Publications by authors named "Jerald P Radich"

173 Publications

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

A graphical, interactive and GPU-enabled workflow to process long-read sequencing data.

BMC Genomics 2021 Aug 23;22(1):626. Epub 2021 Aug 23.

School of Engineering and Technology, University of Washington, 98402, Tacoma, WA, USA.

Background: Long-read sequencing has great promise in enabling portable, rapid molecular-assisted cancer diagnoses. A key challenge in democratizing long-read sequencing technology in the biomedical and clinical community is the lack of graphical bioinformatics software tools which can efficiently process the raw nanopore reads, support graphical output and interactive visualizations for interpretations of results. Another obstacle is that high performance software tools for long-read sequencing data analyses often leverage graphics processing units (GPU), which is challenging and time-consuming to configure, especially on the cloud.

Results: We present a graphical cloud-enabled workflow for fast, interactive analysis of nanopore sequencing data using GPUs. Users customize parameters, monitor execution and visualize results through an accessible graphical interface. The workflow and its components are completely containerized to ensure reproducibility and facilitate installation of the GPU-enabled software. We also provide an Amazon Machine Image (AMI) with all software and drivers pre-installed for GPU computing on the cloud. Most importantly, we demonstrate the potential of applying our software tools to reduce the turnaround time of cancer diagnostics by generating blood cancer (NB4, K562, ME1, 238 MV4;11) cell line Nanopore data using the Flongle adapter. We observe a 29x speedup and a 93x reduction in costs for the rate-limiting basecalling step in the analysis of blood cancer cell line data.

Conclusions: Our interactive and efficient software tools will make analyses of Nanopore data using GPU and cloud computing accessible to biomedical and clinical scientists, thus facilitating the adoption of cost effective, fast, portable and real-time long-read sequencing.
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http://dx.doi.org/10.1186/s12864-021-07927-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381503PMC
August 2021

Capillary-Mediated Single-Cell Dispenser.

Anal Chem 2021 08 28;93(31):10750-10755. Epub 2021 Jul 28.

Department of Chemistry and Bioengineering, University of Washington, Seattle, Washington 98195, United States.

Single-cell manipulation, sorting, and dispensing into multiwell plates is useful for single-cell multiomics studies. Here, we develop a single-cell dispenser inspired by electrohydrodynamic jet printing that achieves accurate droplet generation and single-cell sorting and dispensing using fused silica capillary tubing as both the optical detection window and nozzle for droplet dispensing. Parameters that affect droplet dispensing performance-capillary inner and outer diameter, flow rate, applied voltage, and solution properties-were optimized systematically with COMSOL simulations and experimentation. Small (5-10 nL) droplets were obtained by using 100-μm inner diameter and 160-μm outer diameter capillary tubing and allowed efficient encapsulation and dispensing of single cells. We demonstrate an application of this easy-to-assemble single-cell dispenser by sorting and dispensing cells into multiwell plates for single-cell PCR analysis.
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http://dx.doi.org/10.1021/acs.analchem.1c01879DOI Listing
August 2021

Analysis of the gap in PCR monitoring availability for patients with chronic myeloid leukemia in 60 low- and middle-income countries.

Cost Eff Resour Alloc 2021 Mar 12;19(1):18. Epub 2021 Mar 12.

Global Medicines Program, Department of Global Health, School of Public Health, University of Washington, Seattle, USA.

Purpose: To estimate the resource gap in the polymerase chain reaction (PCR) monitoring for patients with chronic myeloid leukemia (CML) in low- and middle-income countries (LMICs).

Methods: We developed a model of demand and supply of PCR monitoring of CML patients in 60 LMICs. PCR testing was assumed to use Cepheid's GeneXpert® system. We included costs of GeneXpert® instruments, uninterrupted power supplies, warranties, calibration kits, test cartridges, and shipping. We calculated the country-specific monetary gap in PCR monitoring, stratified by country priority defined as the availability of tyrosine kinase inhibitors (TKIs) through The Max Foundation initiatives.

Results: The 5-year gap in PCR monitoring was $29.1 million across all countries, 22% ($6.4 million) in countries with all five TKIs available, 20% ($5.7 million) in countries with four TKIs available, 50% ($14.5 million) in countries with three TKIs available, 8% ($2.2 million) in countries with two TKIs available, and 1% ($0.3 million) in countries with one TKI available. The gap was highest in South Asia (52%; $15.1 million) and lowest in Latin America (6%; $1.9 million). Excluding labor costs, the bulk of the resource needs (86%; $25.2 million) were for procurement of BCR-ABL cartridges.

Conclusion: Removing the 5-year gap in PCR monitoring capacity for CML in LMICs will require the mobilization of significant resources and will likely lead to better treatment outcomes and reduced treatment costs through optimization of treatment, discontinuation of therapy in appropriate patients, and facilitation of clinical research. Development of streamlined monitoring guidelines for resource-limited countries should be considered.
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http://dx.doi.org/10.1186/s12962-021-00271-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953726PMC
March 2021

Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial.

Leukemia 2021 05 11;35(5):1344-1355. Epub 2021 Mar 11.

University of Turin, Orbassano, Italy.

The ENESTfreedom trial assessed the feasibility of treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) following frontline nilotinib treatment. Results for long-term outcomes after a 5-year follow-up are presented herein. Patients who had received ≥2 years of frontline nilotinib therapy and achieved MR underwent a 1-year nilotinib treatment consolidation phase before attempting TFR. At the 5-year data cut-off, 81/190 patients entering the TFR phase (42.6%) were still in TFR, with 76 (40.0%) in MR. Patients who lost major molecular response (MMR) entered a treatment re-initiation phase; 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR. The Kaplan-Meier estimated treatment-free survival rate at 5 years was 48.2%. No disease progression or CML-related deaths were reported. Whereas the incidence of adverse events (AEs) declined from 96 weeks following the start of TFR, an increase in AE frequency was observed for patients in the treatment re-initiation phase. Low Sokal risk score, BCR-ABL1 levels at 48 weeks of TFR and stable MR response for the first year of TFR were associated with higher TFR rates. Overall, these results support the efficacy and safety of attempting TFR following upfront nilotinib therapy of >3 years in patients with CML-CP.
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http://dx.doi.org/10.1038/s41375-021-01205-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102196PMC
May 2021

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

Predictors of tyrosine kinase inhibitor adherence trajectories in patients with newly diagnosed chronic myeloid leukemia.

J Oncol Pharm Pract 2020 Nov 11:1078155220970616. Epub 2020 Nov 11.

The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, University of Washington, Seattle, WA, USA.

Introduction: Although consistent use of tyrosine kinase inhibitors (TKIs) confers significant improvements in long-term survival for individuals with chronic myeloid leukemia (CML), only 70% of CML patients are adherent to TKIs. Understanding the factors that contribute to non-adherence and establishing dynamic adherence patterns in this population are essential aspects of targeted drug monitoring and intervention strategies.

Methods: Newly diagnosed CML patients were identified in the MarketScan database and relevant covariate values extracted. Proportion of days covered (PDC) per 30-day interval was used to calculate adherence over a 12-month follow-up period. We conducted a latent profile analysis (LPA) on these PDC estimates to identify distinct, dynamic patterns of TKI adherence. Identified trajectories were grouped into four clinically relevant categories and predictors of membership in these categories were determined via multinomial logistic regression.

Results: Four broad adherence categories were identified from the LPA: never adherent, initially non-adherent becoming adherent, initially adherent becoming non-adherent, and stable adherent. Results from the subsequent multinomial logistic regression indicated that younger age, female sex, greater monthly financial burden, fewer comorbidities, fewer concomitant medications, year of diagnosis, higher starting dose, TKI type, and a longer duration from diagnosis to treatment were significantly associated with membership in at least one of the three non-stable adherent groups.

Conclusion: Select sociodemographic and clinical characteristics were found to predict membership in clinically meaningful groups of longitudinal TKI adherence. These findings could have major implications for informing personalized monitoring and intervention strategies for individuals who are likely to be non-adherent.
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http://dx.doi.org/10.1177/1078155220970616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110595PMC
November 2020

AML risk stratification models utilizing ELN-2017 guidelines and additional prognostic factors: a SWOG report.

Biomark Res 2020 12;8:29. Epub 2020 Aug 12.

Clinical Research Division, Fred Hutch, 1100 Fairview Ave N, D5-112, Seattle, WA 98109 USA.

Background: The recently updated European LeukemiaNet risk stratification guidelines combine cytogenetic abnormalities and genetic mutations to provide the means to triage patients with acute myeloid leukemia for optimal therapies. Despite the identification of many prognostic factors, relatively few have made their way into clinical practice.

Methods: In order to assess and improve the performance of the European LeukemiaNet guidelines, we developed novel prognostic models using the biomarkers from the guidelines, age, performance status and select transcript biomarkers. The models were developed separately for mononuclear cells and viable leukemic blasts from previously untreated acute myeloid leukemia patients (discovery cohort,  = 185) who received intensive chemotherapy. Models were validated in an independent set of similarly treated patients (validation cohort,  = 166).

Results: Models using European LeukemiaNet guidelines were significantly associated with clinical outcomes and, therefore, utilized as a baseline for comparisons. Models incorporating age and expression of select transcripts with biomarkers from European LeukemiaNet guidelines demonstrated higher area under the curve and C-statistics but did not show a substantial improvement in performance in the validation cohort. Subset analyses demonstrated that models using only the European LeukemiaNet guidelines were a better fit for younger patients (age < 55) than for older patients. Models integrating age and European LeukemiaNet guidelines visually showed more separation between risk groups in older patients. Models excluding results for , , and , demonstrated that these mutations provide a limited overall contribution to risk stratification across the entire population, given the low frequency of mutations and confounding risk factors.

Conclusions: While European LeukemiaNet guidelines remain a critical tool for triaging patients with acute myeloid leukemia, the findings illustrate the need for additional prognostic factors, including age, to improve risk stratification.
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http://dx.doi.org/10.1186/s40364-020-00208-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425159PMC
August 2020

Association of immunophenotype with expression of topoisomerase II α and β in adult acute myeloid leukemia.

Sci Rep 2020 03 26;10(1):5486. Epub 2020 Mar 26.

Levine Cancer Institute, Carolinas Medical Center, Charlotte, NC, USA.

Anthracyclines used in the treatment of acute myelogenous leukemia (AML) inhibit the activity of the mammalian topoisomerase II (topo II) isoforms, topo II α and topo IIβ. In 230 patients with non-M3 AML who received frontline ara-C/daunorubicin we determined expression of topo IIα and topo IIβ by RT-PCR and its relationship to immunophenotype (IP) and outcomes. Treatment outcomes were analyzed by logistic or Cox regression. In 211 patients, available for analysis, topo IIα expression was significantly lower than topo IIβ (P < 0.0001). In contrast to topo IIα, topo IIβ was significantly associated with blast percentage in marrow or blood (P = 0.0001), CD7 (P = 0.01), CD14 (P < 0.0001) and CD54 (P < 0.0001). Event free survival was worse for CD56-negative compared to CD56-high (HR = 1.9, 95% CI [1.0-3.5], p = 0.04), and overall survival was worse for CD-15 low as compared to CD15-high (HR = 2.2, 95% CI [1.1-4.2], p = 0.02). Ingenuity pathway analysis indicated topo IIβ and immunophenotype markers in a network associated with cell-to-cell signaling, hematological system development/function and inflammatory response. Topo IIβ expression reflects disease biology of highly proliferative disease and distinct IP but does not appear to be an independent variable influencing outcome in adult AML patients treated with anthracycline-based therapy.
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http://dx.doi.org/10.1038/s41598-020-62345-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099013PMC
March 2020

Targeted Sequencing Improves DIPSS-Plus Prognostic Scoring in Myelofibrosis Patients Undergoing Allogeneic Transplantation.

Biol Blood Marrow Transplant 2020 07 16;26(7):1371-1374. Epub 2020 Mar 16.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington; Seattle Cancer Care Alliance, Seattle, Washington; Department of Pathology, University of Washington, Seattle, Washington. Electronic address:

Primary myelofibrosis (MF) and secondary MF developing after polycythemia vera or essential thrombocythemia are clonal disorders of hematopoiesis. Currently the sole therapy offering the potential of cure is hematopoietic cell transplantation (HCT). Several risk classification systems including clinical, hematologic, and mutational parameters have been proposed. We analyzed the mutational landscape in addition to the Dynamic International Prognostic Scoring System (DIPSS)-plus in 55 patients with MF to determine the combined impact on post-HCT outcome. Mutations, analyzed in 75 genes, were most common in JAK2, CALR, ASXL1, TET2, GATA2, EZH2, U2AF1, and ETV6. Patients with ≥3 mutations in addition to JAK2 or CALR mutations had a higher post-transplantation relapse rate and nonrelapse mortality than patients with fewer mutations, independent of DIPSS-plus risk. The presence of higher numbers of mutations identified patients at the greatest risk of relapse within the highest overall risk group as determined by DIPSS-plus. These findings are consistent with molecular risk classifications for patients who do not undergo HCT and support the proposed transplantation risk classification incorporating mutational information.
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http://dx.doi.org/10.1016/j.bbmt.2020.03.007DOI Listing
July 2020

Rapid Donor Identification Improves Survival in High-Risk First-Remission Patients With Acute Myeloid Leukemia.

JCO Oncol Pract 2020 06 27;16(6):e464-e475. Epub 2020 Jan 27.

Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT.

Methods: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1.

Results: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 ( < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% 35%, respectively [ = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months).

Conclusion: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.
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http://dx.doi.org/10.1200/JOP.19.00133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291544PMC
June 2020

Phase I/II multisite trial of optimally dosed clofarabine and low-dose TBI for hematopoietic cell transplantation in acute myeloid leukemia.

Am J Hematol 2020 01 8;95(1):48-56. Epub 2019 Nov 8.

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

Clofarabine is an immunosuppressive purine nucleoside analog that may have better anti-leukemic activity than fludarabine. We performed a prospective phase I/II multisite trial of clofarabine with 2 Gy total body irradiation as non-myeloablative conditioning for allogeneic hematopoietic cell transplantation in adults with acute myeloid leukemia who were unfit for more intense regimens. Our main objective was to improve the 6-month relapse rate following non-myeloablative conditioning, while maintaining historic rates of non-relapse mortality (NRM) and engraftment. Forty-four patients, 53 to 74 (median: 69) years, were treated with clofarabine at 150 to 250 mg/m , of whom 36 were treated at the maximum protocol-specified dose. One patient developed multifactorial acute kidney injury and another developed multiorgan failure, but no other grade 3 to 5 non-hematologic toxicities were observed. All patients fully engrafted. The 6-month relapse rate was 16% (95% CI, 5%-27%) among all patients and 14% (95% CI, 3%-26%) among high-risk patients treated at the maximum dose, meeting the pre-specified primary efficacy endpoint. Overall survival was 55% (95% CI, 40%-70%) and leukemia-free survival was 52% (95% CI, 37%-67%) at 2 years. Compared to a historical high-risk cohort treated with the combination of fludarabine at 90 mg/m and 2 Gy TBI, protocol patients treated with the clofarabine-TBI regimen had lower rates of overall mortality (HR of 0.50, 95% CI, 0.28-0.91), disease progression or death (HR 0.48, 95% CI, 0.27-0.85), and morphologic relapse (HR 0.30, 95% CI, 0.13-0.69), and comparable NRM (HR 0.85, 95% CI 0.36-2.00). The combination of clofarabine with TBI warrants further investigation in patients with high-risk AML.
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http://dx.doi.org/10.1002/ajh.25665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904507PMC
January 2020

A Fluorescence-Activated Single-Droplet Dispenser for High Accuracy Single-Droplet and Single-Cell Sorting and Dispensing.

Anal Chem 2019 05 9;91(10):6815-6819. Epub 2019 May 9.

Department of Chemistry , University of Washington , Seattle , Washington 98195 , United States.

The ability to sort and dispense droplets accurately is essential to droplet-based single-cell analysis. Here, we describe a fluorescence-activated single-droplet dispenser (FASD) that is analogous to a conventional fluorescence-activated cell sorter, but sorts droplets containing single cells within an oil emulsion. The FASD system uses cytometric detection and electrohydrodynamic actuation-based single-droplet manipulation, allowing droplet isolation and dispensing with high efficiency and accuracy. The system is compatible with multiwell plates and can be integrated with existing microfluidic devices and large-scale screening systems. By enabling sorting based on single-cell reactions such as PCR, this platform will help expand the basis of cell sorting from mainly protein biomarkers to nucleic acid sequences and secreted biomolecules.
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http://dx.doi.org/10.1021/acs.analchem.9b01017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541233PMC
May 2019

Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms.

Hematol Oncol 2019 Aug 20;37(3):240-252. Epub 2019 Jun 20.

Division of Hematology-Oncology, University of California Irvine, Irvine, California.

The 60th American Society of Hematology (ASH) held in San Diego in December 2018 was followed by the 13th Post-ASH chronic myeloproliferative neoplasms (MPNs) workshop on December 4 and 5, 2018. This closed annual workshop, first introduced in 2006 by Goldman and Mughal, was organized in collaboration with Alpine Oncology Foundation and allowed experts in preclinical and clinical research in the chronic MPNs to discuss the current scenario, including relevant presentations at ASH, and address pivotal open questions that impact translational research and clinical management. This review is based on the presentations and deliberations at this workshop, and rather than provide a resume of the proceedings, we have selected some of the important translational science and treatment issues that require clarity. We discuss the experimental and observational evidence to support the intimate interaction between aging, inflammation, and clonal evolution of MPNs, the clinical impact of the unfolding mutational landscape on the emerging targets and treatment of MPNs, new methods to detect clonal heterogeneity, the challenges in managing childhood and adolescent MPN, and reflect on the treatment of systemic mastocytosis (SM) following the licensing of midostaurin.
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http://dx.doi.org/10.1002/hon.2622DOI Listing
August 2019

Clinical Effect of Combined Mutations in DNMT3A, FLT3-ITD, and NPM1 Among Egyptian Acute Myeloid Leukemia Patients.

Clin Lymphoma Myeloma Leuk 2019 06 14;19(6):e281-e290. Epub 2019 Feb 14.

Fred Hutchinson Cancer Research Center, Seattle, WA.

Background: Genotypic mutation of fms like tyrosine kinase 3 (FLT3), Nucleophosmin (NPM1), and DNA-methyltransferase 3A (DNMT3A) has been involved in the leukemogenesis of acute myeloid leukemia (AML), with the well known poor prognostic role of FLT3 and DNMT3A and favorable role for the NPM1 mutation.

Patients And Methods: A total of 123 patients with AML treated at the National Cancer Institute, Cairo University were examined for mutations in DNMT3A, FLT3, and NPM1 using polymerase chain reaction (PCR) for detecting FLT3 internal tandem duplication (ITD) and allele-specific PCR to detect DNMT3A and NPM1A mutations. Two-way direct sequencing and Gene Mapper version 4.0 software (Fred Hutchinson Cancer Research Center) sequencing were used as confirmatory tests for DNMT3A and NPM1A mutations, respectively.

Results: DNMT3A, FLT3-ITD, and NPM1A gene mutations were detected in 22 (17.9%), 22 (17.9%), and 24 (19.5%) patients, respectively. DNMT3A/FLT3, NPM1A/FLT3, and DNMT3A/NPM1A combined mutant genotypes were detected in 5 (4.1%), 9 (7.3%), and 3 (2.4%) patients, respectively. Two patients (1.6%) had triple mutant genotypes (DNMT3A/FLT3/NPM1A). FLT3 and DNMT3A mutations had a significant negative effect on complete response (CR) rates (P = .016). FLT3-ITD mutation was significantly associated with older age (P = .029), and lower overall survival (OS) rates (P = .046). DNMT3A/FLT3 combined mutant genotypes were significantly associated with a lower OS rate (P = .016). Mutant NPM1/wild type FLT3, wild type DNMT3A/FLT3, and mutant NPM1A/wild type DNMT3A combinations were significantly associated with higher CR rates (P = .006, P = .006, and P = .023, respectively).

Conclusion: DNMT3A, FLT3-ITD, and NPM1A are frequent mutations in Egyptian AML. FLT3-ITD mutations are frequent in older patients. DNMT3A and FLT3-ITD mutations were associated with an unfavorable prognosis, but the NPM1A mutation has tendency to indicate a good prognosis.
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http://dx.doi.org/10.1016/j.clml.2019.02.001DOI Listing
June 2019

PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.

Nat Genet 2019 02 14;51(2):296-307. Epub 2019 Jan 14.

HARP Pharma Consulting, Mystic, CT, USA.

Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription-factor gene PAX5. One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations); a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.
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http://dx.doi.org/10.1038/s41588-018-0315-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525306PMC
February 2019

Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2018 09;16(9):1108-1135

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph), resulting 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 (TKI) therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML (CP-CML). The selection TKI therapy should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CP-CML.
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http://dx.doi.org/10.6004/jnccn.2018.0071DOI Listing
September 2018

Single-Molecule Sequencing Reveals Patterns of Preexisting Drug Resistance That Suggest Treatment Strategies in Philadelphia-Positive Leukemias.

Clin Cancer Res 2018 11 24;24(21):5321-5334. Epub 2018 Jul 24.

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

Sequential treatment with targeted therapies can result in complex combinations of resistance mutations in drug targets. This mutational complexity has spurred the development of pan-target inhibitors, i.e., therapies for which no single target mutation can cause resistance. Because the propensity for on- versus off-target resistance varies across cancer types, a deeper understanding of the mutational burden in drug targets could rationalize treatment outcomes and prioritize pan-target inhibitors for indications where on-target mutations are most likely. To measure and model the mutational landscape of a drug target at high resolution, we integrated single-molecule Duplex Sequencing of the ABL1 gene in Philadelphia-positive (Ph) leukemias with computational simulations. A combination of drug target mutational burden and tumor-initiating cell fraction is sufficient to predict that most patients with chronic myeloid leukemia are unlikely to harbor ABL1 resistance mutations at the time of diagnosis, rationalizing the exceptional success of targeted therapy in this setting. In contrast, our analysis predicts that many patients with Ph acute lymphoblastic leukemia (Ph ALL) harbor multiple preexisting resistant cells with single mutants. The emergence of compound mutations can be traced to initial use of an ABL1 inhibitor that is susceptible to resistance from single point mutations. These results argue that early use of therapies that achieve pan-inhibition of ABL1 resistance mutants might improve outcomes in Ph ALL. Our findings show how a deep understanding of the mutational burden in drug targets can be quantitatively coupled to phenotypic heterogeneity to rationalize clinical phenomena. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214777PMC
November 2018

A Self-Digitization Dielectrophoretic (SD-DEP) Chip for High-Efficiency Single-Cell Capture, On-Demand Compartmentalization, and Downstream Nucleic Acid Analysis.

Angew Chem Int Ed Engl 2018 08 27;57(35):11378-11383. Epub 2018 Jul 27.

Department of Chemistry, University of Washington, Seattle, Washington, 98195, USA.

The design and fabrication of a self-digitization dielectrophoretic (SD-DEP) chip with simple components for single-cell manipulation and downstream nucleic acid analysis is presented. The device employed the traditional DEP and insulator DEP to create the local electric field that is tailored to approximately the size of single cells, enabling highly efficient single-cell capture. The multistep procedures of cell manipulation, compartmentalization, lysis, and analysis were performed in the integrated microdevice, consuming minimal reagents, minimizing contamination, decreasing lysate dilution, and increasing assay sensitivity. The platform developed here could be a promising and powerful tool in single-cell research for precise medicine.
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http://dx.doi.org/10.1002/anie.201807314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457344PMC
August 2018

Self-digitization chip for single-cell genotyping of cancer-related mutations.

PLoS One 2018 2;13(5):e0196801. Epub 2018 May 2.

Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

Cancer is a heterogeneous disease, and patient-level genetic assessments can guide therapy choice and impact prognosis. However, little is known about the impact of genetic variability within a tumor, intratumoral heterogeneity (ITH), on disease progression or outcome. Current approaches using bulk tumor specimens can suggest the presence of ITH, but only single-cell genetic methods have the resolution to describe the underlying clonal structures themselves. Current techniques tend to be labor and resource intensive and challenging to characterize with respect to sources of biological and technical variability. We have developed a platform using a microfluidic self-digitization chip to partition cells in stationary volumes for cell imaging and allele-specific PCR. Genotyping data from only confirmed single-cell volumes is obtained and subject to a variety of relevant quality control assessments such as allele dropout, false positive, and false negative rates. We demonstrate single-cell genotyping of the NPM1 type A mutation, an important prognostic indicator in acute myeloid leukemia, on single cells of the cell line OCI-AML3, describing a more complex zygosity distribution than would be predicted via bulk analysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196801PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931502PMC
July 2018

Comparable outcomes of patients eligible vs ineligible for SWOG leukemia studies.

Blood 2018 06 4;131(25):2782-2788. Epub 2018 Apr 4.

Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.

Patients may be deemed ineligible for a clinical trial for reasons that do not directly impact efficacy or safety. We identified reasons for ineligibility and compared outcomes of ineligible with eligible patients treated on Southwest Oncology Group (SWOG) Leukemia Committee protocols. Patients enrolled in SWOG phase 2, 2/3, or 3 protocols open since 2005 were analyzed for eligibility status, reasons for ineligibility, baseline characteristics, Eastern Cooperative Oncology Group (ECOG) performance status (PS), serious adverse events (SAEs), complete remission (CR) status, and overall survival. A total of 2361 patients were enrolled in the 13 included studies. Of these, 247 (10%) were deemed ineligible; 78 were excluded from analyses, and 169 were included. Of the 169 included in analyses, 60% (101/169) were excluded due to missing baseline documentation. Baseline characteristics comparing ineligible to eligible patients were similar, with the exception of ECOG PS for S0325 ( = .02) and S0530 ( = .002). In multivariable analyses, neither the proportion of patients with ECOG PS ≥ 2 ( = .12) nor the rate of grade 5 SAEs ( = .62) differed between groups. There was no difference in survival between eligible and ineligible patients ( = .25), and CR rates were similar, with the exception of S0325 ( < .001) and S0703 ( = .004). The findings of this study suggest that nonessential eligibility criteria can be less restrictive, thus expanding patient enrollment and avoiding protocol deviations. The clinical trials included in this study were registered at www.clincialtrials.gov as #NCT00085709, #NCT00066794, #NCT00070499, #NCT00109837, #NCT00093418, #NCT00492856, #NCT00337168, #NCT00352365, #NCT00658814, #NCT00792948, #NCT00945815, #NCT00840177, and #NCT01522976.
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http://dx.doi.org/10.1182/blood-2018-01-826693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014358PMC
June 2018

Design and rationale for the life after stopping tyrosine kinase inhibitors (LAST) study, a prospective, single-group longitudinal study in patients with chronic myeloid leukemia.

BMC Cancer 2018 04 2;18(1):359. Epub 2018 Apr 2.

Department of Medicine, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI, 53226, USA.

Background: Treatment of chronic myeloid leukemia with a tyrosine kinase inhibitor (TKI) offers significant improvements over previous treatments in terms of survival and toxicity yet nevertheless is associated with reduced health-related quality of life and very high cost. Several small studies from Europe and Australia suggested that discontinuing TKIs with regular monitoring was safe.

Methods: The Life After Stopping TKIs (LAST) study is a large, U.S.-based study that aims to improve the evidence for clinical decision making regarding TKI discontinuation with monitoring in patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy. The LAST study is a non-randomized, prospective, single-group longitudinal study of 173 patients. The co-primary objectives are to determine the proportion of patients who develop molecular recurrence (> 0.1% BCR-ABL) after discontinuing one of four TKIs (imatinib, dasatinib, nilotinib, or bosutinib) and to compare the patient-reported health status of patients before and after stopping TKIs. Outcomes are assessed at baseline and throughout the 36-month study follow-up period with a central laboratory used for blood samples. All samples with undetectable BCR-ABL are also examined using digital polymerase chain reaction, which is a more sensitive nanofluidic polymerase chain reaction system.

Discussion: Because of their high cost and side effects, discontinuation of TKIs for patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy is a promising approach to treatment. The LAST study is the largest U.S.-based TKI discontinuation study. It is the first to allow participation from patients on any of 4 first- and second-generation TKIs, includes a robust approach to measurement of clinical and patient-reported outcomes, and is using digital polymerase chain reaction to explore better prediction of safe discontinuation.

Trial Registration: This study was registered prospectively on October 21, 2014 and assigned trial number NCT02269267 .
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http://dx.doi.org/10.1186/s12885-018-4273-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879565PMC
April 2018

There is nothing minimal about residual disease.

Authors:
Jerald P Radich

Blood 2018 03;131(12):1269-1270

Fred Hutchinson Cancer Research Center.

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http://dx.doi.org/10.1182/blood-2018-01-824870DOI Listing
March 2018

Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study.

J Cancer Res Clin Oncol 2018 May 22;144(5):945-954. Epub 2018 Feb 22.

Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany.

Purpose: ENESTfreedom is evaluating treatment-free remission (TFR) following frontline nilotinib in patients with chronic myeloid leukemia (CML) in chronic phase. Following our primary analysis at 48 weeks, we here provide an updated 96-week analysis.

Methods: Attempting TFR required ≥ 3 years of nilotinib, a molecular response of MR [BCR-ABL1 ≤ 0.0032% on the International Scale (BCR-ABL1)], and sustained deep molecular response (DMR) during a 1-year consolidation phase. Patients restarted nilotinib following loss of major molecular response (MMR; BCR-ABL1 ≤ 0.1%).

Results: Ninety-six weeks after stopping treatment (3.6-year median prior nilotinib duration), 93 of 190 patients (48.9%) remained in TFR. Of 88 patients who restarted nilotinib following loss of MMR, 87 regained MMR and 81 regained MR by the data cut-off. Ninety-six-week TFR rates were 61.3, 50.0, and 28.6% in patients with low, intermediate, and high Sokal risk scores at diagnosis, respectively. Patients consistently in MR during consolidation had higher TFR rates (50.6%) than patients with ≥ 1 assessment without MR during consolidation (35.0%). In a landmark analysis, 96-week TFR rates for patients with MR, MR (BCR-ABL1 ≤ 0.01%) but not MR, and MMR but not MR at TFR week 12 were 82.6, 23.1, and 0%, respectively. There were no reports of disease progression or death due to CML; overall adverse event frequency decreased following TFR. Within the follow-up period, TFR did not adversely affect disease outcomes.

Conclusions: These results demonstrate the feasibility and durability of TFR following frontline nilotinib and emphasize the importance of sustained DMR for TFR.
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http://dx.doi.org/10.1007/s00432-018-2604-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916993PMC
May 2018

Recent advances in the genomics and therapy of BCR/ABL1-positive and -negative chronic myeloproliferative neoplasms.

Leuk Res 2018 04 14;67:67-74. Epub 2018 Feb 14.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

This review is based on the presentations and deliberations at the 7th John Goldman Chronic Myeloid Leukemia (CML) and Myeloproliferative Neoplasms (MPN) Colloquium which took place in Estoril, Portugal on the 15th October 2017, and the 11th post-ASH International Workshop on CML and MPN which took place on the 6th-7th December 2016, immediately after the 58th American Society of Hematology Annual Meeting. Rather than present a resume of the proceedings, we have elected to address some of the topical translational research and clinically relevant topics in greater detail. We address recent updates in the genetics and epigenetics of MPN, the mechanisms of transformation by mutant calreticulin, advances in the biology and therapy of systemic mastocytosis, clinical updates on JAK2 inhibitors and other therapeutic approaches for patients with MPNs, cardiovascular toxicity related to tyrosine kinase inhibitors and the concept of treatment-free remission for patients with CML.
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http://dx.doi.org/10.1016/j.leukres.2018.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613209PMC
April 2018

Impact of Specimen Heterogeneity on Biomarkers in Repository Samples from Patients with Acute Myeloid Leukemia: A SWOG Report.

Biopreserv Biobank 2018 Feb 27;16(1):42-52. Epub 2017 Nov 27.

1 Clinical Research Division , Fred Hutch, Seattle, Washington.

Introduction: Current prognostic models for acute myeloid leukemia (AML) are inconsistent at predicting clinical outcomes for individual patients. Variability in the quality of specimens utilized for biomarker discovery and validation may contribute to this prognostic inconsistency.

Methods: We evaluated the impact of sample heterogeneity on prognostic biomarkers and methods to mitigate any adverse effects of this heterogeneity in 240 cryopreserved bone marrow and peripheral blood specimens from AML patients enrolled on SWOG (Southwest Oncology Group) trials.

Results: Cryopreserved samples displayed a broad range in viability (37% with viabilities ≤60%) and nonleukemic cell contamination (13% with lymphocyte percentages >20%). Specimen viability was impacted by transport time, AML immunophenotype, and, potentially, patients' age. The viability and cellular heterogeneity in unsorted samples significantly altered biomarker results. Enriching for viable AML blasts improved the RNA quality from specimens with poor viability and refined results for both DNA and RNA biomarkers. For example, FLT3-ITD allelic ratio, which is currently utilized to risk-stratify AML patients, was on average 1.49-fold higher in the viable AML blasts than in the unsorted specimens.

Conclusion: To our knowledge, this is the first study to provide evidence that using cryopreserved specimens can introduce uncontrollable variables that may impact biomarker results and enrichment for viable AML blasts may mitigate this impact.
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http://dx.doi.org/10.1089/bio.2017.0079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808392PMC
February 2018

US Intergroup Study of Chemotherapy Plus Dasatinib and Allogeneic Stem Cell Transplant in Philadelphia Chromosome Positive ALL.

Blood Adv 2016 Dec;1(3):250-259

Fred Hutchinson Cancer Research Center, Seattle, WA.

This multicenter trial was conducted to determine whether the addition of dasatinib to chemotherapy followed by an allogeneic hematopoietic cell transplant (HCT) in patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) was feasible. Patients ≥ 18 and ≤ 60 years of age with newly diagnosed Ph+ ALL received up to 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate with dasatinib. Patients with an available matched sibling or unrelated donor underwent an allogeneic HCT in first complete remission (CR1) followed by daily dasatinib starting from day 100. Others received maintenance therapy with vincristine and prednisone for 2 years and dasatinib indefinitely. 97 patients (94 evaluable) with median age of 44 years (range, 20 - 60) and median WBC at presentation of 10 × 10/L (range, 1 - 410 × 10/L) were accrued. 83 (88%) patients achieved CR or CR with incomplete count recovery (CRi) and 41 underwent ASCT in CR1. Median follow-up is 36 months (range, 9 - 63). For the overall population, overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) at 3 years were 69%, 55%, and 62%, respectively. The 12-month RFS and OS after transplant were 71% and 87%, respectively. Landmark analysis at 175 days from the time of CR/CRi (longest time to HCT), showed statistically superior advantages for RFS and OS (p=0.038 and 0.037, respectively) for the transplanted patients. Addition of dasatinib to chemotherapy and HCT for younger patients with Ph+ ALL is feasible and warrants further testing.
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http://dx.doi.org/10.1182/bloodadvances.2016001495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642915PMC
December 2016
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