The characteristics of CALR mutations in myeloproliferative neoplasms: a clinical experience from a tertiary care center in Qatar and a literature review.

BACKGROUND: Myeloproliferative neoplasms (MPNs) are hematological disorders characterized by abnormal production of myeloid cells due to genetic mutations. Since 2013, researchers have identified somatic mutations in the Calreticulin (CALR) gene, primarily insertions or deletions, in two Philadelphia chromosome-negative MPNs; essential thrombocytosis (ET) and primary myelofibrosis (PMF), and occasionally in chronic myelomonocytic leukemia (CMML). This study aims to identify the various types of CALR mutations and their impact on CALR-positive MPN patients' clinical manifestations and outcomes. METHODS: A single-center retrospective study was conducted. The data was collected from pre-existing records. The study was carried out on Philadelphia-negative MPN patients who were being followed up on at the NCCCR (National Center for Cancer Care and Research) to assess the clinical manifestation and outcome of disease treatment. All patients included, were followed in our center between January 1, 2008, and November 20, 2021. RESULTS: A total of 50 patients with CALR-positive MPN were reviewed with a median follow-up of three years (1-11). This cohort included 31 (62%) patients with ET, 10 (20%) patients with PMF, and 9 (18%) patients with prefibrotic myelofibrosis (pre-MF). The study involved 38 (76%) male and 12 (24%) female patients. There were 16 (32%) patients diagnosed before the age of 40, 24 (48%) patients diagnosed between the ages of 40 and 60; and 10 (20%) patients diagnosed after the age of 60. Molecular analysis showed 24 (48%) patients with CALR type 1, 21 (42%) patients with CALR type 2, and 5 (10%) patients with none Type 1, none Type 2 CALR mutations. Two patients have double mutations; 1(2%) with none Type 1, none Type 2 CALR and JAK2 mutations, and 1(2%) with CALR type 1 and MPL mutations. The thrombotic events were 3 (6%) venous thromboembolisms, 3 (6%) abdominal veins thromboses, 2 (4%) strokes, and 4 (8%) ischemic cardiac events. Only 4 (8%) patients progressed to Myelofibrosis and were carrying CALR 1 mutations, and 1 (2%) patient progressed to AML with CALR 2 mutation. CONCLUSION: The data shows a significant rise in CALR-positive MPN diagnoses in younger people, emphasizing the need for a better assessment tool to improve disease management and reduce complications.

Obstructive Sleep Apnea Does Not Exclude Polycythemia Vera: A Case Report.

Introduction: Polycythemia vera (PV) is one of the myeloproliferative neoplasms (MPN) diagnosed by World Health Organization (WHO) criteria 2016, which requires the presence of 3 major criteria: high hemoglobin/hematocrit, bone marrow findings, and Janus Kinase 2 (JAK2) mutation or two major and one minor criteria, including erythropoietin (EPO) level. However, in clinical practice, difficulties in diagnosis can arise as it may be masked by secondary causes for erythrocytosis such as smoking or obstructive sleep apnea (OSA). Case Presentation: Here, we report a 55-year-old gentleman, morbidly obese with OSA on home continuous positive airway pressure (CPAP) machine, who was incidentally found to have polycythemia. Further evaluation confirmed the diagnosis of PV. Conclusion: PV can be masked by the assumption of secondary polycythemia based on history. This underscores the importance of screening such cohort through JAK2 and EPO testing to avoid missing PV.

Glanzmann Thrombasthenia Associated with Siderotic Synovitis and Arthropathy: A Case Report.

Glanzmann thrombasthenia is a bleeding disorder with a low incidence. It typically manifests as superficial bleeding episodes, which tend to be mild. Deep organ involvement is not uncommon but remains rare due to the rarity of the disease itself and the unusual association between platelet disorders and deep organ implications. A 17-year-old boy with Glanzmann thrombasthenia since infancy developed ankle pain after a minor trauma. His initial workup was negative, but he continued to experience ankle pain. A magnetic resonance imaging (MRI) done after four weeks suggested siderotic synovitis. The patient was lost to follow-up after that and returned after two years with recurrent left ankle pain. Imaging and studies have shown evidence of chronic arthropathy. A specialized orthopedic team assessed the patient. The patient underwent intra-articular steroid injection for pain relief and was referred to continue physical therapy. In conclusion, hemarthrosis is more common in hemophilia than in platelet disorders and has potential morbidity and quality-of-life implications.

A Rare Case of Lambert-Eaton Myasthenia Syndrome Associated with Non-Hodgkin's Lymphoma: A Case Report and Review of the Literature.

Introduction: Lambert-Eaton myasthenia syndrome (LEMS) is a rare autoimmune disorder characterized by autoantibodies targeting presynaptic neuromuscular junctions. It results in muscle weakness and autonomic dysfunction. LEMS can be idiopathic or associated with neoplastic diseases, often small-cell lung cancer. This case report describes a rare instance of paraneoplastic LEMS in a man with non-Hodgkin lymphoma. Case Presentation: A 57-year-old male with non-Hodgkin lymphoma presented with progressive muscle weakness, diminished reflexes, and autonomic symptoms. Diagnosis revealed LEMS with autoantibodies against voltage-gated calcium channels. Immunosuppressive therapy and lymphoma treatment led to significant improvement in his condition. Conclusion: This case highlights the rare occurrence of paraneoplastic LEMS in a patient with non-Hodgkin lymphoma. Recognition and timely management of LEMS alongside lymphoma treatment can lead to significant clinical improvement, emphasizing the need for increased awareness of such complex associations.

Clinical and epidemiological features and therapeutic options of avascular necrosis in patients with sickle cell disease (SCD): a cross-sectional study.

BACKGROUND: Avascular necrosis (AVN) is a debilitating complication in sickle cell disease (SCD) patients, and its management is usually challenging. This study aims to evaluate the clinical and epidemiological features and therapeutic options of AVN in sickle cell patients in Qatar. PATIENTS AND METHODS: A cross-sectional study was conducted on a 49 SCD patients who were diagnosed with AVN and attended the hematology clinic at the National Center for Cancer care & research, Hamad Medical Corporation, Qatar between Jan-2011 to Jan2021.  Results: Forty-nine adult patients with SCD who were diagnosed with AVN were studied. The median age of the study population is 32 years, and the median age at the first AVN diagnosis was 26 years (range: 11-44 yr.). 37 (75.5%) patients suffered from multiple joints AVN while 12(24.5%) had single joint involvement. 31 (63.3%) patients had bilateral hip AVN and 18 (36.7%) had shoulder involvement. 30 patients (61%) were on Hydroxyurea treatment. Based on FICAT and Alert classification of AVN, 57 % of patients had stage III and above at first diagnosis. 20 (40.8%) were managed with a conservative approach, 11 (22.4%) received hyperbaric oxygen with good response, 6(12.2%) underwent hip core decompression and 12(24.5%) underwent hip replacement surgery. CONCLUSION: In SCD patients, AVN occurred more during the 3rd and 4th decades of life. The majority of AVN represented with advanced stage and had multiple joint involvements. We recommend adopting a low threshold of joint imaging for early detection and prevention of further complications.

Toe Gangrene as the First Presenting Symptom of Essential Thrombocythemia: A Case Report.

Essential thrombocythemia is a myeloproliferative neoplasm. Thrombosis and bleeding complications are common with myeloproliferative neoplasms, particularly essential thrombocythemia and polycythemia vera. Here, we report the case of a 52-year-old female who presented initially with painful toe swelling and discoloration. Initial imaging showed a small abscess. An incision and drainage, and debridement of toe dry gangrene were performed twice in two months with no improvement in her complaint and worsening discoloration, ending in a toe amputation. Two years later, the patient was referred to a hematology clinic for a high platelet count. On review of her medical records, the patient had the same numbers during the initial presentation. The patient's condition was diagnosed retrogradely by a hematologist as essential thrombocythemia. This case sheds light on myeloproliferative neoplasm as a differential diagnosis in patients with atypical thrombosis. Thinking in such a way could have diagnosed our patient two years earlier.

Sickle cell leg ulcer successfully managed by hyperbaric oxygen: a case report.

Sickle cell leg ulcers (SCLUs) are usually chronic, painful, and devastating complications of sickle cell disease. Skin vaso-occlusion with compromised blood flow, chronic inflammation, and endothelial dysfunction is thought to be the underlying mechanism. It is usually slow to heal, and it may become chronic and superinfected. The management of SCLUs is usually challenging and requires a multidisciplinary team. Multiple systemic and local therapies have been tried in SCLU treatment. However, the outcome is variable: currently, there are no official recommendations for the best effective treatment. Herein, we report a 34-year-old male patient with non-transfusion-dependent sickle cell disease who was suffering from a chronic left ankle ulcer and was successfully managed with hyperbaric oxygen therapy, resulting in a complete resolution of this devastating complication.

Recurrence of acute chest syndrome post stopping Crizanlizumab, the dilemma of stopping vs continuation in patient with sickle cell disease: case report.

Sickle cell disease (SCD) is one of the most common hematological diseases, which results in variable complications. The treatment of SCD is evolving but limited options are available for now. Acute chest syndrome (ACS) is one of the serious complications observed in SCD and a challenging one in prevention. Crizanlizumab is a monoclonal antibody that binds to P-selectin and improves blood flow by preventing sickle cell adhesion to endothelium, resulting in improvement of vaso-oclusive crises (VOC). It is not well evaluated in terms of ACS prevention. Here we report a 23-year-old patient with SCD and recurrent ACS; she was started on Crizanlizumab and she had no more ACS, but once she was off Crizanlizumab she developed ACS again, later Crizanlizumab was re-started, and the patient has improved significantly.

Omicron-Induced Immune Thrombocytopenia: A Case Report.

Coronavirus disease 2019 is a systemic infection that significantly impacts the hematopoietic system and hemostasis. Among the hematological manifestations described, severe and symptomatic thrombocytopenia is rare. Immune thrombocytopenia (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenic purpura, is an acquired thrombocytopenia caused by autoantibodies against platelet antigens. It is one of the more common causes of thrombocytopenia in otherwise asymptomatic adults. Here, we report the case of a patient who developed ITP after a severe acute respiratory syndrome coronavirus 2 infection to highlight the rarer hematological manifestations of the disease and the changes in treatment.

Congenital Methemoglobinemia: First Confirmed Case in the Arab Population with a Novel Variant in the CYB5R Gene in the State of Qatar: A Case Report.

Methemoglobinemia (MetHb) is a rare hematological condition characterized by high methemoglobin levels in the blood. It happens when hemoglobin is oxidized, resulting in hypoxia and cyanosis, which may occur in inherited or acquired forms. Inherited or congenital methemoglobinemia is a rare autosomal recessive condition and has never been reported in the Arab population. Here we report a case of a 22-year-old Arab man with a positive family history who presented with bluish discoloration of the fingers and lips and was found to have methemoglobinemia. Genetic study on the patient and his family revealed compound heterozygous variants in the CYB5R3 Exon 5 c.431G>A p.Gly144Asp likely pathogenic variant and CYB5R3 Exon 9 c.871G>A p.Val291Met variant of unknown significance. We suggest that the novel c.871G>A p.Val291Met variant could be causative for methemoglobinemia.

Immune Thrombocytopenia Relapse in Patients Who Received mRNA COVID-19 Vaccines.

Background: Immune thrombocytopenia (ITP) is a blood disorder in which antibodies coating platelets cause platelet destruction in the spleen with a resultant low platelet count and an increased tendency for bleeding. Coronavirus disease 2019 (COVID-19) is an illness caused by SARS-CoV-2. Though pneumonia and respiratory failure are major causes of morbidity and mortality, multisystemic complications were identified, including hematological ones. Several ITP relapse cases post-mRNA SARS-CoV-2 vaccines have been reported, and different pathophysiological theories have been proposed. Purpose: The objective of this study is to identify the causal relationship between mRNA COVID-19 vaccines and ITP relapse, to highlight the longer-term effect of these vaccines on the platelet count more than 6 months after receiving the vaccine, and to identify if there is a statistical difference between Comirnaty and Spikevax vaccines on ITP relapse rate. Patients and Methods: In this retrospective study, 67 patients with known ITP were followed before and after receiving the mRNA COVID-19 vaccine. The follow-up parameters included platelet counts when available and bleeding symptoms. All patients were adults over 18 years old, with no other identified causes of thrombocytopenia. Forty-seven patients received the Comirnaty vaccine, and 20 patients received the Spikevax vaccine. Results: Data analysis showed 6% ITP relapse in the first 3 months, and a 10% relapse rate 3-6 months after receiving one of the mRNA COVID-19 vaccines, with no statically significant difference between the two vaccines. Conclusion: mRNA COVID-19 vaccines increase the risk of ITP relapse and can lead to a prolonged reduction in platelet count in a proportion of ITP patients, with no statistically significant difference between Comirnaty and Spikevax vaccines.

Cost savings and cost avoidance with the inpatient clinical pharmacist interventions in a tertiary cancer care hospital.

BACKGROUND: The economic benefit of the clinical pharmacist's role in ensuring the optimum use of medicines is potentially considerable, particularly when it comes to cancer management. We sought to evaluate the overall economic impact of clinical pharmacist interventions in the main cancer setting in Qatar. METHODS: The total economic benefit of the clinical pharmacy interventions were analyzed from the public hospital perspective. Patient records in March 2018, July/August 2018, and January 2019 were retrospectively reviewed at the National Center for Cancer Care and Research, Qatar. The total benefit from interventions was the total cost avoidance due to preventable adverse drug events plus any cost savings associated with therapeutic-based resource use. Sensitivity analyses confirmed the results' robustness and increased generalizability. RESULTS: A total of 1352 interventions based on 281 patients were analyzed. The majority of the drug-related problems were related to the appropriateness of therapy, followed by dosing and administration. The total population benefit over the 3-months study period was QAR 4,879,185 (USD 1,336,763), constituting cost avoidance of QAR 4,234,012 (USD 1,160,003) and negative resource-use cost savings of -QAR 645,174 (-USD 176,760). Projected annual overall benefit was QAR 14,355,354 (USD 3,932,974). The increase in resource use with therapies was mostly because of the addition of other medications. Cost avoidance was mostly driven by recommending additional medications and discontinuation of medications. The uncertainty analysis demonstrated the robustness of outcomes. CONCLUSIONS: The clinical pharmacist intervention increased resource use and its cost. In overall, however, taking avoided cost of adverse drug events in consideration, it is an economically beneficial practice in the National Center for Cancer Care and Research setting, associated with adverse drug events prevention and substantial economic benefits.

A Challenging Case of a Patient With Immune Thrombocytopenic Purpura on Eltrombopag Who Developed Atrial Fibrillation: An Anticoagulation Dilemma.

A 61-year-old female, who was a known case of immune thrombocytopenic purpura (ITP) on eltrombopag, was admitted for atrial fibrillation (AF). Labs showed a platelet count of 116 × 103/µL. AF reverted to sinus rhythm by cardioversion. Therapeutic enoxaparin was started for two days. She was discharged on dabigatran for four weeks. The choice of anticoagulation in these cases (ITP and AF) is not straightforward and needs further research.

Radioactive Iodine-Induced Chronic Myeloid Leukemia in a Patient With Graves' Disease: A Case Report.

Therapy-related leukemia is an increasing concern in hematology. One of these substances that showed to increase the incidence of leukemia is radioactive iodine (RAI). We report here a case of radioactive iodine-induced chronic myeloid leukemia (CML) in a patient with Graves' disease, although most cases in the literature were for thyroid cancer. Also, our patient received a very low dose, which is unique compared to previous case reports in the literature.

Applications of Artificial Intelligence in Philadelphia-Negative Myeloproliferative Neoplasms.

Philadelphia-negative (Ph-) myeloproliferative neoplasms (MPNs) are a group of hematopoietic malignancies identified by clonal proliferation of blood cell lineages and encompasses polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The clinical and laboratory features of Philadelphia-negative MPNs are similar, making them difficult to diagnose, especially in the preliminary stages. Because treatment goals and progression risk differ amongst MPNs, accurate classification and prognostication are critical for optimal management. Artificial intelligence (AI) and machine learning (ML) algorithms provide a plethora of possible tools to clinicians in general, and particularly in the field of malignant hematology, to better improve diagnosis, prognosis, therapy planning, and fundamental knowledge. In this review, we summarize the literature discussing the application of AI and ML algorithms in patients with diagnosed or suspected Philadelphia-negative MPNs. A literature search was conducted on PubMed/MEDLINE, Embase, Scopus, and Web of Science databases and yielded 125 studies, out of which 17 studies were included after screening. The included studies demonstrated the potential for the practical use of ML and AI in the diagnosis, prognosis, and genomic landscaping of patients with Philadelphia-negative MPNs.

The effectiveness of tyrosine kinase inhibitor for chronic myeloid leukemia in tuberous sclerosis. A case report and review of literature.

The relationship between chronic myelogenous leukemia (CML) and tuberous sclerosis (TS) is unusual and uncommon. Here, we report a 24-year-old woman diagnosed with TS and later identified with CML, as the second case reported with such coexistence, treated with Nilotinib. This article proposes a hypothesis to explain the association. Therefore, we propose Nilotinib for the treatment of patients with such coexisting diseases. Further studies are warranted to reveal the dynamics between these conditions.

Polatuzumab Vedotin in a Patient with Refractory Burkitt Lymphoma, a Case Report.

Although Burkitt lymphoma is considered a curable disease due to the progress made in choosing the most effective first-line therapy, relapsed or refractory Burkitt lymphoma (BL) has a very poor outcome. There is a lack of data supporting the treatment regimens. We report a 48-year-old male with stage II Burkitt's lymphoma with no response to the first line of high-intensity chemotherapy. However, treatment with polatuzumab vedotin led to complete clinical remission for more than one year.

Myocardial Infarction as an Initial Presentation of Essential Thrombocythemia With Calreticulin (CALR) Mutation (None Type 1, None Type 2).

Essential thrombocythemia (ET) is one of the classical Philadelphia-negative myeloproliferative neoplasms with different mutations that can be associated with it, like Janus kinase 2 (JAK2), myeloproliferative leukemia protein (MPL), and Calreticulin (CALR) (types 1 and 2). However, there is a lack in the literature concerning other types of CALR mutations and their clinical significance and prognosis. Here we report a 42-year-old male with type 2 diabetes who presented with an inferior ST-elevation myocardial infarction and thrombocytosis. The diagnosis of ET with CALR (neither type 1 nor type 2) was confirmed, which suggests the pathognomonic feature of this mutation.

Delayed Diagnosis of Indolent Systemic Mastocytosis as the Cause of Unexplained Skin Rash: A Case Report.

Mastocytosis is a heterogeneous group of disorders in which mast cells exhibit clonal proliferation that infiltrates one or more organs. In cutaneous mastocytosis, the mast cells infiltrate the skin only, whereas systemic mastocytosis is diagnosed when at least one extra-cutaneous site is involved, with or without the skin being affected. Given the rarity of mastocytosis and the fact that skin rash can be a manifestation of different conditions and many clinicians are not familiar with this disorder, an accurate diagnosis may be delayed. We report a delayed diagnosis of indolent systemic mastocytosis in a 40-year-old gentleman who had been complaining of an unexplained skin rash for 6 years.

The Impact of Tyrosine Kinase Inhibitors on Fatherhood in Patients With Chronic Myeloid Leukemia: A Mixed-Method Study.

INTRODUCTION: Multiple studies have demonstrated that tyrosine kinase inhibitors (TKIs) exert a significant extent of control over chronic myeloid leukemia (CML), as evidenced by studies such as the population-based Swedish CML registry, which found that patients reaching age 70 had a relative survival rate close to one when compared to the general population. Consequently, new perspectives on the safety of treatments have emerged, particularly in the context of their impact on fatherhood in men. According to the authors, this is the first study to examine the effect of TKIs on fatherhood in CML patients.  Methods: A single-center, mixed-design study (retrospective data review and phone interviews) was conducted with CML male patients in the chronic or accelerated phase, evaluating the effect of imatinib, dasatinib, and nilotinib on their fatherhood, irrespective of whether they were administered as a first, second, or third line of treatment. RESULTS: The study included interviews with 150 patients. Included were 27 patients. The average age was approximately 44.5 years. One hundred percent of the patients were in the chronic phase. The median age at first conception following TKI therapy was 36, and the median duration of TKI therapy was approximately seven years. The total number of offspring was 49; 98% were born at term and had a normal birth weight. No reports of stillbirths, fetal deaths, or congenital malformations were made. All the offspring grew and developed normally. No CML-related cancers were reported in any of the newborns. CONCLUSION: Around 98% of male CML patients receiving imatinib, dasatinib, or nilotinib did not experience a negative impact on their fatherhood or the health of their children. However, improved education for patients beginning treatment with TKIs addresses the potential psychological worry of having an unfavorable effect on their fertility or offspring, which may increase medication adherence.