Viral-specific T cells for Cytomegalovirus retinitis following hematopoietic stem cell transplantation: A success story.

Cytomegalovirus retinitis (CMVR) following hematopoietic stem cell transplantation (HCT) for a primary immunodeficiency is a rare but highly morbid condition with potential irreversible consequences despite optimal antiviral pharmacotherapy. Viral-specific T cells (VSTs) pose a promising and safe approach eradicating intractable viral disease. We describe the case of a 21-month-old male with Wiskott-Aldrich syndrome (WAS) and CMVR post HCT with sustained long-term virologic and clinical response after CMV-specific T-cell therapy. This case highlights the need to consider VST as an adjunct upfront strategy in refractory CMVR and for routine ophthalmologic screening and surveillance in high-risk patients post HCT.

Use of cardiac radiation therapy as bridging therapy to CAR-T for relapsed pediatric B-cell acute lymphoblastic leukemia.

The use of radiotherapy as bridging therapy to chimeric antigen receptor T-cell therapy (CAR-T) in pre-B acute lymphoblastic leukemia (B-ALL) has been minimally explored. Here, we present a boy with B-ALL who relapsed after allogeneic bone marrow transplant with disseminated disease, including significant symptomatic cardiovascular and gastrointestinal (GI) involvement. The cardiac and GI leukemic infiltrates were successfully treated with bridging radiation therapy (BRT) prior to CAR-T infusion. Using this approach, he successfully tolerated CAR-T with no evidence of disease or sequelae on 3-month follow-up. This is the first reported case of safe and effective delivery of cardiac BRT in B-ALL.

Connecting the Dots From Fever of Unknown Origin to Myelodysplastic Syndrome: GATA2 Haploinsufficiency.

Leukemia-predisposing conditions, such as GATA2 haploinsufficiency, are known for their high penetrance and expressivity profiles. These disorders pose a difficult diagnostic challenge to even the most experienced clinician when they first present. We describe the case of a 17-year-old male presenting with features of nontuberculous mycobacterial infection, pulmonary fibrinoid granulomatous vasculitis, and myelodysplasia in the setting of a pathogenic GATA2 frameshift mutation confirmed by next-generation sequencing. The broad differential for GATA2 haploinsufficiency requires prompt recognition of key clinical features and laboratory abnormalities towards directing diagnosis and guiding appropriate and perhaps life-saving therapy.

Clinical trial recruitment of people who speak languages other than english: a children's oncology group report.

BACKGROUND: Persons who speak languages other than English (LOE) are underrepresented in clinical trials; this may be due in part to inadequate multilevel resources. We conducted a survey of institutions affiliated with the Children's Oncology Group (COG) to characterize current research recruitment practices and resources regarding translation and interpretation services. METHODS: In October 2022, a 20-item survey was distributed electronically to institutions affiliated with COG to assess consent practices and resources for recruiting participants who speak LOE to COG trials. Descriptive statistics were used to summarize responses; responses were compared by institution size, type, and respondent role. RESULTS: The survey was sent to a total of 230 institutions, and the response rate was 60% (n = 139). In total, 60% (n = 83) had access to short form consents. Full consent form translation was required at 50% of institutions, and 12% of Institutional Review Boards restricted use of centrally translated consent forms. Forty-six percent of institutions reported insufficient funding to support translation costs; 15% had access to no-cost translation services. Forty-four percent (n = 61) were required to use in-person interpreters for consent discussions; the most cited barrier to obtaining consent was lack of available in-person interpreters (56%). Forty-six percent (n = 69) reported that recruiting persons who speak LOE to clinical trials was somewhat or very difficult. CONCLUSIONS: Institutions affiliated with COG face resource-specific challenges that impede recruitment of participants who speak LOE in clinical trials. These findings indicate an urgent need to identify strategies aimed at reducing recruitment barriers to ensure equitable access to clinical trials.

Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS.

An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m2/day IV continuous infusion days 1-3, daunorubicin 45 mg/m2 IV days 1-3, etoposide 400 mg/m2 IV days 8-10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4+ and CD8+ peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4+ and CD8+ T cells.

Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy.

BACKGROUND: Our understanding of phenotypic and functional signatures of CD8+ T cell dysfunction in acute myeloid leukemia (AML) is limited. Deciphering these deranged T cell functional states and how they are impacted by induction chemotherapy is essential for incorporation of novel immune-based strategies to restore and maintain antileukemia immunity. METHODS: We utilized high-dimensional immunophenotyping, gene expression, and functional studies to characterize peripheral blood and bone marrow CD8+ T cells in 72 AML patients at diagnosis and after induction chemotherapy. RESULTS: Our data suggest that multiple aspects of deranged T cell function are operative in AML at diagnosis, with exhaustion and senescence being the dominant processes. Following treatment, the phenotypic and transcriptional profile of CD8+ T cells diverged between responders and nonresponders. Response to therapy correlated with upregulation of costimulatory, and downregulation of apoptotic and inhibitory, T cell signaling pathways, indicative of restoration of T cell function. In functional studies, AML blasts directly altered CD8+ T cell viability, expansion, co-signaling and senescence marker expression. This CD8+ T cell dysfunction was in part reversible upon PD-1 blockade or OX40 costimulation in vitro. CONCLUSION: Our findings highlight the uniqueness of AML in sculpting CD8+ T cell responses and the plasticity of their signatures upon chemotherapy response, providing a compelling rationale for integration of novel immunotherapies to augment antileukemia immunity. FUNDING: This work was supported by the Leukemia & Lymphoma Society grant no. 6449-13; NIH grants UM1-CA186691 and R01-HL110907-01; the American Society for Blood and Marrow Transplantation New Investigator Award/Gabrielle's Angel Foundation; the Vienna Fund for Innovative Cancer Research; and by fellowships from the Wenner-Gren Foundation and the Swedish Society for Medical Research.