Pediatric T- and NK-cell lymphomas: new biologic insights and treatment strategies

T- and natural killer (NK)-cell lymphomas are challenging childhood neoplasms. These cancers have varying presentations, vast molecular heterogeneity, and several are quite unusual in the West, creating diagnostic challenges. Over 20 distinct T- and NK-cell neoplasms are recognized by the 2008 World Health Organization classification, demonstrating the diversity and potential complexity of these cases. In pediatric populations, selection of optimal therapy poses an additional quandary, as most of these malignancies have not been studied in large randomized clinical trials. Despite their rarity, exciting molecular discoveries are yielding insights into these clinicopathologic entities, improving the accuracy of our diagnoses of these cancers, and expanding our ability to effectively treat them, including the use of new targeted therapies. Here, we summarize this fascinating group of lymphomas, with particular attention to the three most common subtypes: T-lymphoblastic lymphoma, anaplastic large cell lymphoma, and peripheral T-cell lymphoma-not otherwise specified. We highlight recent findings regarding their molecular etiologies, new biologic markers, and cutting-edge therapeutic strategies applied to this intriguing class of neoplasms

Novel ALK inhibitors in clinical use and development

Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. ALK-1 was initially found in anaplastic large cell lymphoma (ALCL). ALK mutations have also been implicated in the pathogenesis of non-small cell lung cancer (NSCLC) and other solid tumors. Multiple small molecule inhibitors with activity against ALK and related oncoproteins are under clinical development. Two of them, crizotinib and ceritinib, have been approved by FDA for treatment of locally advanced and metastatic NSCLC. More agents (alectinib, ASP3026, X396) with improved safety, selectivity, and potency are in the pipeline. Dual inhibitors targeting ALK and EGFRm (AP26113), TRK (TSR011), FAK (CEP-37440), or ROS1 (RXDX-101, PF-06463922) are under active clinical development

A Novel Approach in Cinnamic Acid Synthesis: Direct Synthesis of Cinnamic Acids from Aromatic Aldehydes and Aliphatic Carboxylic Acids in the Presence of Boron Tribromide

Cinnamic acids have been prepared in moderate to high yields by a new direct synthesis using aromatic aldehydes and aliphatic carboxylic acids, in the presence of boron tribromide as reagent, 4-dimethylaminopyridine (4-DMAP) and pyridine (Py) as bases and N-methyl-2-pyrolidinone (NMP) as solvent, at reflux (180-190°C) for 8-12 hours

Childhood Mixed Lineage Leukemia: The St. Jude Experience.

Abstract PURPOSE: To report a single institutional experience with presenting features, therapeutic approach and outcomes in pediatric mixed lineage acute leukemias, as defined by the WHO classification (including biphenotypic, bilineal and poorly differentiated leukemias). PATIENTS AND METHODS: Retrospective study of all pediatric patients with acute leukemias fulfilling the EGIL/WHO criteria for mixed-lineage leukemia, treated at St. Jude Children’s Research Hospital from 1985–2006. Features analyzed included morphology, cytochemistry, immunophenotype (flow cytometry), cytogenetics, therapy, response to therapy (including minimal residual disease level as detected by flow cytometry) and outcome. RESULTS: Of 1500 patients with newly diagnosed acute leukemia, 35 (21 boys and 14 girls), were diagnosed to have mixed lineage leukemia. They ranged in age between 2 days and 19 years (median, 10 years) and had a median leukocyte count of 18 × 109/L (range, 1 to 150 × 109/L). Morphologic and flow cytometric studies identified these leukemias as biphenotypic T-lymphoid/myeloid (20 cases), B-lymphoid/myeloid (10 cases), B/T-lymphoid/myeloid (2 cases), bilineal (2 cases) and undifferentiated (1 case). Sixteen cases showed cytochemical positivity for myeloperoxidase (1% to 90%, median 5%) and 9 cases had Auer rods. Twenty-three patients initially received standard induction therapy for AML (cytarabine, daunorubicin, and etoposide) and 12 patients received ALL-directed remission induction [prednisone, vincristine, L-asparaginase (PVA), and daunomycin]. Of the former group, 12 (52%) achieved complete remission (CR), 2 attained partial remission (PR), 8 had no response (NR), and 1 died of toxicity. Ten of the 12 patients (83%) who first received ALL therapy achieved CR and only 2 had NR. Thus, after initial induction therapy, 22 of the 35 patients (63%) achieved CR. However, 8 of the 10 patients who had NR or PR to AML therapy attained CR after receiving standard ALL induction therapy with only PVA, and 1 of 2 patients who had NR to ALL therapy achieved CR after receiving AML therapy, resulting in an overall CR rate of 91% (32 of 35 patients). Notably, of the 8 patients who did not respond to AML therapy but achieved CR after PVA, all 4 tested were MRD-negative after PVA and all 6 who received multiagent chemotherapy without transplantation are alive and in long-term remission for 1.1 to 16.4 years. Seven of these 8 patients had T-lymphoid/myeloid biphenotypic leukemia with expression of CD2, CD7, cytoplasmic CD3, and low MPO positivity (1% to 3.5%). Overall, among patients who achieved CR, 15 of 20 patients treated with chemotherapy alone are alive in remission, compared to only 4 of 11 patients who underwent transplantation. CONCLUSIONS: Pediatric patients with mixed lineage leukemia may benefit from a therapeutic approach directed against both AML and ALL. We suggest that patients who respond well to myeloid-directed therapy should continue to receive this therapy, whereas those who require lymphoid-directed induction should receive prolonged continuation treatment directed against both ALL and AML. Furthermore, our results indicate that patients with mixed lineage leukemias who achieve remission do not require stem cell transplantation to achieve long term survival.</jats:p

Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia.

BACKGROUND: About a fifth of children with acute -lymphoblastic leukaemia (T-ALL) succumb to the disease, suggesting an unrecognised biological heterogeneity that might contribute to drug resistance. We postulated that T-ALL originating from early T-cell precursors (ETPs), a recently defined subset of thymocytes that retain stem-cell-like features, would respond poorly to lymphoid-cell-directed therapy. We studied leukaemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome. METHODS: Leukaemic cells from 239 patients with T-ALL enrolled at St Jude Children's Research Hospital (n=139) and in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000 (n=100) were assessed by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis. Probabilities of survival and treatment failure were calculated for subgroups considered to have ETP-ALL or typical T-ALL. FINDINGS: 30 patients (12.6%) had leukaemic lymphoblasts with an ETP-related gene-expression signature or its associated distinctive immunophenotype (CD1a(-), CD8(-), CD5(weak) with stem-cell or myeloid markers). Cases of ETP-ALL showed increased genomic instability, in terms of number and size of gene lesions, compared with those with typical T-ALL. Patients with this form of leukaemia had high risk of remission failure or haematological relapse (72% [95% CI 40-100] at 10 years vs 10% [4-16] at 10 years for patients with typical T-ALL treated at St Jude Children's Research Hospital; and 57% [25-89] at 2 years vs 14% [6-22] at 2 years for patients treated in the AIEOP trial). INTERPRETATION: ETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. Its early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management strategy. FUNDING: US National Cancer Institute, Cariplo Foundation, Citta della Speranza Foundation, Italian Association for Cancer Research (AIRC), Italian Ministry for University and Research, and American Lebanese Syrian Associated Charities (ALSAC)