48 research outputs found
Beyond CD19: Opportunities for Future Development of Targeted Immunotherapy in Pediatric Relapsed-Refractory Acute Leukemia
Chimeric antigen receptor (CAR) T cell therapy has been used as a targeted approach in cancer therapy. Relapsed and refractory acute leukemia in pediatrics has been difficult to treat with conventional therapy due to dose limiting toxicities. With the recent success of CD 19 CAR in pediatric patients with B cell ALL, this mode of therapy has become a very attractive option for these patients with high risk disease. In this review, we will discuss current treatment paradigms of pediatric acute leukemia, and potential therapeutic targets for additional high risk populations, including T cell ALL, AML, and infant ALL
Genomic characterization of pediatric Bâlymphoblastic lymphoma and Bâlymphoblastic leukemia using formalinâfixed tissues
BackgroundRecurrent genomic changes in Bâlymphoblastic leukemia (BâALL) identified by genomeâwide singleânucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, Bâlymphoblastic lymphoma (BâLBL), is limited by the low incidence and lack of fresh tissue for genomic testing.ProcedureWe used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalinâfixed paraffinâembedded pediatric BâLBL (n = 23) and BâALL (n = 55).ResultsSimilar to BâALL, CDKN2A/B deletions were the most common alteration identified in 6/23 (26%) BâLBL cases. Eleven of 23 (48%) BâLBL patients were hyperdiploid, but none showed triple trisomies (chromosomes 4, 10, and 17) characteristic of BâALL. IKZF1 and PAX5 deletions were observed in 13 and 17% of BâLBL, respectively, which was similar to the reported frequency in BâALL. Immunoglobulin light chain lambda (IGL) locus deletions consistent with normal light chain rearrangement were observed in 5/23 (22%) BâLBL cases, compared with only 1% in BâALL samples. None of the BâLBL cases showed abnormal, isolated VPREB1 deletion adjacent to IGL locus, which we identified in 25% of BâALL.ConclusionsOur study demonstrates that the copy number profile of BâLBL is distinct from BâALL, suggesting possible differences in pathogenesis between these closely related diseases.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137353/1/pbc26363.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137353/2/pbc26363_am.pd
Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukemia
Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2DBCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.This work was supported in part by
the American Lebanese Syrian Associated Charities of St. Jude Childrenâs Research
Hospital; by a Stand Up to Cancer Innovative Research Grant and St. Baldrickâs
Foundation Scholar Award (to C.G.M.); by a St. Baldrickâs Consortium Award (S.P.H.),
by a Leukemia and Lymphoma Society Specialized Center of Research grant (S.P.H. and
C.G.M.), by a Lady Tata Memorial Trust Award (I.I.), by a Leukemia and Lymphoma
Society Special Fellow Award and Alexâs Lemonade Stand Foundation Young Investigator
Awards (K.R.), by an Alexâs Lemonade Stand Foundation Award (M.L.) and by
National Cancer Institute Grants CA21765 (St Jude Cancer Center Support Grant), U01
CA157937 (C.L.W. and S.P.H.), U24 CA114737 (to Dr Gastier-Foster), NCI Contract
HHSN261200800001E (to Dr Gastier-Foster), U10 CA180820 (ECOG-ACRIN
Operations) and CA180827 (E.P.); U10 CA180861 (C.D.B. and G.M.); U24 CA196171
(The Alliance NCTN Biorepository and Biospecimen Resource); CA145707 (C.L.W. and
C.G.M.); and grants to the COG: U10 CA98543 (Chairâs grant and supplement to
support the COG ALL TARGET project), U10 CA98413 (Statistical Center) and U24
CA114766 (Specimen Banking). This project has been funded in whole or in part with
Federal funds from the National Cancer Institute, National Institutes of Health, under
Contract Number HHSN261200800001E
All-trans retinoic acid-induced inflammatory myositis in a patient with acute promyelocytic leukemia
Vincristine and Dactinomycin in Infantile Myofibromatosis With a Review of Treatment Options.
Case report: Tisagenlecleucel for treatment of relapsed B- acute lymphoblastic leukemia in a patient with mutation
BACKGROUND: Germline Checkpoint Kinase 2 gene ( mutations can increase the risk of solid tumors. Recently, they have been identified as risk factors for hematologic malignancies. However, to the best of our knowledge, B-acute lymphoblastic leukemia (B-ALL) has never been described as a presenting manifestation of germline mutation. Chimeric antigen receptor-T (CAR-T) cell therapy directed against CD19 antigen (tisagenlecleucel) is a novel cellular therapy for treatment of relapsed/refractory (R/R) B-ALL. The use of tisagenlecleucel has not been described in patients with mutation. CASE PRESENTATION: We describe a case of a pediatric patient with a heterozygous pathogenic germline mutation (c.1100delC; p.Thr367Metfs*15) successfully treated with tisagenlecleucel for relapsed B-ALL to avoid hematopoietic cell transplant (HCT). The twelve-year-old boy was diagnosed with National Cancer Institute (NCI) high-risk B-ALL (white blood cell count \u3e50,000/mcL), with no extramedullary disease. Cytogenetic analysis revealed normal karyotype but fluorescent hybridization (FISH) showed 93% positivity for rearrangement. He was treated as per Children\u27s Oncology Group (COG) AALL1131 therapy and achieved a complete remission. Seven months after diagnosis, he was found to have papillary thyroid carcinoma with no evidence of metastatic disease. The patient underwent a total thyroidectomy with central lymph node biopsy and radioactive iodine therapy. The patient\u27s biological mother and fraternal twin brother carry the same germline mutation with no history of malignancy. The biological father tested negative for the familial mutation. The patient\u27s genetic panel also identified three variants of unclear significance: (c.37â
°Câ\u3eâT; p.Arg124Cys), (c.62Gâ\u3eâA; p.Cys21Tyr) and (c.139Aâ\u3eâG; p.Met47Val). Extended family history also revealed a diagnosis of anaplastic thyroid cancer in maternal uncle at the age of 44 years. Fifteen months after diagnosis the patient had a relapse of B-ALL (both medullary and extramedullary with blasts in CSF), which was successfully treated with tisagenlecleucel. The patient remains in remission 3 years after receiving tisagenlecleucel. CONCLUSION: As conventional chemotherapy and radiation can potentially increase the risk of DNA damage and development of secondary malignancies, CD19 CAR-T therapy (tisagenlecleucel) can be used as a substitute for intensive re-induction chemotherapy and HCT in patients with a germline mutation
Prolonged Complete Response in a Pediatric Patient With Primary Peripheral T-Cell Lymphoma of the Central Nervous System.
We describe a child with a 2-week history of progressive headaches, blurry vision, and intermittent vomiting. Magnetic resonance imaging (MRI) of the brain showed a deep left hemispheric lesion with extension into the corpus callosum. Histology and immunophenotyping of the lesion was consistent with peripheral T-cell lymphoma, not otherwise specified. Chemotherapy was initiated and a complete remission was achieved. This case illustrates that a chemotherapeutic regimen used in adults with central nervous system (CNS) lymphoma can achieve durable remissions in pediatric patients with peripheral T-cell lymphoma, not otherwise specified of the CNS