CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype Specific Vulnerability in IDH2- and TET2-Mutant Cells.

Clonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial cells to perform CRISPR/Cas9 screens in mutant HSPCs. Our data reveal that loss of the histone demethylase family members Kdm3b and Jmjd1c specifically reduces the fitness of Idh2- and Tet2-mutant HSPCs. Kdm3b loss in mutant cells leads to decreased expression of critical cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to inhibition of downstream JAK2 signaling. Our study nominates an epigenetic regulator and an epigenetically regulated receptor signaling pathway as genotype-specific therapeutic targets and provides a scalable platform to identify genetic dependencies in mutant HSPCs.

Low rate of severe-end-stage kidney disease after SABR for localised primary kidney cancer.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is an emerging treatment for patients with primary renal cell carcinoma (RCC). However, its impact on renal function is unclear. This study aimed to evaluate incidence and clinical factors predictive of severe to end-stage chronic kidney disease (CKD) after SABR for RCC. METHODS AND MATERIALS: This was a Single institutional retrospective analysis of patients with diagnosed primary RCC receiving SABR between 2012-2020. Adult patients with no metastatic disease, baseline estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min/1.73 m2, and at least one post-SABR eGFR at six months or later were included in this analysis. Patients with upper tract urothelial carcinoma were excluded. Primary outcome was freedom from severe to end-stage CKD, determined using the Kaplan-Meier estimator. The impact of baseline CKD, age, hypertension, diabetes, tumor size and fractionation schedule were assessed by Cox proportional hazard models. RESULTS: Seventy-eight consecutive patients were included, with median age of 77.8 years (IQR 70-83), tumor size of 4.5 cm (IQR 3.9-5.8) and follow-up of 42.2 months (IQR 23-60). Baseline median eGFR was 58 mls/min; 55% (n = 43) of patients had baseline CKD stage 3 and the remainder stage 1-2. By last follow-up, 1/35 (2.8%) of baseline CKD 1-2, 7/27 (25.9%) CKD 3a and 11/16 (68.8%) CKD 3b had developed CKD stage 4-5. The estimated probability of freedom from CKD stage 4-5 at 1 and 5 years was 89.6% (CI 83.0-97.6) and 65% (CI 51.4-81.7) respectively. On univariable analysis, worse baseline CKD (p < 0.0001) and multi-fraction SABR (p = 0.005) were predictive for development of stage 4-5 CKD though only the former remained significant in multivariable model. CONCLUSION: In this elderly cohort with pre-existing renal dysfunction, SABR achieved satisfactory nephron sparing with acceptable rates of severe to end-stage CKD. It can be an attractive option in patients who are medically inoperable.

Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms.

Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonly JAK2V617F. Although clinically approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic therapy. We hypothesized this is due to limitations of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a combined Dre-rox/Cre-lox dual-recombinase system. Jak2V617F deletion abrogates MPN features, induces depletion of mutant-specific hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition, including when cooccurring with somatic Tet2 loss. Our data suggest JAK2V617F represents the best therapeutic target in MPNs and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo. SIGNIFICANCE: Current JAK inhibitors to treat myeloproliferative neoplasms are ineffective at eradicating mutant cells. We developed an endogenously expressed Jak2V617F dual-recombinase knock-in/knock-out model to investigate Jak2V617F oncogenic reversion in vivo. Jak2V617F deletion abrogates MPN features and depletes disease-sustaining MPN stem cells, suggesting improved Jak2V617F targeting offers the potential for greater therapeutic efficacy. See related commentary by Celik and Challen, p. 701. This article is featured in Selected Articles from This Issue, p. 695.

Administering [177Lu]Lu-PSMA-617 Prior to Radical Prostatectomy in Men with High-risk Localised Prostate Cancer (LuTectomy): A Single-centre, Single-arm, Phase 1/2 Study.

BACKGROUND: High-risk localised prostate cancer (HRCaP) has high rates of biochemical recurrence; [177Lu]Lu-PSMA-617 is effective in men with advanced prostate cancer. OBJECTIVE: To investigate the dosimetry, safety, and efficacy of upfront [177Lu]Lu-PSMA-617 in men with HRCaP prior to robotic radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: In this single-arm, phase I/II trial, we recruited men with HRCaP (any of prostate-specific antigen [PSA] >20 ng/ml, International Society of Urological Pathology (ISUP) grade group [GG] 3-5, and ≥cT2c), with high tumour uptake on [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PSMA PET/CT), and scheduled for RP. INTERVENTION: Cohort A (n = 10) received one cycle and cohort B (n = 10) received two cycles of [177Lu]Lu-PSMA-617 (5 GBq) followed by surgery 6 weeks later. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was tumour radiation absorbed dose. Adverse events (AEs; Common Terminology Criteria for Adverse Events (CTCAE) version 5.0), surgical safety (Clavien-Dindo), imaging, and biochemical responses were evaluated (ClinicalTrials.gov: NCT04430192). RESULTS AND LIMITATIONS: Between May 29, 2020 and April 28, 2022, 20 patients were enrolled. The median PSA was 18 ng/ml (interquartile range [IQR] 11-35), Eighteen (90%) had GG ≥3, and six (30%) had N1 disease. The median (IQR) highest tumour radiation absorbed dose after cycle 1 for all lesions was 35.5 Gy (19.5-50.1), with 19.6 Gy (11.3-48.4) delivered to the prostate. Five patients received radiation to lymph nodes. Nine (45%) patients achieved >50% PSA decline. The most common AEs related to [177Lu]Lu-PSMA-617 were grade 1 fatigue in eight (40%), nausea in seven (35%), dry mouth in six (30%), and thrombocytopenia in four (20%) patients. No grade 3/4 toxicities or Clavien 3-5 complications occurred. Limitations include small a sample size. CONCLUSIONS: In men with HRCaP and high prostate-specific membrane antigen (PSMA) expression, [177Lu]Lu-PSMA-617 delivered high levels of targeted radiation doses with few toxicities and without compromising surgical safety. Further studies of [177Lu]Lu-PSMA-617 in this population are worthwhile to determine whether meaningful long-term oncological benefits can be demonstrated. PATIENT SUMMARY: In this study, we demonstrate that up to two cycles of [177Lu]Lu-PSMA-617 given prior to radical prostatectomy in patients with high-risk localised prostate cancer are safe and deliver targeted doses of radiation to tumour-affected tissues. It is tolerated well with minimal treatment-related adverse events, and surgery is safe with a low rate of complications. Activity measured through PSA reduction, repeat PSMA PET/CT, and histological response is promising.

A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML.

ABSTRACT: Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

Single-cell genotypic and phenotypic analysis of measurable residual disease in acute myeloid leukemia.

Measurable residual disease (MRD), defined as the population of cancer cells that persist following therapy, serves as the critical reservoir for disease relapse in acute myeloid leukemia and other malignancies. Understanding the biology enabling MRD clones to resist therapy is necessary to guide the development of more effective curative treatments. Discriminating between residual leukemic clones, preleukemic clones, and normal precursors remains a challenge with current MRD tools. Here, we developed a single-cell MRD (scMRD) assay by combining flow cytometric enrichment of the targeted precursor/blast population with integrated single-cell DNA sequencing and immunophenotyping. Our scMRD assay shows high sensitivity of approximately 0.01%, deconvolutes clonal architecture, and provides clone-specific immunophenotypic data. In summary, our scMRD assay enhances MRD detection and simultaneously illuminates the clonal architecture of clonal hematopoiesis/preleukemic and leukemic cells surviving acute myeloid leukemia therapy.

Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia.

Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World Health Organization and International Consensus classifications of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as 1 of the diagnostic criteria for AML, AML-MR, based largely on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined in the clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations into the adverse-risk group. By thoroughly annotating a cohort of 344 newly diagnosed patients with AML treated at the Memorial Sloan Kettering Cancer Center, we show that ontogeny assignments based on the database registry lack accuracy. MR gene mutations are frequently observed in de novo AML. Among the MR gene mutations, only EZH2 and SF3B1 were associated with an inferior outcome in the univariate analysis. In a multivariate analysis, AML ontogeny had independent prognostic values even after adjusting for age, treatment, allo-transplant and genomic classes or ELN risks. Ontogeny also helped stratify the outcome of AML with MR gene mutations. Finally, de novo AML with MR gene mutations did not show an adverse outcome. In summary, our study emphasizes the importance of accurate ontogeny designation in clinical studies, demonstrates the independent prognostic value of AML ontogeny, and questions the current classification and risk stratification of AML with MR gene mutations.

MEN1 mutations mediate clinical resistance to menin inhibition.

Chromatin-binding proteins are critical regulators of cell state in haematopoiesis1,2. Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs3-5. In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin-MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1 (ref. 6). Here we identified somatic mutations in MEN1 at the revumenib-menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor-menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug-target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance.

Disabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance.

Mutations in IDH genes occur frequently in acute myeloid leukemia (AML) and other human cancers to generate the oncometabolite R-2HG. Allosteric inhibition of mutant IDH suppresses R-2HG production in a subset of patients with AML; however, acquired resistance emerges as a new challenge, and the underlying mechanisms remain incompletely understood. Here we establish isogenic leukemia cells containing common IDH oncogenic mutations by CRISPR base editing. By mutational scanning of IDH single amino acid variants in base-edited cells, we describe a repertoire of IDH second-site mutations responsible for therapy resistance through disabling uncompetitive enzyme inhibition. Recurrent mutations at NADPH binding sites within IDH heterodimers act in cis or trans to prevent the formation of stable enzyme-inhibitor complexes, restore R-2HG production in the presence of inhibitors, and drive therapy resistance in IDH-mutant AML cells and patients. We therefore uncover a new class of pathogenic mutations and mechanisms for acquired resistance to targeted cancer therapies. SIGNIFICANCE: Comprehensive scanning of IDH single amino acid variants in base-edited leukemia cells uncovers recurrent mutations conferring resistance to IDH inhibition through disabling NADPH-dependent uncompetitive inhibition. Together with targeted sequencing, structural, and functional studies, we identify a new class of pathogenic mutations and mechanisms for acquired resistance to IDH-targeting cancer therapies. This article is highlighted in the In This Issue feature, p. 1.

Molecular predictors of immunophenotypic measurable residual disease clearance in acute myeloid leukemia.

Measurable residual disease (MRD) is a powerful prognostic factor in acute myeloid leukemia (AML). However, pre-treatment molecular predictors of immunophenotypic MRD clearance remain unclear. We analyzed a dataset of 211 patients with pre-treatment next-generation sequencing who received induction chemotherapy and had MRD assessed by serial immunophenotypic monitoring after induction, subsequent therapy, and allogeneic stem cell transplant (allo-SCT). Induction chemotherapy led to MRD- remission, MRD+ remission, and persistent disease in 35%, 27%, and 38% of patients, respectively. With subsequent therapy, 34% of patients with MRD+ and 26% of patients with persistent disease converted to MRD-. Mutations in CEBPA, NRAS, KRAS, and NPM1 predicted high rates of MRD- remission, while mutations in TP53, SF3B1, ASXL1, and RUNX1 and karyotypic abnormalities including inv (3), monosomy 5 or 7 predicted low rates of MRD- remission. Patients with fewer individual clones were more likely to achieve MRD- remission. Among 132 patients who underwent allo-SCT, outcomes were favorable whether patients achieved early MRD- after induction or later MRD- after subsequent therapy prior to allo-SCT. As MRD conversion with chemotherapy prior to allo-SCT is rarely achieved in patients with specific baseline mutational patterns and high clone numbers, upfront inclusion of these patients into clinical trials should be considered.

Metabolic and magnetic resonance imaging: complementary modalities for the preoperative assessment of lateral pelvic lymph nodes in rectal cancer.

BACKGROUND: The management of lateral pelvic lymph nodes for rectal cancer is a topical and controversial issue. The aim of this study was to assess the relationship between lateral pelvic lymph node features on magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) with oncological outcomes in patients with rectal cancer. METHODS: A retrospective analysis of 284 patients with primary locally advanced rectal cancer treated with neoadjuvant therapy and surgical resection with curative intent between January 2003 and Dec 2018 was undertaken. From this study population, a select cohort of 77 patients with abnormal lateral pelvic lymph nodes on preoperative imaging had imaging re-analysed by radiologists blinded to clinical outcomes. Pre and post neoadjuvant therapy MRI and PET-CT lateral pelvic lymph node features were correlated with oncological outcomes. RESULTS: A lateral pelvic lymph node short axis size ≥5 mm on post neoadjuvant therapy MRI was a significant predictor of worse 3-year local recurrence free survival (HR 8.35, P = 0.001). Lateral pelvic lymph node avidity on post neoadjuvant therapy PET-CT was a significant predictor of worse 3-year distant recurrence free survival (HR 5.62, P = 0.001). No correlation of oncological outcomes with overall survival was identified. CONCLUSION: Lateral pelvic lymph node imaging features on post-neoadjuvant therapy MRI and PET-CT predicted those at risk of rectal cancer recurrence. Further studies are required to confirm these findings that suggest restaging MRI and PET-CT are complementary modalities for the preoperative assessment of lateral pelvic lymph nodes in rectal cancer.

[SENP1 induced protein deSUMO modification increased the chemotherapy sensitivity of endometrial cancer side population cells].

Objective: To inhibit the stemness maintenance potential of endometrial cancer and increase the sensitivity of endometrial cancer side population cells to chemotherapy drugs by inducing extensive deSUMOylation modification of proteins. Methods: Flow cytometry was used to sort and culture CD133(+) CD44(+) KLE endometrial cancer cell clone spheres. Protein expression level of small ubiquitin-related modifier 1 (SUMO1) and two stemness maintenance genes of tumor side population cells, octamer binding transcription factor-4 (Oct4) and sex determining region Y-box2 (Sox2), were detected by western blotting method. Lentivirus-mediated Sentrin/SUMO-specific proteases 1 (SENP1) gene was stably transfected into KLE side population cells. Western blotting was used to detect the protein expressions of SENP1, SUMO1, Oct4 and Sox2. The clone formation rate was compared between KLE side population cells with or without SENP1 overexpression. Flow cytometry was applied to detect cell cycle changes. 3-(4, 5-Dimethylthiazole-2)-2, 5-diphenyl-tetrazolium bromide (MTT) experiment and flow cytometry apoptosis method were used to detect the chemosensitivity of the side population of endometrial cancer cells to cisplatin. Tumor-bearing mouse models of endometrial cancer were established to detect the effect of SENP1 overexpression on the chemotherapy sensitivity of cisplatin. Results: Compared with CD133(-)CD44(-) KLE cells, CD133(+) CD44(+) KLE side population cells could form clonal spheres and express higher levels of SUMO1, Oct4 and Sox2 proteins (P<0.05). Compared with KLE side population cells that were not transfected with SENP1 gene, the expression level of SENP1 protein in KLE side population cells overexpressing SUMO1、Oct4 and Sox2 were lower. The clonal sphere formation rate was reduced from (25.67±5.44)% to (7.46±1.42)%, and cell cycle shifted from G(0)/G(1) phase to G(2) phase. IC(50) of cisplatin decreased from (55.46±6.14) µg/ml to (11.55±3.12) µg/ml, and cell apoptosis rate increased from (9.76±2.09)% to (16.79±3.44)%. Overexpression of SENP1 could reduce the tumorigenesis rate of KLE side population cells in vivo and increase their chemotherapy sensitivity to cisplatin (P<0.05). Conclusion: Overexpression of SENP1 can induce protein deSUMOylation modification, inhibit the stemness maintenance potential of endometrial cancer side population cells, and enhance their chemotherapy sensitivity, which provides a new reference for gene therapy of endometrial cancer.

The Value of Preoperative Phase-Contrast MRI in Predicting the Clinical Outcome of Moyamoya Disease after Encephalo-Duro-Arterial Synangiosis Surgery.

BACKGROUND AND PURPOSE: In patients with Moyamoya disease, the relationship between preoperative hemodynamic status and prognosis after encephalo-duro-arterial synangiosis (EDAS) surgery was unclear. We aimed to explore the value of the preoperative hemodynamic status acquired by cine phase-contrast MR imaging in predicting collateral formation and clinical outcomes after EDAS surgery in patients with Moyamoya disease. MATERIALS AND METHODS: Participants with Moyamoya disease were prospectively recruited and underwent preoperative phase-contrast MR imaging. All participants were classified into good and poor groups according to the collateral formation after EDAS surgery. On the basis of the change in the mRS system, participants were classified into the improved mRS group and the poor response group. Hemodynamic status including mean velocity, peak velocity, and blood volume flow of the superficial temporal artery was compared between groups. Logistic regression was performed to relate the phase-contrast MR imaging parameters to collateral formation and clinical outcomes. RESULTS: A total of 45 patients with Moyamoya disease with unilateral EDAS surgery were finally included. Mean velocity, peak velocity, and blood volume flow of the ipsilateral superficial temporal artery were significantly greater in patients with good collateral formation compared with those with poor collateral formation (P = .011, .004, and .013, respectively). The mean velocity, peak velocity, and blood volume flow were independently associated with postoperative collateral formation after adjusting for confounding factors. Furthermore, the peak velocity of the ipsilateral superficial temporal artery was also significantly associated with improvement of the mRS score. CONCLUSIONS: Good hemodynamic status of the ipsilateral superficial temporal artery as a donor artery evaluated by phase-contrast MR imaging was significantly associated with better collateral formation and improved mRS after EDAS surgery in patients with Moyamoya disease.

Targeting Lysine-Specific Demethylase 1 Rescues Major Histocompatibility Complex Class I Antigen Presentation and Overcomes Programmed Death-Ligand 1 Blockade Resistance in SCLC.

INTRODUCTION: SCLC is a highly aggressive neuroendocrine tumor that is characterized by early acquired therapeutic resistance and modest benefit from immune checkpoint blockade (ICB). Repression of the major histocompatibility complex class I (MHC-I) represents a key mechanism driving resistance to T cell-based immunotherapies. METHODS: We evaluated the role of the lysine-specific demethylase 1 (LSD1) as a determinant of MHC-I expression, functional antigen presentation, and immune activation in SCLC in vitro and in vivo through evaluation of both human SCLC cell lines and immunocompetent mouse models. RESULTS: We found that targeted inhibition of LSD1 in SCLC restores MHC-I cell surface expression and transcriptionally activates genes encoding the antigen presentation pathway. LSD1 inhibition further activates interferon signaling, induces tumor-intrinsic immunogenicity, and sensitizes SCLC cells to MHC-I-restricted T cell cytolysis. Combination of LSD1 inhibitor with ICB augments the antitumor immune response in refractory SCLC models. Together, these data define a role for LSD1 as a potent regulator of MHC-I antigen presentation and provide rationale for combinatory use of LSD1 inhibitors with ICB to improve therapeutic response in SCLC. CONCLUSIONS: Epigenetic silencing of MHC-I in SCLC contributes to its poor response to ICB. Our study identifies a previously uncharacterized role for LSD1 as a regulator of MHC-I antigen presentation in SCLC. LSD1 inhibition enables MHC-I-restricted T cell cytolysis, induces immune activation, and augments the antitumor immune response to ICB in SCLC.

BMP2/SMAD pathway activation in JAK2/p53-mutant megakaryocyte/erythroid progenitors promotes leukemic transformation.

Leukemic transformation (LT) of myeloproliferative neoplasm (MPN) has a dismal prognosis and is largely fatal. Mutational inactivation of TP53 is the most common somatic event in LT; however, the mechanisms by which TP53 mutations promote LT remain unresolved. Using an allelic series of mouse models of Jak2/Trp53 mutant MPN, we identify that only biallelic inactivation of Trp53 results in LT (to a pure erythroleukemia [PEL]). This PEL arises from the megakaryocyte-erythroid progenitor population. Importantly, the bone morphogenetic protein 2/SMAD pathway is aberrantly activated during LT and results in abnormal self-renewal of megakaryocyte-erythroid progenitors. Finally, we identify that Jak2/Trp53 mutant PEL is characterized by recurrent copy number alterations and DNA damage. Using a synthetic lethality strategy, by targeting active DNA repair pathways, we show that this PEL is highly sensitive to combination WEE1 and poly(ADP-ribose) polymerase inhibition. These observations yield new mechanistic insights into the process of p53 mutant LT and offer new, clinically translatable therapeutic approaches.

Venetoclax-based combinations in AML and high-risk MDS prior to and following allogeneic hematopoietic cell transplant.

The role of allogeneic hematopoietic cell transplant (allo-HCT) as consolidation after initial venetoclax therapy and the efficacy of venetoclax salvage therapy for relapse after allo-HCT in patients with acute myeloid leukemia (AML) are unclear. We conducted a retrospective study of patients with AML or myelodysplastic syndrome (MDS) who received venetoclax either before or after allo-HCT at Memorial Sloan Kettering Cancer Center and Yale University from 11 August 2016 to 16 November 2020. Among 39 heavily pretreated patients who received venetoclax before allo-HCT, median OS from allo-HCT was not reached after a median follow up of 12.5 months resulting in a 12-month OS estimate of 79.0%. In 37 patients who had received venetoclax-based combinations as salvage therapy after allo-HCT, the overall response rate was 32% with a median OS of 4.7 months (12-month OS estimate: 43.4%). Four patients underwent a second allo-HCT following venetoclax-based salvage therapy suggesting it as a potential salvage treatment option.

Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML.

Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.

Do antispasmodics or rectal enemas improve image quality on multiparametric prostate MRI? An 'Evidence-Based Practice' review of the literature.

Multiparametric magnetic resonance imaging (mpMRI) of the prostate is increasingly used for the preoperative detection and staging of prostate cancer. Image quality of prostate mpMRI can be significantly degraded by motion related artefact due to bowel peristalsis and susceptibility related artefact, which reduces cancer detection sensitivity. The use of several different methods including anstispasmodic medications and rectal enemas were proposed as potential methods to reduce mpMRI artefacts, but current recommendations in the scientific literature are conflicting and inconsistent. This article seeks to identify the best available evidence to determine which patient preparation method is most effective in improving prostate mpMRI, and provides recommendations for further areas of research. We used the five-step 'Evidence-Based Practice' systematic approach of 'Ask, Search, Appraise, Apply and Evaluate' described by the McMaster University and National Health Service for critical appraisal of topics. We developed a focused clinical question using a PICO format, and performed a primary and secondary literature search through Ovid Medline, Ovid Embase and Cochrane CENTRAL (Wiley). All identified articles were appraised for strength and validity. Seven articles were retrieved which demonstrated conflicting sensitivities and specificities for intravenous hyoscine butylbromide and rectal enema in improving image susceptibility artefact, motion artefact, and anatomic distortion on the T2 or diffusion weighted imaging sequences. Intravenous hysoscine butylbromide is the optimum patient preparation method for improving T2W and DWI image quality in prostate mpMRI. The use of a preparatory rectal enema is not currently recommended, but better quality studies are required.