Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD).

BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

A dynamic 3-factor survival model for acute myeloid leukemia that accounts for response to induction chemotherapy.

The current study was approached with the assumption that response to induction chemotherapy, in acute myeloid leukemia (AML), overshadows pre-treatment risk variables in predicting survival and therefore be used as an anchor for a simplified risk model. We considered 759 intensively-treated patients with AML, not promyelocytic: median age 60 years; primary 66%, secondary 25%, and therapy-related 9%; European LeukemiaNet cytogenetic risk category favorable 8%, intermediate 61%, and adverse 31%. Complete remission with (CR) or without (CRi) count recovery was achieved in 608 (80%) patients. After a median follow-up of 22 months, 503 deaths, 272 relapses, and 257 allogeneic hematopoietic stem cell transplants (AHSCTs) were recorded. Multivariable analysis identified failure to achieve CR/CRi (HR 3.8, 95% CI 3.1-4.8), adverse karyotype (2.2, 1.8-2.8), and age >55 years (2.1, 1.6-2.7) as main risk factors for survival. HR-weighted scoring resulted in four-tiered risk stratification: low (0 points; N = 183), intermediate-1 (1 point; N = 331), intermediate-2 (2 points; N = 117), and high (≥3 points; N = 128), with respective median survival (5-year rate) not reached (68%), 34 (37%), 13 (20%), and 5 (5%) months (p < .001). FLT3-ITD mutation was associated with inferior survival in intermediate-1 (p = .004) and TP53 in intermediate-2 (p = .06) and high (p = .02) risk disease; the latter was fully accounted for by the close association between TP53 mutation and complex/monosomal karyotype while the observations regarding FLT3-ITD were not affected by treatment with midostaurin. AHSCT had a favorable impact on survival, most apparent in intermediate-1 (p < .001), intermediate-2 (p = .03), and high (p = .01) risk disease. The proposed 3-factor survival model offers a novel prototype that is amenable to further enhancement by molecular information and was validated in an external cohort of 1032 intensively-treated AML patients.

Frequency of venous thrombotic events in patients with myelodysplastic syndrome and 5q deletion syndrome during lenalidomide therapy.

Lenalidomide is known to increase the risk of venous thromboembolism in patients with hematologic malignancies. The role of antithrombotic prophylaxis in patients receiving lenalidomide is well established in multiple myeloma. However, when used in patients with a myelodysplastic syndrome (MDS)-in particular, del(5q) patients-the risk of venous thromboembolism and the need for anticoagulation are unknown. We performed a retrospective for MDS patients with 5q deletion. The total number of patients was 64, and 24 (38%) were treated with lenalidomide. Of those who received lenalidomide, venous thrombotic events (VTE) occurred in 4 (17%). All events occurred after 1 year of lenalidomide therapy. Although limited by the cohort size, concurrent erythropoietin-stimulating agents (ESAs) were not associated with increased thrombotic events, and the diagnosis of VTE did not affect survival. Our data suggest an increased incidence of VTE with prolonged lenalidomide treatment, mainly if MDS responds to this therapy.

Medical Students' Knowledge, Familiarity, and Attitudes towards Hematopoietic Stem Cell Donation: Stem Cell Donation Behaviors.

Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients with blood disorders and genetic diseases. Approximately 70% of the HSCTs currently performed in the United States use stems cells from an unrelated donor who donated voluntarily. Medical students (MS) are a young, diverse, influential population whose willingness to engage in altruistic acts, such as donating stem cells, may be correlated with knowledge on the topic. A literature gap exists in MS perspectives towards HSCT and the bone marrow registry (BMR) and prior studies suggest that misconceptions about donation deter MS from participation on the BMR, which may decrease opportunities to educate other potential donors. We performed a cross-sectional survey among the 4-year cohort of MS at Mayo Medical School in Rochester, Minnesota. The questionnaire evaluated multiple areas including whether MS were current members of the BMR and/or prior blood donors, MS current knowledge on donor eligibility (DE) and the donation process (DP), MS familiarity with HSCT and the DP, and MS attitudes towards joining the BMR and towards donating stem cells. The responses were analyzed and assessed alongside a self-reported, standardized scale measuring students' altruistic behaviors. There were 99 out of 247 potential respondents (40%), with 45% (n = 44) of MS in preclinical years 1 or 2, 37% (n = 37) in clinical years 3 or 4, and 18% (n = 18) in research or alternative portions of their training, of which 43% (n = 41) in total were current BMR members. BMR status correlated positively with prior blood donation (P = .015) and female sex (P = .014). Respondents had a 57.7% and 63.7% average correct response rate regarding knowledge of DE and DP, respectively, with knowledge of DE not surprisingly higher in BMR members (P < .0001). The majority of MS surveyed, 68% (n = 65), had learned about HSCT during medical school. BMR status correlated with the following attitudes towards donating stem cells: lower concern with all evaluated aspects of HSCT-time, cost, pain, and side effects (for all subsections, P < .05) but not with the altruism score (P = .32). The mean altruism score for respondents was 59.9 ± 11.3 (of a possible 100 points) with no significant difference in age, race, sex, level of training, or participation in the BMR. Altruism scores did not directly correlate with lower concern with aspects of time, cost, and pain of HSCT but did with long-term side effects (P = .021). This latter correlation was regardless of BMR status. Among MS, positive predictors for participation in the BMR included prior blood donation and female sex. BMR status did not ensure knowledge of all aspects of donating stem cells, but it correlated with less concern regarding the DP and was unrelated to altruism score. Improving knowledge gaps regarding the BMR and HSCT for the next generation of physicians and health care providers through expanded medical education curriculum may be beneficial to for the recruitment and retention of donor populations to the BMR.

The Incidence and Severity of Oral Mucositis among Allogeneic Hematopoietic Stem Cell Transplantation Patients: A Systematic Review.

Oral mucositis (OM) is a debilitating early adverse effect of allogeneic hematopoietic stem cell transplantation (HSCT). The intensity of the conditioning regimen correlates with the incidence and severity of OM, but no studies have analyzed this relationship among various conditioning regimens. We performed a systematic review on the incidence and outcomes of OM in allogeneic HSCT patients and analyzed this association. A comprehensive search of several databases (Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Cochrane CRCT, Cochrane DSR, Scopus) from 1990 to 2014 for studies of OM in allogeneic HSCT patients was conducted. Professional societies' meeting abstracts were also searched. Grade of OM was analyzed based on the World Health Organization (WHO) or National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events scales. Severe mucositis was defined as either grades 2 to 4 or grades 3 and 4, depending on the studies' definition of severity. Cohorts were analyzed based on regimen intensity; ie, reduced-intensity conditioning (RIC) (including nonmyeloablative) and myeloablative (MA). Random effect (RE) and standard logistic models weighted by the number of patients in each cohort were used for comparisons. A total of 624 studies were generated from the search. Of the 395 patients in 8 eligible MA regimen studies, 73.2% experienced any OM, whereas in 245 patients in the 6 eligible RIC regimen studies, 86.5% experienced any OM (chi-square P < .0001; RE, P = .05). Severe (grades 2 to 4) OM occurred among 79.7% of the WHO/NCI-graded MA patients and 71.5% of RIC patients (chi-square, P = .0421; RE, P < .01). In comparing graft-versus-host disease (GVHD) prophylaxis, only 55.4% of patients receiving nonmethotrexate regimens experienced OM; this was lower (chi-square, P < .0001; RE, P = .06) than that found among patients who received methotrexate (83.4%), either standard or reduced dose. Besides NCI and WHO grading scales, other scales included in the studies were Oral Mucositis Index, the Southwest Oncology Group Criteria, and Eastern Cooperative Oncology Group scale. To our knowledge, this is the first analysis on OM in allogeneic HSCT patients with respect to conditioning regimens, and we observed that RIC regimens led to a high incidence of OM similar to that of MA regimens. Clinical trials on treatment of OM are lacking, emphasizing the essential need for prospective studies in this arena. A significant variance in the criteria for grading OM underscores the importance of establishing a standard grading system for OM measurement in future allogeneic HSCT clinical trials.

Venous thromboembolism following hematopoietic stem cell transplantation-a systematic review and meta-analysis.

Venous thromboembolism (VTE) is a common complication of hematopoietic stem cell transplantation (HSCT). Graft-versus-host disease (GVHD) is another complication of HSCT that may modify the risk of VTE. Our objective was to explore the incidence of VTE (deep venous thrombosis and pulmonary embolism) following HSCT and to evaluate its association with GVHD. A comprehensive search of Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus was conducted to search for both retrospective and prospective HSCT studies which had reported VTE. Random-effects meta-analysis was used to pool incidence rates. We included 17 studies reporting on allogeneic- and 10 on autologous-HSCT; enrolling 6693 patients; of which 5 were randomized. The overall incidence of VTE after HSCT was 5 % (4-7 %). Incidence in allogeneic-HSCT was 4 % (2-6 %) and in autologous-HSCT was 4 % (1-15 %). Eleven and nine studies reported data on acute and chronic GVHD, respectively. The incidence of VTE in chronic GVHD was 35 % (20-54 %), whereas in acute GVHD it was 47 % (32-62 %). Based on the results of this meta-analysis, VTE is a fairly common complication after HSCT, emphasizing the importance of assimilating guidelines for both treatment and prophylaxis in this patient population.

A TRIP11:: FLT3 gene fusion in a patient with myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions: a case report and review of the literature.

Myeloid/lymphoid neoplasms with FLT3 gene fusions have recently been included among myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) in the World Health Organization classification and International Consensus Classification. As this entity remains remarkably rare, its scope and phenotypic features are evolving. In this report, we describe a 33-yr-old male with MLN-TK. Conventional chromosome analysis revealed a t(13;14)(q12;q32). Further analysis with mate-pair sequencing (MPseq) confirmed a TRIP11::FLT3 gene fusion. A diagnosis of MLN-TK was rendered. To the best of our knowledge, we report the third case of MLN-TK with a TRIP11::FLT3 gene fusion. In contrast to previously described cases, our case exhibited distinctly mild clinical features and disease behavior, emphasizing the diverse spectrum of MLN-TK at primary presentation and variability in disease course. MLN-TK with FLT3 gene fusions are a genetically defined entity which may be targetable with tyrosine kinase inhibitors with anti-FLT3 activity. Accordingly, from diagnostic and therapeutic viewpoints, genetic testing for FLT3 rearrangements using fluorescence in situ hybridization (FISH) or sequencing-based assays should be pursued for patients with chronic eosinophilia.

TELOMERE LENGTH OF PERIPHERAL BLOOD MONONUCLEAR CELLS IS ASSOCIATED WITH DISCHARGE DISPOSITION IN OLDER TRAUMA PATIENTS.

Introduction: Little is known regarding peripheral blood mononuclear cell telomere length (PBMC-TL) and response to traumatic injury. The objective of this study was to characterize the role of PBMC-TL in coagulation and clinical outcomes after injury. Methods: Plasma and buffy coats were prospectively collected from trauma patients and healthy volunteers. DNA was purified and PBMC-TL quantified by quantitative polymerase chain reaction. Thrombin generation kinetics were expressed as lag time (in minutes), peak height (in nanometers), time to peak (in minutes), and endogenous thrombin potential (in nM × min). Results are in median and quartiles [Q1, Q3]. P < 0.05 was considered significant (Wilcoxon rank sum testing). Results: Forty-two younger patients (21 [20, 22] years, 69% were male) and 39 older patients (62 [61, 64] years, 79% were male) were included. There was no significant difference in Clinical Frailty Scores between groups. Younger patients had longer total PBMC-TL (0.40 Mb [0.30, 0.49] vs. 0.29 Mb [0.23, 0.33], P < 0.001) and longer average PBMC-TL per chromosome (4.3 kb [3.3, 5.3] vs. 3.2 kb [2.5, 3.7], P < 0.001). When older patients were stratified by 50th percentile of PBMC-TL, there were no differences in thrombin generation; however, those with shorter telomeres were less likely to be discharged home (29% vs. 77%, P = 0.004). Older patients in the bottom quartile of PBMC-TL had shorter lag time (2.78 min [2.33, 3.00] vs. 3.33 min [3.24, 3.89], P = 0.030) and were less likely to be discharged home (22% vs. 90%, P = 0.006) than those in the top quartile of PBMC-TL. Multivariable logistic regression models revealed both increased age and shorter PBMC-TL to be independent predictors of discharge disposition other than home. Conclusion: In older trauma patients, shorter PBMC-TL is associated with accelerated initiation of thrombin generation and lower likelihood of being discharged to home.

Utilizing next-generation sequencing to characterize a case of acute myeloid leukemia with t(4;12)(q12;p13) in the absence of ETV6/CHIC2 and ETV6/PDGFRA gene fusions.

The t(4;12)(q12;p13) has been rarely reported in both myeloid/lymphoid neoplasms with eosinophilia (ETV6/PDGFRA gene fusion) and acute myeloid leukemia (AML) (ETV6/CHIC2 gene fusion). The ability to accurately characterize t(4;12) is critical as myeloid neoplasms with PDGFRA rearrangements may be amenable to tyrosine kinase inhibitor (TKI) therapy. Herein, we describe a 60-year-old male with newly diagnosed AML and t(4;12)(q12;p13) by conventional chromosome studies. While the ETV6 break-apart fluorescence in situ hybridization (FISH) probe set demonstrated a balanced ETV6 gene rearrangement, the FIP1L1/CHIC2/PDGFRA tri-color and PDGFRA break-apart FISH probe sets could not resolve the ETV6 gene fusion partner. Mate-pair sequencing (MPseq), a next-generation sequencing assay, was subsequently performed and identified an ETV6 gene rearrangement (at 12p13) that involved an intergenic chromosomal region at 4q12, located between the CHIC2 and PDGFRA gene regions. Having excluded involvement by the PDGFRA gene region, the patient will not be considered for TKI therapy at any point during his medical management. The accurate characterization of structural rearrangements by NGS-based technologies, as demonstrated in this case, highlights the clinical relevance and potential impact on patient medical management of modern cytogenetic techniques.

Risk for Significant Kidney Function Decline After Acute Kidney Injury in Adults With Hematologic Malignancy.

INTRODUCTION: Acute kidney injury (AKI) affects 30% of adults hospitalized with hematologic malignancy. Little is known about the long-term impact on kidney outcomes in this population despite the close relationship between kidney function and malignancy treatment eligibility. The purpose of this population-based cohort study was to determine the effect of AKI on kidney function in the year following a new diagnosis of acute leukemia or lymphoma. METHODS: Participants were adults hospitalized within 3 weeks of malignancy diagnosis. Baseline kidney function was determined and AKI diagnosed using standardized criteria. Cox proportional hazard modeling examined the relationship between AKI and a ≥30% decline in estimated glomerular filtration rate (eGFR) from baseline in the 1 year following hospitalization as the primary endpoint. RESULTS: AKI occurred in 33% of 1064 participants, with 70% of episodes occurring within 48 hours of hospitalization, and significantly increased risk for a ≥ 30% decline in eGFR (hazard ratio [HR] 2.7, 95% confidence interval [CI] 2.2-3.5) and incident chronic kidney disease (HR 2.2, 95% CI 1.7-2.8). AKI remained a significant predictor of eGFR decline in subgroup and multivariable analyses (adjusted HR 1.9, 95% CI 1.4-2.7). A ≥ 30% decline in eGFR increased the risk for death within 1 year in participants with AKI (HR 2.1, 95% CI 1.3-3.3). CONCLUSION: Results aid in identifying individuals at highest risk for poor outcomes and highlight the need for research involving interventions that preserve kidney function from the time of initial hospitalization with a hematologic malignancy into the postdischarge period.