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Refractory leukemia

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https://www.readbyqxmd.com/read/29157092/single-agent-and-synergistic-combinatorial-efficacy-of-first-in-class-small-molecule-imipridone-onc201-in-hematological-malignancies
#1
Varun V Prabhu, Mala K Talekar, Amriti R Lulla, C Leah B Kline, Lanlan Zhou, Junior Hall, A Pieter J Van den Heuvel, David T Dicker, Jawad Babar, Stephan A Grupp, Mathew J Garnett, Ultan McDermott, Cyril H Benes, Jeffrey J Pu, David F Claxton, Nadia Khan, Wolfgang Oster, Joshua E Allen, Wafik S El-Deiry
ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples...
November 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29156206/cytokine-release-syndrome-who-is-at-risk-and-how-to-treat
#2
REVIEW
Noelle Frey
T-cell engaging therapies such as blinatumomab and anti-CD19 chimeric antigen receptor (CAR) T cells have revolutionized our approach to patients with relapsed and refractory acute lymphoblastic leukemia (ALL). However, the immune activation responsible for high remission rates is also responsible for the unique treatment-related toxicity of cytokine release syndrome (CRS). The clinical signs of CRS include fever, hemodynamic instability, and capillary leak, which correlate with T-cell activation and elevated cytokine levels...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29155426/cd22-targeted-car-t-cells-induce-remission-in-b-all-that-is-naive-or-resistant-to-cd19-targeted-car-immunotherapy
#3
Terry J Fry, Nirali N Shah, Rimas J Orentas, Maryalice Stetler-Stevenson, Constance M Yuan, Sneha Ramakrishna, Pamela Wolters, Staci Martin, Cindy Delbrook, Bonnie Yates, Haneen Shalabi, Thomas J Fountaine, Jack F Shern, Robbie G Majzner, David F Stroncek, Marianna Sabatino, Yang Feng, Dimiter S Dimitrov, Ling Zhang, Sang Nguyen, Haiying Qin, Boro Dropulic, Daniel W Lee, Crystal L Mackall
Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent effects in relapsed and/or refractory pre-B cell acute lymphoblastic leukemia (B-ALL), but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed in most cases of B-ALL and is usually retained following CD19 loss. We report results from a phase 1 trial testing a new CD22-targeted CAR (CD22-CAR) in 21 children and adults, including 17 who were previously treated with CD19-directed immunotherapy...
November 20, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29155271/t-cell-replete-haploidentical-transplantation-in-acute-myeloid-leukemia
#4
Luca Castagna, Raynier Devillier, Norbert Vey, Didier Blaise
In the last decade, the number of haploidentical transplantation is enhanced and this because of the widespread use of T cell replete platforms, developed worldwide. Acute myeloid leukemia is the main indication to perform an allogeneic stem cell transplantation. In this paper, we reviewed the clinical results obtained using T cell replete platforms in different clinical situations such as first or further complete remission, refractory disease, and elderly population. Overall, the toxic profile of T cell replete haploidentical transplantation is similar to transplantation from other donors, with some positive aspects such as a reduced incidence of chronic graft versus host disease...
November 16, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29144985/a-phase-1-2-study-of-rigosertib-in-patients-with-myelodysplastic-syndromes-mds-and-mds-progressed-to-acute-myeloid-leukemia
#5
Shyamala C Navada, Steven M Fruchtman, Rosalie Odchimar-Reissig, Erin P Demakos, Michael E Petrone, Patrick S Zbyszewski, James F Holland, Lewis R Silverman
This Phase 1/2, dose-escalating study of rigosertib enrolled 22 patients with higher-risk myelodysplastic syndromes (MDS) (n=9) and acute myeloid leukemia (AML; n=13) who had relapsed or were refractory to standard therapy and for whom no second-line therapies were approved. Patients received 3- to 7-day continuous intravenous infusions of rigosertib, an inhibitor of Ras-effector pathways that interacts with the Ras-binding domains, common to several signaling proteins including Raf and PI3 kinase. Rigosertib was administered at doses of 650-1700mg/m(2)/day in 14-day cycles...
November 11, 2017: Leukemia Research
https://www.readbyqxmd.com/read/29143289/agents-in-development-for-childhood-acute-lymphoblastic-leukemia
#6
REVIEW
Kelly W Maloney, Lia Gore
Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood. Standard chemotherapy has afforded outstanding outcomes for many patients; however, there remain some sub-groups with high-risk features, refractory disease, and patients that  relapse who have a poor prognosis with conventional treatments. Over the past decade, there have been significant advances in newer treatment options, including improved monoclonal antibody therapies, T cell engagers, and chimeric antigen T-cell receptor products, all of which have changed the landscape for patients who relapse...
November 15, 2017: Paediatric Drugs
https://www.readbyqxmd.com/read/29139135/phase-1-study-of-quizartinib-in-combination-with-induction-and-consolidation-chemotherapy-in-patients-with-newly-diagnosed-acute-myeloid-leukemia
#7
Jessica K Altman, James M Foran, Keith W Pratz, Denise Trone, Jorge E Cortes, Martin S Tallman
Novel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline-based induction/consolidation chemotherapy. Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single-agent activity in relapsed or refractory (R/R) AML. This phase 1, open-label, sequential group dose-escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML)...
November 15, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29138996/ichthyosiform-pityriasis-rubra-pilaris-like-eruption-secondary-to-ponatinib-therapy-case-report-and-literature-review
#8
Ariel E Eber, Alyx Rosen, Kate E Oberlin, Alessio Giubellino, Paolo Romanelli
Tyrosine kinase inhibitors have revolutionized the chemotherapy arena as targeted therapies for a multitude of malignancies. They are more selective than conventional chemotherapy, and often elicit fewer systemic adverse events, however toxicities still exist. Cutaneous toxicities are common and their management presents a novel challenge to physicians and patients. Ponatinib is a third-generation tyrosine kinase inhibitor increasingly reported to cause cutaneous eruption. A 50-year-old woman with a history of chronic myelogenous leukemia presented with a 4-month history of worsening atrophic and ichthyosiform pink plaques involving the axillae, thighs and abdomen; red patches were also observed on the cheeks and forehead...
November 14, 2017: Drug Safety—Case Reports
https://www.readbyqxmd.com/read/29137098/scrambler-therapy-for-the-treatment-of-neuropathic-pain-related-to-leukemia-in-a-pediatric-patient-a-case-report
#9
Hahck Soo Park, Won-Joong Kim, Hyung Gon Kim, Seung Hee Yoo
RATIONALE: Cancer-related neuropathic pain often responds poorly to standard pain treatments. Scrambler therapy has relieved refractory chronic pain in several uncontrolled clinical trials. PATIENT CONCERNS: An 11-year-old female patient was suffering from left groin and medial thigh pain after irradiation to the knee. The girl was diagnosed with precursor B-cell lymphoblastic leukemia 2 years ago. Extramedullary relapse of leukemia developed 1 month ago and pain had started...
November 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29133777/acute-lymphoblastic-leukemia-patient-with-variant-atf7ip-pdgfrb-fusion-and-favorable-response-to-tyrosine-kinase-inhibitor-treatment-a-case-report
#10
Ge Zhang, Yanle Zhang, Jianrong Wu, Yan Chen, Zhigui Ma
BACKGROUND Chromosomal translocations involving the PDGFRB gene have been reported in a broad spectrum of hematological malignancies. An ATF7IP/PDGFRB fusion was recently identified in a Philadelphia chromosome-like (Ph-like) B-progenitor acute lymphoblastic leukemia (B-ALL) patient. Here we report on a special case of a Ph-like ALL patient who had a variant ATF7IP/PDGFRB fusion. CASE REPORT In this case, a variant fusion was created between ATF7IP exon 9 (instead of exon 13) and PDGFRB exon 11, resulting in the loss of 411 nucleotides and 137 amino acids in the ATF7IP/PDGFRB fusion cDNA and its encoded chimeric protein, respectively...
November 14, 2017: American Journal of Case Reports
https://www.readbyqxmd.com/read/29132473/-progress-in-clinical-studies-of-chimeric-antigen-receptor-engineered-t-cells-for-treatment-of-childhood-cancer
#11
Ya-Ru Ni, Xiao-Jun Xu, Yong-Min Tang
Nowadays, the 5-year survival rate of childhood cancer patients can be more than 80%, but some patients with relapse and refractory cancers have shown no good response to traditional strategies. Chimeric antigen receptor engineered T (CAR-T) cell therapy is promising for these patients. CAR-T cells recognize the tumor-associated antigens in a non-major histocompatibility complex-restricted manner, so their anti-tumor ability is enhanced. There are four generations of CAR-T cells now. The complete remission rate of pediatric patients with relapse and refractory acute lymphoblastic leukemia can be as high as 90% when treated with CD19-targeting CAR-T cells...
November 2017: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
https://www.readbyqxmd.com/read/29132164/mutational-spectrum-of-fanconi-anemia-associated-myeloid-neoplasms
#12
Mwe Mwe Chao, Kathrin Thomay, Gudrun Goehring, Marcin Wlodarski, Victor Pastor, Brigitte Schlegelberger, Detlev Schindler, Christian Peter Kratz, Charlotte Niemeyer
Individuals with Fanconi anemia (FA) have a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), yet the secondary somatic mutations lending to these malignancies remain to be further elucidated. We employed a next-generation sequencing myeloid neoplasia gene panel to determine the mutational spectrum of FA-related MDS/AML. Ten of 16 patients showed missense, nonsense, insertion or duplication mutations in 13 genes. In contrast to findings in MDS in the general population, mutations in genes involved in RNA splicing were rarely affected...
November 2017: Klinische Pädiatrie
https://www.readbyqxmd.com/read/29131376/method-development-for-quantification-of-quizartinib-in-rat-plasma-by-liquid-chromatography-tandem-mass-spectrometry-for-pharmacokinetic-application
#13
Essam Ezzelddin, Muzaffar Iqbal, Gamal Mostafa, Khalid A Al-Rashood, Toqa El Nahhas
Quizartinib is a highly potent inhibitor of the fms-like tyrosine kinase receptor, which is one of the most commonly mutated genes in acute myeloid leukemia (AML). Quizartinib has shown a significant antileukemic clinical influence among relapsed/refractory acute AML patients. This study aimed at developing and validating an analytical method for the measurement of quizartinib in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method was validated according to FDA guidelines, and the results obtained in this work met the set criteria...
November 13, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/29124996/a-30-year-mortality-and-respiratory-morbidity-study-of-refractory-ceramic-fiber-workers
#14
Grace LeMasters, James E Lockey, Timothy J Hilbert, Linda S Levin, Jeff W Burkle, Ralph Shipley, Charles Perme, Cristopher A Meyer, Carol H Rice
AIM: Report mortality (n = 1119), cancer incidence (n = 1207) and radiographic (n = 1451) findings from a 30-year investigation of current and former refractory ceramic fiber (RCF) workers. METHODS: Cause of death, health and work histories, radiographs and spirometry were collected. Mortality and cancer incidence were analyzed. Logistic regression analysis investigated the associations of latency and cumulative fiber exposure (CFE) on radiographic changes...
August 2017: Inhalation Toxicology
https://www.readbyqxmd.com/read/29122656/programmed-death-1-ligands-pd-l1-and-pd-l2-show-distinctive-and-restricted-patterns-of-expression-in-lymphoma-subtypes
#15
Poonam K Panjwani, Vivek Charu, Monique DeLisser, Hernan Molina-Kirsch, Yasodha Natkunam, Shuchun Zhao
The success of immunotherapy using immune checkpoint blockade in solid tumors and in relapsed/refractory classical Hodgkin lymphoma and chronic lymphocytic leukemia holds promise for targeted therapy in hematologic malignancies. Since efficacy of immunomodulatory therapy is correlated with numbers of cells that express programmed death (PD-1) ligands, we evaluated the expression of PD-L1 and PD-L2 proteins using immunohistochemistry in over 702 diagnostic lymphoma biopsies. In classical Hodgkin lymphoma, PD-L1 and PD-L2 were expressed in 82% and 41% of cases respectively, and PD-L1 but not PD-L2 expression correlated with Epstein Barr Virus in tumor cells...
November 6, 2017: Human Pathology
https://www.readbyqxmd.com/read/29119643/a-phase-i-study-of-lenalidomide-plus-chemotherapy-with-mitoxantrone-etoposide-and-cytarabine-for-the-reinduction-of-patients-with-acute-myeloid-leukemia
#16
Daniel J DeAngelo, Andrew M Brunner, Lillian Werner, David Avigan, Amir T Fathi, Adam S Sperling, Abigail Washington, Dina Stroopinsky, Jacalyn Rosenblatt, Malgorzata McMasters, Katarina Luptakova, Martha Wadleigh, David P Steensma, Gabriela S Hobbs, Eyal C Attar, Philip C Amrein, Benjamin L Ebert, Richard M Stone, Karen K Ballen
Patients with relapsed AML have a poor prognosis and limited responses to standard chemotherapy. Lenalidomide is an immunomodulatory drug that may modulate anti-tumor immunity. We performed a study to evaluate the safety and tolerability of lenalidomide with mitoxantrone, etoposide and cytarabine (MEC) in relapsed/refractory AML. Adult patients with relapsed/refractory AML were eligible for this phase I dose-escalation study. We enrolled 35 patients using a "3 + 3" design, with a 10 patient expansion cohort at the maximum tolerated dose (MTD)...
November 9, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29119293/asparaginase-erwinia-chrysanthemi-effectively-depletes-plasma-glutamine-in-adult-patients-with-relapsed-refractory-acute-myeloid-leukemia
#17
Ashkan Emadi, Jennie Y Law, Erin T Strovel, Rena G Lapidus, Linda J B Jeng, Myounghee Lee, Miriam G Blitzer, Brandon A Carter-Cooper, Danielle Sewell, Isabella Van Der Merwe, Sunita Philip, Mohammad Imran, Stephen L Yu, Hongxia Li, Philip C Amrein, Vu H Duong, Edward A Sausville, Maria R Baer, Amir T Fathi, Zeba Singh, Søren M Bentzen
Depletion of glutamine (Gln) has emerged as a potential therapeutic approach in the treatment of acute myeloid leukemia (AML), as neoplastic cells require Gln for synthesis of cellular components essential for survival. Asparaginases deplete Gln, and asparaginase derived from Erwinia chrysanthemi (Erwinaze) appears to have the greatest glutaminase activity of the available asparaginases. In this Phase I study, we sought to determine the dose of Erwinaze that safely and effectively depletes plasma Gln levels to ≤ 120 μmol/L in patients with relapsed or refractory (R/R) AML...
November 8, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29118813/the-leukemic-stem-cell-niche-adaptation-to-hypoxia-versus-oncogene-addiction
#18
Giulia Cheloni, Martina Poteti, Silvia Bono, Erico Masala, Nathalie M Mazure, Elisabetta Rovida, Matteo Lulli, Persio Dello Sbarba
Previous studies based on low oxygen concentrations in the incubation atmosphere revealed that metabolic factors govern the maintenance of normal hematopoietic or leukemic stem cells (HSC and LSC). The physiological oxygen concentration in tissues ranges between 0.1 and 5.0%. Stem cell niches (SCN) are placed in tissue areas at the lower end of this range ("hypoxic" SCN), to which stem cells are metabolically adapted and where they are selectively hosted. The data reported here indicated that driver oncogenic proteins of several leukemias are suppressed following cell incubation at oxygen concentration compatible with SCN physiology...
2017: Stem Cells International
https://www.readbyqxmd.com/read/29118010/cd38-antibodies-in-multiple-myeloma-back-to-the-future
#19
Niels W C J van de Donk, Paul G Richardson, Fabio Malavasi
CD38 is highly and uniformly expressed on MM cells, and at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of non-hematopoietic origin. CD38 is a transmembrane glycoprotein with ectoenzymatic activity, and also functions as receptor and adhesion molecule. Altogether, this has triggered the development of several CD38 antibodies including daratumumab (fully human), isatuximab (chimeric), and MOR202 (fully human). CD38 antibodies have pleiotropic mechanisms of action including Fc-dependent immune effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD38-positive immunesuppressor cells...
November 8, 2017: Blood
https://www.readbyqxmd.com/read/29118007/pd-1-expression-and-clinical-pd-1-blockade-in-b-cell-lymphomas
#20
Zijun Y Xu-Monette, Jianfeng Zhou, Ken H Young
PD-1 blockade targeting the PD-1 immune checkpoint has demonstrated unprecedented clinical efficacy in the treatment of advanced cancers including hematologic malignancies. This article reviews the landscape of PD-1/PD-L1 expression and current PD-1 blockade immunotherapy trials in B-cell lymphomas. Most notably, in relapsed/refractory classical Hodgkin lymphoma, which frequently has increased PD-1(+) tumor-infiltrating T cells, 9p24 genetic alteration and high PD-L1 expression, anti-PD-1 monotherapy has demonstrated remarkable objective response rates (ORR) of 65-87% and durable disease control in phase I/II clinical trials...
November 8, 2017: Blood
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