bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021–03–21
25 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Safety and Efficacy: Clinical Experience of Venetoclax in Combination With Hypomethylating Agents in Both Newly Diagnosed and Relapsed/Refractory Advanced Myeloid Malignancies.
  2. Chronic myelomonocytic leukemia diagnosis and management.
  3. Novel Targeted Therapeutics in Acute Myeloid Leukemia: an Embarrassment of Riches.
  4. Very long chain fatty acid metabolism is required in acute myeloid leukemia.
  5. Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia.
  6. Impact of PPM1D Mutations in Patients with Myelodysplastic Syndrome and Deletion of Chromosome 5q.
  7. Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes.
  8. Venetoclax enhances T cell-mediated anti-leukemic activity by increasing ROS production.
  9. Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial.
  10. Outcome of secondary Acute Myeloid Leukemia treated with Hypomethylating agent plus Venetoclax (HMA-Ven) or Liposomal Daunorubicin-Cytarabine (CPX-351).
  11. JMJD3-regulated expression of IL-6 is involved in the proliferation and chemosensitivity of acute myeloid leukemia cells.
  12. Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach.
  13. FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming Resistance.
  14. Long-term follow-up of late chronic phase chronic myeloid leukemia patients treated with imatinib after interferon failure: a single center experience.
  15. Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy.
  16. Nivolumab maintenance in high-risk acute myeloid leukemia patients: a single-arm, open-label, phase II study.
  17. Venetoclax combination therapy induces deep AML remission with eradication of leukemic stem cells and remodeling of clonal haematopoiesis.
  18. Bone marrow stromal cells from MDS and AML patients show increased adipogenic potential with reduced Delta-like-1 expression.
  19. Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses.
  20. CD70-specific CAR T-cells have potent activity against Acute Myeloid Leukemia (AML) without HSC toxicity.
  21. Comparison of Azacitidine and Decitabine in Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Network Meta-analysis.
  22. The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis.
  23. Third-line therapy for chronic myeloid leukemia: current status and future directions.
  24. Protein arginine methylation: from enigmatic functions to therapeutic targeting.
  25. Clonal evolution and heterogeneity in advanced systemic mastocytosis revealed by single-cell DNA sequencing.
  1. Hemasphere. 2021 Apr;5(4): e549
    Safety and Efficacy: Clinical Experience of Venetoclax in Combination With Hypomethylating Agents in Both Newly Diagnosed and Relapsed/Refractory Advanced Myeloid Malignancies.
    Jonathan Feld, Douglas Tremblay, Mikaela Dougherty, Tina Czaplinska, Gillian Sanchez, Claudia Brady, Marina Kremyanskaya, Michal Bar-Natan, Alla Keyzner, Bridget K Marcellino, Janice Gabrilove, Shyamala C Navada, Lewis R Silverman, Siraj M El Jamal, John Mascarenhas, Alan H Shih.
      Hypomethylating agents (HMAs) in combination with venetoclax have been widely adopted as the standard of care for patients who cannot tolerate induction chemotherapy and for patients who have relapsed/refractory (R/R) acute myeloid leukemia (AML). This study retrospectively analyzed the outcomes of all patients with AML (n = 65) or myelodysplastic syndrome (n = 7) who received the combination of HMA and venetoclax at our institution. Outcomes measured included complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, duration of response (DOR), and overall survival (OS). Patient mutational profiles and transfusion requirements were also assessed. Of 26 newly diagnosed AML patients, the CR/CRi rate was 53.8%. The median DOR and OS were 6.9 months and not reached, respectively. Of 39 R/R AML patients, the CR/CRi rate was 38.5%. The median DOR and OS were both 8.1 months. Responders to HMA and venetoclax were enriched for TET2, IDH1, and IDH2 mutations, while nonresponders were associated with FLT3 and RAS mutations. Adaptive resistance was observed through various mechanisms including acquired RAS pathway mutations. Of transfusion-dependent patients, 12.2% and 15.2% achieved red blood cell (RBC) and platelet transfusion independence, respectively, while 44.8% and 35.1% of RBC and platelet transfusion independent patients, respectively, became transfusion dependent. In total 59.1% of patients developed a ≥grade 3 infection and 46.5% neutropenic fever. HMA + venetoclax can lead to impressive response rates with moderately durable remissions and survival. However, the benefits of this combination are diminished by the significant toxicities from infection, persistent cytopenias, and transfusion requirements.
    DOI:  https://doi.org/10.1097/HS9.0000000000000549
  2. Leukemia. 2021 Mar 13.
    Chronic myelomonocytic leukemia diagnosis and management.
    Onyee Chan, Aline Renneville, Eric Padron.
      Chronic myelomonocytic leukemia (CMML) is a rare, heterogeneous myeloid malignancy classified as a myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) overlap syndrome by the World Health Organization (WHO). Its initial presentation can be incidental or associated with myelodysplastic or myeloproliferative symptoms and up to 20% of patients harbor a concurrent inflammatory or autoimmune condition. Persistent monocytosis is the hallmark of CMML but diagnosis can be challenging. Increased understanding of human monocyte subsets, chromosomal abnormalities, and somatic gene mutations have led to more accurate diagnosis and improved prognostication. A number of risk stratification systems have been developed and validated but using those that incorporate molecular information such as CMML Prognostic Scoring System (CPSS)-Mol, Mayo Molecular, and Groupe Francophone des Myelodysplasies (GFM) are preferred. Symptom-directed approaches forms the basis of CMML management. Outcomes vary substantially depending on risk ranging from observation for a number of years to rapidly progressive disease and acute myeloid leukemia (AML) transformation. Patients who are low risk but with symptoms from cytopenias or proliferative features such as splenomegaly may be treated with hypomethylating agents (HMAs) or cytoreductive therapy, respectively, with the goal of durable symptoms control. Allogeneic hematopoietic cell transplantation should be considered for intermediate to high risk patients. The lack of effective pharmaceutical options has generated interest in novel therapeutics for this disease, and early phase clinical trial results are promising.
    DOI:  https://doi.org/10.1038/s41375-021-01207-3
  3. Curr Hematol Malig Rep. 2021 Mar 18.
    Novel Targeted Therapeutics in Acute Myeloid Leukemia: an Embarrassment of Riches.
    Nicole R Grieselhuber, Alice S Mims.
       PURPOSE OF REVIEW: Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow that has a poor prognosis with traditional cytotoxic chemotherapy, especially in elderly patients. In recent years, small molecule inhibitors targeting AML-associated IDH1, IDH2, and FLT3 mutations have been FDA approved. However, the majority of AML cases do not have a targetable mutation. A variety of novel agents targeting both previously untargetable mutations and general pathways in AML are currently being investigated. Herein, we review selected new targeted therapies currently in early-phase clinical investigation in AML.
    RECENT FINDINGS: The DOT1L inhibitor pinometostat in KMT2A-rearranged AML, the menin inhibitors KO-539 and SYNDX-5613 in KMT2Ar and NPM1-mutated AML, and the mutant TP53 inhibitor APR-246 are examples of novel agents targeting specific mutations in AML. In addition, BET inhibitors, polo-like kinase inhibitors, and MDM2 inhibitors are promising new drug classes for AML which do not depend on the presence of a particular mutation. AML remains in incurable disease for many patients but advances in genomics, epigenetics, and drug discovery have led to the development of many potential novel therapeutic agents, many of which are being investigated in ongoing clinical trials. Additional studies will be necessary to determine how best to incorporate these novel agents into routine clinical treatment of AML.
    Keywords:  Acute myeloid leukemia; Bromodomain inhibitors; DOT1L; MDM2 inhibitors; Menin inhibitors; Polo-like kinase inhibitors; Targeted therapy
    DOI:  https://doi.org/10.1007/s11899-021-00621-9
  4. Blood. 2021 Mar 15. pii: blood.2020008551. [Epub ahead of print]
    Very long chain fatty acid metabolism is required in acute myeloid leukemia.
    Matthew Tcheng, Alessia Roma, Nawaz Ahmed, Richard William Smith, Preethi Jayanth, Mark D Minden, Aaron D Schimmer, David A Hess, Kristin Hope, Tariq Akhtar, Eric Bohrnsen, Angelo D'Alessandro, Al-Walid Mohsen, Jerry Vockley, Paul A Spagnuolo.
      Acute myeloid leukemia (AML) cells have an atypical metabolic phenotype characterized by increased mitochondrial mass as well as a greater reliance on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) for survival. To exploit this altered metabolism, we assessed publicly available databases to identify FAO enzyme overexpression. VLCAD (ACADVL) was found to be overexpressed and critical to leukemia cell mitochondrial metabolism. Genetic attenuation or pharmacological inhibition of VLCAD hindered mitochondrial respiration and FAO contribution to the TCA cycle, resulting in decreased viability, proliferation, clonogenic growth and AML cell engraftment. Suppression of FAO at VLCAD triggered an increase in PDH activity insufficient to increase glycolysis but resulted in ATP depletion and AML cell death with no effect in normal hematopoietic cells. Together, these results demonstrate the importance of VLCAD in AML cell biology and highlight a novel metabolic vulnerability for this devastating disease.
    DOI:  https://doi.org/10.1182/blood.2020008551
  5. Haematologica. 2021 Mar 18.
    Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia.
    Taeko Kaburagi, Genki Yamato, Norio Shiba, Kenichi Yoshida, Yusuke Hara, Ken Tabuchi, Yuichi Shiraishi, Kentaro Ohki, Manabu Sotomatsu, Hirokazu Arakawa, Hidemasa Matsuo, Akira Shimada, Tomohiko Taki, Nobutaka Kiyokawa, Daisuke Tomizawa, Keizo Horibe, Satoru Miyano, Takashi Taga, Souichi Adachi, Seishi Ogawa, Yasuhide Hayashi.
      RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) out of 328 patients: NF1 (n = 7, 2.1%), PTPN11 (n = 15, 4.6%), CBL (n = 6, 1.8%), NRAS (n = 44, 13.4%), KRAS (n = 12, 3.7%). Most of these alterations were mutually exclusive and were also mutually exclusive with other aberrations of signal transduction pathways such as FLT3-ITD (p = 0.001) and KIT mutation (p = 0.004). NF1 alterations were frequently detected in patients with complex karyotype (p = 0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (p = 0.007). At least four of seven patients with NF1 alterations had bi-allelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis [OS, p = 0.023; event-free survival (EFS), p = 0.037]. Patients with PTPN11 mutations more frequently received stem cell transplantation (p = 0.035) and showed poor EFS than patients without PTPN11 mutations (p = 0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.
    DOI:  https://doi.org/10.3324/haematol.2020.269431
  6. Am J Hematol. 2021 Mar 16.
    Impact of PPM1D Mutations in Patients with Myelodysplastic Syndrome and Deletion of Chromosome 5q.
    Victoria Panagiota, Manja Meggendorfer, Anne Sophie Kubasch, Razif Gabdoulline, Jan Krönke, Anna Mies, Rabia Shaswar, Christian Kandziora, Piroska Klement, Johannes Schiller, Gudrun Göhring, Claudia Haferlach, Christina Ganster, Katayoon Shirneshan, Annika Gutermuth, Christian Thiede, Ulrich Germing, Thomas Schroeder, Guido Kobbe, Sabrina Klesse, Christian Koenecke, Brigitte Schlegelberger, Nicolaus Kröger, Detlef Haase, Konstanze Döhner, Wolfgang R Sperr, Peter Valent, Arnold Ganser, Felicitas Thol, Torsten Haferlach, Uwe Platzbecker, Michael Heuser.
      PPM1D is a serine/threonine phosphatase that inactivates the p53 pathway. PPM1D mutations have been described in myelodysplastic syndromes (MDS), but their prognostic impact in del(5q) MDS is less well defined. We analyzed 234 patients with del(5q) MDS or secondary AML and correlated PPM1D and TP53 mutation status by Sanger and/or next-generation sequencing (NGS) at baseline with clinical outcome. At diagnosis, PPM1D and TP53 mutations were detected in 13 of 234 (5.6%) and 35 of 234 (15%) patients with del(5q) MDS, respectively. PPM1D and TP53 mutations had no impact on the risk of progression to acute myeloid leukemia (AML) or overall survival (OS) in 164 patients with WHO 2016 defined del(5q) MDS. Of the 65 WHO 2016 defined del(5q) MDS patients known to be treated with lenalidomide (LEN), 83% of the patients achieved hematological response, while 38.5% became refractory to LEN or progressed to AML after a median follow-up of 3.1 years, independent of PPM1D and TP53 mutation status. 22 LEN treated patients underwent sequential monitoring of molecular kinetics at the time of response, resistance and disease progression. Compared to baseline, median variant allele frequency (VAF) increased from 10.2% to 23.3% and from 5.9% to 23.2% at the time of LEN resistance or AML progression for PPM1D and TP53 mutations, respectively. Sequential analysis of TP53 and PPM1D mutation burden may help to identify patients at risk of disease progression during LEN treatment. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.26162
  7. Immunity. 2021 Mar 15. pii: S1074-7613(21)00087-X. [Epub ahead of print]
    Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes.
    Grégory Ehx, Jean-David Larouche, Chantal Durette, Jean-Philippe Laverdure, Leslie Hesnard, Krystel Vincent, Marie-Pierre Hardy, Catherine Thériault, Caroline Rulleau, Joël Lanoix, Eric Bonneil, Albert Feghaly, Anca Apavaloaei, Nandita Noronha, Céline M Laumont, Jean-Sébastien Delisle, Luca Vago, Josée Hébert, Guy Sauvageau, Sébastien Lemieux, Pierre Thibault, Claude Perreault.
      Acute myeloid leukemia (AML) has not benefited from innovative immunotherapies, mainly because of the lack of actionable immune targets. Using an original proteogenomic approach, we analyzed the major histocompatibility complex class I (MHC class I)-associated immunopeptidome of 19 primary AML samples and identified 58 tumor-specific antigens (TSAs). These TSAs bore no mutations and derived mainly (86%) from supposedly non-coding genomic regions. Two AML-specific aberrations were instrumental in the biogenesis of TSAs, intron retention, and epigenetic changes. Indeed, 48% of TSAs resulted from intron retention and translation, and their RNA expression correlated with mutations of epigenetic modifiers (e.g., DNMT3A). AML TSA-coding transcripts were highly shared among patients and were expressed in both blasts and leukemic stem cells. In AML patients, the predicted number of TSAs correlated with spontaneous expansion of cognate T cell receptor clonotypes, accumulation of activated cytotoxic T cells, immunoediting, and improved survival. These TSAs represent attractive targets for AML immunotherapy.
    Keywords:  CD8 T cell; acute myeloid leukemia; antigen; antigen discovery; cancer immunotherapy; immunopeptidome; intron; major histocompatibility complex; mass spectrometry; non-canonical translation; tumor-specific
    DOI:  https://doi.org/10.1016/j.immuni.2021.03.001
  8. Blood. 2021 Mar 16. pii: blood.2020009081. [Epub ahead of print]
    Venetoclax enhances T cell-mediated anti-leukemic activity by increasing ROS production.
    JongBok Lee, Dilshad H Khan, Rose Hurren, Mingjing Xu, Yoosu Na, Hyeonjeong Kang, Sara Mirali, Xiaoming Wang, Marcela Victoria Gronda, Yulia Jitkova, Neil MacLean, Andrea Arruda, Zoe Alaniz, Marina Y Konopleva, Michael Andreeff, Mark D Minden, Li Zhang, Aaron D Schimmer.
      Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent, Azacytidine, achieves complete response with or without count recovery in approximately 70% of treatment-naïve elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that Venetoclax directly activated T cells to increase their cytotoxicity against AML in vitro and in vivo. Venetoclax enhanced T cell effector function by increasing ROS generation through inhibition of respiratory chain supercomplexes formation. In addition, Azacytidine induced a viral-mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T-cell mediated cytotoxicity. Similar findings were seen in patients treated with Venetoclax as this treatment increased ROS generation and activated T cells. Collectively, this study demonstrates a new immune mediated mechanism of action for Venetoclax and Azacytidine in the treatment of AML and highlights a potential combination of Venetoclax and adoptive cell therapy for patients with AML.
    DOI:  https://doi.org/10.1182/blood.2020009081
  9. Ann Hematol. 2021 Mar 19.
    Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial.
    Michael Heuser, B Douglas Smith, Walter Fiedler, Mikkael A Sekeres, Pau Montesinos, Brian Leber, Akil Merchant, Cristina Papayannidis, José A Pérez-Simón, Caroline J Hoang, Thomas O'Brien, Weidong Wendy Ma, Mirjana Zeremski, Ashleigh O'Connell, Geoffrey Chan, Jorge E Cortes.
      This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325-0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395-1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151-0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days' therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.
    Keywords:  Acute myeloid leukemia; Clinical trial; Glasdegib; Secondary acute myeloid leukemia
    DOI:  https://doi.org/10.1007/s00277-021-04465-4
  10. Am J Hematol. 2021 Mar 14.
    Outcome of secondary Acute Myeloid Leukemia treated with Hypomethylating agent plus Venetoclax (HMA-Ven) or Liposomal Daunorubicin-Cytarabine (CPX-351).
    Amandeep Salhotra, Ahmed Aribi, Dat Ngo, Jianying Zhang, Karamjeet Sandhu, Monzr Al-Malki, Haris Ali, Paul Koller, Shukaib Arslan, Elizabeth Budde, Samer Khaled, Sanjeet Dadwal, David S Snyder, Andrew Artz, Stephen Forman, Ryotaro Nakamura, Anthony Stein, Guido Marcucci, Ibrahim Aldoss, Vinod Pullarkat.
      
    Keywords:  CPX-351; MA+Ven; secondary AML
    DOI:  https://doi.org/10.1002/ajh.26157
  11. Biol Chem. 2020 Mar 19.
    JMJD3-regulated expression of IL-6 is involved in the proliferation and chemosensitivity of acute myeloid leukemia cells.
    Xiaojun Xu, Yongbin Ye, Xiaobo Wang, Bo Lu, Ziwen Guo, Shunjie Wu.
      Emerging evidence shows that histone modification and its related regulators are involved in the progression and chemoresistance of multiple tumors including acute myeloid leukemia cells (AML). Our present study found that the expression of histone lysine demethylase Jumonji domain containing-3 (JMJD3) was increased in AML cells as compared with that in human primary bone marrow (HPBM) cells. Knockdown of JMJD3 can decrease the proliferation of AML cells and increase the chemosensitivity of daunorubicin (DNR) and cytarabine (Ara-C). By screening the expression of cytokines involved in AML progression, we found that knockdown of JMJD3 can inhibit the expression of interleukin-6 (IL-6). Recombinant IL-6 (rIL-6) can attenuate si-JMJD3-suppressed proliferation of AML cells. Mechanistically, JMJD3 can positively regulate the promoter activity and transcription of IL-6 mRNA, while had no effect on its mRNA stability. Further, JMJD3 can regulate the expression of p65, which can directly bind with promoter of IL-6 to increase its transcription. Over expression of p65 significantly attenuated si-JMJD3-suppressed expression of IL-6. Collectively, we revealed that JMJD3 can regulate the proliferation and chemosensitivity of AML cells via upregulation of IL-6. It suggested that JMJD3 might be a potential therapy target for AML treatment.
    Keywords:  AML; IL-6; JMJD3; proliferation
    DOI:  https://doi.org/10.1515/hsz-2020-0345
  12. Cancer. 2021 Mar 18.
    Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach.
    Hagop M Kantarjian, Tapan M Kadia, Courtney D DiNardo, Mary Alma Welch, Farhad Ravandi.
      The unraveling of the pathophysiology of acute myeloid leukemia (AML) has resulted in rapid translation of the information into clinical practice. After more than 40 years of slow progress in AML research, the US Food and Drug Administration has approved nine agents for different AML treatment indications since 2017. In this review, we detail the progress that has been made in the research and treatment of AML, citing key publications related to AML research and therapy in the English literature since 2000. The notable subsets of AML include acute promyelocytic leukemia (APL), core-binding factor AML (CBF-AML), AML in younger patients fit for intensive chemotherapy, and AML in older/unfit patients (usually at the age cutoff of 60-70 years). We also consider within each subset whether the AML is primary or secondary (therapy-related, evolving from untreated or treated myelodysplastic syndrome or myeloproliferative neoplasm). In APL, therapy with all-trans retinoic acid and arsenic trioxide results in estimated 10-year survival rates of ≥80%. Treatment of CBF-AML with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin (GO) results in estimated 10-year survival rates of ≥75%. In younger/fit patients, the "3+7" regimen (3 days of daunorubicin + 7 days of cytarabine) produces less favorable results (estimated 5-year survival rates of 35%; worse in real-world experience); regimens that incorporate high-dose cytarabine, adenosine nucleoside analogs, and GO are producing better results. Adding venetoclax, FLT3, and IDH inhibitors into these regimens has resulted in encouraging preliminary data. In older/unfit patients, low-intensity therapy with hypomethylating agents (HMAs) and venetoclax is now the new standard of care. Better low-intensity regimens incorporating cladribine, low-dose cytarabine, and other targeted therapies (FLT3 and IDH inhibitors) are emerging. Maintenance therapy now has a definite role in the treatment of AML, and oral HMAs with potential treatment benefits are also available. In conclusion, AML therapy is evolving rapidly and treatment results are improving in all AML subsets as novel agents and strategies are incorporated into traditional AML chemotherapy. LAY SUMMARY: Ongoing research in acute myeloid leukemia (AML) is progressing rapidly. Since 2017, the US Food and Drug Administration has approved 10 drugs for different AML indications. This review updates the research and treatment pathways for AML.
    Keywords:  acute myelogenous leukemia; new drugs; progress; research; therapy
    DOI:  https://doi.org/10.1002/cncr.33477
  13. J Med Chem. 2021 Mar 10.
    FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming Resistance.
    Zhijie Wang, Jiongheng Cai, Jie Cheng, Wenqianzi Yang, Yifan Zhu, Hongmei Li, Tao Lu, Yadong Chen, Shuai Lu.
      Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are often present in newly diagnosed acute myeloid leukemia (AML) patients with an incidence rate of approximately 30%. Recently, many FLT3 inhibitors have been developed and exhibit positive preclinical and clinical effects against AML. However, patients develop resistance soon after undergoing FLT3 inhibitor treatment, resulting in short durable responses and poor clinical effects. This review will discuss the main mechanisms of resistance to clinical FLT3 inhibitors and summarize the emerging strategies that are utilized to overcome drug resistance. Basically, medicinal chemistry efforts to develop new small-molecule FLT3 inhibitors offer a direct solution to this problem. Other potential strategies include the combination of FLT3 inhibitors with other therapies and the development of multitarget inhibitors. It is hoped that this review will provide inspiring insights into the discovery of new AML therapies that can eventually overcome the resistance to current FLT3 inhibitors.
    DOI:  https://doi.org/10.1021/acs.jmedchem.0c01851
  14. Leuk Lymphoma. 2021 Mar 16. 1-6
    Long-term follow-up of late chronic phase chronic myeloid leukemia patients treated with imatinib after interferon failure: a single center experience.
    Sara Pepe, Emilia Scalzulli, Gioia Colafigli, Alessio Di Prima, Marco Mancini, Daniela Diverio, Roberto Latagliata, Maurizio Martelli, Robin Foà, Massimo Breccia.
      We report the long-term outcome of 139 patients treated with imatinib in late chronic phase after IFN failure. Median follow-up was 16.6 years and the estimated 18-year OS was 64.8%. 18-year EFS and PFS were 69% and 64.4%, respectively. Fifty (36%) patients stopped imatinib, 72% received a second line. b2a2 transcript was associated with a significantly inferior 18-year OS (p = 0.008), FFS (p = 0.036), PFS (p = 0.013) compared to the b3a2 type, whilst the type of transcript did not influence the time to response achievement. Failure to achieve MMR at 12 months significantly reduced the chance of reaching a DMR (p = 0.001). Imatinib discontinuation after achieving a sustained deep molecular response was attempted in 14 patients; 12 (86%) are still in treatment-free remission (TFR) at the last follow-up. Our experience confirms the long-term efficacy of imatinib after IFNα failure in real-life setting and documents the possibility of attempting a TFR in this subset of patients.
    Keywords:  Chronic myeloid leukemia; failure; interferon; outcome; tyrosin kinase inhibitors
    DOI:  https://doi.org/10.1080/10428194.2021.1901094
  15. Cell Death Differ. 2021 Mar 19.
    Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy.
    Magali Humbert, Kristina Seiler, Severin Mosimann, Vreni Rentsch, Katyayani Sharma, Amit V Pandey, Sharon L McKenna, Mario P Tschan.
      Fatty acid synthase (FASN) is the only human lipogenic enzyme available for de novo fatty acid synthesis and is often highly expressed in cancer cells. We found that FASN mRNA levels were significantly higher in acute myeloid leukemia (AML) patients than in healthy granulocytes or CD34+ hematopoietic progenitors. Accordingly, FASN levels decreased during all-trans retinoic acid (ATRA)-mediated granulocytic differentiation of acute promyelocytic leukemia (APL) cells, partially via autophagic degradation. Furthermore, our data suggest that inhibition of FASN expression levels using RNAi or (-)-epigallocatechin-3-gallate (EGCG) accelerated the differentiation of APL cell lines and significantly re-sensitized ATRA refractory non-APL AML cells. FASN reduction promoted translocation of transcription factor EB (TFEB) to the nucleus, paralleled by activation of CLEAR network genes and lysosomal biogenesis. Together, our data demonstrate that inhibition of FASN expression in combination with ATRA treatment facilitates granulocytic differentiation of APL cells and may extend differentiation therapy to non-APL AML cells.
    DOI:  https://doi.org/10.1038/s41418-021-00768-1
  16. Blood Cancer J. 2021 Mar 17. 11(3): 60
    Nivolumab maintenance in high-risk acute myeloid leukemia patients: a single-arm, open-label, phase II study.
    Patrick K Reville, Hagop M Kantarjian, Farhad Ravandi, Elias Jabbour, Courtney D DiNardo, Naval Daver, Naveen Pemmaraju, Maro Ohanian, Yesid Alvarado, Lianchun Xiao, Gheath Alatrash, Sanam Loghavi, Caitlin R Rausch, Gautam Borthakur, Marina Konopleva, Jorge Cortes, Tapan M Kadia.
      
    DOI:  https://doi.org/10.1038/s41408-021-00453-z
  17. Blood Cancer J. 2021 Mar 19. 11(3): 62
    Venetoclax combination therapy induces deep AML remission with eradication of leukemic stem cells and remodeling of clonal haematopoiesis.
    Romain Vazquez, Claire Breal, Loria Zalmai, Chloe Friedrich, Carole Almire, Adrien Contejean, Sylvain Barreau, Eric Grignano, Lise Willems, Benedicte Deau-Fischer, Patricia Franchi, Marguerite Vignon, Justine Decroocq, Rudy Birsen, Lauriane Goldwirt, Sophie Kaltenbach, Lucile Couronne, Michaela Fontenay, Olivier Kosmider, Didier Bouscary, Nicolas Chapuis.
      
    DOI:  https://doi.org/10.1038/s41408-021-00448-w
  18. Sci Rep. 2021 Mar 15. 11(1): 5944
    Bone marrow stromal cells from MDS and AML patients show increased adipogenic potential with reduced Delta-like-1 expression.
    Marie-Theresa Weickert, Judith S Hecker, Michèle C Buck, Christina Schreck, Jennifer Rivière, Matthias Schiemann, Katharina Schallmoser, Florian Bassermann, Dirk Strunk, Robert A J Oostendorp, Katharina S Götze.
      Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell disorders with a poor prognosis, especially for elderly patients. Increasing evidence suggests that alterations in the non-hematopoietic microenvironment (bone marrow niche) can contribute to or initiate malignant transformation and promote disease progression. One of the key components of the bone marrow (BM) niche are BM stromal cells (BMSC) that give rise to osteoblasts and adipocytes. It has been shown that the balance between these two cell types plays an important role in the regulation of hematopoiesis. However, data on the number of BMSC and the regulation of their differentiation balance in the context of hematopoietic malignancies is scarce. We established a stringent flow cytometric protocol for the prospective isolation of a CD73+ CD105+ CD271+ BMSC subpopulation from uncultivated cryopreserved BM of MDS and AML patients as well as age-matched healthy donors. BMSC from MDS and AML patients showed a strongly reduced frequency of CFU-F (colony forming unit-fibroblast). Moreover, we found an altered phenotype and reduced replating efficiency upon passaging of BMSC from MDS and AML samples. Expression analysis of genes involved in adipo- and osteogenic differentiation as well as Wnt- and Notch-signalling pathways showed significantly reduced levels of DLK1, an early adipogenic cell fate inhibitor in MDS and AML BMSC. Matching this observation, functional analysis showed significantly increased in vitro adipogenic differentiation potential in BMSC from MDS and AML patients. Overall, our data show BMSC with a reduced CFU-F capacity, and an altered molecular and functional profile from MDS and AML patients in culture, indicating an increased adipogenic lineage potential that is likely to provide a disease-promoting microenvironment.
    DOI:  https://doi.org/10.1038/s41598-021-85122-8
  19. Blood Adv. 2021 Mar 23. 5(6): 1719-1728
    Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses.
    Tara L Lin, David A Rizzieri, Daniel H Ryan, Gary J Schiller, Jonathan E Kolitz, Geoffrey L Uy, Donna E Hogge, Scott R Solomon, Matthew J Wieduwilt, Robert J Ryan, Stefan Faderl, Jorge E Cortes, Jeffrey E Lancet.
      CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). In a pivotal phase 3 study, patients aged 60 to 75 years with newly diagnosed, high-risk/secondary AML were randomized to receive CPX-351 or conventional 7+3 chemotherapy. In the primary endpoint analysis, CPX-351 demonstrated significantly prolonged median overall survival (OS) vs 7+3. These exploratory post hoc subgroup analyses evaluated the impact of achieving complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 (73/153 [48%]) vs conventional 7+3 (52/56 [33%]) on outcomes. CPX-351 improved median OS vs 7+3 in patients who achieved CR or CRi (25.43 vs 10.41 months; hazard ratio = 0.49; 95% confidence interval, 0.31, 0.77). Improved median OS was seen across AML subtypes (t-AML, AML-MRC), age subgroups (60 to 69 vs 70 to 75 years), patients with prior hypomethylating agent exposure, and patients who did not undergo transplantation. Patients who achieved CR or CRi with CPX-351 also had a higher rate of transplantation, a longer median OS landmarked from the date of transplantation (not reached vs 11.65 months; hazard ratio = 0.43; 95% confidence interval, 0.21, 0.89), and a safety profile that was consistent with the known safety profile of 7+3. These results suggest deeper remissions may be achieved with CPX-351, leading to improved OS. This study was registered at www.clinicaltrials.gov as #NCT01696084.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003510
  20. Blood. 2021 Mar 15. pii: blood.2020008221. [Epub ahead of print]
    CD70-specific CAR T-cells have potent activity against Acute Myeloid Leukemia (AML) without HSC toxicity.
    Tim Sauer, Kathan Parikh, Sandhya Sharma, Bilal Omer, David Nikolov Sedloev, Qian Chen, Linus Angenendt, Christoph Schliemann, Michael Schmitt, Carsten Müller-Tidow, Stephen Gottschalk, Cliona M Rooney.
      The prognosis of patients with acute myeloid leukemia (AML) remains dismal highlighting the need for novel innovative treatment strategies. The application of chimeric antigen receptor (CAR) T-cell therapy to AML patients has been limited in particular by the lack of a tumor-specific target antigen. CD70 is a promising antigen to target AML as it is expressed on the majority of leukemic blasts, whereas little or no expression is detectable in normal bone marrow samples. To target CD70 on AML cells, we generated a panel of CD70-CARs that contained a common single chain variable fragment (scFv) for antigen detection but differed in size and flexibility of the extracellular spacer, and in the transmembrane and the co-stimulatory domains. These CD70scFv CARs were compared with a CAR construct that contained the human CD27, the ligand of CD70 fused to the CD3z chain (CD27z). The structural composition of the CAR strongly influenced expression levels, viability, expansion and cytotoxic capacities of CD70scFv CAR T-cells, but the CD27z-CAR T-cells demonstrated superior proliferation and anti-tumor activity in vitro and in vivo, compared to all CD70scFv-CARs. While CD70-CAR T-cells recognized activated virus-specific T-cells (VSTs) that expressed CD70, they did not prevent colony formation by normal hematopoietic stem cells (HSCs). Thus, CD70-targeted immunotherapy is a promising new treatment strategy for patients with CD70-positive AML that does not affect normal hematopoiesis but will require monitoring of virus-specific T-cell responses.
    DOI:  https://doi.org/10.1182/blood.2020008221
  21. Clin Lymphoma Myeloma Leuk. 2021 Feb 24. pii: S2152-2650(21)00042-2. [Epub ahead of print]
    Comparison of Azacitidine and Decitabine in Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Network Meta-analysis.
    Weiyang Liu, Zhirui Zhou, Lingxiao Chen, Xiaoqin Wang.
       BACKGROUND: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies that mostly affect the elderly and have a poor prognosis. Azacitidine (AZA) and decitabine (DAC) are the most widely used hypomethylating agents. However, few randomized controlled trials (RCTs) have compared AZA and DAC head to head in MDS or AML. This study intended to conduct a network meta-analysis to compare the 2 drugs to provide more guidance using evidence-based medicine.
    PATIENTS AND METHODS: A comprehensive search for RCTs was performed till July 31, 2020. The network meta-analysis was conducted using the Markov chain Monte Carlo method. The primary endpoints were overall survival (OS) and the incidence of adverse events, and the secondary endpoints were complete remission (CR) rate, overall remission rate (ORR), and AML-free survival. There were 6 RCTs with 1072 MDS patients, and 3 RCTs with 1256 AML patients.
    RESULTS: In MDS, AZA showed better AML-free survival (hazard ratio = 0.62; 95% CI, 0.43-0.9), whereas DAC had the possibility of achieving better CR and ORR, and AZA had the possibility of obtaining better OS with lower toxicity. As for elderly AML patients, DAC had the possibility of achieving superior CR, ORR, and OS, while the toxicity was relatively higher. Furthermore, subgroup analysis for patients ≥ 75 years old or of high risk in MDS suggested that AZA achieved better OS.
    CONCLUSION: For MDS, especially patients with intermediate or high risk disease with advanced age and poor general condition, AZA may be a better choice, while DAC may be of more benefit in elderly AML patients.
    Keywords:  AML; Hypomethylating agents (HMAs); Indirect comparison; MDS
    DOI:  https://doi.org/10.1016/j.clml.2021.01.024
  22. Nature. 2021 Mar 17.
    The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis.
    Trevor P Fidler, Chenyi Xue, Mustafa Yalcinkaya, Brian Hardaway, Sandra Abramowicz, Tong Xiao, Wenli Liu, David G Thomas, Mohammad Ali Hajebrahimi, Joachim Pircher, Carlos Silvestre-Roig, Andriana G Kotini, Larry L Luchsinger, Ying Wei, Marit Westerterp, Hans-Willem Snoeck, Eirini P Papapetrou, Christian Schulz, Steffen Massberg, Oliver Soehnlein, Benjamin Ebert, Ross L Levine, Muredach P Reilly, Peter Libby, Nan Wang, Alan R Tall.
      Clonal haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors1. Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2V617F (JAK2VF) mutation, which increases JAK-STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease1,2. Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2VF selectively in macrophages, and in chimeric mice that model clonal haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2VF lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2VF lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1β reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2VF macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1β or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk.
    DOI:  https://doi.org/10.1038/s41586-021-03341-5
  23. J Hematol Oncol. 2021 Mar 18. 14(1): 44
    Third-line therapy for chronic myeloid leukemia: current status and future directions.
    Jorge Cortes, Fabian Lang.
      Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 fusion protein, formed by a translocation between chromosomes 9 and 22 that creates the Philadelphia chromosome. The BCR-ABL1 fusion protein is an optimal target for tyrosine kinase inhibitors (TKIs) that aim for the adenosine triphosphate (ATP) binding site of ABL1. While these drugs have greatly improved the prognosis for CML, many patients ultimately fail treatment, some requiring multiple lines of TKI therapy. Mutations can occur in the ATP binding site of ABL1, causing resistance by preventing the binding of many of these drugs and leaving patients with limited treatment options. The approved TKIs are also associated with adverse effects that may lead to treatment discontinuation in some patients. Efficacy decreases with each progressive line of therapy; data suggest little clinical benefit of treatment with a third-line (3L), second-generation tyrosine kinase inhibitor (2GTKI) after failure of a first-generation TKI and a 2GTKI. Novel treatment options are needed for the patient population that requires treatment in the 3L setting and beyond. This review highlights the need for clear guidelines and new therapies for patients requiring 3L treatment and beyond.
    Keywords:  Chronic myeloid leukemia; Emerging therapies; Third line; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1186/s13045-021-01055-9
  24. Nat Rev Drug Discov. 2021 Mar 19.
    Protein arginine methylation: from enigmatic functions to therapeutic targeting.
    Qin Wu, Matthieu Schapira, Cheryl H Arrowsmith, Dalia Barsyte-Lovejoy.
      Protein arginine methyltransferases (PRMTs) are emerging as attractive therapeutic targets. PRMTs regulate transcription, splicing, RNA biology, the DNA damage response and cell metabolism; these fundamental processes are altered in many diseases. Mechanistically understanding how these enzymes fuel and sustain cancer cells, especially in specific metabolic contexts or in the presence of certain mutations, has provided the rationale for targeting them in oncology. Ongoing inhibitor development, facilitated by structural biology, has generated tool compounds for the majority of PRMTs and enabled clinical programmes for the most advanced oncology targets, PRMT1 and PRMT5. In-depth mechanistic investigations using genetic and chemical tools continue to delineate the roles of PRMTs in regulating immune cells and cancer cells, and cardiovascular and neuronal function, and determine which pathways involving PRMTs could be synergistically targeted in combination therapies for cancer. This research is enhancing our knowledge of the complex functions of arginine methylation, will guide future clinical development and could identify new clinical indications.
    DOI:  https://doi.org/10.1038/s41573-021-00159-8
  25. Blood Adv. 2021 Mar 23. 5(6): 1733-1736
    Clonal evolution and heterogeneity in advanced systemic mastocytosis revealed by single-cell DNA sequencing.
    Ken-Hong Lim, Jo-Ning Wu, To-Yu Huang, Jie-Yang Jhuang, Yu-Cheng Chang, Huan-Chau Lin, Yi-Hao Chiang, Ying-Wen Su, Caleb Gon-Shen Chen, Yi-Fang Chang, Johnson Lin.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2020003980
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