Publications by authors named "Steven Kornblau"

209 Publications

RPPA-based proteomics recognizes distinct epigenetic signatures in chronic lymphocytic leukemia with clinical consequences.

Leukemia 2021 Oct 8. Epub 2021 Oct 8.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The chronic lymphocytic leukemia (CLL) armamentarium has evolved significantly, with novel therapies that inhibit Bruton Tyrosine Kinase, PI3K delta and/or the BCL2 protein improving outcomes. Still, the clinical course of CLL patients is highly variable and most previously recognized prognostic features lack the capacity to predict response to modern treatments indicating the need for new prognostic markers. In this study, we identified four epigenetically distinct proteomic signatures of a large cohort of CLL and related diseases derived samples (n = 871) using reverse phase protein array technology. These signatures are associated with clinical features including age, cytogenetic abnormalities [trisomy 12, del(13q) and del(17p)], immunoglobulin heavy-chain locus (IGHV) mutational load, ZAP-70 status, Binet and Rai staging as well as with the outcome measures of time to treatment and overall survival. Protein signature membership was identified as predictive marker for overall survival regardless of other clinical features. Among the analyzed epigenetic proteins, EZH2, HDAC6, and loss of H3K27me3 levels were the most independently associated with poor survival. These findings demonstrate that proteomic based epigenetic biomarkers can be used to better classify CLL patients and provide therapeutic guidance.
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http://dx.doi.org/10.1038/s41375-021-01438-4DOI Listing
October 2021

Effective therapy of AML with RUNX1 mutation by co-treatment with inhibitors of protein translation and BCL2.

Blood 2021 Oct 3. Epub 2021 Oct 3.

MD Anderson Cancer Center, Houston, Texas, United States.

Majority of RUNX1 mutations in AML are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared to AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1 and c-Myc. Compared to AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. HHT treatment repressed enhancers and their BRD4 occupancy, as well as was associated with reduced levels of c-Myc, c-Myb, MCL1 and Bcl-xL. Consistent with this, co-treatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared to each agent alone, co-treatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.
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http://dx.doi.org/10.1182/blood.2021013156DOI Listing
October 2021

Single-cell Polyfunctional Proteomics of CD4 Cells from Patients with AML Predicts Responses to Anti-PD-1-based therapy.

Blood Adv 2021 Sep 23. Epub 2021 Sep 23.

MD Anderson Cancer Center, Houston, Texas, United States.

Acute myeloid leukemia (AML) remains a difficult disease to treat disease. In a phase 2 clinical trial in patients with relapsed/refractory AML, combining the hypomethylating agent, azacitidine, with the PD-1 checkpoint inhibitor, nivolumab, demonstrated encouraging response rates (33%), median event-free and overall survival, compared with a historical cohort of contemporary patients treated with azacitidine-based therapies, with an acceptable safety profile. Biomarkers of response are yet to be determined. In this study, we leveraged a multiplexed immune assay to assess the functional states of CD4+ and CD8+ cells at a single-cell level in pretherapy bone marrows in 16 patients with R/R AML treated with azacitidine/nivolumab. Effector CD4+ but not CD8+ cells had distinct polyfunctional groups and were associated with responses and better outcomes. Further evaluation of the polyfunctional strength index composition across cell types revealed that IFN-g and TNF-a were the major drivers of enhanced polyfunctionality index of pretherapy CD4+ subset, while Granzyme B, IFN-g, MIP-1b and TNF-a drove the non-significantly enhanced pretreatment PSI of CD8+ subset in the responders. Single cell polyfunctional assays were predictive of response in AML and may have a potential role as a biomarker in the wider sphere of immunotherapy.
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http://dx.doi.org/10.1182/bloodadvances.2021004583DOI Listing
September 2021

Identification of mutations that cooperate with defects in B cell transcription factors to initiate leukemia.

Oncogene 2021 Sep 17. Epub 2021 Sep 17.

Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA.

The transcription factors PAX5, IKZF1, and EBF1 are frequently mutated in B cell acute lymphoblastic leukemia (B-ALL). We demonstrate that compound heterozygous loss of multiple genes critical for B and T cell development drives transformation, including Pax5xEbf1, Pax5xIkzf1, and Ebf1xIkzf1 mice for B-ALL, or Tcf7xIkzf1 mice for T-ALL. To identify genetic defects that cooperate with Pax5 and Ebf1 compound heterozygosity to initiate leukemia, we performed a Sleeping Beauty (SB) transposon screen that identified cooperating partners including gain-of-function mutations in Stat5b (~65%) and Jak1 (~68%), or loss-of-function mutations in Cblb (61%) and Myb (32%). These findings underscore the role of JAK/STAT5B signaling in B cell transformation and demonstrate roles for loss-of-function mutations in Cblb and Myb in transformation. RNA-Seq studies demonstrated upregulation of a PDK1>SGK3>MYC pathway; treatment of Pax5xEbf1 leukemia cells with PDK1 inhibitors blocked proliferation in vitro. In addition, we identified a conserved transcriptional gene signature between human and murine leukemias characterized by upregulation of myeloid genes, most notably involving the GM-CSF pathway, that resemble a B cell/myeloid mixed-lineage leukemia. Thus, our findings identify multiple mechanisms that cooperate with defects in B cell transcription factors to generate either progenitor B cell or mixed B/myeloid-like leukemias.
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http://dx.doi.org/10.1038/s41388-021-02012-zDOI Listing
September 2021

Vecabrutinib inhibits B-cell receptor signal transduction in chronic lymphocytic leukemia cell types with wild-type or mutant Bruton's tyrosine kinase.

Haematologica 2021 Sep 9. Epub 2021 Sep 9.

Department of Experimental Therapeutics; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.

Not available.
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http://dx.doi.org/10.3324/haematol.2021.279158DOI Listing
September 2021

Decoupling Lineage-Associated Genes in Acute Myeloid Leukemia Reveals Inflammatory and Metabolic Signatures Associated With Outcomes.

Front Oncol 2021 4;11:705627. Epub 2021 Aug 4.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Acute myeloid leukemia (AML) is a heterogeneous disease with variable responses to therapy. Cytogenetic and genomic features are used to classify AML patients into prognostic and treatment groups. However, these molecular characteristics harbor significant patient-to-patient variability and do not fully account for AML heterogeneity. RNA-based classifications have also been applied in AML as an alternative approach, but transcriptomic grouping is strongly associated with AML morphologic lineages. We used a training cohort of newly diagnosed AML patients and conducted unsupervised RNA-based classification after excluding lineage-associated genes. We identified three AML patient groups that have distinct biological pathways associated with outcomes. Enrichment of inflammatory pathways and downregulation of pathways were associated with improved outcomes, and this was validated in 2 independent cohorts. We also identified a group of AML patients who harbored high metabolic and mTOR pathway activity, and this was associated with worse clinical outcomes. Using a comprehensive reverse phase protein array, we identified higher mTOR protein expression in the highly metabolic group. We also identified a positive correlation between degree of resistance to venetoclax and mTOR activation in myeloid and lymphoid cell lines. Our approach of integrating RNA, protein, and genomic data uncovered lineage-independent AML patient groups that share biologic mechanisms and can inform outcomes independent of commonly used clinical and demographic variables; these groups could be used to guide therapeutic strategies.
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http://dx.doi.org/10.3389/fonc.2021.705627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372368PMC
August 2021

Development of TP53 mutations over the course of therapy for acute myeloid leukemia.

Am J Hematol 2021 Nov 19;96(11):1420-1428. Epub 2021 Aug 19.

The Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

TP53 mutations in acute myeloid leukemia (AML) are associated with resistance to standard treatments and dismal outcomes. The incidence and prognostic impact of the emergence of newly detectable TP53 mutations over the course of AML therapy has not been well described. We retrospectively analyzed 200 patients with newly diagnosed TP53 wild type AML who relapsed after or were refractory to frontline therapy. Twenty-nine patients (15%) developed a newly detectable TP53 mutation in the context of relapsed/refractory disease. The median variant allelic frequency (VAF) was 15% (range, 1.1%-95.6%). TP53 mutations were more common after intensive therapy versus lower-intensity therapy (23% vs. 10%, respectively; p = 0.02) and in patients who had undergone hematopoietic stem cell transplant versus those who had not (36% vs. 12%, respectively; p = 0.005). Lower TP53 VAF was associated with an increased likelihood of complete remission (CR) or CR with incomplete hematologic recovery (CRi) compared to higher TP53 VAF (CR/CRi rate of 41% for VAF < 20% vs. 13% for VAF ≥ 20%, respectively). The median overall survival (OS) after acquisition of TP53 mutation was 4.6 months, with a 1-year OS rate of 19%. TP53 VAF at relapse was significantly associated with OS; the median OS of patients with TP53 VAF ≥ 20% was 3.5 months versus 6.1 months for those with TP53 VAF < 20% (p < 0.05). In summary, new TP53 mutations may be acquired throughout the course of AML therapy. Sequential monitoring for TP53 mutations is likely to be increasingly relevant in the era of emerging TP53-targeting therapies for AML.
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http://dx.doi.org/10.1002/ajh.26314DOI Listing
November 2021

Venetoclax plus intensive chemotherapy with cladribine, idarubicin, and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a cohort from a single-centre, single-arm, phase 2 trial.

Lancet Haematol 2021 Aug;8(8):e552-e561

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Addition of the BCL2 inhibitor venetoclax to lower intensity therapy has been shown to improve overall survival in older (aged 75 years or older) and unfit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to investigate the activity of venetoclax combined with intensive chemotherapy in patients aged 65 years or younger with acute myeloid leukaemia.

Methods: This cohort study was done at the MD Anderson Cancer Center in the USA, as part of the single-centre, single arm, phase 2, CLIA trial. Here we report on the independent cohort investigating the safety and activity of venetoclax added to intensive chemotherapy (the CLIA regimen [cladribine, high-dose cytarabine, idarubicin]). Eligible patients were aged 18-65 years with a new diagnosis of acute myeloid leukaemia, mixed phenotype acute leukaemia, or high-risk myelodysplastic syndrome (≥10% blasts or International Prognostic Scoring System ≥2 [intermediate]), who received no previous potentially curative therapy for leukaemia. Patients received cladribine (5 mg/m) and cytarabine (1·5 g/m for patients aged <60 years, 1 g/m for patients aged ≥60 years) intravenously on days 1-5 and idarubicin (10 mg/m) intravenously on days 1-3. Consolidation was cladribine (5 mg/m) and cytarabine (1 g/m for patients aged <60 years and 0·75 g/m for patients aged ≥60 years) on days 1-3 and idarubicin (8 mg/m) on days 1-2. Venetoclax (400 mg) was given on days 2-8 with each course. Patients with a known FLT3-ITD or FLT3-TKD mutation received midostaurin or gilteritinib. The primary outcome was composite complete response (complete response plus complete response with incomplete blood count recovery). Secondary outcomes were overall response, duration of response, event-free survival, overall survival, and safety. This trial was registered with ClinicalTrials.gov, NCT02115295.

Findings: Between Feb 25, 2019, and March 23, 2021, 77 patients were assessed for eligibility, 50 of whom were enrolled. Median age was 48 years (IQR 37-56). 47 (94% [95% CI 83-98]) patients had composite complete response, with the same proportion also having an overall response; two (4% [1-14]) patients did not respond, and one (2% [0-11]) patient died during induction. 37 (82% [95% CI 68-92]) of 45 patients had undetectable measurable residual disease (MRD). At a median follow-up of 13·5 months (IQR 6·4-19·5), the median duration of response, event-free survival, and overall survival were not reached. At 12 months, the estimated duration of response was 74% (95% CI 60-92), event-free survival was 68% (54-85), and overall survival was 85% (75-97). The most common adverse events of grade 3 or worse were febrile neutropenia (42 [84%] patients), infection (six [12%]), and alanine aminotransferase elevations (six [12%]). There was one death during induction in a patient treated with CLIA-venetoclax plus a FLT3 inhibitor. Two patients died of infectious complications while in complete response in consolidation cycles, both of whom had FLT3-mutated acute myeloid leukaemia and were receiving combined therapy with a FLT3 inhibitor. No deaths were deemed to be treatment related.

Interpretation: Venetoclax added to CLIA was safe and active in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, producing high rates of durable MRD-negative remissions and encouraging event-free survival and overall survival.

Funding: MD Anderson Cancer Center.
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http://dx.doi.org/10.1016/S2352-3026(21)00192-7DOI Listing
August 2021

BTK inhibition sensitizes Acute Lymphoblastic Leukemia to asparaginase by suppressing the Amino Acid Response pathway.

Blood 2021 Jul 19. Epub 2021 Jul 19.

Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.

Asparaginase (ASNase) therapy has been a mainstay of Acute Lymphoblastic Leukemia (ALL) protocols for decades and shows promise in the treatment of a variety of other cancers. To improve the efficacy of ASNase treatment, we employed a CRISPR/Cas9-based screen to identify actionable signaling intermediates that improve the response to ASNase. Both genetic inactivation of Bruton's Tyrosine Kinase (BTK) and pharmacological inhibition by the BTK inhibitor ibrutinib strongly synergize with ASNase by inhibiting the amino acid response pathway, a mechanism involving c-Myc mediated suppression of GCN2 activity. This synthetic lethal interaction was observed in 90% of patient derived xenografts, irrespective of the genomic subtype. Moreover, ibrutinib substantially improved ASNase treatment response in a murine PDX model. Hence, ibrutinib may be used to enhance the clinical efficacy of ASNase in ALL.
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http://dx.doi.org/10.1182/blood.2021011787DOI Listing
July 2021

Multivariate transcriptome analysis identifies networks and key drivers of chronic lymphocytic leukemia relapse risk and patient survival.

BMC Med Genomics 2021 06 29;14(1):171. Epub 2021 Jun 29.

Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, 720 Westview Dr SW, HG 341B, Atlanta, GA, 30310, USA.

Background: Chronic lymphocytic leukemia (CLL) is an indolent heme malignancy characterized by the accumulation of CD5 CD19 B cells and episodes of relapse. The biological signaling that influence episodes of relapse in CLL are not fully described. Here, we identify gene networks associated with CLL relapse and survival risk.

Methods: Networks were investigated by using a novel weighted gene network co-expression analysis method and examining overrepresentation of upstream regulators and signaling pathways within co-expressed transcriptome modules across clinically annotated transcriptomes from CLL patients (N = 203). Gene Ontology analysis was used to identify biological functions overrepresented in each module. Differential Expression of modules and individual genes was assessed using an ANOVA (Binet Stage A and B relapsed patients) or T-test (SF3B1 mutations). The clinical relevance of biomarker candidates was evaluated using log-rank Kaplan Meier (survival and relapse interval) and ROC tests.

Results: Eight distinct modules (M2, M3, M4, M7, M9, M10, M11, M13) were significantly correlated with relapse and differentially expressed between relapsed and non-relapsed Binet Stage A CLL patients. The biological functions of modules positively correlated with relapse were carbohydrate and mRNA metabolism, whereas negatively correlated modules to relapse were protein translation associated. Additionally, M1, M3, M7, and M13 modules negatively correlated with overall survival. CLL biomarkers BTK, BCL2, and TP53 were co-expressed, while unmutated IGHV biomarker ZAP70 and cell survival-associated NOTCH1 were co-expressed in modules positively correlated with relapse and negatively correlated with survival days.

Conclusions: This study provides novel insights into CLL relapse biology and pathways associated with known and novel biomarkers for relapse and overall survival. The modules associated with relapse and overall survival represented both known and novel pathways associated with CLL pathogenesis and can be a resource for the CLL research community. The hub genes of these modules, e.g., ARHGAP27P2, C1S, CASC2, CLEC3B, CRY1, CXCR5, FUT5, MID1IP1, and URAHP, can be studied further as new therapeutic targets or clinical markers to predict CLL patient outcomes.
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http://dx.doi.org/10.1186/s12920-021-01012-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243588PMC
June 2021

A phase 1b/2 study of azacitidine with PD-L1 antibody avelumab in relapsed/refractory acute myeloid leukemia.

Cancer 2021 Oct 25;127(20):3761-3771. Epub 2021 Jun 25.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. In preclinical models of AML, inhibition of the PD-1/PD-L1 axis demonstrated antileukemic activity. Avelumab is an anti-PD-L1 immune checkpoint inhibitor (ICI) approved in multiple solid tumors. The authors conducted a phase 1b/2 clinical trial to assess the safety and efficacy of azacitidine with avelumab in patients with R/R AML.

Methods: Patients aged ≥18 years who had R/R AML received azacitidine 75 mg/m on days 1 through 7 and avelumab on days 1 and 14 of 28-day cycles.

Results: Nineteen patients were treated. The median age was 66 years (range, 22-83 years), 100% had European LeukemiaNet 2017 adverse-risk disease, and 63% had prior exposure to a hypomethylating agent. Avelumab was dosed at 3 mg/kg for the first 7 patients and at 10 mg/kg for the subsequent 12 patients. The most common grade ≥3 treatment-related adverse events were neutropenia and anemia in 2 patients each. Two patients experienced immune-related adverse events of grade 2 and grade 3 pneumonitis, respectively. The overall complete remission rate was 10.5%, and both were complete remission with residual thrombocytopenia. The median overall survival was 4.8 months. Bone marrow blasts were analyzed for immune-related markers by mass cytometry and demonstrated significantly higher expression of PD-L2 compared with PD-L1 both pretherapy and at all time points during therapy, with increasing PD-L2 expression on therapy.

Conclusions: Although the combination of azacitidine and avelumab was well tolerated, clinical activity was limited. High expression of PD-L2 on bone marrow blasts may be an important mechanism of resistance to anti-PD-L1 therapy in AML.

Lay Summary: This report describes the results of a phase 1b/2 study of azacitidine with the anti-PD-L1 immune checkpoint inhibitor avelumab for patients with relapsed/refractory acute myeloid leukemia (AML). The clinical activity of the combination therapy was modest, with an overall response rate of 10.5%. However, mass cytometry analysis revealed significantly higher expression of PD-L2 compared with PD-L1 on AML blasts from all patients who were analyzed at all time points. These data suggest a novel potential role for PD-L2 as a means of AML immune escape.
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http://dx.doi.org/10.1002/cncr.33690DOI Listing
October 2021

Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia.

Nat Cancer 2021 Mar 21;2(3):284-299. Epub 2021 Jan 21.

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and novel therapeutics are much needed. Profiling patient leukemia' drug sensitivities , we discovered that 44.4% of childhood and 16.7% of adult T-ALL cases exquisitely respond to dasatinib. Applying network-based systems pharmacology analyses to examine signal circuitry, we identified preTCR-LCK activation as the driver of dasatinib sensitivity, and T-ALL-specific LCK dependency was confirmed in genome-wide CRISPR-Cas9 screens. Dasatinib-sensitive T-ALLs exhibited high BCL-XL and low BCL2 activity and venetoclax resistance. Discordant sensitivity of T-ALL to dasatinib and venetoclax is strongly correlated with T-cell differentiation, particularly with the dynamic shift in LCK vs. BCL2 activation. Finally, single-cell analysis identified leukemia heterogeneity in LCK and BCL2 signaling and T-cell maturation stage, consistent with dasatinib response. In conclusion, our results indicate that developmental arrest in T-ALL drives differential activation of preTCR-LCK and BCL2 signaling in this leukemia, providing unique opportunities for targeted therapy.
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http://dx.doi.org/10.1038/s43018-020-00167-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208590PMC
March 2021

Enhancer Hijacking Drives Oncogenic Expression in Lineage-Ambiguous Stem Cell Leukemia.

Cancer Discov 2021 Jun 8. Epub 2021 Jun 8.

Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.

Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of , a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to . Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed allele and association of with activated hematopoietic progenitor cell -regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. SIGNIFICANCE: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of driven by diverse structural alterations, including superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0145DOI Listing
June 2021

Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia.

J Clin Oncol 2021 Sep 27;39(25):2768-2778. Epub 2021 May 27.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML.

Materials And Methods: The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML.

Results: Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease-negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML.

Conclusion: Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation.
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http://dx.doi.org/10.1200/JCO.20.03736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407653PMC
September 2021

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells.

Blood Cancer J 2021 05 20;11(5):98. Epub 2021 May 20.

The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.
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http://dx.doi.org/10.1038/s41408-021-00487-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138012PMC
May 2021

Mesothelin is a novel cell surface disease marker and potential therapeutic target in acute myeloid leukemia.

Blood Adv 2021 05;5(9):2350-2361

Fred Hutchinson Cancer Research Center, Seattle, WA.

In an effort to identify acute myeloid leukemia (AML)-restricted targets for therapeutic development in AML, we analyzed the transcriptomes of 2051 children and young adults with AML and compared the expression profile with normal marrow specimens. This analysis identified a large cohort of AML-restricted genes with high expression in AML, but low to no expression in normal hematopoiesis. Mesothelin (MSLN), a known therapeutic target in solid tumors, was shown to be highly overexpressed in 36% of the AML cohort (range, 5-1077.6 transcripts per million [TPM]) and virtually absent in normal marrow (range, 0.1-10.7 TPM). We verified MSLN transcript expression by quantitative reverse transcription polymerase chain reaction, confirmed cell surface protein expression on leukemic blasts by multidimensional flow cytometry, and demonstrated that MSLN expression was associated with promoter hypomethylation. MSLN was highly expressed in patients with KMT2A rearrangements (P < .001), core-binding factor fusions [inv(16)/t(16;16), P < .001; t(8;21), P < .001], and extramedullary disease (P = .001). We also demonstrated the presence of soluble MSLN in diagnostic serum specimens using an MSLN-directed enzyme-linked immunosorbent assay. In vitro and in vivo preclinical efficacy of the MSLN-directed antibody-drug conjugates (ADCs) anetumab ravtansine and anti-MSLN-DGN462 were evaluated in MSLN+ leukemia cell lines in vitro and in vivo, as well as in patient-derived xenografts. Treatment with ADCs resulted in potent target-dependent cytotoxicity in MSLN+ AML. In this study, we demonstrate that MSLN is expressed in a significant proportion of patients with AML and holds significant promise as a diagnostic and therapeutic target in AML, and that MSLN-directed therapeutic strategies, including ADCs, warrant further clinical investigation.
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http://dx.doi.org/10.1182/bloodadvances.2021004424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114558PMC
May 2021

Venetoclax with decitabine vs intensive chemotherapy in acute myeloid leukemia: A propensity score matched analysis stratified by risk of treatment-related mortality.

Am J Hematol 2021 03 24;96(3):282-291. Epub 2020 Dec 24.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Hypomethylating agents (HMA) with venetoclax is a new standard for older/unfit patients with acute myeloid leukemia (AML). However, it is unknown how HMA with venetoclax compare to intensive chemotherapy (IC) in patients who are "fit" or "unfit" for IC. We compared outcomes of older patients with newly diagnosed AML receiving 10-day decitabine with venetoclax (DEC10-VEN) vs IC. DEC10-VEN consisted of daily venetoclax with decitabine 20 mg/m for 10 days for induction and decitabine for 5 days as consolidation. The IC cohort received regimens containing cytarabine ≥1 g/m /d. A validated treatment-related mortality score (TRMS) was used to classify patients at high-risk or low-risk for TRM with IC. Propensity scores were used to match patients to minimize bias. Median age of the DEC10-VEN cohort (n = 85) was 72 years (range 63-89) and 28% patients were at high-risk of TRM with IC. The comparator IC group (n = 85) matched closely in terms of baseline characteristics. DEC10-VEN was associated with significantly higher CR/CRi compared to IC (81% vs 52%, P < .001), and lower rate of relapse (34% vs 56%, P = .01), 30-day mortality (1% vs 24%, P < .01), and longer overall survival (OS; 12.4 vs 4.5 months, HR = 0.48, 95%CI 0.29-0.79, P < .01). In patients at both at high-risk and low-risk of TRM, DEC10-VEN showed significantly higher CR/CRi, lower 30-day mortality, and longer OS compared to IC. Patients at both high-risk and low-risk of TRM had comparable outcomes with DEC10-VEN. In conclusion, DEC10-VEN offers better outcomes compared to intensive chemotherapy in older patients with newly diagnosed AML, particularly in those at high-risk of TRM.
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http://dx.doi.org/10.1002/ajh.26061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128145PMC
March 2021

The effects of sample handling on proteomics assessed by reverse phase protein arrays (RPPA): Functional proteomic profiling in leukemia.

J Proteomics 2021 02 16;233:104046. Epub 2020 Nov 16.

Departments of Leukemia and Stem Cell Transplantation and Cellular Therapy, University of Texas, M.D. Anderson Cancer Center, Houston, TX, United States.

Reverse phase protein arrays (RPPA) can assess protein expression and activation states in large numbers of samples (n > 1000) and evidence suggests feasibility in the setting of multi-institution clinical trials. Despite evidence in solid tumors, little is known about protein stability in leukemia. Proteins collected from leukemia cells in blood and bone marrow biopsies must be sufficiently stable for analysis. Using 58 leukemia samples, we initially assessed protein/phospho-protein integrity for the following preanalytical variables: 1) shipping vs local processing, 2) temperature (4 °C vs ambient temperature), 3) collection tube type (heparin vs Cell Save (CS) preservation tubes), 4) treatment effect (pre- vs post-chemotherapy) and 5) transit time. Next, we assessed 1515 samples from the Children's Oncology Group Phase 3 AML clinical trial (AAML1031, NCT01371981) for the effects of transit time and tube type. Protein expression from shipped blood samples was stable if processed in ≤72 h. While protein expression in pre-chemotherapy samples was stable in both heparin and CS tubes, post-chemotherapy samples were stable in only CS tubes. RPPA protein extremes is a successful quality control measure to identify and exclude poor quality samples. These data demonstrate that a majority of shipped proteins can be accurately assessed using RPPA. SIGNIFICANCE: RPPA can assess protein abundance and activation states in large numbers of samples using small amounts of material, making this method ideal for use in multi-institution clinical trials. However, there is little known about the effect of preanalytical handling variables on protein stability and the integrity of protein concentrations after sample collection and shipping. In this study, we used RPPA to assess preanalytical variables that could potentially affect protein concentrations. We found that the preanalytical variables of shipping, transit time, and temperature had minimal effects on RPPA protein concentration distributions in peripheral blood and bone marrow, demonstrating that these preanalytical variables could be successfully managed in a multi-site clinical trial setting.
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http://dx.doi.org/10.1016/j.jprot.2020.104046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877245PMC
February 2021

Heat shock factor 1 (HSF1-pSer326) predicts response to bortezomib-containing chemotherapy in pediatric AML: a COG report.

Blood 2021 02;137(8):1050-1060

Department of Pediatrics, Baylor College of Medicine/Dan L. Duncan Cancer Center and Texas Children's Cancer and Hematology Centers, Houston, TX.

Bortezomib (BTZ) was recently evaluated in a randomized phase 3 clinical trial by the Children's Oncology Group (COG) that compared standard chemotherapy (cytarabine, daunorubicin, and etoposide [ADE]) vs standard therapy with BTZ (ADEB) for de novo pediatric acute myeloid leukemia (AML). Although the study concluded that BTZ did not improve outcome overall, we examined patient subgroups benefiting from BTZ-containing chemotherapy using proteomic analyses. The proteasome inhibitor BTZ disrupts protein homeostasis and activates cytoprotective heat shock responses. Total heat shock factor 1 (HSF1) and phosphorylated HSF1 (HSF1-pSer326) were measured in leukemic cells from 483 pediatric patients using reverse phase protein arrays. HSF1-pSer326 phosphorylation was significantly lower in pediatric AML compared with CD34+ nonmalignant cells. We identified a strong correlation between HSF1-pSer326 expression and BTZ sensitivity. BTZ significantly improved outcome of patients with low-HSF1-pSer326 with a 5-year event-free survival of 44% (ADE) vs 67% for low-HSF1-pSer326 treated with ADEB (P = .019). To determine the effect of HSF1 expression on BTZ potency in vitro, cell viability with HSF1 gene variants that mimicked phosphorylated (S326A) and nonphosphorylated (S326E) HSF1-pSer326 were examined. Those with increased HSF1 phosphorylation showed clear resistance to BTZ vs those with wild-type or reduced HSF1-phosphorylation. We hypothesize that HSF1-pSer326 expression could identify patients who benefit from BTZ-containing chemotherapy.
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http://dx.doi.org/10.1182/blood.2020005208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907722PMC
February 2021

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial.

Lancet Haematol 2020 Oct 5;7(10):e724-e736. Epub 2020 Sep 5.

Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Venetoclax combined with hypomethylating agents is a new standard of care for newly diagnosed patients with acute myeloid leukaemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine that has shown promising results in patients with high-risk AML in phase 2 trials. We hypothesised that venetoclax with 10-day decitabine could have improved activity in patients with newly diagnosed AML and those with relapsed or refractory AML, particularly in high-risk subgroups.

Methods: This single centre, phase 2 trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). The study enrolled older patients (aged >60 years) with newly diagnosed AML, not eligible for intensive chemotherapy; secondary AML (progressed after myelodysplastic syndrome or chronic myelomonocytic leukaemia); and relapsed or refractory AML. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or less, white blood cell count less than 10 × 10 per L, and adequate end-organ function. Patients with favourable-risk cytogenetics (eg, t[15;17] or core-binding factor AML) or who had received previous BCL2-inhibitor therapy were excluded. Patients received decitabine 20 mg/m intravenously for 10 days with oral venetoclax 400 mg daily for induction, followed by decitabine for 5 days with daily venetoclax for consolidation. The primary endpoint was overall response rate. The secondary endpoints analysed within this report include safety, overall survival, and duration of response, in keeping with recommendations of European LeukemiaNet 2017 guidelines. All patients who received at least one dose of treatment were eligible for safety and response assessments. The trial was registered on ClinicalTrials.gov (NCT03404193) and continues to accrue patients.

Findings: Between Jan 19, 2018, and Dec 16, 2019, we enrolled 168 patients; 70 (42%) had newly diagnosed AML, 15 (9%) had untreated secondary AML, 28 (17%) had treated secondary AML, and 55 (33%) had relapsed or refractory AML. The median age was 71 years (IQR 65-76) and 30% of patients had ECOG performance status of 2 or higher. The median follow-up for all patients was 16 months (95% CI 12-18; actual follow-up 6·5 months; IQR 3·4-12·4). The overall response rate was 74% (125 of 168 patients; 95% CI 67-80) and in disease subgroups were: 89% in newly diagnosed AML (62 of 70 patients; 79-94), 80% in untreated secondary AML (12 of 15 patients; 55-93), 61% in treated secondary AML (17 of 28 patients; 42-76), and 62% in relapsed or refractory AML (34 of 55 patients; 49-74). The most common treatment-emergent adverse events included infections with grades 3 or 4 neutropenia (n=79, 47%) and febrile neutropenia (n=49, 29%). 139 (83%) of 168 patients had serious adverse events, most frequently neutropenic fever (n=63, 38%), followed by pneumonia (n=17, 10%) and sepsis (n=16, 10%). The 30-day mortality for all patients was 3·6% (n=6, 95% CI 1·7-7·8). The median overall survival was 18·1 months (95% CI 10·0-not reached) in newly diagnosed AML, 7·8 months (2·9-10·7) in untreated secondary AML, 6·0 months (3·4-13·7) in treated secondary AML, and 7·8 months (5·4-13·3) relapsed or refractory AML. The median duration of response was not reached (95% CI 9·0-not reached) in newly diagnosed AML, 5·1 months (95% CI 0·9-not reached) in untreated secondary AML, not reached (95% CI 2·5-not reached) in previously treated secondary AML, and 16·8 months (95% CI 6·6-not reached) in relapsed or refractory AML.

Interpretation: Venetoclax with 10-day decitabine has a manageable safety profile and showed high activity in newly diagnosed AML and molecularly defined subsets of relapsed or refractory AML. Future larger and randomised studies are needed to clarify activity in high-risk subsets.

Funding: US National Institutes of Health and National Cancer Institute.
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http://dx.doi.org/10.1016/S2352-3026(20)30210-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549397PMC
October 2020

Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia.

Nat Cancer 2020 Mar 9;1(3):329-344. Epub 2020 Mar 9.

Division of Hematology and Department of Internal Medicine, Mayo Clinic., Rochester, Minnesota, USA.

Identification of genomic and epigenomic determinants of drug resistance provides important insights for improving cancer treatment. Using agnostic genome-wide interrogation of mRNA and miRNA expression, DNA methylation, SNPs, CNAs and SNVs/Indels in primary human acute lymphoblastic leukemia cells, we identified 463 genomic features associated with glucocorticoid resistance. Gene-level aggregation identified 118 overlapping genes, 15 of which were confirmed by genome-wide CRISPR screen. Collectively, this identified 30 of 38 (79%) known glucocorticoid-resistance genes/miRNAs and all 38 known resistance pathways, while revealing 14 genes not previously associated with glucocorticoid-resistance. Single cell RNAseq and network-based transcriptomic modelling corroborated the top previously undiscovered gene, CELSR2. Manipulation of CELSR2 recapitulated glucocorticoid resistance in human leukemia cell lines and revealed a synergistic drug combination (prednisolone and venetoclax) that mitigated resistance in mouse xenograft models. These findings illustrate the power of an integrative genomic strategy for elucidating genes and pathways conferring drug resistance in cancer cells.
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http://dx.doi.org/10.1038/s43018-020-0037-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467080PMC
March 2020

Survivorship in AML - a landmark analysis on the outcomes of acute myelogenous leukemia patients after maintaining complete remission for at least 3 years.

Leuk Lymphoma 2020 12 5;61(13):3120-3127. Epub 2020 Aug 5.

Georgia Cancer Center, Augusta University, Augusta, GA, USA.

Acute myeloid leukemia (AML) carries poor survival and high recurrence rate. We conducted a retrospective analysis of AML patients ( = 453) treated with chemotherapy only or chemotherapy + hematopoietic cell transplant (HCT) who maintained their first complete remission (CR) for ≥3 years. Prior comorbidities, new comorbidities, secondary malignancies, late relapse, and causes of death (COD) were documented. New comorbidities for chemotherapy only patients ( = 304) included renal disease (10%), and osteopenia/osteoporosis (38%) for HCT patients ( = 149). Incidence of hypertension was similar in the chemotherapy only cohort and chemotherapy + HCT cohort (14% vs 17%). Secondary malignancies occurred in 13%, commonly skin, prostate and breast cancers. Common COD included: secondary malignancy (4%), HCT complications (3%), and late relapses (5%). Overall, 12% had a late relapse. Median overall survival for chemotherapy only and HCT was 10.7 and 12.7 years, respectively. Long-term AML survivors need routine monitoring for comorbidities, secondary malignancies, and late relapses.
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http://dx.doi.org/10.1080/10428194.2020.1802450DOI Listing
December 2020

RSK inhibitor BI-D1870 inhibits acute myeloid leukemia cell proliferation by targeting mitotic exit.

Oncotarget 2020 Jun 23;11(25):2387-2403. Epub 2020 Jun 23.

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.

The 90 kDa Ribosomal S6 Kinase (RSK) drives cell proliferation and survival in cancers, although its oncogenic mechanism has not been well characterized. Phosphorylated level of RSK (T573) was increased in acute myeloid leukemia (AML) patients and associated with poor survival. To examine the role of RSK in AML, we analyzed apoptosis and the cell cycle profile following treatment with BI-D1870, a potent inhibitor of RSK. BI-D1870 treatment increased the G2/M population and induced apoptosis in AML cell lines and patient AML cells. Characterization of mitotic phases showed that the metaphase/anaphase transition was significantly inhibited by BI-D1870. BI-D1870 treatment impeded the association of activator CDC20 with APC/C, but increased binding of inhibitor MAD2 to CDC20, preventing mitotic exit. Moreover, the inactivation of spindle assembly checkpoint or MAD2 knockdown released cells from BI-D1870-induced metaphase arrest. Therefore, we investigated whether BI-D1870 potentiates the anti-leukemic activity of vincristine by targeting mitotic exit. Combination treatment of BI-D1870 and vincristine synergistically increased mitotic arrest and apoptosis in acute leukemia cells. These data show that BI-D1870 induces apoptosis of AML cells alone and in combination with vincristine through blocking mitotic exit, providing a novel approach to overcoming vincristine resistance in AML cells.
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http://dx.doi.org/10.18632/oncotarget.27630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321696PMC
June 2020

Phase II trial of CPX-351 in patients with acute myeloid leukemia at high risk for induction mortality.

Leukemia 2020 11 16;34(11):2914-2924. Epub 2020 Jun 16.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

CPX-351 is a liposomal formulation of cytarabine/daunorubicin with a 5:1 fixed molar ratio. We investigated the safety and efficacy of escalating doses of CPX-351 in patients with acute myeloid leukemia (AML) at high risk of induction mortality with standard chemotherapy determined through assessment of leukemia and patient-related risk factors for intensive chemotherapy in an open-label, phase II trial. Patients were randomized to receive 50 or 75 units/m on days 1, 3, and 5. Once safety was established, a 100 units/m arm was opened. Fifty-six patients were enrolled, 16, 24, and 16 in the 50, 75, and 100 units/m arms, respectively. The composite complete remission rate (complete remission + complete remission with incomplete blood count recovery) was lowest with 50 units/m (19%) compared with 75 units/m (38%) and 100 units/m (44%) (P = 0.35). The 50 units/m arm had a median OS of 4.3 months, compared with 8.6 and 6.2 months for the 75 and 100 units/m respectively (P = 0.04). Nonhematologic grade 3/4 treatment-emergent adverse events included febrile neutropenia (34%), pneumonia (23%), and sepsis (16%). CPX-351 at 75 units/m has favorable safety and efficacy for AML patients at high risk of induction mortality with some tolerating the standard dose of 100 units/m.
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http://dx.doi.org/10.1038/s41375-020-0916-8DOI Listing
November 2020

Ultra-accurate Duplex Sequencing for the assessment of pretreatment ABL1 kinase domain mutations in Ph+ ALL.

Blood Cancer J 2020 05 26;10(5):61. Epub 2020 May 26.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Mutations of ABL1 are the dominant mechanism of relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). We performed highly accurate Duplex Sequencing of exons 4-10 of ABL1 on bone marrow or peripheral blood samples from 63 adult patients with previously untreated Ph + ALL who received induction with intensive chemotherapy plus a BCR-ABL1 TKI. We identified ABL1 mutations prior to BCR-ABL1 TKI exposure in 78% of patients. However, these mutations were generally present at extremely low levels (median variant allelic frequency 0.008% [range, 0.004%-3.71%] and did not clonally expand and lead to relapse in any patient, even when the pretreatment mutation was known to confer resistance to the TKI received. In relapse samples harboring a TKI-resistant ABL1 mutation, the corresponding mutation could not be detected pretreatment, despite validated sequencing sensitivity of Duplex Sequencing down to 0.005%. In samples under the selective pressure of ongoing TKI therapy, we detected low-level, emerging resistance mutations up to 5 months prior to relapse. These findings suggest that pretreatment ABL1 mutation assessment should not guide upfront TKI selection in Ph + ALL, although serial testing while on TKI therapy may allow for early detection of clinically actionable resistant clones.
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http://dx.doi.org/10.1038/s41408-020-0329-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250857PMC
May 2020

Clinical value of event-free survival in acute myeloid leukemia.

Blood Adv 2020 04;4(8):1690-1699

Department of Leukemia and.

The value of event-free survival (EFS) as an end point in acute myeloid leukemia (AML) trials has been questioned. We hypothesized that rather than a surrogate for overall survival (OS), improvement in EFS may decrease the use of health care. In this retrospective study, we identified 400 patients with AML who were treated on first-line therapy trials and had OS between 2 and 36 months. We captured health care use from diagnosis until death or until the patient was censored at stem cell transplantation (SCT). We used correlation and regression analysis to determine the relation between health care use and EFS. Among patients with newly diagnosed AML, 35% had adverse-risk AML, 48% received intensive chemotherapy, and 28% received hypomethylating agents. The median EFS censored at SCT was 9.7 months. Longer EFS led to a significant decline in health care use regardless of OS. This held true for all observations, including overall health care use (r = -0.45), sum of clinic visits, emergency room visits, hospitalizations, consultations (r = -0.44), sum of invasive procedures, laboratory and imaging studies (r = -0.51), and blood product transfusions (r = -0.19). These correlations were stronger for patients who achieved a complete remission and held true across age, treatment, and disease risk subgroups. In patients with newly diagnosed AML, improvement in EFS correlates with a decrease in all health care use irrespective of OS duration.
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http://dx.doi.org/10.1182/bloodadvances.2019001150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189295PMC
April 2020

Targeted next-generation sequencing of circulating cell-free DNA vs bone marrow in patients with acute myeloid leukemia.

Blood Adv 2020 04;4(8):1670-1677

Department of Leukemia and.

Circulating cell-free DNA (ccfDNA) allows for noninvasive peripheral blood sampling of cancer-associated mutations and has established clinical utility in several solid tumors. We performed targeted next-generation sequencing of ccfDNA and bone marrow at the time of diagnosis and after achieving remission in 22 patients with acute myeloid leukemia (AML). Among 28 genes sequenced by both platforms, a total of 39 unique somatic mutations were detected. Five mutations (13%) were detected only in ccfDNA, and 15 (38%) were detected only in bone marrow. Among the 19 mutations detected in both sources, the concordance of variant allelic frequency (VAF) assessment by both methods was high (R2 = 0.849). Mutations detected in only 1 source generally had lower VAF than those detected in both sources, suggesting that either method may miss small subclonal populations. In 3 patients, sequencing of ccfDNA detected new or persistent leukemia-associated mutations during remission that appeared to herald overt relapse. Overall, this study demonstrates that sequencing of ccfDNA in patients with AML can identify clinically relevant mutations not detected in the bone marrow and may play a role in the assessment of measurable residual disease. However, mutations were missed by both ccfDNA and bone marrow analyses, particularly when the VAF was <10%, suggesting that ccfDNA and bone marrow may be complementary in the assessment and monitoring of patients with AML.
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http://dx.doi.org/10.1182/bloodadvances.2019001156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189293PMC
April 2020

The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability.

Sci Transl Med 2020 04;12(538)

Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.

Neurolysin (NLN) is a zinc metallopeptidase whose mitochondrial function is unclear. We found that NLN was overexpressed in almost half of patients with acute myeloid leukemia (AML), and inhibition of NLN was selectively cytotoxic to AML cells and stem cells while sparing normal hematopoietic cells. Mechanistically, NLN interacted with the mitochondrial respiratory chain. Genetic and chemical inhibition of NLN impaired oxidative metabolism and disrupted the formation of respiratory chain supercomplexes (RCS). Furthermore, NLN interacted with the known RCS regulator, LETM1, and inhibition of NLN disrupted LETM1 complex formation. RCS were increased in patients with AML and positively correlated with NLN expression. These findings demonstrate that inhibiting RCS formation selectively targets AML cells and stem cells and highlights the therapeutic potential of pharmacologically targeting NLN in AML.
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http://dx.doi.org/10.1126/scitranslmed.aaz8264DOI Listing
April 2020
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