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Background: The Janus kinase (JAK)/signal transducers and activators of transcription pathway has been implicated in the pathogenesis and progression of various hematologic malignancies. JAK1-regulated cytokines stimulate proliferation and growth of malignant cells and resistance to certain therapies., Patients and Methods: This phase 1/2 study evaluated 2 oral, novel JAK1 inhibitors (INCB052793 and itacitinib) in advanced hematologic malignancies. Phase 1a assessed dose escalation and expansion of INCB052793 monotherapy. Phase 1b evaluated INCB052793 plus standard therapy in relapsed/refractory multiple myeloma, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS). Phase 2 evaluated INCB052793 or itacitinib plus azacitidine in DNA methyltransferase inhibitor (DNMTi)-refractory AML or MDS. Primary endpoints included safety and tolerability for phase 1, and objective response rate for phase 2., Results: Fifty-eight patients were enrolled, all received study treatment and discontinued either treatment or participation in the study. The most common reasons for treatment discontinuation were progressive disease (35.4% and 50.0%) and adverse events (22.9% and 20.0%) for INCB052793 and itacitinib plus azacitidine, respectively. In phase 1, 12 of 39 patients (31%) achieved an objective response; 35 mg once daily was selected as the phase 2 dose. Two patients with DNMTi-refractory disease had an objective response in phase 2. The study was terminated for lack of efficacy., Conclusion: Inhibition of JAK1 with INCB052793 (monotherapy or combination therapy) or itacitinib plus azacitidine did not demonstrate clinically meaningful responses in these patients with hematopoietic malignancies., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: Cytokine release syndrome (CRS) is a potentially severe complication of COVID-19 most commonly resulting in respiratory failure. This ten-patient study was designed to determine the efficacy of therapeutic plasma exchange (TPE) in improving oxygenation and in reducing the cytokine load in a critically ill subset of patients., Methods: Five single volume plasma exchanges over eight days within a 14-day study period. In mechanically ventilated patients, oxygenation was measured via the PaO2/FiO2 (P/F) ratio and the oxygenation index (OI) daily for 14 days. Supplemental oxygen requirements were tracked daily for non-ventilated patients., Results: Non-ventilated patients were liberated from supplemental oxygen after TPE. The response was rapid with an 87% average reduction in oxygenation requirements following and average time to return to room air of 5.25 days. All mechanically ventilated patients demonstrated improvement in oxygenation with a 78% average improvement in the P/F ratio and a 43% improvement in OI. C-reactive protein (CRP) and serum levels of IL-6, IL-8, IL-10, TNFα, IFNγ and GM-CSF, were measured daily with immediate post TPE levels drawn on days 1, 2, 4, 6 and 8. All patients demonstrated significant reductions in CRP, IL-6, IL-10 and TNFα., Conclusions: In the majority of patients with Penn class 3 and 4 CRS complicating COVID-19, TPE demonstrated a prompt improvement in oxygenation and reduction in cytokine load without compromising patient safety. As this pilot study was envisioned to be hypothesis generating, expanded trials using TPE alone and in conjunction with novel pharmacologic agents are warranted., Registration: ClinicalTrials.gov NCT04374149., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This phase 1/2 study assessed parsaclisib (INCB050465), a next-generation, potent, and highly selective phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor, in patients with relapsed or refractory B-cell malignancies, alone or in combination with a Janus kinase 1 inhibitor (itacitinib) or chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide). Seventy-two patients received parsaclisib monotherapy (5-45 mg once daily). Expansion doses were 20 and 30 mg once daily; intermittent dosing at 20 mg (once daily for 9 weeks, then once weekly) was explored. No dose-limiting toxicities were identified, and maximum tolerated dose was not reached. Most common nonhematologic treatment-emergent adverse events (TEAEs) were diarrhea/colitis (36%), nausea (36%), fatigue (31%), and rash (31%). Grade 3/4 neutropenia occurred in 19% of patients. Serious TEAEs (>2 patients) were diarrhea/colitis (n = 9), pyrexia (n = 4), hypotension (n = 3), and sepsis (n = 3). Aspartate and alanine transaminase elevations occurring before treatment discontinuation were grade 1, except 1 grade 3 event each, secondary to sepsis. Two patients experienced 3 fatal parsaclisib-unrelated TEAEs (respiratory failure; respiratory failure and sepsis). In non-Hodgkin lymphoma (NHL), objective response rates to monotherapy were 71% in follicular lymphoma, 78% in marginal zone lymphoma, 67% in mantle cell lymphoma, and 30% in diffuse large B-cell lymphoma; 93% of responses occurred at first assessment (∼9 weeks). Parsaclisib has demonstrated antitumor activity in relapsed or refractory B-cell NHL with the potential for improved long-term patient outcomes. Phase 2 studies in relapsed or refractory B-cell NHL subtypes are ongoing. This trial was registered at www.clinicaltrials.gov as #NCT02018861., (© 2019 by The American Society of Hematology.)

Introduction: Metaplastic breast carcinoma (MBC) is a rare and aggressive histologic subtype of breast cancer comprising approximately 0.5% to 5.0% of all invasive breast cancers with a poor prognosis and limited therapeutic options., Patients and Methods: We investigated MBC at our institution to evaluate outcomes and investigate the molecular profile of our cohort to determine the presence of mutations for which there are targeted therapies., Results: We found our cohort to consist mainly of the matrix-producing variant (72%) with 48% having the stereotypical estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor-2-negative phenotype. While the overall survival of our cohort was an average of 1679 days (4.6 years), we had a surprising number of patients with second primaries (40%) and distant metastases (40%), yet few recurrences (12%). Molecular analysis of the tumors indicated that one gene mutation, CSFIR, was significantly associated with outcome (P = .021); however, the cohort was defined by frequent mutations in ERBB4 (36%), PIK3CA (48%), and FLT3 (60%), for which there are now targeted therapies., Conclusion: While surgery is the appropriate first step in the management of this aggressive malignancy, the collection of data pertaining to the use of targeted agents, although anecdotal, may provide clues to better treatment for these patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Survival rates from mechanical ventilation (MV) in allogeneic bone marrow transplantation are poor, but little is known about the need for and outcomes from MV in patients who undergo autologous hematopoietic stem cell transplantation (AHSCT)., Study Objective: To determine the frequency of and risk factors for the use of MV in recipients of AHSCT and to identify predictors of survival in mechanically ventilated AHSCT patients., Design: Retrospective, cohort analysis, Setting: Tertiary-care, university-affiliated medical center., Patients: One hundred fifty-nine consecutive patients who underwent AHSCT., Interventions: Patient surveillance and data collection., Measurements and Results: The primary outcome measure was the need for MV, and the secondary end point was survival after MV. Of 159 patients, 17 required MV (10. 7%). Three variables were associated with the need for MV: increasing age, use of total body irradiation in the conditioning regimen, and treatment with amphotericin B. As a screening test to predict the need for MV, no risk factor had a sensitivity or specificity > 82%. Three of the 17 mechanically ventilated patients (17.6%) survived to discharge. Only the mean APACHE (acute physiology and chronic health evaluation) II score separated survivors from nonsurvivors (21.7 vs 31.4; p = 0.029). Both the duration of MV and the length of stay in the ICU were similar in survivors and nonsurvivors., Conclusions: We conclude that MV is infrequently needed following AHSCT. Although survival after MV in these patients is limited, clinical variables do not reliably allow clinicians to prospectively identify patients destined to die.