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Relapse In Pediatric Acute Lymphoid Leukemia

Juanjuan Zhao, Yongping Song, Delong Liu
The current treatment for pediatric acute lymphoblastic leukemia (ALL) is highly successful with high cure rate. However, the treatment of adult ALL remains a challenge, particularly for refractory and/or relapsed (R/R) ALL. The advent of new targeted agents, blinatumomab, inotuzumab ozogamycin, and chimeric antigen receptor (CAR) T cells, are changing the treatment paradigm for ALL. Tisagenlecleucel (kymriah, Novartis) is an autologous CD19-targeted CAR T cell product approved for treatment of R/R B cell ALL and lymphoma...
February 14, 2019: Journal of Hematology & Oncology
Martin Stanulla, Elif Dagdan, Marketa Zaliova, Anja Möricke, Chiara Palmi, Giovanni Cazzaniga, Cornelia Eckert, Geertruy Te Kronnie, Jean-Pierre Bourquin, Beat Bornhauser, Rolf Koehler, Claus R Bartram, Wolf-Dieter Ludwig, Kirsten Bleckmann, Stefanie Groeneveld-Krentz, Denis Schewe, Stefanie V Junk, Laura Hinze, Norman Klein, Christian P Kratz, Andrea Biondi, Arndt Borkhardt, Andreas Kulozik, Martina U Muckenthaler, Giuseppe Basso, Maria Grazia Valsecchi, Shai Izraeli, Britt-Sabina Petersen, Andre Franke, Petra Dörge, Doris Steinemann, Oskar A Haas, Renate Panzer-Grümayer, Hélène Cavé, Richard S Houlston, Gunnar Cario, Martin Schrappe, Martin Zimmermann
Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22...
April 20, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Francine Marie Foss, Terri Parker
LESSONS LEARNED: Clofarabine can be active in relapsed and refractory lymphoid malignancies on a weekly dosing schedule.Responses were seen in patients with T-cell lymphomas, including cutaneous T-cell lymphoma, but not in patients with aggressive B-cell lymphomas. BACKGROUND: Clofarabine is a second-generation purine nucleoside analog currently approved for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. In adults, clofarabine has been investigated in several phase I and II trials as a single agent and in combination for relapsed or refractory acute leukemia...
April 2018: Oncologist
Fan Yang, Houshun Fang, Dan Wang, Yao Chen, Yonggong Zhai, Bin-Bing S Zhou, Hui Li
Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Thiopurine is a widely used drug in the maintaining treatment of ALL. After a period of chemotherapy, 20% of pediatric patients and over 50% of adult patients will relapse. To investigate the mechanisms of drug resistance in vitro , we established the thiopurine resistant cell lines Reh-6MPR (6-MP Resistant cell) and Reh-6TGR (6-TG Resistant cell) by stepwise selection of the ALL cell line Reh...
January 5, 2018: Oncotarget
Karen L Bride, Tiffaney L Vincent, Soo-Yeon Im, Richard Aplenc, David M Barrett, William L Carroll, Robin Carson, Yunfeng Dai, Meenakshi Devidas, Kimberly P Dunsmore, Tori Fuller, Tina Glisovic-Aplenc, Terzah M Horton, Stephen P Hunger, Mignon L Loh, Shannon L Maude, Elizabeth A Raetz, Stuart S Winter, Stephan A Grupp, Michelle L Hermiston, Brent L Wood, David T Teachey
As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-cell ALL; however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL...
March 1, 2018: Blood
Nina Rolf, Kinga K Smolen, Amina Kariminia, Adam Velenosi, Mario Fidanza, Caron Strahlendorf, Alix E Seif, Gregor S D Reid
Several retrospective studies in children with B cell precursor (BCP) acute lymphoblastic leukemia (ALL) provided clinical evidence that higher absolute lymphocyte counts (ALC) early into treatment significantly correlated with improved relapse-free and overall survival. It still remains unknown, however, whether the predictive role of higher ALCs reflects general bone marrow recovery or a more specific attribute of immune function. To investigate this question, we implemented a prospective observational cohort study in 20 children with BCP ALL on day 29 (D29) of induction chemotherapy and immunophenotyped their lymphoid (T, B and natural killer cells) and myeloid (neutrophils, monocytes, dendritic cells) compartments...
February 2018: Cancer Immunology, Immunotherapy: CII
J Krzanowski, J Madzio, A Pastorczak, A Tracz, M Braun, J Tabarkiewicz, A Pluta, W Młynarski, I Zawlik
The clinical outcome of children with high-risk relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is poor. The present study assessed the utility and prognostic value of selected microRNA (miRNA/miR) in BCP-ALL. The changes in the expression levels of these miRNAs regarding known gene lesions affecting lymphoid development [early B-cell factor 1 (EBF1), ETS variant 6 (ETV6), IKAROS family zinc finger 1 (IKZF1), paired box 5 (PAX5), cyclin dependent kinase inhibitor (CDKN) 2A/CDKN2B, retinoblastoma 1 (RB1), pseudoautosomal region 1 (PAR1), B-cell translocation gene 1 protein (BTG1)] were analyzed...
September 2017: Oncology Letters
Bartlomiej M Getta, Mikhail Roshal, Junting Zheng, Jae H Park, Eytan M Stein, Ross Levine, Esperanza B Papadopoulos, Ann A Jakubowski, Nancy A Kernan, Peter Steinherz, Richard J O'Reilly, Miguel-Angel Perales, Sergio A Giralt, Martin S Tallman, Brian C Shaffer
Mixed phenotype acute leukemia (MPAL) represents a poorly characterized group of acute leukemias that lack an accepted therapeutic approach and are typically associated with poor outcomes. We present our experience of genomic profiling, pretransplantation therapy, and transplantation outcomes for 36 well-characterized pediatric and adult patients with MPAL, defined according to the 2016 World Health Organization leukemia update. A predominance of acute lymphoid leukemia (ALL)-associated mutations and cytogenetic abnormalities was noted...
November 2017: Biology of Blood and Marrow Transplantation
Shoko Goto, Hiroaki Goto, Tomoko Yokosuka
Bendamustine combined with other drugs is clinically efficacious for some adult lymphoid malignancies, but to date there are no reports of the use of such combinatorial approaches in pediatric patients. We investigated the in vitro activity of bendamustine combined with other antimetabolite drugs on B cell precursor acute lymphoblastic leukemia (BCP-ALL) cell lines established from pediatric patients with refractory or relapsed ALL. We also developed a mathematically drown improved isobologram method to assess the data objectively...
May 2016: International Journal of Hematology
Marijana Vujkovic, Aaron Kershenbaum, Lisa Wray, Thomas McWilliams, Shannon Cannon, Meenakshi Devidas, Linda Stork, Richard Aplenc
Genetic variation in drug detoxification pathways may influence outcomes in pediatric acute lymphoblastic leukemia (ALL). We evaluated relapse risk and 24 variants in 17 genes in 714 patients in CCG-1961. Three TPMT and 1 MTR variant were associated with increased risks of relapse (rs4712327, OR 3.3, 95%CI 1.2-8.6; rs2842947, OR 2.7, 95%CI 1.1-6.8; rs2842935, OR 2.5, 95%CI 1.1-5.0; rs10925235, OR 4.9, 95%CI 1.1-25.1). One variant in SLC19A1 showed a protective effect (rs4819128, OR 0.5, 95%CI 0.3-0.9). Our study provides data that relapse risk in pediatric ALL is associated with germline variations in TPMT, MTR and SLC19A1...
2015: Leukemia Research Reports
Elizabeth G Salazar, Gerald B Wertheim, Jaclyn A Biegel, William Hwang, Sarah K Tasian, Susan R Rheingold
We describe the case of a 16 year-old female with mixed phenotype acute leukemia B/myeloid, NOS (formerly biphenotypic leukemia) with masked hypodiploidy and somatic TP53 and CDKN2A/B deletions. She achieved morphologic remission with lymphoid-directed multi-agent chemotherapy, but experienced an early medullary relapse 11 months from initial diagnosis. Her case details the unusual finding of hypodiploidy in a patient with ambiguous lineage leukemia and highlights the complexity of therapy selection for these high-risk patients...
2015: Journal of Pediatric Oncology
Zafar Iqbal, Tanveer Akhtar, Tashfin Awan, Aamer Aleem, Noreen Sabir, Mahmood Rasool, Muhammad Absar, Afia M Akram, Masood A Shammas, Ijaz H Shah, Muhammad Khalid, Abid S Taj, Abid Jameel, Abdullah Alanazi, Ammara T Gill, Jamil Amjad Hashmi, Akhtar Hussain, Muhammad Farooq Sabar, Ahmad M Khalid, Mehmood Hussain Qazi, Sajjad Karim, Muhammad Hassan Siddiqi, Aamir Mahmood, Mudassar Iqbal, Anjum Saeed, Muhammad Imran Irfan
BACKGROUND: Fusion oncogenes (FOs) resulting from chromosomal abnormalities have an important role in leukemogenesis in pediatric B cell acute lymphoblastic leukemia (ALL). The most common FOs are BCR-ABL, MLL-AF4, ETV6-RUNX1, and TCF3-PBX1, all of which have important prognostic and drug selection implications. Moreover, frequencies of FOs have ethnic variations. We studied Pakistani frequencies of FOs, clinical pattern, and outcome in pediatric B-ALL. METHODS: FOs were studied in 188 patients at diagnosis using reverse transcriptase-polymerase chain reaction (RT-PCR) and interphase fluorescent in situ hybridization (FISH)...
October 2015: Molecular Diagnosis & Therapy
Adriana Reyes-León, Rocío Juárez-Velázquez, Alma Medrano-Hernández, Teresa Cuenca-Roldán, Consuelo Salas-Labadía, María Del Pilar Navarrete-Meneses, Roberto Rivera-Luna, Gerardo López-Hernández, Rogelio Paredes-Aguilera, Patricia Pérez-Vera
Expression of the 6 and 8 dominant-negative Ikaros isoforms in pediatric patients with acute lymphoblastic leukemia has been associated with a high risk of relapse and death; due to these isoforms disrupting the differentiation and proliferation of lymphoid cells. The aim of this study was to know the frequency of Ik6 and Ik8 in 113 Mexican ALL-children treated within the National Popular Medical Insurance Program to determine whether there was an association with relapse-free survival, event-free survival and overall survival, and to assess its usefulness in the initial stratification of patients...
2015: PloS One
Kaat Durinck, Steven Goossens, Sofie Peirs, Annelynn Wallaert, Wouter Van Loocke, Filip Matthijssens, Tim Pieters, Gloria Milani, Tim Lammens, Pieter Rondou, Nadine Van Roy, Barbara De Moerloose, Yves Benoit, Jody Haigh, Frank Speleman, Bruce Poppe, Pieter Van Vlierberghe
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood cancer that accounts for about 15% of pediatric and 25% of adult acute lymphoblastic leukemia (ALL) cases. It is considered as a paradigm for the multistep nature of cancer initiation and progression. Genetic and epigenetic reprogramming events, which transform T-cell precursors into malignant T-ALL lymphoblasts, have been extensively characterized over the past decade. Despite our comprehensive understanding of the genomic landscape of human T-ALL, leukemia patients are still treated by high-dose multiagent chemotherapy, potentially followed by hematopoietic stem cell transplantation...
August 2015: Experimental Hematology
Mark R Litzow, Adolfo A Ferrando
T-cell immunophenotype of acute lymphoblastic leukemia (T-ALL) is an uncommon aggressive leukemia that can present with leukemic and/or lymphomatous manifestations. Molecular studies are enhancing our understanding of the pathogenesis of T-ALL, and the discovery of activating mutations of NOTCH1 and FBXW7 in a majority of patients has been a seminal observation. The use of pediatric intensive combination chemotherapy regimens in adolescents and young adults has significantly improved the outcome of patients with T-ALL...
August 13, 2015: Blood
Gail J Roboz, Elias J Jabbour, Stefan Faderl, Dan Douer
Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic malignancy characterized by proliferation of immature lymphoid cells throughout the bone marrow and peripheral blood. Most cases are diagnosed before the age of 20 years. Adults have a worse prognosis than children. Approximately half of adult ALL patients relapse after their initial treatment. There is no standard treatment for ALL; strategies vary according to the patient’s age, comorbidities, and Philadelphia chromosome status. Regimens used in pediatric patients are being adapted for use in adults...
December 2014: Clinical Advances in Hematology & Oncology: H&O
Anna K Andersson, Jing Ma, Jianmin Wang, Xiang Chen, Amanda Larson Gedman, Jinjun Dang, Joy Nakitandwe, Linda Holmfeldt, Matthew Parker, John Easton, Robert Huether, Richard Kriwacki, Michael Rusch, Gang Wu, Yongjin Li, Heather Mulder, Susana Raimondi, Stanley Pounds, Guolian Kang, Lei Shi, Jared Becksfort, Pankaj Gupta, Debbie Payne-Turner, Bhavin Vadodaria, Kristy Boggs, Donald Yergeau, Jayanthi Manne, Guangchun Song, Michael Edmonson, Panduka Nagahawatte, Lei Wei, Cheng Cheng, Deqing Pei, Rosemary Sutton, Nicola C Venn, Albert Chetcuti, Amanda Rush, Daniel Catchpoole, Jesper Heldrup, Thoas Fioretos, Charles Lu, Li Ding, Ching-Hon Pui, Sheila Shurtleff, Charles G Mullighan, Elaine R Mardis, Richard K Wilson, Tanja A Gruber, Jinghui Zhang, James R Downing
Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations...
April 2015: Nature Genetics
Fatih M Uckun, Sanjive Qazi, Hong Ma, Gregory H Reaman, Lloyd G Mitchell
Our recent studies have demonstrated that the CD22 exon 12 deletion (CD22ΔE12) is a characteristic genetic defect of therapy-refractory clones in pediatric B-precursor acute lymphoblastic leukemia (BPL) and implicated the CD22ΔE12 genetic defect in the aggressive biology of relapsed or therapy-refractory pediatric BPL. The purpose of the present study was to further evaluate the biologic significance of the CD22ΔE12 molecular lesion and determine if it could serve as a molecular target for corrective repair using RNA trans-splicing therapy...
February 2015: Integrative Biology: Quantitative Biosciences From Nano to Macro
Craig W Freyer, Neha Gupta, Meir Wetzler, Eunice S Wang
Originally studied in lymphoid diseases, cladribine (CdA) is an adenosine deaminase resistant analog of adenosine that was later discovered to induce myeloid cell apoptosis. The activity of CdA in myeloid malignancies was first reported in relapsed/refractory (RR) pediatric acute myeloid leukemia (AML) with complete response (CR) rates of up to 47%. Consequently, several studies have confirmed the efficacy of single agent CdA or CdA combination regimens in AML. Established CR rates for combination regimens in RR adults are approximately 50%, while CR rates for newly diagnosed (ND) adults are approximately 70% and show similar toxicity profiles to previously used regimens...
January 2015: American Journal of Hematology
Françoise Huguet, Thibaut Leguay, Emmanuel Raffoux, Philippe Rousselot, Norbert Vey, Arnaud Pigneux, Norbert Ifrah, Hervé Dombret
Clofarabine, a second-generation purine analog displaying potent inhibition of DNA synthesis and favorable pharmacologic profile, is approved for the treatment of acute lymphoblastic leukemia (ALL) after failure of at least two previous regimens in patients up to 21 years of age at diagnosis. Good neurologic tolerance, synergy with alkylating agents, management guidelines defined through pediatric ALL and adult acute myeloid leukemia, have also prompted its administration in more than 100 adults with Philadelphia chromosome-positive and negative B lineage and T lineage ALL, as single agent (40 mg/m(2)/ day for 5 days), or in combination...
April 2015: Leukemia & Lymphoma
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