bims-tremyl 2020-10-11 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2020–10–11
twenty papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study.
Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A.
HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia.
SUV39H1 regulates the progression of MLL-AF9-induced acute myeloid leukemia.
(2R,3S)-Dihydroxybutanoic Acid Synthesis as a Novel Metabolic Function of Mutant Isocitrate Dehydrogenase 1 and 2 in Acute Myeloid Leukemia.
Clinical Outcomes in Patients With FLT3-ITD-Mutated Relapsed/Refractory Acute Myeloid Leukemia Undergoing Hematopoietic Stem Cell Transplant After Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial.
FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome.
In vivo CRISPR/Cas9 targeting of fusion oncogenes for selective elimination of cancer cells.
DNA Repair Expression Profiling to Identify High-Risk Cytogenetically Normal Acute Myeloid Leukemia and Define New Therapeutic Targets.
Targeting mitochondrial respiration for the treatment of acute myeloid leukemia.
MLL-TFE3: a novel and aggressive KMT2A fusion identified in infant leukemia.
Non-genetic mechanisms of therapeutic resistance in cancer.
The hepatic microenvironment uniquely protects leukemia cells through induction of growth and survival pathways mediated by LIPG.
Multiple donor-derived leukemias in a recipient of allogeneic hematopoietic cell transplantation for myeloid malignancy.
Association of Measurable Residual Disease With Survival Outcomes in Patients With Acute Myeloid Leukemia: A Systematic Review and Meta-analysis.
Dasatinib treatment long-term results among imatinib-resistant/intolerant patients with chronic phase chronic myeloid leukemia are favorable in daily clinical practice.
Leukemic evolution of polycythemia vera and essential thrombocythemia: genomic profiles predict time to transformation.
Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML.
Comparable outcomes of haploidentical transplant with TBF conditioning versus matched unrelated donor with fludarabine/busulfan conditioning for acute myeloid leukemia.
Targeting CXCR4 in AML and ALL.

Blood. 2020 Sep 05. pii: blood.2020007233. [Epub ahead of print]

Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study.

Eytan M Stein, Courtney D DiNardo, Amir T Fathi, Alice S Mims, Keith W Pratz, Michael R Savona, Anthony S Stein, Richard M Stone, Eric S Winer, Christopher S Seet, Hartmut Döhner, Daniel A Pollyea, James McCloskey, Olatoyosi Odenike, Bob Löwenberg, Gert J Ossenkoppele, Prapti Arvind Patel, Mikhail Roshal, Mark G Frattini, Frederik Lersch, Aleksandra Franovic, Salah Nabhan, Bin Fan, Sung Choe, Hongfang Wang, Bin Wu, Lei Hua, Caroline Almon, Michael Cooper, Hagop M Kantarjian, Martin S Tallman.

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted, oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.

DOI: https://doi.org/10.1182/blood.2020007233
Proc Natl Acad Sci U S A. 2020 Oct 05. pii: 202014732. [Epub ahead of print]

Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A.

Marius Bill, Krzysztof Mrózek, Jessica Kohlschmidt, Ann-Kathrin Eisfeld, Christopher J Walker, Deedra Nicolet, Dimitrios Papaioannou, James S Blachly, Shelley Orwick, Andrew J Carroll, Jonathan E Kolitz, Bayard L Powell, Richard M Stone, Albert de la Chapelle, John C Byrd, Clara D Bloomfield.

  Balanced rearrangements involving the KMT2A gene, located at 11q23, are among the most frequent chromosome aberrations in acute myeloid leukemia (AML). Because of numerous fusion partners, the mutational landscape and prognostic impact of specific 11q23/KMT2A rearrangements are not fully understood. We analyzed clinical features of 172 adults with AML and recurrent 11q23/KMT2A rearrangements, 141 of whom had outcome data available. We compared outcomes of these patients with outcomes of 1,097 patients without an 11q23/KMT2A rearrangement categorized according to the 2017 European LeukemiaNet (ELN) classification. Using targeted next-generation sequencing, we investigated the mutational status of 81 leukemia/cancer-associated genes in 96 patients with 11q23/KMT2A rearrangements with material for molecular studies available. Patients with 11q23/KMT2A rearrangements had a low number of additional gene mutations (median, 1; range 0 to 6), which involved the RAS pathway (KRAS, NRAS, and PTPN11) in 32% of patients. KRAS mutations occurred more often in patients with t(6;11)(q27;q23)/KMT2A-AFDN compared with patients with the other 11q23/KMT2A subsets. Specific gene mutations were too infrequent in patients with specific 11q23/KMT2A rearrangements to assess their associations with outcomes. We demonstrate that younger (age <60 y) patients with t(9;11)(p22;q23)/KMT2A-MLLT3 had better outcomes than patients with other 11q23/KMT2A rearrangements and those without 11q23/KMT2A rearrangements classified in the 2017 ELN intermediate-risk group. Conversely, outcomes of older patients (age ≥60 y) with t(9;11)(p22;q23) were poor and comparable to those of the ELN adverse-risk group patients. Our study shows that patients with an 11q23/KMT2A rearrangement have distinct mutational patterns and outcomes depending on the fusion partner.

Keywords:  KMT2A; acute myeloid leukemia; clinical outcome; gene mutations; next-generation sequencing

DOI:  https://doi.org/10.1073/pnas.2014732117
Front Cell Dev Biol. 2020 ;8 844

HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia.

Marco Spreafico, Alicja M Gruszka, Debora Valli, Mara Mazzola, Gianluca Deflorian, Arianna Quintè, Maria Grazia Totaro, Cristina Battaglia, Myriam Alcalay, Anna Marozzi, Anna Pistocchi.

  Histone deacetylase 8 (HDAC8), a class I HDAC that modifies non-histone proteins such as p53, is highly expressed in different hematological neoplasms including a subtype of acute myeloid leukemia (AML) bearing inversion of chromosome 16 [inv(16)]. To investigate HDAC8 contribution to hematopoietic stem cell maintenance and myeloid leukemic transformation, we generated a zebrafish model with Hdac8 overexpression and observed an increase in hematopoietic stem/progenitor cells, a phenotype that could be reverted using a specific HDAC8 inhibitor, PCI-34051 (PCI). In addition, we demonstrated that AML cell lines respond differently to PCI treatment: HDAC8 inhibition elicits cytotoxic effect with cell cycle arrest followed by apoptosis in THP-1 cells, and cytostatic effect in HL60 cells that lack p53. A combination of cytarabine, a standard anti-AML chemotherapeutic, with PCI resulted in a synergistic effect in all the cell lines tested. We, then, searched for a mechanism behind cell cycle arrest caused by HDAC8 inhibition in the absence of functional p53 and demonstrated an involvement of the canonical WNT signaling in zebrafish and in cell lines. Together, we provide the evidence for the role of HDAC8 in hematopoietic stem cell differentiation in zebrafish and AML cell lines, suggesting HDAC8 inhibition as a therapeutic target in hematological malignancies. Accordingly, we demonstrated the utility of a highly specific HDAC8 inhibition as a therapeutic strategy in combination with standard chemotherapy.

Keywords:  AML; HDAC8; PCI-34051; WNT; p53; zebrafish

DOI:  https://doi.org/10.3389/fcell.2020.00844
Oncogene. 2020 Oct 09.

SUV39H1 regulates the progression of MLL-AF9-induced acute myeloid leukemia.

Yajing Chu, Yangpeng Chen, Huidong Guo, Mengke Li, Bichen Wang, Deyang Shi, Xuelian Cheng, Jinxia Guan, Xiaomin Wang, Chenghai Xue, Tao Cheng, Jun Shi, Weiping Yuan.

Epigenetic regulations play crucial roles in leukemogenesis and leukemia progression. SUV39H1 is the dominant H3K9 methyltransferase in the hematopoietic system, and its expression declines with aging. However, the role of SUV39H1 via its-mediated repressive modification H3K9me3 in leukemogenesis/leukemia progression remains to be explored. We found that SUV39H1 was down-regulated in a variety of leukemias, including MLL-r AML, as compared with normal individuals. Decreased levels of Suv39h1 expression and genomic H3K9me3 occupancy were observed in LSCs from MLL-r-induced AML mouse models in comparison with that of hematopoietic stem/progenitor cells. Suv39h1 overexpression increased leukemia latency and decreased the frequency of LSCs in MLL-r AML mouse models, while Suv39h1 knockdown accelerated disease progression with increased number of LSCs. Increased Suv39h1 expression led to the inactivation of Hoxb13 and Six1, as well as reversion of Hoxa9/Meis1 downstream target genes, which in turn decelerated leukemia progression. Interestingly, Hoxb13 expression is up-regulated in MLL-AF9-induced AML cells, while knockdown of Hoxb13 in MLL-AF9 leukemic cells significantly prolonged the survival of leukemic mice with reduced LSC frequencies. Our data revealed that SUV39H1 functions as a tumor suppressor in MLL-AF9-induced AML progression. These findings provide the direct link of SUV39H1 to AML development and progression.

DOI: https://doi.org/10.1038/s41388-020-01495-6
Cancers (Basel). 2020 Oct 01. pii: E2842. [Epub ahead of print]12(10):

(2R,3S)-Dihydroxybutanoic Acid Synthesis as a Novel Metabolic Function of Mutant Isocitrate Dehydrogenase 1 and 2 in Acute Myeloid Leukemia.

Jeffrey R Idle, Katja Seipel, Ulrike Bacher, Thomas Pabst, Diren Beyoğlu.

  Acute myeloid leukemia (AML) frequently harbors mutations in isocitrate 1 (IDH1) and 2 (IDH2) genes, leading to the formation of the oncometabolite (2R)-hydroxyglutaric acid (2R-HG) with epigenetic consequences for AML proliferation and differentiation. To investigate if broad metabolic aberrations may result from IDH1 and IDH2 mutations in AML, plasma metabolomics was conducted by gas chromatography-mass spectrometry (GC-MS) on 51 AML patients, 29 IDH1/2 wild-type (WT), 9 with IDH1R132, 12 with IDH2R140 and one with IDH2R172 mutations. Distinct metabolic differences were observed between IDH1/2 WT, IDH1R132 and IDH2R140 patients that comprised 22 plasma metabolites that were mainly amino acids. Only two plasma metabolites were statistically significantly different (p < 0.0001) between both IDH1R132 and WT IDH1/2 and IDH2R140 and WT IDH1/2, specifically (2R)-hydroxyglutaric acid (2R-HG) and the threonine metabolite (2R,3S)-dihydroxybutanoic acid (2,3-DHBA). Moreover, 2R-HG correlated strongly (p < 0.0001) with 2,3-DHBA in plasma. One WT patient was discovered to have a D-2-hydroxyglutarate dehydrogenase (D2HGDH) A426T inactivating mutation but this had little influence on 2R-HG and 2,3-DHBA plasma concentrations. Expression of transporter genes SLC16A1 and SLC16A3 displayed a weak correlation with 2R-HG but not 2,3-DHBA plasma concentrations. Receiver operating characteristic (ROC) analysis demonstrated that 2,3-DHBA was a better biomarker for IDH mutation than 2R-HG (Area under the curve (AUC) 0.861; p < 0.0001; 80% specificity; 87.3% sensitivity). It was concluded that 2,3-DHBA and 2R-HG are both formed by mutant IDH1R132, IDH2R140 and IDH2R172, suggesting a potential role of 2,3-DHBA in AML pathogenesis.

Keywords:  (2R)-hydroxyglutaric acid; (2R,3S)-dihydroxybutanoic acid; acute myeloid leukemia; biomarker; isocitrate dehydrogenase 1; isocitrate dehydrogenase 2; metabolomics; oncometabolite

DOI:  https://doi.org/10.3390/cancers12102842
Biol Blood Marrow Transplant. 2020 Oct 02. pii: S1083-8791(20)30629-7. [Epub ahead of print]

Clinical Outcomes in Patients With FLT3-ITD-Mutated Relapsed/Refractory Acute Myeloid Leukemia Undergoing Hematopoietic Stem Cell Transplant After Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial.

Siddhartha Ganguly, Jorge E Cortes, Alwin Krämer, Mark J Levis, Giovanni Martinelli, Alexander E Perl, Nigel H Russell, Meena Arunachalam, Cedric Dos Santos, Guy Gammon, Arnaud Lesegretain, Derek E Mires, Hoang Pham, Yibin Wang, Samer K Khaled.

  Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD‒positive acute myeloid leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplant (allo-HSCT). Quizartinib, a once-daily, oral, highly potent and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 vs 4.7 months; hazard ratio [HR], 0.76 [95% CI, 0.58-0.98]; P = 0.018; composite complete remission [CRc] rate, 48% vs 27%; median duration of CRc, 2.8 vs 1.2 months; mortality rates, 0.8% vs 14% [by day 30], 7% vs 24% [by day 60]) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent an on-study HSCT in QuANTUM-R per investigator discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent an on-study allo-HSCT without any intervening therapy for AML after quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median OS in transplanted patients vs those treated without a transplant (12.2 vs 4.4 months; HR, 0.315 [95% CI, 0.233-0.427]). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT vs patients without a CRc (20.1 vs 8.8 months; HR, 0.506 [95% CI, 0.296-0.864]). By treatment arm, the median OS was 25.1 months with quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc prior to allo-HSCT. Forty-eight patients in the quizartinib arm continued quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc prior to allo-HSCT who continued quizartinib after allo-HSCT, median OS was 27.1 months. Continuation of quizartinib after allo-HSCT was tolerable and no new safety signals were identified. These results suggest that post-transplant survival following salvage chemotherapy and quizartinib treatment are similar. However, quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplant and achieve durable clinical benefit. Additionally, post-HSCT quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML.

Keywords:  FMS-like tyrosine kinase 3 internal tandem duplication; acute myeloid leukemia; allogeneic hematopoietic stem cell transplantation; quizartinib; relapsed/refractory

DOI:  https://doi.org/10.1016/j.bbmt.2020.09.036
Blood Cancer J. 2020 Oct 06. 10(10): 98

FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome.

Michael Schieber, Christian Marinaccio, Lyndsey C Bolanos, Wendy D Haffey, Kenneth D Greis, Daniel T Starczynowski, John D Crispino.

Myelodysplastic syndrome (MDS) is a heterogeneous myeloid malignancy characterized by blood cell morphological dysplasia, ineffective clonal hematopoiesis, and risk of transformation to secondary acute myeloid leukemia (sAML). A number of genetic abnormalities have been identified in MDS and sAML, but sensitive sequencing methods can detect these mutations in nearly all healthy individuals by 60 years of age. To discover novel cellular pathways that accelerate MDS and sAML, we performed a CRISPR/Cas9 screen in the human MDS-L cell line. We report here that loss of the F-Box protein FBXO11, a component of the SCF ubiquitin ligase complex, confers cytokine independent growth to MDS-L cells, suggesting a tumor suppressor role for FBXO11 in myeloid malignancies. Putative FBXO11 substrates are enriched for proteins with functions in RNA metabolism and, of note, spliceosome mutations that are commonly found in MDS/sAML are rare in patients with low FBXO11 expression. We also reveal that loss of FBXO11 leads to significant changes in transcriptional pathways influencing leukocyte proliferation, differentiation, and apoptosis. Last, we find that FBXO11 expression is reduced in patients with secondary AML. We conclude that loss of FBXO11 is a mechanism for disease transformation of MDS into AML, and may represent a future therapeutic target.

DOI: https://doi.org/10.1038/s41408-020-00362-7
Nat Commun. 2020 10 08. 11(1): 5060

In vivo CRISPR/Cas9 targeting of fusion oncogenes for selective elimination of cancer cells.

M Martinez-Lage, R Torres-Ruiz, P Puig-Serra, P Moreno-Gaona, M C Martin, F J Moya, O Quintana-Bustamante, S Garcia-Silva, A M Carcaboso, P Petazzi, C Bueno, J Mora, H Peinado, J C Segovia, P Menendez, S Rodriguez-Perales.

Fusion oncogenes (FOs) are common in many cancer types and are powerful drivers of tumor development. Because their expression is exclusive to cancer cells and their elimination induces cell apoptosis in FO-driven cancers, FOs are attractive therapeutic targets. However, specifically targeting the resulting chimeric products is challenging. Based on CRISPR/Cas9 technology, here we devise a simple, efficient and non-patient-specific gene-editing strategy through targeting of two introns of the genes involved in the rearrangement, allowing for robust disruption of the FO specifically in cancer cells. As a proof-of-concept of its potential, we demonstrate the efficacy of intron-based targeting of transcription factors or tyrosine kinase FOs in reducing tumor burden/mortality in in vivo models. The FO targeting approach presented here might open new horizons for the selective elimination of cancer cells.

DOI: https://doi.org/10.1038/s41467-020-18875-x
Cancers (Basel). 2020 Oct 06. pii: E2874. [Epub ahead of print]12(10):

DNA Repair Expression Profiling to Identify High-Risk Cytogenetically Normal Acute Myeloid Leukemia and Define New Therapeutic Targets.

Ludovic Gabellier, Caroline Bret, Guillaume Bossis, Guillaume Cartron, Jérôme Moreaux.

  Cytogenetically normal acute myeloid leukemias (CN-AML) represent about 50% of total adult AML. Despite the well-known prognosis role of gene mutations such as NPM1 mutations of FLT3 internal tandem duplication (FLT3-ITD), clinical outcomes remain heterogeneous in this subset of AML. Given the role of genomic instability in leukemogenesis, expression analysis of DNA repair genes might be relevant to sharpen prognosis evaluation in CN-AML. A publicly available gene expression profile dataset from two independent cohorts of patients with CN-AML were analyzed (GSE12417). We investigated the prognostic value of 175 genes involved in DNA repair. Among these genes, 23 were associated with a prognostic value. The prognostic information provided by these genes was summed in a DNA repair score, allowing to define a group of patients (n = 87; 53.7%) with poor median overall survival (OS) of 233 days (95% CI: 184-260). These results were confirmed in two validation cohorts. In multivariate Cox analysis, the DNA repair score, NPM1, and FLT3-ITD mutational status remained independent prognosis factors in CN-AML. Combining these parameters allowed the identification of three risk groups with different clinical outcomes in both training and validation cohorts. Combined with NPM1 and FLT3 mutational status, our GE-based DNA repair score might be used as a biomarker to predict outcomes for patients with CN-AML. DNA repair score has the potential to identify CN-AML patients whose tumor cells are dependent on specific DNA repair pathways to design new therapeutic avenues.

Keywords:  DNA repair; acute myeloid leukemia; normal karyotype; precision medicine; risk score

DOI:  https://doi.org/10.3390/cancers12102874
Biochem Pharmacol. 2020 Oct 01. pii: S0006-2952(20)30489-5. [Epub ahead of print] 114253

Targeting mitochondrial respiration for the treatment of acute myeloid leukemia.

Jenna L Carter, Katie Hege, Hasini A Kalpage, Holly Edwards, Maik Hüttemann, Jeffrey W Taub, Yubin Ge.

  Acute myeloid leukemia (AML) is a heterogeneous disease with variable presentation, molecular phenotype, and cytogenetic abnormalities and has seen very little improvement in patient survival over the last few decades. This heterogeneity supports poor prognosis partially through the variability in response to the standard chemotherapy. Further understanding of molecular heterogeneity has promoted the development of novel treatments, some of which target mitochondrial metabolism and function. This review discusses the relative dependency that AML cells have on mitochondrial function, and the ability to pivot this reliance to target important subsets of AML cells, including leukemia stem cells (LSCs). LSCs are tumor-initiating cells that are resistant to standard chemotherapy and promote the persistence and relapse of AML. Historically, LSCs have been targeted based on immunophenotype, but recent developments in the understanding of LSC metabolism has demonstrated unique abilities to target LSCs while sparing normal hematopoietic stem cells (HSCs) through inhibition of mitochondrial function. Here we highlight the use of small molecules that have been demonstrated to effectively target mitochondrial function. IACS-010759 and ME-344 target the electron transport chain (ETC) to inhibit oxidative phosphorylation (OXPHOS). The imipridone family (ONC201, ONC206, ONC212) of inhibitors target mitochondria through activation of ClpP mitochondrial protease and reduce function of essential pathways. These molecules offer a new mechanism for developing clinical therapies in AML and support novel strategies to target LSCs in parallel with conventional therapies.

Keywords:  Acute myeloid leukemia; IACS-010759; ME-344; Mitochondria; ONC201; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.bcp.2020.114253
Blood Adv. 2020 Oct 13. 4(19): 4918-4923

MLL-TFE3: a novel and aggressive KMT2A fusion identified in infant leukemia.

Hansen J Kosasih, Nadia M Davidson, Stefan Bjelosevic, Emma Morrish, Margs S Brennan, Alicia Oshlack, Ricky W Johnstone, Gabriela Brumatti, Seong L Khaw, Paul G Ekert.

DOI: https://doi.org/10.1182/bloodadvances.2020002708
Nat Rev Cancer. 2020 Oct 08.

Non-genetic mechanisms of therapeutic resistance in cancer.

Jean-Christophe Marine, Sarah-Jane Dawson, Mark A Dawson.

Therapeutic resistance continues to be an indominable foe in our ambition for curative cancer treatment. Recent insights into the molecular determinants of acquired treatment resistance in the clinical and experimental setting have challenged the widely held view of sequential genetic evolution as the primary cause of resistance and brought into sharp focus a range of non-genetic adaptive mechanisms. Notably, the genetic landscape of the tumour and the non-genetic mechanisms used to escape therapy are frequently linked. Remarkably, whereas some oncogenic mutations allow the cancer cells to rapidly adapt their transcriptional and/or metabolic programme to meet and survive the therapeutic pressure, other oncogenic drivers convey an inherent cellular plasticity to the cancer cell enabling lineage switching and/or the evasion of anticancer immunosurveillance. The prevalence and diverse array of non-genetic resistance mechanisms pose a new challenge to the field that requires innovative strategies to monitor and counteract these adaptive processes. In this Perspective we discuss the key principles of non-genetic therapy resistance in cancer. We provide a perspective on the emerging data from clinical studies and sophisticated cancer models that have studied various non-genetic resistance pathways and highlight promising therapeutic avenues that may be used to negate and/or counteract the non-genetic adaptive pathways.

DOI: https://doi.org/10.1038/s41568-020-00302-4
Cancer Discov. 2020 Oct 07. pii: CD-20-0318. [Epub ahead of print]

The hepatic microenvironment uniquely protects leukemia cells through induction of growth and survival pathways mediated by LIPG.

Haobin Ye, Mohammad Minhajuddin, Anna Krug, Shanshan Pei, Chih-Hsing Chou, Rachel Culp-Hill, Jessica Ponder, Erik De Bloois, Björn Schniedewind, Maria L Amaya, Anagha Inguva, Brett M Stevens, Daniel A Pollyea, Uwe Christians, H Leighton Grimes, Angelo D'Alessandro, Craig T Jordan.

Due to the disseminated nature of leukemia, malignant cells are exposed to many different tissue microenvironments, including a variety of extramedullary sites. In the present study, we demonstrate that leukemic cells residing in the liver display unique biological properties, and also contribute to systemic changes that influence physiological responses to chemotherapy. Specifically, the liver microenvironment induces metabolic adaptations via up-regulating expression of endothelial lipase (LIPG) in leukemia cells, which not only stimulates tumor cell proliferation through polyunsaturated fatty acid (PUFA) mediated pathways, but also promotes survival by stabilizing anti-apoptotic proteins. Additionally, hepatic infiltration and tissue damage caused by malignant cells induces release of liver-derived enzymes capable of degrading chemotherapy drugs, an event which further protects leukemia cells from conventional therapies. Together, these studies demonstrate a unique role for liver in modulating the pathogenesis of leukemic disease and suggest that the hepatic microenvironment may protect leukemia cells from chemotherapeutic challenge.

DOI: https://doi.org/10.1158/2159-8290.CD-20-0318
Blood Adv. 2020 Oct 13. 4(19): 4798-4801

Multiple donor-derived leukemias in a recipient of allogeneic hematopoietic cell transplantation for myeloid malignancy.

Ibrahim Aldoss, Joo Y Song, Peter T Curtin, Stephen J Forman.

DOI: https://doi.org/10.1182/bloodadvances.2020002803
JAMA Oncol. 2020 Oct 08.

Association of Measurable Residual Disease With Survival Outcomes in Patients With Acute Myeloid Leukemia: A Systematic Review and Meta-analysis.

Nicholas J Short, Shouhao Zhou, Chenqi Fu, Donald A Berry, Roland B Walter, Sylvie D Freeman, Christopher S Hourigan, Xuelin Huang, Graciela Nogueras Gonzalez, Hyunsoo Hwang, Xinyue Qi, Hagop Kantarjian, Farhad Ravandi.

Importance: Measurable residual disease (MRD) refers to neoplastic cells that cannot be detected by standard cytomorphologic analysis. In patients with acute myeloid leukemia (AML), determining the association of MRD with survival may improve prognostication and inform selection of efficient clinical trial end points.
Objective: To examine the association between MRD status and disease-free survival (DFS) and overall survival (OS) in patients with AML using scientific literature.
Data Sources: Clinical studies on AML published between January 1, 2000, and October 1, 2018, were identified via searches of PubMed, Embase, and MEDLINE.
Study Selection: Literature search and study screening were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Studies that assessed DFS or OS by MRD status in patients with AML were included. Reviews, non-English-language articles, and studies reporting only outcomes after hematopoietic cell transplantation or those with insufficient description of MRD information were excluded.
Data Extraction and Synthesis: Study sample size, median patient age, median follow-up time, MRD detection method, MRD assessment time points, AML subtype, specimen source, and survival outcomes were extracted. Meta-analyses were performed separately for DFS and OS using bayesian hierarchical modeling.
Main Outcomes and Measures: Meta-analyses of survival probabilities and hazard ratios (HRs) were conducted for OS and DFS according to MRD status.
Results: Eighty-one publications reporting on 11 151 patients were included. The average HR for achieving MRD negativity was 0.36 (95% bayesian credible interval [CrI], 0.33-0.39) for OS and 0.37 (95% CrI, 0.34-0.40) for DFS. The estimated 5-year DFS was 64% for patients without MRD and 25% for those with MRD, and the estimated OS was 68% for patients without MRD and 34% for those with MRD. The association of MRD negativity with DFS and OS was significant for all subgroups, with the exception of MRD assessed by cytogenetics or fluorescent in situ hybridization.
Conclusions and Relevance: The findings of this meta-analysis suggest that achievement of MRD negativity is associated with superior DFS and OS in patients with AML. The value of MRD negativity appears to be consistent across age groups, AML subtypes, time of MRD assessment, specimen source, and MRD detection methods. These results support MRD status as an end point that may allow for accelerated evaluation of novel therapies in AML.

DOI: https://doi.org/10.1001/jamaoncol.2020.4600
Leuk Lymphoma. 2020 Oct 06. 1-9

Dasatinib treatment long-term results among imatinib-resistant/intolerant patients with chronic phase chronic myeloid leukemia are favorable in daily clinical practice.

Daniela Zackova, Hana Klamova, Petra Belohlavkova, Lukas Stejskal, Tereza Necasova, Lukas Semerad, Barbora Weinbergerova, Dana Srbova, Jaroslava Voglova, Petra Cicatkova, Zuzana Sustkova, Tomas Hornak, Jana Baranova, Jirina Prochazkova, Jiri Mayer.

  To evaluate long-term real-life results of dasatinib therapy among chronic phase chronic myeloid leukemia patients resistant or intolerant to imatinib, we retrospectively analyzed data of 118 patients treated in centers participating in the database INFINITY. With median follow-up of 37 months, estimated 5-year cumulative incidences of complete cytogenetic and major molecular responses were 78% and 68%, respectively. The estimated 5-year probability of overall survival (OS) and event-free survival (EFS) were 86% and 83%, respectively. Both OS and EFS were significantly improved among patients with BCR-ABL1 transcript level ≤10% at 3 months. Dasatinib toxicity was tolerable however persistent in almost half our patients, even after years of therapy. Pleural effusion occurred in 29% of patients and was responsible for 30% of dasatinib discontinuations. Our results confirmed very good efficacy and acceptable toxicity of dasatinib in second line setting and support the evidence and importance of high-quality real-life CML patient management.

Keywords:  Chronic myeloid leukemia; chronic phase; daily clinical practice; dasatinib; imatinib; second line

DOI:  https://doi.org/10.1080/10428194.2020.1827242
Blood Adv. 2020 Oct 13. 4(19): 4887-4897

Leukemic evolution of polycythemia vera and essential thrombocythemia: genomic profiles predict time to transformation.

Damien Luque Paz, Rébecca Jouanneau-Courville, Jérémie Riou, Jean-Christophe Ianotto, Françoise Boyer, Aurélie Chauveau, Maxime Renard, Jean-Claude Chomel, Emilie Cayssials, Maria-Pilar Gallego-Hernanz, Cédric Pastoret, Anne Murati, Frédéric Courtier, Marie-Christine Rousselet, Isabelle Quintin-Roué, Laurane Cottin, Corentin Orvain, Sylvain Thépot, Jean-Marie Chrétien, Yves Delneste, Norbert Ifrah, Odile Blanchet, Mathilde Hunault-Berger, Eric Lippert, Valérie Ugo.

Among myeloproliferative neoplasms, polycythemia vera (PV) and essential thrombocythemia (ET) are the 2 entities associated with the most chronic disease course. Leukemic evolution occurs rarely but has a grim prognosis. The interval between diagnosis and leukemic evolution is highly variable, from a few years to >20 years. We performed a molecular evaluation of 49 leukemic transformations of PV and ET by targeted next-generation sequencing. Using a hierarchical classification, we identified 3 molecular groups associated with a distinct time to leukemic transformation. Short-term transformations were mostly characterized by a complex molecular landscape and mutations in IDH1/2, RUNX1, and U2AF1 genes, whereas long-term transformations were associated with mutations in TP53, NRAS, and BCORL1 genes. Studying paired samples from chronic phase and transformation, we detected some mutations already present during the chronic phase, either with a significant allele burden (short-term transformation) or with a very low allele burden (especially TP53 mutations). However, other mutations were not detected even 1 year before leukemic transformation. Our results suggest that the leukemic transformation of PV and ET may be driven by distinct time-dependent molecular mechanisms.

DOI: https://doi.org/10.1182/bloodadvances.2020002271
J Hematol Oncol. 2020 Oct 08. 13(1): 132

Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML.

Musa Yilmaz, Mansour Alfayez, Courtney D DiNardo, Gautam Borthakur, Tapan M Kadia, Marina Y Konopleva, Sanam Loghavi, Rashmi Kanagal-Shamanna, Keyur P Patel, Elias J Jabbour, Guillermo Garcia-Manero, Naveen Pemmaraju, Sherry A Pierce, Issa Ghayas, Nicholas J Short, Guillermo Montalban-Bravo, Koichi Takahashi, Rita Assi, Ahmad S Alotaibi, Maro Ohanian, Michael Andreeff, Jorge E Cortes, Hagop M Kantarjian, Farhad Ravandi, Naval G Daver.

   BACKGROUND: Second-generation FLT3-inhibitors (FLT3i) demonstrated single-agent composite CR rates (CRc) of 45-55% in patients with relapsed/refractory (R/R) FLT3-mutated AML in phase II/III trials. However, > 85% of patients treated were prior FLT3i naïve. The response rates to sequential FLT3i exposure remain poorly defined.
METHODS: We retrospectively reviewed patients with FLT3-mutated AML between November 2006 and December 2019.
RESULTS: In frontline patients treated with a FLT3i (cohort 1), the CRc rates and median overall survival (OS) with the first (n = 56), second (n = 32), and third FLT3i-based (n = 8) therapy were 77%, 31%, and 25%, and 16.7 months, 6.0 months, and 1.4 months, respectively. In patients receiving a FLT3i-based therapy for the first time in a R/R AML setting (cohort 2), the CRc rates and median OS were 45%, 21%, and 10%, and 7.9 months, 4.0 months, and 4.1 months with the first (n = 183), second (n = 89), and third/fourth (n = 29) FLT3i-based therapy, respectively. In cohort 1, CRc rates with single-agent FLT3i (n = 21) versus FLT3i-based combinations (n = 19) in second/third sequential FLT3i exposures were 19% versus 42%, respectively. In cohort 2, the CRc rates with single-agent FLT3i (n = 82) versus FLT3i-based combinations (n = 101) in first FLT3i exposure were 34% versus 53%, respectively, and those with single-agent FLT3i (n = 63) versus FLT3i-based combinations (n = 55) in second/third/fourth sequential FLT3i exposures were 13% versus 25%, respectively.
CONCLUSION: CRc rates drop progressively with sequential exposure to FLT3i's in FLT3-mutated AML. In all settings, CRc rates were higher with FLT3i-based combinations compared with single-agent FLT3i therapy in similar FLT3i exposure settings.

Keywords:  FLT3 mutations; FLT3-PCR; Gilteritinib; Low-intensity therapy; Midostaurin; Quizartinib; Sequential FLT3 inhibitors; Sorafenib

DOI:  https://doi.org/10.1186/s13045-020-00964-5
Bone Marrow Transplant. 2020 Oct 06.

Comparable outcomes of haploidentical transplant with TBF conditioning versus matched unrelated donor with fludarabine/busulfan conditioning for acute myeloid leukemia.

Ali Bazarbachi, Myriam Labopin, Didier Blaise, Edouard Forcade, Gerard Socié, Ana Berceanu, Emanuele Angelucci, Claude Eric Bulabois, Nicolaus Kröger, Alessandro Rambaldi, Patrice Ceballos, Stephan Mielke, Jean El Cheikh, Ibrahim Yakoub-Agha, Bipin Savani, Alexandros Spyridonidis, Arnon Nagler, Mohamad Mohty.

We compared transplant outcomes of 708 acute myeloid leukemia (AML) patients receiving haploidentical allogeneic hematopoietic-cell transplantation using thiotepa/busulfan/fludarabine (TBF) conditioning with posttransplant cyclophosphamide (ptCy), to 2083 patients receiving matched unrelated donor (MUD) transplantation using fludarabine/busulfan (FB) conditioning and in vivo T-cell depletion. For intermediate cytogenetic risk AML transplanted in first complete remission (CR1), multivariate analysis revealed that haplo-TBF significantly increased nonrelapse mortality (NRM) (HR 2.1; p = 0.0006) but did not affect relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS), or graft-versus-host disease-free, relapse-free survival (GRFS). For high cytogenetic risk AML transplanted in CR1, haplo-TBF significantly increased NRM (HR = 2.7; p = 0.02), decreased RI (HR = 0.45; p = 0.03) but had no influence on LFS, OS, or GRFS. For AML transplanted in CR2, haplo-TBF significantly increased NRM (HR = 2.36; p = 0.008), decreased RI (HR = 0.38; p = 0.005), but had no influence on LFS, OS, or GRFS. Finally, for AML patients transplanted with active disease, haplo-TBF had no influence on transplant outcomes. In conclusion, compared to MUD-FB, haplo-TBF increased NRM, reduced RI in high-risk AML in CR, resulting in similar LFS, OS, and GRFS. These results comparing two different approaches support the use of a haploidentical family donor for high-risk AML patients lacking a matched sibling donor.

DOI: https://doi.org/10.1038/s41409-020-01074-z
Front Oncol. 2020 ;10 1672

Targeting CXCR4 in AML and ALL.

Daniel Cancilla, Michael P Rettig, John F DiPersio.

  The interaction of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) blasts with the bone marrow microenvironment regulates self-renewal, growth signaling, as well as chemotherapy resistance. The chemokine receptor, CXC receptor 4 (CXCR4), with its ligand chemokine ligand 12 (CXCL12), plays a key role in the survival and migration of normal and malignant stem cells to the bone marrow. High expression of CXCR4 on AML and ALL blasts has been shown to be a predictor of poor prognosis for these diseases. Several small molecule inhibitors, short peptides, antibodies, and antibody drug conjugates have been developed for the purposes of more effective targeting and killing of malignant cells expressing CXCR4. In this review we will discuss recent results and strategies in targeting CXCR4 with these agents in patients with AML or ALL.

Keywords:  ALL; AML; CXCL12; CXCR4; chemosensitization

DOI:  https://doi.org/10.3389/fonc.2020.01672