Vijayvargiya, Pooja

Abstract Introduction: The landscape of classical hematology has undergone substantial evolution over the last decade, marked by new diagnostic tools, nuanced therapeutic strategies, and an expanding understanding of underlying pathophysiology. This increasing complexity often presents unique diagnostic and therapeutic challenges. These challenges are further compounded by workforce shortages in classical hematology marked by educational gaps, geographic limitations, and difficulty accessing prompt specialty care. Unlike the well-established “Tumor Boards” in oncology, a comparable dedicated, widely accessible forum for classical hematology has largely been absent. This gap contributes to potential practice heterogeneity and isolation, especially across dissimilar care settings and geographic regions, impacting the consistent application of evidence-based practices and access to specialized expertise. To address this critical need, the “Blood Board” initiative was created to serve as an informal, virtual resource for discussing classical hematology topics and cases, fostering diverse perspectives, and collaborative problem-solving. Methods: The Blood Board was formally launched in April 2025, operating as a bi-monthly, hour-long virtual meeting conducted via non-recorded videoconferencing. The forum was designed with broad inclusivity in mind, welcoming all healthcare professionals involved in the care of adult patients with classical hematologic disorders, including trainees such as hematology/oncology fellows, academic and community-based hematologists, and any other interested providers. To date, dissemination of this initiative has been by word of mouth and e-mails containing a calendar invitation have been sent to anyone interested in participating (https://forms.gle/doyHNSx1SVFBJZmy8). To facilitate participation from various practice models and geographical locations, the virtual format was prioritized, eliminating barriers of travel and time commitment often associated with traditional in-person conferences. Participation is voluntary, encouraging an open and informal environment for de-identified case presentations, didactic discussions, and expert opinion sharing. Self-reported data on participant demographics (e.g., role, practice setting) and geographical representation have been collected to assess the initiative's reach and impact. Results: To date, sessions have consistently garnered engagement with a median of five participants in attendance at each session. There have been over 20 unique participants representing a broad spectrum of roles including both trainees and practicing hematologists/hematologist-oncologists and drawing from private practice, community-based hospitals, and academic medical centers. Over half of all participants were either in fellowship or within five years of completion of training. The virtual format has successfully overcome geographical limitations, attracting attendees from numerous states including Alabama, Florida, Georgia, Maryland, Minnesota, Missouri, Pennsylvania, South Dakota, and Wisconsin highlighting its broad appeal and potential for knowledge dissemination across a wide professional network. Conclusions: The Blood Board has demonstrated utility and met a previously unaddressed need. Sustained intellectual interest in Blood Board, coupled with a wide geographical and professional reach underscores a critical role for accessible, free, and multidisciplinary collaborative platforms in the evolving field of classical hematology. Similar to Tumor Boards, Blood Board promotes knowledge exchange and evidence-based care, garners expert support for challenging cases, and harmonizes clinical approaches, which we hope may ultimately improve patient care outcomes across diverse settings. Furthermore, this platform facilitates a national classical hematology community to support workforce development. Future goals include expanding dissemination efforts, measuring specific educational benefits, analyzing impacts on patient care, and increasing participant diversity, including recruitment of advanced practice providers and pharmacists.

SummaryBackgroundWhen opioid‐induced constipation is treated with centrally acting opioid antagonists, there may be opioid withdrawal or aggravation of pain due to inhibition of μ‐opioid analgesia. This led to the development of peripherally acting μ‐opioid receptor antagonists (PAMORAs).AimTo evaluate the efficacy of available PAMORAs and other approved or experimental treatments for relieving constipation in patients with opioid‐induced constipation, based on a systematic review and meta‐analysis of published studies.MethodsA search of MEDLINE, EMBASE and EBM Reviews Cochrane Central Register of Controlled Trials was completed in July 2019 for randomised trials compared to placebo. FDA approved doses or highest studied dose was evaluated. Efficacy was based on diverse endpoints, including continuous variables (the bowel function index, number of spontaneous bowel movements and stool consistency based on Bristol Stool Form Scale), or responder analysis (combination of >3 spontaneous bowel movements or complete spontaneous bowel movements plus 1 spontaneous bowel movement or complete spontaneous bowel movements, respectively, over baseline [so‐called FDA endpoints]). Adverse effects evaluated included central opioid withdrawal, serious adverse events, abdominal pain and diarrhoea.ResultsWe included 35 trials at low risk of bias enrolling 13 566 patients. All PAMORAs demonstrated efficacy on diverse patient response endpoints. There was greater efficacy with approved doses of the PAMORAs (methylnaltrexone, naloxegol and naldemidine), with lower efficacy or lower efficacy and greater adverse effects with combination oxycodone with naloxone, lubiprostone and linaclotide.ConclusionsTherapeutic response in opioid‐induced constipation is best achieved with the PAMORAs, methylnaltrexone, naloxegol and naldemidine, which are associated with low risk of serious adverse events.

Abstract Background : Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) is a provisional entity in the MDS/MPN overlap syndromes, with diagnostic features of RARS, along with a platelet count > 450 x 10(9)/L and large atypical megakaryocytes. Mutations involving SF3B1 (~80%), JAK2 (~60%), TET2 (~25%) and ASXL1 (~15%) have been reported. The frequency of thrombotic events in RARS-T is thought to be similar to that of essential thrombocytosis (ET) (3.6 vs 3.9/100 patient years; Hematologica 2012; 1036-41). However, unlike in ET, it remains unclear as to whether thrombotic events in RARS-T impact overall (OS) or thrombosis-free (TFS) survival. Methods : 82 patients with WHO-defined RARS-T were included in the study. All patients had bone marrow (BM) biopsies, iron stains for detection of BM ring sideroblasts (RS) and cytogenetics performed at diagnosis. Mutational analysis for JAK2, CALR, MPL, SF3B1, SRSF2 and ASXL1 was carried out on BM DNA obtained at the time of diagnosis. Details of type of thrombotic event and cardiovascular (CV) risk factors including; hypertension, diabetes, smoking and dyslipidemia were obtained by careful review of the medical record. OS was calculated from time of initial diagnosis to the time of last follow-up or death. TFS was calculated from the time of diagnosis of RARS-T to development of thrombosis in uncensored patients and date of last follow up or death in patients censored for thrombosis. Conventional statistics were utilized for all analyses. Results: Among the 82 study patients, 46 (56%) were males and median age was 72 years (range, 48-93). At a median follow-up of 26.5 months; 48 (59%) deaths and 2 leukemic transformations were documented. Median OS was 44 months. Karyotype was diploid in 61 (74%) and analyzed mutational frequencies were; SF3B1 67% (28/42), JAK2 V617F 40% (25/61), ASXL1 21% (9/41), SRSF2 6% (2/31), MPL 1% (2/41) and CALR 0, respectively. Cardiovascular risk factors were present in 52 (63%). a) Thrombotic events and their impact on thrombosis free survival: Eight (10%) patients had a thrombotic event prior to or at the time of diagnosis of RARS-T (venous-8, arterial-0). Nine (11%) patients developed subsequent thrombotic events (venous-7, arterial-2), with no fatalities. In univariate analysis, lower hemoglobin level (p=0.008), lower BM RS % (p=0.04), history of thrombosis (p=0.02), and absence of SF3B1 mutations (p=0.017) were associated with an inferior TFS. Age (p=0.07), JAK2 mutation status (p=0.56) and CV risk factors (p=0.95) did not have prognostic impact. Given the association between SF3B1 mutations and BM RS, in a multivariable model that included these two as covariates, only the absence of SF3B1 mutations retained prognostic significance (p=0.02). Absence of SF3B1 mutation remained significant when history of thrombosis or lower hemoglobin level were introduced into the multivariable model. b) Risk factors for overall survival: In univariate analysis, hemoglobin <10 gm/dl (p=0.007), presence of circulating blasts (p=0.002) and presence of CV risk factors (p=0.04) were associated with an inferior OS. Neither history of thrombosis (p=0.59) nor SF3B1 (p=0.12) mutations affected OS. In multivariable analysis, hemoglobin <10 gm/dl (p=0.03) [HR 1.9; 95% CI 1.1-3.5] and circulating blasts (p=0.002) [HR 1.3; 95% CI 1.1-1.6] remained significant. Conclusions: In contrast to what is observed in ET, thrombosis history does not appear to affect either overall or thrombosis-free survival in RARS-T. The current study suggests a lower thrombosis risk in SF3B1 -mutated patients with RARS-T, compared to their SF3B1 wild-type counterparts. Disclosures No relevant conflicts of interest to declare.

Abstract Background : Gene mutations are common (~90%) in patients with chronic myelomonocytic leukemia (CMML) and involve epigenetic regulators (TET2 ~ 60%, ASXL1 ~40%), spliceosome components (SRSF2 ~40%) and signal pathways (RAS ~30%). Of these, thus far, only ASXL1 mutations have been shown to adversely impact overall survival (OS). In the current study, we used a 27-gene panel assay to identify additional prognostically-relevant mutations in CMML and to also determine if number of mutations carries prognostic relevance. Methods : 175 patients with WHO-defined CMML were included in the study. All patients had bone marrow (BM) biopsies and cytogenetics performed at diagnosis. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for the following genes; TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF, and SETBP1. Paired-end indexed libraries were prepared from individual patient DNA using the NEBNext Ultra Library prep protocol on the Agilent Bravo liquid handler. Capture libraries were assembled according to Nimblegen standard library protocol. Base-calling was performed using Illumina's RTA version 1.17.21.3. Genesifter software was utilized to analyze targeted sequence data. Specific variants were deemed as mutations if they were associated with a hematological malignancy (as identified by COSMIC database), or if they were not associated with a dbSNP Results: Among the 175 study patients, 66% were males and median age was 70 years. 146 (83%) patients were subclassified as CMML-1. At a median follow-up of 23 months, 146 (83%) deaths and 25 (14%) leukemic transformations were documented. Median survivals were 24 months for CMML-1 and 16 months for CMML-2 (p=0.38). Mutational frequencies were; TET2 46%, ASXL1 45%, SRSF2 45%, SETBP1 19%, CBL 14%, RUNX1 14%, NRAS 12%, U2AF1 8%, SF3B1 6%, ZRSR2 6%, Tp53 5%, DNMT3A 5%, IDH2 5%, PTPN11 5%, SH2B3 5%, JAK2 4%, NPM1 3%, CSF3R 2%, IDH1 2%, EZH2 1%, SUZ12 1%, KIT 1%, FLT3 1%, CALR 1%. 172 patients (98%) had at least one mutation, 21 (12%) had 2, 24 (14%) had 3, 20 (11%) had 4, 9 (5%) had 5, while one (1%) patient had 6 concurrent mutations. Risk stratification was based on Mayo prognostic model: 25% high, 32% intermediate and 43 % low risk. In univariate analysis, presence of ASXL1 mutations (p=0.01), absence of TET2 mutations (p=0.005) and presence of DNMT3A mutations (p=0.02) were associated with inferior survival; in multivariable analysis, ASXL1 (p=0.01) and TET2 (p=0.03) mutations remained significant. In order to determine prognostic interaction between these two mutations, patients were stratified into four mutational categories: ASXL1wt/TET2wt (n =56), ASXL1mut/TET2wt (n =31), ASXL1mut/TET2mut (n =50) and ASXL1wt/TET2mut (n =38). Survival data in these four groups showed significant difference in favor of ASXL1wt/TET2mut (median survival 38 months; p=0.016), compared to those with ASXL1wt/TET2wt (19 months), ASXL1mut/TET2wt (31 months)and ASXL1mut/TET2mut (16 months); there was no significant difference in survival among the latter three groups (p=0.3) (Figure). The number of mutations per patient did not affect outcome (p=0.3). In multivariable analysis, presence of ASXL1 mutations (P=0.01) and absence of TET2 mutations (p=0.003) remained significant when risk factors used in the Mayo prognostic model (HB <10 gm/dl, AMC >10 x 10(9)/L, platelets <100 x 10(9)/L, circulating IMC) were added to the model; the same was true for ASXL1wt/TET2mut (p=0.036). In a separate multivariable analysis that included the Mayo prognostic model as a single variable along with presence of ASXL1 and absence of TET2 mutations; or absence of ASXL1wt/TET2mut mutational status, the respective hazard ratios were 1.4 (95% CI 1.07-2.1; p=0.012), 1.5 (95% CI 1.07-2.1; p=0.03) and 1.8 (95% CI 1.2-2.7; p=0.001). Leukemia-free survival was worse in ZRSR2 -mutated cases (p=0.03). Conclusions: Almost 100% of patients with CMML express one or more myeloid neoplasm-relevant mutations. The current study suggests a favorable prognostic impact from TET2 mutations, unless accompanied by ASXL1 mutations. Disclosures No relevant conflicts of interest to declare.

Abstract Background : Celiac disease (gluten sensitive enteropathy) is a systemic disease with hematological manifestations including; iron deficiency anemia, vitamin B12 and folate deficiency, leukopenia/neutropenia, hyposplenism, venous thromboembolism, and the enteropathy associated T cell lymphoma (E-TCL). Leukopenia/neutropenia is rare, and can result from folate or copper deficiency, but in many cases remains idiopathic. The consequences of neutropenia and neutrophil responses to a gluten free diet are not well described. We carried out this study to assess the incidence and outcomes of neutropenia in patients with celiac disease. Methods : The Mayo clinic celiac disease database (n=1729) was retrospectively analyzed for all patients with a confirmed diagnosis of celiac disease that had leukopenia (<3.5 x10(9)/L) and/or neutropenia (<1.5 x 10(9)/L). The diagnosis of celiac disease was established by positive tissue transglutaminase antibodies (TTG) and confirmatory small bowel biopsy findings. Additional causes of neutropenia such as copper and folate deficiency, drugs, benign ethnic and cyclic neutropenia, chemotherapy, hematological malignancies, combined variable immunodeficiency (CVID), and autoimmune diseases were meticulously excluded. Data abstracted included demographics, temporal association with diagnosis, nadir counts, associated hematological findings, relationship with infections, the use and effect of G-CSF, response to gluten free diet and survival outcomes. Results: 21(1.2%) of 1729 cases screened had idiopathic-celiac related neutropenia; 17 (81%) Caucasian, 15 (48%) females. In 12(57%) patients the neutropenia preceded or occurred near the time of the diagnosis of celiac disease, while in 7 (33.3%) it occurred subsequently. In 2 cases the temporal association could not be established. The median age at diagnosis of celiac disease was 46 years (10-67) and the median follow up for this group was 41.7 months (0-207.3). At last follow up 1 (4.8%) death has been documented; 0 from infectious complications, with no cases of E-TCL. The median laboratory values at diagnosis of celiac disease were available in 11 (52%) patients and included; hemoglobin 12.9 g/dL (10.5-16.8), MCV 91.5 fl (79.6-102.8), WBC 3.2 x109/L (2.3-5.2), ANC 1.29x109/L (0.33-3.24), ALC 1.34x109/L (0.75-2.17), AMC 0.39x109/L (0.15-0.71), and platelet counts 225x109/L (168-711). Anti-granulocyte antibodies were assessed in 7 patients and were negative in all cases. None of these patients had coexistent hyposplenism and three cases of neutropenia that occurred in the setting of celiac disease and CVID were excluded. In 15 (71%) patients the neutropenia was incidentally detected during routine laboratory work and in 4 (19%) it came to light secondary to infections. Ten (48%) patients had recurrent infections (≥1) as documented by their providers, including 7 with sinopulmonary infections, 1 with urinary tract infections, and 1 with skin and soft tissue infections. Additional immunological assessments were not available in these patients. Three (14%) patients had an ANC <500 (significant neutropenia); of which 2 had recurrent sinopulmonary infections. The third patient remained largely asymptomatic. Two of the 3 patients received G-CSF support during infections and responded adequately (ANC improvement > 1 x 10(9)/L). The ANC in patients in this cohort did not correlate with severity of infections. Five (23%) of 21 patients had improvement in neutrophil counts after adopting a gluten free diet, while there was no response in 10 and data was unavailable in 6. The median time to ANC response was 14.5 months (10-15.3) and the median increment in ANC was 0.67 x 10(9)/L (0.48-0.98). Conclusions: Celiac disease associated neutropenia, especially significant neutropenia (ANC <500) is a rare occurrence (~1%). It can often pre-date the diagnosis of celiac disease or occur subsequently. It is potentially associated with an increased incidence of infections, with-out good correlation with the severity of neutropenia. Less than half the patients do seem to respond to a gluten free diet. G-CSF responses seem to be adequate and G-CSF can be used in the setting of severe infections. Disclosures No relevant conflicts of interest to declare.