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BCR-ABL1 -negative myeloproliferative neoplasms are burdened by a reduced life expectancy mostly due to an increased risk of thrombo-hemorrhagic events, fibrotic progression/leukemic evolution, and infectious complications. In these clonal myeloid malignancies, JAK2 V617F is the main driver mutation, leading to an aberrant activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Therefore, its inhibition represents an attractive therapeutic strategy for these disorders. Several JAK inhibitors have entered clinical trials, including ruxolitinib, the first JAK1/2 inhibitor to become commercially available for the treatment of myelofibrosis and polycythemia vera. Due to interference with the JAK-STAT pathway, JAK inhibitors affect several components of the innate and adaptive immune systems such as dendritic cells, natural killer cells, T helper cells, and regulatory T cells. Therefore, even though the clinical use of these drugs in MPN patients has led to a dramatic improvement of symptoms control, organ involvement, and quality of life, JAK inhibitors–related loss of function in JAK-STAT signaling pathway can be a cause of different adverse events, including those related to a condition of immune suppression or deficiency. This review article will provide a comprehensive overview of the current knowledge on JAK inhibitors’ effects on immune cells as well as their clinical consequences, particularly with regards to infectious complications.

Polycythemia vera (PV) is mainly characterized by elevated blood cell counts, thrombotic as well as hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. Major changes to its diagnostic criteria were made in the 2016 revision of the World Health Organization (WHO) classification, with both hemoglobin and hematocrit diagnostic thresholds lowered to 16.5 g/dL and 49% for men, and 16 g/dL and 48% for women, respectively. The main reason leading to these changes was represented by the recognition of a new entity, namely the so-called “masked PV”, as individuals suffering from this condition have a worse outcome, possibly owing to missed or delayed diagnoses and lower intensity of treatment. Thrombotic risk stratification is of crucial importance to evaluate patients’ prognosis at diagnosis. Currently, patients are stratified into a low-risk group, in the case of younger age (<60 years) and no previous thromboses, and a high-risk group, in the case of patients older than 60 years and/or with a previous thrombotic complication. Furthermore, even though they have not yet been formally included in a scoring system, generic cardiovascular risk factors, particularly hypertension, smoking, and leukocytosis, contribute to the thrombotic overall risk. In the absence of agents proven to modify its natural history and prevent progression, PV management has primarily been focused on minimizing the thrombotic risk, representing the main cause of morbidity and mortality. When cytoreduction is necessary, conventional therapies include hydroxyurea as a first-line treatment and ruxolitinib and interferon in resistant/intolerant cases. Each therapy, however, is burdened by specific drawbacks, underlying the need for improved strategies. Currently, the therapeutic landscape for PV is still expanding, and includes several molecules that are under investigation, like long-acting pegylated interferon alpha-2b, histone deacetylase inhibitors, and murine double minute 2 (MDM2) inhibitors.

We report the clinical presentation and risk factors for survival in 175 patients with myeloproliferative neoplasms (MPN) and COVID-19, diagnosed between February and June 2020. After a median follow-up of 50 days, mortality was higher than in the general population and reached 48% in myelofibrosis (MF). Univariate analysis, showed a significant relationship between death and age, male gender, decreased lymphocyte counts, need for respiratory support, comorbidities and diagnosis of MF, while no association with essential thrombocythemia (ET), polycythemia vera (PV), and prefibrotic-PMF (pre-PMF) was found. Regarding MPN-directed therapy ongoing at the time of COVID-19 diagnosis, Ruxolitinib (Ruxo) was significantly more frequent in patients who died in comparison with survivors ( p  = 0.006). Conversely, multivariable analysis found no effect of Ruxo alone on mortality, but highlighted an increased risk of death in the 11 out of 45 patients who discontinued treatment. These findings were also confirmed in a propensity score matching analysis. In conclusion, we found a high risk of mortality during COVID-19 infection among MPN patients, especially in MF patients and/or discontinuing Ruxo at COVID-19 diagnosis. These findings call for deeper investigation on the role of Ruxo treatment and its interruption, in affecting mortality in MPN patients with COVID-19.

Opinion Statement The introduction of TKIs into the therapeutic armamentarium of CML has changed the disease paradigm, increasing long-term survival from 20% to over 80%, with a life expectancy now approaching that of the general population. Although highly effective, TKIs also have a toxicity profile that is often mild to moderate, but sometimes severe, with multiple kinases involved in the development of adverse events (AEs). Among others, cardiovascular AEs observed in TKI-treated CML patients may represent a significant cause of morbidity and mortality, and their pathogenesis is still only partially understood. In view of the recent introduction into daily clinical practice of new TKIs, namely the STAMP inhibitor asciminib, with a distinct safety profile, hematologists now more than ever have the opportunity to select the most suitable TKI for each patient, an aspect that will be fundamental in terms of personalized preventive and therapeutic strategies. Furthermore, physicians should be aware of the feasibility of TKI dose modifications at all stages of the patients’ treatment journey, both at diagnosis for frail or elderly subjects or with multiple comorbidities, and during follow-up for those patients who experience toxicity, as well as to prevent it, with the main objective of reducing side effects while maintaining the response. Consequently, preserving the cardiovascular health of CML patients will likely be a more urgent topic in the near future, with specific measures aimed at controlling cardiovascular risk factors through a multidisciplinary approach involving a panel of healthcare professionals together with the hematologist.

Myelofibrosis (MF) is a clonal disorder of the pluripotent hematopoietic stem cell, whose clinical manifestations can be extremely heterogeneous, including cytopenias, organomegaly, constitutional symptoms, and cachexia. Median survival ranges from approximately 3.5 to 5.5 years; while the most frequent cause of death is the evolution to acute myeloid leukemia, also other conditions such as progression without transformation, complications due to cytopenias including infections or bleeding, and cardiovascular events may be fatal. Myelofibrosis is still orphan of curative treatments: allogeneic hematopoietic stem cell transplant (HSCT), the only therapeutic approach that has clearly demonstrated an impact on disease progression, is associated with relevant morbidity and mortality and only a minority of patients is eligible for such an intensive procedure. While the discovery of the crucial role of JAK2 mutations and the consequent clinical use of JAK inhibitors has led to a dramatic improvement of symptoms control and quality of life, yet these drugs do not significantly modify the natural history of the disease. A better understanding of the molecular pathogenesis will hopefully foster the development of new targeted therapies aimed at improving MF prognosis. Herein, we review the most recent advances about JAK inhibitors and other molecules which are under investigation.

We conducted a large international nested case-control study including 1881 patients with Philadelphia-negative myeloproliferative neoplasms (MPN). Cases ( n  = 647) were patients with second cancer (SC: carcinoma, non-melanoma skin cancer, hematological second cancer, and melanoma) and controls ( n  = 1234) were patients without SC, matched with cases for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration. The aim was to evaluate the risk of SC after exposure to cytoreductive drugs. Patients exposed to hydroxyurea (HU) (median: 3 years) had a risk of SC similar to unexposed patients (OR = 1.06, 95% CI 0.82–1.38). In contrast, in cancer-specific stratified multivariable analysis, HU had two-fold higher risk of non-melanoma (NM) skin cancer (OR = 2.28, 95% CI 1.15–4.51). A significantly higher risk of NM-skin cancer was also documented for pipobroman (OR = 3.74, 95% CI 1.00–14.01), ruxolitinib (OR = 3.87, 95% CI 1.18–12.75), and for drug combination (OR = 3.47, 95% CI 1.55–7.75). These three drugs did not show excess risk of carcinoma and hematological second cancer compared with unexposed patients. Exposure to interferon, busulfan, and anagrelide did not increase the risk. In summary, while it is reassuring that no excess of carcinoma was documented, a careful dermatologic active surveillance before and during the course of treatments is recommended.

Myelofibrosis (MF) is a BCR-ABL1–negative myeloproliferative neoplasm that is mainly characterised by reactive bone marrow fibrosis, extramedullary haematopoiesis, anaemia, hepatosplenomegaly, constitutional symptoms, leukaemic progression, and shortened survival. As such, this malignancy is still orphan of curative treatments; indeed, the only treatment that has a clearly demonstrated impact on disease progression is allogeneic haematopoietic stem cell transplantation, but only a minority of patients are eligible for such intensive therapy. However, more recently, the discovery of JAK2 mutations has also led to the development of small-molecule JAK1/2 inhibitors, the first of which, ruxolitinib, has been approved for the treatment of MF in the United States and Europe. In this article, we report on old and new therapeutic strategies that proved effective in early preclinical and clinical trials, and subsequently in the daily clinical practice, for patients with MF, particularly concerning the topics of anaemia, splenomegaly, iron overload, and allogeneic stem cell transplantation.

Polycythemia vera (PV) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow, mainly due to a Janus kinase 2 gene mutation (JAK2V617F). Givinostat, a histone-deacetylase inhibitor that selectively targets JAK2V617F cell growth, has demonstrated good efficacy and safety in three phase 1/2 studies in patients with PV. This manuscript focuses on the 4-year mean (2.8 year median) follow-up of an open-label, long-term study that enrolled 51 patients with PV (out of a total of 54 with MPN) who received clinical benefit from givinostat in these previous studies or on compassionate use, and who continued to receive givinostat at the last effective and tolerated dose. The primary objectives are to determine givinostat’s long-term safety and tolerability, and efficacy evaluated by the investigators according to internationally recognized response criteria. During follow-up, only 10% of PV patients reported Grade 3 treatment-related adverse events (AEs), while none had Grade 4 or 5 treatment-related AEs. The overall response rate for the duration of follow-up was always greater than 80% in patients with PV. In conclusion, givinostat demonstrated a good safety and efficacy profile in patients with PV, data supporting long-term use in this population.