COVID-19 vaccination in patients with immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder that is characterized by low platelet count and increased bleeding risk. COVID-19 vaccination has been described as a risk factor for de novo ITP, but the effects of COVID-19 vaccination in patients with ITP are unknown. We aimed to investigate the effects of COVID-19 vaccination in patients with ITP on platelet count, bleeding complications, and ITP exacerbation (≥50% decline in platelet count, or nadir platelet count < 30 × 109/L with a >20% decrease from baseline, or use of rescue therapy). Platelet counts in patients with ITP and healthy controls were collected immediately before and 1 and 4 weeks after the first and second vaccinations. Linear mixed-effects modeling was applied to analyze platelet counts over time. We included 218 patients with ITP (50.9% female; mean age, 55 years; and median platelet count, 106 × 109/L) and 200 healthy controls (60.0% female; mean age, 58 years; median platelet count, 256 × 109/L). Platelet counts decreased by 6.3% after vaccination. We did not observe any difference in decrease between the groups. Thirty patients with ITP (13.8%; 95% confidence interval [CI], 9.5-19.1) had an exacerbation and 5 (2.2%; 95% CI, 0.7-5.3) suffered from a bleeding event. Risk factors for ITP exacerbation were platelet count < 50 × 109/L (odds ratio [OR], 5.3; 95% CI, 2.1-13.7), ITP treatment at time of vaccination (OR, 3.4; 95% CI, 1.5-8.0), and age (OR, 0.96 per year; 95% CI, 0.94-0.99). Our study highlights the safety of COVID-19 vaccination in patients with ITP and the importance of the close monitoring of platelet counts in a subgroup of patients with ITP. Patients with ITP with exacerbation responded well on therapy.

Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach.

The use of novel B-cell receptor signaling inhibitors results in high response rates and long progression-free survival in patients with indolent B-cell malignancies, such as chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinemia. Ibrutinib, the first-in-class inhibitor of Bruton tyrosine kinase, and idelalisib, the first-in-class inhibitor of phosphatidylinositol 3-kinase δ, have recently been approved for the treatment of several indolent B-cell malignancies. These drugs are especially being used for previously unmet needs, i.e., for patients with relapsed or refractory disease, high-risk cytogenetic or molecular abnormalities, or with comorbidities. Treatment with ibrutinib and idelalisib is generally well tolerated, even by elderly patients. However, the use of these drugs may come with toxicities that are distinct from the side effects of immunochemotherapy. In this review we discuss the most commonly reported and/or most clinically relevant adverse events associated with these B-cell receptor inhibitors, with special emphasis on recommendations for their management.

BCR-ABL negative myeloproliferative neoplasia: a review of involved molecular mechanisms.

The clonal bone marrow stem cell disorders essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) belong to the group of Philadelphia chromosome negative myeloproliferative neoplasia (Ph- MPN). In 2005 the JAK2(V617F) mutation was discovered which has generated more insight in the pathogenetic mechanism of the MPNs. More mutations have been detected in MPN patients since. However, the underlying cause of MPN has not been discovered so far. The mechanism of increased angiogenesis in MPNs and the development of fibrosis in the bone marrow in PMF patients and in some ET and PV patients is still not known. This review will focus on the most important molecular pathogenetic mechanisms in MPN patients.

Anti-apoptotic pathways in bone marrow and megakaryocytes in myeloproliferative neoplasia.

OBJECTIVE: Proliferative activity contributes to bone marrow cellularity in myeloproliferative neoplasia (MPN). Megakaryocytes are the most important cells in MPN bone marrow pathology. JAK2(V617F) mutation constitutively activates JAK2, pErk (phosphorylating extracellular signal-regulated kinase) and PI3K (phosphatidylinositol 3-kinase)-Akt signaling. Erk is involved in megakaryocyte differentiation, PI3K-Akt inhibits megakaryocyte apoptosis via Bcl-xL and two downstream effectors (p70S6k and Bnip3). Immunohistochemic expression of phosphorylated Erk, Akt, p70S6k and Bnip3 was studied along with microvessel density (MVD) in MPN bone marrow and megakaryocytes. METHODS: 36 essential thrombocythemia (ET), 25 polycythemia vera and 45 primary myelofibrosis patients were analyzed for pErk, pAkt, Bnip3, p70S6k and MVD expression by immunostaining bone marrow biopsy sections followed by automated image analysis. JAK2(V617F) was analyzed through real-time PCR in blood samples. RESULTS: pErk and pAkt were significantly higher expressed in MPN megakaryocytes, mainly in ET patients, compared to controls. Bnip3 was higher expressed in bone marrow of control patients and in MPN megakaryocytes. Mainly in ET patients, MPN megakaryocytes showed higher p70S6k expression compared to controls. CONCLUSION: Increased bone marrow cellularity in MPN patients might be influenced by increased pErk, pAkt and decreased Bnip3 expression. A dominant role for megakaryocytes in ET patients was shown. Increased amounts of megakaryocytes in MPN patients can be due to increased pAkt and p70S6k.

The involvement of Galectins in the modulation of the JAK/STAT pathway in myeloproliferative neoplasia.

BACKGROUND: In patients with myeloproliferative neoplasia (MPN) the development of fibrosis and increased vessel density correlate with poor prognosis. The JAK2(V617F) mutation constitutively activates JAK2, which phosphorylates signal transducer activator of transcription (STAT), up-regulating vascular endothelial growth factor (VEGF), which might be responsible for angiogenesis in MPN. Galectins are involved in the development of fibrosis and angiogenesis and might also be involved in activation of the JAK/STAT pathway in MPN. METHODS: 106 MPN patients, 36 essential thrombocythemia (ET), 25 polycythemia vera (PV) and 45 primary myelofibrosis (PMF), were analyzed for the expression pattern of galectin-1, galectin-3, pSTAT3, pSTAT5 and MVD by immunostaining of bone marrow biopsy sections followed by automated image analysis. The JAK2 mutational status was analysed through real time PCR in blood samples. RESULTS: The expression of galectin-1 was significantly higher in all MPN patients compared to normal controls. Galectin-3 was expressed more in PV patients. MVD was significantly higher in all MPN patients and correlated with galectin-1 and pSTAT5 expression. pSTAT5 expression showed a trend of higher expression in patients carrying the JAK2(V617F) mutation as well as in PV patients. PMF patients and all JAK2(V617F) positive patients showed a significantly higher pSTAT3 expression compared to control and ET patients. CONCLUSION: The findings suggest the involvement of galectin-1 in MPN development, regardless of the subtype. Furthermore involvement of galectin-3 in PV development, pSTAT5 in that of PV and JAK2(V617F) positive patients and angiogenesis, as well as pSTAT3 is involved in the pathogenesis of PMF.

Reproducibility of histologic classification in nonfibrotic myeloproliferative neoplasia.

Early phases of polycythemia vera, essential thrombocythemia, and primary myelofibrosis (PMF) can be difficult to distinguish by morphologic studies alone because they share many morphologic characteristics. Histologic criteria according to the 2008 World Health Organization (WHO) classification are part of the myeloproliferative neoplasia (MPN) diagnosis. Our aim was to assess the reproducibility of morphologic characteristics and determine their relative importance for histologic diagnoses on selected trephine biopsy sections. For the study, 56 prefibrotic MPN trephine specimens were blindly reviewed by 4 hematopathologists using a scoring list of 16 histologic characteristics mentioned in the WHO classification. Consensus was defined as agreement by 3 of 4 hematopathologists. High degrees of consensus were reached for individual major morphologic features used in the WHO classification, especially for the nuclear features of megakaryocytes (83%). Some of the features correlated positively or negatively with the histologic diagnosis of PMF. Consensus for the histologic classification of MPN was reached in 39 (70%) of 56 cases without knowledge of clinical data. This finding indicates a difference in the relative importance assigned to individual histologic characteristics by different hematopathologists.