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refractory acute leukemia

Xiao-Hui Zhang, Lin Yang, Xiao-Jun Liu, Ying Zhan, Yu-Xia Pan, Xing-Zhe Wang, Jian-Min Luo
Suppressor of cytokine signaling‑1 (SOCS1) is a widely recognized tumor suppressor gene. Silencing of SOCS1 expression as a result of promoter methylation is associated with occurrence and development of solid tumors such as liver, cervical and pancreatic cancer. However, the association between SOCS1 gene methylation and acute myeloid leukemia (AML) has not been well explored. In the present study, we examined whether gene expression and methylation status of SOCS1 was altered in AML, and whether this was related to disease occurrence and development...
June 19, 2018: Oncology Reports
Mark B Geyer, Isabelle Rivière, Brigitte Sénéchal, Xiuyan Wang, Yongzeng Wang, Terence J Purdon, Meier Hsu, Sean M Devlin, Elizabeth Halton, Nicole Lamanna, Jurgen Rademaker, Michel Sadelain, Renier J Brentjens, Jae H Park
Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab...
June 14, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Hanna Janiszewska, Aneta Bąk, Katarzyna Skonieczka, Anna Jaśkowiec, Marek Kiełbiński, Anna Jachalska, Maria Czyżewska, Bożena Jaźwiec, Małgorzata Kuliszkiewicz-Janus, Jarosław Czyż, Kazimierz Kuliczkowski, Olga Haus
CHEK2 plays a key role in cellular response to DNA damage, and also in regulation of mitosis and maintenance of chromosomal stability. In patients newly diagnosed with myelodysplastic syndrome (MDS, n = 107) or acute myeloid leukemia (AML, n = 117) congenital CHEK2 mutations (c.444 + 1G > A, c.1100delC, del5395, p.I157 T) were tested by PCR and sequencing analysis. The karyotype of bone marrow cells of each patient was assessed at disease diagnosis using classical cytogenetic methods and fluorescence in situ hybridization...
June 3, 2018: Leukemia Research
Sarah K Tasian
Chemotherapy resistance and relapse remain significant sources of mortality for children and adults with acute myeloid leukemia (AML). Further intensification of conventional cytotoxic chemotherapy is likely not feasible due to the severity of acute and long-term side effects upon normal tissues commonly induced by these drugs. Successful development and implementation of new precision medicine treatment approaches for patients with AML, which may improve leukemia remission and diminish toxicity, is thus a major priority...
June 2018: Therapeutic Advances in Hematology
Katherine Tarlock, Shan Zhong, Yuting He, Rhonda Ries, Eric Severson, Mark Bailey, Samantha Morley, Sohail Balasubramanian, Rachel Erlich, Doron Lipson, Geoff A Otto, Jo-Anne Vergillo, E Anders Kolb, Jeffrey S Ross, Tariq Mughal, Philip J Stephens, Vincent Miller, Soheil Meshinchi, Jie He
Large scale comprehensive genomic profiling (CGP) has led to an improved understanding of oncogenic mutations in acute myeloid leukemia (AML), as well as identification of alterations that can serve as targets for potential therapeutic intervention. We sought to gain insight into age-associated variants in AML through comparison of extensive DNA and RNA-based GP results from pediatric and adult AML. Sequencing of 932 AML specimens (179 pediatric (age 0-18), 753 adult (age ≥ 19)) from diagnostic, relapsed, and refractory times points was performed...
May 29, 2018: Oncotarget
Trudy Straetemans, Guido J J Kierkels, Ruud Doorn, Koen Jansen, Sabine Heijhuurs, Joao M Dos Santos, Anna D D van Muyden, Henri Vie, Béatrice Clemenceau, Reinier Raymakers, Moniek de Witte, Zsolt Sebestyén, Jürgen Kuball
γ9δ2T cells play a critical role in daily cancer immune surveillance by sensing cancer-mediated metabolic changes. However, a major limitation of the therapeutic application of γ9δ2T cells is their diversity and regulation through innate co-receptors. In order to overcome natural obstacles of γ9δ2T cells, we have developed the concept of T cells engineered to express a defined γδT cell receptor (TEGs). This next generation of chimeric antigen receptor engineered T (CAR-T) cells not only allows for targeting of hematological but also of solid tumors and, therefore, overcomes major limitations of many CAR-T and γδT cell strategies...
2018: Frontiers in Immunology
Jessica Hochberg, Stacey Zahler, Mark B Geyer, Nan Chen, Jennifer Krajewski, Lauren Harrison, Olga Militano, M Fevzi Ozkaynak, Alexandra C Cheerva, Julie Talano, Theodore B Moore, Alfred P Gillio, Mark C Walters, Lee Ann Baxter-Lowe, Carl Hamby, Mitchell S Cairo
Acute leukemias in children with CR3, refractory relapse, or induction failure (IF) have a poor prognosis. Clofarabine has single agent activity in relapsed leukemia and synergy with cytarabine. We sought to determine the safety and overall survival in a Phase I/II trial of conditioning with clofarabine (doses 40 - 52 mg/m2 ), cytarabine 1000 mg/m2 , and 1200 cGy TBI followed by alloSCT in children, adolescents, and young adults with poor-risk leukemia. Thirty-seven patients; Age 12 years (1-22 years); ALL/AML: 34:3 (18 IF, 10 CR3, 13 refractory relapse); 15 related, 22 unrelated donors...
June 13, 2018: Bone Marrow Transplantation
Christos Demosthenous, Chrysavgi Lalayanni, Michalis Iskas, Vassiliki Douka, Nikoleta Pastelli, Achilles Anagnostopoulos
Blinatumomab, a bispecific T-cell engager antibody construct targeting CD19, has been shown to improve the outcome in patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia. Treatment with blinatumomab demonstrated significant survival benefit over chemotherapy, supporting its use as a bridge therapy to allogeneic hematopoietic stem cell transplantation. Unfortunately, following initial response, approximately 50% of responding patients eventually relapse. At the time of failure, the majority of patients have CD19-positive blasts, yet a concerning number of CD19-negative relapses has been reported...
May 7, 2018: Current Problems in Cancer
Sarah Bertoli, Suzanne Tavitian, Emilie Berard, Noemie Gadaud, Isabelle Luquet, Anne Huynh, Audrey Sarry, Françoise Huguet, Christian Récher
No abstract text is available yet for this article.
June 12, 2018: Leukemia & Lymphoma
Jennifer R Molina, Yuting Sun, Marina Protopopova, Sonal Gera, Madhavi Bandi, Christopher Bristow, Timothy McAfoos, Pietro Morlacchi, Jeffrey Ackroyd, Ahmed-Noor A Agip, Gheath Al-Atrash, John Asara, Jennifer Bardenhagen, Caroline C Carrillo, Christopher Carroll, Edward Chang, Stefan Ciurea, Jason B Cross, Barbara Czako, Angela Deem, Naval Daver, John Frederick de Groot, Jian-Wen Dong, Ningping Feng, Guang Gao, Jason Gay, Mary Geck Do, Jennifer Greer, Virginia Giuliani, Jing Han, Lina Han, Verlene K Henry, Judy Hirst, Sha Huang, Yongying Jiang, Zhijun Kang, Tin Khor, Sergej Konoplev, Yu-Hsi Lin, Gang Liu, Alessia Lodi, Timothy Lofton, Helen Ma, Mikhila Mahendra, Polina Matre, Robert Mullinax, Michael Peoples, Alessia Petrocchi, Jaime Rodriguez-Canale, Riccardo Serreli, Thomas Shi, Melinda Smith, Yoko Tabe, Jay Theroff, Stefano Tiziani, Quanyun Xu, Qi Zhang, Florian Muller, Ronald A DePinho, Carlo Toniatti, Giulio F Draetta, Timothy P Heffernan, Marina Konopleva, Philip Jones, M Emilia Di Francesco, Joseph R Marszalek
Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain...
June 11, 2018: Nature Medicine
Yusuke Noguchi, Daisuke Tomizawa, Haruka Hiroki, Satoshi Miyamoto, Mari Tezuka, Reiji Miyawaki, Mari Tanaka-Kubota, Tubasa Okano, Chika Kobayashi, Noriko Mitsuiki, Yuki Aoki, Kohsuke Imai, Michiko Kajiwara, Hirokazu Kanegane, Tomohiro Morio, Masatoshi Takagi
Myeloid/natural killer cell precursor acute leukemia (MNKPL) is a rare leukemia subtype characterized by a high incidence of extramedullary infiltration. No appropriate treatment strategy has so far been developed. Acute myelogenous leukemia-type chemotherapy combined with L-Asparaginase is an effective treatment for MNKPL. Hematopoietic cell transplantation is a second option in refractory cases.
June 2018: Clinical Case Reports
Bianca D Santomasso, Jae H Park, Darin Salloum, Isabelle Rivière, Jessica Flynn, Elena Mead, Elizabeth Halton, Xiuyan Wang, Brigitte Senechal, Terence Purdon, Justin R Cross, Hui Liu, Behroze Vachha, Xi Chen, Lisa M DeAngelis, Daniel Li, Yvette Bernal, Mithat Gonen, Hans-Guido Wendel, Michel Sadelain, Renier J Brentjens
CD19-specific chimeric antigen receptor (CAR) T cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T cell expansion and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood-cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF...
June 7, 2018: Cancer Discovery
Motohiro Kato
The prognosis of pediatric acute lymphoblastic leukemia (ALL) has dramatically improved, both basic research and clinical studies are continuously conducted in pursuit of further improvement. Recent advances in genomic analysis technology have enabled us to comprehensively identify genomic alterations in leukemic cells and thus have contributed to the better understanding of the molecular pathogenesis underlying ALL development. These genomic alterations can be applied not only as prognostic factors but also as therapeutic targets...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Jorge E Cortes, Martin S Tallman, Gary J Schiller, Denise Trone, Guy Gammon, Stuart L Goldberg, Alexander E Perl, Jean-Pierre Marie, Giovanni Martinelli, Hagop M Kantarjian, Mark J Levis
This randomized, open-label, phase 2b study (NCT01565668) evaluated efficacy and safety of two dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3-internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML) who previously underwent transplant or one second-line salvage therapy. Patients (N=76) were randomized to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride...
June 6, 2018: Blood
Kankan Chen, Yue Chen, Zhi Chen, Yuye Shi, Zhengmei He, Banghe Ding, Chunling Wang, Liang Yu
The relapse and resistance to cytarabine (Ara-C) therapy is still a dominating obstacle to the successful clinical treatment of acute myeloid leukemia (AML). Recent studies have shown that dysregulation of miRNAs might modulate the resistance of cancer cells to anticancer drugs; yet, the mechanism is not fully understood. In this study, we showed a significant downregulation of miR-134 in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Overexpression of miR-134 sensitized K562/A02 and HL-60/ADM cells to Ara-C, inhibited cell colony formation, and enhanced the ability of Ara-C to induce apoptosis...
2018: OncoTargets and Therapy
Ioanna Sakellari, Eleni Gavriilaki, Konstantinos Chatziioannou, Maria Papathanasiou, Despina Mallouri, Ioannis Batsis, Zoi Bousiou, Stella Bouziana, Varnavas Constantinou, Vassiliki Douka, Chrysa Apostolou, Michalis Iskas, Chrysavgi Lalayanni, Anastasia Athanasiadou, Damianos Sotiropoulos, Evangelia Yannaki, Vasilis Gianouzakos, Achilles Anagnostopoulos
The role of total body irradiation (TBI) in allogeneic hematopoietic stem cell transplantation (HCT) for adult acute lymphoblastic leukemia (ALL) remains controversial. Therefore, we investigated long-term treatment outcomes of transplanted ALL patients aiming to identify prognostic factors and the impact of conditioning. We enrolled consecutive ALL patients transplanted from 1990 to 2016, following TBI- or busulfan (Bu)-based conditioning regimen. We studied 151 ALL patients transplanted in first complete remission (CR) (60), other CR (33), or relapsed/refractory disease (58) from sibling (87), and HLA-matched (42) or mismatched (17) unrelated and alternative donors (5)...
June 5, 2018: Annals of Hematology
Takeshi Kishida
No abstract text is available yet for this article.
June 4, 2018: International Journal of Urology: Official Journal of the Japanese Urological Association
Cheng Zhang, Pei-Yan Kong, Shiqi Li, Ting Chen, Xun Ni, Yunyan Li, Meiling Wang, Yao Liu, Lei Gao, Li Gao, Xian-Gui Peng, Ai-Hua Sun, Ping Wang, Zhi Yang, Xi Zhang, Cheng Qian
BACKGROUND: Reduced-intensity conditioning (RIC) regimens with low tolerable toxicities have been used for allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the relapse rate by this treatment is high. Treatment of CD19 B-cell relapsed/refractory acute lymphoblastic leukemia (r/r ALL) with allogeneic chimeric antigen receptor-modified T (CAR-T) cells is safe and effective. Use of allogeneic CD19-CAR-T cells as a part of RIC regimens for treatment of r/r ALL patients with haploidentical HSCT has not been investigated yet...
July 2018: Journal of Immunotherapy
Courtney D DiNardo, Eytan M Stein, Stéphane de Botton, Gail J Roboz, Jessica K Altman, Alice S Mims, Ronan Swords, Robert H Collins, Gabriel N Mannis, Daniel A Pollyea, Will Donnellan, Amir T Fathi, Arnaud Pigneux, Harry P Erba, Gabrielle T Prince, Anthony S Stein, Geoffrey L Uy, James M Foran, Elie Traer, Robert K Stuart, Martha L Arellano, James L Slack, Mikkael A Sekeres, Christophe Willekens, Sung Choe, Hongfang Wang, Vickie Zhang, Katharine E Yen, Stephanie M Kapsalis, Hua Yang, David Dai, Bin Fan, Meredith Goldwasser, Hua Liu, Sam Agresta, Bin Wu, Eyal C Attar, Martin S Tallman, Richard M Stone, Hagop M Kantarjian
Background Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. Methods We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up...
June 2, 2018: New England Journal of Medicine
Gail J Roboz
No abstract text is available yet for this article.
May 2018: Clinical Advances in Hematology & Oncology: H&O
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