Publications by authors named "Eunice S Wang"

154 Publications

Prediction of Life-threatening and Disabling Bleeding in Patients with AML Receiving Intensive Induction Chemotherapy.

Blood Adv 2022 Jan 26. Epub 2022 Jan 26.

Dana-Farber Cancer Institute, Boston, Massachusetts, United States.

Bleeding in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy is multifactorial and contributes to early death. We sought to define incidence and risk factors of grade 4 bleeding to support strategies for risk mitigation. Bleeding events were retrospectively assessed between day-14 and day+60 of induction treatment according to the WHO bleeding assessment scale, which includes grade 4 bleeding as fatal, life-threatening, retinal with visual impairment, or involving the central nervous system. Predictors were considered pretreatment or prior to grade 4 bleeding. Using multivariable competing-risk regression analysis with grade 4 bleeding as the primary outcome, we identified risk factors in the development cohort (n=341), which were tested in an independent cohort (n=143). Grade 4 bleeding occurred in 5.9% and 9.8% of patients in the development and validation cohort, respectively. Risk factors that were independently associated with grade 4 bleeding included baseline platelet count <40 x109/L compared with >40 x109/L, and baseline PT-INR >1.5 or >1.3-1.5 compared with <1.3. These variables were allocated points, which allowed for stratification of patients with low- and high-risk for grade 4 bleeding. Cumulative incidence of grade 4 bleeding at day+60 was significantly higher among patients with high- versus low-risk (development: 31+7% vs. 2+1%, P<0.001, validation: 25+9% vs. 7+2%, P=0.008). In both cohorts, high bleeding risk was associated with disseminated intravascular coagulation (DIC) and proliferative disease. We developed and validated a simple risk model for grade 4 bleeding, which enables development of rational risk mitigation strategies to improve early mortality of intensive induction treatment.
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http://dx.doi.org/10.1182/bloodadvances.2021006166DOI Listing
January 2022

Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial.

Blood 2022 Jan 26. Epub 2022 Jan 26.

Johns Hopkins University, Baltimore, Maryland, United States.

The phase 3 ADMIRAL trial demonstrated superior overall survival (OS) in relapsed/refractory FLT3-mutation-positive acute myeloid leukemia patients randomized 2:1 to the oral FLT3 inhibitor, gilteritinib, versus those randomized to salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203/247 and 97/124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-arm patients remained on treatment. The median OS for gilteritinib and SC arms was 9.3 and 5.6 months, respectively (HR=0.665; 95% CI: 0.518, 0.853; two-sided P=0.0013); 2-year estimated survival rates were 20.6% (95% CI: 15.8, 26.0) and 14.2% (95% CI: 8.3, 21.6), respectively. The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49/247 patients in the gilteritinib arm and 14/124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-arm patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (HSCT) and 16 restarted gilteritinib as post-HSCT maintenance therapy. Most common adverse events (AEs) of interest during Years 1 and 2 of gilteritinib therapy were increased liver transaminases; AE incidence decreased in Year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival versus SC. www.clinicaltrials.gov NCT02997202.
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http://dx.doi.org/10.1182/blood.2021011583DOI Listing
January 2022

Menin Inhibitors in Acute Myeloid Leukemia-What Does the Future Hold?

Cancer J 2022 Jan-Feb 01;28(1):62-66

From the Department of Leukemia, Roswell Park Comprehensive Cancer Center, Buffalo, NY.

Abstract: Menin inhibitors constitute a novel class of agents targeting the underlying biology of nucleophosmin (NPM1) mutant and KMT2A (formerly known as MLL1) rearranged (KMT2Ar) acute leukemias. KMT2Ar acute leukemias constitute 5% to 10% of acute leukemias, and NPM1 mutations are identified in 30% of newly diagnosed acute myeloid leukemias (AMLs). In preclinical AML models, small molecule inhibitors of the menin-KMT2A protein-protein interaction induce differentiation, downregulate critical gene expression programs, and confer a survival advantage in patient-derived xenograft models of NPM1 mutant and KMT2Ar AML. Multiple clinical trials evaluating oral menin inhibitors in acute leukemias are ongoing. Preliminary results in relapsed/refractory NPM1 mutant and KMT2Ar AML have shown on-target effects, tolerable toxicity, and promising clinical activity. This review details the current clinical experience of menin inhibitors in AML and discusses how these agents can be successfully integrated into future therapeutic approaches.
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http://dx.doi.org/10.1097/PPO.0000000000000571DOI Listing
January 2022

Mutant - and -Driven Hematopoiesis Populates the Hematopoietic Compartment in Response to Peptide Receptor Radionuclide Therapy.

JCO Precis Oncol 2022 Jan;6:e2100309

Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN.

Purpose: Hematologic toxic effects of peptide receptor radionuclide therapy (PRRT) can be permanent. Patients with underlying clonal hematopoiesis (CH) may be more inclined to develop hematologic toxicity after PRRT. However, this association remains understudied.

Materials And Methods: We evaluated pre- and post-PRRT blood samples of patients with neuroendocrine tumors. After initial screening, 13 cases of interest were selected. Serial blood samples were obtained on 4 of 13 patients. Genomic DNA was analyzed using a 100-gene panel. A variant allele frequency cutoff of 1% was used to call CH.

Result: Sixty-two percent of patients had CH at baseline. Persistent cytopenias were noted in 64% (7 of 11) of the patients. Serial sample analysis demonstrated that PRRT exposure resulted in clonal expansion of mutant DNA damage response genes (, , and ) and accompanying cytopenias in 75% (3 of 4) of the patients. One patient who had a normal baseline hemogram and developed persistent cytopenias after PRRT exposure showed expansion of mutant (variant allele frequency increased to 20% after exposure from < 1% at baseline). In the other two patients, expansion of mutant , , and clones was also noted along with cytopenia development.

Conclusion: The shifts in hematopoietic clonal dynamics in our study were accompanied by emergence and persistence of cytopenias. These cytopenias likely represent premalignant state, as -, -, and -mutant clones by themselves carry a high risk for transformation to therapy-related myeloid neoplasms. Future studies should consider CH screening and longitudinal monitoring as a key risk mitigation strategy for patients with neuroendocrine tumors receiving PRRT.
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http://dx.doi.org/10.1200/PO.21.00309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769150PMC
January 2022

BCOR and BCORL1 mutations drive epigenetic reprogramming and oncogenic signaling by unlinking PRC1.1 from target genes.

Blood Cancer Discov 2021 Dec 17. Epub 2021 Dec 17.

Medical Oncology, Dana-Farber Cancer Institute

Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. Unlike polycomb repressive complex 2 (PRC2), the role of PRC1 in oncogenesis and therapy resistance is not well defined. Here, we demonstrate that highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a non-canonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin targeting auxiliary subcomplex. As a result, BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. We define a set of functional targets that drive aberrant oncogenic signaling programs in PRC1.1 mutated cells and primary patient samples. Activation of these PRC1.1 targets in BCOR-mutated cells confers acquired resistance to treatment while sensitizing to targeted kinase inhibition. Our study thus reveals a novel epigenetic mechanism that explains PRC1.1 tumor suppressive activity and identifies a therapeutic strategy in PRC1.1 mutated cancer.
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http://dx.doi.org/10.1158/2643-3230.BCD-21-0115DOI Listing
December 2021

Emerging trends of therapy related myeloid neoplasms following modern cancer therapeutics in the United States.

Sci Rep 2021 12 2;11(1):23284. Epub 2021 Dec 2.

Department of Medicine-Hematology, University of Tennessee Health Science Center, Memphis, TN, USA.

Clonal hematopoiesis (CH) is a risk factor for the development of therapy-related myelodysplastic syndromes (tMDS) and acute myeloid leukemia (tAML). Adoption of targeted-immunotherapeutics since 2011, may alter the risk of CH progression to tMDS/AML. To study this, we evaluated risk of tMDS and tAML in 667 588 ≥ 1-year survivors of non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma and multiple-myeloma (MM) diagnosed during: 2000-2005, 2006-2010 and 2011-2016. The risk of tMDS increased significantly after NSCLC across all time periods (P = 0.002) while tAML risk decreased from 2006-2010 to 2011-2016, coinciding with increasing use of non-chemotherapeutic agents. tAML risk after RCC decreased (P = 0.007) whereas tMDS risk did not significantly change over time. After melanoma, tMDS and tAML risks were similar to the general population. tMDS and tAML risk after MM increased from the first to second time-period, however, only risk of tMDS decreased during last period. We report diverging trends in the risk of tAML and tMDS after adoption of modern cancer therapies for specific cancers. It is imperative to further explore impact of contemporary treatment strategies on clonal evolution. Modern treatments via their discrete mechanism of actions on pre-existing CH may alter the risk of subsequent tMDS and tAML.
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http://dx.doi.org/10.1038/s41598-021-02497-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639740PMC
December 2021

Molecular associations, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia (Alliance).

Blood Adv 2021 Nov 30. Epub 2021 Nov 30.

The Ohio State University, United States.

Prognostic factors associated with chemotherapy outcomes in patients with acute myeloid leukemia (AML) are extensively reported, and one gene whose mutation is recognized as conferring resistance to several newer targeted therapies is protein tyrosine phosphatase non-receptor type 11 (PTPN11). The broader clinical implications of PTPN11 mutations in AML are still not well understood. The objective of this study was to determine which cytogenetic abnormalities and gene mutations co-occur with PTPN11 mutations and how PTPN11 mutations impact outcomes of patients treated with intensive chemotherapy. We studied 1,725 newly diagnosed AML patients (excluding acute promyelocytic leukemia) enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. In 140 PTPN11-mutated patient samples, PTPN11 most commonly co-occurred with mutations in NPM1, DNMT3A, and TET2. PTPN11 mutations were relatively common in patients with an inv(3)(q21q26)/t(3;3)(q21;q26) and a normal karyotype but were very rare in patients with typical complex karyotype and core-binding factor AML. Mutations in the N-terminal SH2 domain of PTPN11 were associated with a higher early death rate than those in the phosphatase domain. PTPN11 mutations did not affect outcomes of NPM1-mutated patients, but these patients were less likely to have co-occurring kinase mutations (i.e., FLT3-ITD), suggesting activation of overlapping signaling pathways. However, in AML patients with wild-type NPM1, PTPN11 mutations were associated with adverse patient outcomes providing a rationale to study the biology and treatment approaches in this molecular group.
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http://dx.doi.org/10.1182/bloodadvances.2021006242DOI Listing
November 2021

Eosinophilia characterized by a rare CCT6B mutation and responsive to tyrosine kinase inhibition: Case report and literature review.

Leuk Res Rep 2021 2;16:100279. Epub 2021 Nov 2.

Department of Medicine, Section of Hematology, Roswell Park Comprehensive Cancer Centre, Buffalo, United States of America.

Hypereosinophilic syndrome is a rare disorder arising from neoplastic, or idiopathic causes. The availability of NGS panels has increasingly identified rare mutations as underlying pathogenic events and have led to reclassification of cases of idiopathic hypereosinophilic syndrome as chronic eosinophilic leukemia(CEL). In this report, we describe a case of a young man with hypereosinophilia whose disease initially did not fit the WHO criteria for CEL but harbored a rare mutation in gene. We report our experience in successfully treating this patient with multiple tyrosine kinase inhibitors and provide literature review of this rare entity including potential treatment strategies.
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http://dx.doi.org/10.1016/j.lrr.2021.100279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602046PMC
November 2021

Targeting acute myeloid leukemia through multimodal immunotherapeutic approaches.

Leuk Lymphoma 2021 Nov 25:1-10. Epub 2021 Nov 25.

Departments of Medicine and Immunology, Leukemia Service, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a dismal prognosis. Immunotherapeutic approaches using single agent checkpoint inhibitors have thus far shown limited success. We hypothesized that successful adaptive anti-AML specific immune responses require additional modulation of innate immunity. DMXAA exposure resulted in modest apoptosis of C1498 AML cells with a subtle increase in PD-L1 expression and limited production of IL-6 and IFN-β. In contrast, DMXAA + anti-PD-1 ab, but not either agent alone, significantly decreased disease burden and prolonged overall survival in C1498 engrafted leukemic mice. Combination-treated mice demonstrated increased memory T-cells and mature dendritic cells, lower numbers of regulatory T-cells and evidence of leukemia apoptosis. Furthermore, these effects were associated with markedly increased serum levels of type I interferon (IFN) and IFN gamma. We demonstrate that combining an innate immune agonist with a checkpoint inhibitor synergistically improved anti-tumor activity in a preclinical AML model.
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http://dx.doi.org/10.1080/10428194.2021.1992614DOI Listing
November 2021

Harnessing the benefits of available targeted therapies in acute myeloid leukaemia.

Lancet Haematol 2021 Dec 20;8(12):e922-e933. Epub 2021 Oct 20.

Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA.

Research has resulted in regulatory approval of nine agents for acute myeloid leukaemia indications by the US Food and Drug Administration since 2017: the Bcl-2 inhibitor, venetoclax; two FLT3 inhibitors, midostaurin and gilteritinib; two IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor); the anti-CD33 antibody-drug conjugate, gemtuzumab ozogamicin; the oral, poorly absorbable hypomethylating agent, azacitidine; the liposomal formulation of cytarabine and daunorubicin (5:1 ratio), CPX-351; and the hedgehog signalling pathway inhibitor, glasdegib. A 100% absorbable oral formulation of the hypomethylating agent decitabine was approved for the treatment of myelodysplastic syndrome and chronic myelomonocytic leukaemia, and might be used as an alternative to parenteral hypomethylating agents. Several of the approvals are as single-agent therapies or in specific combinations for narrow indications, thus offering poor treatment value. In this Review, we discuss ongoing research into combinations containing these commercially available targeted therapies for acute myeloid leukaemia.
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http://dx.doi.org/10.1016/S2352-3026(21)00270-2DOI Listing
December 2021

Multisite 11-year experience of less-intensive vs intensive therapies in acute myeloid leukemia.

Blood 2021 08;138(5):387-400

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.
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http://dx.doi.org/10.1182/blood.2020008812DOI Listing
August 2021

Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia.

Haematologica 2021 Jul 15. Epub 2021 Jul 15.

The Ohio State University, Comprehensive Cancer Center, Columbus.

Expression levels of long non-coding RNAs (lncRNAs) have been shown to associate with clinical outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNAs in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged.
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http://dx.doi.org/10.3324/haematol.2021.266643DOI Listing
July 2021

Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance).

Blood Adv 2021 07;5(13):2775-2787

University of Chicago Comprehensive Cancer Center, Chicago, IL.

Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to cytarabine (100 mg/m2 per day on days 4-10) and daunorubicin (60 mg/m2 per day on days 4-6) followed by cytarabine consolidation (2000 mg/m2 per day on days 4-8) with (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age <70 years in arm A had improved OS by 1 month vs those in arm B (P = .04), and patients with secondary AML in arm A had better DFS vs those in arm B (P = .04). We conclude that addition of G3139 to chemotherapy failed to improve outcomes of older AML patients. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML. This trial was registered at www.clinicaltrials.gov as #NCT00085124.
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http://dx.doi.org/10.1182/bloodadvances.2021004233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288671PMC
July 2021

Acute Myeloid Leukemia: Historical Perspective and Progress in Research and Therapy Over 5 Decades.

Clin Lymphoma Myeloma Leuk 2021 09 29;21(9):580-597. Epub 2021 May 29.

Department of Clinical Hematology, The Alfred Hospital and Monash University, Melbourne, Australia.

With the Food and Drug Administration approval of 9 agents for different acute myeloid leukemia (AML) indications, the prognosis and management of AML is evolving rapidly. Herein, we review the important milestones in the history of AML research and therapy, discuss insights regarding prognostic assessment and prediction of treatment outcome, detail practical supportive care measures, and summarize the current treatment landscape and areas of evolving research.
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http://dx.doi.org/10.1016/j.clml.2021.05.016DOI Listing
September 2021

Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms.

Leukemia 2021 12 25;35(12):3542-3550. Epub 2021 Jun 25.

H3 Biomedicine, Cambridge, MA, USA.

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1-40 mg, n = 65) and schedule II (21 days on/7 days off, 7-20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.
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http://dx.doi.org/10.1038/s41375-021-01328-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632688PMC
December 2021

A precision medicine classification for treatment of acute myeloid leukemia in older patients.

J Hematol Oncol 2021 06 23;14(1):96. Epub 2021 Jun 23.

The Ohio State University Comprehensive Cancer Center, 320 West 10th Avenue, Starling Loving Hall B302, Columbus, OH, 43210, USA.

Background: Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Beat AML is a Leukemia and Lymphoma Society-sponsored, multicenter umbrella study that algorithmically segregates AML patients based upon cytogenetic and dominant molecular abnormalities (variant allele frequencies (VAF) ≥ 0.2) into different cohorts to select for targeted therapies. During the conception of the Beat AML design, a historical dataset was needed to help in the design of the genomic algorithm for patient assignment and serve as the basis for the statistical design of individual genomic treatment substudies for the Beat AML study.

Methods: We classified 563 newly diagnosed older AML patients treated with standard intensive chemotherapy on trials conducted by Cancer and Leukemia Group B based on the same genomic algorithm and assessed clinical outcomes.

Results: Our classification identified core-binding factor and NPM1-mutated/FLT3-ITD-negative groups as having the best outcomes, with 30-day early death (ED) rates of 0 and 20%, respectively, and median overall survival (OS) of > 1 year and 3-year OS rates of ≥ 20%. All other genomic groups had ED rates of 17-42%, median OS ≤ 1 year and 3-year OS rates of ≤ 15%.

Conclusions: By classifying patients through this genomic algorithm, outcomes were poor and not unexpected from a non-algorithmic, non-dominant VAF approach. The exception is 30-day ED rate typically is not available for intensive induction for individual genomic groups and therefore difficult to compare outcomes with targeted therapeutics. This Alliance data supported the use of this algorithm for patient assignment at the initiation of the Beat AML study. This outcome data was also used for statistical design for Beat AML substudies for individual genomic groups to determine goals for improvement from intensive induction and hopefully lead to more rapid approval of new therapies. Trial registration ClinicalTrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00900224 (CALGB 20202), NCT00003190 (CALGB 9720), NCT00085124 (CALGB 10201), NCT00742625 (CALGB 10502), NCT01420926 (CALGB 11002), NCT00039377 (CALGB 10801), and NCT01253070 (CALGB 11001).
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http://dx.doi.org/10.1186/s13045-021-01110-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220739PMC
June 2021

Outcomes of Adult Acute Myeloid Leukemia Treated With Gemtuzumab-Ozogamicin: Cue To Optimized Chemotherapy Backbone.

Clin Lymphoma Myeloma Leuk 2021 09 12;21(9):613-620. Epub 2021 Apr 12.

Department of Medicine, Roswell Park Comprehensive Cancer Centre, Buffalo, NY, United States (USA).

Background: The optimal approach to combine gemtuzumab-ozogamicin (GO) with various chemotherapy backbones and other newer agents safely remains to be determined.

Materials And Methods: We performed a retrospective analysis of the safety and outcomes of adult patients with newly diagnosed acute myeloid leukemia (AML) treated with GO with intensified versus standard anthracycline doses (daunorubicin dose 90 mg/m vs 60 mg/m) ± FLT3 inhibitors. The χ test and Mann-Whitney U test were used to compare categorical and continuous data. Survival estimates were calculated by Kaplan-Meier method and survival comparisons made using log-rank test.

Results: We report a 97% overall response rate in 34 patients with newly diagnosed AML with a median age of 54 years (19-75 years) treated with GO and standard induction. The 11 patients (100%) receiving GO plus daunorubicin dose 90 mg/m as part of 7 + 3 induction achieved complete response versus 91% (20/22) complete response in the standard daunorubicin dose group (P = NS). No increased toxicity was noted with the higher daunorubicin dose or when GO and 7 + 3 were combined with FLT3 inhibitors in 3 younger patients (<60 years). Two older patients treated with GO+7 + 3 and FLT3i experienced grade 3 or higher cardiotoxicity. We observed a longer estimated event-free survival for patients with newly diagnosed AML in our cohort (median, 24 months; 95% confidence interval, 17.2 to not reached) compared with historical data.

Conclusion: We demonstrate that anthracycline dose intensification with GO may offer higher response rates without increased toxicity in younger patients presenting with de novo AML across European Leukemia Net risk categories.
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http://dx.doi.org/10.1016/j.clml.2021.04.007DOI Listing
September 2021

A phase 2 trial of single low doses of rasburicase for treatment of hyperuricemia in adult patients with acute leukemia.

Leuk Res 2021 08 24;107:106588. Epub 2021 Apr 24.

Section of Leukemia, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Background: Rasburicase can markedly and rapidly decrease uric acid (UA) levels, thereby preventing and treating tumor lysis syndrome. However, rasburicase is expensive, especially when used as per the manufacturer's recommended dosage of 0.2 mg/kg/day for up to 5 days. Numerous reports have shown that lower, and even single doses are effective in lowering UA levels but prospective randomized studies comparing low doses have not been performed.

Objectives: To prospectively determine the efficacy and safety of two single low doses of rasburicase in adult patients (pts) with acute leukemia and elevated plasma UA.

Methods: Eligible pts aged ≥ 18 years old with acute leukemia and UA ≥ 7.5 mg/dL were randomized to receive an initial single dose of rasburicase 1.5 mg (Arm A) or 3 mg (Arm B) on day 1 in an unblinded fashion. All pts received allopurinol 300 mg daily on days 1-6.

Results: Twenty-four pts (median age 69 years; 14 males and 10 females) were enrolled in this phase 2 study (12 on each arm). Twenty pts had acute myeloid leukemia while 3 had acute lymphoblastic leukemia, and 1 had acute promyelocytic leukemia. Median initial UA level was 9.8 mg/dL. Eighty-three percent of pts in both arms achieved UA < 7.5 mg/dL by 24 h after therapy. Five pts (21 %; 2 from Arm A and 3 from Arm B) required additional doses of rasburicase. The majority (23/24) of pts achieved UA goals after 1-2 doses of rasburicase. None had worsening renal function. Both doses were well tolerated, and no treatment related adverse events were reported.

Conclusions: Single doses of rasburicase (as low as 1.5-3 mg) used in addition to allopurinol were well tolerated and highly efficacious (83 % response rate) in decreasing UA levels within 24 h of administration in adult acute leukemia pts with hyperuricemia.
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http://dx.doi.org/10.1016/j.leukres.2021.106588DOI Listing
August 2021

Multi-Site 11-Year Experience of Less-Intensive versus Intensive Therapies in Acute Myeloid Leukemia.

Blood 2021 04 28. Epub 2021 Apr 28.

University of Washington School of Medicine, United States.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia, assuming they are better than intensive induction. Using an AML-composite model (AML-CM) that assigns higher scores to older age, increased comorbidity-burdens and adverse cytogenetic-risks, we defined three distinct prognostic groups, and within each, compared outcomes after less-intensive versus intensive induction therapies in a multicenter retrospective cohort (n=1292) treated at six institutions from 2008-2012 and a prospective cohort (n=695) treated at thirteen institutions from 2013-2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physicians' perceptions of cure. In the retrospective cohort, recipients of less-intensive therapies were older, had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks for mortality in AML-CM scores of 4-6, 7-9, and ≥10. Results were independent from receipt of allogeneic transplants and similar in those aged 70-79 years old. In the Prospective cohort, the two groups were similar in baseline QOL, geriatric assessment, and patients' outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS and chances of cure, mortality risks and QOL were similar. Less-intensive recipients had lessened length of hospitalization (LOH). Our studies question the survival or QOL, except LOH, benefits from less-intensive therapies in patients with AML, including those aged 70-79 years or with high comorbidity-burden. A randomized trial in older/medically infirm patients is needed to better assess the value of less-intensive, intensive, or a combination of both therapies. ClinicalTrials.gov #NCT01929408.
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http://dx.doi.org/10.1182/blood.2020008812DOI Listing
April 2021

Inhibiting autophagy targets human leukemic stem cells and hypoxic AML blasts by disrupting mitochondrial homeostasis.

Blood Adv 2021 04;5(8):2087-2100

Department of Medicine and.

Leukemia stem cells (LSCs) and therapy-resistant acute myeloid leukemia (AML) blasts contribute to the reinitiation of leukemia after remission, necessitating therapeutic interventions that target these populations. Autophagy is a prosurvival process that allows for cells to adapt to a variety of stressors. Blocking autophagy pharmacologically by using mechanistically distinct inhibitors induced apoptosis and prevented colony formation in primary human AML cells. The most effective inhibitor, bafilomycin A1 (Baf A1), also prevented the in vivo maintenance of AML LSCs in NSG mice. To understand why Baf A1 exerted the most dramatic effects on LSC survival, we evaluated mitochondrial function. Baf A1 reduced mitochondrial respiration and stabilized PTEN-induced kinase-1 (PINK-1), which initiates autophagy of mitochondria (mitophagy). Interestingly, with the autophagy inhibitor chloroquine, levels of enhanced cell death and reduced mitochondrial respiration phenocopied the effects of Baf A1 only when cultured in hypoxic conditions that mimic the marrow microenvironment (1% O2). This indicates that increased efficacy of autophagy inhibitors in inducing AML cell death can be achieved by concurrently inducing mitochondrial damage and mitophagy (pharmacologically or by hypoxic induction) and blocking mitochondrial degradation. In addition, prolonged exposure of AML cells to hypoxia induced autophagic flux and reduced chemosensitivity to cytarabine (Ara-C), which was reversed by autophagy inhibition. The combination of Ara-C with Baf A1 also decreased tumor burden in vivo. These findings demonstrate that autophagy is critical for mitochondrial homeostasis and survival of AML cells in hypoxia and support the development of autophagy inhibitors as novel therapeutic agents for AML.
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http://dx.doi.org/10.1182/bloodadvances.2020002666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095145PMC
April 2021

A Phase II Trial of Imatinib Mesylate as Maintenance Therapy for Patients With Newly Diagnosed C-kit-positive Acute Myeloid Leukemia.

Clin Lymphoma Myeloma Leuk 2021 02 3;21(2):113-118. Epub 2020 Dec 3.

Department of Hematology/ Oncology, Cleveland Clinic Taussig Cancer Institute Leukemia Program, Cleveland, OH.

Introduction: Adults with acute myeloid leukemia (AML) have a high rate of remission; however, more than 50% relapse. C-kit is expressed in approximately 60% of patients with de novo AML and represents a potential therapeutic target.

Materials And Methods: Patients with newly diagnosed AML received 12 months of imatinib mesylate as maintenance therapy after the completion of post-remission therapy. The primary objective was to determine whether this approach improved progression-free survival (defined as no relapse and no death) compared with historical controls.

Results: The median progression-free survival of patients < 60 years of age was 52.1 months (historical control, 13 months) and for patients ≥ 60 years of age was 10.7 months (historical control, 8 months). The median level of AF1q expression was high (9.59), and 84% of patients had moderate or high levels of drug-resistance factors.

Conclusions: Imatinib maintenance therapy may improve the outcome of newly diagnosed patients with AML who are < 60 years of age.
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http://dx.doi.org/10.1016/j.clml.2020.11.018DOI Listing
February 2021

Novel therapies for AML: a round-up for clinicians.

Expert Rev Clin Pharmacol 2020 Dec 7;13(12):1389-1400. Epub 2021 Jan 7.

Leukemia Service, Department of Medicine, Roswell Park Comprehensive Cancer Center , Buffalo, NY, USA.

: Acute myeloid leukemia (AML) is a deadly disease associated with poor outcomes. For over four decades, therapeutic options for AML were limited to high dose cytotoxic chemotherapy. Scientific breakthroughs have not only enhanced our understanding of the molecular underpinnings of this disease but also resulted in the development of several targeted therapies with superior efficacy and lesser toxicities than conventional chemotherapy. The FDA approval of small molecule inhibitors for specific AML subsets highlights the importance of genetic and molecular profiling to optimally personalize AML therapy in the modern era. : In this article, we review the medical literature from PubMed on recent FDA approved drugs for AML by their mechanism of action: small molecule inhibitors, antibody-drug conjugate, cytotoxic, and epigenetic agents. We describe how to incorporate these agents into the current treatment paradigm for specific AML patients. : Knowing the molecular characteristics of patients with AML is of utmost importance to plan the best management. There are promising drugs targeting leukemogenesis by various mechanisms. It is important to consider clinical trial options for patients if and when available. We have provided a brief overview of the most promising agents on the horizon for AML therapy.
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http://dx.doi.org/10.1080/17512433.2020.1850255DOI Listing
December 2020

Management of toxicities associated with targeted therapies for acute myeloid leukemia: when to push through and when to stop.

Hematology Am Soc Hematol Educ Program 2020 12;2020(1):57-66

Department of Pharmacy, Roswell Park Comprehensive Cancer Center, Buffalo, NY.

The recent advent of myriad targeted therapies for acute myeloid leukemia (AML) has led to new hope for our patients but has also introduced new challenges in managing the disease. For clinicians, the ability to treat AML in the outpatient setting with novel agents of equal or greater efficacy than 7+3 has been transformative. Despite the enthusiasm, however, the reality is that many patients are still frail and remain at risk for treatment-related complications. Translating the results of clinical trials into improved outcomes for these individuals requires an understanding of how best to manage the adverse effects of these agents. Which patients benefit most and what to watch for? When to stop therapy? Using illustrative case presentations, this review details the unique toxicities associated with each of the approved mutation-specific and nonspecific targeted drugs for AML. The goal of this review is to help clinicians determine the risk:benefit ratio in decision making for individual patients with AML.
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http://dx.doi.org/10.1182/hematology.2020000089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727512PMC
December 2020

Phase 2 study of ruxolitinib and decitabine in patients with myeloproliferative neoplasm in accelerated and blast phase.

Blood Adv 2020 10;4(20):5246-5256

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Myeloproliferative neoplasms (MPN) that have evolved into accelerated or blast phase disease (MPN-AP/BP) have poor outcomes with limited treatment options and therefore represent an urgent unmet need. We have previously demonstrated in a multicenter, phase 1 trial conducted through the Myeloproliferative Neoplasms Research Consortium that the combination of ruxolitinib and decitabine is safe and tolerable and is associated with a favorable overall survival (OS). In this phase 2 trial, 25 patients with MPN-AP/BP were treated at the recommended phase 2 dose of ruxolitinib 25 mg twice daily for the induction cycle followed by 10 mg twice daily for subsequent cycles in combination with decitabine 20 mg/m2 for 5 consecutive days in a 28-day cycle. Nineteen patients died during the study follow-up. The median OS for all patients on study was 9.5 months (95% confidence interval, 4.3-12.0). Overall response rate (complete remission + incomplete platelet recovery + partial remission) was 11/25 (44%) and response was not associated with improved survival. We conclude that the combination of decitabine and ruxolitinib was well tolerated, demonstrated favorable OS, and represents a therapeutic option for this high-risk patient population. This trial was registered at www.clinicaltrials.gov as #NCT02076191.
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http://dx.doi.org/10.1182/bloodadvances.2020002119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594401PMC
October 2020

Prevention, recognition, and management of adverse events associated with gemtuzumab ozogamicin use in acute myeloid leukemia.

J Hematol Oncol 2020 10 15;13(1):137. Epub 2020 Oct 15.

Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Gemtuzumab ozogamicin (GO), a humanized anti-CD33 monoclonal antibody conjugated to the cytotoxic antibiotic agent calicheamicin, is approved for the treatment of newly-diagnosed CD33 + AML in adults and children ≥ 1 month old, and relapsed or refractory CD33 + AML in adults and children ≥ 2 years old. GO treatment has been associated with an increased risk of hepatotoxicity and hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), especially following hematopoietic stem cell transplantation. Other non-specific serious adverse events (SAEs) associated with GO treatment are myelosuppression, bleeding/thrombocytopenia, infusion-related reaction, and tumor lysis syndrome. This report summarizes an expert panel of physicians' recommendations for the evaluation and management of SAEs following GO, emphasizing the prevention and management of VOD/SOS.
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http://dx.doi.org/10.1186/s13045-020-00975-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559451PMC
October 2020

A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia.

Clin Cancer Res 2020 12 30;26(23):6132-6140. Epub 2020 Sep 30.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Purpose: The Polo-like kinase 1 (PLK1) is a master regulator of mitosis and overexpressed in acute myeloid leukemia (AML). We conducted a phase Ib study of the PLK1 inhibitor, onvansertib, in combination with either low-dose cytarabine (LDAC) or decitabine in patients with relapsed or refractory (R/R) AML.

Patients And Methods: Onvansertib was administered orally, in escalating doses, on days 1-5 in combination with either LDAC (20 mg/m; days 1-10) or decitabine (20 mg/m; days 1-5) in a 28-day cycle. The primary endpoint was to evaluate first-cycle dose-limiting toxicities and the MTD. Secondary and exploratory endpoints included safety, pharmacokinetics, antileukemic activity, and response biomarkers.

Results: Forty patients were treated with onvansertib (12-90 mg/m) in combination with LDAC ( = 17) or decitabine ( = 23). Onvansertib was well tolerated with most grades 3 and 4 adverse events related to myelosuppression. In the decitabine arm, the MTD was established at 60 mg/m, and 5 (24%) of the 21 evaluable patients achieved complete remission with or without hematologic count recovery. Decrease in mutant circulating tumor DNA (ctDNA) during the first cycle of therapy was associated with clinical response. Engagement of the PLK1 target, TCTP, was measured in circulating blasts and was associated with greater decrease in bone marrow blasts.

Conclusions: The onvansertib and decitabine combination was well tolerated and had antileukemic activity particularly in patients with target engagement and decreased mutant ctDNA following treatment. This combination will be further investigated in the ongoing phase II trial.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2586DOI Listing
December 2020
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