Infliximab Tissue Concentrations in Patients With Stable Ulcerative Colitis Are Correlated With More Durable Infliximab-associated Disease Remission.

BACKGROUND: We aimed to determine the correlation between tissue and plasma infliximab concentrations in an outpatient ulcerative colitis (UC) cohort based on histologic disease activity in addition to their relationship with long-term clinical outcomes. We assessed intraparticipant variability in infliximab concentrations between adjacent intestinal samples and the correlation between disease activity and tumor necrosis factor-α (TNF-α). METHODS: A prospective cohort study was conducted in participants with UC receiving infliximab. Blood and 2 sigmoid colon biopsies were obtained at the index colonoscopy for infliximab and TNF-α quantification. Histological disease activity was assessed. Participants were followed for 2 years for the occurrence of hospitalization, surgery, disease relapse, and infliximab discontinuation. RESULTS: A positive correlation was observed between mean plasma and uninflamed tissue infliximab concentrations only (Rs = 0.75, P = .0071). Lower mean tissue infliximab concentrations correlated with a shorter time to disease relapse vs those with higher mean tissue concentrations (Rs = 0.77, P = .032). This was not seen when using plasma infliximab concentrations. Additionally, no significant intraparticipant variability of infliximab concentrations was observed for all participants independent of disease activity. Neither plasma nor tissue TNF-α correlated with disease activity. CONCLUSIONS: These findings support data generated in patients with Crohn's disease: plasma infliximab concentrations are reflective of infliximab exposure in tissue in the UC patient in remission, but not for those with active disease. Increasing tissue concentrations in the noninflamed tissues may improve durability of infliximab. Neither plasma nor tissue TNF-α appear to correlate with UC disease activity. Larger follow-up studies would be of benefit.

Plasma infliximab concentrations are reflective of infliximab exposure in tissue in the UC patient in remission, but not for those with active disease. Increasing tissue concentrations in the noninflamed tissues may improve durability of infliximab.

Neurocysticercosis of the third ventricle: illustrative case.

BACKGROUND: Neurocysticercosis is a parasitic infection of the central nervous system. Cysts located in the ventricles, intraventricular neurocysticercosis (IVNCC), can cause symptoms of increased intracranial pressure and, if untreated, can be fatal. Neuroendoscopic removal of IVNCC is recommended as the first-line treatment. OBSERVATIONS: The authors present the case of a healthy 30-year-old male originally from Mexico who presented with headaches and vomiting. He was found to have a cyst in the third ventricle on imaging, consistent with IVNCC. The authors successfully performed neuroendoscopic surgery with removal of the cyst en bloc. LESSONS: A multidisciplinary team of neurosurgery and infectious disease specialists is recommended for successful management of patients with IVNCC. These patients typically require neuroendoscopic surgical removal for definitive treatment. In this case, the authors show surgery resulted in an effective cure without the need for antiparasitic medication and excellent long-term outcomes.

CCR2 and CCR5 co-inhibition modulates immunosuppressive myeloid milieu in glioma and synergizes with anti-PD-1 therapy.

Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.

Microneedle-Mediated Delivery of Immunomodulators Restores Immune Privilege in Hair Follicles and Reverses Immune-Mediated Alopecia.

Disorders in the regulatory arm of the adaptive immune system result in autoimmune-mediated diseases. While systemic immunosuppression is the prevailing approach to manage them, it fails to achieve long-lasting remission due to concomitant suppression of the regulatory arm and carries the risk of heightened susceptibility to infections and malignancies. Alopecia areata is a condition characterized by localized hair loss due to autoimmunity. The accessibility of the skin allows local rather than systemic intervention to avoid broad immunosuppression. It is hypothesized that the expansion of endogenous regulatory T cells (Tregs) at the site of antigen encounter can restore the immune balance and generate a long-lasting tolerogenic response. A hydrogel microneedle (MN) patch is therefore utilized for delivery of CCL22, a Treg-chemoattractant, and IL-2, a Treg survival factor to amplify them. In an immune-mediated murine model of alopecia, local bolstering of Treg numbers is shown, leading to sustained hair regrowth and attenuation of inflammatory pathways. In a humanized skin transplant mouse model, expansion of Tregs within human skin is confirmed without engendering peripheral immunosuppression. The patch offers high-loading capacity and shelf-life stability for prospective clinical translation. By harmonizing immune responses locally, the aim is to reshape the landscape of autoimmune skin disease management.

Fifth Edition of the World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues: Acute Lymphoblastic Leukemias, Mixed-Phenotype Acute Leukemias, Myeloid/Lymphoid Neoplasms With Eosinophilia, Dendritic/Histiocytic Neoplasms, and Genetic Tumor Syndromes.

This manuscript represents a review of lymphoblastic leukemia/lymphoma (acute lymphoblastic leukemia/lymphoblastic lymphoma), acute leukemias of ambiguous lineage, mixed-phenotype acute leukemias, myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangements, histiocytic and dendritic neoplasms, and genetic tumor syndromes of the 5th edition of the World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The diagnostic, clinicopathologic, cytogenetic, and molecular genetic features are discussed. The differences in comparison to the 4th revised edition of the World Health Organization classification of hematolymphoid neoplasms are highlighted.

A narrow T cell receptor repertoire instructs thymic differentiation of MHC class Ib-restricted CD8+ regulatory T cells.

Although most CD8+ T cells are equipped to kill infected or transformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CD8 lineage that is instructed to differentiate into CD8 T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self-peptides. Recognition and elimination of pathogenic target cells that express these Qa-1-self-peptide complexes selectively inhibits pathogenic antibody responses without generalized immune suppression. Immunization with synthetic agonist peptides that mobilize CD8 Tregs in vivo efficiently inhibit antigraft antibody responses and markedly prolong heart and kidney organ graft survival. Definition of TCR-dependent differentiation and target recognition by this lineage of CD8 Tregs may open the way to new therapeutic approaches to inhibit pathogenic antibody responses.

Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young.

PURPOSE: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease. METHODS: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts. RESULTS: γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10], P =9.5 x 10 -5 ) and 5-year overall survival (49% v. 78% [age 3-<10] and 81% [age ≥10], P =0.002), differences not observed in non-γδ T-ALL. γδ T-ALL in this age group was enriched for genomic alterations activating LMO2 activation and inactivating STAG2 inactivation ( STAG2/LMO2 ). Mechanistically, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping resulting in deregulation of gene expression associated with T-cell differentiation. Drug screening showed resistance to prednisolone, consistent with clinical slow treatment response, but identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which was efficaciously targeted by Poly(ADP-ribose) polymerase (PARP) inhibition, with synergism with HDAC inhibitors. Ex-vivo drug screening on PDX cells validated the efficacy of PARP inhibitors as well as other potential targets including nelarabine. CONCLUSION: γδ T-ALL in children under the age of three is extremely high-risk and enriched for STAG2/LMO2 ALL. STAG2 loss perturbs chromatin conformation and differentiation, and STAG2/LMO2 ALL is sensitive to PARP inhibition. These data provide a diagnostic and therapeutic framework for pediatric γδ T-ALL. SUPPORT: The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173. DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.

Matched-pair analysis of patients with ischemic stroke undergoing thrombectomy using next-generation balloon guide catheters.

BACKGROUND: Balloon guide catheters (BGCs) have not been widely adopted, possibly due to the incompatibility of past-generation BGCs with large-bore intermediate catheters. The next-generation BGC is compatible with large-bore catheters. We compared outcomes of thrombectomy cases using BGCs versus conventional guide catheters. METHODS: We conducted a retrospective study of 110 thrombectomy cases using BGCs (n=55) and non-BGCs (n=55). Sixty consecutive thrombectomy cases in whom the BOBBY BGC was used at a single institution between February 2021 and March 2022 were identified. Of these, 55 BGC cases were 1:1 matched with non-BGC cases by proceduralists, age, gender, stent retriever + aspiration device versus aspiration-only, and site of occlusion. First-pass effect was defined as Thrombolysis In Cerebral Infarction 2b or higher with a single pass. RESULTS: The BGC and non-BGC cohorts had similar mean age (67.2 vs 68.9 years), gender distribution (43.6% vs 47.3% women), median initial National Institutes of Health Stroke Scale score (14 vs 15), and median pretreatment ischemic core volumes (12 mL vs 11.5 mL). BGC and non-BGC cases had similar rates of single pass (60.0% vs 54.6%), first-pass effect (58.2% vs 49.1%), and complications (1.8% vs 9.1%). In aspiration-only cases, the BGC cohort had a significantly higher rate of first-pass effect (100% vs 50.0%, p=0.01). BGC was associated with a higher likelihood of achieving a modified Rankin Scale score of 2 at discharge (OR 7.76, p=0.02). No additional procedural time was required for BGC cases (46.7 vs 48.2 min). CONCLUSION: BGCs may be safely adopted with comparable procedural efficacy, benefits to aspiration-only techniques, and earlier functional improvement compared with conventional guide catheters.

Optimizing the synergy between stereotactic radiosurgery and immunotherapy for brain metastases.

Solid tumors metastasizing to the brain are a frequent occurrence with an estimated incidence of approximately 30% of all cases. The longstanding conventional standard of care comprises surgical resection and whole-brain radiotherapy (WBRT); however, this approach is associated with limited long-term survival and local control outcomes. Consequently, stereotactic radiosurgery (SRS) has emerged as a potential alternative approach. The primary aim of SRS has been to improve long-term control rates. Nevertheless, rare observations of abscopal or out-of-field effects have sparked interest in the potential to elicit antitumor immunity via the administration of high-dose radiation. The blood-brain barrier (BBB) has traditionally posed a significant challenge to the efficacy of systemic therapy in managing intracranial metastasis. However, recent insights into the immune-brain interface and the development of immunotherapeutic agents have shown promise in preclinical and early-phase clinical trials. Researchers have investigated combining immunotherapy with SRS to enhance treatment outcomes in patients with brain metastasis. The combination approach aims to optimize long-term control and overall survival (OS) outcomes by leveraging the synergistic effects of both therapies. Initial findings have been encouraging in the management of various intracranial metastases, while further studies are required to determine the optimal order of administration, radiation doses, and fractionation regimens that have the potential for the best tumor response. Currently, several clinical trials are underway to assess the safety and efficacy of administering immunotherapeutic agents concurrently or consecutively with SRS. In this review, we conduct a comprehensive analysis of the advantages and drawbacks of integrating immunotherapy into conventional SRS protocols for the treatment of intracranial metastasis.

Rituximab administration in pediatric patients with newly diagnosed acute lymphoblastic leukemia.

Polyethylene glycol (PEG)-asparaginase (pegaspargase) is a key agent in chemotherapy for acute lymphoblastic leukemia (ALL), but recipients frequently experience allergic reactions. We hypothesized that by decreasing antibody-producing CD20-positive B cells, rituximab may reduce these reactions. Children and adolescents (aged 1-18 years) with newly diagnosed B-ALL treated on the St. Jude Total XVII study were randomized to induction therapy with or without rituximab on day 3 (cohort 1) or on days 6 and 24 (cohort 2). Patient clinical demographics, CD20 expression, minimal residual disease (MRD), rituximab reactions, pegaspargase allergy, anti-pegaspargase antibodies, and pancreatitis were evaluated. Thirty-five patients received rituximab and 37 did not. Among the 35 recipients, 16 (45.7%) experienced a grade 2 or higher reaction to rituximab. There were no differences between recipients and non-recipients in the incidence of pegaspargase reactions (P > 0.999), anti-pegaspargase antibodies (P = 0.327), or pancreatitis (P = 0.480). CD20 expression on day 8 was significantly lower in rituximab recipients (P < 0.001), but there were no differences in MRD levels on day 8, 15, or at the end of induction. Rituximab administration during induction in pediatric patients with B-ALL was associated with a high incidence of infusion reactions with no significant decrease in pegaspargase allergies, anti-pegaspargase antibodies, or MRD.

Utility of end of induction bone marrow biopsy and survival outcomes in acute promyelocytic leukemia treated with fixed-dose induction regimen.

Significant variations exist related to the end of induction practices in the management of Acute Promyelocytic Leukemia (APL). These variations include all-trans retinoic acid (ATRA)-arsenic trioxide (ATO) in fixed doses versus continuation until hematologic complete remission (CR) and performance versus omission of post-induction bone marrow biopsy to confirm morphological CR. A retrospective chart review was conducted of 61 patients (42 low/intermediate-risk and 19 high-risk) aged ≥ 18 years with newly diagnosed APL treated with fixed duration ATRA-ATO +/- cytoreduction at a tertiary medical center from December 2012 through March 2020. Of the 54 patients with post-induction bone marrow biopsy results, 52 (96%) demonstrated no morphologic evidence of APL while the remaining were equivocal. After 2.6 years median follow-up, no relapses occurred. The estimated 2-year overall survival rate of 95% suggests excellent outcomes with a fixed ATO induction regimen and safe omission of post-induction bone marrow biopsy irrespective of hematologic parameters.

OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs.

Effective depletion of immune suppressive regulatory T cells (Tregs) in the tumor microenvironment without triggering systemic autoimmunity is an important strategy for cancer immunotherapy. Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus with a long history of human use. Here, we report rational engineering of an immune-activating recombinant MVA (rMVA, MVA∆E5R-Flt3L-OX40L) with deletion of the vaccinia E5R gene (encoding an inhibitor of the DNA sensor cyclic GMP-AMP synthase, cGAS) and expression of two membrane-anchored transgenes, Flt3L and OX40L. Intratumoral (IT) delivery of rMVA (MVA∆E5R-Flt3L-OX40L) generates potent antitumor immunity, dependent on CD8+ T cells, the cGAS/STING-mediated cytosolic DNA-sensing pathway, and type I IFN signaling. Remarkably, IT rMVA (MVA∆E5R-Flt3L-OX40L) depletes OX40hi regulatory T cells via OX40L/OX40 interaction and IFNAR signaling. Single-cell RNA-seq analyses of tumors treated with rMVA showed the depletion of OX40hiCCR8hi Tregs and expansion of IFN-responsive Tregs. Taken together, our study provides a proof-of-concept for depleting and reprogramming intratumoral Tregs via an immune-activating rMVA.

Uncovering a novel role of focal adhesion and interferon-gamma in cellular rejection of kidney allografts at single cell resolution.

Background: Kidney transplant recipients are currently treated with nonspecific immunosuppressants that cause severe systemic side effects. Current immunosuppressants were developed based on their effect on T-cell activation rather than the underlying mechanisms driving alloimmune responses. Thus, understanding the role of the intragraft microenvironment will help us identify more directed therapies with lower side effects. Methods: To understand the role of the alloimmune response and the intragraft microenvironment in cellular rejection progression, we conducted a Single nucleus RNA sequencing (snRNA-seq) on one human non-rejecting kidney allograft sample, one borderline sample, and T-cell mediated rejection (TCMR) sample (Banff IIa). We studied the differential gene expression and enriched pathways in different conditions, in addition to ligand-receptor (L-R) interactions. Results: Pathway analysis of T-cells in borderline sample showed enrichment for allograft rejection pathway, suggesting that the borderline sample reflects an early rejection. Hence, this allows for studying the early stages of cellular rejection. Moreover, we showed that focal adhesion (FA), IFNg pathways, and endomucin (EMCN) were significantly upregulated in endothelial cell clusters (ECs) of borderline compared to ECs TCMR. Furthermore, we found that pericytes in TCMR seem to favor endothelial permeability compared to borderline. Similarly, T-cells interaction with ECs in borderline differs from TCMR by involving DAMPS-TLRs interactions. Conclusion: Our data revealed novel roles of T-cells, ECs, and pericytes in cellular rejection progression, providing new clues on the pathophysiology of allograft rejection.

Distinct Myeloid Derived Suppressor Cell Populations Promote Tumor Aggression in Glioblastoma.

The diversity of genetic programs and cellular plasticity of glioma-associated myeloid cells, and thus their contribution to tumor growth and immune evasion, is poorly understood. We performed single cell RNA-sequencing of immune and tumor cells from 33 glioma patients of varying tumor grades. We identified two populations characteristic of myeloid derived suppressor cells (MDSC), unique to glioblastoma (GBM) and absent in grades II and III tumors: i) an early progenitor population (E-MDSC) characterized by strong upregulation of multiple catabolic, anabolic, oxidative stress, and hypoxia pathways typically observed within tumor cells themselves, and ii) a monocytic MDSC (M-MDSC) population. The E-MDSCs geographically co-localize with a subset of highly metabolic glioma stem-like tumor cells with a mesenchymal program in the pseudopalisading region, a pathognomonic feature of GBMs associated with poor prognosis. Ligand-receptor interaction analysis revealed symbiotic cross-talk between the stemlike tumor cells and E-MDSCs in GBM, whereby glioma stem cells produce chemokines attracting E-MDSCs, which in turn produce growth and survival factors for the tumor cells. Our large-scale single-cell analysis elucidated unique MDSC populations as key facilitators of GBM progression and mediators of tumor immunosuppression, suggesting that targeting these specific myeloid compartments, including their metabolic programs, may be a promising therapeutic intervention in this deadly cancer. One-Sentence Summary: Aggressive glioblastoma harbors two unique myeloid populations capable of promoting stem-like properties of tumor cells and suppressing T cell function in the tumor microenvironment.

Lumbar arthroplasty for treatment of primary or recurrent lumbar disc herniation.

PURPOSE: Microdiscectomy is the current gold standard surgical treatment for primary lumbar disc herniations that fail non-surgical measures. Herniated nucleus pulposus is the manifestation of underlying discopathy that remains unaddressed with microdiscectomy. Therefore, risk remains of recurrent disc herniation, progression of the degenerative cascade, and on-going discogenic pain. Lumbar arthroplasty allows for complete discectomy, complete direct and indirect decompression of neural elements, restoration of alignment, restoration of foraminal height, and preservation of motion. In addition, arthroplasty avoids disruption of posterior elements and musculoligamentous stabilizers. The purpose of this study is to describe the feasibility of the use of lumbar arthroplasty in the treatment of patients with primary or recurrent disc herniations. In addition, we describe the clinical and peri-operative outcomes associated with this technique. METHODS: All patients that underwent lumbar arthroplasty by a single surgeon at a single institution from 2015 to 2020 were reviewed. All patients with radiculopathy and pre-operative imaging demonstrating disc herniation that received lumbar arthroplasty were included in the study. In general, these patients were those with large disc herniations, advanced degenerative disc disease, and a clinical component of axial back pain. Patient-reported outcomes of VAS back, VAS leg, and ODI pre-operatively, at three months, one year, and at last follow-up were collected. Reoperation rate, patient satisfaction, and return to work were documented at last follow-up. RESULTS: Twenty-four patients underwent lumbar arthroplasty during the study period. Twenty-two (91.6%) patients underwent lumbar total disc replacement (LTDR) for a primary disc herniation. Two patients (8.3%) underwent LTDR for a recurrent disc herniation after prior microdiscectomy. The mean age was 40 years. The mean pre-operative VAS leg and back pain were 9.2 and 8.9, respectively. The mean pre-operative ODI was 22.3. Mean VAS back and leg pain was 1.2 and 0.5 at three months post-operative. The mean VAS back and leg pain was 1.3 and 0.6 at one year post-operative. The mean ODI was 3.0 at one year post-operative. One patient (4.2%) underwent re-operation for migrated arthroplasty device which required repositioning. At last follow-up, 92% of patients were satisfied with their outcome and would undergo the same treatment again. The mean time for return-to-work was 4.8 weeks. After returning to work, 89% of patients required no further leave of absence for recurrent back or leg pain at last follow-up. Forty-four percent of patients were pain free at last follow-up. CONCLUSION: Most patients with lumbar disc herniations can avoid surgical intervention altogether. Of those that require surgical treatment, microdiscectomy may be appropriate for certain patients with preserved disc height and extruded fragments. In a subset of patients with lumbar disc herniation that require surgical treatment, lumbar total disc replacement is an effective option by performing complete discectomy, restoring disc height, restoring alignment, and preserving motion. The restoration of physiologic alignment and motion may result in durable outcomes for these patients. Longer follow-up and comparative and prospective trials are needed to determine how the outcomes of microdiscectomy may differ from lumbar total disc replacement in the treatment of primary or recurrent disc herniation.

Subdural CMOS optical probe (SCOPe) for bidirectional neural interfacing.

Optical neurotechnologies use light to interface with neurons and can monitor and manipulate neural activity with high spatial-temporal precision over large cortical extents. While there has been significant progress in miniaturizing microscope for head-mounted configurations, these existing devices are still very bulky and could never be fully implanted. Any viable translation of these technologies to human use will require a much more noninvasive, fully implantable form factor. Here, we leverage advances in microelectronics and heterogeneous optoelectronic packaging to develop a transformative, ultrathin, miniaturized device for bidirectional optical stimulation and recording: the subdural CMOS Optical Probe (SCOPe). By being thin enough to lie entirely within the subdural space of the primate brain, SCOPe defines a path for the eventual human translation of a new generation of brain-machine interfaces based on light.

Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia.

Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.

Laboratory Aspects of Minimal / Measurable Residual Disease Testing in B-Lymphoblastic Leukemia.

Minimal residual disease detection provides critical prognostic predictor of treatment outcome and is the standard of care for B lymphoblastic leukemia. Flow cytometry-based minimal residual disease detection is the most common test modality and has high sensitivity (0.01%) and a rapid turnaround time (24 hours). This article details the leukemia associated immunophenotype analysis approach for flow cytometry-based minimal residual disease detection used at St. Jude Children's Research Hospital and importance of using guide gates and back-gating.