JAK inhibitors in the treatment of myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm driven by constitutive activation of the JAK/STAT pathway, resulting in clonal hematopoiesis, fibrotic replacement of the bone marrow, extramedullary hematopoiesis, splenomegaly, and debilitating constitutional symptoms. The advent of JAK inhibitors has changed the landscape of treatment options for patients with MF, providing relatively tolerable drug options that control symptoms, reduce splenomegaly, and improve quality of life, but often at the expense of worsening cytopenias. JAK inhibitors do not appear to halt the progression of disease or prevent leukemic transformation, and their effect on survival is debated. Here, we review both the US Food and Drug Administration-approved JAK inhibitors and those in late-phase clinical trials, with a focus on clinical activity and unique adverse effects. We also provide a schema for choosing among these options for patients with MF.

Immunoglobulin repletion during blinatumomab therapy does not reduce the rate of secondary hypogammaglobulinemia and associated infectious risk.

Background: Blinatumomab has demonstrated efficacy in minimal residual disease (MRD) positive and relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) by inciting rapid and sustained B-cell depletion. Methods: Owing to its effect on B-cells, blinatumomab is associated with a higher rate of secondary hypogammaglobulinemia compared to chemotherapy. To mitigate blinatumomab-induced hypogammaglobulinemia, patients were pre-emptively repleted with intravenous immune globulin (IVIG) during blinatumomab therapy. In this retrospective study, we compared outcomes of 23 blinatumomab treated adults with ALL. Seventeen patients routinely received IVIG and 6 patients were in the control cohort. Results: Our findings demonstrated no difference between the two cohorts in immunoglobulin G (IgG) nadir (338 mg/dL vs. 337 mg/dL, P=0.641), days to IgG nadir (120.5 vs. 85.5 days, P=0.13), infection rate (82.4% vs. 66.7%, P=0.58), infections requiring ICU admission (23.5% vs. 16.7%, P=1), and infection related mortality (17.6% vs. 16.7%, P=1). Conclusion: Pre-emptive IVIG repletion during blinatumomab did not prevent hypogammaglobulinemia and associated infection risk.

Impact of rituximab on COVID-19 outcomes.

Rituximab is associated with prolonged B-cell depletion and secondary hypogammaglobulinemia and is associated with a dampened humoral response and increased infectious complications. To describe the potential impact of prior rituximab therapy on clinical outcomes from SARS-CoV-2 infection and development of COVID-19 antibodies, we conducted a retrospective study of adults across the Mount Sinai Health System diagnosed with COVID-19 who received rituximab for any indication from February 2019 to October 2020. Patients' baseline characteristics, markers of disease severity, clinical outcomes, and antibody development were examined. Of the 49 patients included in the analysis, 63.2% required hospitalization for COVID-19, 24.5% required an ICU admission, and 32.7% died. Proximity of last rituximab infusion and COVID-19 diagnosis did not affect rates of hospitalization, admission to intensive care units or death. Over half (51.7%) of those whose antibodies were checked developed neutralizing anti-spike protein antibodies. The median time between rituximab administration and COVID-19 diagnosis was not significantly different between those who developed antibodies and those who did not (p = .323). Of the 14 patients with documented negative COVID-19 antibody titers, 11 of them survived SARS-CoV-2 infection, indicating that development of neutralizing antibodies may not be necessary for recovery from COVID-19.

A Novel t(1;9)(p36;p24.1) JAK2 Translocation and Review of the Literature.

The JAK2V617F point mutation has been implicated in the pathogenesis of the vast majority of myeloproliferative neoplasms (MPNs), but translocations involving JAK2 have increasingly been identified in patients with JAK2V617F-negativeMPNs. Here, we present a case of a patient diagnosed with JAK2V617F-negativepolycythemia vera (PV) that transformed to the MPN-blast phase. Cytogenetic and FISH analysis revealed a novel translocation of t(1;9)(p36;p24.1), causing a PEX14-JAK2 gene fusion product. The t(1;9)(p36;p24.1) represents a new addition to the list of known translocations involving JAK2that have been identified in hematologic malignancies. Although the prognostic and treatment implications of JAK2 translocations in MPNs have not been elucidated, positive outcomes have been described in case reports describing the use of JAK inhibitors in these patients. Further research into the role of JAK2 translocations in the pathogenesis and outcomes of hematologic malignancies is warranted.