Myelodysplastic Neoplasms (MDS) with Ring Sideroblasts or SF3B1 Mutations: The Improved Clinical Utility of World Health Organization and International Consensus Classification 2022 Definitions, a Single-Centre Retrospective Chart Review.

Myelodysplastic neoplasms (MDS) with ring sideroblasts (RS) are diagnosed via bone marrow aspiration in the presence of either (i) ≥15% RS or (ii) 5-14% RS and an SF3B1 mutation. In the MEDALIST trial and in an interim analysis of the COMMANDS trial, lower-risk MDS-RS patients had decreased transfusion dependency with luspatercept treatment. A total of 6817 patients with suspected hematologic malignancies underwent molecular testing using a next-generation-sequencing-based genetic assay and 395 MDS patients, seen at our centre from 1 January 2018 to 31 May 2023, were reviewed. Of these, we identified 39 evaluable patients as having lower-risk MDS with SF3B1 mutations: there were 20 (51.3%) males and 19 (48.7%) females, with a median age of 77 years (range of 57 to 92). Nineteen (48.7%) patients had an isolated SF3B1 mutation with a mean variant allele frequency of 35.2% +/- 8.1%, ranging from 7.4% to 46.0%. There were 29 (74.4%) patients with ≥15% RS, 6 (15.4%) with 5 to 14% RS, one (2.6%) with 1% RS, and 3 (7.7%) with no RS. Our study suggests that a quarter of patients would be missed based on the morphologic criterion of only using RS greater than 15% and supports the revised 2022 definitions of the World Health Organization (WHO) and International Consensus Classification (ICC), which shift toward molecularly defined subtypes of MDS and appropriate testing.

Access to Oncology Medicines in Canada: Consensus Forum for Recommendations for Improvement.

Patient access to new oncology drugs in Canada is only possible after navigating multiple sequential systemic checkpoints for national regulatory approval, health technology assessment (HTA) and collective government price negotiation. These steps delay access and prevent health care providers from being able to prescribe optimal therapy. Eighteen Canadian oncology clinicians from the medicine, nursing and pharmacy professions met to develop consensus recommendations for defining reasonable government performance standards around process and timeliness to improve Canadian cancer patients' access to best care. A modified Delphi methodology was used to identify consensus on 30 questions involving five themes: accountability, disparities, endpoints, timeliness, and cost-effectiveness. It was agreed that greater transparency is required across regulatory and HTA processes. Health professionals in oncology are frustrated for their patients because they are unable to deliver the modern guideline-supported therapies they want to provide due to delays in approval or funding. Canadian health care providers request improvements in timely access to life-saving therapeutics in line with other comparator countries. Clinicians expect urgent improvements in Canadian health systems to give our patients their best chance of survival.

Thrombopoietin Receptor Agonists and Other Second-Line Therapies for Immune Thrombocytopenia: A Narrative Review With a Focus on Drug Access in Canada.

INTRODUCTION: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. After corticosteroids with or without intravenous immune globulin (first-line treatment), second-line treatment options include rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RAs), and fostamatinib. In Canada, the choice of second-line therapy is influenced by access to medications. The goals of this narrative review are to 1) summarize the evidence for the use of TPO-RAs and other second-line therapies in ITP and 2) highlight differences in public funding criteria for TPO-RAs across provinces and territories in Canada. METHODS: We conducted a literature review of second-line therapies for ITP. We solicited information on public funding programs for TPO-RAs in Canada from health care providers, pharmacists, and provincial ministries of health. RESULTS: Head-to-head trials involving TPO-RAs, rituximab, splenectomy, and fostamatinib are lacking. There is substantial evidence of effect for TPO-RAs in improving platelet count levels, health-related quality of life, bleeding, and fatigue from placebo-controlled trials and observational studies; however, access to TPO-RAs through provincial funding programs in Canada is variable. Splenectomy failure is a prerequisite for the funding of TPO-RAs in Ontario, Manitoba, and Saskatchewan, but not in Alberta or Quebec. Other provinces either do not have access to public funding or funding is provided on a case-by-case basis. DISCUSSION: TPO-RAs are effective second-line therapies for the treatment of ITP; however, access is variable across Canada, which results in health disparities and poor uptake of international treatment guidelines.

Merkel cell carcinoma mimicking acute leukemia.

Bone marrow aspirate showed diffuse infiltration by a population of monomorphic cells with scant cytoplasm, markedly increased nuclear-to-cytoplasmic ratio, and numerous indistinct nucleoli. Bone marrow biopsy confirmed extensive marrow infiltration by a malignant neoplasm with strong and diffuse expression of synaptophysin by immunohistochemistry, consistent with metastases from Merkel Cell carcinoma.

An Approach to the Investigation of Thrombocytosis: Differentiating between Essential Thrombocythemia and Secondary Thrombocytosis.

Background: Thrombocytosis is a common reason for referral to Hematology. Differentiating between secondary causes of thrombocytosis and essential thrombocythemia (ET) is often clinically challenging. A practical diagnostic approach to identify secondary thrombocytosis could reduce overinvestigation such as next generation sequencing (NGS) panel. Methods and Results: All adult patients with thrombocytosis (≥450 × 109/L) who underwent molecular testing at a single tertiary care centre between January 1, 2018 and May 31, 2021 were evaluated. Clinical and laboratory variables were compared between patients with secondary thrombocytosis vs. ET. Clinical variables included smoking, thrombosis, splenectomy, active malignancy, chronic inflammatory disease, and iron deficiency anemia. Laboratory variables included complete blood count (CBC), ferritin, and myeloid mutations detected by NGS. The overall yield of molecular testing was 52.4%; 92.1% of which were mutations in JAK2, CALR, and/or MPL. Clinical factors predictive of ET included history of arterial thrombosis (p < 0.05); active malignancy, chronic inflammatory disease, splenectomy, and iron deficiency were associated with secondary thrombocytosis (p < 0.05). A diagnosis of ET was associated with higher hemoglobin, mean corpuscular volume (MCV), red cell distribution width (RDW), and mean platelet volume (MPV), while secondary thrombocytosis was associated with higher body mass index, white blood cells, and neutrophils (p < 0.01). Conclusion: A practical approach to investigating patients with persistent thrombocytosis based on clinical characteristics such as active malignancy, chronic inflammatory disease, splenectomy, and iron deficiency may assist in accurately identifying patients more likely to have secondary causes of thrombocytosis and reduce overinvestigation, particularly costly molecular testing.

Urticaria pigmentosa and systemic mastocytosis.

Key Clinical Message: Additional investigations for systemic involvement should be initiated once the diagnosis of cutaneous mastocytosis has been established in an adult patient. A serum tryptase can serve as a screening test for systemic mastocytosis, and persistent elevations should prompt further investigations, such as bone marrow studies. Abstract: Urticaria pigmentosa (UP) is the most common form of cutaneous mastocytosis, presenting as a wide variety of macroscopic appearances. Cutaneous mastocytosis in pediatric patients usually does not present with systemic involvement, but more than half of adult patients with cutaneous mastocytosis demonstrate systemic involvement. Currently, there is no guidance surrounding systemic testing in patients with UP. A 50-year-old Caucasian male was referred to the Clinical Immunology and Allergy clinic with a history of a rash. He initially presented to hospital 12 years prior with group A beta hemolytic streptococcus bacteremia treated with multiple different antibiotics. One week following discharge, he developed erythematous brown spots on his right leg which were flat, non-pruritic, and not painful. The rash later expanded to his trunk and extremities. A skin biopsy performed 2 years prior to referral to our clinic demonstrated urticaria pigmentosa. The CD117 immunohistochemical stain showed increased perivascular and interstitial mast cells in the superficial dermis. Darier's sign was negative on physical examination, and venom testing was also negative. Although he had no symptoms of systemic involvement, his serum tryptase was elevated at 47.6 ng/mL in the context of normal kidney and liver function. A skeletal survey was normal, and an abdominal ultrasound ruled out splenomegaly. Bone marrow biopsy demonstrated a mild increase in paratrabecular and perivascular atypical mast cells, in keeping with systemic mastocytosis. Adult patients with cutaneous mastocytosis have a high likelihood of having an underlying systemic mast cell disorder. Therefore, any patient presenting with characteristic skin findings should be investigated as having a cutaneous manifestation of systemic mastocytosis. This case demonstrates the utility of serum tryptase and its role in triggering additional investigations and guiding appropriate therapy.

Transfusion camp: A retrospective study of self-reported impact on postgraduate trainee transfusion practice.

BACKGROUND: The optimal method of postgraduate transfusion medicine (TM) education remains understudied. One novel approach is Transfusion Camp, a longitudinal 5-day program that delivers TM education to Canadian and international trainees. The purpose of this study was to determine the self-reported impact of Transfusion Camp on trainee clinical practice. STUDY DESIGN AND METHODS: A retrospective analysis of anonymous survey evaluations from Transfusion Camp trainees over three academic years (2018-2021) was conducted. Trainees were asked, "Have you applied any of your learning from Transfusion Camp into your clinical practice?". Through an iterative process, responses were categorized into topics according to program learning objectives. The primary outcome was the rate of self-reported impact of Transfusion Camp on clinical practice. Secondary outcomes were to determine impact based on specialty and postgraduate year (PGY). RESULTS: Survey response rate was 22%-32% over three academic years. Of 757 survey responses, 68% of respondents indicated that Transfusion Camp had an impact on their practice, increasing to 83% on day 5. The most frequent areas of impact included transfusion indications (45%) and transfusion risk management (27%). Impact increased as PGY increased with 75% of PGY-4+ trainees reporting impact. In multivariable analysis, the impact of specialty and PGY varied depending on the objective. DISCUSSION: The majority of trainees report applying learnings from Transfusion Camp to their clinical practice with variations based on PGY and specialty. These findings support Transfusion Camp as an effective means of TM education and help identify high-yield areas and gaps for future curriculum planning.

Pericardial Extramedullary Hematopoiesis Associated with Metastatic Adenocarcinoma of Gastrointestinal or Pancreaticobiliary Origin: A Case Report.

Extramedullary hematopoiesis (EMH) is a rare complication of solid tumor malignancies. We describe the first case of a patient who developed EMH in the pericardium secondary to metastatic gastrointestinal or pancreaticobiliary cancer. A 58-year-old man presented with recurrent episodes of fatigue and shortness of breath and was treated with thoracocentesis and pericardiocentesis for pleural and pericardial effusions, respectively. Owing to a markedly elevated alkaline phosphatase, a bone scan was performed and demonstrated diffuse sclerotic lesions. Evaluation of pleural effusion diagnosed metastatic adenocarcinoma, and cytospin morphology of the pericardial fluid demonstrated EMH. While EMH secondary to solid tumors is commonly suggested to be due to cytokine signaling, we propose the mechanism of EMH in this patient was due to extensive disruption of bone marrow hematopoiesis, similar to what is seen in myeloproliferative neoplasms.

A Rational Approach to JAK2 Mutation Testing in Patients with Elevated Hemoglobin: Results from the JAK2 Prediction Cohort (JAKPOT) Study.

BACKGROUND: Erythrocytosis, most often measured as an increase in hemoglobin and/or hematocrit, is a common reason for referral to internal medicine and hematology clinics and a rational approach is required to effectively identify patients with polycythemia vera while avoiding over-investigation. AIM: We aimed to develop and validate a simple rule to predict JAK2 mutation positivity based on complete blood count parameters to aid in the diagnostic approach to patients referred for elevated hemoglobin. SETTING: Internal medicine and hematology clinics at an academic tertiary referral center. PARTICIPANTS: The JAK2 Prediction Cohort (JAKPOT), a large retrospective cohort (n = 901) of patients evaluated by internal medicine and hematology specialists for elevated hemoglobin. DESIGN: JAK2 mutation analysis was performed in all patients and clinical and laboratory variables were collected. Patients were randomly divided into derivation and validation cohorts. A prediction rule was developed using data from the derivation cohort and tested in the validation cohort. KEY RESULTS: The JAKPOT prediction rule included three variables: (i) red blood cell count >6.45×1012/L, (ii) platelets >350×109/L, and (iii) neutrophils >6.2×109/L; absence of all criteria was effective at ruling out JAK2-positivity with sensitivities 94.7% and 100%, and negative predictive values of 98.8% and 100% in the derivation and validation cohorts, respectively, with an overall low false negative rate of 0.4%. The rule was validated for three different methods of JAK2 testing. Applying this rule to our entire cohort would have resulted in over 50% fewer tests. CONCLUSION: In patients with elevated hemoglobin, the use of a simple prediction rule helps to accurately identify patients with a low likelihood of having a JAK2 mutation, potentially limiting costly over-investigation in this common referral population.

Secondary causes of elevated hemoglobin in patients undergoing molecular testing for suspected polycythemia vera in southwestern Ontario: a chart review.

BACKGROUND: Molecular testing for JAK2 mutations is part of the standard diagnostic workup for patients with suspected polycythemia vera. We sought to characterize evolving practice patterns in the investigation of erythrocytosis and the prevalence of secondary causes, including use of medications such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, among patients who underwent molecular testing. METHODS: We reviewed charts of all consecutive patients investigated for erythrocytosis (hemoglobin > 160 g/L for women, > 165 g/L for men) with JAK2 testing between 2015 and 2021 at London Health Sciences Centre, a tertiary referral centre in Ontario, Canada, to assess changes in rates of JAK2 mutation positivity, average hemoglobin levels and the prevalence of secondary causes of erythrocytosis. RESULTS: A total of 891 patients with erythrocytosis underwent JAK2 mutation testing with an increase in number of tests (particularly from 2017 to 2018), a decrease in the rate of JAK2 positivity and similar average hemoglobin levels over the study period. We observed a high proportion of patients with secondary causes of erythrocytosis, ranging from 59% to 74% over the study period, including medications associated with erythrocytosis, namely testosterone (6%-11%) and SGLT2 inhibitors (2%-19%). Stopping SGLT2 inhibitors was associated with a significant decrease in hemoglobin levels (mean -14.7 g/L, 95% confidence interval -18.9 to -10.5 g/L) compared with continuation. INTERPRETATION: Use of SGLT2 inhibitors may be a common and underrecognized secondary cause of elevated hemoglobin levels in patients investigated for erythrocytosis. Our findings underscore the importance of a detailed medical history to support judicious use of molecular testing, in adherence with the current guideline on the investigation of erythrocytosis.

T-cell clonality testing for the diagnosis of T-cell large granular lymphocytic leukemia: Are we identifying pathology or incidental clones?

INTRODUCTION: T-cell clonality testing by T-cell receptor (TCR) gene rearrangement is key to the diagnosis of T-cell lymphoproliferative disorders such as T-cell large granular lymphocytic (T-LGL) leukemia. Benign clonal T-cell expansions, however, are commonly found in patients without identifiable disease, a condition referred to as T-cell clones of uncertain significance (T-CUS). In practice, T-cell clonality testing is performed for a range of reasons and results are often challenging to interpret given the overlap between benign and malignant clonal T-cell proliferations and uncertainties in the management of T-CUS. METHODS: We conducted a 5-year retrospective cohort study of 211 consecutive patients who underwent PCR-based T-cell clonality testing for suspected T-LGL leukemia at our institution to characterize the use of T-cell clonality testing and its impact on patient management. RESULTS: Overall, 46.4% (n = 98) of individuals tested had a clonal T-cell population identified. Patients with a monoclonal T-cell population were more likely to be older, have rheumatoid arthritis and have higher lymphocyte counts compared to patients with polyclonal populations. The majority of patients eventually diagnosed and treated for T-LGL leukemia had rheumatoid arthritis and lower neutrophil counts compared to untreated patients with monoclonal T-cell populations. A diagnosis of T-LGL leukemia was made in only a minority of patients (n = 48, 22.7%), and only a small proportion were treated (n = 17, 8.1%). CONCLUSION: Our study suggests that T-cell clonality testing most commonly identifies incidental T-cell clones with only a minority of patients receiving a diagnosis of T-LGL leukemia and fewer requiring active treatment. These finding indicate an opportunity to improve utilization of T-cell clonality testing in clinical practice to better target patients where the results of testing would impact clinical management.

The Efficacy and Safety of Fostamatinib in Elderly Patients with Immune Thrombocytopenia: A Single-Center, Real-World Case Series.

Fostamatinib is a small molecule spleen tyrosine kinase (Syk) inhibitor that was approved for the treatment of adult patients with immune thrombocytopenia (ITP) in second-line therapy. Syk inhibition prevents cytoskeletal rearrangements during phagocytosis, allowing platelet survival in ITP. However, fostamatinib treatment in elderly patients with ITP has not been well established. We performed a retrospective review of all elderly patients (age greater than or equal to 65 years) who had started on fostamatinib for the treatment of ITP at a single tertiary care centre to evaluate its efficacy and safety. Seven patients, median age 80 years (range 78-94), four women and three men, all of Caucasian background, with various comorbidities, started fostamatinib 100 mg orally twice daily as second or subsequent line therapy. Patients had a diagnosis of ITP for a median of 6 years (range approximately 6 months-30 years), had six comorbidities (range 2-14), and experienced 2 unique prior lines of ITP therapy (range 1 to 6). Over 1290 days of fostamatinib exposure, two patients required dose escalation to 150 mg orally twice daily, while five patients remained on the initial starting dose of 100 mg twice daily. The median platelet count at the time of initiating fostamatinib was 25 × 109/L (range less than 10-193). The median time to response (defined as any first platelet count greater than or equal to 30 × 109/L) was 19 days (range 0-181 days), with two patients responding rapidly (5 days and 19 days). Two patients required dose escalation and rescue therapy, and these same two patients discontinued fostamatinib after 175 days and 216 days of treatment. Treatment was tolerated in all patients with no thromboembolic events observed. One death was noted and unrelated to treatment. Overall, fostamatinib was effective and safe for the majority of these very elderly patients with ITP.

Mutational Landscape of Patients Referred for Elevated Hemoglobin Level.

Background: Since the identification of JAK2 V617F and exon 12 mutations as driver mutations in polycythemia vera (PV) in 2005, molecular testing of these mutations for patients with erythrocytosis has become a routine clinical practice. However, the incidence of myeloid mutations other than the common JAK2 V617F mutation in unselected patients referred for elevated hemoglobin is not well studied. This study aimed to characterize the mutational landscape in a real-world population of patients referred for erythrocytosis using a targeted next-generation sequencing (NGS)-based assay. Method: A total of 529 patients (hemoglobin levels >160 g/L in females or >165 g/L in males) were assessed between January 2018 and May 2021 for genetic variants using the Oncomine Myeloid Research Assay (ThermoFisher Scientific, Waltham, MA, USA) targeting 40 key genes with diagnostic and prognostic implications in hematological conditions (17 full genes and 23 genes with clinically relevant "hotspot" regions) and a panel of 29 fusion driver genes (>600 fusion partners). Results: JAK2 mutations were detected in 10.9% (58/529) of patients, with 57 patients positive for JAK2 V617F, while one patient had a JAK2 exon 12 mutation. Additional mutations were detected in 34.5% (20/58) of JAK2-positive patients: TET2 (11; 19%), DNMT3A (2;3.4%), ASXL1 (2; 3.4%), SRSF2 (2; 3.4%), BCOR (1; 1.7%), TP53 (1; 1.7%), and ZRSR2 (1; 1.7%). Diagnosis of PV was suspected in 2 JAK2-negative patients based on the 2016 World Health Organization (WHO) diagnostic criteria. Notably, one patient carried mutations in the SRSF2 and TET2 genes, and the other patient carried mutations in the SRSF2, IDH2, and ASXL1 genes. Three JAK2-negative patients with elevated hemoglobin who tested positive for BCR/ABL1 fusion were diagnosed with chronic myeloid leukemia (CML) and excluded from further analysis. The remaining 466 JAK2-negative patients were diagnosed with secondary erythrocytosis and mutations were found in 6% (28/466) of these cases. Conclusion: Mutations other than JAK2 mutations were frequently identified in patients referred for erythrocytosis, with mutations in the TET2, DNMT3A, and ASXL1 genes being detected in 34.5% of JAK2-positive PV patients. The presence of additional mutations, such as ASXL1 mutations, in this population has implications for prognosis. Both the incidence and mutation type identified in patients with secondary erythrocytosis likely reflects incidental, age-associated clonal hematopoiesis of indeterminate potential (CHIP).

Plasma transfusion practices: A multicentre electronic audit.

BACKGROUND AND OBJECTIVES: Plasma is often transfused to patients with bleeding or requiring invasive procedures and with abnormal tests of coagulation. Chart audits find half of plasma transfusions unnecessary, resulting in avoidable complications and costs. This multicentre electronic audit was conducted to determine the proportion of plasma transfused without an indication and/or at a sub-therapeutic dose. METHODS: Data were extracted on adult inpatients in 2017 at five academic sites from the hospital electronic chart, laboratory information systems and the Canadian Institute for Health Information Discharge Abstract Database. Electronic criteria for plasma transfusion outside recommended indications were: (1) international normalized ratio (INR) < 1.5 with no to moderate bleeding; (2) INR ≥ 1.5, with no to mild bleeding and no planned procedures; and (3) no INR before or after plasma infusion. Sub-therapeutic dose was defined as ≤2 units transfused. RESULTS: In 1 year, 2590 patients received 6088 plasma transfusions encompassing 11,490 units of plasma occurred at the five sites. 77.7% of events were either outside indications or under-dosed. Of these, 34.8% of plasma orders had no indication identified, and 62% of these occurred in non-bleeding patients and no planned procedure with an isolated elevated INR. 70.7% of transfusions were under-dosed. Most plasma transfusions occurred in the intensive care unit or the operating room. Inter-hospital variability in peri-transfusion testing and dosing was observed. CONCLUSION: The majority of plasma transfusions are sub-optimal. Local hospital culture may be an important driver. Electronic audits, with definitions employed in this study, may be a practical alternative to costly chart audits.