Clinical Research Training Institute Research Articles

An Ode to the ASH Clinical Research Training Institute (CRTI) on Its 20th Anniversary

An Ode to the ASH Clinical Research Training Institute (CRTI) on Its 20th Anniversary

Influence of participant and reviewer characteristics in application scores for a hematology research training program

AbstractThe American Society of Hematology Clinical Research Training Institute (CRTI) is a clinical research training program with a competitive application process. The objectives were to compare application scores based on applicant and reviewer sex and underrepresented minority (URM) status. We included applications to CRTI from 2003 to 2019. The application scores were transformed into a scale from 0 to 100 (100 was the strongest). The factors considered were applicant and reviewer sex and URM status. We evaluated whether there was an interaction between the characteristics and time related to application scores. In total, 713 applicants and 2106 reviews were included. There was no significant difference in scores according to applicant sex. URM applicants had significantly worse scores than non-URM applicants (mean [standard error] 67.9 [1.56] vs 71.4 [0.63]; P = .0355). There were significant interactions between reviewer sex and time (P = .0030) and reviewer URM status and time (P = .0424); thus, results were stratified by time. For the 2 earlier time periods, male reviewers gave significantly worse scores than did female reviewers; this difference did not persist for the most recent time period. The URM reviewers did not give significantly different scores across time periods. URM applicants received significantly lower scores than non-URM applicants. The impact of reviewer sex and URM status changed over time. Although male reviewers gave lower scores in the early periods, this effect did not persist in the late period. Efforts are required to mitigate the impact of applicant URM status on application scores.

Self-reported positive impact of mentored clinical research training is associated with academic success in hematology

The American Society of Hematology Clinical Research Training Institute (CRTI) is a mentored training program for hematology fellows and junior faculty. Our objective was to determine whether the self-reported impact of CRTI on research retention, career development, and connectedness to hematology investigators was associated with academic success. A survey was distributed in January 2020 to alumni who participated in the program from 2003 to 2019. It focused on the impact of CRTI on retention in research, facilitation of career development, understanding of requirements to succeed, and feelings of connectedness to investigators. These questions were scored on a 5-point Likert scale ranging from strongly disagree to strongly agree. Outcomes were grants, publications, and invited lectures; these were abstracted from a submitted curriculum vitae. Of 334 eligible alumni, 321 responded (response rate of 96.1%). Of these, 250 (77.9%) agreed that CRTI was instrumental to research retention, 268 (83.5%) agreed that CRTI facilitated career development, 296 (92.2%) agreed that CRTI allowed a better understanding of requirements to succeed in research, and 289 (90.0%) agreed that CRTI increased connectedness to hematology investigators. Those who agreed with these CRTI impacts had significantly more first-author publications. Those who agreed that CRTI was instrumental to retention, facilitated career development, and increased connectedness had significantly more protected time for research. Self-reported perception that CRTI had an impact on research retention, career development, and connectedness to hematology investigators was significantly associated with more publications and percent effort in research. Clinical research training programs should identify and implement approaches to enhance these characteristics.

Impact of gender and caregiving responsibilities on academic success in hematology

AbstractWe previously identified gender disparities in academic success during evaluation of the American Society of Hematology (ASH) Clinical Research Training Institute (CRTI) and hypothesized that it may be related to caregiving. The objective was to evaluate the impact of gender and caregiving responsibilities on academic success. A cross-sectional survey that included a question about caregiving responsibilities was distributed to alumni who participated in CRTI from 2003 to 2016 and asked about academic productivity in the previous 3 years. Publications and grants were abstracted from submitted curriculum vitae. Academic success was defined as number of first- or senior-author publications, total publications, grants, and percent effort in research. Of 280 potential respondents, 258 responded (92% response rate), 169 (66%) had caregiving responsibilities, and 110 (43%) were men. Respondents with caregiving responsibilities had fewer first- or senior-author publications (median, 3 vs 5; P = .003) and less percent effort in research (median, 40% vs 50%; P = .006). Men had more first- or senior-author publications (median, 4 vs 3; P = .002) and more total publications (median, 12 vs 6.5; P = .0002) than women. When stratified by those without (P = .0001) or with (P = .042) caregiving responsibilities, men had more publications than women. Among men, caregiving responsibilities significantly reduced all outcomes. However, among women, caregiving did not have an impact. In conclusion, men had more publications than women whether or not they had caregiving responsibilities. However, among men, caregiving reduced academic productivity whereas among women, caregiving did not have impact. The scientific community will need to continue to identify the reasons for disparities and implement changes to address them.

The effect of an intense mentoring program on junior investigators' preparation for a patient-oriented clinical research career.

There is a recognized need to translate scientific discoveries to patient-oriented clinical research (POCR). Several obstacles interfere with the successful recruitment and retention of physicians for POCR careers. The American Society of Hematology developed a yearlong educational and mentoring experience, the Clinical Research Training Institute (CRTI), for early-career physician-scientists from multiple institutions throughout the United States and Canada pursuing POCR careers. Several academic outcome measures of the 140 participants in the first seven years (2003-2010) of CRTI were evaluated by reviewing former trainee participants' curriculum vitae and survey responses. Ethnic, racial, and gender diversity of CRTI trainees was reflective of the proportions represented across U.S. hematology/oncology fellowship programs. Eighty-six percent (109/126) of trainees reported success establishing a POCR study; nearly half (62/126) had primarily research-focused jobs. Former CRTI trainees received at least 262 external grant awards and published 1,035 peer-reviewed manuscripts, 173 chapters, and 115 review articles. Because mentorship is key to developing a successful career, the CRTI program is being modified to enhance longitudinal mentorship by CRTI faculty mentors and mentors at trainees' home institutions, as well as to encourage the establishment of collaborations and the potential for research project success. Efforts to make the CRTI experience available to more phy sicians, include more CRTI graduates as faculty, and increase participation by hematologists from backgrounds under represented in medicine are under way.

‘Everyone is an Individual’: Providing Individualized Treatment in Oncology

Michael A Thompson* speaks to Stella Bennett, Commissioning Editor: Michael A Thompson, MD, PhD is a hematologist/oncologist and researcher at Aurora Health Care (AHC) and the Aurora Research Institute (ARI). Dr Thompson is a native of Minnesota. He received his BS degree in Molecular Biology from the University of Wisconsin – Madison, his MD from Mayo Medical School and PhD in Molecular Pharmacology and Experimental Therapeutics from the Mayo Graduate School. He completed his Internal Medicine Residency at the Mayo Clinic College of Medicine. He obtained his Hematology/Oncology Fellowship at the University of Texas MD Anderson Cancer Center. Dr Thompson received the American Society of Clinical Oncology (ASCO) Young Investigator Award in 2006 and the American Society of Hematology Clinical Research Training Institute (ASH CRTI). After fellowship, he moved back to the Midwest, where he served as the Medical Director of Cancer Research at ProHealth Care Regional Cancer Center, as well as the local site Clinical Trials Lead Investigator of the NCI Community Cancer Centers Program (NCCCP) and national Co-Chair of the NCCCP Clinical Trials Portfolio/Accrual Log Working Group. He also was on the NCCCP Early Phase Working Group which focused on bringing new drugs to the community setting. In 2013 he joined AHC as the Medical Director of the Early Phase Cancer Research Program. Dr Thompson was a recipient of a Vince Lombardi Cancer Foundation (VLCF) funded Aurora Cancer Care Research Award (ACCRA) 'The Immune Response Following Vaccination in Multiple Myeloma Patients' which is an ongoing Aurora-based research study. In 2014, AHC received the NCI Community Oncology Research Program (NCORP) grant. Dr Thompson is the co-primary investigator. Dr Thompson has studied and published in the area of hematologic malignancies – myeloma, lymphoma, leukemia and other cancers. He is on the ECOG Myeloma Core Committee and the NCI Myeloma Steering Committee. He has a strong interest in clinical research in hematologic cancers as well as in new drug development in a variety of cancer types. He is currently on the ASCO Cancer Research Committee, ASCO Community Research Forum, and on various research subcommittees. He is active in social media (Twitter: @mtmdphd) with national presentations on the topic of the use of social media in oncology.

Feasibility and Tolerability of Quantitative Sensory Testing in Patients with Sickle Cell Disease at the End of a Vasoocclusive Episode

Title: Feasibility and Tolerability of Quantitative Sensory Testing in Patients with Sickle Cell Disease at the End of a Vasocclusive EpisodeBackground: Children with Sickle Cell Disease (SCD) have increased sensitivity to heat and cold pain (Brandow et al) during steady state. It is unknown if sensitivity to pain varies with a Vaso-Occlusive Episode (VOE).Characterization of pain sensitivity during acute VOE is essential to the understanding of the transition to chronic pain. While the administration of pain stimuli associated with QST during a VOE is obviously untenable, it is unknown if patients will tolerate QST procedures at the end of a VOE.Aim: To determine feasibility and tolerability of QST procedures at the end of VOE.Methods: Patients with SCD were offered quantitative sensory testing (QST) at steady state (at least 2 weeks following a VOE) and prior to or following discharge from the hospital for a VOE-related admission. Patients were contacted during hospitalization for VOE and timing of QST was determined by patient preference and taking into account readiness for discharge from the hospital. QST procedures included estimation of pressure, mechanical and thermal pain thresholds and tolerance (excluding cold tolerance) as well as windup values. At each time point, participants completed the PROMIS measures of pain intensity, pain interference, anxiety, depressive symptoms, sleep, fatigue and peer relationships. Participants also completed the Pain Catastrophizing Scale ((PCS)-Sullivan et al), Child Somatization Inventory (Walker et al), Pain Coping Inventory (Varni et al)* as well as Peds QL Generic and SCD specific measures of Quality of life*. After the QST procedures, participants completed the Gracely box scales (0-20 scale rating pain unpleasantness/intensity).Results: Ten patients who had an episode of VOE during the study period underwent QST at a median of 3.8 days after admission. The median age of participants who underwent testing was 16.5 years (IQR 11-20). 6 of 10 patients were female. Sixteen patients in VOE were offered QST testing. Eight of 12 patients who had undergone QST testing at steady state and 2 of 4 patients who had not previously undergone QST testing consented to QST testing. Nine patients completed testing at both steady state and following a VOE. Thermal testing was well tolerated by all participants (n=1 not offered due to equipment unavailability). Mechanical pain testing/windup was partially omitted (n=1) by patient request. The median Gracely Box Scale (0-20) score following QST was 0.5 (IQR 0-4, range 0-6) for pain unpleasantness and was 0 (IQR 0-6, range 0-8) for pain intensity.Conclusions: Quantitative Sensory Testing is well accepted, feasible and well tolerated in patients with SCD at the end of a Vasoocclusive Episode.Acknowledgments: 1- ASH Clinical Research Training Institute 2- Sickle Cell Disease Association of America 3- *PedsQL™ contact information and permission to use: Mapi Research Trust, Lyon, France. E-mail: PROinformation@mapi-trust.org – Internet: www.Mapi-trust.org and http://www.pedsql.org/index.html DisclosuresNo relevant conflicts of interest to declare.

Preclinical Activity of a New Proteasome Inhibitor, MLN9708, in Acute Myelogenous Leukemias Expressing NPM1 Mutated Protein

ABSTRACT: The nucleophosmin-1 (NPM1) mutation represents the most common genetic lesion (30-35%) in adult acute myeloid leukemia (AML) with the mutation resulting in the cytoplasmic delocalization of the NPM protein (NPMc+, most commonly mutation type A, c.860_863dupTCTG). Outside of conventional chemotherapy, treatment options for those with relapsed disease are extremely limited. We have previously discovered that leukemic cells expressing NPMc+ are preferentially sensitive to the cytotoxic effects of the first generation proteasome inhibitor, bortezomib, as result of the induction of superoxide in these cells (Huang M, et al., Leukemia, 2013). However, bortezomib has demonstrated only modest anti-leukemic activity as a single agent in early phase clinical trials that have included primarily heavily pretreated patients not stratified according to mutational genotype. In addition, the high incidence of clinically significant peripheral neuropathy in these studies led to early discontinuation of treatment. MLN9708 (Ixazomib) is a novel second generation proteasome inhibitor that is orally bioavailable and has shown promising activity and improved tolerability in early phase clinical trials in lymphoma and in multiple myeloma, where it is currently in a Phase III clinical trial. The efficacy of MLN9708 in relapsed patients with AML has not yet been examined. We have investigated the in vitro effects of MLN9708 on the cytotoxicity, generation of reactive oxygen species (ROS), and cellular glutathione in both cultured NPMc+ AML cell lines and primary leukemic samples. Cultured OCI-AML3 cells (human AML cell line featuring the NPMc+ mutation) were approximately 50-fold more sensitive to MLN9708 with a mean half inhibitory concentrations (IC50 ± SD) of 67 nM ± 1.83 nM at 24 hours than were an AML cell line (THP-1) expressing wild type NPM1. Knockdown of both NPM1/NPMc+ by inducible NPM1 shRNA expression significantly attenuated the MLN9708-mediated cytotoxicity, as determined by MTS colorimetric and flow cytometric apoptosis assays. As with bortezomib, MLN9708 treatment at 75 nM induced a 2.1-fold (p < 0.002) increase in superoxide-specific DHE (PE)-derived fluorescence as compared to controls. Pre-incubation of cells with 25 mM N-acetylcysteine, a ROS scavenger, dramatically reduced cytotoxicity, strongly implicating the generation of ROS in the mechanism of MLN9708-induced cytotoxicity. Knockdown of NPM1/ NPMc+ expression resulted in an increase of glutathione levels of 2.6-fold (p < 0.04) in untreated cells, and 2.3-fold (p < 0.005) and 2.9-fold (p < 0.004) after a 22 hour incubation with MLN9708 at pharmacologically achievable doses of 75 nM and 150 nM, respectively (Figure 1). In addition, a concomitant 4-fold reduction (p < 0.04) in the NADP+/NADPH ratio was observed in the NPM1/NPMc+ depleted OCI-AML3 cells. In vitro apoptosis assays of primary leukemic blasts isolated from five patients with relapsed NPMc+ AML showed an IC50 for MLN9708 ranging from 49.963-467.487nM (183.8 nM ± 176.8 nM). Based on these promising in vitro studies, a Phase 2 clinical trial of single-agent oral MLN9708 (clinicaltrials.gov identifier: NCT02030405) has been initiated for patients with relapsed or refractory NPMc+ AML.We conclude that the expression of NPMc+ renders AML cells more susceptible to MLN9708 toxicity and that this effect results at least in part from the generation of superoxide. Lower glutathione levels in NPMc+ expressing cells suggests an underlying defect in the antioxidant defense pathway. Demonstration of the sensitivity of NPMc+ AML cells to MLN9708 as a single agent may serve as a platform for the development of novel combination strategies with this drug.Acknowledgments: Research was facilitated by the ASH Clinical Research Training Institute and AACR/ASCO Clinical Cancer Research training program. J.S.G is funded by the Leukemia & Lymphoma Society Career Development Award and ASCO YIA award through a grant supported by Mr. Aaron Sasson. J.S.G. is further supported by the Stanford Hematology Fellowship Program. [Display omitted] DisclosuresOff Label Use: MLN9708 is an investigational compound by Millennium Pharmaceuticals, Inc. (MPI). Through an MTA we have secured the compound for in vitro analysis. This data has led to a clinical trial and drug for that study is supplied by MPI.. Medeiros:Agios: Consulting - Ad board Other.

Challenges in Measuring Benefit of Clinical Research Training Programs--the ASH Clinical Research Training Institute Example.

The American Society of Hematology developed the Clinical Research Training Institute (CRTI) to address the lack of training in patient-oriented research among hematologists. As the program continues, we need to consider metrics for measuring the benefits of such a training program. This article addresses the benefits of clinical research training programs. The fundamental and key components are education and mentorship. However, there are several other benefits including promotion of collaboration, job and advancement opportunities, and promotion of work-life balance. The benefits of clinical research training programs need to be measured so that funders and society can judge if they are worth the investment in time and resources. Identification of elements that are important to program benefit is essential to measuring the benefit of the program as well as program planning. Future work should focus on the constructs which contribute to benefits of clinical research training programs such as CRTI.

The ASH Clinical Research Training Institute (CRTI) Positively Impacts The Success Of Early Career Hematologists In Patient-Oriented Clinical Research

There is a recognized need to translate scientific discoveries to patient-oriented clinical research (POCR) in order to improve human health. To overcome obstacles that interfere with the recruitment and retention of physicians for POCR careers, in 2003 the American Society of Hematology (ASH) developed the Clinical Research Training Institute (CRTI), an enhanced and extensive mentored experience for early career POCR investigators. The ASH CRTI is limited to 20 trainees/year (senior fellows or junior faculty) with an equivalent number of faculty mentors. The year-long Institute includes a 1 week workshop with didactic sessions on a variety of POCR and career development topics, disease-specific small group sessions focusing on research protocol development with biostatistician participation, and one-on-one interactions with faculty and representatives with expertise in career-development awards from the U.S. National Institutes of Health. Trainees have additional interactions with their small groups and CRTI mentors throughout the ensuing year to promote career development and research collaborations. Communications between the trainees' CRTI and home institution mentors are a vital component of the program. Evaluation of the POCR career development successes of the first 7 CRTI classes (140 trainees) was performed by reviewing trainees' curriculum vitaes and their responses to an electronically distributed survey. Gender, racial and ethnic distributions were similar to that of U.S. Hematology/Oncology fellowship programs. The majority (66%) of trainees were senior fellows or graduates of adult hematology/oncology training programs, 31% of pediatric hematology/oncology programs and the remainder of other hematology-related programs. Eighty-six percent of trainees had self-described success establishing a POCR study and 85% considered themselves clinical investigators. Nearly half of trainees had positions that were primarily research focused. CRTI trainees received at least 144 external grant awards plus additional internal awards, and had published 1035 peer-reviewed manuscripts,173 chapters and 115 review articles. Over 95% of trainees were satisfied with their CRTI experience and testimonials supported their impression that CRTI had a significant impact on their career success. Enhancements introduced into the CRTI program, as a result of ongoing program evaluations, include broadening participant eligibility to include up to 5 international trainees per class to enhance global research collaborations and further enhancements to the trainee-mentor interactions. The outcomes of the ASH CRTI support the hypothesis that enhanced mentoring experiences contribute to the successful career development of physicians pursuing POCR careers. Disclosures:Clayton:American Society of Hematology: Employment.

The Ultimate Mentorship: Q&amp;A With Dr. John Byrd, Co-Director of the 2009 Clinical Research Training Institute

The Ultimate Mentorship: Q&amp;A With Dr. John Byrd, Co-Director of the 2009 Clinical Research Training Institute

Origins and Evolution of the ASH Clinical Research Training Institute – Now Five Years Old

Origins and Evolution of the ASH Clinical Research Training Institute – Now Five Years Old

ASH Clinical Research Training Institute: A Remarkable Example for Young Investigators in Any Area of Medicine

ASH Clinical Research Training Institute: A Remarkable Example for Young Investigators in Any Area of Medicine