How to customize common data models for rare diseases: an OMOP-based implementation and lessons learned.

BACKGROUND: Given the geographical sparsity of Rare Diseases (RDs), assembling a cohort is often a challenging task. Common data models (CDM) can harmonize disparate sources of data that can be the basis of decision support systems and artificial intelligence-based studies, leading to new insights in the field. This work is sought to support the design of large-scale multi-center studies for rare diseases. METHODS: In an interdisciplinary group, we derived a list of elements of RDs in three medical domains (endocrinology, gastroenterology, and pneumonology) according to specialist knowledge and clinical guidelines in an iterative process. We then defined a RDs data structure that matched all our data elements and built Extract, Transform, Load (ETL) processes to transfer the structure to a joint CDM. To ensure interoperability of our developed CDM and its subsequent usage for further RDs domains, we ultimately mapped it to Observational Medical Outcomes Partnership (OMOP) CDM. We then included a fourth domain, hematology, as a proof-of-concept and mapped an acute myeloid leukemia (AML) dataset to the developed CDM. RESULTS: We have developed an OMOP-based rare diseases common data model (RD-CDM) using data elements from the three domains (endocrinology, gastroenterology, and pneumonology) and tested the CDM using data from the hematology domain. The total study cohort included 61,697 patients. After aligning our modules with those of Medical Informatics Initiative (MII) Core Dataset (CDS) modules, we leveraged its ETL process. This facilitated the seamless transfer of demographic information, diagnoses, procedures, laboratory results, and medication modules from our RD-CDM to the OMOP. For the phenotypes and genotypes, we developed a second ETL process. We finally derived lessons learned for customizing our RD-CDM for different RDs. DISCUSSION: This work can serve as a blueprint for other domains as its modularized structure could be extended towards novel data types. An interdisciplinary group of stakeholders that are actively supporting the project's progress is necessary to reach a comprehensive CDM. CONCLUSION: The customized data structure related to our RD-CDM can be used to perform multi-center studies to test data-driven hypotheses on a larger scale and take advantage of the analytical tools offered by the OHDSI community.

Impact of Facility Type on Survival in Chronic Myelomonocytic Leukemia: A Propensity Score Matched, National Cancer Database Analysis.

BACKGROUND: Chronic myelomonocytic leukemia (CMML) is a rare and likely underdiagnosed hematologic malignancy. Due to its rarity and nuances in diagnosis, many patients are referred to tertiary referral centers, although many continue to be cared for in the community setting. Given discrepancies in outcomes based on facility type in related myeloid malignancies, we hypothesized that CMML patients treated at academic centers may have improved survival as compared to patients treated at nonacademic centers (NACs). PATIENTS AND METHODS: Using the National Cancer Database (NCDB), we identified 6290 patients with CMML and collected data on demographics, comorbidities, treatment, and survival. We also performed a propensity matched analysis to control for baseline differences. RESULTS: We found that patients at academic centers had higher median overall survival (OS) (17.7 months vs 14.7 months) and 5-year OS (19.1% vs 15.3%) than patients at NACs. In addition, patients treated at an academic center were also more likely to receive hematopoietic stem cell transplant as compared to those treated at NACs. Time to treatment initiation was overall similar between academic and NACs. CONCLUSION: Our study of one of the largest available datasets of CMML patients supports the importance of referring CMML patients to academic centers upon diagnosis to optimize outcomes in this rare hematologic malignancy.

Evaluating the role of Day 14 bone marrow biopsy and European LeukemiaNet risk classification in predicting overall and relapse-free survival in acute myeloid leukemia.

Multivariable analysis for overall survival and relapse-free survival demonstrating lack of significant for D14 BM status.

Oral Decitabine/Cedazuridine Is an Effective Ambulatory Therapy for Patients With Myelofibrosis Refractory to JAK2 Inhibitor Therapy.

BACKGROUND: Outcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF. METHODS: We conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C +/- JAKi at Mount Sinai Hospital from 2021 to 2024. RESULTS: The cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (n = 9) receiving > 4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3 per cycle. CONCLUSIONS: This report demonstrates the feasibility, tolerability, and clinical benefit of an exclusively ambulatory regimen for high-risk, elderly patients with advanced MF which warrants further evaluation in a prospective clinical trial.

Equivalent thrombotic risk with Warfarin, Dabigatran, or Enoxaparin after failure of initial direct oral anticoagulation (DOAC) therapy.

BACKGROUND: The direct oral anticoagulants (DOACs) are now commonly regarded as first line anticoagulants in most cases of venous thromboembolism (VTE). However, the optimal choice of subsequent anticoagulant in instances of first line DOAC failure is unclear. OBJECTIVES: To describe and compare outcomes with second line anticoagulants used after DOAC failure. METHODS: Patients seen at an urban hospital system for an episode of acute VTE initially treated with either apixaban or rivaroxaban who experienced a subsequent recurrent thrombosis while on anticoagulation (1st recurrent thrombosis) were included. RESULTS: In total, 166 patients after apixaban or rivaroxaban failure were included. Following DOAC failure (1st recurrent thrombosis), the subsequent anticoagulant was warfarin in 60 patients (36%), dabigatran in 42 patients (25%), and enoxaparin in 64 patients (39%). Enoxaparin was preferentially prescribed in patients with a malignancy-associated etiology for 1st recurrent thrombosis (p < 0.01). The median follow-up time in our cohort was 16 months. There was no difference in 2nd recurrent thrombosis-free survival (p = 0.72) or risk for major bleeding event (p = 0.30) among patients treated with dabigatran, warfarin, or enoxaparin. CONCLUSIONS: In this retrospective analysis of patients failing first line DOAC therapy, rates of 2nd recurrent thrombosis and bleeding did not differ among subsequently chosen anticoagulants. Our study provides evidence that the optimal 2nd anticoagulant is not clear, and the choice of 2nd anticoagulant should continue to balance patient preference, cost, and provider experience.

Conventional Cytogenetic Analysis and Array CGH + SNP Identify Essential Thrombocythemia and Prefibrotic Primary Myelofibrosis Patients Who Are at Risk for Disease Progression.

The Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) are a heterogeneous group of clonal hematopoietic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (prePMF). In this study, we retrospectively reviewed the karyotypes from conventional cytogenetics (CC) and array Comparative Genomic Hybridization + Single Nucleotide Polymorphism (aCGH + SNP) in patients with ET or prePMF to determine whether the combined analysis of both methodologies can identify patients who may be at a higher risk of disease progression. We performed a comprehensive genomic review on 169 patients with a clinical diagnosis of ET (154 patients) or prePMF (15 patients). Genomic alterations detected by CC or array-CGH + SNP were detected in 36% of patients. In patients who progressed, 68% had an abnormal genomic finding by either technology. There was a shorter progression-free survival (PFS) among patients who were cytogenetically abnormal or who were cytogenetically normal but had an abnormal aCGH + SNP result. Leveraging the ability to detect submicroscopic copy number alterations and regions of copy neutral-loss of heterozygosity, we identified a higher number of patients harboring genomic abnormalities than previously reported. These results underscore the importance of genomic analysis in prognostication and provide valuable information for clinical management and treatment decisions.

Systematic review and meta-analysis evaluating clinical outcomes in adult acute myeloid leukemia patients with central nervous system involvement.

Patients with acute myeloid leukemia (AML) may experience extramedullary involvement when disease is present outside of the blood and bone marrow. In particular, the presence of central nervous system (CNS) involvement has traditionally been thought of as a poor prognostic factor. In the presently available literature, there is a paucity of conclusive data surrounding CNS AML given its rarity and lack of unified screening practices. Thus, we performed a systematic review and meta-analysis in order to more definitively characterize survival outcomes in this patient population. In this meta-analysis, we evaluated survival outcomes and response rates from clinical studies on patients with AML stratified by the presence of CNS involvement. Twelve studies were included in the meta-analysis with a resulting hazard ratio (HR) for overall survival (OS) of 1.34 with a 95 % CI of 1.14 to 1.58. These findings suggest that CNS involvement in adult patients with AML is associated with an increased hazard of mortality compared to those patients without CNS involvement. As such, CNS involvement should be viewed as negative prognostic marker, and attention should be made to ensure prompt identification and treatment of patients who experience this complication.

Discontinuation Syndrome With JAK2 Selective Agents: Case Presentation and Mechanistic Insights.

We report the first case of pacritinib-withdrawal syndrome with in vitro elucidation of underlying mechanisms.

Understanding triple negative myeloproliferative neoplasms: pathogenesis, clinical features, and management.

ABSTRACTMyeloproliferative neoplasms (MPNs) that lack the classical "driver mutations," termed triple negative MPNs, remain a poorly understood entity. Despite considerable progress toward understanding MPN pathobiology, the mechanisms leading to the development of these MPNs remains inadequately elucidated. While triple negative primary myelofibrosis (TN-PMF) portends a poor prognosis, triple negative essential thrombocythemia (TN-ET) is more favorable as compared with JAK2 mutated ET. In this review, we summarize the clinical features and prognosis of TN-PMF and -ET as well as diagnostic challenges including identification of non-canonical driver mutations. We also discuss additional molecular drivers to better understand possible pathogenic mechanisms underlying triple negative MPNs. Finally, we highlight current therapeutic approaches as well as novel targets, particularly in the difficult to treat TN-PMF population.

Cytoreduction for ET and PV: who, what, when, and how?

Thrombotic complications are the primary contributor to morbidity and mortality in essential thrombocythemia (ET) and polycythemia vera (PV). Cytoreductive therapy is the main tool for primary or tertiary thrombosis prevention in these diseases. In general, high-thrombotic-risk patients and those with symptoms that may be ameliorated from cytoreductive therapy are candidates for this treatment, although the decision is highly individualized. Approved options for cytoreduction in ET and PV include hydroxyurea, long-acting interferons, anagrelide in ET, and ruxolitinib in PV. Selecting the ideal agent requires careful consideration of the toxicity profiles and individual treatment goals. In this review the existing literature on cytoreductive decisions in ET and PV is summarized, with an emphasis on risk-stratification, highlighting the need for personalized care in order to maximize the benefit of these therapies while minimizing toxicities.

Dasatinib-Associated Acneiform Eruption Successfully Treated With Sarecycline in a Patient With Chronic Myeloid Leukemia.

Dasatinib is a second-generation tyrosine inhibitor that is used for the treatment of patients with chronic myeloid leukemia (CML). It can cause a myriad of skin toxicities, including pruritis, pigmentary abnormalities of hair and skin, and maculopapular rashes. Rarely, it can be associated with acneiform eruptions, which are typically treated with doxycycline. However, doxycycline may not be an ideal therapy, especially for long-term use, due to the risk of gut flora disruption, antimicrobial resistance, and side effects. We present a case of a CML patient who developed an acneiform eruption associated with dasatinib and was successfully treated with sarecycline, a narrow-spectrum tetracycline. Given its targeted spectrum of activity, sarecycline has a lower risk of antimicrobial resistance and an improved safety profile compared to first- and second-generation tetracyclines such as doxycycline. As acneiform drug eruptions can have a significant impact on a patient's quality of life, effective management by dermatologists is paramount. Sarecycline may be a suitable treatment with a favorable safety profile, making it an appropriate choice for patients, especially those who require long-term therapy.

Exclusion of Acute Myeloid Leukemia Patients with Central Nervous System Involvement from Clinical Trials: An Analysis of the National Institutes of Health Clinical Trials Registry from 2012-2022.

INTRODUCTION: Central nervous system (CNS) involvement in acute myeloid leukemia (AML) can be successfully treated with intrathecal chemotherapy and carries debatable prognostic impact. However, patients with CNS involvement are commonly excluded from clinical trials at an unknown rate. We systematically evaluated exclusion criteria of AML clinical trials based on CNS involvement and determined associations with clinical trial characteristics. METHODS: The National Institutes of Health Clinical Trials Registry was searched for interventional adult AML trials between 2012-2022 that were phase I, II, or III and relevant trial characteristics were extracted. RESULTS: 1270 trials were included in the analysis with 790 trials (62.1%) explicitly excluding CNS involvement. There was no significant change in rates of CNS exclusion over the past decade. CNS exclusion was higher in trials that included the non-transplant population compared to trials exclusive to the transplant population (66.9% vs. 43.8%, p<0.01). Non-transplant trials were also more likely to exclude patients with a history of or ambiguous timing of CNS involvement (p<0.01). Phase III trials were associated with more liberal definitions of CNS exclusion (history or ambiguous timing) as compared to phase I and II trials that had higher rates of excluding patients with only active CNS involvement (P<0.01). CONCLUSION: A majority of AML clinical trials, particularly in the non-transplant setting, exclude patients with CNS involvement. Many of these trials, most notably phase 3 trials, exclude patients not only with active, but any history of CNS involvement. Further research is needed to determine optimal management of these patients in order to increase representation in large clinical trials.

Multi-institutional analysis of outcomes in acute myeloid leukemia patients with central nervous system involvement.

We evaluated outcomes of AML patients with central nervous system (CNS) involvement at two academic institutions. Fifty-two adult patients were identified. Neurologic symptoms were reported in 69% of patients, with headache the most common (33%). 84% (n = 42) of patients cleared their cerebrospinal fluid (CSF), with a median number of one dose of intrathecal (IT) chemotherapy. Of these patients, 21% (n = 9) had a CSF relapse, with 67% (n = 6) of those experiencing CSF relapse also having concurrent bone marrow relapse. Of the 36 patients with baseline neurologic symptoms, 69% had improvement in symptoms post-IT therapy. The median overall survival was 9.3 months and 3.5 months for patients with CNS involvement diagnosed before/during induction and at relapse, respectively. In this study, IT therapy was rapidly effective in clearing CSF blasts and improving neurologic symptoms in most patients. Few patients experienced CSF relapse, which predominantly occurred in the setting of concomitant bone marrow relapse.

Energy expenditure in myelofibrosis patients treated with a JAK1/2 inhibitor.

Weight gain is a known adverse effect of ruxolitinib, a JAK1/2 inhibitor that is the mainstay of treatment for many patients with myelofibrosis. The mechanisms behind weight increase with ruxolitinib is incompletely understood, although decreased adipose tissue lipolysis and increased appetite due to blocking the effects of leptin in the hypothalamus have been proposed. In order to explore the metabolic changes in ruxolitinib-treated patients with myelofibrosis, we performed a pilot study to assess the feasibility of using a portable indirect calorimeter to quantify energy expenditure before and during ruxolitinib treatment and report the results of two patients. Waist circumference increased during ruxolitinib treatment in both patients. Energy expenditure initially increased followed by a decrease and then increase again, but to levels below baseline. These results suggest that weight gain secondary to ruxolitinib may be related to changes in whole body energy expenditure.

An overlooked mimic? Autoimmune myelofibrosis-A scoping review of the literature.

BACKGROUND AND OBJECTIVES: Autoimmune myelofibrosis (AIMF) is a rare cause of bone marrow fibrosis (BMF) occurring in the presence or absence of a defined autoimmune disease (secondary or primary AIMF, sAIMF/pAIMF, respectively). Unlike primary myelofibrosis (PMF), AIMF responds well to immunosuppressive therapy with a benign clinical course. Diagnostic criteria for AIMF in opposition to PMF have been lacking, though recent work has helped better characterise molecular and pathological features of AIMF, improving diagnostic precision. METHODS: Using a modern clinical and pathophysiological understanding of AIMF, we apply scoping review methodology and rigorous case-criteria to retrospectively analyse the case literature. We examine its patient-population, describing patient-associated factors, presentation, bone marrow pathology, genetics, treatment and outcomes. RESULTS: Fifty-five studies were identified, describing 139 AIMF patients. Patients were mostly young females (~4:1 ratio female:male, median age 40.8 years) and typically presented with cytopenias. Splenomegaly was rare. sAIMF was more common than pAIMF (~3:1 ratio), and most cases responded well to immunosuppressive therapy. CONCLUSIONS: Our results strengthen the emerging picture of AIMF's patient population, natural history and response to treatment. Further work should continue to use reproducible diagnostic criteria, and explore AIMF's pathophysiology, response to different therapies, and sequelae over larger timescales, as well as differences between pAIMF, sAIMF and PMF.

The core concepts of core binding factor acute myeloid leukemia: Current considerations for prognosis and treatment.

Core binding factor acute myeloid leukemia (CBF AML), defined by t(8;21) or inv(16), is a subset of favorable risk AML. Despite its association with a high complete remission rate after induction and relatively good prognosis overall compared with other subtypes of AML, relapse risk after induction chemotherapy remains high. Optimizing treatment planning to promote recurrence free survival and increase the likelihood of survival after relapse is imperative to improving outcomes. Recent areas of research have included evaluation of the role of gemtuzumab in induction and consolidation, the relative benefit of increased cycles of high dose cytarabine in consolidation, the utility of hypomethylating agents and kinase inhibitors, and the most appropriate timing of stem cell transplant. Surveillance with measurable residual disease testing is increasingly being utilized for monitoring disease in remission, and ongoing investigation seeks to determine how to use this tool for early identification of patients who would benefit from proceeding to transplant. In this review, we outline the current therapeutic approach from diagnosis to relapse while highlighting the active areas of investigation in each stage of treatment.

Emerging Treatment Options for Myelofibrosis: Focus on Anemia.

Myelofibrosis (MF) is a hematologic malignancy characterized by abnormal proliferation of myeloid cells and the release of pro-inflammatory cytokines, leading to progressive bone marrow dysfunction. The introduction of ruxolitinib just over a decade ago marked a significant advancement in MF therapy, with JAK inhibitors now being the first-line treatment for reducing spleen size and managing symptoms. However, early JAK inhibitors (ruxolitinib and fedratinib) are often associated with cytopenias, particularly thrombocytopenia and anemia, which limit their tolerability. To address these complications, pacritinib has been developed and recently approved for patients with thrombocytopenia, while momelotinib is in development for those with anemia. Although JAK inhibitors have significantly improved the quality of life of MF patients, they have not demonstrated the ability to reduce leukemic transformation and their impact on survival is debated. Numerous drugs are currently being developed and investigated in clinical trials, both as standalone therapy and in combination with JAK inhibitors, with promising results enhancing the benefits of JAK inhibitors. In the near future, MF treatment strategies will involve selecting the most suitable JAK inhibitor based on individual patient characteristics and prior therapy. Ongoing and future clinical trials are crucial for advancing the field and expanding therapeutic options for MF patients.