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Black race and Hispanic ethnicity are associated with higher mortality in severe combined immunodeficiency (SCID) following hematopoietic cell transplantation (HCT), though mechanisms remain unclear. We evaluated 796 children with SCID who received nonsibling HCT between 1982 and 2020 using data from the Primary Immune Deficiency Treatment Consortium. Overall survival for Black (aHR 2.47, 95%CI 1.64, 3.71) and Asian/Pacific Islander patients (aHR 1.82, 95%CI 1.00, 3.30) was significantly lower compared with non-Hispanic White patients, while Hispanic patients had lower event-free survival (aHR 1.83, 95%CI 1.27, 2.63) compared with non-Hispanic White patients. Even after adjusting for age and infection, Black patients with SCID had more than twofold hazard of death compared with non-Hispanic White patients. NBS was associated with earlier diagnosis, reduced infection at HCT, and elimination of survival disparities between Black and non-Hispanic White patients. These findings suggest that universal, system-level interventions such as NBS can mitigate disparities in outcomes for children with SCID.

Importance Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. Objective To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. Design, Setting, and Participants Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. Exposures Entrance into an MRI surveillance program. Main Outcomes and Measures Cox proportional hazards modeling was used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. Results A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0.20 (95% CI, 0.10-0.43; P < .001) for women with BRCA1 sequence variations and 0.87 (95% CI, 0.10-17.25; P = .93) for women with BRCA2 sequence variations. Conclusion and Relevance Results of this cohort study suggest that among women with a BRCA1 sequence variation, MRI surveillance was associated with a significant reduction in breast cancer mortality compared with no MRI surveillance. Further studies of women with BRCA2 sequence variations are needed to ascertain these women obtain the same benefits associated with MRI surveillance.

PURPOSE Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD). METHODS This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or severe) or relapse-free survival (CRFS). RESULTS Among 346 patients enrolled, 327 received HCT, 300 per protocol. Intent-to-treat rates of 2-year CRFS were 50.6% for CD34 selection (hazard ratio [HR] compared with control, 0.80; 95% CI, 0.56 to 1.15; P = .24), 48.1% for PTCy (HR, 0.86; 0.61 to 1.23; P = .41), and 41.0% for control. Corresponding rates of overall survival were 60.1% (HR, 1.74; 1.09 to 2.80; P = .02), 76.2% (HR, 1.02; 0.60 to 1.72; P = .95), and 76.1%. CD34 selection was associated with lower moderate to severe cGVHD (HR, 0.25; 0.12 to 0.52; P = .02) but higher transplant-related mortality (HR, 2.76; 1.26 to 6.06; P = .01). PTCy was associated with comparable cGVHD and survival outcomes to control, and a trend toward lower disease relapse (HR, 0.52; 0.28 to 0.96; P = .037). CONCLUSION CNI-free interventions as performed herein did not result in superior CRFS compared with tacrolimus and methotrexate with BM. Lower rates of moderate and severe cGVHD did not translate into improved survival.

Abstract The Wilms tumor protein,WT1, is a potentially targetable tumor associated antigen that is overexpressed in a majority of pediatric leukemias. T cells with cytotoxic activity restricted to WT1 peptide can be expanded from the peripheral blood of normal donors using pulsed EBV transformed BLCLs as stimulators. As part of an ongoing clinical trial, a patient with multiply relapsed leukemia cutis was successfully treated with donor derived WT1 CTLs. The patient was initially diagnosed with MLL rearranged AML at 3 months of age with marrow and cutaneous involvement. By 3.5 years of age, he had undergone two stem cell transplants (SCT) from a sex-mismatched HLA matched unrelated donor. Multiple episodes of isolated cutaneous relapse starting two months after the second SCT were treated with DLI at escalating doses (3.3 x 10e8/kg) as well as local radiotherapy with continued development of new lesions. He was started on Interferon 2b alpha five months after second SCT with good response but was taken off of it for clinical intolerance and one month later again developed cutaneous lesions for which he received DLI, radiotherapy and was restarted on low dose Interferon 2b alpha with stabilization of disease. Biopsy of one of the lesions demonstrated the presence of MLL rearranged leukemic blasts that by PCR demonstrated WT1 expression. WT1 directed CTLs were generated from his SCT donor. These WT1 CTLs were restricted by HLA-DRB1 0801. The immunodominant epitopes presented by this allele were defined (281- 292 and 425-436) using overlapping pools of pentadecapeptides. The CTLs were cytotoxic at 25:1 E:T ratio against autologous BLCLs (33%) and autologous BLCLs loaded with the WT1 peptides (65%) but not against HLA mismatched BLCLs (2%) or K562 cells (0%). The line was composed of a mix of CD8 (64%) and CD4 (30%) T cells. The patient was treated on Day 0,7, 21 and 35 with 30 x 10e6/m2 of WT1 CTLs. The first cycle of therapy was associated with resolution of one of the skin lesions and he went on to receive two additional cycles of WT1 CTLs. Expansion of circulating WT1 and EBV specific precursors in the blood was detected after these infusions. One of two residual skin lesions was biopsied and demonstrated no active leukemic infiltrate and the presence of donor derived T cells. However, at no time prior to or following the WT-1 specific T-cell infusions has he developed any cutaneous or other evidence of GvHD. Based on uncertainty about the duration of WT1 CTL maintenance in vivo the patient has received multiple cycles of T cell infusions. Strikingly, each cycle of cells has resulted in an expansion of circulating WT1 and EBV specific precursors. The patient is now 5 years old and has been in continuous remission for 20 months. Prior studies have focused almost exclusively on vaccines and T-cell therapies specific for immunogenic epitopes of WT-1 presented by prevalent class I HLA alleles. This patient provides evidence underscoring the therapeutic potential of T-cells specific for immunogenic WT-1 peptides presented by HLA class II alleles. Disclosures: No relevant conflicts of interest to declare.