Page 360 - Haematologica Vol. 109 - July 2024

CASE REPORT
(N; black) as determined by enzyme-linked immunosorbent assay (ELISA) are shown. The temporal relationship to IVIG infusion is indicated by a green dashed vertical line. (D) Quantitative immunoglobulins (IgG, IgM, IgA) over time and temporal relationship to IVIG infusion (green dashed vertical line). Absolute serum concentrations of the different immunoglobulins were measured using human IgG, IgM, and IgA ELISA kits (Invitrogen, Cat. No. BMS2091, BMS2098, BMS2096) as per the manufacturer’s instruc- tions. (E) Reciprocal IgG antibody endpoint titers against microbial proteins influenza A nucleoprotein (Flu; red), tetanus toxoid (TT; orange), adenovirus type 5 hexon protein (Adv; green), varicella zoster virus envelope glycoprotein E (gE) protein (VZV; blue) and respiratory syncytial virus nucleoprotein (RSV; yellow) as determined by ELISA are shown. The temporal relationship to IVIG infusion is indicated by a green dashed vertical line. Serum antibody responses against recombinant, full-length SARS-CoV-2 proteins or viral control proteins were determined by ELISA as previously described.
ciltacabtagene autoleucel (ciltacel) CAR T for relapsed, penta-refractory disease after standard cyclophospha- mide and fludarabine lymphodepleting chemotherapy in October 2022. His course was notable for grade 2 CRS which was treated with single-dose tocilizumab. After discharge, he had neutropenia that responded to granu- locyte colony-stimlating factor (G-CSF) and achieved full count recovery. Approximately 1.5 months after CAR T-cell infusion, he developed fever, chills, cough, and exertion- al dyspnea and was readmitted with severe SARS-CoV-2 infection. He refused nirmatrelvir-ritonavir (paxlovid), but quickly became hypoxemic, and was transferred to the ICU. Computed tomography (CT) imaging showed diffuse ground-glass consolidations and ruled out pulmonary em- bolism (Figure 1A). For the majority of his 21-day admission, he remained symptomatic with cough and on high-flow O2 (15 days) despite a prolonged course of high-dose ste- roids and remdesivir but did not require intubation. After a 10-day course of intravenous (i.v.) steroids, he received intravenous immuoglobulin (IVIG), and 1 day later (on his 14th day of ICU stay), he was started on i.v. defibrotide for 7 days. Although there was some variation in fraction of inspired oxygen (FIO2) levels before the administration of defibrotide, a marked drop in FiO2, O2 flow rate, and most importantly a rapid clinical improvement only occurred after the application of the treatment (Figure 1B). After his discharge, he had bacteremias (pseudomonas and rothria) and cytomegalovirus (CMV) viremia which were successfully treated with appropriate anti-microbial therapy. Immediately before his clinical recovery from COVID-19 in- fection, he was treated with defibrotide which is most likely what led to the improvement in clinical status. Before his CAR T treatment, he had been receiving monthly IVIG infu- sions, and his pre-IVIG serum IgG level was within normal limits, making this a less likely contributor. We do not use tocilizumab routinely for the treatment of COVID; however, two of the studies leading to an emergency use authorization (EUA) by the Food and Drug Administration (FDA) reported different medians of 6 and 14 days for time to significant clinical improvement. Our patient did not have a meaning- ful improvement and remained on high-flow oxygen during his 14-day ICU stay despite tocilizumab. Another possible explanation for his clinical improvement may be immune reconstitution. However, at 2 months, although he was not neutropenic, he still had low T-cell counts (CD4+ 138 cells/ μL) and at 4 months, he only had partial immune reconsti-
tution (CD4+ 800 cells/μL, IgA <8 mg/dL). His bone marrow biopsy at 5.5 months was normocellular with trilineage hematopoiesis and no monoclonal plasma cell population was identified by morphology, immunohistochemistry or measurable residual disease (next generation sequencing [NGS]). His SARS-CoV-2 polymerase chain recation (PCR) was positive at 6 months but subsequently cleared. Defibrotide is a multifunctional endothelial stabilizing agent that received US regulatory approval for severe hepatic sinu- soidal obstruction syndrome/veno-occlusive disease (VOD/ SOS) in 2016, and European Medicines Agency approval in 2013.4 Given the high mortality rate of severe VOD/SOS, it is now broadly used in real-world practice.5 The postulated primary mechanism of action is the stabilization and/or re- versal of endothelial cell dysfunction. Moreover, defibrotide has also been shown to abrogate the deleterious effects of CD8+ and regulatory T cells on human microvascular endothelial cells (MVEC).6 These findings paved the way for the initial clinical trials in allogeneic transplant settings for VOD/SOS. A large CIBMTR study reported a 22.1% difference in the resolution of severe VOD/SOS at day +100.7 Given its favorable effects on endothelial dysfunction,8 defibrotide was also investigated in non-VOD/SOS conditions that complicate infectious and non-infectious inflammation characterized by endotheliopathy, or so-called endothe- liitis.9,10 In a preclinical study, defibrotide mitigated the en- dothelial cell injury induced by plasma from patients with COVID-19-related vasculopathies.11 Specifically, MVEC were exposed to primary samples with either acute COVID-19 infection or acute TMA in the presence and absence of defibrotide. Caspase-8 which was used as an endothelial cell activation surrogate marker was suppressed with de- fibrotide and signaling pathway alterations were noted.11 In acute malaria, defibrotide interfered with the coagula- tion/inflammation cycle, inhibited TLR-mediated dendritic cell activation, and reduced interferon-γ production.9 One proposed mechanism for SARS-CoV-2-related pulmonary organ damage is the formation of neutrophil extracellular traps (NET) associated with an abundance of neutrophils in autopsy specimens from COVID-19 patients.12 Interestingly, in the setting of antiphospholipid syndrome, defibrotide was demonstrated to inhibit NET formation and venous thrombosis.13-15 An open-label, single-center phase I study investigated the safety and efficacy of a 7-day course of defibrotide in patients with COVID-19-related acute respi- ratory distress syndrome (ARDS).16 Of 12 patients treated
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