Prolonged persistence of HIV-infected cells in tissues after allogeneic hematopoietic transplant

Background: HIV persistence during antiretroviral therapy (ART), prevents HIV eradication or control. Mechanisms responsible for HIV persistence, including in tissues, are not well understood. Here we investigated persistence of HIV-infected cells in tissues for >200 days in an individual who had successful allogeneic hematopoietic cell transplant (Allo-HCT;donor CCR5 wild-type) but developed acute lymphocytic interstitial pneumonia after COVID vaccination and expired. Method(s): Clinical and autopsy records were reviewed. HIV in tissue samples and mononuclear cells (prepared by ficoll from lung and spleen) were studied by single genome sequencing (SGS, 1.1 kb gag) and single-copy PCR for HIV DNA. Result(s): Study participant was a 38 yo man with HIV/AIDS on ART with HIV RNA<50 c/ml for >3 years who had reducedintensity conditioning, HLA-mismatched unrelated donor allo-HCT for primary refractory ALK-negative anaplastic large cell lymphoma. His course was remarkably uncomplicated:100% engraftment of donor CD3 and myeloid subsets confirmed by day +42 post-HCT;100% donor cells (CD4, CD8, CD19, CD14, CD56) confirmed by day +100. Per protocol, he was off all immunosuppression on day +60, did not develop acute graft-versus-host disease (GVHD), and maintained ART with HIV RNA<20 c/ml. Immune reconstitution was robust: NK, CD8, and B cells within normal range, CD4=172 cells/muL at d+100. He received SARS-CoV2 mRNAvaccine (Moderna) on days +107 and +144. On d+155, he developed dyspnea, hypoxia with acute lymphocytic interstitial pneumonia, presumed vaccinerelated, with no signs of GVHD, pulmonary infection, or lymphoma. HIV-1 RNA remained <20 except 21 c/ml noted shortly before expiring on d+207. Postmortem notable only for diffuse alveolar damage with fibrosis and a small white pulpdepleted spleen. Single copy assay detected HIV DNA in brain (thalamus, frontal lobe, midbrain), lymph node, and jejunum (1.6-16 copies/106 tissue cells) but not liver, spleen, or affected lung (<0.2 copies/106 cells). SGS revealed HIV sequences were non-identical, demonstrating multiple distinct populations of infected cells were present. Conclusion(s): HIV populations are diverse in tissues even after extensive lymphodepleting chemotherapy and allo-HCT. Complete donor engraftment in tissues, including brain, may take significantly longer than engraftment measured in peripheral blood. Eradication strategies will require evaluation of tissue compartments. Copyright © 2022 Elsevier Ltd

A Real World Experience of Combined Treatment with Romidepsin and Azacitidine in Patients with Peripheral T-Cell Lymphoma

BACKGROUND Patients with peripheral T-cell lymphoma (PTCL) lack good treatment options, particularly in the relapsed and refractory setting (Mak V et al. J Clin Oncol 2013). The development of the targeted therapies in PTCL has been lagging behind those developed for B cell lymphomas. Our work suggested that combinations of epigenetic therapies can be a safe and effective approach for patients with PTCL, particularly those with T-cell lymphomas with a follicular helper phenotype (Marchi E et al. Br. J Haematol 2015;O'Connor O.A. et al;Blood 2019;Falchi L et al. Blood 2020). While the reason for this is not clear, it is thought recurrent mutations in epigenetic factors, including Ten-Eleven Translocation-2 (TET2), DNA methyl transferase-3A (DNMT3A) and isocitrate dehydrogenase-2 (IDH2) may contribute for their increased vulnerability (Couronné L. et al. N Eng J Med 2012;Lemonnier F et al. Blood 2012). Despite these presumptions, a direct explanation for the sensitivity to epigenetic based treatment remains to be established. OBJECTIVES To evaluate the merits of romidepsin plus subcutaneous azacitidine in patients with PTCL when administered in a ‘real-world’ scenario. METHODS We retrospectively identified PTCL patients that were treated with azacitidine and romidepsin outside of a clinical trial based upon queries regarding off study use. The study was reviewed and approved by each Medical Center Institutional Review Board. We have identified 13 patients world-wide whose pretreatment characteristics are shown in Table 1. These patients were treated using 3 different schedules: Schedule A: azacitidine 75mg/m2 s.c. on days 1-7, romidepsin 14 mg/m2 on day 1, 8 and 15 of a 28 day cycle (total of 6 patients);Schedule B: azacitidine 75mg/m2 s.c. on days 1-5, romidepsin 14 mg/m2 on day 8, 15 and 22 of a 35 day cycle;and Schedule C (total of 2 patients): azacitidine 75mg/m2 s.c. on days 1-7, romidepsin 12-14 mg/m2 on day 8, 15 and 22 of a 28 day cycle (total of 5 patients). RESULTS We retrospectively identified 13 patients that were treated with romidepsin and azacitidine off study. Ten patients had angioimmunoblastic lymphoma (AITL), 2 had adult T-cell leukemia/lymphoma (ATLL) and 1 had PTCL-NOS. Eight of the 13 patients had next generation sequencing performed. Most common mutations found were those of TET2 (5 pts), RHOA (4pts), IDH2 (3pts) and DNMT3A (1 pt). One ATLL patient had mutations in TRAF3, FAT1 and MED12. Among these 13 patients, overall response rate (ORR) was 84% and the complete response rate (CR) was 61%. Median number of cycles was 3 (range 1-12). Treatment was well tolerated but notable adverse effects included nausea, fatigue, rash, neutropenia and thrombocytopenia. One patient experienced febrile neutropenia while another had pulmonary infiltrates (differential diagnosis included drug toxicity versus infection). Thrombocytopenia was the most common reason for dose reduction of romidepsin (to 12mg/m2) or its omission on day 8, 15 or 22. In 3 patients, azacitidine and romidepsin were used to achieve remission prior to allogeneic transplant (range of cycles 1-3), with all 3 patients were in CR at their last disease assessment. One patient died of transplant related mortality 8 months after his allogeneic stem cell transplant. There was 1 patient with AITL (treatment naïve) noted to have progression of disease at first imaging following 2 cycles of romidepsin and azacitidine. On the day of her PET/CT, she was however diagnosed with symptomatic Covid19 infection and was hospitalized. A repeat PET/CT 6 weeks later (without any additional lymphoma treatment) revealed PR. CONCLUSIONS Subcutaneous azacitidine and romidepsin administered in a ‘real-world’ situation is highly effective in patients with relapsed PTCL with tolerable toxicity, and can be used to successfully bridge patients to stem cell transplant. Notably, the efficacy was similar to the one reported on a clinical study with oral azacitidine and romidepsin. [Formula presented] Disclosures: Kalac: Astra Zeneca: Consultancy;Kyowa Kirin Consultancy;Gilead: Consultancy;Johnson and Johnson: Research Funding;Guidepoint: Consultancy;GLG: Consultancy. Tam: Beigene: Research Funding;Janssen: Research Funding;Abbvie: Research Funding;Loxo: Honoraria;Beigene: Honoraria;Janssen: Honoraria;Abbvie: Honoraria. Montanari: Seattle Genetics: Research Funding. O'Connor: Servier: Research Funding;Mundipharma: Honoraria;Myeloid Therapeutics: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees;Kymera: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees;Astex: Research Funding;BMS: Research Funding;Merck: Research Funding;TG Therapeutics: Current Employment, Current equity holder in publicly-traded company. Marchi: BMS: Research Funding;Astex: Research Funding;Merck: Research Funding;Myeloid Therapeutics: Honoraria;Kyowa Kirin: Honoraria;Kymera Therapeutics: Other: Scientific Advisor.