Publications by authors named "Michael Deininger"

259 Publications

Carfilzomib Enhances the Suppressive Effect of Ruxolitinib in Myelofibrosis.

Cancers (Basel) 2021 Sep 28;13(19). Epub 2021 Sep 28.

Centre for Haematology, Department of Immunology and Inflammation, Imperial College, London W12 0NN, UK.

As the first FDA-approved tyrosine kinase inhibitor for treatment of patients with myelofibrosis (MF), ruxolitinib improves clinical symptoms but does not lead to eradication of the disease or significant reduction of the mutated allele burden. The resistance of MF clones against the suppressive action of ruxolitinib may be due to intrinsic or extrinsic mechanisms leading to activity of additional pro-survival genes or signalling pathways that function independently of JAK2/STAT5. To identify alternative therapeutic targets, we applied a pooled-shRNA library targeting ~5000 genes to a -positive cell line under a variety of conditions, including absence or presence of ruxolitinib and in the presence of a bone marrow microenvironment-like culture medium. We identified several proteasomal gene family members as essential to HEL cell survival. The importance of these genes was validated in MF cells using the proteasomal inhibitor carfilzomib, which also enhanced lethality in combination with ruxolitinib. We also showed that proteasome gene expression is reduced by ruxolitinib in MF CD34 cells and that additional targeting of proteasomal activity by carfilzomib enhances the inhibitory action of ruxolitinib in vitro. Hence, this study suggests a potential role for proteasome inhibitors in combination with ruxolitinib for management of MF patients.
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http://dx.doi.org/10.3390/cancers13194863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507927PMC
September 2021

Anticoagulation management post-transjugular intrahepatic portosystemic shunt in portal hypertension associated with myeloproliferative neoplasms.

Blood Coagul Fibrinolysis 2021 Oct 4. Epub 2021 Oct 4.

Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, The University of Utah, Salt Lake City, Utah, USA.

Portal hypertension (pHTN) complicates myeloproliferative neoplasms (MPNs), and usually occurs due to Budd-Chiari syndrome or splanchnic vein thrombosis. Current management modalities for MPN-associated pHTN include anticoagulation, transjugular intrahepatic portosystemic shunt (TIPS), and orthotopic liver transplant. Data on the thrombotic and bleeding outcomes of this practice is of poor quality, and whether direct oral anticoagulants (DOACs) are effective in this setting is unknown. We describe failure of DOACs to prevent post-TIPS complications in two case reports of patients with MPN-associated pHTN and review the associated literature. We conducted a comprehensive search in Embase (embase.com), Scopus (scopus.org), and PubMed for existing data on MPN-associated pHTN post-TIPS procedure. Four studies (n = 251) of patients with pHTN post-TIPS were eligible (MPN, n = 143). A review of the literature suggests that patients with MPN-associated pHTN may be at higher risk for post-TIPS complications including stent thrombosis and stenosis, compared with other causes of thrombotic pHTN. DOAC use has not been studied in this setting. While further studies to guide optimal management of MPN-associated pHTN post-TIPS are needed, available evidence suggests that life-long anticoagulation is warranted. DOACs should not be considered standard of care because of lack of evidence of efficacy.
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http://dx.doi.org/10.1097/MBC.0000000000001087DOI Listing
October 2021

Patient-Reported Functional Outcomes in Patients with Chronic Myeloid Leukemia after Stopping Tyrosine Kinase Inhibitors.

J Natl Cancer Inst 2021 Sep 7. Epub 2021 Sep 7.

Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Treatment-free remission (TFR) is a goal for patients with chronic myeloid leukemia (CML). Functional outcomes after discontinuing Tyrosine Kinase Inhibitor (TKI) treatment have not been described. PROMIS patient-reported outcome measures (PROMs) of social, physical, cognitive, and sexual function were assessed over 36 months in 172 adult patients with chronic phase CML from 14 sites at baseline (on TKI) and after discontinuation. Linear mixed-effects models described the average trajectories for each PROM after discontinuation and in those who restarted TKI. Of 112 patients in TFR at 12 months, 103 (92.0%) had a ≥ 3-point improvement in social function, 80 (71.4%) in social isolation, 11 (9.8%) in satisfaction with sex life, 4 (3.6%) in physical function, and no patients had a ≥ 3-point improvement in cognitive function or interest in sexual activity. Patients' scores worsened after restarting TKI. This novel information on functional outcomes in TFR can help guide patient and clinician decision-making.
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http://dx.doi.org/10.1093/jnci/djab184DOI Listing
September 2021

Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult AML patients.

Blood 2021 Sep 5. Epub 2021 Sep 5.

Oregon Health & Science University, The Knight Cancer Institute, Portland, Oregon, United States.

Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 ACMG guidelines for variant interpretation, we curated 1,547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 AML patients (13.6%) in 34 genes. 41% of variants were in DNA damage response genes, and the most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). 44% of the pathogenic germline variants were in genes considered clinically actionable (tier 1). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, six patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in-silico approach that applies ACMG/AMP curation in an automated manner using the tool for assessment and prioritization in exome studies (TAPES), which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families.
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http://dx.doi.org/10.1182/blood.2021011354DOI Listing
September 2021

Ponatinib Dose-Ranging Study in Chronic-Phase Chronic Myeloid Leukemia: A Randomized, Open-Label Phase 2 Clinical Trial.

Blood 2021 Aug 18. Epub 2021 Aug 18.

The University of Utah, Salt Lake City, Utah, United States.

In PACE, a phase 2 trial of ponatinib that included patients with chronic phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit:risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel response-based dose-reduction strategy for a TKI in CP-CML. Adults with CP-CML resistant/intolerant to at least 2 prior BCR-ABL1 TKIs, or with a BCR-ABL1 T315I mutation, were randomized 1:1:1 to ponatinib 45mg (45mg cohort), 30mg (30mg cohort), or 15mg (15mg cohort) once daily. Patients who received 45 or 30mg daily reduced their dose to 15mg upon achievement of response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. Between August 2015 and May 2019, 283 patients were randomized; 282 (94/group) received treatment (data cutoff, 5/31/20). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45mg cohort, 29.0% (18.4-41.6) in the 30mg cohort, and 23.1% (13.4-35.3) in the 15mg cohort. Independently confirmed grade 3/4 treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45, 30, and 15mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit:risk outcomes occurred with the 45mg starting dose reducing to 15mg upon achievement of response (ClinicalTrials.gov number, NCT02467270).
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http://dx.doi.org/10.1182/blood.2021012082DOI Listing
August 2021

SIRT5 IS A DRUGGABLE METABOLIC VULNERABILITY IN ACUTE MYELOID LEUKEMIA.

Blood Cancer Discov 2021 May 2;2(3):266-287. Epub 2019 Dec 2.

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype-agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML.
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http://dx.doi.org/10.1158/2643-3230.bcd-20-0168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133360PMC
May 2021

Phenotypic characterization of leukemia-initiating stem cells in chronic myelomonocytic leukemia.

Leukemia 2021 Mar 30. Epub 2021 Mar 30.

Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

Chronic myelomonocytic leukemia (CMML) is a stem cell-derived neoplasm characterized by dysplasia, uncontrolled expansion of monocytes, and substantial risk to transform to secondary acute myeloid leukemia (sAML). So far, little is known about CMML-initiating cells. We found that leukemic stem cells (LSC) in CMML reside in a CD34/CD38 fraction of the malignant clone. Whereas CD34/CD38 cells engrafted NSGS mice with overt CMML, no CMML was produced by CD34/CD38 progenitors or the bulk of CD34 monocytes. CMML LSC invariably expressed CD33, CD117, CD123 and CD133. In a subset of patients, CMML LSC also displayed CD52, IL-1RAP and/or CLL-1. CMML LSC did not express CD25 or CD26. However, in sAML following CMML, the LSC also expressed CD25 and high levels of CD114, CD123 and IL-1RAP. No correlations between LSC phenotypes, CMML-variant, mutation-profiles, or clinical course were identified. Pre-incubation of CMML LSC with gemtuzumab-ozogamicin or venetoclax resulted in decreased growth and impaired engraftment in NSGS mice. Together, CMML LSC are CD34/CD38 cells that express a distinct profile of surface markers and target-antigens. During progression to sAML, LSC acquire or upregulate certain cytokine receptors, including CD25, CD114 and CD123. Characterization of CMML LSC should facilitate their enrichment and the development of LSC-eradicating therapies.
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http://dx.doi.org/10.1038/s41375-021-01227-zDOI Listing
March 2021

Chronic Myeloid Leukemia: Modern therapies, current challenges and future directions.

Blood Rev 2021 09 16;49:100825. Epub 2021 Mar 16.

Division of Hematology & Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by a reciprocal translocation [t(9;22)(q34;q11.2)] that leads to the fusion of ABL1 gene sequences (9q34) downstream of BCR gene sequences (22q11) and is cytogenetically visible as Philadelphia chromosome (Ph). The resulting BCR/ABL1 chimeric protein is a constitutively active tyrosine kinase that activates multiple signaling pathways, which collectively lead to malignant transformation. During the early (chronic) phase of CML (CP-CML), the myeloid cell compartment is expanded, but differentiation is maintained. Without effective therapy, CP-CML invariably progresses to blast phase (BP-CML), an acute leukemia of myeloid or lymphoid phenotype. The development of BCR-AB1 tyrosine kinase inhibitors (TKIs) revolutionized the treatment of CML and ignited the start of a new era in oncology. With three generations of BCR/ABL1 TKIs approved today, the majority of CML patients enjoy long term remissions and near normal life expectancy. However, only a minority of patients maintain remission after TKI discontinuation, a status termed treatment free remission (TFR). Unfortunately, 5-10% of patients fail TKIs due to resistance and are at risk of progression to BP-CML, which is curable only with hematopoietic stem cell transplantation. Overcoming TKI resistance, improving the prognosis of BP-CML and improving the rates of TFR are areas of active research in CML.
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http://dx.doi.org/10.1016/j.blre.2021.100825DOI Listing
September 2021

Proceedings from the Inaugural American Initiative in Mast Cell Diseases (AIM) Investigator Conference.

J Allergy Clin Immunol 2021 06 11;147(6):2043-2052. Epub 2021 Mar 11.

Division of Allergy and Immunology, University of Michigan, Ann Arbor, Mich.

The American Initiative in Mast Cell Diseases (AIM) held its inaugural investigator conference at Stanford University School of Medicine in May 2019. The overarching goal of this meeting was to establish a Pan-American organization of physicians and scientists with multidisciplinary expertise in mast cell disease. To serve this unmet need, AIM envisions a network where basic, translational, and clinical researchers could establish collaborations with both academia and biopharma to support the development of new diagnostic methods, enhanced understanding of the biology of mast cells in human health and disease, and the testing of novel therapies. In these AIM proceedings, we highlight selected topics relevant to mast cell biology and provide updates regarding the recently described hereditary alpha-tryptasemia. In addition, we discuss the evaluation and treatment of mast cell activation (syndromes), allergy and anaphylaxis in mast cell disorders, and the clinical and biologic heterogeneity of the more indolent forms of mastocytosis. Because mast cell disorders are relatively rare, AIM hopes to achieve a coordination of scientific efforts not only in the Americas but also in Europe by collaborating with the well-established European Competence Network on Mastocytosis.
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http://dx.doi.org/10.1016/j.jaci.2021.03.008DOI Listing
June 2021

Precision Medicine in Hematology 2021: Definitions, Tools, Perspectives, and Open Questions.

Hemasphere 2021 Mar 17;5(3):e536. Epub 2021 Feb 17.

Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria.

During the past few years, our understanding of molecular mechanisms and cellular interactions relevant to malignant blood cell disorders has improved substantially. New insights include a detailed knowledge about disease-initiating exogenous factors, endogenous (genetic, somatic, epigenetic) elicitors or facilitators of disease evolution, and drug actions and interactions that underlie efficacy and adverse event profiles in defined cohorts of patients. As a result, precision medicine and personalized medicine are rapidly growing new disciplines that support the clinician in making the correct diagnosis, in predicting outcomes, and in optimally selecting patients for interventional therapies. In addition, precision medicine tools are greatly facilitating the development of new drugs, therapeutic approaches, and new multiparametric prognostic scoring models. However, although the emerging roles of precision medicine and personalized medicine in hematology and oncology are clearly visible, several questions remain. For example, it remains unknown how precision medicine tools can be implemented in healthcare systems and whether all possible approaches are also affordable. In addition, there is a need to define terminologies and to relate these to specific and context-related tools and strategies in basic and applied science. To discuss these issues, a working conference was organized in September 2019. The outcomes of this conference are summarized herein and include a proposal for definitions, terminologies, and applications of precision and personalized medicine concepts and tools in hematologic neoplasms. We also provide proposals aimed at reducing costs, thereby making these applications affordable in daily practice.
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http://dx.doi.org/10.1097/HS9.0000000000000536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892291PMC
March 2021

Eradicating residual chronic myeloid leukaemia: basic research lost in translation.

Lancet Haematol 2021 02;8(2):e101-e104

Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT 84112, USA. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(21)00001-6DOI Listing
February 2021

Femoral Heads from Total Hip Arthroplasty as a Source of Adult Hematopoietic Cells.

Acta Haematol 2021 7;144(4):458-464. Epub 2021 Jan 7.

Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA,

Normal human bone marrow cells are critical for studies of hematopoiesis and as controls to assess toxicity. As cells from commercial vendors are expensive, many laboratories resort to cancer-free bone marrow specimens obtained during staging or to umbilical cord blood cells, which may be abnormal or reflect a much younger age group compared to the disease samples under study. We piloted the use of femoral heads as an alternative and inexpensive source of normal bone marrow. Femoral heads were obtained from 21 successive patients undergoing elective hip arthroplasty. Mononuclear cells (MNCs) were purified with Ficoll, and CD3+, CD14+, and CD34+ cells were purified with antibody-coated microbeads. The median yield of MNCs was 8.95 × 107 (range, 1.62 × 105-2.52 × 108), and the median yield of CD34+ cells was 1.40 × 106 (range, 3.60 × 105-9.90 × 106). Results of downstream applications including qRT-PCR, colony-forming assays, and ex vivo proliferation analysis were of high quality and comparable to those obtained with standard bone marrow aspirates. We conclude that femoral heads currently discarded as medical waste are a cost-efficient source of bone marrow cells for research use.
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http://dx.doi.org/10.1159/000511953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260615PMC
August 2021

Genetic complexity of chronic myelomonocytic leukemia.

Leuk Lymphoma 2021 05 18;62(5):1031-1045. Epub 2020 Dec 18.

Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA.

In recent years CMML has received increased attention as the most commonly observed MDS/MPN overlap syndrome. Renewed interest has occurred in part due to widespread adoption of next-generation sequencing panels that help render the diagnosis in the absence of morphologic dysplasia. Although most CMML patients exhibit somatic mutations in epigenetic modifiers, spliceosome components, transcription factors and signal transduction genes, it is increasingly clear that a small subset harbors an inherited predisposition to CMML and other myeloid neoplasms. More intriguing is the fact that the mutational spectrum observed in CMML is found in other types of myeloid leukemias, begging the question of how similar genetic backgrounds can lead to such divergent clinical phenotypes. In this review we present a contemporary snapshot of the genetic complexity inherent to CMML, explore the relationship between genotype-phenotype and present a stepwise model of CMML pathogenesis and progression.
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http://dx.doi.org/10.1080/10428194.2020.1856837DOI Listing
May 2021

Dasatinib response in acute myeloid leukemia is correlated with FLT3/ITD, PTPN11 mutations and a unique gene expression signature.

Haematologica 2020 12 1;105(12):2795-2804. Epub 2020 Dec 1.

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.

Novel targeted therapies demonstrate improved survival in specific subgroups (defined by genetic variants) of acute myeloid leukemia (AML) patients, validating the paradigm of molecularly targeted therapy. However, identifying correlations between AML molecular attributes and effective therapies is challenging. Recent advances in high-throughput in vitro drug sensitivity screening applied to primary AML blasts were used to uncover such correlations; however, these methods cannot predict the response of leukemic stem cells (LSCs). Our study aimed to predict in vitro response to targeted therapies, based on molecular markers, with subsequent validation in LSCs. We performed ex vivo sensitivity screening to 46 drugs on 29 primary AML samples at diagnosis or relapse. Using unsupervised hierarchical clustering analysis we identified group with sensitivity to several tyrosine kinase inhibitors (TKIs), including the multi-TKI, dasatinib, and searched for correlations between dasatinib response, exome sequencing and gene expression from our dataset and from the Beat AML dataset. Unsupervised hierarchical clustering analysis of gene expression resulted in clustering of dasatinib responders and non-responders. In vitro response to dasatinib could be predicted based on gene expression (AUC=0.78). Furthermore, mutations in FLT3/ITD and PTPN11 were enriched in the dasatinib sensitive samples as opposed to mutations in TP53 which were enriched in resistant samples. Based on these results, we selected FLT3/ITD AML samples and injected them to NSG-SGM3 mice. Our results demonstrate that in a subgroup of FLT3/ITD AML (4 out of 9) dasatinib significantly inhibits LSC engraftment. In summary we show that dasatinib has an anti-leukemic effect both on bulk blasts and, more importantly, LSCs from a subset of AML patients that can be identified based on mutational and expression profiles. Our data provide a rational basis for clinical trials of dasatinib in a molecularly selected subset of AML patients.
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http://dx.doi.org/10.3324/haematol.2019.240705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726833PMC
December 2020

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial.

JAMA Oncol 2021 Jan;7(1):42-50

Department of Medicine, Medical College of Wisconsin, Milwaukee.

Importance: Tyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients.

Objective: To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML.

Design, Setting, And Participants: The Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020.

Intervention: Discontinuation of TKIs.

Main Outcomes And Measures: Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR).

Results: Of 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P < .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P < .001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P ≤ .001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs.

Conclusions And Relevance: In this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of MRec; clinical application of this finding should be confirmed in other studies.

Trial Registration: ClinicalTrials.gov Identifier: NCT02269267.
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http://dx.doi.org/10.1001/jamaoncol.2020.5774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662490PMC
January 2021

Inter-hemispheric synchroneity of Holocene precipitation anomalies controlled by Earth's latitudinal insolation gradients.

Nat Commun 2020 10 28;11(1):5447. Epub 2020 Oct 28.

Institute of Geosciences, Johannes Gutenberg University Mainz, J.-J.-Becher-Weg 21, 55128, Mainz, Germany.

Atmospheric circulation is a fundamental component of Earth's climate system, transporting energy poleward to partially offset the latitudinal imbalance in insolation. Changes in the latitudinal distribution of insolation thus force variations in atmospheric circulation, in turn altering regional hydroclimates. Here we demonstrate that regional hydroclimates controlled by the Northern Hemisphere mid-latitude storm tracks and the African and South American Monsoons changed synchronously during the last 10 kyrs. We argue that these regional hydroclimate variations are connected and reflect the adjustment of the atmospheric poleward energy transport to the evolving differential heating of the Northern and Southern Hemispheres. These results indicate that changes in latitudinal insolation gradients and associated variations in latitudinal temperature gradients exert important control on atmospheric circulation and regional hydroclimates. Since the current episode of global warming strongly affects latitudinal temperature gradients through Arctic amplification, our results can inform projections of likely inter-hemispheric precipitation changes in the future.
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http://dx.doi.org/10.1038/s41467-020-19021-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595035PMC
October 2020

Imatinib, cheese and migraines.

Leuk Lymphoma 2021 03 28;62(3):746-748. Epub 2020 Oct 28.

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

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http://dx.doi.org/10.1080/10428194.2020.1839652DOI Listing
March 2021

Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial.

Nat Med 2020 12 26;26(12):1852-1858. Epub 2020 Oct 26.

Foundation Medicine, Cambridge, MA, USA.

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient's leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.
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http://dx.doi.org/10.1038/s41591-020-1089-8DOI Listing
December 2020

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 10 1;18(10):1385-1415. Epub 2020 Oct 1.

National Comprehensive Cancer Network.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.
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http://dx.doi.org/10.6004/jnccn.2020.0047DOI Listing
October 2020

Pregnancy outcomes in patients treated with bosutinib.

Int J Hematol Oncol 2020 May 29;9(2):IJH26. Epub 2020 May 29.

Clinic for Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Universitätsklinikum RWTH Aachen, Aachen, Germany.

Aim: Preclinical studies have shown reproductive toxicity with bosutinib, but little is known about its effects during conception or pregnancy in humans.

Methods: Pregnancy cases in patients receiving bosutinib were identified from the Pfizer safety database.

Results: Thirty-three pregnancy reports were identified. Sixteen cases of maternal exposure: six live births, four abortions and six with unknown outcomes. Seventeen instances of paternal exposure: nine live births, five abortions and three with unknown outcomes.

Conclusion: Adverse effects of bosutinib exposure at conception or during pregnancy in humans cannot be excluded, particularly if therapy is not interrupted upon recognition of pregnancy. Contraceptive use is recommended for female patients receiving bosutinib, and patients should be made aware of the potential risks associated with bosutinib use during pregnancy.
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http://dx.doi.org/10.2217/ijh-2020-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510513PMC
May 2020

Imatinib is not a potent anti-SARS-CoV-2 drug.

Leukemia 2020 11 30;34(11):3085-3087. Epub 2020 Sep 30.

Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.

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http://dx.doi.org/10.1038/s41375-020-01045-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527150PMC
November 2020

Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on Antiproliferative and PP2A-Activating Functions.

Blood Cancer Discov 2020 Jul;1(1):48-67

Department of Haematology, Hammersmith Hospital, Imperial College London, London, United Kingdom.

Persistence of drug-resistant quiescent leukemic stem cells (LSC) and impaired natural killer (NK) cell immune response account for relapse of chronic myelogenous leukemia (CML). Inactivation of protein phosphatase 2A (PP2A) is essential for CML-quiescent LSC survival and NK cell antitumor activity. Here we show that has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively. is upregulated in CML LSCs and NK cells by bone marrow microenvironment (BMM) signals to induce quiescence and impair immune response, respectively. Conversely, BCR-ABL1 downregulates in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating long noncoding RNA that uncouples and limits function to cytostasis. Genetic and pharmacologic modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis and in patient-derived xenografts; hence, the importance of and PP2A activity for CML development and therapy.
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http://dx.doi.org/10.1158/0008-5472.BCD-19-0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510943PMC
July 2020

Declaration of Bcr-Abl1 independence.

Leukemia 2020 11 10;34(11):2827-2836. Epub 2020 Sep 10.

Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.

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http://dx.doi.org/10.1038/s41375-020-01037-9DOI Listing
November 2020

Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 09;18(9):1248-1269

The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute.

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.
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http://dx.doi.org/10.6004/jnccn.2020.0042DOI Listing
September 2020

Prototyping for context: exploring stakeholder feedback based on prototype type, stakeholder group and question type.

Res Eng Des 2019 Oct 18;30(4):453-471. Epub 2019 Jun 18.

University of Michigan, 3454 George G. Brown Laboratory, 2350 Hayward Street, Ann Arbor, MI 48109, United States of America.

Engineering designers frequently use prototypes to gather input from stakeholders. Design guidelines recommend the use of quick and simple prototypes early and often in a design process. However, the type and quality of a prototype can influence how stakeholders perceive a new design concept and can therefore impact their responses. Additionally, different levels of experience, expertise, and preparedness for providing input to designers may lead stakeholders from different geographical or cultural settings to provide different responses, making the format of a prototype even more influential. Although design practitioners are known to intentionally align their prototyping approach with the specific design question to be answered, it is unclear the extent to which prototyping approaches should vary based on the stakeholders, context, and setting of a design project. To investigate how the format and quality of prototypes influence stakeholders' responses, we conducted a field study with various medical professionals in Ghana. We presented prototypes for a medical device in different formats to stakeholders and collected responses to the design through semi-structured interviews. We found that professional expertise, prototype format, and question type influenced the types of responses that stakeholders provided. These findings suggest that designers seeking input from stakeholders on new concepts should consider context-specific prototyping strategies, especially when designing at distance and across cultures.
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http://dx.doi.org/10.1007/s00163-019-00317-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451731PMC
October 2019

Use of dasatinib dose-reduction periods to remedy poor surgical wound healing in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Leuk Lymphoma 2020 12 24;61(14):3507-3510. Epub 2020 Aug 24.

Division of Hematology and Blood and Marrow Transplantation, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA.

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http://dx.doi.org/10.1080/10428194.2020.1808210DOI Listing
December 2020

No advantage of Imatinib in combination with hydroxyurea over Imatinib monotherapy: a study of the East German Study Group (OSHO) and the German CML study group.

Leuk Lymphoma 2020 12 16;61(12):2821-2830. Epub 2020 Jul 16.

School of Medicine, University Leipzig, Leipzig Germany.

Introduction: The combination of Imatinib (IM) and hydroxyurea (HU) was explored for the treatment of chronic myelogenous leukemia (CML).

Method: After testing and a phase I study ( = 20), 59 patients were randomized in the IM/HU and 29 in the IM arm. According to protocol, 49 propensity-score matched IM patients were included from the CML-IV study.

Results: Additive specific inhibition of CML cells by IM/HU was detected . HU 500 mg qd in combination with IM 400 mg qd proved feasible in the phase I study. Overall, no significant difference with respect to major molecular response (MMR) at 18 months (IM/HU and IM 66%; primary endpoint) was observed. Significant differences were noted for MMR at 6 months ( = 0.04) and for cumulative incidences of adverse events ( = 0.03) in favor of IM monotherapy (secondary endpoints).

Conclusion: IM/HU combination was more potent in selectively inhibiting CML cells , but not superior to IM . (NCT02480608).
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http://dx.doi.org/10.1080/10428194.2020.1786556DOI Listing
December 2020

Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts.

Lancet Haematol 2020 Aug 18;7(8):e601-e612. Epub 2020 Jun 18.

Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts.
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http://dx.doi.org/10.1016/S2352-3026(20)30205-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302757PMC
August 2020

Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms.

Leukemia 2020 11 14;34(11):2981-2991. Epub 2020 May 14.

Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA.

FLT3-ITD mutations occur in 20-30% of AML patients and are associated with aggressive disease. Patients with relapsed FLT3-mutated disease respond well to 2nd generation FLT3 TKIs but inevitably relapse within a short timeframe. In this setting, until overt relapse occurs, the bone marrow microenvironment facilitates leukemia cell survival despite continued on-target inhibition. We demonstrate that human bone marrow derived conditioned medium (CM) protects FLT3-ITD AML cells from the 2nd generation FLT3 TKI quizartinib and activates STAT3 and STAT5 in leukemia cells. Extrinsic activation of STAT5 by CM is the primary mediator of leukemia cell resistance to FLT3 inhibition. Combination treatment with quizartinib and dasatinib abolishes STAT5 activation and significantly reduces the IC of quizartinib in FLT3-ITD AML cells cultured in CM. We demonstrate that CM protects FLT3-ITD AML cells from the inhibitory effects of quizartinib on glycolysis and that this is partially reversed by treating cells with the combination of quizartinib and dasatinib. Using a doxycycline-inducible STAT5 knockdown in the FLT3-ITD MOLM-13 cell line, we show that dasatinib-mediated suppression of leukemia cell glycolytic activity is STAT5-independent and provide a preclinical rationale for combination treatment with quizartinib and dasatinib in FLT3-ITD AML.
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http://dx.doi.org/10.1038/s41375-020-0858-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606260PMC
November 2020
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