bims-tremyl 2023-04-30 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2023‒04‒30
38 papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London

Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics.
Therapy-Resistant Acute Myeloid Leukemia Stem Cells Are Resensitized to Venetoclax + Azacitidine by Targeting Fatty Acid Desaturases 1 and 2.
Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia.
A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1-mutated myeloid malignancies.
Impact of Type of Induction Therapy on Outcomes in Older Adults with AML after Allogeneic Stem Cell Transplantation.
Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial.
SRSF2-P95H decreases JAK/STAT signaling in hematopoietic cells and delays myelofibrosis development in mice.
Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia.
Clonal Hematopoiesis in Young Women Treated for Breast Cancer.
NGS-defined measurable residual disease (MRD) after initial chemotherapy as a prognostic biomarker for acute myeloid leukemia.
Murine double minute X plays a central role in leukemic transformation and may be a promising target for leukemia prevention strategies.
Adapter CAR T cells to counteract T-cell exhaustion and enable flexible targeting in AML.
A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia.
The E592K variant of SF3B1 creates unique RNA missplicing and associates with high-risk MDS without ring sideroblasts.
Inactivation of p53 provides a competitive advantage to del(5q) myelodysplastic syndrome hematopoietic stem cells during inflammation.
Blocking the CD47-SIRPα interaction reverses the disease phenotype in a polycythemia vera mouse model.
FLT3-mutated acute myeloid leukaemia: a new opportunity.
Epigenetic reversal of hematopoietic stem cell aging in Phf6-knockout mice.
Apoptotic cell death in disease-Current understanding of the NCCD 2023.
HIF1α-mediated transactivation of WTAP promotes AML cell proliferation via m6A-dependent stabilization of KDM4B mRNA.
New approaches to idiopathic neutropenia in the era of clonal hematopoiesis.
Advances in molecular evaluation of myeloproliferative neoplasms.
Physical biomarkers for human hematopoietic stem and progenitor cells.
The Clinicogenomic Landscape of Induction Failure in Childhood and Young Adult T-Cell Acute Lymphoblastic Leukemia.
Newly revised 2023 MDS response criteria.
Predictive nonlinear modeling of malignant myelopoiesis and tyrosine kinase inhibitor therapy.
Transcription factor Nkx2-3 maintains the self-renewal of hematopoietic stem cells by regulating mitophagy.
The EGR3 regulome of infant KMT2A-r acute lymphoblastic leukemia identifies differential expression of B-lineage genes predictive for outcome.
Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice.
Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a refined classification from the European society for blood and marrow transplantation (EBMT).
The NPM1 mutant defines AML irrespective of blast count.
BCR-ABL triggers a glucose-dependent survival program during leukemogenesis through the suppression of TXNIP.
Secretory MPP3 reinforce myeloid differentiation trajectory and amplify myeloid cell production.
Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with MLL rearrangement or NPM1 mutation to venetoclax.
Efficacy and tolerability of isocitrate dehydrogenase inhibitors in patients with acute myeloid leukemia: A systematic review of clinical trials.
A druggable copper-signalling pathway that drives inflammation.
Management of chronic myeloid leukemia in 2023 - common ground and common sense.
Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia.

Blood Cancer J. 2023 04 24. 13(1): 57

Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics.

Bing Z Carter, Po Yee Mak, Wenjing Tao, Edward Ayoub, Lauren B Ostermann, Xuelin Huang, Sanam Loghavi, Steffen Boettcher, Yuki Nishida, Vivian Ruvolo, Paul E Hughes, Phuong K Morrow, Torsten Haferlach, Steven Kornblau, Muharrem Muftuoglu, Michael Andreeff.

TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53-mutant compared to TP53-wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53-knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53-mutant compared to TP53-WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced cell death in TP53-mutant AML and stem/progenitor cells. The BH3 mimetic-driven stress response and cell death patterns after dual inhibition were largely independent of TP53 status and affected by apoptosis induction. Co-targeting, but not individual targeting of BCL-2 and MCL-1 in mice xenografted with TP53-WT and TP53-R248W Molm13 cells suppressed both TP53-WT and TP53-mutant cell growth and significantly prolonged survival. Our results demonstrate that co-targeting BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance to individual BH3 mimetics in TP53-mutant cells, thus shifting cell fate from survival to death in TP53-deficient and -mutant AML. This concept warrants clinical evaluation.

DOI: https://doi.org/10.1038/s41408-023-00830-w
Metabolites. 2023 Mar 24. pii: 467. [Epub ahead of print]13(4):

Therapy-Resistant Acute Myeloid Leukemia Stem Cells Are Resensitized to Venetoclax + Azacitidine by Targeting Fatty Acid Desaturases 1 and 2.

Rachel Culp-Hill, Brett M Stevens, Courtney L Jones, Shanshan Pei, Monika Dzieciatkowska, Mohammad Minhajuddin, Craig T Jordan, Angelo D'Alessandro.

  Recent advances in targeting leukemic stem cells (LSCs) using venetoclax with azacitidine (ven + aza) has significantly improved outcomes for de novo acute myeloid leukemia (AML) patients. However, patients who relapse after traditional chemotherapy are often venetoclax-resistant and exhibit poor clinical outcomes. We previously described that fatty acid metabolism drives oxidative phosphorylation (OXPHOS) and acts as a mechanism of LSC survival in relapsed/refractory AML. Here, we report that chemotherapy-relapsed primary AML displays aberrant fatty acid and lipid metabolism, as well as increased fatty acid desaturation through the activity of fatty acid desaturases 1 and 2, and that fatty acid desaturases function as a mechanism of recycling NAD+ to drive relapsed LSC survival. When combined with ven + aza, the genetic and pharmacologic inhibition of fatty acid desaturation results in decreased primary AML viability in relapsed AML. This study includes the largest lipidomic profile of LSC-enriched primary AML patient cells to date and indicates that inhibition of fatty acid desaturation is a promising therapeutic target for relapsed AML.

Keywords:  acute myeloid leukemia; fatty acid metabolism; leukemic stem cells; lipidomics

DOI:  https://doi.org/10.3390/metabo13040467
Cell Stem Cell. 2023 Apr 19. pii: S1934-5909(23)00119-4. [Epub ahead of print]

Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia.

Sergi Beneyto-Calabuig, Anne Kathrin Merbach, Jonas-Alexander Kniffka, Magdalena Antes, Chelsea Szu-Tu, Christian Rohde, Alexander Waclawiczek, Patrick Stelmach, Sarah Gräßle, Philip Pervan, Maike Janssen, Jonathan J M Landry, Vladimir Benes, Anna Jauch, Michaela Brough, Marcus Bauer, Birgit Besenbeck, Julia Felden, Sebastian Bäumer, Michael Hundemer, Tim Sauer, Caroline Pabst, Claudia Wickenhauser, Linus Angenendt, Christoph Schliemann, Andreas Trumpp, Simon Haas, Michael Scherer, Simon Raffel, Carsten Müller-Tidow, Lars Velten.

  Inter-patient variability and the similarity of healthy and leukemic stem cells (LSCs) have impeded the characterization of LSCs in acute myeloid leukemia (AML) and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. Although residual healthy and preleukemic cells dominated the dormant stem cell compartment, active LSCs resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors constituted a highly aberrant, disease-defining compartment: their gene expression and differentiation state affected both the chemotherapy response and leukemia's ability to differentiate into transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers misregulated specifically in leukemic cells. Taken together, CloneTracer reveals a differentiation landscape that mimics its healthy counterpart and may determine biology and therapy response in AML.

Keywords:  AML; CSC; HSC; LSC; acute myeloid leukemia; cancer stem cells; cellular differentiation; computational biology; computational method; hematopoietic stem cells; leukemic stem cells; single-cell RNA-seq; single-cell genomics; single-cell transcriptomics

DOI:  https://doi.org/10.1016/j.stem.2023.04.001
Blood Cancer Discov. 2023 Apr 27. pii: BCD-22-0205. [Epub ahead of print]

A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1-mutated myeloid malignancies.

Curtis A Lachowiez, Sanam Loghavi, Zhihong Zeng, Tomoyuki Tanaka, Yi June Kim, Hidetaka Uryu, Sven Turkalj, Niels Asger Jakobsen, Marlise R Luskin, Dzifa Y Duose, Rebecca S S Tidwell, Nicholas J Short, Gautam Borthakur, Tapan M Kadia, Lucia Masarova, George D Tippett, Prithviraj Bose, Elias J Jabbour, Farhad Ravandi, Naval G Daver, Guillermo Garcia-Manero, Hagop Kantarjian, Jacqueline S Garcia, Paresh Vyas, Koichi Takahashi, Marina Konopleva, Courtney D DiNardo.

The safety and efficacy of combining the IDH1 inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO+VEN) +/- azacitidine (AZA; IVO+VEN+AZA) was evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n=31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO+VEN+AZA vs. IVO+VEN was 90% vs. 83%. Among MRD-evaluable patients (N=16) 63% attained MRD-negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (N=14). Median EFS and OS were 36 (95% CI: 23-NR) and 42 (95% CI: 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked co-occurring mutations, anti-apoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1 mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.

DOI: https://doi.org/10.1158/2643-3230.BCD-22-0205
Blood Adv. 2023 Apr 27. pii: bloodadvances.2022009632. [Epub ahead of print]

Impact of Type of Induction Therapy on Outcomes in Older Adults with AML after Allogeneic Stem Cell Transplantation.

Nicholas J Short, Faustine Ong, Farhad Ravandi, Graciela M Nogueras Gonzalez, Tapan M Kadia, Naval G Daver, Courtney D DiNardo, Marina Y Konopleva, Gautam Borthakur, Betul Oran, Gheath Al-Atrash, Rohtesh S Mehta, Elias J Jabbour, Musa Yilmaz, Ghayas C Issa, Abhishek Maiti, Richard E Champlin, Hagop M Kantarjian, Elizabeth J Shpall, Uday R Popat.

Although venetoclax-based lower-intensity regimens have greatly improved outcomes for older adults with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy, the optimal induction for older patients with newly diagnosed AML who are suitable candidates for hematopoietic stem cell transplant (HSCT) is controversial. We retrospectively analyzed post-HSCT outcomes of 127 patients ≥60 years of age who received induction therapy at our institution with intensive chemotherapy (IC, n=44), lower-intensity therapy (LIT) without venetoclax (n=29) or LIT with venetoclax (n=54) and who underwent allogeneic HSCT in first remission. The 2-year relapse-free survival with LIT with venetoclax was 60%, versus 54% with IC and 41% with LIT without venetoclax, and 2-year overall survival for LIT with venetoclax was 72%, versus 58% with IC and 41% with LIT without venetoclax. The benefit to LIT with venetoclax induction was greatest in patients with adverse-risk AML (2-year OS 74%, 46%, and 29%, respectively). Induction with LIT, with or without venetoclax, was associated with the lowest rate of non-relapse mortality (NRM) (2-year NRM 17% versus 27% with IC; P=0.04). By multivariate analysis, type of induction therapy did not significantly impact any of the post-HSCT outcomes evaluated; hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was the only factor that independently predicted for RFS and OS. LIT plus venetoclax followed by HSCT is feasible treatment strategy in older, fit, and HSCT-eligible patients with newly diagnosed AML and may be particularly beneficial in those with adverse-risk disease.

DOI: https://doi.org/10.1182/bloodadvances.2022009632
Lancet. 2023 Apr 25. pii: S0140-6736(23)00464-6. [Epub ahead of print]

Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial.

QuANTUM-First Study Group

BACKGROUND: Patients with acute myeloid leukaemia (AML) positive for internal tandem duplication (ITD) mutations of FLT3 have poor outcomes. Quizartinib, an oral, highly potent, selective, type 2 FLT3 inhibitor, plus chemotherapy showed antitumour activity with an acceptable safety profile in patients with FLT3-ITD-positive newly diagnosed AML. The aim of the study was to compare the effect of quizartinib versus placebo on overall survival in patients with FLT3-ITD-positive newly diagnosed AML aged 18-75 years.METHODS: We conducted a randomised, double-blind, placebo-controlled, phase 3 trial comparing quizartinib and placebo in combination with chemotherapy in induction and consolidation, followed by quizartinib or placebo single-agent continuation, in patients with FLT3-ITD-positive newly diagnosed AML at 193 hospitals and clinics in 26 countries in Europe; North America; and Asia, Australia, and South America. Patients aged 18-75 years were eligible. Patients were randomly assigned (1:1) to the quizartinib group or the placebo group by an independent biostatistician through an interactive web and voice response system, stratified by region, age, and white blood cell count at diagnosis. Patients, investigators, funders, and contract research organisations were masked to treatments assigned. Induction therapy comprised a standard 7 + 3 induction regimen of cytarabine 100 mg/m2 per day (or 200 mg/m2 per day allowed if institutional or local standard) by continuous intravenous infusion from day 1 to day 7 and anthracycline (daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day) by intravenous infusion on days 1, 2, and 3, then quizartinib 40 mg orally or placebo once per day, starting on day 8, for 14 days. Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery received standard consolidation with high-dose cytarabine plus quizartinib (40 mg per day orally) or placebo, allogeneic haematopoietic cell transplantation (allo-HCT), or both as consolidation therapy, followed by continuation of single-agent quizartinib or placebo for up to 3 years. The primary outcome was overall survival, defined as time from randomisation until death from any cause and assessed in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of quizartinib or placebo. This study is registered with ClinicalTrials.gov (NCT02668653).
FINDINGS: Between Sept 27, 2016, and Aug 14, 2019, 3468 patients with AML were screened and 539 patients (294 [55%] male patients and 245 [45%] female patients) with FLT3-ITD-positive AML were included and randomly assigned to the quizartinib group (n=268) or placebo group (n=271). 148 (55%) of 268 patients in the quizartinib group and 168 (62%) of 271 patients in the placebo group discontinued the study, primarily because of death (133 [90%] of 148 in the quizartinib group vs 158 [94%] of 168 in the placebo group) or withdrawal of consent (13 [9%] of 148 in the quizartinib group vs 9 [5%] of 168 in the placebo group). Median age was 56 years (range 20-75, IQR 46·0-65·0). At a median follow-up of 39·2 months (IQR 31·9-45·8), median overall survival was 31·9 months (95% CI 21·0-not estimable) for quizartinib versus 15·1 months (13·2-26·2) for placebo (hazard ratio 0·78, 95% CI 0·62-0·98, p=0·032). Similar proportions of patients in the quizartinib and placebo groups had at least one adverse event (264 [100%] of 265 in the quizartinib group and 265 [99%] of 268 in the placebo group) and one grade 3 or higher adverse event (244 [92%] of 265 in the quizartinib group and 240 [90%] of 268 in the placebo group). The most common grade 3 or 4 adverse events were febrile neutropenia, hypokalaemia, and pneumonia in both groups and neutropenia in the quizartinib group.
INTERPRETATION: The addition of quizartinib to standard chemotherapy with or without allo-HCT, followed by continuation monotherapy for up to 3 years, resulted in improved overall survival in adults aged 18-75 years with FLT3-ITD-positive newly diagnosed AML. Based on the results from the QuANTUM-First trial, quizartinib provides a new, effective, and generally well tolerated treatment option for adult patients with FLT3-ITD-positive newly diagnosed AML.
FUNDING: Daiichi Sankyo.

DOI: https://doi.org/10.1016/S0140-6736(23)00464-6
Leukemia. 2023 Apr 26.

SRSF2-P95H decreases JAK/STAT signaling in hematopoietic cells and delays myelofibrosis development in mice.

Christophe Willekens, Lucie Laplane, Tracy Dagher, Camelia Benlabiod, Nicolas Papadopoulos, Catherine Lacout, Philippe Rameau, Cyril Catelain, Alexia Alfaro, Valérie Edmond, Nicolas Signolle, Valentine Marchand, Nathalie Droin, Remco Hoogenboezem, Rebekka K Schneider, Alex Penson, Omar Abdel-Wahab, Stephane Giraudier, Florence Pasquier, Caroline Marty, Isabelle Plo, Jean-Luc Villeval, Stefan N Constantinescu, Françoise Porteu, William Vainchenker, Eric Solary.

Heterozygous mutation targeting proline 95 in Serine/Arginine-rich Splicing Factor 2 (SRSF2) is associated with V617F mutation in Janus Activated Kinase 2 (JAK2) in some myeloproliferative neoplasms (MPNs), most commonly primary myelofibrosis. To explore the interaction of Srsf2P95H with Jak2V617F, we generated Cre-inducible knock-in mice expressing these mutants under control of the stem cell leukemia (Scl) gene promoter. In transplantation experiments, Srsf2P95H unexpectedly delayed myelofibrosis induced by Jak2V617F and decreased TGFβ1 serum level. Srsf2P95H reduced the competitiveness of transplanted Jak2V617F hematopoietic stem cells while preventing their exhaustion. RNA sequencing of sorted megakaryocytes identified an increased number of splicing events when the two mutations were combined. Focusing on JAK/STAT pathway, Jak2 exon 14 skipping was promoted by Srsf2P95H, an event detected in patients with JAK2V617F and SRSF2P95 co-mutation. The skipping event generates a truncated inactive JAK2 protein. Accordingly, Srsf2P95H delays myelofibrosis induced by the thrombopoietin receptor agonist Romiplostim in Jak2 wild-type animals. These results unveil JAK2 exon 14 skipping promotion as a strategy to reduce JAK/STAT signaling in pathological conditions.

DOI: https://doi.org/10.1038/s41375-023-01878-0
Cancer Discov. 2023 Apr 24. pii: CD-22-0601. [Epub ahead of print]

Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia.

Christina Glytsou, Xufeng Chen, Emmanouil Zacharioudakis, Wafa Al-Santli, Hua Zhou, Bettina Nadorp, Soobeom Lee, Audrey Lasry, Zhengxi Sun, Dimitrios Papaioannou, Michael Cammer, Kun Wang, Tomasz Zal, Malgorzata Anna Zal, Bing Z Carter, Jo Ishizawa, Raoul Tibes, Aristotelis Tsirigos, Michael Andreeff, Evripidis Gavathiotis, Iannis Aifantis.

BH3-mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML. Moreover, MCL-1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetics therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3-mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 overexpression is sufficient to drive resistance to BH3-mimetics in AML. Insensitivity to BH3-mimetics is accompanied by enhanced mitochondria-endoplasmic reticulum interactions and augmented mitophagy flux which acts as a pro-survival mechanism to eliminate mitochondrial damage. Genetic or pharmacologic MFN2 targeting synergizes with BH3-mimetics by impairing mitochondrial clearance and enhancing apoptosis in AML.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0601
Clin Cancer Res. 2023 Apr 28. pii: CCR-23-0050. [Epub ahead of print]

Clonal Hematopoiesis in Young Women Treated for Breast Cancer.

Christopher J Gibson, Geoffrey G Fell, Tal Sella, Adam S Sperling, Craig Snow, Shoshana M Rosenberg, Gregory Kirkner, Ashka Patel, Deborah Dillon, Alexander G Bick, Donna Neuberg, Ann H Partridge, Peter G Miller.

BACKGROUND: Young women treated for breast cancer with cytotoxic therapies are at risk for clonal hematopoiesis of indeterminate potential (CHIP), a condition in which blood cells carrying a somatic mutation associated with hematologic malignancy comprise at least 4% of the total blood system. CHIP has primarily been studied in older patient cohorts with limited clinical phenotyping.MATERIALS AND METHODS: We performed targeted sequencing on longitudinal blood samples to characterize the clonal hematopoietic landscape of 878 women treated for breast cancer enrolled in the prospective Young Women's Breast Cancer Study.
RESULTS: We identified somatic driver mutations in 252 study subjects (28.7%), but only 24 (2.7%) had clones large enough to meet criteria for CHIP. The most commonly mutated genes were DNMT3A and TET2, similar to mutations observed in non-cancer cohorts. At nine years median follow up, we found no association between the presence of a somatic blood mutation (regardless of clone size) and adverse breast cancer (distant relapse-free survival) or non-breast cancer-related outcomes in this cohort. A subset of paired blood samples obtained over four years showed no evidence of mutant clonal expansion, regardless of genotype. Finally, we identified a subset of patients with likely germline mutations in genes known to contribute to inherited cancer risk, such as TP53 and ATM.
CONCLUSIONS: Our data show that for young women with early-stage breast cancer, CHIP is uncommon after cytotoxic exposure, is unlikely to contribute to adverse outcomes over the decade-long follow up and may not require additional monitoring if discovered incidentally.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-0050
Blood Cancer J. 2023 04 24. 13(1): 59

NGS-defined measurable residual disease (MRD) after initial chemotherapy as a prognostic biomarker for acute myeloid leukemia.

Yonghong Li, Jose Solis-Ruiz, Fei Yang, Nicola Long, Carmen H Tong, Felicitas L Lacbawan, Frederick K Racke, Richard D Press.

Treated AML patients often have measurable residual disease (MRD) due to persisting low-level clones. This study assessed whether residual post-treatment somatic mutations, detected by NGS, were significantly prognostic for subsequent clinical outcomes. AML patients (n = 128) underwent both pre-and post-treatment testing with the same 42-gene MRD-validated NGS assay. After induction, 59 (46%) patients were mutation-negative (0.0024 VAF detection limit) and 69 (54%) had ≥1 persisting NGS-detectable mutation. Compared with NGS-negative patients, NGS-positive patients had shorter overall survival (17 months versus median not reached; P = 0.004; hazard ratio = 2.2 [95% CI: 1.3-3.7]) and a shorter time to relapse (14 months versus median not reached; P = 0.014; HR = 1.9 [95% CI: 1.1-3.1]). Among 95 patients with a complete morphologic remission (CR), 43 (45%) were MRD-positive by NGS and 52 (55%) were MRD-negative. These MRD-positive CR patients had a shorter overall survival (16.8 months versus median not reached; P = 0.013; HR = 2.1 [95% CI: 1.2-3.9]) than did the MRD-negative CR patients. Post-treatment persisting MRD positivity, defined by the same NGS-based test used at diagnosis, is thus a more sensitive biomarker for low-level leukemic clones compared to traditional non-molecular methods and is prognostic of subsequent relapse and death.

DOI: https://doi.org/10.1038/s41408-023-00833-7
Exp Hematol. 2023 Apr 20. pii: S0301-472X(23)00161-3. [Epub ahead of print]

Murine double minute X plays a central role in leukemic transformation and may be a promising target for leukemia prevention strategies.

Koki Ueda.

Acute myeloid leukemia (AML) is a fatal disease resulting from preleukemic hematopoietic conditions, including asymptomatic clonal hematopoiesis. The accumulation of genetic changes is one of the causes of leukemic transformation. However, nongenetic factors, including the overexpression of specific genes also contribute to preleukemic to leukemic transition. Among them, the p53 inhibitor murine double minute X (MDMX) plays crucial roles, especially in leukemia initiation. MDMX is broadly overexpressed in the vast majority of AML cases, including in hematopoietic stem/progenitor cell (HSPC) level. Recently, high expression of MDMX in HSPC has been shown to be associated with leukemic transformation in patients with myelodysplastic syndromes, and preclinical studies have demonstrated that MDMX overexpression accelerates the transformation of preleukemic murine models, including models of clonal hematopoiesis. MDMX inhibition, through activation of cell-intrinsic p53 activity, shows antileukemic effects. However, the molecular mechanisms of MDMX in provoking leukemic transformation are complicated. Both p53-dependent and -independent mechanisms are involved in the progression of the disease. This review discusses the canonical and noncanonical functions of MDMX and how these functions are involved in the maintenance, expansion, and progression to malignancy of preleukemic stem cells. Moreover, strategies on how leukemic transformation could be prevented by targeting MDMX in preleukemic stem cells are discussed.

DOI: https://doi.org/10.1016/j.exphem.2023.04.001
Leukemia. 2023 Apr 27.

Adapter CAR T cells to counteract T-cell exhaustion and enable flexible targeting in AML.

D Nixdorf, M Sponheimer, D Berghammer, F Engert, U Bader, N Philipp, M Kazerani, T Straub, L Rohrbacher, L Wange, S Dapa, D Atar, C M Seitz, K Brandstetter, A Linder, M von Bergwelt, H Leonhardt, J Mittelstaet, A Kaiser, V Bücklein, M Subklewe.

Although the landscape for treating acute myeloid leukemia (AML) patients has changed substantially in recent years, the majority of patients will eventually relapse and succumb to their disease. Allogeneic stem cell transplantation provides the best anti-AML treatment strategy, but is only suitable in a minority of patients. In contrast to B-cell neoplasias, chimeric antigen receptor (CAR) T-cell therapy in AML has encountered challenges in target antigen heterogeneity, safety, and T-cell dysfunction. We established a Fab-based adapter CAR (AdCAR) T-cell platform with flexibility of targeting and control of AdCAR T-cell activation. Utilizing AML cell lines and a long-term culture assay for primary AML cells, we were able to demonstrate AML-specific cytotoxicity using anti-CD33, anti-CD123, and anti-CLL1 adapter molecules in vitro and in vivo. Notably, we show for the first time the feasibility of sequential application of adapter molecules of different specificity in primary AML co-cultures. Importantly, using the AML platform, we were able to demonstrate that chronic T-cell stimulation and exhaustion can be counteracted through introduction of treatment-free intervals. As T-cell exhaustion and target antigen heterogeneity are well-known causes of resistance, the AdCAR platform might offer effective strategies to ameliorate these limitations.

DOI: https://doi.org/10.1038/s41375-023-01905-0
Hematol Oncol. 2023 Apr 22.

A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia.

Brian A Jonas, Jing-Zhou Hou, Gail J Roboz, Caroline L Alvares, Deepa Jeyakumar, John R Edwards, Harry P Erba, Richard J Kelly, Christoph Röllig, Walter Fiedler, Deanna Brackman, Satya R Siddani, Brenda Chyla, Jacqueline Hilger-Rolfe, Justin M Watts.

  Relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) is a genetically complex and heterogeneous disease with a poor prognosis and limited treatment options. Thus, there is an urgent need to develop therapeutic combinations to overcome drug resistance in AML. This open-label, multicenter, international, phase 1b study evaluated the safety, efficacy, and pharmacokinetics of venetoclax in combination with alvocidib in patients with R/R AML. Patients were treated with escalating doses of venetoclax (400, 600, and 800 mg QD, orally, days 1-28) and alvocidib (45 and 60 mg/m2 , intravenously, days 1-3) in 28-day cycles. The combination was found to be safe and tolerable, with no maximum tolerated dose reached. Drug-related Grade ≥3 adverse events were reported in 23 (65.7%) for venetoclax and 24 (68.6%) for alvocidib. No drug-related AEs were fatal. Gastrointestinal toxicities, including diarrhea, nausea, and vomiting were notable and frequent; otherwise, the toxicities reported were consistent with the safety profile of both agents. The response rate was modest (complete remission [CR] + incomplete CR [CRi], 11.4%; CR + CRi + partial response rate + morphologic leukemia-free state, 20%). There was no change in alvocidib pharmacokinetics with increasing doses of venetoclax. However, when venetoclax was administered with alvocidib, AUC24 and Cmax decreased by 18% and 19%, respectively. A recommended phase 2 dose was not established due to lack of meaningful increase in efficacy across all cohorts compared to what was previously observed with each agent alone. Future studies could consider the role of the sequence, dosing, and the use of a more selective MCL1 inhibitor for the R/R AML population.

Keywords:  BCL-2; MCL-1; acute myeloid leukemia; alvocidib; drug resistance; venetoclax

DOI:  https://doi.org/10.1002/hon.3159
Res Sq. 2023 Apr 14. pii: rs.3.rs-2802265. [Epub ahead of print]

The E592K variant of SF3B1 creates unique RNA missplicing and associates with high-risk MDS without ring sideroblasts.

In Young Choi, Jonathan Ling, Jian Zhang, Eric Helmenstine, Wencke Walter, Riley Bergman, Céline Philippe, James Manley, Kevin Rouault-Pierre, Bing Li, Daniel Wiseman, Madhu Ouseph, Elsa Bernard, Xiao Li, Torsten Haferlach, Salman Fazal, Tania Jain, Christopher Gocke, Amy DeZern, W Brian Dalton.

Among the most common genetic alterations in the myelodysplastic syndromes (MDS) are mutations in the spliceosome gene SF3B1 . Such mutations induce specific RNA missplicing events, directly promote ring sideroblast (RS) formation, generally associate with more favorable prognosis, and serve as a predictive biomarker of response to luspatercept. However, not all SF3B1 mutations are the same, and here we report that the E592K variant of SF3B1 associates with high-risk disease features in MDS, including a lack of RS, increased myeloblasts, a distinct co-mutation pattern, and decreased survival. Moreover, in contrast to canonical SF3B1 mutations, E592K induces a unique RNA missplicing pattern, retains an interaction with the splicing factor SUGP1 , and preserves normal RNA splicing of the sideroblastic anemia genes TMEM14C and ABCB7. These data expand our knowledge of the functional diversity of spliceosome mutations, and they suggest that patients with E592K should be approached differently from low-risk, luspatercept-responsive MDS patients with ring sideroblasts and canonical SF3B1 mutations.

DOI: https://doi.org/10.21203/rs.3.rs-2802265/v1
Haematologica. 2023 Apr 27.

Inactivation of p53 provides a competitive advantage to del(5q) myelodysplastic syndrome hematopoietic stem cells during inflammation.

Tomoya Muto, Callum S Walker, Puneet Agarwal, Eric Vick, Avery Sampson, Kwangmin Choi, Madeline Niederkorn, Chiharu Ishikawa, Kathleen Hueneman, Melinda Varney, Daniel T Starczynowski.

Inflammation is associated with the pathogenesis of Myelodysplastic syndromes (MDS) and emerging evidence suggests that MDS hematopoietic stem and progenitor cells (HSPCs) exhibit an altered response to inflammation. Deletion of chromosome 5 (del(5q)) is the most common chromosomal abnormality in MDS. Although this MDS subtype contains several haploinsufficient genes that impact innate immune signaling, the effects of inflammation on del(5q) MDS HSPCs remains undefined. Utilizing a model of del(5q)-like MDS, inhibiting the IRAK1/4-TRAF6 axis improved cytopenias, suggesting that activation of innate immune pathways contributes to certain clinical features underlying the pathogenesis of low-risk MDS. However, low-grade inflammation in the del(5q)-like MDS model did not contribute to more severe disease but instead impaired the del(5q)-like HSPCs as indicated by their diminished numbers, premature attrition and increased p53 expression. Del(5q)-like HSPCs exposed to inflammation became less quiescent, but without affecting cell viability. Unexpectedly, the reduced cellular quiescence of del(5q) HSPCs exposed to inflammation was restored by p53 deletion. These findings uncovered that inflammation confers a competitive advantage of functionally defective del(5q) HSPCs upon loss of p53. Since TP53 mutations are enriched in del(5q) AML following an MDS diagnosis, increased p53 activation in del(5q) MDS HSPCs due to inflammation may create a selective pressure for genetic inactivation of p53 or expansion of a pre-existing TP53-mutant clone.

DOI: https://doi.org/10.3324/haematol.2022.282349
Leukemia. 2023 Apr 24.

Blocking the CD47-SIRPα interaction reverses the disease phenotype in a polycythemia vera mouse model.

Veronika Lysenko, Patrick M Schürch, Selma Tuzlak, Nicole Wildner-Verhey van Wijk, Larisa V Kovtonyuk, Burkhard Becher, Markus G Manz, Stefanie Kreutmair, Alexandre P A Theocharides.

Polycythemia vera (PV) is a hematopoietic stem cell neoplasm driven by somatic mutations in JAK2, leading to increased red blood cell (RBC) production uncoupled from mechanisms that regulate physiological erythropoiesis. At steady-state, bone marrow macrophages promote erythroid maturation, whereas splenic macrophages phagocytose aged or damaged RBCs. The binding of the anti-phagocytic ("don't eat me") CD47 ligand expressed on RBCs to the SIRPα receptor on macrophages inhibits phagocytic activity protecting RBCs from phagocytosis. In this study, we explore the role of the CD47-SIRPα interaction on the PV RBC life cycle. Our results show that blocking CD47-SIRPα in a PV mouse model due to either anti-CD47 treatment or loss of the inhibitory SIRPα-signal corrects the polycythemia phenotype. Anti-CD47 treatment marginally impacted PV RBC production while not influencing erythroid maturation. However, upon anti-CD47 treatment, high-parametric single-cell cytometry identified an increase of MerTK+ splenic monocyte-derived effector cells, which differentiate from Ly6Chi monocytes during inflammatory conditions, acquire an inflammatory phagocytic state. Furthermore, in vitro, functional assays showed that splenic JAK2 mutant macrophages were more "pro-phagocytic," suggesting that PV RBCs exploit the CD47-SIRPα interaction to escape innate immune attacks by clonal JAK2 mutant macrophages.

DOI: https://doi.org/10.1038/s41375-023-01903-2
Lancet. 2023 Apr 25. pii: S0140-6736(23)00617-7. [Epub ahead of print]

FLT3-mutated acute myeloid leukaemia: a new opportunity.

Amanda C Przespolewski, Elizabeth A Griffiths.

DOI: https://doi.org/10.1016/S0140-6736(23)00617-7
Nat Aging. 2022 Nov;2(11): 1008-1023

Epigenetic reversal of hematopoietic stem cell aging in Phf6-knockout mice.

Agnieszka A Wendorff, S Aidan Quinn, Silvia Alvarez, Jessie A Brown, Mayukh Biswas, Thomas Gunning, Teresa Palomero, Adolfo A Ferrando.

Aging is characterized by an accumulation of myeloid-biased hematopoietic stem cells (HSCs) with reduced developmental potential. Genotoxic stress and epigenetic alterations have been proposed to mediate age-related HSC loss of regenerative and self-renewal potential. However, the mechanisms underlying these changes remain largely unknown. Genetic inactivation of the plant homeodomain 6 (Phf6) gene, a nucleolar and chromatin-associated factor, antagonizes age-associated HSC decline. Immunophenotyping, single-cell transcriptomic analyses and transplantation assays demonstrated markedly decreased accumulation of immunophenotypically defined HSCs, reduced myeloid bias and increased hematopoietic reconstitution capacity with preservation of lymphoid differentiation potential in Phf6-knockout HSCs from old mice. Moreover, deletion of Phf6 in aged mice rejuvenated immunophenotypic, transcriptional and functional hallmarks of aged HSCs. Long-term HSCs from old Phf6-knockout mice showed epigenetic rewiring and transcriptional programs consistent with decreased genotoxic stress-induced HSC aging. These results identify Phf6 as an important epigenetic regulator of HSC aging.

DOI: https://doi.org/10.1038/s43587-022-00304-x
Cell Death Differ. 2023 Apr 26.

Apoptotic cell death in disease-Current understanding of the NCCD 2023.

Ilio Vitale, Federico Pietrocola, Emma Guilbaud, Stuart A Aaronson, John M Abrams, Dieter Adam, Massimiliano Agostini, Patrizia Agostinis, Emad S Alnemri, Lucia Altucci, Ivano Amelio, David W Andrews, Rami I Aqeilan, Eli Arama, Eric H Baehrecke, Siddharth Balachandran, Daniele Bano, Nickolai A Barlev, Jiri Bartek, Nicolas G Bazan, Christoph Becker, Francesca Bernassola, Mathieu J M Bertrand, Marco E Bianchi, Mikhail V Blagosklonny, J Magarian Blander, Giovanni Blandino, Klas Blomgren, Christoph Borner, Carl D Bortner, Pierluigi Bove, Patricia Boya, Catherine Brenner, Petr Broz, Thomas Brunner, Rune Busk Damgaard, George A Calin, Michelangelo Campanella, Eleonora Candi, Michele Carbone, Didac Carmona-Gutierrez, Francesco Cecconi, Francis K-M Chan, Guo-Qiang Chen, Quan Chen, Youhai H Chen, Emily H Cheng, Jerry E Chipuk, John A Cidlowski, Aaron Ciechanover, Gennaro Ciliberto, Marcus Conrad, Juan R Cubillos-Ruiz, Peter E Czabotar, Vincenzo D'Angiolella, Mads Daugaard, Ted M Dawson, Valina L Dawson, Ruggero De Maria, Bart De Strooper, Klaus-Michael Debatin, Ralph J Deberardinis, Alexei Degterev, Giannino Del Sal, Mohanish Deshmukh, Francesco Di Virgilio, Marc Diederich, Scott J Dixon, Brian D Dynlacht, Wafik S El-Deiry, John W Elrod, Kurt Engeland, Gian Maria Fimia, Claudia Galassi, Carlo Ganini, Ana J Garcia-Saez, Abhishek D Garg, Carmen Garrido, Evripidis Gavathiotis, Motti Gerlic, Sourav Ghosh, Douglas R Green, Lloyd A Greene, Hinrich Gronemeyer, Georg Häcker, György Hajnóczky, J Marie Hardwick, Ygal Haupt, Sudan He, David M Heery, Michael O Hengartner, Claudio Hetz, David A Hildeman, Hidenori Ichijo, Satoshi Inoue, Marja Jäättelä, Ana Janic, Bertrand Joseph, Philipp J Jost, Thirumala-Devi Kanneganti, Michael Karin, Hamid Kashkar, Thomas Kaufmann, Gemma L Kelly, Oliver Kepp, Adi Kimchi, Richard N Kitsis, Daniel J Klionsky, Ruth Kluck, Dmitri V Krysko, Dagmar Kulms, Sharad Kumar, Sergio Lavandero, Inna N Lavrik, John J Lemasters, Gianmaria Liccardi, Andreas Linkermann, Stuart A Lipton, Richard A Lockshin, Carlos López-Otín, Tom Luedde, Marion MacFarlane, Frank Madeo, Walter Malorni, Gwenola Manic, Roberto Mantovani, Saverio Marchi, Jean-Christophe Marine, Seamus J Martin, Jean-Claude Martinou, Pier G Mastroberardino, Jan Paul Medema, Patrick Mehlen, Pascal Meier, Gerry Melino, Sonia Melino, Edward A Miao, Ute M Moll, Cristina Muñoz-Pinedo, Daniel J Murphy, Maria Victoria Niklison-Chirou, Flavia Novelli, Gabriel Núñez, Andrew Oberst, Dimitry Ofengeim, Joseph T Opferman, Moshe Oren, Michele Pagano, Theocharis Panaretakis, Manolis Pasparakis, Josef M Penninger, Francesca Pentimalli, David M Pereira, Shazib Pervaiz, Marcus E Peter, Paolo Pinton, Giovanni Porta, Jochen H M Prehn, Hamsa Puthalakath, Gabriel A Rabinovich, Krishnaraj Rajalingam, Kodi S Ravichandran, Markus Rehm, Jean-Ehrland Ricci, Rosario Rizzuto, Nirmal Robinson, Cecilia M P Rodrigues, Barak Rotblat, Carla V Rothlin, David C Rubinsztein, Thomas Rudel, Alessandro Rufini, Kevin M Ryan, Kristopher A Sarosiek, Akira Sawa, Emre Sayan, Kate Schroder, Luca Scorrano, Federico Sesti, Feng Shao, Yufang Shi, Giuseppe S Sica, John Silke, Hans-Uwe Simon, Antonella Sistigu, Anastasis Stephanou, Brent R Stockwell, Flavie Strapazzon, Andreas Strasser, Liming Sun, Erwei Sun, Qiang Sun, Gyorgy Szabadkai, Stephen W G Tait, Daolin Tang, Nektarios Tavernarakis, Carol M Troy, Boris Turk, Nicoletta Urbano, Peter Vandenabeele, Tom Vanden Berghe, Matthew G Vander Heiden, Jacqueline L Vanderluit, Alexei Verkhratsky, Andreas Villunger, Silvia von Karstedt, Anne K Voss, Karen H Vousden, Domagoj Vucic, Daniela Vuri, Erwin F Wagner, Henning Walczak, David Wallach, Ruoning Wang, Ying Wang, Achim Weber, Will Wood, Takahiro Yamazaki, Huang-Tian Yang, Zahra Zakeri, Joanna E Zawacka-Pankau, Lin Zhang, Haibing Zhang, Boris Zhivotovsky, Wenzhao Zhou, Mauro Piacentini, Guido Kroemer, Lorenzo Galluzzi.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

DOI: https://doi.org/10.1038/s41418-023-01153-w
Leukemia. 2023 Apr 22.

HIF1α-mediated transactivation of WTAP promotes AML cell proliferation via m6A-dependent stabilization of KDM4B mRNA.

Yang-Liu Shao, Yu-Qing Li, Meng-Yue Li, Li-Li Wang, Hui-Sheng Zhou, Dai-Hong Liu, Li Yu, Ji Lin, Xiao-Ning Gao.

Hypoxia inducible factor 1α (HIF1α) is abnormally overexpressed in t(8;21) acute myeloid leukemia (AML) and functions as an oncogene through transactivating DNA methyltransferase 3 alpha leading to DNA hypermethylation. However, it remains unclear whether HIF1α influences RNA N6-methyladenosine (m6A) methyltransferases. Here, we show that HIF1α promotes the expression of Wilms tumor 1-associated protein (WTAP), a main component of the m6A methyltransferase complex, markedly alters the transcriptome-wide m6A distribution and enhances cell proliferation in t(8;21) AML. In agreement with this, WTAP is overexpressed and predicts poor prognosis in t(8;21) AML patients. Moreover, WTAP knockdown inhibits growth, and induces apoptosis and differentiation of leukemia cells. Mechanistically, HIF1α transactivates WTAP gene expression by directly binding to the hypoxia-response element of its promoter region. Pharmacological or genetic intervention in the HIF1α-WTAP axis results in the reduction of m6A level on lysine demethylase 4B (KDM4B) transcripts and increased its degradation, correlated with lower expression of KDM4B and higher trimethylation levels of histone H3 on lysine 9. KDM4B knockdown inhibits leukemia cell growth in vitro and in mice. Thus, HIF1α-mediated WTAP high expression enhances the malignant behavior of leukemia cells and drives a crosstalk between m6A RNA methylation and histone methylation through monitoring m6A-dependant KDM4B translation.

DOI: https://doi.org/10.1038/s41375-023-01904-1
Exp Hematol Oncol. 2023 Apr 28. 12(1): 42

New approaches to idiopathic neutropenia in the era of clonal hematopoiesis.

Olisaemeka D Ogbue, Tariq Kewan, Waled S Bahaj, Carmelo Gurnari, Valeria Visconte, Jaroslaw P Maciejewski.

  Isolated chronic idiopathic neutropenia (CIN) is a rare disease with multiple contributing etiologies that must be ruled out before establishing a diagnosis. We studied clinical and molecular data of 238 consecutive adult patients with CIN. Autoimmune neutropenia was present in 28% of our cohort. In contrast, T cell-mediated neutropenia was the main underlying pathological mechanism among patients with T cell expansions, such as T-cell large granular lymphocytic leukemia (T-LGL) and T cell clonopathy of undetermined significance, found in 37% and 8% of cases, respectively. Patients with neutropenia also had hypogammaglobulinemia (6%) and/or monoclonal gammopathy of undetermined significance (5%). NGS application has further broadened the spectrum of causes of CIN by including manifestations of clonal hematopoiesis, present in 12% of cases. TET2 (3%), TP53 (2%), and IDH1/IDH2 (2%) mutations were the most commonly found and were enriched in cases with T-LGL. We show that these clinico-molecular associations can be simultaneously present, complicating a proper diagnostic distinction within the broader entity of seemingly idiopathic neutropenia of autoimmune origin. Identification of etiologic culprits may also guide rational selection of therapies.

Keywords:  Clonal hematopoiesis; Neutropenia; T-cell mediated

DOI:  https://doi.org/10.1186/s40164-023-00403-4
Semin Diagn Pathol. 2023 Apr 13. pii: S0740-2570(23)00036-9. [Epub ahead of print]

Advances in molecular evaluation of myeloproliferative neoplasms.

Nianyi Li, Mingyi Chen, C Cameron Yin.

  Myeloproliferative neoplasms (MPN) are a group of clonal hematopoietic stem cell disorders with uncontrolled proliferation of one or more hematopoietic cell types, including myeloid, erythroid and megakaryocytic lineages, and minimal defect in maturation. Most MPN are associated with well-defined molecular abnormalities involving genes that encode protein tyrosine kinases that lead to constitutive activation of the downstream signal transduction pathways and confer cells proliferative and survival advantage. Genome-wide sequencing analyses have discovered secondary cooperating mutations that are shared by most of the MPN subtypes as well as other myeloid neoplasms and play a major role in disease progression. Without appropriate management, the natural history of most MPN consists of an initial chronic phase and a terminal blast phase. Molecular aberrations involving protein tyrosine kinases have been used for the diagnosis, classification, detection of minimal/measurable residual disease, and target therapy. We review recent advances in molecular genetic aberrations in MPN with a focus on MPN associated with gene rearrangements or mutations involving tyrosine kinase pathways.

Keywords:  Chronic eosinophilic leukemia; Chronic myeloid leukemia; Chronic neutrophilic leukemia; JAK2/CALR/MPL-mutated myeloproliferative neoplasm; Juvenile myelomonocytic leukemia; Myeloproliferative neoplasm, unclassifiable

DOI:  https://doi.org/10.1053/j.semdp.2023.04.007
Cells Dev. 2023 Apr 26. pii: S2667-2901(23)00021-9. [Epub ahead of print] 203845

Physical biomarkers for human hematopoietic stem and progenitor cells.

Motomu Tanaka, Judith Thoma, Laura Poisa-Beiro, Patrick Wuchter, Volker Eckstein, Sascha Dietrich, Caroline Pabst, Carsten Müller-Tidow, Takao Ohta, Anthony D Ho.

  Adhesion of hematopoietic stem and progenitor cells (HSPCs) to the bone marrow niche plays critical roles in the maintenance of the most primitive HSPCs. The interactions of HSPC-niche interactions are clinically relevant in acute myeloid leukemia (AML), because (i) leukemia-initiating cells adhered to the marrow niche are protected from the cytotoxic effect by chemotherapy and (ii) mobilization of HSPCs from healthy donors' bone marrow is crucial for the effective stem cell transplantation. However, although many clinical agents have been developed for the HSPC mobilization, the effects caused by the extrinsic molecular cues were traditionally evaluated based on phenomenological observations. This review highlights the recent interdisciplinary challenges of hematologists, biophysicists and cell biologists towards the design of defined in vitro niche models and the development of physical biomarkers for quantitative indexing of differential effects of clinical agents on human HSPCs.

Keywords:  Acute myeloid leukemia; Celsl adhesion; Clinical agent; Human hematopoietic stem and progenitor cell; Spatio-temporal dynamics

DOI:  https://doi.org/10.1016/j.cdev.2023.203845
J Clin Oncol. 2023 Apr 25. JCO2202734

The Clinicogenomic Landscape of Induction Failure in Childhood and Young Adult T-Cell Acute Lymphoblastic Leukemia.

David O'Connor, Jonas Demeulemeester, Lucia Conde, Amy Kirkwood, Kent Fung, Foteini Papaleonidopoulou, Gianna Bloye, Nadine Farah, Sunniyat Rahman, Jeremy Hancock, Caroline Bateman, Sarah Inglott, Jon Mee, Javier Herrero, Peter Van Loo, Anthony V Moorman, Ajay Vora, Marc R Mansour.

PURPOSE: Failure to respond to induction chemotherapy portends a poor outcome in childhood acute lymphoblastic leukemia (ALL) and is more frequent in T-cell ALL (T-ALL) than B-cell ALL. We aimed to address the limited understanding of clinical and genetic factors that influence outcome in a cohort of patients with T-ALL induction failure (IF).METHODS: We studied all cases of T-ALL IF on two consecutive multinational randomized trials, UKALL2003 and UKALL2011, to define risk factors, treatment, and outcomes. We performed multiomic profiling to characterize the genomic landscape.
RESULTS: IF occurred in 10.3% of cases and was significantly associated with increasing age, occurring in 20% of patients age 16 years and older. Five-year overall survival (OS) rates were 52.1% in IF and 90.2% in responsive patients (P < .001). Despite increased use of nelarabine-based chemotherapy consolidated by hematopoietic stem-cell transplant in UKALL2011, there was no improvement in outcome. Persistent end-of-consolidation molecular residual disease resulted in a significantly worse outcome (5-year OS, 14.3% v 68.5%; HR, 4.10; 95% CI, 1.35 to 12.45; P = .0071). Genomic profiling revealed a heterogeneous picture with 25 different initiating lesions converging on 10 subtype-defining genes. There was a remarkable abundance of TAL1 noncoding lesions, associated with a dismal outcome (5-year OS, 12.5%). Combining TAL1 lesions with mutations in the MYC and RAS pathways produces a genetic stratifier that identifies patients highly likely to fail conventional therapy (5-year OS, 23.1% v 86.4%; HR, 6.84; 95% CI, 2.78 to 16.78; P < .0001) and who should therefore be considered for experimental agents.
CONCLUSION: The outcome of IF in T-ALL remains poor with current therapy. The lack of a unifying genetic driver suggests alternative approaches, particularly using immunotherapy, are urgently needed.

DOI: https://doi.org/10.1200/JCO.22.02734
Blood. 2023 Apr 27. 141(17): 2035-2036

Newly revised 2023 MDS response criteria.

Rafael Bejar.

DOI: https://doi.org/10.1182/blood.2023019821
Elife. 2023 Apr 28. pii: e84149. [Epub ahead of print]12

Predictive nonlinear modeling of malignant myelopoiesis and tyrosine kinase inhibitor therapy.

Jonathan Rodriguez, Abdon Iniguez, Nilamani Jena, Prasanthi Tata, Joan Liu, Arthur D Lander, John Lowengrub, Richard Van Etten.

  Chronic myeloid leukemia (CML) is a blood cancer characterized by dysregulated production of maturing myeloid cells driven by the product of the Philadelphia chromosome, the BCR-ABL1 tyrosine kinase. Tyrosine kinase inhibitors (TKI) have proved effective in treating CML but there is still a cohort of patients who do not respond to TKI therapy even in the absence of mutations in the BCR-ABL1 kinase domain that mediate drug resistance. To discover novel strategies to improve TKI therapy in CML, we developed a nonlinear mathematical model of CML hematopoiesis that incorporates feedback control and lineage branching. Cell-cell interactions were constrained using an automated model selection method together with previous observations and new in vivo data from a chimeric BCR-ABL1 transgenic mouse model of CML. The resulting quantitative model captures the dynamics of normal and CML cells at various stages of the disease and exhibits variable responses to TKI treatment, consistent with those of CML patients. The model predicts that an increase in the proportion of CML stem cells in the bone marrow would decrease the tendency of the disease to respond to TKI therapy, in concordance with clinical data and confirmed experimentally in mice. The model further suggests that, under our assumed similarities between normal and leukemic cells, a key predictor of refractory response to TKI treatment is an increased maximum probability of self-renewal of normal hematopoietic stem cells. We use these insights to develop a clinical prognostic criterion to predict the efficacy of TKI treatment and to design strategies to improve treatment response. The model predicts that stimulating the differentiation of leukemic stem cells while applying TKI therapy can significantly improve treatment outcomes.

Keywords:  cancer biology; computational biology; mouse; systems biology

DOI:  https://doi.org/10.7554/eLife.84149
Leukemia. 2023 Apr 24.

Transcription factor Nkx2-3 maintains the self-renewal of hematopoietic stem cells by regulating mitophagy.

Mengjia Hu, Naicheng Chen, Mo Chen, Fang Chen, Yukai Lu, Yang Xu, Lijing Yang, Hao Zeng, Mingqiang Shen, Xuehong Chen, Shilei Chen, Fengchao Wang, Song Wang, Junping Wang.

Hematopoietic stem cells (HSCs) reside at the top of the hematopoietic hierarchy, exhibiting a unique capacity to self-renew and differentiate into all blood cells throughout the lifetime. However, how to prevent HSC exhaustion during long-term hematopoietic output is not fully understood. Here, we show that the homeobox transcription factor Nkx2-3 is required for HSC self-renewal by preserving metabolic fitness. We found that Nkx2-3 is preferentially expressed in HSCs with excessive regenerative potential. Mice with conditional deletion of Nkx2-3 displayed a reduced HSC pool and long-term repopulating capacity as well as increased sensitivity to irradiation and 5-flurouracil treatment due to impaired HSC quiescence. In contrast, overexpression of Nkx2-3 improved HSC function both in vitro and in vivo. Furthermore, mechanistic studies revealed that Nkx2-3 can directly control the transcription of the critical mitophagy regulator ULK1, which is essential for sustaining metabolic homeostasis in HSCs by clearing activated mitochondria. More importantly, a similar regulatory role of NKX2-3 was observed in human cord blood-derived HSCs. In conclusion, our data demonstrate an important role of the Nkx2-3/ULK1/mitophagy axis in regulating the self-renewal of HSCs, therefore providing a promising strategy to improve the function of HSCs in the clinic.

DOI: https://doi.org/10.1038/s41375-023-01907-y
Leukemia. 2023 Apr 26.

The EGR3 regulome of infant KMT2A-r acute lymphoblastic leukemia identifies differential expression of B-lineage genes predictive for outcome.

Marius Külp, Patrizia Larghero, Julia Alten, Gunnar Cario, Cornelia Eckert, Aurélie Caye-Eude, Hélène Cavé, Tessa Schmachtel, Michela Bardini, Giovanni Cazzaniga, Paola De Lorenzo, Maria Grazia Valsecchi, Halvard Bonig, Claus Meyer, Michael A Rieger, Rolf Marschalek.

KMT2A-rearranged acute lymphoblastic infant leukemia (KMT2A-r iALL) is associated with outsize risk of relapse and relapse mortality. We previously reported strong upregulation of the immediate early gene EGR3 in KMT2A::AFF1 iALL at relapse; now we provide analyses of the EGR3 regulome, which we assessed through binding and expression target analysis of an EGR3-overexpressing t(4;11) cell culture model. Our data identify EGR3 as a regulator of early B-lineage commitment. Principal component analysis of 50 KMT2A-r iALL patients at diagnosis and 18 at relapse provided strictly dichotomous separation of patients based on the expression of four B-lineage genes. Absence of B-lineage gene expression translates to more than two-fold poorer long-term event-free survival. In conclusion, our study presents four B-lineage genes with prognostic significance, suitable for gene expression-based risk stratification of KMT2A-r iALL patients.

DOI: https://doi.org/10.1038/s41375-023-01895-z
Blood Adv. 2023 Apr 26. pii: bloodadvances.2022008462. [Epub ahead of print]

Mecom mutation related to radioulnar synostosis with amegakaryocytic thrombocytopenia reduces HSPCs in mice.

Koki Nagai, Tetsuya Niihori, Akihiko Muto, Yoshikazu Hayashi, Taiki Abe, Kazuhiko Igarashi, Yoko Aoki.

Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome characterized by congenital fusion of the forearm bones. RUSAT is largely caused by missense mutations that are clustered in a specific region of the MDS1 and EVI1 complex locus (MECOM). EVI1, a transcript variant encoded by MECOM, is a zinc finger transcription factor involved in hematopoietic stem cell maintenance that induce leukemic transformation when overexpressed. Mice with exonic deletions in Mecom show reduced hematopoietic stem and progenitor cells (HSPCs). However, the pathogenic roles of RUSAT-associated MECOM mutations in vivo have not yet been elucidated. To investigate the impact of the RUSAT-associated MECOM mutation on the phenotype, we generated knock-in mice harboring a point mutation (translated into EVI1 p.H752R and MDS1-EVI1 p.H942R), which corresponds to an EVI1 p.H751R and MDS1-EVI1 p.H939R mutation identified in a patient with RUSAT. Homozygous mutant mice died at embryonic day 10.5-11.5. Heterozygous mutant mice (Evi1KI/+ mice) grew normally without radioulnar synostosis. Male Evi1KI/+ mice aged 5-15 weeks exhibited lower body weight and those aged 16 weeks and older showed low platelet counts. Flow cytometric analysis of bone marrow cells revealed a decrease in HSPCs in Evi1KI/+ mice at 8-12 weeks. Moreover, Evi1KI/+ mice showed delayed leukocyte and platelet recovery after 5-fluorouracil-induced myelosuppression. These findings suggest that Evi1KI/+ mice recapitulate the bone marrow dysfunction in RUSAT, similar to that caused by loss-of-function Mecom alleles.

DOI: https://doi.org/10.1182/bloodadvances.2022008462
Bone Marrow Transplant. 2023 Apr 24.

Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a refined classification from the European society for blood and marrow transplantation (EBMT).

Mohamad Mohty, Florent Malard, Ahmed S Alaskar, Mahmoud Aljurf, Mutlu Arat, Peter Bader, Frederic Baron, Ali Bazarbachi, Didier Blaise, Eolia Brissot, Fabio Ciceri, Selim Corbacioglu, Jean-Hugues Dalle, Fiona Dignan, Anne Huynh, Michelle Kenyon, Arnon Nagler, Antonio Pagliuca, Zinaida Perić, Paul G Richardson, Annalisa Ruggeri, Tapani Ruutu, Ibrahim Yakoub-Agha, Rafael F Duarte, Enric Carreras.

Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell transplantation (HCT). A new definition for diagnosis, and a severity grading system for SOS/VOD in adult patients, was reported a few years ago on behalf of the European Society for Blood and Marrow Transplantation (EBMT). The aim of this work is to update knowledge regarding diagnosis and severity assessment of SOS/VOD in adult patients, and also its pathophysiology and treatment. In particular, we now propose to refine the previous classification and distinguish probable, clinical and proven SOS/VOD at diagnosis. We also provide an accurate definition of multiorgan dysfunction (MOD) for SOS/VOD severity grading based on Sequential Organ Failure Assessment (SOFA) score.

DOI: https://doi.org/10.1038/s41409-023-01992-8
Am J Hematol. 2023 Apr 29.

The NPM1 mutant defines AML irrespective of blast count.

Brunangelo Falini, Maria Paola Martelli, Lorenzo Brunetti, Bjorn T Gjertsen, Vibeke Andresen.

DOI: https://doi.org/10.1002/ajh.26946
Cell Death Dis. 2023 Apr 24. 14(4): 287

BCR-ABL triggers a glucose-dependent survival program during leukemogenesis through the suppression of TXNIP.

Lin Feng, Ruxin Ding, Xuan Qu, Yuanchun Li, Tong Shen, Lei Wang, Ruikai Li, Juan Zhang, Yi Ru, Xin Bu, Yang Wang, Min Li, Wenqi Song, Liangliang Shen, Pengxia Zhang.

Imatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but the primary and acquired imatinib resistance remains the big hurdle. Molecular mechanisms for CML resistance to tyrosine kinase inhibitors, beyond point mutations in BCR-ABL kinase domain, still need to be addressed. Here, we demonstrated that thioredoxin-interacting protein (TXNIP) is a novel BCR-ABL target gene. Suppression of TXNIP was responsible for BCR-ABL triggered glucose metabolic reprogramming and mitochondrial homeostasis. Mechanistically, Miz-1/P300 complex transactivates TXNIP through the recognition of TXNIP core promoter region, responding to the c-Myc suppression by either imatinib or BCR-ABL knockdown. TXNIP restoration sensitizes CML cells to imatinib treatment and compromises imatinib resistant CML cell survival, predominantly through the blockage of both glycolysis and glucose oxidation which results in the mitochondrial dysfunction and ATP production. In particular, TXNIP suppresses expressions of the key glycolytic enzyme, hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA), potentially through Fbw7-dependent c-Myc degradation. In accordance, BCR-ABL suppression of TXNIP provided a novel survival pathway for the transformation of mouse bone marrow cells. Knockout of TXNIP accelerated BCR-ABL transformation, whereas TXNIP overexpression suppressed this transformation. Combination of drug inducing TXNIP expression with imatinib synergistically kills CML cells from patients and further extends the survival of CML mice. Thus, the activation of TXNIP represents an effective strategy for CML treatment to overcome resistance.

DOI: https://doi.org/10.1038/s41419-023-05811-2
J Exp Med. 2023 Aug 07. pii: e20230088. [Epub ahead of print]220(8):

Secretory MPP3 reinforce myeloid differentiation trajectory and amplify myeloid cell production.

Yoon-A Kang, Hyojung Paik, Si Yi Zhang, Jonathan J Chen, Oakley C Olson, Carl A Mitchell, Amelie Collins, James W Swann, Matthew R Warr, Rong Fan, Emmanuelle Passegué.

Hematopoietic stem cells (HSC) and downstream lineage-biased multipotent progenitors (MPP) tailor blood production and control myelopoiesis on demand. Recent lineage tracing analyses revealed MPPs to be major functional contributors to steady-state hematopoiesis. However, we still lack a precise resolution of myeloid differentiation trajectories and cellular heterogeneity in the MPP compartment. Here, we found that myeloid-biased MPP3 are functionally and molecularly heterogeneous, with a distinct subset of myeloid-primed secretory cells with high endoplasmic reticulum (ER) volume and FcγR expression. We show that FcγR+/ERhigh MPP3 are a transitional population serving as a reservoir for rapid production of granulocyte/macrophage progenitors (GMP), which directly amplify myelopoiesis through inflammation-triggered secretion of cytokines in the local bone marrow (BM) microenvironment. Our results identify a novel regulatory function for a secretory MPP3 subset that controls myeloid differentiation through lineage-priming and cytokine production and acts as a self-reinforcing amplification compartment in inflammatory stress and disease conditions.

DOI: https://doi.org/10.1084/jem.20230088
Haematologica. 2023 Apr 27.

Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with MLL rearrangement or NPM1 mutation to venetoclax.

Johanna Rausch, Margarita M Dzama, Nadezda Dolgikh, Hanna L Stiller, Stephan R Bohl, Catharina Lahrmann, Kerstin Kunz, Linda Kessler, Hakim Echchannaoui, Chun-Wei Chen, Thomas Kindler, Konstanze Döhner, Francis Burrows, Matthias Theobald, Daniel Sasca, Michael W M Kühn.

Not available.

DOI: https://doi.org/10.3324/haematol.2022.282160
Leuk Res. 2023 Apr 14. pii: S0145-2126(23)00062-0. [Epub ahead of print]129 107077

Efficacy and tolerability of isocitrate dehydrogenase inhibitors in patients with acute myeloid leukemia: A systematic review of clinical trials.

Wajeeha Aiman, Muhammad Ashar Ali, Muhammad Abdul Basit, Zainab Omar, Muhammad Suleman, Muhammad Hassan, Taimoor Jamil, Muhammad Saad Anwar, Zubair Shafique, Gurneel Dhanesar, Muhammad Salman Faisal, Michael J Akerman, Michael Maroules, Faiz Anwer.

  BACKGROUND: Acute myeloid leukemia (AML) is a hematological malignancy due to anomalous differentiation and proliferation of hematopoietic stem cells with myeloid blast buildup. Induction chemotherapy is considered the first line of treatment in most patients with AML. However, targeted therapy in the form of FLT-3, IDH, BCL-2, and immune checkpoint inhibitors, can be considered as the first line depending on their molecular profile, resistance to chemotherapy, comorbidities, etc. This review aims to assess the tolerability and efficacy of isocitrate dehydrogenase (IDH) inhibitors in AML.METHODS: We searched Medline, WOS, Embase, and clinicaltrials.gov. PRISMA guidelines were followed in this systematic review. 3327 articles were screened, and 9 clinical trials (N = 1119) were included.
RESULTS: In randomized clinical trials (RCTs), objective response (OR) was reported in 63-74% of the patients with IDH inhibitors + azacitidine as compared to 19-36 % of the patients with azacitidine monotherapy in newly diagnosed (ND) medically unfit patients. Survival rates were significantly improved with the use of ivosidenib. OR was reported in 39.1-46 % of the patients who relapsed/refractory to chemotherapy. ≥Grade 3 IDH differentiation syndrome and QT prolongation were reported in 3.9-10 % and 2-10 % of the patients, respectively.
CONCLUSION: IDH inhibitors (ivosidenib for IDH-1 and enasidenib for IDH-2) are safe and effective in treating ND medically unfit or relapsed refractory patients with IDH mutation. However, no survival benefit was reported with enasidenib. More randomized multicenter double-blinded clinical studies are needed to confirm these results and compare them with other targeting agents.

Keywords:  AML; Clinical trials; IDH inhibitors; IDH mutation; Isocitrate dehydrogenase

DOI:  https://doi.org/10.1016/j.leukres.2023.107077
Nature. 2023 Apr 26.

A druggable copper-signalling pathway that drives inflammation.

Stéphanie Solier, Sebastian Müller, Tatiana Cañeque, Antoine Versini, Arnaud Mansart, Fabien Sindikubwabo, Leeroy Baron, Laila Emam, Pierre Gestraud, G Dan Pantoș, Vincent Gandon, Christine Gaillet, Ting-Di Wu, Florent Dingli, Damarys Loew, Sylvain Baulande, Sylvère Durand, Valentin Sencio, Cyril Robil, François Trottein, David Péricat, Emmanuelle Näser, Céline Cougoule, Etienne Meunier, Anne-Laure Bègue, Hélène Salmon, Nicolas Manel, Alain Puisieux, Sarah Watson, Mark A Dawson, Nicolas Servant, Guido Kroemer, Djillali Annane, Raphaël Rodriguez.

Inflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2-4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

DOI: https://doi.org/10.1038/s41586-023-06017-4
Blood Cancer J. 2023 04 24. 13(1): 58

Management of chronic myeloid leukemia in 2023 - common ground and common sense.

Jayastu Senapati, Koji Sasaki, Ghayas C Issa, Jeffrey H Lipton, Jerald P Radich, Elias Jabbour, Hagop M Kantarjian.

With the improving knowledge of CML and its management, the goals of therapy need to be revisited to ensure an optimal use of the BCR::ABL1 TKIs in the frontline and later-line therapy of CML. In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results. The second-generation TKIs may produce earlier deep molecular responses, hence reducing the time to reaching a treatment-free remission (TFR). The choice of the second-generation TKI versus imatinib in frontline therapy is based on the treatment aims (survival, TFR), the CML risk, the drug cost, and the toxicity profile with respect to the patient's comorbidities. The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI. In patients who are not candidates for TFR, BCR::ABL1 (International Scale) transcripts levels <1% are acceptable, result in virtually similar survival as with deeper molecular remissions, and need not warrant a change of TKI. For patients with true resistance to second-generation TKIs or with the T315I gatekeeper mutation, the third-generation TKIs are preferred. Ponatinib should be considered first because of the cumulative experience and results in the CML subsets, including in T315I-mutated CML. A response-based dosing of ponatinib is safe and leads to high TKI compliance. Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results.

DOI: https://doi.org/10.1038/s41408-023-00823-9
N Engl J Med. 2023 Apr 27. 388(17): 1572-1581

Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia.

Inge M van der Sluis, Paola de Lorenzo, Rishi S Kotecha, Andishe Attarbaschi, Gabriele Escherich, Karsten Nysom, Jan Stary, Alina Ferster, Benoit Brethon, Franco Locatelli, Martin Schrappe, Peggy E Scholte-van Houtem, Maria G Valsecchi, Rob Pieters.

BACKGROUND: KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants is an aggressive disease with 3-year event-free survival below 40%. Most relapses occur during treatment, with two thirds occurring within 1 year and 90% within 2 years after diagnosis. Outcomes have not improved in recent decades despite intensification of chemotherapy.METHODS: We studied the safety and efficacy of blinatumomab, a bispecific T-cell engager molecule targeting CD19, in infants with KMT2A-rearranged ALL. Thirty patients younger than 1 year of age with newly diagnosed KMT2A-rearranged ALL were given the chemotherapy used in the Interfant-06 trial with the addition of one postinduction course of blinatumomab (15 μg per square meter of body-surface area per day; 28-day continuous infusion). The primary end point was clinically relevant toxic effects, defined as any toxic effect that was possibly or definitely attributable to blinatumomab and resulted in permanent discontinuation of blinatumomab or death. Minimal residual disease (MRD) was measured by polymerase chain reaction. Data on adverse events were collected. Outcome data were compared with historical control data from the Interfant-06 trial.
RESULTS: The median follow-up was 26.3 months (range, 3.9 to 48.2). All 30 patients received the full course of blinatumomab. No toxic effects meeting the definition of the primary end point occurred. Ten serious adverse events were reported (fever [4 events], infection [4], hypertension [1], and vomiting [1]). The toxic-effects profile was consistent with that reported in older patients. A total of 28 patients (93%) either were MRD-negative (16 patients) or had low levels of MRD (<5×10-4 [i.e., <5 leukemic cells per 10,000 normal cells], 12 patients) after the blinatumomab infusion. All the patients who continued chemotherapy became MRD-negative during further treatment. Two-year disease-free survival was 81.6% in our study (95% confidence interval [CI], 60.8 to 92.0), as compared with 49.4% (95% CI, 42.5 to 56.0) in the Interfant-06 trial; the corresponding values for overall survival were 93.3% (95% CI, 75.9 to 98.3) and 65.8% (95% CI, 58.9 to 71.8).
CONCLUSIONS: Blinatumomab added to Interfant-06 chemotherapy appeared to be safe and had a high level of efficacy in infants with newly diagnosed KMT2A-rearranged ALL as compared with historical controls from the Interfant-06 trial. (Funded by the Princess Máxima Center Foundation and others; EudraCT number, 2016-004674-17.).

DOI: https://doi.org/10.1056/NEJMoa2214171