Myeloproliferative Research Articles

Diagnosis and Treatment of Polycythemia Vera

ImportancePolycythemia vera (PV), a myeloproliferative neoplasm characterized by an increased red blood cell mass and increased risk of thrombosis, affects approximately 65 000 people in the US, with an annual incidence of 0.5 to 4.0 cases per 100 000 persons.ObservationsErythrocytosis (hemoglobin >16.5 mg/dL in men or >16.0 mg/dL in women) is a required diagnostic criterion, although thrombocytosis (53%) and leukocytosis (49%) are common. Patients may have pruritus (33%), erythromelalgia (5.3%), transient visual changes (14%), and splenomegaly (36%) with abdominal discomfort. More than 95% of patients have a JAK2 gene variant, which helps distinguish PV from secondary causes of erythrocytosis, such as tobacco smoking or sleep apnea. Among 7 cohorts (1545 individuals), the median survival from diagnosis was 14.1 to 27.6 years. Prior to or at the time of PV diagnosis, arterial thrombosis occurred in 16% of patients and 7% had venous thrombotic events, which could involve unusual sites, such as splanchnic veins. PV is also associated with an increased bleeding risk, especially in patients with acquired von Willebrand disease, which can occur with extreme thrombocytosis (platelet count, ≥1000 × 109/L). All patients with PV should receive therapeutic phlebotomy (goal hematocrit, <45%) and low-dose aspirin (if no contraindications). Patients who are at higher risk of thrombosis include those aged 60 years or older or with a prior thrombosis. These patients and those with persistent PV symptoms may benefit from cytoreductive therapy with hydroxyurea or interferon to lower thrombosis risk and decrease symptoms. Ruxolitinib is a Janus kinase inhibitor that can alleviate pruritus and decrease splenomegaly in patients who are intolerant of or resistant to hydroxyurea. About 12.7% of patients with PV develop myelofibrosis and 6.8% develop acute myeloid leukemia.Conclusions and RelevancePV is a myeloproliferative neoplasm characterized by erythrocytosis and is almost universally associated with a JAK2 gene variant. PV is associated with an increased risk of arterial and venous thrombosis, hemorrhage, myelofibrosis, and acute myeloid leukemia. To decrease the risk of thrombosis, all patients with PV should be treated with aspirin and therapeutic phlebotomy to maintain a hematocrit of less than 45%. Cytoreductive therapies, such as hydroxyurea or interferon, are recommended for patients at high risk of thrombosis.

Abstract C049: Implementing human bone marrow organoids to interrogate microenvironmental influences on the efficacy of blood cancer immunotherapies

Abstract Cancers perpetuate immunosuppressive niches that fuel progression and hinder the clinical utility of immunotherapies. Pre-clinical validation of immunotherapies often relies on 2D models that lack spatial complexity, or mouse models that do not fully recapitulate the human tumor microenvironment (TME). We recently developed a human induced pluripotent stem cell (iPSC)-derived bone marrow organoid platform, creating a robust system to interrogate cancer-stroma cross talk. Here, we further develop the model to create the first in vitro system for evaluation of blood cancer immunotherapies in a human tissue environment. We focused on targeting myeloproliferative neoplasms (MPNs) – chronic blood cancers affecting ∼400,000 individuals in the US that are currently largely incurable. 1/3 of MPNs are driven by a mutation in calreticulin (mutCALR), and the mutCALR oncoprotein is displayed on the cell surface of disease-initiating stem cells and fibrosis-driving megakaryocytes. MPNs are characterized by pronounced inflammation and fibrosis (“myelofibrosis”). Therapeutic antibodies have entered first-in-human trials, and we recently presented pre-clinical data for the first mutCALR-directed CAR-T cell therapy. However, it is unclear how the TME may limit the efficiency of these agents. To address this, we first tested the utility of the organoid platform to evaluate target killing of leukemic cell lines and cells from patients using the anti-CD33 antibody-drug conjugate (ADC) gemtuzumab. The ADC showed good penetration and potent target cell killing in organoids, with only minimal reduction in efficacy in TGFβ-rich/fibrotic microenvironments. We then developed more sophisticated ‘chimeroids’ comprising the iPSC organoid scaffold engrafted with malignant stem cells plus CAR-Ts. Addition of mutCALR-directed CAR-Ts induced highly selective killing of mutCALR+ stem/progenitor cells with minimal toxicity to non-malignant cells including niche cells (n=5 donors), replicating the highly specific and robust killing seen in 2D cultures. To evaluate the impact of TME perturbations on CAR-T phenotype and function, we generated a scRNAseq dataset of 161,970 cells from ‘healthy’ and ‘myelofibrotic’ organoids engrafted with patient-derived mutCALR+ cells plus CAR-Ts, pre-stimulating organoids with two immunoregulatory cytokines highly abundant in myelofibrosis -TGFβ and Galectin-1. CAR- Ts exposed to mutCALR+ cells showed a 2x expansion of CD8+ effector memory cells, with significant enrichment of IFNγ, TNFα and IL-2 signaling gene-sets. The proportion of immunosuppressive Tregs increased in a high TGFβ TME, but not with Galectin-1. Ongoing analyses are further interrogating crosstalk between CAR-T, target cells, and niche components, and exploring the pro-inflammatory impact of CAR-T killing on the marrow niche – a potential mediator of delayed hematopoietic recovery. These studies demonstrate the utility of human organoids to evaluate blood cancer-targeting immunotherapies within a relevant human TME, with broad relevance for mechanistic and translational studies. Citation Format: Zoë C. Wong, Yuqi Shen, Alex Rampotas, Isaac Gannon, Charlotte Brierley, Camelia Benlabiod, Nawshad Hayder, Eleanor Murphy, Aude-Anaïs Olijnik, Claire Roddie, Martin Pulé, Adam J. Mead, Abdullah O. Khan, Bethan Psaila. Implementing human bone marrow organoids to interrogate microenvironmental influences on the efficacy of blood cancer immunotherapies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C049.

How I approach the treatment of thrombotic complications in patients with myeloproliferative neoplasms.

Arterial and venous thromboses are the most significant complications in patients with myeloproliferative neoplasms (MPN), with the primary treatment goal being thrombotic risk reduction. In MPN with no history of thrombosis, primary prevention mainly involves the use of aspirin and cytoreduction is added in high-risk patients. However, thrombotic complications can unveil an MPN in approximately 20% of cases, necessitating the initiation of both antithrombotic therapy for the thrombosis and cytoreductive treatment for the MPN. The duration of anticoagulant therapy following an initial venous thromboembolic event (VTE) is subject to discussion. Furthermore, the occurrence of a thrombotic complication in patients with a known diagnosis of MPN prompts a reconsideration of both antithrombotic and hematological management. This review employs case-based discussions to explore the management of thrombotic complications in MPN patients. It addresses the nature and duration of antithrombotic treatments, as well as the approach to cytoreduction. Special attention is given to the place of direct oral anticoagulants and to the management of MPN patients with splanchnic vein thrombosis, which is disproportionately common in this group.

Betulinic Acid Acts in Synergism with Imatinib Mesylate, Triggering Apoptosis in MDR Leukemia Cells.

Chronic myeloid leukemia (CML) is a myeloproliferative disease, characterized by the presence of the oncogene BCR-ABL. Imatinib mesylate (IMA) is the first-line treatment for CML, and some treatment resistance has been reported. Natural products are rich sources of bioactive compounds with biological effects, opening a possibility to alter cell susceptibility to drugs such as imatinib. Herein, we evaluated the interference of betulinic acid and ursolic acid in glycoprotein P (P-gp) activity and the possible synergistic effect when associated with IMA by the Chou-Talalay method. Ursolic acid presented an IC50 of 14.0 µM and 19.6 µM for K562 and Lucena 1, respectively, whilst betulinic acid presented an IC50 of 8.6 µM and 12.5 µM for these cell lines. Evaluation of the combination of terpenoids and imatinib mesylate revealed that ursolic acid or betulinic acid acts in synergism with IMA, as indicated by the combination indexes (CI<1). Analysis of annexin V labeling demonstrated that a combination of IMA with betulinic acid enhances the inhibition on cell proliferation via the apoptosis pathway, with caspases 3/7 activation after 24 hours of treatment and inhibition of the STAT5/survivin pathway, decreasing cell viability. The combination of natural products and IMA on a multidrug-resistant leukemia cell line is a promising strategy for CML treatment.

Neutrophil-to-lymphocyte ratio (NLR) at diagnosis in essential thrombocythemia: A new promising predictor of thrombotic events.

Myeloproliferative neoplasms represent a heterogeneous group of acquired hematopoietic stem cell diseases in which chronic inflammation is essential for both clonal evolution and thrombotic complications. The neutrophil-to-lymphocyte ratio (NLR), reflecting the imbalance between systemic inflammation and immunity, is emerging as a prognostic biomarker in several diseases, including hematological ones. A total of 473 patients with essential thrombocythemia (ET), the relationship between NLR value at diagnosis and the risk of thrombotic events in the follow-up, in addition to conventional clinical and biological variables, were retrospectively analyzed. A total of 78 thrombotic events were reported for an incidence rate of 1.8 × 100 patients/year. In multivariate analysis, NLR value≥4 at diagnosis was associated with higher cumulative thrombotic risk (hazard ratio [HR], 2.05; 95% CI, 1.29-2.28; p=.0001) as well International Prognostic Score for Thrombosis in Essential Thrombosis score intermediate-high (HR, 2.69; 95% CI, 1.27-5.72; p=.01) and diabetes (HR, 2.49; 95% CI, 1.23-3.05; p=.010). Concerning arterial thrombotic events, in multivariate analysis, NLR value at diagnosis ≥4 was predictive for thrombosis (HR, 2.13; 95% CI, 1.31-4.04; p=.001 as well diabetes (HR, 2.44; 95% CI, 1.05-5.68; p=.04) and hypertension (HR, 2.46; 95% CI, 1.05-5.68; p=.01). About venous thrombotic events, NLR value≥5 was a marker predictive for venous thrombosis (HR, 2.99; 95% CI, 2.45-6.48; p=.01) as well age >60 years old (HR, 2.26; 95% CI, 1.0-5.10; p=.05). NLR value is a simple, cost-effective, and easy-to-obtain inflammatory marker that can predict a diagnosis the risk of thrombosis in ET. Our results suggest that NLR value could be integrated into conventional cardiovascular risk scores, to better classify high-risk patients who are candidates for cytoreductive therapy. Further larger and prospective studies are warranted.

Real-world data on direct oral anticoagulants in BCR::ABL1-negative myeloproliferative neoplasms (MPNs): a multicenter retrospective study on behalf of scientific subcommittee on MPNs for Turkish society of hematology.

BCR::ABL1-negative myeloproliferative neoplasms (MPNs) pose a substantial risk of thrombosis, leading to significant morbidity and mortality. Anticoagulant therapy, historically based on vitamin K antagonists (VKAs), has limitations in preventing recurrent thrombotic events and managing bleeding complications. Direct oral anticoagulants (DOACs) offer a potential alternative with improved pharmacokinetics and compliance. However, evidence on DOAC efficacy and safety in MPNs remains limited, necessitating further investigation. In this multicenter retrospective study in Türkiye, we assessed real-world usage patterns and outcomes of DOACs in MPN patients. Data from 220 patients with PV, ET, or PMF receiving DOACs or VKAs for thrombosis or nonvalvular atrial fibrillation (NVAF) were collected from medical records. Thrombotic events and bleeding episodes were documented based on ISTH criteria. DOACs were used in 126 patients as first-line anticoagulant therapy or following VKAs. Ninety-four patients were on VKAs, of which 83 as a first-line treatment. There were eight thromboses (6.3%) seen in 126 DOAC patients, and similarly, seven episodes (9.4%) of thrombosis were observed in 94 patients using VKA. Major bleeding occurred in seven patients (5.6%) on DOAC and 3 (3.2%) in VKA. Thrombotic and bleeding risks were comparable between DOACs and VKAs (p = 0.708 and p = 0.158, respectively). The incidence rate of thrombosis in the VKA group is 1.1% and in the DOAC group is 1.9%. The incidence of major bleeding in the VKA group is 0.6% and 1.6% in the DOAC group. To the best of our knowledge, our study included the largest number of MPN patients to date, comparing DOACs with VKA in terms of both efficacy and safety, which suggests DOACs as promising alternatives to VKAs for managing thrombotic risk in MPNs with manageable toxicity. Despite the limitations of retrospective studies, DOACs' benefits in terms of efficacy and compliance warrant further investigation through prospective trials. Individualized treatment decisions should consider patient-specific factors, emphasizing collaborative efforts between specialists to optimize DOAC therapy in patients with MPNs. Comparable efficacy and safety between DOACs and VKAs were observed in MPN patients.

Iron deficiency and phlebotomy in patients with polycythemia vera.

Polycythemia vera (PV) is a myeloproliferative neoplasm that is associated with an elevated risk of thrombosis. Treatment strategies are based on thrombosis risk classification. Phlebotomy is a commonly recommended treatment for all patients with PV, regardless of their risk classification, and reduces the incidence of thrombosis by lowering hematocrit levels. However, patients with PV frequently present with iron deficiency at diagnosis due to increased erythropoiesis, which repeated phlebotomy can exacerbate. This can produce symptoms that diminish quality of life, such as fatigue, lethargy, and impaired concentration. Recently, hepcidin mimetics have been developed to suppress iron utilization in erythropoiesis. Among them, rusfertide has been shown to control hematocrit levels without requiring phlebotomy. Further studies are needed to identify new treatment strategies for PV that also consider iron deficiency.

Liver cirrhosis combined with Myeloproliferative neoplasms: A case report

Liver cirrhosis combined with Myeloproliferative neoplasms: A case report

Hematological profile and its correlation with reverse transcription–polymerase chain reaction-based serial quantitative detection of BCR-ABL in chronic myeloid leukemia patients at a referral cancer center

Abstract BACKGROUND: There are variations in the hematological profile among the Indian population affected with chronic myeloid leukemia (CML). The range of white blood cell count (WBC) was 0.46 × 109/mm3 to 1.86 × 109/mm3. Similarly, range for hemoglobin was 9–11 g/dl. WBC count can be as low as 0.18 × 109/mm3 even though CML is a myeloproliferative disorder. OBJECTIVE: The objective of this study was to correlate BCR-ABL expression with the hematological and myeloid proliferative parameters. METHODS: The present study was a single-center, hospital-based follow-up study among 66 cases of CML. The sample of patients was analyzed for BCR-ABL gene expression; hematological parameters and myeloid proliferative parameters such as band forms, myelocytes, metamyelocytes, and blast were also measured. Some patients reported twice, some thrice, and the total count after all follow-up for all 66 cases was 179. RESULTS: The mean age was 43.15 years. Men were more than women with male-to-female ratio of 1.6:1. The mean hemoglobin was lesser at 10.8 g/dl. Median total count was normal at 5610 (interquartile range = 2750) per μl. Mean neutrophils, lymphocytes, monocytes, basophils, and platelets were normal. The eosinophil count was raised. The BCR-ABL gene expression was positively and significantly correlated with total count. It was negatively and significantly correlated with lymphocytes and monocytes. It was not correlated with other hematological parameters. All the myeloid proliferative parameters, namely, band forms, myelocytes, metamyelocytes, and blast, were positively and significantly correlated with BCR-ABL gene expression. CONCLUSION: Total count and all myeloid proliferative parameters were positively and significantly correlated with BCR-ABL gene expression. Lymphocytes and monocytes were negatively correlated. These parameters can be used to track the disease progression in patients with CML.

PU-H71 (NSC 750424): a molecular masterpiece that targets HSP90 in cancer and beyond

Heat shock protein 90 (HSP90) is a pivotal molecular chaperone with multifaceted roles in cellular health and disease. Herein, we explore how HSP90 orchestrates cellular stress responses, particularly through its partnership with heat shock factor 1 (HSF-1). PU-H71, a selective inhibitor of HSP90, demonstrates significant potential in cancer therapy by targeting a wide array of oncogenic pathways. By inducing the degradation of multiple client proteins, PU-H71 disrupts critical signaling pathways such as MAPK, PI3K/Akt, JAK/STAT, EGFR, and mTOR, which are essential for cancer cell survival, proliferation, and metastasis. We examined its impact on combating triple-negative breast cancer and enhancing the effectiveness of carbon-ion beam therapy, offering new avenues for cancer treatment. Furthermore, the dual inhibition of HSP90A and HSP90B1 by PU-H71 proves highly effective in the context of myeloma, providing fresh hope for patients with this challenging malignancy. We delve into its potential to induce apoptosis in B-cell lymphomas that rely on Bcl6 for survival, highlighting its relevance in the realm of hematologic cancers. Shifting our focus to hepatocellular carcinoma, we explore innovative approaches to chemotherapy. Moreover, the current review elucidates the potential capacity of PU-H71 to suppress glial cell activation paving the way for developing novel therapeutic strategies for neuroinflammatory disorders. Additionally, the present report also suggests the promising role of PU-H71 in JAK2-dependent myeloproliferative neoplasms. Eventually, our report sheds more light on the multiple functions of HSP90 protein as well as the potential therapeutic benefit of its selective inhibitor PU-H71 in the context of an array of diseases, laying the foundations for the development of novel therapeutic approaches that could achieve better treatment outcomes.

Bone Mineral Density, C-Terminal Telopeptide of Type I Collagen, and Osteocalcin as Monitoring Parameters of Bone Remodeling in CML Patients Undergoing Imatinib Therapy: A Basic Science and Clinical Review

Background: Chronic myeloid leukemia (CML) is one of the most commonly found types of myeloproliferative neoplasms, characterized by increased proliferation of granulocytic cells without losing their differentiation ability. Imatinib, a tyrosine kinase inhibitor (TKI), can be effectively used as therapy for CML. However, Imatinib can affect bone turnover thus having clinical implications on the bones of CML patients undergoing long-term Imatinib therapy. However, parameters that can accurately describe the bone condition in CML patients receiving Imatinib still need further study. A combination of imaging techniques such as bone mineral density (BMD) and bone turnover activity markers such as C-terminal telopeptide of type I collagen (CTX-1) and osteocalcin has the potential to be used as monitoring parameters for bone density abnormalities in CML patients receiving Imatinib. Objectives: This article explains the rationale for using BMD, CTX-1, and osteocalcin as monitoring parameters of bone remodeling in CML patients receiving Imatinib. Results: First, the physiological process of bone turnover will be explained. Then, we describe the role of tyrosine kinase in bone metabolism. Next, the impact of Imatinib on BMD, CTX-1, and osteocalcin will be explained. Conclusion: The assessment of bone health of CML patients on Imatinib should include both BMD tests and bone turnover marker assays such as CTX-1 and osteocalcin.

Vitamin K2 Protects Against SARS-CoV-2 Envelope Protein-Induced Cytotoxicity in Chronic Myeloid Leukemia Cells and Enhances Imatinib Activity.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by excessive proliferation of myeloid cells. The COVID-19 pandemic has raised concerns regarding the impact of SARS-CoV-2 on patients with malignancies, particularly those with CML. This study aimed to investigate the effects of SARS-CoV-2 proteins on CML cell viability and the protective role of vitamin K2 (VK2) in conjunction with imatinib. Experiments conducted on K562 CML cells demonstrated that the SARS-CoV-2 envelope protein induces cytotoxicity and activates caspase 3/7, which are key markers of apoptosis. VK2 mitigated these cytotoxic effects and decreased cytokine production while inhibiting colony formation. Furthermore, the combination of VK2 with imatinib significantly reduced cellular proliferation, diminished mitochondrial membrane potential, and markedly suppressed colony formation. These findings suggest that VK2 protects CML cells from SARS-CoV-2-induced cytotoxicity and enhances the therapeutic efficacy of imatinib, presenting a potential strategy to improve CML treatment during the COVID-19 pandemic.

Analysis of Molecular Testing for Suspected Myeloproliferative Neoplasm at a Hybrid Community-Academic Health System

Testing for somatic mutations in JAK2, MPL, and CALR genes is a crucial element in the diagnosis of myeloproliferative neoplasms (MPN). This may have inadvertently led to increased requests for testing to “rule out MPN,” including clinical situations with low pre-test probability. This paper examines JAK2, MPL, and CALR testing by next generation sequencing (NGS) with the goal of formulating practical guidelines to make test utilization more efficient and effective. NGS results from 1482 patients tested between 2015 and March 2022 were retrieved, along with corresponding bone marrow biopsies and CBC results performed within 90 days prior to NGS and 245 (16.5%) cases were positive for pathogenic variants in JAK2, MPL, or CALR genes.The findings showed an increase in the proportion of positive cases with patient age, and a statistically significant difference in RBC counts and platelet counts among patients with positive versus negative results. Utilizing these factors, simple algorithms were constructed to predict positive results with a maximum sensitivity of 91%, while potentially eliminating 28% of negative tests. However, these models still failed to identify ∼9% of patients with MPNs. Among these “missed” patients, many had either primary myelofibrosis or MDS/MPN. Considering a simple triage model to help guide MPN testing could represent a more cost effective approach, particularly if “missed” patients could be further reduced.

Imetelstat, a novel, first‐in‐class telomerase inhibitor: Mechanism of action, clinical, and translational science

AbstractMost cancers and neoplastic progenitor cells have elevated telomerase activity and preservation of telomeres that promote cellular immortality, making telomerase a rational target for the treatment of cancer. Imetelstat is a first‐in‐class, 13‐mer oligonucleotide that binds with high affinity to the template region of the RNA component of human telomerase and acts as a competitive inhibitor of human telomerase enzymatic activity. Pharmacokinetics, pharmacodynamics, exposure‐response analyses, efficacy, and safety of imetelstat have been evaluated in vitro, in vivo, and clinically in solid tumor and hematologic malignancies, including lower‐risk myelodysplastic syndromes (LR‐MDS) and myeloproliferative neoplasms. Imetelstat was approved in the United States in June 2024 for the treatment of adult patients with LR‐MDS with transfusion‐dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis‐stimulating agents, with a recommended dosing regimen of 7.1 mg/kg administered via 2‐h intravenous infusion every 4 weeks. In the pivotal trial, significantly more patients treated with imetelstat versus placebo achieved ≥8‐week and ≥24‐week red blood cell‐transfusion independence, and imetelstat was associated with a manageable safety profile characterized primarily by short‐lived and manageable neutropenia and thrombocytopenia. This mini‐review summarizes the mechanism of action, pharmacokinetic and pharmacodynamic characteristics, clinical development, and clinical efficacy and safety data of imetelstat.

Readmission outcomes after acute coronary syndrome among patients with myeloproliferative neoplasms

Readmission outcomes after acute coronary syndrome among patients with myeloproliferative neoplasms

Chronic myelogenous leukemia: a case report from Azal Hospital, Sana'a, Yemen

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder that is always associated with the presence of the BCR-ABL gene. In this article, we report the case of a 38-year-old male patient who presented with fever, fatigue, abdominal pain, and blurred vision. Investigations confirmed CML with leukemic-like retinal hemorrhages and anemia. The patient was immediately given imatinib 400 mg daily for 2 weeks, and then hydroxyurea 500 mg daily was added. After 4 months, the white blood cells, hemoglobin, and basophils returned to normal values, the retinal hemorrhages improved, and the patient's general health improved.

Myeloproliferative Neoplasm-like Mutations of Calreticulin Induce Phenotypes Associated with Calreticulin Dysfunction in C. elegans.

In previous research, we created a C. elegans model with homozygous mutations in calreticulin similar to those found in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), two myeloproliferative neoplasms (MPNs). This model, lacking JAK orthologs, enabled us to examine the transcriptomic effects caused by mutant calreticulin without the influence of JAK/STAT activation, the primary pathogenic mechanism associated with calreticulin mutations known to date. Most of the gene expression changes observed seemed to be due to a partial loss of protein function, with the alteration of the extracellular matrix being particularly notable. In this study, our aim was to determine whether this model exhibited any phenotype related to these transcriptomic alterations. The results demonstrate that these strains exhibit multiple phenotypes related to the alteration of the extracellular matrix, fat levels, and fertility, which could be a possible consequence of a partial loss of calreticulin function. These phenotypes resemble some of the clinical and molecular characteristics described in patients with MPNs, but they had never before been linked to a loss of protein function in humans. Thus, these results collectively suggest that CALR mutations could have significant effects on MPNs due to loss of protein function. Delving deeper into these effects to develop innovative therapies for these patients offers considerable potential and interest, given that targeted therapies for these patients have not yielded very promising results so far.

Comprehensive analysis of mesenchymal cells reveals a dysregulated TGF-β/Wnt/HOXB7 axis in patients with myelofibrosis.

Despite the advances in the understanding and treatment of myeloproliferative neoplasm (MPN), the disease remains incurable with the risk of evolution to AML or myelofibrosis (MF). Unfortunately, the evolution of the disease to MF remains still poorly understood impeding preventive and therapeutic options. Recent studies in solid tumor microenvironment and organ fibrosis have shed instrumental insights on their respective pathogenesis and drug resistance, yet such precise data are lacking in MPN. In this study, through a patient-sample driven transcriptomic and epigenetic description of the MF microenvironment landscape and cell-based analyses, we identify HOXB7 overexpression and more precisely a novel TGFβ-Wnt-HOXB7 pathway as associated to a pro-fibrotic and pro-osteoblastic biased differentiation of mesenchymal stromal cells (MSCs). Using gene-based and chemical inhibition of this pathway we reverse the abnormal phenotype of MSCs from myelofibrosis patients, providing the MPN field with a potential novel target to prevent and manage evolution to MF.

Hemato-oncology services and COVID-19 Pandemic: The experience of Kazakhstan

Abstract Objectives The COVID-19 pandemic in Kazakhstan disrupted numerous healthcare services, including those critical for hemato-oncology patients, due to the strained healthcare system. This study examines how the COVID-19 pandemic has affected access to hemato-oncology healthcare services in Almaty, Kazakhstan. Methods We retrospectively analyzed patient data from two tertiary centers, City Clinical Hospital 7 (H7) and Kazakh Institute of Oncology and Radiology (KazIOR), from March 1, 2019, to February 28, 2022. Variables included age, gender, residence, hospitalization rate, treatment outcomes (discharged/deceased/transferred), diagnoses (acute leukemia, lymphoproliferative diseases, myeloproliferative diseases), and referral sources. The Statistical Yearbook of Kazakhstan provided comparative data. Results From 2019-2022, 6,763 hemato-oncology hospitalizations were registered: 3,583 in H7 and 3,180 in KazIOR. The mean age was 55.04 (SD = 16.07) for females and 51.2 (SD = 16.7) for males. Urban and rural patient proportions were 6,191 (92%) and 571 (8.4%), respectively (Chi-square 13.8, P = 0.001). Fewer patients were discharged in 2020-2021 (n = 2,047) compared to 2019-2020 (n = 2,387) and 2021-2022 (n = 2,081) (Chi-square 20.09, P = 0.003). The death rate was higher in 2020-2021 (3.5%) than in 2019-2020 (3.2%) and 2021-2022 (2.6%) (Chi-square 20.09, P = 0.003). Emergency admissions were 403 (19%) in 2020-2021, 368 (14.8%) in 2019-2020, and 394 (18.3%) in 2021-2022 (Chi-square 2,231, P &amp;lt; 0.001). Transfers from other hospitals increased by 12.4% in 2020-2021. Conclusions The COVID-19 pandemic negatively impacted access to hemato-oncology services, increasing mortality. Further studies are needed to understand the factors affecting hospitalization and mortality trends during healthcare crises. Funding: Grant No. AP09260497. Key messages • Access to healthcare services during COVID-19 pandemic for hemato-oncology patients. • Impact of the pandemic on access to healthcare.

Treatment of concomitant persistent chylothorax and superior vena cava syndrome through innominate vein-right atrial bypass.

Persistent chylothorax is a major challenge in paediatric patients. We present a case of a 6.5-kg, one-year-old boy with SVCS and persistent chylothorax, who underwent successful surgery without cardiopulmonary bypass. His medical history included multiple co-morbidities such as myeloproliferative disease, short bowel syndrome, and central vein catheterizations. The patient also had IV thrombosis, progressing to SVC, and was on anticoagulants. Despite dietary changes and somatostatin, his high-output chylous pleural effusion persisted. He was treated with innominate vein-to-right atrial bypass using a 6 mm Dacron graft. Postoperatively, there was a significant reduction in effusion and accelerated recovery. Somatostatin failure was likely due to mechanical obstruction of the thoracic duct.