bims-tremyl 2022-01-09 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2022–01–09
nineteen papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Oral azacitidine prolongs survival of patients with AML in remission independent of measurable residual disease status.
Improved outcomes among newly diagnosed patients with FMS-like tyrosine kinase 3 internal tandem duplication mutated acute myeloid leukemia treated with contemporary therapy: Revisiting the European LeukemiaNet adverse risk classification.
Marrow ring sideroblasts are highly predictive for TP53 mutation in MDS with excess blasts.
Acquired WT1 mutations contribute to relapse of NPM1-mutated acute myeloid leukemia following allogeneic hematopoietic stem cell transplant.
Cytogenetic risk classification maintains its prognostic significance in transplanted FLT3-ITD mutated acute myeloid leukemia patients: On behalf of the acute leukemia working party/European society of blood and marrow transplantation.
Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes.
Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors.
AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia.
ELN 2017 classification significantly impacts the risk of early death in acute myeloid leukemia patients receiving intensive induction chemotherapy.
Conditioning Intensity and Peri-Transplant Flow Cytometric MRD Dynamics in Adult AML.
LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation.
Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee.
Differential Implications of CSF3R Mutations in t(8;21) and CEBPA Double Mutated Acute Myeloid Leukemia.
The UK SPIRIT 1 trial in newly diagnosed chronic myeloid leukaemia.
Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia.
Assessing the impact of the 2017 European LeukemiaNet recommendations on FLT3 allelic ratio calculation and reporting in acute myeloid leukaemia.
Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation.
Chronic Myelomonocytic Leukemia: 2022 Update on Diagnosis, Risk Stratification and Management.
MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases.

Blood. 2022 Jan 07. pii: blood.2021013404. [Epub ahead of print]

Oral azacitidine prolongs survival of patients with AML in remission independent of measurable residual disease status.

Gail J Roboz, Farhad Ravandi, Andrew H Wei, Hervé Dombret, Felicitas Thol, Maria Teresa Voso, Andre C Schuh, Kimmo Porkka, Ignazia La Torre, Barry S Skikne, Jianhua Zhong, C L Beach, Alberto Risueño, Daniel Lopes de Menezes, Gert J Ossenkoppele, Hartmut Döhner.

Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor survival. Post-remission maintenance therapy that prolongs MRD negativity or converts MRD positive (MRD+) patients to MRD negative (MRD-) status may delay or prevent relapse and improve overall survival (OS). In the phase 3 QUAZAR AML-001 trial, oral azacitidine (Oral-AZA; formerly CC-486), a hypomethylating agent, significantly prolonged OS and relapse-free survival (RFS) compared with placebo in patients aged ≥55 years with AML in first remission after intensive chemotherapy who were not candidates for hematopoietic stem cell transplantation. In this trial, MRD (≥0.1% leukemic cells in bone marrow) was assessed by multiparameter flow cytometry in serial samples collected at baseline and on day 1 of every 3 cycles. As expected, baseline MRD status was significantly associated with both OS and RFS. Multivariate analyses showed Oral-AZA significantly improved OS and RFS vs. placebo independent of baseline MRD status. Oral-AZA treatment also extended the duration of MRD negativity by 6 months vs. placebo, and resulted in a higher rate of conversion from MRD+ at baseline to MRD- during treatment: 37% vs. 19%, respectively. In the Oral-AZA arm, 24% of MRD responders achieved MRD negativity >6 months after treatment initiation. While presence or absence of MRD was a strong prognostic indicator of OS and RFS, there were added survival benefits with Oral-AZA maintenance therapy compared with placebo, independent of patients' MRD status at baseline. NCT01757535 Clinicaltrials.gov.

DOI: https://doi.org/10.1182/blood.2021013404
Am J Hematol. 2022 Jan 03.

Improved outcomes among newly diagnosed patients with FMS-like tyrosine kinase 3 internal tandem duplication mutated acute myeloid leukemia treated with contemporary therapy: Revisiting the European LeukemiaNet adverse risk classification.

Patrick K Reville, Koji Sasaki, Hagop M Kantarjian, Naval G Daver, Musa Yilmaz, Courtney D Dinardo, Nicholas J Short, Gautam Borthakur, Naveen Pemmaraju, Rohtesh S Mehta, Sherry Pierce, Sergej N Konoplev, Joseph D Khoury, Guillermo Garcia-Manero, Marina Y Konopleva, Elias Jabbour, Farhad Ravandi, Tapan M Kadia.

Mutations in fms-like tyrosine kinase 3 (FLT3) gene are common genomic alterations in acute myeloid leukemia (AML). FLT3 internal tandem duplication mutations (FLT3-ITD) have consistently been shown to be adversely prognostic, particularly those with high allelic ratio (AR). Current AML treatment strategies, including high dose cytarabine, purine analogs, FLT3 inhibitors (FLT3i), and with or without allogeneic stem cell transplant (SCT) have been shown to improve the outcomes in patients with FLT3 mutations. We analyzed a consecutive cohort of newly diagnosed patients with AML treated at a large academic medical center from January 2012 to January 2020. A total of 1576 patients with a new diagnosis of AML were reviewed. Among these, 1438 (91%) had molecular testing for FLT3 mutations and 21% (304/1438) had an FLT3 mutation, including 17% with an FLT3-ITD mutation. We show that FLT3-ITD high AR with NPM1 wild-type have significantly improved survival compared with other European LeukemiaNet (ELN) adverse risk disease. In multivariable cox proportional hazards model of patients receiving intensive or low-intensity induction regimens, FLT3 mutations did not have prognostic significance. The use of allogeneic SCT in CR1 for patients with FLT3 mutations appears to improve survival, particularly in those with ELN adverse risk disease. Overall, this data highlights the changing prognostic impact of FLT3 mutations in a contemporary era with appropriate use of induction therapy combined with targeted agents and allogenic SCT.

DOI: https://doi.org/10.1002/ajh.26451
Leukemia. 2022 Jan 03.

Marrow ring sideroblasts are highly predictive for TP53 mutation in MDS with excess blasts.

David M Swoboda, Rashmi Kanagal-Shamanna, Andrew M Brunner, Thomas Cluzeau, Onyee Chan, Najla Al Ali, Guillermo Montalban-Bravo, Quinto J Gesiotto, Alexander Gavralidis, Anthony M Hunter, Jung-Hoon Lee, Andrew T Kuykendall, Chetasi Talati, Kendra L Sweet, Jeffrey E Lancet, Eric Padron, Mohammad Hussaini, Jinming Song, Guillermo Garcia-Manero, Rami S Komrokji, David A Sallman.

DOI: https://doi.org/10.1038/s41375-021-01486-w
Bone Marrow Transplant. 2022 Jan 07.

Acquired WT1 mutations contribute to relapse of NPM1-mutated acute myeloid leukemia following allogeneic hematopoietic stem cell transplant.

Siba El Hussein, Courtney D DiNardo, Koichi Takahashi, Joseph D Khoury, Hong Fang, Ken Furudate, Kirill A Lyapichev, Sofia Garces, Rashmi Kanagal-Shamanna, Chi Young Ok, Keyur P Patel, Mark J Routbort, Farhad Ravandi, L Jeffrey Medeiros, Sa A Wang, Sanam Loghavi.

The role of WT1 protein in hematopoiesis and leukemogenesisis incompletely elucidated. WT1 overexpression is common in acute myeloid leukemia (AML); however, WT1 mutations occur in only about 10% of cases, with increasing incidence in the setting of relapse. In this study, we investigated the clinical and molecular characteristics of WT1 mutations in NPM1-mutated AML, to enhance our understanding of the biology and potential therapeutic implications of WT1 mutations. Our study cohort included 67 patients with NPM1 mutated AML and a median follow-up of 13.7 months. WT1 mutations were identified in 7% (n = 5) of patients at the time of initial diagnosis. WT1 mutant clones were presumed to be present as co-dominant clones in 3/5 and in subclonal populations in 2/5 cases based on variant allelic frequency (VAF) when compared with NPM1 mutation VAF. All WT1 mutations became undetectable at time of MRD-negative (NPM1-wild type) remission. None of these patients experienced relapse at the time of last follow-up (median, 15 months; range, 4.5-20.2 months). A total of 15/67 (22%) patients relapsed; among these patient, four (27%) relapsed with WT1 mutant AML. Three of four patients had undergone allogeneic hematopoietic stem cell transplantation (HSCT). None of these patients had detectable WT1 mutations at the time of initial diagnosis. WT1 mutations were presumed clonal in two cases and subclonal in the other two cases, based on VAF. Our results indicate that WT1 mutations contribute to relapse in NPM1 mutated AML, especially in the setting of HSCT. These findings suggest that emerging WT1 mutations may serve as a conduit for relapse in NPM1-mutated AML, and that sequential molecular profiling to evaluate potential emergent WT1 mutations during surveillance and particularly at relapse likely has prognostic value in patients with NPM1 mutated AML.

DOI: https://doi.org/10.1038/s41409-021-01538-w
Am J Hematol. 2022 Jan 03.

Cytogenetic risk classification maintains its prognostic significance in transplanted FLT3-ITD mutated acute myeloid leukemia patients: On behalf of the acute leukemia working party/European society of blood and marrow transplantation.

Arnon Nagler, Myriam Labopin, Charles Craddock, Gerard Socié, Ibrahim Yakoub-Agha, Tobias Gedde-Dahl, Riitta Niittyvuopio, Jennifer Louise Byrne, Jan J Cornelissen, Hélène Labussière-Wallet, William Arcese, Noel Milpied, Jordi Esteve, Jonathan Canaani, Mohamad Mohty.

FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutational status is a pivotal prognosticator in acute myeloid leukemia (AML) patients and significantly increases the risk of disease relapse. However, it remains unclear whether in FLT3-ITD patients referred for allogeneic stem cell transplantation (allo-SCT), baseline cytogenetics significantly impacts clinical outcome. Using the European Society of Blood and Marrow Transplantation registry, we performed a retrospective analysis of 1631 FLT3-ITD AML patients who underwent allo-SCT with the aim of determining the influence of cytogenetic risk category on patient outcomes. Median patient age was 49 years and median follow-up duration was 36 months. Two-year leukemia-free survival (LFS) and incidence of relapse were 54% and 31.6%, respectively. Non-relapse mortality was experienced by 14.4% with a 2-year overall survival (OS) of 60.1%. On multivariate analysis, LFS was significantly lower in patients with intermediate and adverse risk cytogenetics compared with those with favorable risk cytogenetics, (hazard ratio [HR] = 1.48, 95% confidence interval [CI], 1.06-2.06; p = .02), and (HR = 01.65, 95% CI, 1.13-2.40; p = .009), respectively. OS was significantly lower in patients with adverse risk cytogenetics compared with patients with favorable risk cytogenetics (HR = 1.74, 95% CI, 1.16-2.61; p = .008) with a trend toward lower OS in patients with intermediate risk cytogenetics compared to those with favorable risk cytogenetics (HR = 1.43, 95% CI, 1.00-2.05; p = .052). In addition, adverse risk patients and intermediate risk patients experienced higher relapse rates compared with favorable risk patients (HR = 1.83, 95% CI, 1.13-2.94; p = .013 and HR = 1.82, 95% CI, 1.19-2.77; p = .005). Overall, cytogenetic studies aid in refinement of risk stratification in transplanted FLT3-ITD AML patients.

DOI: https://doi.org/10.1002/ajh.26442
Ann Hematol. 2022 Jan 04.

Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes.

Amer M Zeidan, Daniel J DeAngelo, Jeanne Palmer, Christopher S Seet, Martin S Tallman, Xin Wei, Heather Raymon, Priya Sriraman, Stephan Kopytek, Jan Philipp Bewersdorf, Michael R Burgess, Kristen Hege, Wendy Stock.

  CC-90002 is an anti-CD47 antibody that inhibits CD47-SIRPα interaction and enables macrophage-mediated killing of tumor cells in hematological cancer cell lines. In this first clinical, phase 1, dose-escalation and -expansion study (CC-90002-AML-001; NCT02641002), we evaluated CC-90002 in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). CC-90002 was administered in escalating doses of 0.1-4.0 mg/kg, using a modified 3 + 3 design. Primary endpoints included dose-limiting toxicities (DLTs), non-tolerated dose (NTD), maximum tolerated dose (MTD), and recommended phase 2 dose. Secondary endpoints included preliminary efficacy, pharmacokinetics, and presence/frequency of anti-drug antibodies (ADAs). Between March 2016 and July 2018, 28 patients were enrolled (24 with AML and 4 with MDS) at 6 sites across the USA. As of July 18, 2018, all patients had discontinued, mainly due to death or progressive disease. The most common treatment-emergent adverse events were diarrhea (46.4%), thrombocytopenia (39.3%), febrile neutropenia (35.7%), and aspartate aminotransferase increase (35.7%). Four patients experienced DLTs (1 patient had grade 4 disseminated intravascular coagulation and grade 5 cerebral hemorrhage, 1 had grade 3 purpura, 1 had grade 4 congestive cardiac failure and grade 5 acute respiratory failure, and another had grade 5 sepsis). The NTD and MTD were not reached. No objective responses occurred. CC-90002 serum exposure was dose-dependent. ADAs were present across all doses, and the proportion of ADA-positive patients in cycle 1 increased over time. Despite no unexpected safety findings, the CC-90002-AML-001 study was discontinued in dose escalation for lack of monotherapy activity and evidence of ADAs. However, as other anti-CD47 agents in clinical trials are showing promising early results for AML and MDS, understanding preclinical and clinical differences between individual agents in this class will be of high importance.

Keywords:  Hematological cancer; IgG4PE; Macrophages; SIRPα; Safety

DOI:  https://doi.org/10.1007/s00277-021-04734-2
Am J Hematol. 2022 Jan 03.

Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors.

Yazan Numan, Zaid Abdel Rahman, Justin Grenet, Stephanie Boisclair, Jan Philipp Bewersdorf, Cailin Collins, Dylan Barth, Martina Fraga, Dale L Bixby, Amer M Zeidan, Musa Yilmaz, Pankil Desai, Gabriel Mannis, Yehuda E Deutsch, Yasmin Abaza, Shira Dinner, Olga Frankfurt, Mark Litzow, Aref Al-Kali, James M Foran, Lisa Z Sproat, Borko Jovanovic, Naval Daver, Alexander E Perl, Jessica K Altman.

Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3-mutation (FLT3mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen-activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.

DOI: https://doi.org/10.1002/ajh.26447
Cell Rep. 2022 Jan 04. pii: S2211-1247(21)01701-0. [Epub ahead of print]38(1): 110197

AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia.

Adrien Grenier, Laury Poulain, Johanna Mondesir, Arnaud Jacquel, Claudie Bosc, Lucille Stuani, Sarah Mouche, Clement Larrue, Ambrine Sahal, Rudy Birsen, Victoria Ghesquier, Justine Decroocq, Fetta Mazed, Mireille Lambert, Mamy Andrianteranagna, Benoit Viollet, Patrick Auberger, Andrew A Lane, Pierre Sujobert, Didier Bouscary, Jean-Emmanuel Sarry, Jerome Tamburini.

  AMP-activated protein kinase (AMPK) regulates the balance between cellular anabolism and catabolism dependent on energy resources to maintain proliferation and survival. Small-compound AMPK activators show anti-cancer activity in preclinical models. Using the direct AMPK activator GSK621, we show that the unfolded protein response (UPR) is activated by AMPK in acute myeloid leukemia (AML) cells. Mechanistically, the UPR effector protein kinase RNA-like ER kinase (PERK) represses oxidative phosphorylation, tricarboxylic acid (TCA) cycle, and pyrimidine biosynthesis and primes the mitochondrial membrane to apoptotic signals in an AMPK-dependent manner. Accordingly, in vitro and in vivo studies reveal synergy between the direct AMPK activator GSK621 and the Bcl-2 inhibitor venetoclax. Thus, selective AMPK-activating compounds kill AML cells by rewiring mitochondrial metabolism that primes mitochondria to apoptosis by BH3 mimetics, holding therapeutic promise in AML.

Keywords:  AML; AMPK; GSK621; PERK; mitochondrial apoptosis; unfolded protein response; venetoclax

DOI:  https://doi.org/10.1016/j.celrep.2021.110197
Ann Hematol. 2022 Feb;101(2): 309-316

ELN 2017 classification significantly impacts the risk of early death in acute myeloid leukemia patients receiving intensive induction chemotherapy.

Naama Keren-Froim, Gabriel Heering, Gal Sharvit, Maya Zlotnik, Arnon Nagler, Avichai Shimoni, Abraham Avigdor, Jonathan Canaani.

  Early mortality remains a challenging therapeutic facet of the initial induction phase of intensive chemotherapy in patients with acute myeloid leukemia (AML). The impact of standard molecular evaluation and risk category of the European LeukemiaNet (ELN) 2017 classification model on early mortality has not been rigorously evaluated thus far. We reviewed the medical records of 320 consecutive adult patients with newly diagnosed AML treated with intensive induction chemotherapy in our center from 2007 to 2021. The median age was 56 years; 33 patients (10%) died during induction. Patient age, white blood cell count, hemoglobin level, platelet level, creatinine, uric acid, lactate dehydrogenase serum levels, and FLT3-ITD and CEBPA mutational status did not significantly impact early mortality. NPM1mut patients had a lower likelihood of early death compared to NPM1wt (5% versus 13%; p = 0.023) whereas patients with high-risk cytogenetic studies experienced higher rates of induction mortality compared with intermediate and favorable risk patients (20% versus 8 and 7%, respectively; p = 0.049). Adverse risk ELN 2017 was significantly more likely to die during induction compared with intermediate and favorable risk patients (20% versus 10 and 4%, respectively; p = 0.001). Patients treated in 2007-2011 experienced a significantly higher rate of induction death compared with patients in 2012-2021 (17% versus 8%; p = 0.039). Multivariate analysis confirmed adverse ELN 2017 [odds ratio (OR), 6.7; 95% confidence interval (CI), 1.74-25.3; p = 0.006) and treatment timeframe (OR, 0.35; 95% CI, 0.14-0.85; p = 0.019) as pivotal predictors of early mortality. ELN 2017 is a robust prognosticator of early mortality in intensively treated AML patients.

Keywords:  Acute myeloid leukemia; ELN 2017; Early mortality; Induction chemotherapy

DOI:  https://doi.org/10.1007/s00277-021-04716-4
Blood. 2022 Jan 07. pii: blood.2021014804. [Epub ahead of print]

Conditioning Intensity and Peri-Transplant Flow Cytometric MRD Dynamics in Adult AML.

Gabrielle Paras, Linde M Morsink, Megan Othus, Filippo Milano, Brenda M Sandmaier, Lucas C Zarling, Raffaele Palmieri, Gary Schoch, Chris Davis, Marie Bleakley, Mary Ed Flowers, H Joachim Deeg, Frederick R Appelbaum, Rainer F Storb, Roland B Walter.

In acute myeloid leukemia (AML), measurable residual disease (MRD) before or after allogeneic hematopoietic cell transplantation (HCT) is an established, independent indicator of poor outcome. To address how peri-HCT MRD dynamics could refine risk assessment across different conditioning intensities, we analyzed 810 adults transplanted in remission after myeloablative conditioning (MAC; n=515) or non-MAC (n=295) who underwent multiparameter flow cytometry-based MRD testing before and 20-40 days after allografting. Patients without pre- and post-HCT MRD (MRDneg/MRDneg) had the lowest risks of relapse and highest relapse-free survival (RFS) and overall survival (OS). Relative to those patients, outcomes for MRDpos/MRDpos and MRDneg/MRDpos patients were poor regardless of conditioning intensity. Outcomes for MRDpos/MRDneg patients were intermediate. Among 161 patients with MRD before HCT, MRD was cleared more commonly with a MAC (85/104 [81.7%]) than non-MAC (33/57 [57.9%]) regimen (P=0.002). Although non-MAC regimens were less likely to clear MRD, if they did the impact on outcome was greater. Thus, there was a significant interaction between conditioning intensity and "MRD conversion" for relapse (P=0.020), RFS (P=0.002), and OS (P=0.001). Similar findings were obtained in the subset of 590 patients receiving HLA-matched allografts. C-statistic values were higher (indicating higher predictive accuracy) for peri-HCT MRD dynamics compared to the isolated use of pre-HCT MRD status and post-HCT MRD status for prediction of relapse, RFS, and OS. Across conditioning intensities, peri-HCT MRD dynamics improve risk assessment over isolated pre- or post-HCT MRD assessments.

DOI: https://doi.org/10.1182/blood.2021014804
J Clin Invest. 2022 Jan 06. pii: e153157. [Epub ahead of print]

LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation.

Jamie A Moore, Jayna J Mistry, Charlotte Hellmich, Rebecca H Horton, Edyta E Wojtowicz, Aisha Jibril, Matthew Jefferson, Thomas Wileman, Naiara Beraza, Kristian M Bowles, Stuart A Rushworth.

  The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to, and growth of, solid tumors. Here we investigated the role of macrophage LC3-associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages increased AML growth in-vivo. We showed that LAP is the predominate method of BM macrophage phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to accumulation of apoptotic cells (AC) and apoptotic bodies (AB) resulting in accelerated leukemia growth. Mechanistically, LAP of AMLderived-AB by BM macrophages, resulted in STING pathway activation. We identified that AML derived mitochondrial damage associated molecular patterns were processed by BM macrophages via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML derived-AB showed that it is this mtDNA which was responsible for the induction of STING signalling in BM macrophages. Phenotypically we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.

Keywords:  Autophagy; Hematology; Leukemias; Mitochondria; Oncology

DOI:  https://doi.org/10.1172/JCI153157
J Hematol Oncol. 2022 Jan 06. 15(1): 1

Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee.

James L Januzzi, Joseph M Garasic, Scott E Kasner, Vickie McDonald, Mark C Petrie, Jonathan Seltzer, Michael Mauro, Kevin Croce, Ellin Berman, Michael Deininger, Andreas Hochhaus, Javier Pinilla-Ibarz, Franck Nicolini, Dong-Wook Kim, Daniel J DeAngelo, Hagop Kantarjian, Jing Xu, Tracey Hall, Shouryadeep Srivastava, Daniel Naranjo, Jorge Cortes.

   BACKGROUND: The phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust long-term benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting. However, AOE rates vary depending on the definitions and reporting approach used.
METHODS: To better understand clinically relevant AOEs with ponatinib, an independent cardiovascular adjudication committee reviewed 5-year AOE data from the PACE trial according to a charter-defined process and standardized event definitions.
RESULTS: A total of 449 patients with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) received ponatinib (median age 59 y; 47% female; 93% ≥ 2 prior tyrosine kinase inhibitors (TKIs); median follow-up, 37.3 months). The adjudicated AOE rate (17%) was lower than the non-adjudicated rate (i.e., rate before adjudication; 25%). The only adjudicated AOE in > 2% of patients was peripheral arterial occlusive disease (4%). Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Patients with multiple baseline cardiovascular risk factors had higher adjudicated AOE rates than those without risk factors.
CONCLUSIONS: This independent adjudication study identified lower AOE rates than previously reported, suggesting earlier overestimation that may inaccurately reflect AOE risk with ponatinib. This trial was registered under ClinicalTrials.gov identifier NCT01207440 on September 23, 2010 ( https://clinicaltrials.gov/ct2/show/NCT01207440 ).

Keywords:  Acute lymphoblastic leukemia; Chronic myeloid leukemia; Safety; Tyrosine kinase inhibitor

DOI:  https://doi.org/10.1186/s13045-021-01221-z
Clin Lymphoma Myeloma Leuk. 2021 Dec 02. pii: S2152-2650(21)02445-9. [Epub ahead of print]

Differential Implications of CSF3R Mutations in t(8;21) and CEBPA Double Mutated Acute Myeloid Leukemia.

Biao Wang, Lijun Wen, Zheng Wang, Suning Chen, Huiying Qiu.

   BACKGROUND: Few data are available exploring mutations of the colony-stimulating factor 3 receptor (CSF3R) in acute myeloid leukemia (AML) in an all-round and systematic manner. The purpose of this study was to analyze the CSF3R mutations (CSF3Rmut) in AML with recurrent genetic abnormalities for potential synergistic pathomechanism.
PATIENTS AND METHODS: We retrospectively screened 1102 adult de novo AML patients with available next-generation sequencing (NGS) information on 132 genes related to hematologic disorders. The χ2, Mann-Whitney U tests were used to analyze their associations with clinicopathologic characteristics, and a propensity score matching (PSM) followed by Kaplan-Meier method was applied to measure their prognostic effects.
RESULTS: Overall, CSF3Rmut were detected in 40 (3.6%) of 1102 patients with adult de novo AML. CSF3Rmut were predominantly enriched in AML with the CEBPA double mutations (CEBPAdm) (16/122, 13.1%), t(8;21) (12/186, 6.5%) and mutated RUNX1 (3/50, 6.0%), respectively. The CSF3Rmut loci and types differed according to AML subtypes, with frameshift-indels and premature stop confined in the t(8;21) AML [10/12 (83.3%)], and missense recurrently aggregated in the CEBPAdm AML [16/16 (100%)]. Cases with CSF3Rmut had a lower WBC count versus those with CSF3R wild-type (CSF3Rwt) in the t(8;21) AML cohort, with a borderline significance [median 5.45 (range 0.94-20.30) × 109/L) vs. 8.80 (range 0.96-155.00) × 109/L, P = .046]. CSF3Rmut were non-significantly associated with higher WBC counts [median 33.6 (range 6.8-287.6) × 109/L vs. 18.1 (range 1.7-196.0) × 109/L, P = .156] and significantly with lower immunophenotypic CD15 positivity [0/8 (0%) vs. 44/80 (55%), P = .009] as compared to CSF3Rwt in the CEBPAdm AML cohort. After propensity score matching followed by Kaplan-Meier analysis, CSF3Rmut cases had comparable disease-free survival (DFS) and overall survival (OS) to those with CSF3Rwt (P = .607 and P = .842, respectively) in the t(8;21) AML cohort. By contrast, CSF3Rmut showed an inclination towards inferior DFS compared to CSF3Rwt in the CEBPAdm AML cohort [median DFS 19.8 (95%CI 3.1-36.5) months vs. not reached (NR), P = .086]. No significant difference was found for OS between CSF3Rmut and CSF3Rwt cases (P = .943).
CONCLUSION: We concluded that CSF3Rmut were frequently enriched in patients with t(8;21) and CEBPAdm subtypes among AML, but showed divergent clinicopathologic features, mutation loci and types and differing prognostic aspects.

Keywords:  Acute myeloid leukemia; CEBPA; CSF3R; Mutation; Propensity score matching; t(8,21)

DOI:  https://doi.org/10.1016/j.clml.2021.11.013
Br J Haematol. 2022 Jan 06.

The UK SPIRIT 1 trial in newly diagnosed chronic myeloid leukaemia.

Paolo Gallipoli, Richard E Clark, Jenny Byrne, Jane F Apperley, Dragana Milojkovic, Letizia Foroni, John M Goldman, Stephen O'Brien.



Keywords:  chronic myeloid leukaemia; clinical trials; interferon; molecular responses; side-effects; tolerability

DOI:  https://doi.org/10.1111/bjh.17961
N Engl J Med. 2022 01 06. 386(1): 11-23

Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia.

Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation

BACKGROUND: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia.
METHODS: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months.
RESULTS: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome.
CONCLUSIONS: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.).

DOI: https://doi.org/10.1056/NEJMoa2109965
Br J Haematol. 2022 Jan 03.

Assessing the impact of the 2017 European LeukemiaNet recommendations on FLT3 allelic ratio calculation and reporting in acute myeloid leukaemia.

Ashley Cartwright, Stuart Scott, Sebastian Francis, Liam Whitby.

DOI: https://doi.org/10.1111/bjh.18023
J Clin Oncol. 2022 Jan 06. JCO2101422

Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation.

Abdelrahman H Elsayed, Xueyuan Cao, Amit K Mitra, Huiyun Wu, Susana Raimondi, Christopher Cogle, Zeina Al-Mansour, Raul C Ribeiro, Alan Gamis, Edward Anders Kolb, Richard Aplenc, Todd A Alonzo, Soheil Meshinchi, Jeffrey Rubnitz, Stanley Pounds, Jatinder K Lamba.

PURPOSE: To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment.
MATERIALS AND METHODS: Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial.
RESULTS: In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low v high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; P = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; P = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, P = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, P = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms).
CONCLUSION: Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.

DOI: https://doi.org/10.1200/JCO.21.01422
Am J Hematol. 2022 Jan 05.

Chronic Myelomonocytic Leukemia: 2022 Update on Diagnosis, Risk Stratification and Management.

Mrinal M Patnaik, Ayalew Tefferi.

DISEASE OVERVIEW: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (~15% over 3-5 years).
DIAGNOSIS: Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 x 109 /L; monocytes ≥10%), usually with accompanying bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ~ 30% of patients, while >90% have somatic gene mutations. Mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%) and the oncogenic RAS pathway (~30%) are frequent, while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact over-all survival.
RISK STRATIFICATION: Molecularly integrated prognostic models include the Groupe Français des Myélodysplasies (GFM), Mayo Molecular Model (MMM) and the CMML specific prognostic model (CPSS-Mol). Risk factors incorporated into the MMM include presence of truncating ASXL1 mutations, absolute monocyte count>10 × 109 /L, hemoglobin <10 gm/dl, platelet count <100 × 109 /L and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into 4 groups: high (≥3 risk factors), intermediate-2 (2 risk factors), intermediate-1 (1 risk factor) and low (no risk factors), with median survivals of 16, 31, 59 and 97 months, respectively.
RISK-ADAPTED THERAPY: Hypomethylating agents such as 5-azacitidine and decitabine are commonly used, with overall response rates of ~40-50% and complete remission rates of ~7-17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option but is associated with significant morbidity and mortality. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ajh.26455
Leukemia. 2022 Jan 08.

MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases.

An-Ping Lin, Zhijun Qiu, Purushoth Ethiraj, Binu Sasi, Carine Jaafar, Dinesh Rakheja, Ricardo C T Aguiar.

Mitochondria can function as signaling organelles, and part of this output leads to epigenetic remodeling. The full extent of this far-reaching interplay remains undefined. Here, we show that MYC transcriptionally activates IDH2 and increases alpha-ketoglutarate (αKG) levels. This regulatory step induces the activity of αKG-dependent DNA hydroxylases and RNA demethylases, thus reducing global DNA and RNA methylation. MYC, in a IDH2-dependent manner, also promotes the nuclear accumulation of TET1-TET2-TET3, FTO and ALKBH5. Notably, this subcellular movement correlated with the ability of MYC, in an IDH2-dependent manner, and, unexpectedly, of αKG to directly induce O-GlcNAcylation. Concordantly, modulation of the activity of OGT and OGA, enzymes that control the cycling of this non-canonical mono-glycosylation, largely recapitulated the effects of the MYC-IDH2-αKG axis on the subcellular movement of DNA and RNA demethylases. Together, we uncovered a hitherto unsuspected crosstalk between MYC, αKG and O-GlcNAcylation which could influence the epigenome and epitranscriptome homeostasis.

DOI: https://doi.org/10.1038/s41375-021-01489-7