Highlights Narsoplimab down-modulates SARS-CoV-2-induced activation of the lectin pathway and endothelial cell damage. Narsoplimab can reduce the thrombotic risk of Covid-19 patients. All patients treated with narsoplimab improved and survived without any drug-related adverse events.

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Several guidelines have been published about management of chronic GvHD (cGvHD), but the clinical practice still remains demanding. The Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has planned a prospective observational study on cGvHD, supported by a dedicated software, including the updated recommendations. In view of this study, two surveys have been conducted, focusing the management of cGvHD and ancillary therapy in cGvHD, to address the current 'real life' situation. The two surveys were sent to all 57 GITMO centers, performing allografting in Italy; the response rate was 57% and 66% of the interviewed centers, respectively. The first survey showed a great disparity especially regarding steroid-refractory cGvHD, although extracorporeal photo-apheresis resulted as the most indicated treatment in this setting. Another challenging issue was the strategy for tapering steroid: our survey showed a great variance, and this disagreement could be a real bias in evaluating outcomes in prospective studies. As for the second survey, the results suggest that the ancillary treatments are not standardized in many centers. All responding centers reported a strong need to standardize management of cGvHD and to participate in prospective trials. Before starting observational and/or interventional studies, a detailed knowledge of current practice should be encouraged.

Background Despite prophylaxis, GVHD remains a significant cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation (HCT). ITA is a potent, selective Janus kinase (JAK) 1 inhibitor that has been combined safely with steroids in patients (pts) with acute GVHD. We describe results from a proof-of-concept study evaluating ITA + CNI-based regimens for GVHD prophylaxis. Study Design and Methods GRAVITAS-119 (NCT03320642) was a single-arm, open-label study enrolling pts aged ≥18 y undergoing allogeneic HCT using peripheral blood stem cells from 8/8 or 7/8 matched related or unrelated donors for a hematologic malignancy. Eligible pts were candidates for reduced-intensity conditioning with Karnofsky Performance Status ≥70%. Pts were excluded for prior HCT, JAK inhibitor therapy, or active uncontrolled infection. Pts received oral ITA 200 mg once daily (QD) beginning 3 d before HCT + tacrolimus (Tac)/methotrexate (MTX) or cyclosporine A (CSA)/mycophenolate mofetil (MMF) ± antithymocyte globulin (ATG) per institutional practice. ITA dose reduction/interruption was permitted for toxicity. ITA was reduced to 100 mg QD by Day 90 and discontinued by Day 180 unless pts required systemic GVHD treatment (tx), had malignancy relapse or unacceptable toxicity, or withdrew consent. The primary endpoint was Day 28 hematologic recovery (absolute neutrophil count [ANC] ≥500/mm3 for 3 consecutive measurements and platelets [plt] ≥20,000/mm3 with no transfusions in the preceding 3 d). Secondary endpoints included incidence of acute and chronic GVHD, GVHD- and relapse-free survival (GRFS), overall survival, and safety. Results Sixty-five pts were enrolled and treated with ITA + Tac/MTX (n=41; +ATG, n=8; no ATG, n=33) or ITA + CSA/MMF (n=24; +ATG, n=16; no ATG, n=8). Median (range) age was 65 (25-76) y, and 57% were male. The most common underlying malignancies were acute myeloid leukemia (40%) and myelodysplastic syndrome (26%). Disease risk index was classified as low, intermediate, and high in 11%, 66%, and 23% of pts, respectively. Pts received grafts from matched related (51%), matched unrelated (40%), or single-antigen mismatched unrelated (9%) donors. Busulfan/fludarabine (51%) and a fludarabine/melphalan reduced-intensity regimen (18%) were the most common conditioning regimens; 11% of regimens contained total body irradiation. Median (range) exposure to ITA was 140 (10-187) d; 74% received ITA for >90 d. All pts achieved hematologic recovery. Median (range) time to ANC and plt recovery among patients who had count nadir (ANC <500/mm3 and/or plt <20,000/mm3) was 17 (4-31) and 14 (9-26) d, respectively. ANC recovery was on Day 31 for 1 pt with secondary myelofibrosis (MF). Two pts had secondary graft failure, 1 on tx (Tac/MTX/ATG; Day 65), with no evidence of viral infection, and 1 during post-tx follow-up (Tac/MTX; Day 182); both underwent retransplantation. Malignancy relapse (median follow-up, 363 d) occurred in 12 pts (18%), including 3 pts with molecular/cytogenetic relapse requiring intervention. In 63 evaluable pts, cumulative incidence of grade III/IV acute GVHD at Day 180 was 4.8% and 1-y GRFS was 38.5%. Secondary efficacy endpoints by tx group are in Table 1. The most common grade 3/4 hematologic adverse events (AEs) were thrombocytopenia (49%) and anemia (31%). 17 pts (26%) had cytomegalovirus reactivations (n=10 +ATG), 8 (12%) had Epstein-Barr virus (EBV) infection (no post-transplant lymphoproliferative disorder cases; all +ATG), and 1 pt (2%) had invasive bronchopulmonary aspergillosis (Tac/MTX +ATG). AEs (22%) and relapse (17%) were the most common reasons for ITA discontinuation; the most common AEs leading to discontinuation were mixed chimerism (6%), thrombocytopenia (3%), and hypertriglyceridemia (3%). 8 pts in the +ATG group received post-transplant rituximab for EBV infection (n=7) and/or azaciditine maintenance therapy (n=3). 15 pts (24%) in the per-protocol population died. 3 deaths occurred on tx due to infections (n=2) and intracranial hemorrhage (n=1; Table 2). Conclusions Results from this small open-label trial in a heterogeneous pt population demonstrated that GVHD prophylaxis with ITA + CNI-based regimens was well tolerated and rates of severe acute GVHD were low. 1 pt with MF did not achieve ANC recovery on Day 28. An ITA + Tac + post-transplant cyclophosphamide cohort is currently being investigated in GRAVITAS-119. Disclosures Shah: Cell Vault: Research Funding; Celgene: Consultancy, Honoraria; Miltenyi Biotec: Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Incyte: Consultancy; TG Therapeutics: Consultancy; Verastim: Consultancy; Lily: Consultancy, Honoraria. Chevallier:Incyte Corporation: Honoraria. Rubio:Medac: Consultancy; MSD: Honoraria; Gilead: Honoraria; Neovii: Research Funding; Novartis: Honoraria. Schroeder:Astellas: Other; Dova Pharmaceuticals: Other; FlatIron Inc: Other; GSK: Other; Gilead Sciences Inc: Other; Novo Nordisk: Other; Genentech Inc: Research Funding; Merck: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Cellect Inc: Research Funding; Janssen: Research Funding; Partners Therapeutics: Other; Pfizer: Other; AbbVie: Consultancy, Honoraria, Speakers Bureau; Fortis: Research Funding; Seattle Genetics: Research Funding; Amgen: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Celgene: Research Funding; PBD Incorporated: Research Funding; Genzyme Sanofi: Other: served on advisory boards and received honoraria or consultant fees, Research Funding. Hardy:Incyte Corporation: Other: Advisory Board Member; Kite/Gilead: Other: Advisory Board Member; American Gene Technologies: Other: DSMB Member. Stiff:Kite, a Gilead Company: Research Funding; Amgen: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding. Solano:Incyte Corporation: Other: Received fees for an advisory role. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Rowley:AbbVie: Current equity holder in publicly-traded company; FATE Therapeutics: Consultancy. Duarte:Incyte Corporation: Other: Has received speaker and advisor fees. Morariu-Zamfir:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Arbushites:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Ding:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Perales:Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Servier: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. OffLabel Disclosure: Itacitinib is a novel JAK1 inhibitor that has not been approved for use in acute GVHD or for any other indication.

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The translocation t(8;9)(p22;p24) results in the production of a chimeric PCM1 ‐ JAK2 fusion protein leading to the constitutive activation of the Janus Kinase 2 that renders this disease potentially sensitive to ruxolitinib. Here, we report an interesting case of PCM1 ‐ JAK2 myeloproliferative neoplasm evolving in myeloid sarcoma and B precursor ALL.

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