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acute refractory myeloid leukemia

Maximilian Fleischmann, Ulf Schnetzke, Karin G Schrenk, Volker Schmidt, Herbert G Sayer, Inken Hilgendorf, Andreas Hochhaus, Sebastian Scholl
BACKGROUND: Activating mutations of the receptor tyrosine kinase FLT3 (fms-related tyrosine kinase 3) reflect the most frequent molecular aberration in acute myeloid leukemia (AML). In particular, FLT3 internal tandem duplications (FLT3-ITD) are characterized by an unfavorable prognosis and allogeneic stem cell transplantation (allogeneic SCT) in first complete remission is recommended. In case of imminent or frank relapse following allogeneic SCT, treatment with FLT3 tyrosine kinase inhibitors (TKI) constitutes a promising clinical approach to induce hematologic remission without conventional chemotherapy...
October 24, 2016: Journal of Cancer Research and Clinical Oncology
David P Steensma
The term "refractory anemia" was used in 1937 by Cornelius Parker Rhoads to describe patients whose anemia did not improve after treatment with liver extract or iron salts, and this term has been used to denote patients with certain subtypes of myelodysplastic syndromes (MDS) since the 1976 and 1982 French-American-British (FAB) classifications of acute leukemias and MDS. In 2016, the World Health Organization (WHO) proposed elimination of "refractory anemia" in a more general proposal for reclassification of myeloid neoplasia...
October 17, 2016: Leukemia Research
Iván Martín, Esperanza Such, Blanca Navarro, Ana Vicente, María López-Pavía, Mariam Ibáñez, Mar Tormo, Eva Villamón, Inés Gómez-Seguí, Irene Luna, Silvestre Oltra, Laia Pedrola, Miguel Angel Sanz, Jose Cervera, Guillermo Sanz
The incidence of SF3B1 mutations in patients with RARS is high. Recently, it has been shown that SF3B1 and DNMT3A mutations overlap more often than expected, although it is not clear how this could affect the disease. We studied SF3B1 and DNMT3A in 123 RARS patients: 101 out of 123 samples (82%) had somatic mutations in SF3B1, and 13 of them (13%) showed a co-mutation (SF3B1(mut)DNMT3A(mut)). All co-mutated patients had a normal karyotype, and 12 of them (92%) were lower-risk patients (IPSS and IPSS-R). Despite their favorable profile, SF3B1(mut)DNMT3A(mut) patients showed a higher RBC transfusion dependency (92% versus 48%, p = ...
October 24, 2016: Leukemia & Lymphoma
Beejal R Ganti, Bernard L Marini, Jerod Nagel, Dale Bixby, Anthony J Perissinotti
PURPOSE: This study evaluated the impact of antibacterial prophylaxis with levofloxacin in relapsed/refractory acute myeloid leukemia (AML) patients. METHODS: This was a retrospective, single-center, cohort study. Adult patients with relapsed/refractory AML admitted for reinduction chemotherapy between November 1, 2006 and June 15, 2015 were screened for inclusion. A protocol initiating levofloxacin prophylaxis was implemented on December 1, 2013. Patients receiving hypomethylating agents (decitabine/azacitidine) were not administered antibacterial prophylaxis and thus not included in this analysis...
October 14, 2016: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
Gregory A Reed, Gary J Schiller, Suman Kambhampati, Martin S Tallman, Dan Douer, Mark D Minden, Karen W Yee, Vikas Gupta, Joseph Brandwein, Yulia Jitkova, Marcela Gronda, Rose Hurren, Aisha Shamas-Din, Andre C Schuh, Aaron D Schimmer
Acute myeloid leukemia (AML) cells meet the higher energy, metabolic, and signaling demands of the cell by increasing mitochondrial biogenesis and mitochondrial protein translation. Blocking mitochondrial protein synthesis through genetic and chemical approaches kills human AML cells at all stages of development in vitro and in vivo. Tigecycline is an antimicrobial that we found inhibits mitochondrial protein synthesis in AML cells. Therefore, we conducted a phase 1 dose-escalation study of tigecycline administered intravenously daily 5 of 7 days for 2 weeks to patients with AML...
October 13, 2016: Cancer Medicine
Takahiro Yamauchi
Standard induction chemotherapy regimens achieve complete remission rates of 80% in younger adult patients with acute myeloid leukemia (AML). However, because of disease relapse only 40-50% of patients achieve long-term survival. Five-year survival rates in older patients are only one third of those achieved in younger cases. The adverse prognostic impact of advanced age is attributable to the chemotherapy-resistant nature of the blasts and the limited tolerability these patients have for intensive chemotherapy...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
B C Medeiros, A T Fathi, C D DiNardo, D A Pollyea, S M Chan, R Swords
Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation, and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (TCA, also called the 'citric acid' or Krebs) cycle...
October 10, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Christoph Schliemann, Joachim Gerss, Stefanie Wiebe, Jan-Henrik Mikesch, Nicola Knoblauch, Tim Sauer, Linus Angenendt, Tobias Kewitz, Marc Urban, Trude Butterfass-Bahloul, Sabine Edemir, Kerstin Vehring, Carsten Müller-Tidow, Wolfgang E Berdel, Utz Krug
: Nintedanib (BIBF 1120), a potent multikinase inhibitor of VEGFR-1/-2/-3, FGFR-1/-2/-3 and PDGFR-α/-β, exerts growth inhibitory and pro-apoptotic effects in myeloid leukemic cells, especially when used in combination with cytarabine. This phase I study evaluated nintedanib in combination with low-dose cytarabine (LDAC) in elderly patients with untreated or relapsed/refractory acute myeloid leukemia (AML) ineligible for intensive chemotherapy in a 3+3 design. Nintedanib (dose levels 100, 150, and 200 mg orally twice daily) and LDAC (20 mg subcutaneous injection twice daily for 10 days) were administered in 28-day cycles...
2016: PloS One
Stephen S Y Lam, Eric S K Ho, Bai-Liang He, Wui-Wing Wong, Chae-Yin Cher, Nelson K L Ng, Cheuk-Him Man, Harinder Gill, Alice M S Cheung, Ho-Wan Ip, Chi-Chiu So, Jerome Tamburini, Chi Wai Eric So, Dona N Ho, Chun-Hang Au, Tsun-Leung Chan, Edmond S K Ma, Raymond Liang, Yok-Lam Kwong, Anskar Y H Leung
An in vitro drug-screening platform on patient samples was developed and validated to design personalized treatment for relapsed/refractory acute myeloid leukemia (AML). Unbiased clustering and correlation showed that homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential antileukemia effect against AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). It worked synergistically with FLT3 inhibitors to suppress leukemia growth in vitro and in xenograft mouse models...
October 5, 2016: Science Translational Medicine
Mixue Xie, Qi Jiang, Li Li, Jingjing Zhu, Lixia Zhu, De Zhou, Yanlong Zheng, Xiudi Yang, Mingyu Zhu, Jianai Sun, Wanzhuo Xie, Xiujin Ye
BACKGROUND: In China, the combination of homoharringtonine, cytarabine, and G-CSF (HAG) has been extensively applied for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). METHODS: We performed a meta-analysis of 2,314 patients (AML, n = 1754; MDS, n = 560) to determine the overall safety and efficacy of this regimen. RESULTS: The complete response (CR) rate of AML patients (53%) was significantly higher than that of MDS/transformed-AML patients (45%; P = 0...
2016: PloS One
Vinod A Pullarkat, Edward M Newman
Venetoclax is an oral drug with an excellent side-effect profile that has the potential to revolutionize acute myeloid leukemia (AML) therapy in two areas. Venetoclax-based combination therapies could be a bridge to hematopoietic cell transplant with curative intent for patients with refractory/relapsed AML, and venetoclax-based therapy could provide meaningful survival prolongation for older patients with AML who are not candidates for more aggressive therapies. Cancer Discov; 6(10); 1082-3. ©2016 AACR.See related article by Konopleva and colleagues, p...
October 2016: Cancer Discovery
John M Bennett
In comparison with the 2008 World Health Organization "Blue Book" on hematopoietic neoplasms, a small number of changes have been made in the classification. In the lower-risk patients, Refractory Cytopenias with Multilineage Dysplasia and Ring Sideroblasts (RCMD-RS) has been separated from RCMD to recognize the importance of the SF3B1 mutation. Often there has been confusion as to the degree of morphologic dysplasia and/or cytopenias to define some of the lower-risk subtypes. In addition, the type of dysplasia or cytopenias is not always concordant...
August 12, 2016: Clinical Lymphoma, Myeloma & Leukemia
Brittany Knick Ragon, Hagop Kantarjian, Elias Jabbour, Farhad Ravandi, Jorge Cortes, Gautam Borthakur, LaKiesha DeBose, Zhihong Zeng, Heather Schneider, Naveen Pemmaraju, Guillermo Garcia-Manero, Steven Kornblau, William Wierda, Jan Burger, Courtney D DiNardo, Michael Andreeff, Marina Konopleva, Naval Daver
Phosphatidylinositol-3-kinase (PI3K) signaling plays a crucial role in oncogene-mediated tumor growth and proliferation. Buparlisib (BKM120) is an oral pan-class I PI3K inhibitor. This phase I study was conducted to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of BKM120 in patients (pts) with relapsed/refractory acute leukemias. Fourteen pts (12 acute myeloid leukemia, 1 acute lymphoblastic leukemia, 1 mixed phenotype leukemia) were enrolled. Twelve pts received BKM-120 80 mg/day and two 100 mg/day...
September 27, 2016: American Journal of Hematology
Shyam A Patel
Acute myeloid leukemia (AML) involvement of the central nervous system is relatively rare, and detection of leptomeningeal disease typically occurs only after a patient presents with neurological symptoms. The case herein describes a 48-year-old man with relapsed/refractory AML of the mixed lineage leukemia rearrangement subtype, who presents with monocular vision loss due to leukemic eye infiltration. MRI revealed right optic nerve sheath enhancement and restricted diffusion concerning for nerve ischemia and infarct from hypercellularity...
2016: Case Reports in Hematology
Alvaro Muñoz-López, Damià Romero-Moya, Cristina Prieto, Verónica Ramos-Mejía, Antonio Agraz-Doblas, Ignacio Varela, Marcus Buschbeck, Anna Palau, Xonia Carvajal-Vergara, Alessandra Giorgetti, Anthony Ford, Majlinda Lako, Isabel Granada, Neus Ruiz-Xivillé, Sandra Rodríguez-Perales, Raul Torres-Ruíz, Ronald W Stam, Jose Luis Fuster, Mario F Fraga, Mahito Nakanishi, Gianni Cazzaniga, Michela Bardini, Isabel Cobo, Gustavo F Bayon, Agustin F Fernandez, Clara Bueno, Pablo Menendez
Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes...
October 11, 2016: Stem Cell Reports
Marjorie Poggi, Matthias Canault, Marie Favier, Ernest Turro, Paul Saultier, Dorsaf Ghalloussi, Veronique Baccini, Lea Vidal, Anna Mezzapesa, Nadjim Chelghoum, Badreddine Mohand-Oumoussa, Cé Line Falaise, Rémi Favier, Willem H Ouwehand, Mathieu Fiore, Franck Peiretti, Pierre Emmanuel Morange, Noémie Saut, Denis Bernot, Andreas Greinacher, Alan T Nurden, Paquita Nurden, Kathleen Freson, David-Alexandre Trégouët, Hana Raslova, Marie-Christine Alessi
Variants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants and variants located in the E26 transformation-specific binding domain (encoding p.A377T, p...
September 23, 2016: Haematologica
Akifumi Endo, Daisuke Tomizawa, Yuki Aoki, Tomohiro Morio, Shuki Mizutani, Masatoshi Takagi
The Ewing sarcoma breakpoint region 1 (EWSR1) gene is known to fuse with various partner genes to promote the development of the Ewing sarcoma family of tumors and other sarcomas. In contrast, the association of EWSR1 chimeric fusion genes with leukemia has been rarely reported. We identified a novel EWSR1 associated chimeric fusion gene in a patient with acute myeloid leukemia (AML) harboring 46, XY, t (11; 22) (p13; q12) karyotype abnormality. The patient was refractory to intensified chemotherapy including hematopoietic stem cell transplantation...
September 14, 2016: Cancer Science
Lucia Silla, Frederico Dulley, Rosaura Saboya, Fabio Kerbauy, Adriano de Moraes Arantes, Annelise Pezzi, Luisa Grave Gross, Eduardo Paton, Nelson Hamerschlak
INTRODUCTION/OBJECTIVES: Acute myeloid leukemia (AML) accounts for 90% of all cases of acute leukemia in adults. In Brazil, the mortality from myeloid leukemia is 1.74/100 000 men and 1.37/100 000 women. Our aim was to review and update guidelines of the Brazilian Society of Bone Marrow Transplantation on indications of hematopoietic stem cell transplantation (HSCT) for the treatment AML. CONCLUSIONS: (i) Allo-HSCT is recommended for high-risk AML (IA); (ii) allo-HSCT is recommended for AML of intermediate risk (IA); (iii) allo-HSCT is recommended for AML relapsed/refractory (C4); (iv) auto-HSCT is recommended for AML after 1 consolidation (C4); (v) auto-HSCT is recommended for AML in CR1 (higher than QT in the Brazilian experience) (C4); (vi) auto-HSCT is accepted for AML M3 in second molecular complete remission (2B); (vii) peripheral blood instead of Bone Marrow HSC for advanced disease (2A); (viii) recommended conditioning protocols: Bu-Cy/Bu-Mel, Bu-Flu, TBI-Cy...
September 13, 2016: European Journal of Haematology
Christopher B Benton, Farhad Ravandi
Vosaroxin is a quinolone compound that intercalates DNA and induces TP53-independent apoptosis, demonstrating activity against acute myeloid leukemia (AML) in Phase I-III trials. Here, we examine vosaroxin's mechanism of action and pharmacology, and we review its use in AML to date, focusing on details of individual clinical trials. Most recently, when combined with cytarabine in a randomized Phase III trial (VALOR), vosaroxin improved outcomes versus cytarabine alone for relapsed/refractory AML in patients older than 60 years and for patients in early relapse...
September 12, 2016: Future Oncology
Ramandeep Singh Arora, Brijesh Arora
Acute leukemias are the most common diagnostic group of childhood cancer. This review summarizes the published literature on reported current outcomes of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) from India. Overall survival in ALL ranged from 45% to 81% (commonly >60%) and event-free survival ranged from 41% to 70% (commonly >50%). Outcome data for AML was patchy with varying duration of follow-up, but it can be inferred that 50-80% of treated patients had experienced an event (toxic death, refractory disease or relapse)...
July 2016: South Asian Journal of Cancer
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