We describe a case of Epstein‐Barr virus (EBV) positive, diffuse large B‐cell lymphoma in a 2‐year‐old female who went on to develop relapsed/refractory central nervous system (CNS) disease, ...manifesting as cranial nerve neurolymphomatosis. Although her atypical presentation was thought to be associated with an immune deficiency, extensive work‐up was negative. Despite subsequent treatment with third‐party EBV‐specific cytotoxic T‐lymphocytes, she died of progressive disease. This case report raises questions as to whether tailored treatment approaches should be considered for atypical presentations of pediatric lymphoma (e.g., CNS and virus‐associated).
•In this R/R population with high unmet need, patients responding to tabelecleucel demonstrated a clinically meaningful survival benefit.•Tabelecleucel has a favorable safety profile and shows ...durable clinical benefit in R/R EBV+ PTLD after HCT or SOT.
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Patients with Epstein-Barr virus (EBV)–positive posttransplant lymphoproliferative disease (EBV+ PTLD) in whom initial treatment fails have few options and historically low median overall survival (OS) of 0.7 months after allogeneic hematopoietic cell transplant (HCT) and 4.1 months after solid organ transplant (SOT). Tabelecleucel is an off-the-shelf, allogeneic EBV-specific cytotoxic T-lymphocyte immunotherapy for EBV+ PTLD. Previous single-center experience showed responses in patients with EBV+ PTLD after HCT or SOT. We now report outcomes from a multicenter expanded access protocol in HCT (n = 14) and SOT (n = 12) recipients treated with tabelecleucel for EBV+ PTLD that was relapsed/refractory (R/R) to rituximab with/without chemotherapy. The investigator-assessed objective response rate was 65.4% overall (including 38.5% with a complete and 26.9% with a partial response), 50.0% in HCT, and 83.3% in SOT. The estimated 1- and 2-year OS rates were both 70.0% (95% confidence interval CI, 46.5-84.7) overall, both 61.5% (95% CI, 30.8-81.8) in HCT, and both 81.5% (95% CI, 43.5-95.1) in SOT (median follow-up: 8.2, 2.8, and 22.5 months, respectively). Patients responding to tabelecleucel had higher 1- and 2-year OS rates (94.1%) than nonresponders (0%). Treatment was well tolerated, with no reports of tumor flare, cytokine release syndrome, or rejection of marrow and SOT. Results demonstrate clinically meaningful outcomes across a broad population treated with tabelecleucel, indicating a potentially transformative and accessible treatment advance for R/R EBV+ PTLD after HCT or SOT. This trial was registered at www.ClinicalTrials.gov as #NCT02822495.
T cell differentiation in the thymus depends on sequential interactions
between lymphoid progenitors and stromal cells in discrete regions of the cortex.
Here, we show that despite α
E
β
7
expression ...by a subset of the earliest intrathymic
precursors (and E-cadherin expression by thymic stroma), interaction of these
elements is not required for proper localization of early progenitors into the cortex,
or for successful steady state differentiation. These findings indicate that despite
in vitro
data demonstrating
α
E
β
7
mediated adhesion and proliferation
of intrathymic
T cell precursor populations, T lymphocyte development can proceed
independently of α
E
β
7
/E-cadherin
interactions.
T-cell-depleted (TCD) allogeneic hematopoietic stem cell transplantation demonstrates similar efficacy and reduced incidence and severity of graft-versus-host disease (GVHD) in appropriately selected ...patients versus T-cell-replete transplantation. The histopathology of cutaneous acute GVHD (aGVHD) after TCD peripheral blood stem cell transplants (PBSCTs) is not described. We identified 13 cases of patients after TCD PBSCT, with definitive aGVHD, and 20 cases of non-aGVHD skin rash in patients after TCD PBSCT, during multidisciplinary review by a dermatopathologist, dermatologist, and transplant physician, incorporating clinical presentation, therapeutic response, and histopathology data. Histopathologic features of aGVHD and non-aGVHD skin rash in TCD PBSCT patients were compared to each other, and also to features recently reported for non-TCD transplant recipients. aGVHD and non-aGVHD skin rash in TCD PBSCT patients' biopsies had similar rates of epidermal acanthosis, dermal melanophages, neutrophils, plasma cells, eosinophils, and extravasated erythrocytes. While satellitosis, exocytosis and adnexal involvement slightly favored aGVHD, more notable differential findings favoring aGVHD were diffuse (vs. focal/absent) basal vacuolization (77% aGVHD vs. 25% non-aGVHD rash), involvement of the entire epidermis (vs. partial thickness) by necrotic keratinocytes (42% aGVHD vs. 0% non-aGVHD rash), and nondense (rather than exuberant) inflammatory infiltrates (77% vs. 20%). After filtering features seen in all TCD samples (epidermal acanthosis, dermal melanophages, neutrophils, plasma cells, eosinophils, and extravasated erythrocytes), the most distinct features belonging to aGVHD-positive TCD samples were diffuse basal vacuolization, slight rather than dense inflammatory infiltrates, and necrotic keratinocytes involving the entire epidermis. Awareness of these features may help when evaluating a skin rash occurring after a TCD transplant.
Mutations of the recombinase-activating genes 1 and 2 (
and
) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell ...transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that
natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in
and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56
CD16
CD57
cells, yet increased degranulation and high perforin content. Correlation was observed between
recombinase activity of the mutant proteins, NK cell abnormalities, and
clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.
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