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Acute lymphoblastic leukemia and philadelphia chromosome positive

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https://www.readbyqxmd.com/read/28711932/the-pan-bcl-2-blocker-obatoclax-gx15-070-and-the-pi3-kinase-mtor-inhibitor-bez235-produce-cooperative-growth-inhibitory-effects-in-all-cells
#1
Gabriele Stefanzl, Daniela Berger, Sabine Cerny-Reiterer, Katharina Blatt, Gregor Eisenwort, Wolfgang R Sperr, Gregor Hoermann, Karin Lind, Alexander W Hauswirth, Peter Bettelheim, Heinz Sill, Junia V Melo, Ulrich Jäger, Peter Valent
Acute lymphoblastic leukemia (ALL) is characterized by leukemic expansion of lymphoid blasts in hematopoietic tissues. Despite improved therapy only a subset of patients can be cured. Therefore, current research is focusing on new drug-targets. Members of the BCL-2 family and components of the PI3-kinase/mTOR pathway are critically involved in the regulation of growth and survival of ALL cells. We examined the effects of the pan-BCL-2 blocker obatoclax and the PI3-kinase/mTOR-inhibitor BEZ235 on growth and survival of ALL cells...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28683103/combination-therapeutics-of-nilotinib-and-radiation-in-acute-lymphoblastic-leukemia-as-an-effective-method-against-drug-resistance
#2
Kamran Kaveh, Yutaka Takahashi, Michael A Farrar, Guy Storme, Marcucci Guido, Jamie Piepenburg, Jackson Penning, Jasmine Foo, Kevin Z Leder, Susanta K Hui
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is characterized by a very poor prognosis and a high likelihood of acquired chemo-resistance. Although tyrosine kinase inhibitor (TKI) therapy has improved clinical outcome, most ALL patients relapse following treatment with TKI due to the development of resistance. We developed an in vitro model of Nilotinib-resistant Ph+ leukemia cells to investigate whether low dose radiation (LDR) in combination with TKI therapy overcome chemo-resistance...
July 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28654842/haploidentical-hematopoietic-stem-cell-transplantation-for-pediatric-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-in-the-imatinib-era
#3
Huan Chen, Kai-Yan Liu, Lan-Ping Xu, Yu-Hong Chen, Xiao-Hui Zhang, Yu Wang, Ya-Zhen Qin, Yan-Rong Liu, Yue-Yun Lai, Xiao-Jun Huang
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains an important curative option for children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who have a poor response to chemotherapy plus imatinib. For such children, if there are no matched related or unrelated donors, alternative donor transplantation may be a choice. The role of haploidentical donor (HID) HSCT in pediatric patients with Ph+ ALL has not been reported. The study population included pediatric patients with Ph+ ALL who underwent HID-HSCT...
June 1, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28654205/driving-toward-precision-medicine-for-acute-leukemias-are-we-there-yet
#4
Clement Chung, Hilary Ma
Despite recent progress in the understanding of the molecular basis of acute leukemias, treatment options for these diseases have not shown significant changes over the last few decades. In this review, we present a nonexhaustive key summary of the current cytogenetic and molecular changes associated with acute leukemias in disease prognostication and potential targeted therapies. An emerging paradigm is that many genetic or molecular alterations target similar signal transduction, transcriptional, and epigenetic pathways...
June 27, 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/28644853/the-novel-phospholipid-mimetic-kpc34-is-highly-active-against-preclinical-models-of-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#5
Peter M Alexander, David L Caudell, Gregory L Kucera, Kristin M Pladna, Timothy S Pardee
Philadelphia chromosome positive B cell acute lymphoblastic leukemia (Ph+ ALL) is an aggressive cancer of the bone marrow. The addition of tyrosine kinase inhibitors (TKIs) has improved outcomes but many patients still suffer relapse and novel therapeutic agents are needed. KPC34 is an orally available, novel phospholipid conjugate of gemcitabine, rationally designed to overcome multiple mechanisms of resistance, inhibit the classical and novel isoforms of protein kinase C, is able to cross the blood brain barrier and is orally bioavailable...
2017: PloS One
https://www.readbyqxmd.com/read/28606225/-clinical-characteristics-and-prognostic-analysis-of-children-and-adolescents-over-10-years-of-age-with-acute-lymphoblastic-leukemia
#6
Jun Wu, Ai-Dong Lu, Le-Ping Zhang
OBJECTIVE: To explore the clinical characteristics and prognosis of children and adolescents over 10 years of age with acute lymphoblastic leukemia (ALL). METHODS: A total of 86 newly diagnosed ALL children and adolescents over 10 years of age (62 cases of B-ALL and 24 cases of T-ALL) were enrolled. Clinical characteristics, therapeutic effect and prognostic factors were retrospectively analyzed. Event-free survival (EFS) and overall survival (OS) rates were estimated by the Kaplan-Meier method...
June 2017: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
https://www.readbyqxmd.com/read/28592975/prognostic-factors-and-treatment-of-pediatric-acute-lymphoblastic-leukemia
#7
REVIEW
Jae Wook Lee, Bin Cho
The event-free survival (EFS) for pediatric acute lymphoblastic leukemia (ALL) has shown remarkable improvement in the past several decades. In Korea also, a recent study showed 10-year EFS of 78.5%. Much of the improved outcome for pediatric ALL stems from the accurate identification of prognostic factors, the designation of risk group based on these factors, and treatment of appropriate duration and intensity according to risk group, done within the setting of cooperative clinical trials. The schema of first-line therapy for ALL remains mostly unchanged, although many groups have now reported on the elimination of cranial irradiation in all patients with low rates of central nervous system relapse...
May 2017: Korean Journal of Pediatrics
https://www.readbyqxmd.com/read/28579617/hdac1-2-inhibition-and-doxorubicin-impair-mre11-dependent-dna-repair-and-disc-to-override-bcr-abl1-driven-dsb-repair-in-philadelphia-chromosome-positive-b-cell-precursor-acute-lymphoblastic-leukemia
#8
S Tharkar-Promod, D P Johnson, S E Bennett, E M Dennis, B G Banowsky, S S Jones, J R Shearstone, S N Quayle, C Min, M Jarpe, T Mosbruger, A D Pomicter, R R Miles, W Y Chen, K N Bhalla, P A Zweidler-McKay, D C Shrieve, M W Deininger, M B Chandrasekharan, S Bhaskara
Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL) expressing BCR-ABL1 oncoprotein is a major subclass of ALL with poor prognosis. BCR-ABL1-expressing leukemic cells are highly dependent on double-strand break (DSB) repair signals for their survival. Here we report that a first-in-class HDAC1,2 selective inhibitor and doxorubicin (a hyper-CVAD chemotherapy regimen component) impair DSB repair networks in Ph+ B-cell precursor ALL cells using common as well as distinct mechanisms...
June 5, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28559835/cytarabine-induced-acute-cerebellar-syndrome-during-hyper-cvad-treatment-for-b-cell-acute-lymphoblastic-leukemia
#9
Phu Ngoc Tran, Xiao-Tang Kong
Acute cerebellar syndrome can be caused by high doses of cytarabine, but it has not been described in patients with acute lymphoblastic leukemia (ALL) who received hyper-CVAD chemotherapy. Herein, we report two cases with histories of positive Philadelphia chromosome B-cell ALL who developed acute cerebellar syndrome after the exposure to relatively low doses of cytarabine in the second cycle of hyper-CVAD regimen. The cerebellar symptoms were attenuated by cytarabine discontinuation and administration of steroids...
January 2017: Case Reports in Neurology
https://www.readbyqxmd.com/read/28549237/haploidentical-allogeneic-hematopoietic-stem-cell-transplantation-compared-to-matched-unrelated-transplantation-for-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#10
Bin Gu, Xiaojin Wu, Guanghua Chen, Xiao Ma, Zhengming Jin, Xiaowen Tang, Yue Han, Chengcheng Fu, Huiying Qiu, Aining Sun, Depei Wu
To investigate the effect of haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the outcome of 58 patients with Ph+ ALL who received Haplo-HCT (n=42) or matched unrelated donor transplantation (MUD-HCT) (n=16) during the same period were analyzed retrospectively. All patients received a tyrosine kinase inhibitor (TKI)-based regimen before transplantation, and TKI was resumed primarily after transplantation...
May 16, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28445932/high-cftr-expression-in-philadelphia-chromosome-positive-acute-leukemia-protects-and-maintains-continuous-activation-of-bcr-abl-and-related-signaling-pathways-in-combination-with-pp2a
#11
Xi Yang, Tianyou Yan, Yuping Gong, Xuehua Liu, Huaqin Sun, Wenming Xu, Chunsen Wang, Duolan Naren, Yuhuan Zheng
Cystic fibrosis transmembrane conductance regulator (CFTR) is classified as an anion channel transporter of Cl- and HCO3-. Through interactions with its PDZ domain, CFTR is capable of regulating other proteins, such as protein phosphatase 2A (PP2A). The aberrant expression and mutation of CFTR have been observed in several tumor, but not in philadelphia chromosome-positive(Ph+) acute leukemia, including Ph+ B cell acute lymphoblastic leukemia(Ph+ B-ALL) and chronic myelogenous leukemia blast crisis phases (CML-BC)...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28444644/ponatinib-in-japanese-patients-with-philadelphia-chromosome-positive-leukemia-a-phase-1-2-study
#12
Arinobu Tojo, Taiichi Kyo, Kazuhito Yamamoto, Hirohisa Nakamae, Naoto Takahashi, Yukio Kobayashi, Tetsuzo Tauchi, Shinichiro Okamoto, Koichi Miyamura, Kiyohiko Hatake, Hiromi Iwasaki, Itaru Matsumura, Noriko Usui, Tomoki Naoe, Meera Tugnait, Narayana I Narasimhan, Stephanie Lustgarten, Heinrich Farin, Frank Haluska, Kazuma Ohyashiki
In this ongoing Phase 1/2 study (NCT01667133), we evaluated ponatinib and assessed its recommended dose in Japanese patients with chronic myeloid leukemia (CML) resistant/intolerant to dasatinib or nilotinib, or with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) resistant/intolerant to ≥1 tyrosine kinase inhibitor (TKI). The primary endpoints were safety of the recommended dose (Phase 1) and major cytogenetic response (MCyR) by 12 months in chronic-phase CML (CP-CML) patients or major hematologic response (MaHR) by 6 months in patients with advanced phase disease (Phase 2)...
April 25, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28419558/age-but-not-philadelphia-positivity-impairs-outcome-in-older-elderly-patients-with-acute-lymphoblastic-leukemia-in-sweden
#13
Piotr Kozlowski, Emma Lennmyr, Lucia Ahlberg, Per Bernell, Erik Hulegårdh, Holger Karbach, Karin Karlsson, Beata Tomaszewska-Toporska, Maria Åström, Heléne Hallböök
OBJECTIVES: Older/elderly patients with acute lymphoblastic leukemia (ALL) are poorly represented in clinical trials. METHODS: Using Swedish national leukemia registries, we investigated disease/patient characteristics, treatment choices, outcome, and the impact of an age-adapted protocol (introduced in 2009) in this population-based study of patients aged 55-85 years, diagnosed with ALL 2005-2012. RESULTS: Of 174 patients, 82% had B-phenotype, 11% Burkitt leukemia (excluded), and 7% T-phenotype...
April 18, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28401025/adult-acute-precursor-b-cell-lymphoblastic-leukemia-presenting-as-hypercalcemia-and-osteolytic-bone-lesions
#14
Nikki Charlotta Paul Granacher, Zwi N Berneman, Wilfried Schroyens, Ann L R Van de Velde, Anke Verlinden, Alain P A Gadisseur
BACKGROUND: Osteolytic bone lesions and hypercalcemia without peripheral blasts B-cell acute lymphoblastic leukemia (B-ALL) is reported in children but rarely seen in adults. CASE PRESENTATION: We describe the case of a 34-year old man presenting with hypercalcemia and symptomatic osteolytic bone lesions of vertebrae and ribs who was initially suspected as having a solid malignancy. Diagnostic work-up including peripheral blood examination, radiographic and nuclear studies could, however, not detect a primary tumor...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/28395443/-clinical-analysis-of-adult-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-with-p16-gene-deletion
#15
B L He, N Xu, Y L Li, C Y Pan, R Cao, L B Liao, C X Yin, Y Q Lan, Z Y Lu, J X Huang, H S Zhou, Q F Liu, X L Liu
Objective: To investigate the clinical implications of p16 gene deletion in adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) . Methods: Retrospective analysis of clinical, immunophenotypic, cytogenetics, molecular characteristics and prognosis of 80 newly diagnosed Ph(+) ALL patients with p16 deletion. Results: Of 80 adult Ph(+) ALL, the prevalence of p16 gene deletion was 31.3%. p16 gene deletion carriers frequently accompanied with high WBC counts (WBC≥30×10(9)/L) and CD20 expression...
March 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28390196/pi3k-isoform-inhibition-associated-with-anti-bcr-abl-drugs-shows-in-vitro-increased-anti-leukemic-activity-in-philadelphia-chromosome-positive-b-acute-lymphoblastic-leukemia-cell-lines
#16
Simona Ultimo, Carolina Simioni, Alberto M Martelli, Giorgio Zauli, Camilla Evangelisti, Claudio Celeghini, James A McCubrey, Giorgia Marisi, Paola Ulivi, Silvano Capitani, Luca M Neri
B-acute lymphoblastic leukemia (B-ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. Philadelphia chromosome-positive (Ph+) B-ALL is a subtype that expresses the Bcr-Abl fusion protein which represents a negative prognostic factor. Constitutive activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) network is a common feature of B-ALL, influencing cell growth and survival. In the present study, we aimed to investigate the efficacy of PI3K isoform inhibition in B-ALL cell lines harboring the Bcr-Abl fusion protein...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28387926/overall-survival-with-ponatinib-versus-allogeneic-stem-cell-transplantation-in-philadelphia-chromosome-positive-leukemias-with-the-t315i-mutation
#17
Franck E Nicolini, Grzegorz W Basak, Dong-Wook Kim, Eduardo Olavarria, Javier Pinilla-Ibarz, Jane F Apperley, Timothy Hughes, Dietger Niederwieser, Michael J Mauro, Charles Chuah, Andreas Hochhaus, Giovanni Martinelli, Maral DerSarkissian, Mei Sheng Duh, Lisa J McGarry, Hagop M Kantarjian, Jorge E Cortes
BACKGROUND: Effective treatment options for patients with chronic myeloid leukemia (CML) or Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) who have the threonine to isoleucine mutation at codon 315 (T315I) are few. The objective of this study was to compare overall survival (OS) between patients with CML and those with Ph+ ALL who received treatment with ponatinib versus allogeneic stem cell transplantation (allo-SCT). METHODS: A post hoc, retrospective, indirect comparison of OS among patients who received single-agent ponatinib in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial with those who underwent allo-SCT as reported to the European Bone Marrow Transplant registry, stratified by CML disease phase and Ph+ ALL, was conducted...
April 7, 2017: Cancer
https://www.readbyqxmd.com/read/28355115/complete-hematologic-and-molecular-response-in-adult-patients-with-relapsed-refractory-philadelphia-chromosome-positive-b-precursor-acute-lymphoblastic-leukemia-following-treatment-with-blinatumomab-results-from-a-phase-ii-single-arm-multicenter-study
#18
Giovanni Martinelli, Nicolas Boissel, Patrice Chevallier, Oliver Ottmann, Nicola Gökbuget, Max S Topp, Adele K Fielding, Alessandro Rambaldi, Ellen K Ritchie, Cristina Papayannidis, Lulu Ren Sterling, Jonathan Benjamin, Anthony Stein
Purpose Few therapeutic options are available for patients with Philadelphia chromosome-positive (Ph(+)) B-precursor acute lymphoblastic leukemia (ALL) who progress after failure of tyrosine kinase inhibitor (TKI) -based therapy. Here, we evaluated the efficacy and tolerability of blinatumomab in patients with relapsed or refractory Ph(+) ALL. Patients and Methods This open-label phase II study enrolled adults with Ph(+) ALL who had relapsed after or were refractory to at least one second-generation or later TKI or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib...
June 1, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28349299/efficacy-and-prognostic-factors-of-imatinib-plus-callg2008-protocol-in-adult-patients-with-newly-diagnosed-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#19
Yinjun Lou, Yafang Ma, Chenyin Li, Sansan Suo, Hongyan Tong, Wenbin Qian, Wenyuan Mai, Haitao Meng, Wenjuan Yu, Liping Mao, Juyin Wei, Weilei Xu, Jie Jin
A CALLG2008 protocol was developed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult acute lymphoblastic leukemia (ALL). We retrospectively analyzed 153 newly diagnosed adult patients with Philadelphia chromosome (Ph)-positive ALL enrolled into imatinib (400 mg/d) plus CALLG2008 regimen between 2009 and 2015. The median age was 40 years (range, 18-68 years), with 81 (52.3%) males. The overall hematologic complete remission (CR) rate was 96.7% after induction. With a median follow-up of 24...
March 27, 2017: Frontiers of Medicine
https://www.readbyqxmd.com/read/28326207/dasatinib-and-prednisolone-induction-therapy-for-a-case-of-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-with-dilated-cardiomyopathy-accompanied-by-life-threatening-ventricular-tachycardia
#20
Mitsutaka Nishimoto, Hirohisa Nakamae, Kana Matsumoto, Kunihiko Morita, Yuki Koga, Dai Momose, Masayuki Hino
A 56-year-old man being treated for dilated cardiomyopathy presented with epigastralgia. He was diagnosed with ventricular tachycardia and Philadelphia chromosome-positive acute lymphoblastic leukemia. After treating incessant ventricular tachycardia, we commenced induction therapy for leukemia with dasatinib and prednisolone to minimize toxicity towards cardiomyocytes and the cardiac conduction system. Although dasatinib was temporarily withheld because of a recurrence of ventricular tachycardia, we rechallenged dasatinib while using bisoprolol and amiodarone and achieved a complete hematological response three weeks later...
2017: Case Reports in Hematology
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