate medical countermeasures for SM-induced hematologic toxicity.

Refereed/Peer-reviewed The genetic basis of the predisposition for Down Syndrome (DS) patients to develop cytokine receptor-like factor 2 rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) is currently unknown. Genes located on chromosome 21 and expressed in hematopoietic cells are likely candidates for investigation of CRLF2r DS-ALL pathogenesis. We explored the high-mobility group nucleosome-binding protein 1 (HMGN1), located in the DS critical region, in an inducible CRISPR/Cas9 knockout (KO) xenograft model to assess the effect of HMGN1 loss of function on the leukemic burden. We demonstrated HMGN1 KO-mitigated leukemic phenotypes including hepatosplenomegaly, thrombocytopenia, and anemia, commonly observed in leukemia patients, and significantly increased survival in vivo. HMGN1 overexpression in murine stem cells and Ba/F3 cells in vitro, in combination with P2RY8-CRLF2, resulted in cytokine-independent transformation and upregulation of cell signaling pathways associated with leukemic development. Finally, in vitro screening demonstrated successful targeting of P2RY8-CRLF2 and HMGN1 co-expressing cell lines and patient samples with fedratinib (JAK2 inhibitor), and GSK-J4 (demethylase inhibitor) in combination. Together, these data provide critical insight into the development and persistence of CRLF2r DS-ALL and identify HMGN1 as a potential therapeutic target to improve outcomes and reduce toxicity in this high-risk cohort of young patients.

Acute lymphoblastic leukaemia (ALL) remains a leading cause of non-traumatic death in children, and the majority of adults diagnosed will succumb to the disease. Recent advances in molecular biology and bioinformatics have enabled more detailed genomic analysis and a better understanding of the molecular biology of ALL. A number of recurrent genomic drivers have recently been described, which not only aid in diagnosis and prognostication, but also may offer opportunities for specific therapeutic targeting. The present review summarises B-ALL genomic pathology at diagnosis, including lesions detectable using traditional cytogenetic methods as well as those detected only through advanced molecular techniques.

Rearrangements of Janus kinase 2 (JAK2r) form a subtype of acute lymphoblastic leukaemia (ALL) associated with poor patient outcomes. We present a high-risk case of B-cell ALL (B-ALL) where retrospective mRNA sequencing identified a novel GOLGA4-JAK2 fusion gene. Expression of GOLGA4-JAK2 in murine pro-B cells promoted factor-independent growth, implicating GOLGA4-JAK2 as an oncogenic driver. Cells expressing GOLGA4-JAK2 demonstrated constitutive activation of JAK/STAT signalling and were sensitive to JAK inhibitors. This study contributes to the diverse collection of JAK2 fusion genes identified in B-ALL and supports the incorporation of JAK inhibitors into treatment strategies to improve outcomes for this subtype.

Myositis is a known complication of chronic graft-vs-host disease (cGVHD) following allogeneic haematopoietic stem cell transplantation, but can be difficult to diagnose and manage. We present the case of a 57 year old man with cGVHD in whom the full manifestations of myositis were suppressed for some time, likely due to partial treatment of his condition with immunosuppression including ibrutinib. Though initial muscle biopsy showed necrotising myopathy without significant inflammation, on cessation of ibrutinib he developed increasing weakness and creatine kinase levels, with repeat muscle biopsy showing histological changes more in keeping with dermatomyositis. The close temporal correlation of his clinical course with commencement and cessation of ibrutinib suggests a potential role for ibrutinib in treating inflammatory myopathy in cGVHD.

Vesicants, from vesica (Latin for blister), can cause local and systemic toxicity. They include the chemotherapy drug nitrogen mustard and chemical warfare agents sulfur mustard, Lewisite, and phosgene oxime. These agents are commonly released in vapor form and consequently, eyes and skin are the most vulnerable. The ocular and cutaneous injuries can be acute, subacute, or chronic, and can predispose casualties to secondary deleterious effects. Underlying these broad organ responses are shared and tissue-specific cellular and molecular biological cascades that attempt to counteract such chemical injuries. Depending on the severity of the chemical insult, biological responses often lead to inadequate wound healing and result in long-term pathology instead. Exposure to other toxic industrial chemicals such as acrolein, chloropicrin, and hydrogen fluoride, can also cause prominent eye and skin damage. There are currently no FDA-approved drugs to counteract these injuries. Hence, the possibility of a mass casualty emergency involving these chemicals is a major public health concern. Recognizing this critical challenge, the United States Department of Health and Human Services (HHS) is committed to the development of medical countermeasures to advance national health and medical preparedness against these highly toxic chemicals. Here, we provide an overview of various HHS funding and scientific opportunities available in this space, emphasizing parallels between eye and skin response to chemical injury. We also discuss a main limitation of existing data and suggest ways to overcome it.

Benzodiazepines are the primary treatment option for organophosphate (OP)-induced status epilepticus (SE), but these antiseizure drugs (ASDs) lose efficacy as treatment is delayed. In the event of a mass civilian or military exposure, significant treatment delays are likely. New ASDs that combat benzodiazepine-resistant, OP-induced SE are critically needed, particularly if they can be efficacious after a long treatment delay. This study evaluated the efficacy of the Kv7 channel modulator, retigabine, as a novel therapy for OP-induced SE. Adult, male rats were exposed to soman or diisopropyl fluorophosphate (DFP) to elicit SE and monitored by electroencephalogram (EEG) recording. Retigabine was administered alone or adjunctive to midazolam (MDZ) at delays of 20- or 40-min in the soman model, and 60-min in the DFP model. Following EEG recordings, rats were euthanized and brain tissue was collected for Fluoro-Jade B (FJB) staining to quantify neuronal death. In the DFP model, MDZ + 15 mg/kg retigabine suppressed seizure activity and was neuroprotective. In the soman model, MDZ + 30 mg/kg retigabine suppressed seizures at 20- and 40-min delays. Without MDZ, 15 mg/kg retigabine provided partial antiseizure and neuroprotectant efficacy in the DFP model, while 30 mg/kg without MDZ failed to attenuate soman-induced SE. At 60 mg/kg, retigabine without MDZ strongly reduced seizure activity and neuronal degeneration against soman-induce SE. This study demonstrates the antiseizure and neuroprotective efficacy of retigabine against OP-induced SE. Our data suggest retigabine could be a useful adjunct to standard-of-care and has potential for use in the absence of MDZ.

Ganciclovir (GCV) and valganciclovir (VGCV) are the first-line agents used to prevent and treat cytomegalovirus (CMV) infection in allogeneic haematopoietic stem cell transplant (alloHCT) patients. The aim of this work was to describe available data for the clinical pharmacokinetics, pharmacodynamics and toxicodynamics of GCV and VGCV and the potential of a therapeutic drug monitoring strategy to improve outcomes in the alloHCT population. We systematically reviewed the pharmacokinetics (dose-exposure), pharmacodynamics (exposure-efficacy) and toxicodynamics (exposure-toxicity) of GCV and VGCV in alloHCT patients with CMV infection. Studies including alloHCT patients treated for CMV infection reporting the pharmacokinetics, pharmacodynamics and toxicodynamics of GCV or VGCV were searched for using the PUBMED and EMBASE databases from 1946 to 2019. Only studies involving participants > 12 years of age and available in the English language were included. A total of 179 patients were included in the 14 studies that met the inclusion criteria, of which 6 examined GCV pharmacokinetics only, while 8 also examined GCV pharmacodynamics and toxicodynamics. Reported pharmacokinetic parameters showed considerable interpatient variability and were different from other populations, such as solid organ transplant and human immunodeficiency virus-infected patients. Only one study found a correlation between neutropenia and elevated peak and trough GCV concentrations, with no other significant pharmacodynamic and toxicodynamic relationships identified. While therapeutic drug monitoring of GCV is performed in some institutions, no association between GCV therapeutic drug monitoring and clinical outcomes was identified. Further studies of the pharmacokinetics, pharmacodynamics and toxicodynamics of GCV/VGCV in alloHCT patients are required to identify a more robust therapeutic range and to subsequently quantify the potential value of therapeutic drug monitoring of GCV/VGCV in the alloHCT population.

Children with neurofibromatosis have a higher risk of developing juvenile myelomonocytic leukemia and acute myeloid leukemia, but rarely develop B-cell acute lymphoblastic leukemia (B-ALL). Through in-vitro modeling, a novel NF1 p.L2467 frameshift (fs) mutation identified in a relapsed/refractory Ph-like B-ALL patient with neurofibromatosis demonstrated cytokine independence and increased RAS signaling, indicative of leukemic transformation. Furthermore, these cells were sensitive to the MEK inhibitors trametinib and mirdametinib. Bi-allelic NF1 loss of function may be a contributing factor to relapse and with sensitivity to MEK inhibitors, suggests a novel precision medicine target in the setting of neurofibromatosis patients with B-ALL.

The therapeutic potential of donor-derived mesenchymal stromal cells (MSCs) has been investigated in diverse diseases1, including steroid-resistant acute graft versus host disease (SR-aGvHD)2. However, conventional manufacturing approaches are hampered by challenges with scalability and interdonor variability, and clinical trials have shown inconsistent outcomes3,4. Induced pluripotent stem cells (iPSCs) have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation5,6. Nonetheless, human clinical trials of iPSC-derived cells have not previously been completed. CYP-001 (iPSC-derived MSCs) is produced using an optimized, good manufacturing practice (GMP)-compliant manufacturing process. We conducted a phase 1, open-label clinical trial (no. NCT02923375) in subjects with SR-aGvHD. Sixteen subjects were screened and sequentially assigned to cohort A or cohort B (n = 8 per group). One subject in cohort B withdrew before receiving CYP-001 and was excluded from analysis. All other subjects received intravenous infusions of CYP-001 on days 0 and 7, at a dose level of either 1 × 106 cells per kg body weight, to a maximum of 1 × 108 cells per infusion (cohort A), or 2 × 106 cells per kg body weight, to a maximum dose of 2 × 108 cells per infusion (cohort B). The primary objective was to assess the safety and tolerability of CYP-001, while the secondary objectives were to evaluate efficacy based on the proportion of participants who showed a complete response (CR), overall response (OR) and overall survival (OS) by days 28/100. CYP-001 was safe and well tolerated. No serious adverse events were assessed as related to CYP-001. OR, CR and OS rates by day 100 were 86.7, 53.3 and 86.7%, respectively. The therapeutic application of iPSC-derived MSCs may now be explored in diverse inflammatory and immune-mediated diseases. A GMP-compliant process for generating human iPSC-derived mesenchymal stromal cells tested in a phase 1 trial is safe and well tolerated in subjects with acute steroid-resistant graft versus host disease.

Barbara J. McClure, Susan L. Heatley, Jacqueline Rehn, James Breen, Rosemary Sutton, Timothy P. Hughes, Ram Suppiah, Tamas Revesz, Michael Osborn, Daniel White, David T. Yeung, Deborah L. White

Hematopoietic stem cell transplantation (HSCT) recipients are vulnerable to invasive pneumococcal disease (IPD), with reported IPD rates ranging from 3.81 to 22.5/1000 HSCT. This IPD risk could relate to immunodeficiency, low vaccination uptake, and poor immunogenicity of pneumococcal polysaccharide vaccine (PPV). Literature comparing the clinical effectiveness of pneumococcal conjugate vaccination (PCV) and PPV after HSCT is limited. In this retrospective analysis of HSCT recipients at our center from 2004 to 2015, we evaluated vaccination uptake and compared IPD rates in patients receiving PPV (pre-2010 group) and PCV (post-2010 group). IPD was determined from microbiological results for all HSCT recipients from January 2004 to June 30, 2019. Eight hundred patients had a total of 842 HSCT events, including autologous HSCT (auto-HSCT; n = 562) and allogeneic HSCT (allo-HSCT; n = 280). More than 90% of the HSCT recipients were enrolled, and93% of surviving HSCT recipients completed the vaccination protocol. Fifteen IPD episodes occurred in 13 patients between 2004 and June 30, 2019. Thirteen episodes occurred in the pre-2010 group, even though 9 of 13 (69%) serotyped isolates were covered by PPV. Two episodes occurred in the post-2010 group; neither serotype was covered by PCV. Thus, with PCV introduction, IPD rate was significantly reduced from 38.5/1000 unique HSCTs pre-2010 to 4.0/1000 unique HSCTs post-2010 (P.001). A significant reduction was seen in both auto-HSCTs (from 29.4 to 3.1 /1000 unique auto-HSCTs; P = .011) and allo-HSCTs (from 58.3 to 5.6/1000 unique allo-HSCTs; P = .011). PCV demonstrated superior clinical effectiveness over PPV, highlighting its importance in preventing infectious complications after HSCT. Robust vaccination programs at transplantation centers are needed to optimize vaccination uptake and completion.

Organophosphorus (OP) compounds are deadly chemicals that exert their intoxicating effects through the irreversible inhibition of acetylcholinesterase (AChE). In addition to an excess of peripheral ailments, OP intoxication induces status epilepticus (SE) which if left untreated may lead to permanent brain damage or death. Benzodiazepines are typically the primary therapies for OP-induced SE, but these drugs lose efficacy as treatment time is delayed. The CounterACT Neurotherapeutic Screening (CNS) Program was therefore established by the National Institutes of Health (NIH) to discover novel treatments that may be administered adjunctively with the currently approved medical countermeasures for OP-induced SE in a delayed treatment scenario. The CNS program utilizes in vivo EEG recordings and Fluoro-Jade B (FJB) histopathology in two established rat models of OP-induced SE, soman (GD) and diisopropylfluorophosphate (DFP), to evaluate the anticonvulsant and neuroprotectant efficacy of novel adjunct therapies when administered at 20 or 60 min after the induction of OP-induced SE. Here we report the results of multiple compounds that have previously shown anticonvulsant or neuroprotectant efficacy in other models of epilepsy or trauma. Drugs tested were ganaxolone, diazoxide, bumetanide, propylparaben, citicoline, MDL-28170, and chloroquine. EEG analysis revealed that ganaxolone demonstrated the most robust anticonvulsant activity, whereas all other drugs failed to attenuate ictal activity in both models of OP-induced SE. FJB staining demonstrated that none of the tested drugs had widespread neuroprotective abilities. Overall these data suggest that neurosteroids may represent the most promising anticonvulsant option for OP-induced SE out of the seven unique mechanisms tested here. Additionally, these results suggest that drugs that provide significant neuroprotection from OP-induced SE without some degree of anticonvulsant activity are elusive, which further highlights the necessity to continue screening novel adjunct treatments through the CNS program.

Asciminib, a first-in-class allosteric inhibitor of BCR::ABL1 kinase activity, is now approved for the treatment of patients with chronic-phase chronic myeloid leukemia who failed 2 lines of therapy or in patients with the T315I mutation. Promising attributes include high specificity and potency against BCR::ABL1, activity against most kinase domain mutations, and potential for combination therapy with ATP-competitive tyrosine kinase inhibitors. Clinicians now have expanded third-line options, which in most cases will involve a choice between asciminib and ponatinib.

Asciminib is the first tyrosine kinase inhibitor (TKI) to Specifically Target the ABL Myristoyl Pocket (STAMP). In the ASCEMBL Phase 3 randomised study comparing asciminib to bosutinib in patients with CML in chronic phase (CP) after ³2 prior TKIs, asciminib demonstrated superior efficacy and tolerability vs bosutinib (major molecular response (MMR) rate at week 96: 37.6% vs 15.8%, treatment discontinuation 7.7% vs 26.3%) (Rea et al, EHA 2022). Here we present the real-world clinical outcomes of TKI-resistant/ intolerant CML patients in Australia who received asciminib through a MAP approved by Novartis.

Chromosomal rearrangements involving the KMT2A gene occur frequently in acute lymphoblastic leukaemia (ALL). KMT2A-rearranged ALL (KMT2Ar ALL) has poor long-term survival rates and is the most common ALL subtype in infants less than 1 year of age. KMT2Ar ALL frequently occurs with additional chromosomal abnormalities including disruption of the IKZF1 gene, usually by exon deletion. Typically, KMT2Ar ALL in infants is accompanied by a limited number of cooperative le-sions. Here we report a case of aggressive infant KMT2Ar ALL harbouring additional rare IKZF1 gene fusions. Comprehensive genomic and transcriptomic analyses were performed on sequential samples. This report highlights the genomic complexity of this particular disease and describes the novel gene fusions IKZF1::TUT1 and KDM2A::IKZF1.

OBJECTIVE: To develop a novel inhalation exposure system capable of delivering a controlled inhaled HD dose through an endotracheal tube to anesthetized rats to investigate the lung pathophysiology and evaluate potential medical countermeasures. MATERIALS AND METHODS: Target HD vapor exposures were generated by a temperature-controlled vapor generator, while concentration was monitored near real-time by gas chromatography. Animal breathing parameters were monitored real-time by in-line EMKA/SciReq pulmonary analysis system. Individual exposures were halted when the target inhaled doses were achieved. Animals were observed daily for clinical observations and lethality with scheduled termination at 28 days post-exposure. Upon scheduled or unscheduled death, animals underwent a gross necropsy and lung and trachea were collected for histopathology. RESULTS: Controlled HD concentrations ranged from 60 to 320 mg/m(3). Delivered inhaled doses range from 0.3 to 3.20 mg/kg with administered doses within 3% of the target. The 28-day inhaled LD(50) is 0.80 mg/kg (95% CI = 0.42–1.18 mg/kg). Post exposure respiratory abnormalities were observed across all dose levels though the higher dose levels had earlier onset and higher frequency of occurrence. Histopathologic alterations were not qualitatively altered in accordance with dose but instead showed a relationship to an animals’ time of death, with early deaths demonstrating acute damage and later deaths displaying signs of repair. DISCUSSION/CONCLUSION: This novel exposure system administers targeted HD inhaled doses to generate a small animal model that can be used to evaluate physiological toxicities of inhaled HD on the lungs and for evaluation of potential medical countermeasure treatments.

Key Points Pediatric ALL therapy is equally as deliverable in AYA patients as in children.MRD assessment and body mass index predict survival in AYA ALL., Visual Abstract, Pediatric regimens have improved outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL). However, results remain inferior to children with ALL. The Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study (anzctr.org.au/ACTRN12611000814976) was designed to assess whether a pediatric ALL regimen (Australian and New Zealand Children’s Haematology and Oncology Group [ANZCHOG] Study 8) could be administered to patients aged 15 to 39 years in a comparable time frame to children as assessed by the proportion of patients completing induction/consolidation and commencing the next phase of therapy (protocol M or high-risk [HR] treatment) by day 94. Minimal residual disease (MRD) response stratified patients to HR treatment and transplantation. From 2012 to 2018, a total of 86 patients were enrolled; 82 were eligible. Median age was 22 years (range, 16-38 years). Induction/consolidation was equally deliverable in ALL06 as in Study 8. In ALL06, 41.5% (95% confidence interval [CI], 30.7-52.9) commenced protocol M or HR therapy by day 94 vs 39.3% in Study 8 (P = .77). Median time to protocol M/HR treatment was 96 days (interquartile range, 87.5-103 days) in ALL06 vs 98 days in Study 8 (P = .80). Induction mortality was 3.6%. With a median follow-up of 44 months (1-96 months), estimated 3-year disease-free survival was 72.8% (95% CI, 62.8-82.7), and estimated 3-year overall survival was 74.9% (95% CI, 65.3-84.5). End induction/consolidation MRD negativity rate was 58.6%. Body mass index ≥30 kg/m2 and day 79 MRD positivity were associated with poorer disease-free survival and overall survival. Pediatric therapy was safe and as deliverable in AYA patients as in children with ALL. Intolerance of pediatric ALL induction/consolidation is not a major contributor to inferior outcomes in AYA ALL.

The Chemical Countermeasures Research Program (CCRP) was established in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID/NIH) on behalf of the National Institutes of Health Office of the Director (NIH OD). It is a trans-NIH initiative to expedite the discovery and early development of medical countermeasures (MCMs) that can reduce mortality and serious morbidity during and after large consequence public health emergency involving the deliberate or accidental large-scale release of highly toxic chemicals (HTCs).

Approximately half of patients with chronic myeloid leukemia (CML) in sustained deep molecular response who discontinue tyrosine kinase inhibitors (TKIs) remain in treatment-free remission (TFR). Some of these patients have measurable residual disease (MRD) by BCR-ABL1 mRNA testing, and most have detectable BCR-ABL1 DNA by highly sensitive methods. We used fluorescence-activated cell sorting and BCR-ABL1 DNA PCR to investigate the lineage of residual CML cells in TFR. Twenty patients in TFR for >1 year provided blood for sorting into granulocytes, monocytes, B cells, T cells, and NK cells. MRD was identified predominantly in the lymphoid compartment and never in granulocytes. B cells were more often BCR-ABL1 positive than T cells (18 vs 11/20 patients) and at higher levels (median 10−4.9 vs 10−5.7; P = 0.014). In 13 CML patients studied at diagnosis lymphocytes expressing BCR-ABL1 mRNA comprised a small proportion of total leukocytes. These data improve our understanding of TFR biology, since it is now clear that MRD in the blood of TFR patients need not imply the persistence of multipotent CML cells. Lineage-specific assessment of MRD could be explored as a means to improve the prediction of TFR Refereed/Peer-reviewed

In chronic-phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR; EMR failure: BCR-ABL1 >10% on the international scale at 3 months) is predictive of inferior outcomes. Identifying patients at high-risk of EMR failure at diagnosis provides an opportunity to intensify frontline therapy and potentially avoid EMR failure. We studied blood samples from 96 CP-CML patients at diagnosis and identified 365 genes that were aberrantly expressed in 13 patients who subsequently failed to achieve EMR, with a gene signature significantly enriched for stem cell phenotype (eg, Myc, β-catenin, Hoxa9/Meis1), cell cycle, and reduced immune response pathways. We selected a 17-gene panel to predict EMR failure and validated this signature on an independent patient cohort. Patients classified as high risk with our gene expression signature (HR-GES) exhibited significantly higher rates of EMR failure compared with low-risk (LR-GES) patients (78% vs 5%; P < .0001), with an overall accuracy of 93%. Furthermore, HR-GES patients who received frontline nilotinib had a relatively low rate of EMR failure (10%). However, HR-GES patients still had inferior deep molecular response achievement rate by 24 months compared with LR-GES patients. This novel multigene signature may be useful for selecting patients at high risk of EMR failure on standard therapy who may benefit from trials of more potent kinase inhibitors or other experimental approaches.

Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinib-associated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%). VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years. Multivariate analysis identified age (P = .022) and dyslipidemia (P = .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued (P = .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.

Leucèmia mieloide crònica; Diferenciació eritroïdal; Polycomb Leucemia mieloide crónica; Diferenciación eritroide; Polycomb Chronic myeloid leukemia; Erythroid differentiation; Polycomb Polycomb group (PcG) of proteins are a group of highly conserved epigenetic regulators involved in many biological functions, such as embryonic development, cell proliferation, and adult stem cell determination. PHD finger protein 19 (PHF19) is an associated factor of Polycomb repressor complex 2 (PRC2), often upregulated in human cancers. In particular, myeloid leukemia cell lines show increased levels of PHF19, yet little is known about its function. Here, we have characterized the role of PHF19 in myeloid leukemia cells. We demonstrated that PHF19 depletion decreases cell proliferation and promotes chronic myeloid leukemia (CML) differentiation. Mechanistically, we have shown how PHF19 regulates the proliferation of CML through a direct regulation of the cell cycle inhibitor p21. Furthermore, we observed that MTF2, a PHF19 homolog, partially compensates for PHF19 depletion in a subset of target genes, instructing specific erythroid differentiation. Taken together, our results show that PHF19 is a key transcriptional regulator for cell fate determination and could be a potential therapeutic target for myeloid leukemia treatment. This work was supported by the Di Croce Laboratory is supported by grants from the Spanish Ministry of Science and Innovation (BFU2016-75008-P and PID2019-108322GB-100), “Fundación Vencer El Cancer” (VEC), the European Regional Development Fund (FEDER), and from AGAUR (SGR 2017-2019). We acknowledge the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya. PV was supported by the Fundación Científica de la Asociación Española Contra el Cáncer. SA was funded by the Ramon y Cajal program of the Ministerio de Ciencia, Innovación y Universidades, the European Social Fund under the reference number RYC-2018-025002-I, and the Instituto de Salud Carlos III-FEDER (PI19/01814).

Benzodiazepines are the primary treatment option for organophosphate (OP)-induced status epilepticus (SE), but these antiseizure drugs (ASDs) lose efficacy as treatment is delayed. In the event of a mass civilian or military exposure, significant treatment delays are likely. New ASDs that combat benzodiazepine-resistant, OP-induced SE are critically needed, particularly if they can be efficacious after a long treatment delay. This study evaluated the efficacy of the K(v)7 channel modulator, retigabine, as a novel therapy for OP-induced SE. Adult, male rats were exposed to soman or diisopropyl fluorophosphate (DFP) to elicit SE and monitored by electroencephalogram (EEG) recording. Retigabine was administered alone or adjunctive to midazolam (MDZ) at delays of 20- or 40-min in the soman model, and 60-min in the DFP model. Following EEG recordings, rats were euthanized and brain tissue was collected for Fluoro-Jade B (FJB) staining to quantify neuronal death. In the DFP model, MDZ + 15 mg/kg retigabine suppressed seizure activity and was neuroprotective. In the soman model, MDZ + 30 mg/kg retigabine suppressed seizures at 20- and 40-min delays. Without MDZ, 15 mg/kg retigabine provided partial antiseizure and neuroprotectant efficacy in the DFP model, while 30 mg/kg without MDZ failed to attenuate soman-induced SE. At 60 mg/kg, retigabine without MDZ strongly reduced seizure activity and neuronal degeneration against soman-induce SE. This study demonstrates the antiseizure and neuroprotective efficacy of retigabine against OP-induced SE. Our data suggest retigabine could be a useful adjunct to standard-of-care and has potential for use in the absence of MDZ.

With treatment-free remission (TFR) rapidly becoming the ultimate goal of therapy in chronic myeloid leukemia (CML), there is a need to develop strategies to maximize sustained TFR by improving our understanding of its key determinants. Chronic-phase CML patients attempting TFR were evaluated to identify the impact of multiple variables on the probability of sustained TFR. Early molecular response dynamics were included as a predictive variable, assessed by calculating the patient-specific halving time of BCR-ABL1 after commencing tyrosine kinase inhibitor (TKI) therapy. Overall, 115 patients attempted TFR and had ≥12 months of follow-up. The probability of sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, was 55%. The time taken for the BCR-ABL1 value to halve was the strongest independent predictor of sustained TFR: 80% in patients with a halving time of 21.85 days (last quartile) (P < .001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR. A more rapid initial BCR-ABL1 decline after commencing TKI also correlated with an increased likelihood of achieving TFR eligibility. The association between sustained TFR and the time taken for BCR-ABL1 to halve after commencing TKI was validated using an independent dataset. These data support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.

BackgroundTo assess the effects of consumer engagement in health care policy, research and services.MethodsWe updated a review published in 2006 and 2009 and revised the previous search strategies for key databases (The Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; PsycINFO; CINAHL; Web of Science) up to February 2020. Selection criteria included randomised controlled trials assessing consumer engagement in developing health care policy, research, or health services. The International Association for Public Participation, Spectrum of Public Participation was used to identify, describe, compare and analyse consumer engagement. Outcome measures were effects on people; effects on the policy/research/health care services; or process outcomes.ResultsWe included 23 randomised controlled trials with a moderate or high risk of bias, involving 136,265 participants. Most consumer engagement strategies adopted a consultative approach during the development phase of interventions, targeted to health services. Based on four large cluster-randomised controlled trials, there is evidence that consumer engagement in the development and delivery of health services to enhance the care of pregnant women results in a reduction in neonatal, but not maternal, mortality. From other trials, there is evidence that involving consumers in developing patient information material results in material that is more relevant, readable and understandable for patients, and can improve knowledge. Mixed effects are reported of consumer-engagement on the development and/or implementation of health professional training. There is some evidence that using consumer interviewers instead of staff in satisfaction surveys can have a small influence on the results. There is some evidence that consumers may have a role in identifying broader range of health care priorities that are complementary to those from professionals. There is some evidence that consumer engagement in monitoring and evaluating health services may impact perceptions of patient safety or quality of life.ConclusionsThere is growing evidence from randomised controlled trials of the effects of consumer engagement on the relevance and positive outcomes of health policy, research and services. Health care consumers, providers, researchers and funders should continue to employ evidence-informed consumer engagement in their jurisdictions, with embedded evaluation. Systematic review registrationPROSPERO CRD42018102595.