Philadelphia-Negative Myeloproliferative Neoplasms Around the COVID-19 Pandemic.

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19) is associated with a high rate of respiratory failure, thromboembolism, bleeding, and death. Patients with myeloproliferative neoplasms (MPNs) are prone to both thrombosis and bleeding, calling for special care during COVID-19. We reviewed the clinical features of MPN patients with COVID-19, suggesting guidance for treatment. RECENT FINDINGS: One study by the European LeukemiaNet collected 175 MPN patients with COVID-19 during the first wave of the pandemic, from February to May 2020. Patients with primary myelofibrosis (PMF) were at higher risk of mortality (48%) in comparison with essential thrombocythemia (ET) (25%) and polycythemia vera (19%); the risk of death was higher in those patients who abruptly discontinued ruxolitinib. In patients followed at home, in regular wards, or in ICU, the thrombosis rate was 1.0%, 2.8%, and 18.4%, respectively. Independent risk factors for thrombosis were ET phenotype, transfer to ICU, and neutrophil/lymphocyte ratio; major bleeding occurred in 4.3% of patients, particularly those with PMF. MPN patients with non-severe COVID-19 treated at home should continue their primary or secondary antithrombotic prophylaxis with aspirin or oral anticoagulants. In the case of hospitalization, patients assuming aspirin should add low molecular weight heparin (LMWH) at standard doses. In contrast, LMWH at intermediate/therapeutic doses should replace oral anticoagulants prescribed for atrial fibrillation or previous venous thromboembolism. Intermediate/high doses of LMWH can also be considered in ICU patients with ET, particularly in the case of a rapid decline in the number of platelets and progressive respiratory failure.

Accelerated Phase of Atypical Chronic Myeloid Leukemia with Severe Disseminated Intravascular Coagulation at Initial Presentation.

Patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) are often asymptomatic and thus can remain undiagnosed until they become symptomatic due to progression to the accelerated phase (AP) or transformation to acute leukemia (leukemic transformation; LT). We herein report the case of a previously healthy 38-year-old man who had hyperleukocytosis with dysplastic myeloid precursor cells and severe disseminated intravascular coagulation. Hematopoietic recovery with features of atypical chronic myeloid leukemia (aCML) after induction chemotherapy was a diagnostic clue. Although rare, this case highlights the limitation of the diagnostic approach for aCML with AP or LT at the initial presentation.

Rapid detection of CALR type 1 and type 2 mutations using PNA-LNA clamping loop-mediated isothermal amplification on a CD-like microfluidic chip.

Bleeding and thrombosis represent common complications in myeloproliferative neoplasms (MPN) and significantly contribute to morbidity and mortality. Molecular markers, including CALR mutations, were considered not only as diagnostic markers, but also as risk factors for bleeding and thrombosis associated with MPN, especially for patients in remote primary hospitals. We sought to develop an easy-to-use assay for the rapid detection of CALR type 1 (CALR-1) and type 2 (CALR-2) mutations in Philadelphia chromosome-negative MPN patients. Peptide nucleic acid-locked nucleic acid (PNA-LNA) clamping loop-mediated isothermal amplification (LAMP) assays were established, which were integrated into a centrifugal compact disc (CD) microfluidic platform. A total of 158 clinical blood samples were tested simultaneously by this microfluidic platform and an in-house real time PCR assay. The detection performance of the LAMP arrays was validated and conflicting results were identified by Sanger sequencing. The results suggested that the LAMP methods we developed exhibited good sensitivity, specificity, and precision. By real time fluorescence assay the detection limit for CALR-1 and CALR-2 mutations could reach as low as 1% and 0.5% respectively, and 10% and 5% respectively by visual method. There were no nonspecific background amplifications among different detection systems. For the CALR-1 and CALR-2 LAMP detection systems, intra-batch CV values of 1% mutated plasmid were 10.56% and 10.51% respectively, and the inter-batch CV values were 19.55% and 18.39%, respectively. The products were all analyzed by melting curve analysis and electrophoresis followed by Sanger sequencing analysis, which were consistent with the database sequences. The microfluidic platform could complete rapid detection of CALR-1/2 mutations within 60 min. The results of clinical samples detected by our CD-like microfluidic chipLAMP assay and rtPCR assay suggested that 133 samples were CALR wild type, 15 were CALR-1 mutation type, and 9 were CALR-2 mutation type. The correlation coefficient value (Kendall's tau_b) of the two assays was 0.99. Interestingly, by the newly established detection platform, we were surprised to find that one patient of Chinese origin harbored both CALR-1 and CALR-2 mutations. This result was verified by Sanger sequencing analysis. The LAMP detection systems developed herein displayed good sensitivity, specificity, and stability. Additionally, the detection results could be directly judged by color changes of the reaction systems without any auxiliary equipment. Thus, the platform we developed has the potential of being widely used in remote and economically undeveloped areas in the future.

Thrombosis in Philadelphia negative classical myeloproliferative neoplasms: a narrative review on epidemiology, risk assessment, and pathophysiologic mechanisms.

Thrombosis is common in cancer patients and is associated with increased morbidity and mortality. Myeloproliferative neoplasms (MPN) are common malignancies in elderly individuals and are known for a high incidence of thrombotic complications. Different risk factors have been identified in studies, and risk models have been developed to identify patients with MPN at higher risk for thrombosis. Several pathophysiological mechanisms help explain the increased likelihood of thrombosis in these patients. Factors, such as leukocyte and platelet activation leading to the formation of leukocyte-platelet aggregates, activation of the coagulation cascade by microparticles, high levels of inflammatory cytokines, and endothelial dysfunction have a crucial role in thrombosis in MPN patients. Recent studies have demonstrated a significant association between the allele burden of specific genetic mutations (mainly JAK2V617F) associated with MPN and the incidence of thrombotic events, thus suggesting a possible role for these mutations in thrombogenesis.

Diagnosis, prevention, and management of bleeding episodes in Philadelphia-negative myeloproliferative neoplasms: recommendations by the Hemostasis Working Party of the German Society of Hematology and Medical Oncology (DGHO) and the Society of Thrombosis and Hemostasis Research (GTH).

Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) comprise a heterogeneous group of chronic hematologic malignancies. The quality of life, morbidity, and mortality of patients with MPN are primarily affected by disease-related symptoms, thromboembolic and hemorrhagic complications, and progression to myelofibrosis and acute leukemia. Major bleeding represents a common and important complication in MPN, and the incidence of such bleeding events will become even more relevant in the future due to the increasing disease prevalence and survival of MPN patients. This review discusses the causes, differential diagnoses, prevention, and management of bleeding episodes in patients with MPN, aiming at defining updated standards of care in these often challenging situations.

Evaluation of Inflammation Parameters in Philadelphia Negative Chronic Myeloproliferative Neoplasia Patients.

BACKGROUND: Chronic myeloproliferative diseases are clonal stem cell diseases which occur as a result of uncontrollable growth and reproduction of hematopoietic stem cells, which are the myeloid series source in bone marrow. Recent studies have suggested that chronic inflammation can be a triggering factor in the clonal change in chronic myeloproliferative neoplasia (CMPN). In our study, we evaluated the existence of a chronic inflammation process in our Philadelphia negative (Ph-)CMPN patients using inflammation parameters in combination with demographic, laboratory and clinical characteristics of the patients. MATERIALS AND METHODS: Demographic characteristics, clinical and laboratorial data, and thrombosis histories of 99 Ph-CMPN patients, who were diagnosed at our outpatient clinic of hematology in accordance with WHO 2008 criteria, were analyzed retrospectively,with 80 healthy individuals of matching gender and age included as controls. Complete blood counts, sedimentation, C reactive protein (CRP), JAK V617F gene mutations, abdomen ultrasound images and previous thrombosis histories of these patients were retrospectively analyzed. RESULTS: Ph-CMPN and healthy control groups included 99 and 80 cases, respectively. PV, ET and MF diagnoses of patients were 43 (%43.4), 44 (44.4%) and 12 (12.1%), respectively. JAK V617F gene mutation was found to be positive in 64 (71.1%) of all cases and in 27(65.8%), 32 (82%), 5 (50%) of the cases in PV, ET and PMF groups, respectively. Thrombosis was determined as 12 (12%) in the entire group, 12.5% in the JAK V617F negative and 15.3% in the positive patients, with no statistical significance (p=0.758). No significant difference was observed between patients with and without previous thrombosis history in respect to hemogram parameters, sedimentation and CRP (p>0.05), neutrophil to lymphocyte ratio (NLR), erythrocyte distribution width (RDW), mean platelet volume (MPV) and sedimentation levels of the patient.

Transformation from atypical chronic myeloid leukemia to chronic myelomonocytic leukemia as progression of myeloid neoplasm with platelet-derived growth factor ß rearrangement.

Myeloid neoplasms associated with platelet-derived growth factor b (PDGFRB) rearrangement usually keep only one morphologic type unless blast crisis. We describe a unique case of hematological features transformation from atypical chronic myeloid leukemia to chronic myelomonocytic leukemia, and imatinib showed no clinical therapeutic effects. The phenomenon indicates that different types of myeloid neoplasms associated with PDGFRB rearrangement can transform into one another with the progression of the disease, and to some extent, this transformation suggests the aggravation of disease.

Prophylaxis and management of venous thromboembolism in patients with myeloproliferative neoplasms: consensus statement of the Haemostasis Working Party of the German Society of Hematology and Oncology (DGHO), the Austrian Society of Hematology and Oncology (ÖGHO) and Society of Thrombosis and Haemostasis Research (GTH e.V.).

Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) like polycythemia vera and essential thrombocythemia are at increased risk of arterial and venous thrombosis. Strategies of prevention may consist of platelet aggregation inhibitors and/or cytoreductive agents depending on the underlying disease and the individual risk. Clinical evidence for management of acute venous thromboembolic events in MPN patients is limited. Modality and duration of therapeutic anticoagulation after venous thrombosis has to be evaluated critically with special regard to the increased risk for spontaneous bleeding events associated with the underlying diseases. Both for therapy of the acute event and for secondary prophylaxis, low-molecular-weight heparins should preferentially be used. A prolongation of the therapeutic anticoagulation beyond the usual 3 to 6 months can only be recommended in high-risk settings and after careful evaluation of potential risks and benefits for the individual patient. New direct oral anticoagulants (NOAC) should not preferentially be used due to lack of clinical experience in patients with MPN and potential drug interactions (e.g. with JAK inhibitors). Consequent treatment of the underlying myeloproliferative disease and periodical evaluation of the response to therapy is crucial for optimal secondary prophylaxis of thromboembolic events in those patients.

Chronic kidney disease in patients with the Philadelphia-negative chronic myeloproliferative neoplasms.

BACKGROUND: The progression of kidney function and frequency of chronic kidney disease (CKD) in patients with the Philadelphia-negative myeloproliferative neoplasms (MPN) is unknown, although CKD is linked to increased mortality. METHODS: This longitudinal retrospective study evaluates the estimated glomerular filtration rate (eGFR) in 143 MPN patients over a period of 9 years. RESULTS: 29% of patients had CKD stage 3 or 4 at time of diagnosis. 20% of patients had a rapid annual loss of eGFR (>3mL/min/1.73m(2)) and eGFR was negatively correlated to monocyte and neutrophil counts. CONCLUSION: Kidney impairment might contribute to the increased mortality observed in MPN patients.

Cyclical thrombocytosis, acquired von Willebrand syndrome and aggressive non-melanoma skin cancers are common in patients with Philadelphia-negative myeloproliferative neoplasms treated with hydroxyurea.

Abstract Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea complications have been reported in Philadelphia-negative myeloproliferative neoplasms (MPNs), but their incidence and clinical consequences have not been defined in a large cohort of patients. We conducted a retrospective analysis of 188 consecutive patients with MPNs specifically addressing the incidence of these complications. Cyclical thrombocytosis was documented in 29 patients (15%), the majority of whom were receiving hydroxyurea. Acquired von Willebrand syndrome was identified in 17 of the 84 screened patients (20%), but was not associated with any major bleeding complications. Non-melanoma skin cancers were reported in 51 patients (27%). Hydroxyurea-related fever occurred in nine of 149 patients (6%) who received hydroxyurea. Seventy-three patients (39%) experienced a total of 98 major thrombotic events, with the majority of these occurring prior to or within 3 months of the diagnosis. Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea-related complications are not infrequent in MPNs and have important clinical consequences for management.

Clinical risk factors of thrombosis in patients with Ph-negative myeloproliferative neoplasms, who had experienced radiation exposure due to the Chornobyl accident.

OBJECTIVE: The objective of this study was to determine the predictive value of a factor of age over 60 years, history of thrombosis, and cardiac risk factors (CRF) for the thrombosis in patients with Ph-negative myeloproliferative neoplasm (Ph-negative MPN), namely the essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (IMF), who had experienced radiation exposure due to the Chornobyl accident and without radiation anamnesis. MATERIALS AND METHODS: There were 216 patients with Ph-negative MPN included in the study. Prevalence of thrombosis and presence of CRF were determined by processing the medical documentation. RESULTS: The age older than 60 years (RR=1.73, 95% confidence interval [CI] 1.00-2.98; p=0.043 and RR=2.04, 95% CI =1.12-3.68; p=0.02) and CRF (RR=2.25, 95% CІ =1.21-4.16; p=0.005 and RR=2.31, 95% CІ =1.20-4.41; p=0.008) are predictors of thrombosis in all patients with PV and with spontaneous PV, respectively. Age over 60 years and CRF in all patients with ET associates with an increase of the relative risk of thrombosis (RR=2.5, 95% CІ =1.05-5.92; p=0.047 and RR=2.74, 95% CІ =1.18-6.23; p=0.026). Frequency of recurrent thrombotic complications in patients with ET and thrombosis in anamnesis is significantly higher than in patient's without history of thrombotic complication (RR=2.75, 95% CІ =1.15-6.51; p=0.035). CONCLUSIONS: Our findings confirm previous results of other studies reporting that the age over 60 years, history of thrombosis, CRF influences on thrombosis development in Ph-negative MPN patients.

Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms.

The evidence that leukocytes may contribute to the pathogenesis of thrombosis in Chronic Myeloproliferative Neoplasms is increasing but not definitive. To further enforces whether an increased leukocyte count is associated with thrombosis and whether this effect can be modulated by cytoreductive therapy, we analyzed the clinical course of 187 patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) followed at two Italian Institutions over a period of 7 years. The association was measured at diagnosis or before thrombotic events: a multivariable analysis was carried out using data at baseline and time-dependent covariates. We found that white blood cells (WBC) count above 9.5 x 10(9)/L at diagnosis (baseline analysis) was associated with thrombosis during the follow-up (Hazard Ratio [HR] of 1.8, p 0.03). At the time-dependent analysis, therapy with hydroxyurea (HU), lowering by 35% the baseline WBC level, reduced such strength of association giving a HR of 1.3 (p value non significant). We found a trend between WBC level and thrombosis in untreated low-risk patients (RR of 1.9, 95% CI 0.9 to 3.1); in high-risk patients treated with HU this correlation was clearly lost (RR 1.1, 95% CI 0.2 to 2.7). Finally, we could not identify the presence of JAK2 (V617F) as a risk factor for thrombosis. Properly designed prospective studies should corroborate such results.

Spontaneous splenic rupture in atypical (Philadelphia chromosome negative) chronic myeloid leukaemia following blastic crisis.

Philadelphia chromosome negative and bcr/abl negative chronic myeloid leukaemia (CML) is an uncommon atypical CML. We describe a patient with this disorder who experienced an acute blastic transformation that resulted in rapid splenic enlargement and subsequent atraumatic splenic rupture. Clinically, spontaneous splenic rupture may be a difficult diagnosis to make and this case highlights the importance of considering atraumatic splenic rupture as a cause for unexplained abdominal pain in a patient with a haematological malignancy.

[Acute thrombotic complication at the debute of the Philadelphia chromosome-negative myeloproliferative syndrome]. / Akut trombotisk komplikation ved debut af det Philadelphia-kromosom-negative myeloproliferative syndrom.

METHODS: We describe eight patients with a diagnosis of a chronic myeloproliferative disorder, characterised in most patients by severe thrombotic complications at the debut of the disease. RESULTS: The symptoms were life-threatening in seven patients: acute upper gastrointestinal haemorrhage from oesophageal varices in four, an acute abdominal catastrophy owing to mesenteric vein thrombosis with intestinal gangrene in two, and a large cerebral infarction, which was lethal, in one. The same patient also suffered a thrombosis of the axillary and subclavian veins. Neurological symptoms, with headache, visual disturbances, dizziness, and impaired memory, were initial cardinal symptoms. In two patients, explorative laparotomy was performed with intestinal resection owing to gangrene. One patient had a toe amputation. DISCUSSION: The above symptoms are explained by thrombosis in the microcirculation because of thrombocytosis and circulating platelet aggregates. In patients with polycythaemia vera, the elevated haematocrit contributes significantly to the impaired microcirculation. Early diagnosis and management of these disorders are of utmost importance to prevent the potentially life-threatening complications described above.

Extensive cytogenetic studies of clonality following interferon-alpha therapy in chronic myeloid leukemia occurring in monosomic cells in a patient with Turner syndrome mosaic.

In a 27-year-old female with Turner syndrome mosaic, Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) occurred only in the monosomic cells (45, Xc). Extensive cytogenetic studies, including triple-color fluorescence in situ hybridization (FISH), revealed that Ph-positive monosomic cells (45, Xc), Ph-negative monosomic cells and normal diploid cells (46, XX) were present in her bone marrow at diagnosis. After successful interferon therapy, the non-leukemia cells expanded and reconstituted normal hematopoiesis resulting in complete cytogenetic response, following the selective suppression of the monosomic Ph-positive leukemia clone. The ratio of Xc to XX cells in bone marrow cells was significantly increased to that in skin fibroblasts. Moreover, the ratio of Ph-positive cells to Ph-negative cells was found to be significantly different between karyotyping and FISH. Studies of this quite unique case not only confirmed the clonality of CML, effectiveness of interferon-alpha and X chromosome imbalance among different tissues, but also demonstrated a discrepant increase of the BCR/ABL-positive clone in CML. The latter supports the hypothesis that reduced programmed cell death may be the primary mechanism responsible for the expansion of the leukemia clone in CML. Our study verifies the importance of extensive analysis of a neoplastic disease in patients with a constitutional chromosomal abnormality.

[Blast crisis accompanied by severe DIC of Ph negative chronic myeloid leukemia showing t(9;16) and positive M-BCR/ABL rearrangement].

A 66-year-old woman complained of chest discomfort in January 1995. In March the accelerated phase of chronic myeloid leukemia (CML) was diagnosed. Chromosomal analysis demonstrated negative Ph and positive t(9;16) (q34;p11) with positive major BCR/ABL chimeric mRNA. Administration of hydroxycarbamide was initiated, but in May she developed high fever and severe left hypochondralgia. Her WBC was 62,100/microliter (blast 64%), and LDH was 3,590 IU/l. Bone marrow examination showed 78.6% blasts, with a nucleated cell count of 74 x 10(3)/microliter. Blasts were negative for esterase stain and partially positive for both peroxidase stain and PAS reaction. Surface marker analysis revealed that blasts were positive for CD13, CD19, CD33, CD34, and HLA-DR. A diagnosis of blast crisis was made and she was treated with the VDS-CP regimen with heparin for DIC. After temporary improvement her disease recurred rapidly with severe DIC. Treatment with low molecular weight heparin and fresh frozen plasma failed to control DIC and she died of subarachnoid hemorrhage on the 48th hospital day. This is the first veprted of case Ph-negative, M-BCR/ABL-positive CML with t(9;16) accompanied by severe DIC.

[Radiotherapy in advanced osseous destruction in chronic myeloid leukemia. A case report]. / Radiotherapie bei fortgeschrittener ossärer Destruktion bei chronischer myeloischer Leukämie. Ein Fallbericht.

PURPOSE: Chronic myelocytic leukemia is a disease of myeloproliferative disorder. In chronic myelocytic leukemia occasionally myelosarcomas occur as defined tumors which can cause localized symptoms. We report a case of successful palliative radiotherapy. PATIENT AND METHODS: A 44-year-old patient with total destruction of the left humerus caused by myelosarcoma of the bone in chronic myelocytic leukemia was treated with percutaneous megavoltage radiotherapy, the total applied dose was 40 Gy. After radiotherapy the patient was free of pain. The tumorous swelling of soft tissue subsided completely, there was total formation of callus in the affected humerus and the patient could be mobilized. CONCLUSIONS: This case report confirms the high effectiveness of palliative radiotherapy even in advanced cases of myelosarcomas which has been described in literature.

Fatal Haemophilus influenzae septicemia following bronchoscopy in a splenectomized patient.

We describe a 46-year-old splenectomized patient who died of Haemophilus influenzae septicemia 16 h following bronchoscopy. Although rare, postsplenectomy overwhelming sepsis is always a danger in splenectomized patients undergoing invasive procedures. Chemoprophylaxis should be considered in asplenic patients peribronchoscopy.