bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2020‒09‒06
seventeen papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London

  1. Clin Lymphoma Myeloma Leuk. 2020 Sep;pii: S2152-2650(20)30441-9. [Epub ahead of print]20 Suppl 1 S5-S6
    Smith CC.
      Mutations in the FLT3 receptor tyrosine kinase are the most frequently found mutations in acute myeloid leukemia (AML). Patients with FLT3 internal tandem duplication (ITD) mutations have poor prognoses. The approved FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and gilteritinib improve survival in AML with FLT3 mutations. Multiple other FLT3 inhibitors are in clinical development. Patients frequently relapse after response to FLT3 inhibitors and the optimal use of FLT3 inhibitors in the upfront, relapse, and maintenance settings remain to be established. We will discuss the biology of FLT3, approved and investigational FLT3 inhibitors, resistance mechanisms, and emerging FLT3 TKI combination clinical trials.
    Keywords:  Tyrosine kinase inhibitors; resistance; targeted therapy
  2. Blood. 2020 Sep 01. pii: blood.2020007897. [Epub ahead of print]
    Xiao W, Chan A, Waarts MR, Mishra T, Liu Y, Cai SF, Yao J, Gao Q, Bowman RL, Koche RP, Csete IS, DelGaudio NL, Derkach A, Baik J, Yanis S, Famulare CA, Patel M, Arcila ME, Stahl M, Rampal R, Tallman MS, Zhang Y, Dogan A, Goldberg AD, Roshal M, Levine RL.
      Plasmacytoid dendritic cells (pDC) are the principal natural type I interferon producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN) and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia (CMML). The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here we characterize AML patients with pDC expansion (pDC-AML), which we observe in approximately 5% of AML. pDC-AML often possess cross-lineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without pDC expansion and BPDCN. We demonstrate that pDCs are clonally related to, and originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells towards pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.
  3. Yonsei Med J. 2020 Sep;61(9): 762-773
    Kim Y, Jeung HK, Cheong JW, Song J, Bae SH, Lee JI, Min YH.
      PURPOSE: Pharmacological inhibition of mutant isocitrate dehydrogenase (IDH) reduces R-2-hydroxyglutarate (2-HG) levels and restores cellular differentiation in vivo and in vitro. The IDH2 inhibitor enasidenib (AG-221) has been approved by the FDA as a first-in-class inhibitor for the treatment of relapsed or refractory (R/R) IDH2-mutant acute myeloid leukemia (AML). In this study, the effects of a combination of all-trans retinoic acid (ATRA) and AG-221 on AML cell differentiation was explored, along with the mechanisms employed by IDH2-mutant cells in AML.MATERIALS AND METHODS: We treated the human AML cell line, IDH2-mutant-TF-1, and primary human AML cells carrying IDH2 mutation with 30 μM AG-221 and 100 nM ATRA, alone or in combination.
    RESULTS: Combined treatment with AG-221 and ATRA inhibited 2-HG production and resulted in synergistic effects on differentiation among IDH2-mutant AML cells and primary AML cells expressing IDH2 mutation. Combined treatment with AG-221 and ATRA altered autophagic activity. AG-221 and ATRA treatment-induced differentiation of IDH2-mutant AML cells was associated with autophagy induction, without suppressing autophagy flux at maturation and degradation stages. A RAF-1/MEK/ERK pathway was founded to be associated with AG-221 and ATRA-induced differentiation in IDH2-mutant AML cells. IDH-associated changes in histone methylation markers decreased after AG-221 and ATRA combination treatment.
    CONCLUSION: Our preliminary evidence indicates that the addition of ATRA to treatments with IDH2 inhibitor may lead to further improvements or increases in response rates in IDH2-mutant AML patients who do not appear to benefit from treatments with IDH2 inhibitor alone.
    Keywords:  Isocitrate dehydrogenase 2-mutant acute myeloid leukemia; all-trans retinoic acid; combination treatment; differentiation; isocitrate dehydrogenase 2 inhibitor
  4. Cancer Res. 2020 Sep 01. pii: canres.0531.2020. [Epub ahead of print]
    Nguyen CH, Schlerka A, Grandits AM, Koller E, van der Kouwe E, Vassiliou GS, Staber PB, Heller G, Wieser R.
      Overexpression of IL2RA, which encodes the alpha chain of the interleukin-2 receptor, is associated with chemotherapy resistance and poor outcome in acute myeloid leukemia (AML). The clinical potential of anti-IL2RA therapy is therefore being explored in early-stage clinical trials. Notwithstanding, only very limited information regarding the biological function of IL2RA in AML is available. Using genetic manipulation of IL2RA expression as well as antibody-mediated inhibition of IL2RA in human cell lines, mouse models, and primary patient samples, we investigated the effects of IL2RA on AML cell proliferation and apoptosis, and on pertinent signalling pathways. The impact of IL2RA on the properties of leukemic stem cells (LSC) and on leukemogenesis were queried. IL2RA promoted proliferation and cell cycle activity and inhibited apoptosis in human AML cell lines and primary cells. These phenotypes were accompanied by corresponding alterations in cell cycle machinery and in pathways associated with cell survival and apoptosis. The biological roles of IL2RA were confirmed in two genetically distinct AML mouse models, revealing that IL2RA inhibits differentiation, promotes stem cell-related properties, and is required for leukemogenesis. IL2RA antibodies inhibited leukemic, but not normal, hematopoietic cells and synergised with other anti-leukemic agents in this regard. Collectively, these data show for the first time that IL2RA plays key biological roles in AML and underscore its value as a potential therapeutic target in this disease.
  5. Biol Blood Marrow Transplant. 2020 Aug 28. pii: S1083-8791(20)30542-5. [Epub ahead of print]
    Sandhu KS, Dadwal S, Yang D, Mei M, Palmer J, Salhotra A, Al Malki M, Aribi A, Ali H, Khaled S, Forman SJ, Snyder D, Nakamura R, Stein AS, Marcucci G, Aldoss I, Pullarkat V.
      The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (HMA-VEN) has emerged as a highly active regimen in acute myeloid leukemia (AML) both in the upfront as well as relapsed/refractory (r/r) setting. We report our early experience with a cohort of patients who were able to proceed to allogeneic hematopoietic cell transplantation (alloHCT) after HMA-VEN therapy. Thirty two AML patients (19 r/r and 13 de novo) with a median age of 62 years underwent alloHCT after HMA-VEN therapy. Twenty two (68.8%) were in CR/CRi at time of HCT. With a median follow up of 14.4 months, the 1-year overall survival was 62.5% and disease-free survival was 43.8%. The 1-year non relapse mortality rate was 18.8 % and cumulative incidence of relapse was 37.5 %. Among patients who underwent alloHCT in CR, the 1-year OS was 77.3% and cumulative incidence of NRM was 9.1%. Cumulative incidence of Grade II-IV acute GVHD was 43.8%. We conclude that HCT post HMA-VEN is associated with favorable allogeneic HCT outcomes in newly diagnosed older AML patients as well as those with r/r AML.
    Keywords:  Acute myeloid leukemia; Allogeneic; Hematopoietic cell transplantation; Hypomethylating agents; Venetoclax
  6. Cancer Chemother Pharmacol. 2020 Sep 03.
    Lin S, Shaik N, Chan G, Cortes JE, Ruiz-Garcia A.
      PURPOSE: Glasdegib, an oral inhibitor of the Hedgehog signaling pathway, is approved in the United States in combination with low-dose cytarabine (LDAC) to treat patients with newly diagnosed acute myeloid leukemia (AML) ineligible to receive intensive chemotherapy. This population pharmacokinetic/pharmacodynamic analysis characterized the time course of survival with glasdegib + LDAC relative to LDAC alone, and explored whether the differences in glasdegib exposure at the clinical dose of 100 mg once daily (QD) significantly affected overall survival (OS).METHODS: Data from the BRIGHT AML 1003 trial in patients with AML were included in treatment-response (glasdegib + LDAC, n = 78; LDAC alone, n = 38) and exposure-response (glasdegib + LDAC, n = 75) analyses.
    RESULTS: The analyses demonstrate that patients treated with glasdegib + LDAC (vs LDAC alone) at any time point during the study period were 58% less likely to die, translating to prolonging of median OS by ~ 5 months (hazard ratio 0.42 [95% confidence interval 0.28-0.66]). Variability in glasdegib exposures did not impact the risk of death. Additionally, potential covariates such as patient demographics, prior treatment with a hypomethylating agent, baseline safety laboratory values, and disease characteristics, did not impact the probability of OS.
    CONCLUSION: Together these results confirm that glasdegib + LDAC treatment (vs. LDAC alone) is associated with a significant survival benefit in patients with newly diagnosed AML, and that variability in glasdegib doses (e.g., for dose reductions) and exposures do not compromise the survival benefit of glasdegib 100 mg QD.
    Keywords:  Acute myeloid leukemia; Exposure–response; Hedgehog; Overall survival; Smoothened inhibitor
  7. Cell Metab. 2020 Sep 01. pii: S1550-4131(20)30421-6. [Epub ahead of print]32(3): 321-323
    Stuani L, Sarry JE.
      Metabolic dialogue between tumors and their microenvironment emerges as a key regulator of chemoresistance, the major barrier for the treatment of several cancers. In this issue of Cell Metabolism, van Gastel et al. decipher the pivotal role of stromal glutamine-derived aspartate to sustain pyrimidine biosynthesis in chemoresistant acute myeloid leukemia (AML) and thus state it as a target for anti-cancer therapy.
  8. Nature. 2020 Sep 02.
    Watkins TBK, Lim EL, Petkovic M, Elizalde S, Birkbak NJ, Wilson GA, Moore DA, Grönroos E, Rowan A, Dewhurst SM, Demeulemeester J, Dentro SC, Horswell S, Au L, Haase K, Escudero M, Rosenthal R, Bakir MA, Xu H, Litchfield K, Lu WT, Mourikis TP, Dietzen M, Spain L, Cresswell GD, Biswas D, Lamy P, Nordentoft I, Harbst K, Castro-Giner F, Yates LR, Caramia F, Jaulin F, Vicier C, Tomlinson IPM, Brastianos PK, Cho RJ, Bastian BC, Dyrskjøt L, Jönsson GB, Savas P, Loi S, Campbell PJ, Andre F, Luscombe NM, Steeghs N, Tjan-Heijnen VCG, Szallasi Z, Turajlic S, Jamal-Hanjani M, Van Loo P, Bakhoum SF, Schwarz RF, McGranahan N, Swanton C.
      Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.
  9. Mol Cancer Ther. 2020 Sep 02. pii: molcanther.0407.2020. [Epub ahead of print]
    Anami Y, Deng M, Gui X, Yamaguchi A, Yamazaki CM, Zhang N, Zhang C, An Z, Tsuchikama K.
      Acute myeloid leukemia (AML) is the most common and aggressive blood cancer in adults. In particular, significant unmet medical needs exist for effective treatment strategies for M4 and M5 AML subtypes. Antibody-drug conjugates (ADCs) are a promising drug class for AML therapy, as demonstrated by the FDA-approved anti-CD33 ADC gemutuzumab ozogamicin (Mylotarg®). However, CD33 is expressed in normal hematopoietic stem cells, highlighting the critical need to identify AML-specific targets to minimize the risk of potential adverse effects. We have demonstrated that the leukocyte immunoglobulin-like receptor subfamily B4 (LILRB4) is expressed at significantly higher levels on monocytic M4 and M5 AML cells than on normal counterparts. Here, we test whether LILRB4 is a promising ADC target to kill monocytic AML cells while sparing healthy counterparts. To this end, we generated ADCs from a humanized anti-LILRB4 monoclonal antibody and the antimitotic payload monomethyl auristatin F (MMAF). The conjugates constructed were characterized and evaluated for LILRB4-specific cell killing potency, toxicity to progenitor cells, pharmacokinetics, and therapeutic efficacy. Our ADC linker technology platform efficiently generated homogeneous anti-LILRB4 ADCs with defined drug-to-antibody ratios. The homogeneous anti-LILRB4 ADCs demonstrated the capacity for LILRB4-mediated internalization, suitable physicochemical properties, and high cell killing potency against LILRB4-positive AML cells. Importantly, our data indicate that these ADCs spare normal progenitor cells. One of our homogeneous conjugates exerts a remarkable therapeutic effect and no significant toxicity in a xenograft mouse model of disseminated human AML. Our findings highlight the clinical potential of anti-LILRB4 ADCs in monocytic AML therapy.
  10. Blood Adv. 2020 Sep 08. 4(17): 4124-4135
    Spriano F, Gaudio E, Cascione L, Tarantelli C, Melle F, Motta G, Priebe V, Rinaldi A, Golino G, Mensah AA, Aresu L, Zucca E, Pileri S, Witcher M, Brown B, Wahlestedt C, Giles F, Stathis A, Bertoni F.
      Bromodomain and extra-terminal domain (BET) proteins, cyclic adenosine monophosphate response element-binding protein (CBP), and the E1A-binding protein of p300 (EP300) are important players in histone acetylation. Preclinical evidence supports the notion that small molecules targeting these proteins individually or in combination can elicit antitumor activity. Here, we characterize the antitumor activity of the pan BET/CBP/EP300 inhibitor NEO2734 and provide insights into its mechanism of action through bromodomain-binding assays, in vitro and in vivo treatments of cancer cell lines, immunoblotting, and transcriptome analyses. In a panel of 60 models derived from different tumor types, NEO2734 exhibited antiproliferative activity in multiple cell lines, with the most potent activity observed in hematologic and prostate cancers. Focusing on lymphoma cell lines, NEO2374 exhibited a pattern of response and transcriptional changes similar to lymphoma cells exposed to either BET or CBP/EP300 inhibitors alone. However, NEO2734 was more potent than single-agent BET or CBP/EP300 inhibitors alone. In conclusion, NEO2734 is a novel antitumor compound that shows preferential activity in lymphomas, leukemias, and prostate cancers.
  11. Sci Rep. 2020 Aug 31. 10(1): 14297
    Kim B, Yun W, Lee ST, Choi JR, Yoo KH, Koo HH, Jung CW, Kim SH.
      Acute myeloid leukemia (AML) is one of the most common types of leukemia. With the recent advances in sequencing technology and the growing body of knowledge on the genetics of AML, there is increasing concern about cancer predisposing germline mutations as well as somatic mutations. As familial cases sharing germline mutations are constantly reported, germline predisposition gene mutations in patients with AML are gaining attention. We performed genomic sequencing of Korean patients diagnosed with AML to identify the prevalence and characteristics of germline predisposition mutations. Among 180 patients, germline predisposition mutations were identified in 13 patients (13/180, 7.2%, eight adults and five children). Germline mutations of BLM, BRCA1, BRCA2, CTC1, DDX41, ERCC4, ERCC6, FANCI, FANCM, PALB2, and SBDS were identified. Most of the mutations are in genes involved in DNA repair and genomic stability maintenance. Patients harboring germline mutations tended to have earlier onset of AML (p = 0.005), however, the presence of germline mutations did not showed significant association with other clinical characteristics or treatment outcome. Since each mutation was rare, further study with a larger number of cases would be needed to establish the effect of the mutations.
  12. CPT Pharmacometrics Syst Pharmacol. 2020 Aug 29.
    Goliaei A, Woods HA, Tron AE, Belmonte MA, Secrist JP, Ferguson D, Drew L, Fretland AJ, Aldridge BB, Gibbons FD.
      Anti-cancer efficacy is driven not just by dose, but by frequency and duration of treatment. We describe a multi-scale model combining cell-cycle, cellular heterogeneity of Bcl2-family proteins, and pharmacology of AZD5991, a potent small-molecule inhibitor of Mcl1. The model was calibrated using in vitro viability data for the MV-4-11 acute myeloid leukemia (AML) cell line under continuous incubation for 72h, at concentrations 0.03-30μM. Using a virtual screen, we identified two schedules as having significantly different predicted efficacy, and showed experimentally that a 'short' schedule (treating cells for 6h out of 24) is significantly better able to maintain the rate of cell kill during treatment, than a 'long' one (18h out of 24). This work suggests that resistance can be driven by heterogeneity in protein expression of Mcl1 alone, without requiring mutation or resistant subclones, and demonstrates the utility of mathematical models in efficiently identifying regimens for experimental exploration.
  13. Cancer Lett. 2020 Aug 26. pii: S0304-3835(20)30432-8. [Epub ahead of print]
    Yang W, Liu S, Li Y, Wang Y, Deng Y, Sun W, Huang H, Xie J, He A, Chen H, Tao A, Yan J.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy that gradually develops resistance to current chemotherapy treatments. The available chemotherapy drugs show serious non-specific cytotoxicity to healthy normal cells, resulting in relapse and low survival rates. Natural small molecules with less toxicity and high selectivity for AML are urgently needed. In this study, we confirmed that pyridoxine (vitamin B6) selectively induces monocyte macrophages to undergo programmed cell death in two different modes: caspase-3-dependent apoptosis in U937 cells or GSDME-mediated pyroptosis in THP-1 cells. Further molecular analysis indicated that blocking the caspase pathway could switch the death to MLKL-dependent necroptosis and subsequent extensive inflammatory response. Pyridoxine also delayed the disease progression in a THP-1 leukemia mouse model. In addition, it induced the death of primary AML cells from AML patients by activating caspase-8/3. Overall, our results identify pyridoxine, a low-toxicity natural small molecule, as a potential therapeutic drug for AML treatment.
    Keywords:  AML; Apoptosis; Monocytes; Pyroptosis; Vitamin B6
  14. Bone Marrow Transplant. 2020 Sep 02.
    Rautenberg C, Bergmann A, Pechtel S, Fischermanns C, Haas R, Germing U, Kobbe G, Schroeder T.
      Hypomethylating agents (HMA) for relapsed acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) after allogeneic transplantation (allo-SCT) are most effective when used at the stage of molecular relapse. As Wilm's Tumor 1 (WT1)- expression has proven to serve as broadly applicable, sensitive and specific minimal residual disease (MRD) marker, we measured WT1-expression in 35 AML and MDS patients using a standardized assay for the guidance of therapy with HMA and donor lymphocyte infusions (DLI). Molecular relapse was detected in median 168 days post-transplant prompting therapy with a median of six HMA cycles and at least one DLI (n = 22, 63%). Hereby, 13 patients (37%) achieved major response (=MRD- complete remission [CR]), and 7 patients (20%) achieved minor response (=MRD+ CR), whereas 15 patients (43%) progressed into hematologic relapse. Two-year overall survival (OS) rate was 35% including 11 patients (31%) with ongoing MRD- remission for a median of 21 months. Patients with the major response after six cycles had significantly better OS suggesting that those not achieving MRD negativity after six cycles are candidates for alternative therapies. Combining MRD-monitoring of WT1-expression and preemptive therapy with HMA and DLI appears as a practicable and efficient approach for imminent relapse after allo-SCT.
  15. Clin Lymphoma Myeloma Leuk. 2020 Sep;pii: S2152-2650(20)30450-X. [Epub ahead of print]20 Suppl 1 S25-S26
    Pollyea DA.
      The developmental path for venetoclax in acute myeloid leukemia (AML) has been rapid and stands in stark contrast to the incremental progress that has characterized the field in previous decades. For perspective, on December 31, 2013, the first AML patient was enrolled into a study using venetoclax; 59 months later, on November 21, 2018, venetoclax received accelerated approval by the FDA for use in AML. In June 2020, Dr. DiNardo presented the results of the required confirmatory study at the European Hematology Association meeting, showing that venetoclax with azacitidine resulted in a superior response rate and overall survival compared to azacitidine alone for older, newly diagnosed AML patients. This swift progress has provided a welcome and potent new therapy for patients with AML; with it come questions about how its role can be expanded, and how its use can be optimized.
    Keywords:  BCL-2; fitness; hypomethylating agent; older; untreated
  16. Blood. 2020 Sep 01. pii: blood.2020005514. [Epub ahead of print]
    Shanmuganathan N, Pagani IS, Ross DM, Park S, Yong AS, Braley JA, Altamura HK, Hiwase DK, Yeung DT, Kim DW, Branford S, Hughes TP.
      With treatment-free remission (TFR) rapidly becoming the ultimate goal of therapy in chronic myeloid leukemia (CML), there is a need to develop strategies to maximise sustained TFR by improving our understanding of its key determinants. Chronic phase CML patients attempting TFR were evaluated to identify the impact of multiple variables on the probability of sustained TFR. Early molecular response dynamics were included as a predictive variable, assessed by calculating the patient-specific halving time of BCR-ABL1 after commencing tyrosine kinase inhibitor (TKI) therapy. Overall, 115 patients attempted TFR and had ≥12 months follow-up. The probability of sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, was 55%. The time taken for the BCR-ABL1 value to halve was the strongest independent predictor of sustained TFR: 80% in patients with a halving time of <9.35 days (first quartile) compared with only 4% if the halving time was >21.85 days (last quartile) (P<.001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR. A more rapid initial BCR-ABL1 decline after commencing TKI also correlated with an increased likelihood of achieving TFR eligibility. The association between sustained TFR and the time taken for BCR-ABL1 to halve after commencing TKI was validated using an independent dataset. These data support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.
  17. Clin Lymphoma Myeloma Leuk. 2020 Sep;pii: S2152-2650(20)30440-7. [Epub ahead of print]20 Suppl 1 S3-S4
    de Botton S.
    Keywords:  AML; IDH; inhibition