UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor.
J Med Chem. 2014 Jul 28;
Authors: Zhang W, DeRyckere D, Hunter D, Liu J, Stashko M, Minson KA, Cummings C, Lee M, Glaros TG, Newton DL, Sather S, Zhang D, Kireev DB, Janzen WP, Earp HS, Graham DK, Frye SV, Wang X
We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar sub-nanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.
PMID: 25068800 [PubMed - as supplied by publisher]
An exploratory phase 2 study of investigational Aurora A kinase inhibitor alisertib (MLN8237) in acute myelogenous leukemia and myelodysplastic syndromes.
Leuk Res Rep. 2014;3(2):58-61
Authors: Goldberg SL, Fenaux P, Craig MD, Gyan E, Lister J, Kassis J, Pigneux A, Schiller GJ, Jung J, Jane Leonard E, Fingert H, Westervelt P
Alisertib (MLN8237) is an investigational, oral, selective, Aurora A kinase (AAK) inhibitor. In this phase 2 trial, 57 patients with acute myeloid leukemia (AML) or high-grade myelodysplastic syndrome received alisertib 50 mg BID for 7 days in 21-day cycles. Responses in 6/35 AML patients (17% response rate with an additional 49% stable disease, 34% transfusion independence) included 1 complete response lasting >1 year. No responses were observed in MDS patients. Adverse events >30% included diarrhea, fatigue, nausea, febrile neutropenia, and stomatitis. Results suggest modest activity in AML, supporting further research to better understand how AAK inhibition may induce leukemic cell senescence.
PMID: 25068104 [PubMed]
The clinical significance of ABCC3 as an imatinib transporter in chronic myeloid leukaemia.
Leukemia. 2014 Jun;28(6):1360-3
Authors: Giannoudis A, Davies A, Harris RJ, Lucas CM, Pirmohamed M, Clark RE
PMID: 24441286 [PubMed - indexed for MEDLINE]
BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP.
Leukemia. 2014 Jun;28(6):1326-33
Authors: Morotti A, Panuzzo C, Crivellaro S, Pergolizzi B, Familiari U, Berger AH, Saglio G, Pandolfi PP
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the t(9;22) translocation coding for the chimeric protein p210 BCR-ABL. The tumor suppressor phosphatase and tensin homolog (PTEN) has recently been shown to have a critical role in the pathogenesis of CML. Nuclear localization and proper nuclear-cytoplasmic shuttling are crucial for PTEN’s tumor suppressive function. In this study, we show that BCR-ABL enhances HAUSP-induced de-ubiquitination of PTEN in turn favoring its nuclear exclusion. We further demonstrate that BCR-ABL physically interacts with and phosphorylates HAUSP on tyrosine residues to trigger its activity. Importantly, we also find that PTEN delocalization induced by BCR-ABL does not occur in the leukemic stem cell compartment due to high levels of PML, a potent inhibitor of HAUSP activity toward PTEN. We therefore identify a new proto-oncogenic mechanism whereby BCR-ABL antagonizes the nuclear function of the PTEN tumor suppressor, with important therapeutic implications for the eradication of CML minimal residual disease.
PMID: 24317448 [PubMed - indexed for MEDLINE]
[Mechanisms of resistance to BCR-ABL kinase inhibitors].
Acta Med Port. 2013 Jul-Aug;26(4):402-8
Authors: Diamond J, da Silva MG
Since the introduction of imatinib mesylate for the treatment of chronic myeloid leukaemia, impressive clinical responses were observed in the majority of patients in chronic phase. However, not all patients experience an optimal response to imatinib mesylate or even to the more potent, second generation tyrosine kinase inhibitors. Furthermore, responses are not sustained in a number of patients, and it is yet unclear whether the inhibitors can be safely discontinued in patients who achieve long-term remission. The emergence of resistance to second generation tyrosine kinase inhibitors has become a significant problem that led to extensive studies on the causal mechanisms. This review will describe our current state of knowledge on why and how chronic myeloid leukaemia cells can develop resistance to second generation tyrosine kinase inhibitors.
PMID: 24016650 [PubMed - indexed for MEDLINE]
Low?dose radiation?induced apoptosis in human leukemia K562 cells through mitochondrial pathways.
Mol Med Rep. 2014 Sep;10(3):1569-1575
Authors: Xin Y, Zhang HB, Tang TY, Liu GH, Wang JS, Jiang G, Zhang LZ
High?dose total body irradiation (TBI) has an established role as preparative regimen for bone?marrow transplantation in the treatment of chronic myelogenous leukemia (CML), but this regimen still has a relatively high rate of acute and late toxicity. Low?dose radiation (LDR) induces apoptosis of tumor cells and has numerous beneficial effects on normal tissues, including radiation homeostasis and adaptive response. Based on the previous evidence, in the present study, K562 cells were exposed to LDR, high?dose radiation (HDR), and LDR in combination with HDR to investigate the possible mechanism of the apoptotic effect and hypersensitivity induced by LDR. The apoptotic rate increased in all radiation groups in a time?dependent manner. An upregulation of Bax protein expression and a downregulation of Bcl?xl in a dose?dependent manner in human leukemia K562 cells was observed. However, the expression of p53 protein did not change in all of the radiation cell groups. The mitochondrial membrane potential (??m) in K562 cells decreased in all of the radiation cell groups in a dose?dependent manner. Furthermore, the decrease of ??m was enhanced in the LDR/HDR group compared with that in the LDR or HDR groups. The activity of caspase?3 was enhanced in all of the radiation groups. In the LDR/HDR group, the activity of caspase?3 was higher than that in the HDR or LDR groups. The present study provided preliminary experimental evidence of LDR being beneficial in combination with TBI in the treatment of CML.
PMID: 25060925 [PubMed - as supplied by publisher]
Emerg Med Clin North Am. 2014 Aug;32(3):597-612
Authors: Meier B, Burton JH
The emergency providers generally encounters myeloproliferative disorders (MPNs) in 1 of 2 ways: as striking laboratory abnormalities of seeming unknown consequence, or in previously diagnosed patients presenting with complications. The course of patients with MPNs is highly variable, but major complications can arise. Emergent conditions related to hyperviscosity need to be recognized early and treated aggressively. Rapid hydration, transfusion, cytoreduction, and early hematology consultation can be lifesaving. Likewise, although management is not altered, a high index of suspicion for thrombotic complications is required in patients with known MPNs as these are a significant cause of morbidity and mortality.
PMID: 25060252 [PubMed - as supplied by publisher]
Emerg Med Clin North Am. 2014 Aug;32(3):579-596
Authors: Rose-Inman H, Kuehl D
Although great progress has been made in the understanding and treatment of acute leukemia, this disease has not been conquered. For emergency providers (EPs), the presentation of these patients to an emergency department presents a host of challenges. A patient may present with a new diagnosis of leukemia or with complications of the disease process or associated chemotherapy. It is incumbent on EPs to be familiar with the manifestations of leukemia in its various stages and maintain some suspicion for this diagnosis, given the nebulous and insidious manner in which leukemia can present.
PMID: 25060251 [PubMed - as supplied by publisher]
[Additional chromosomal abnormalities in dynamic of target therapy for chronic myeloid leukemia in children and adolescents].
Lik Sprava. 2014 Jan-Feb;(1-2):55-9
Authors: Andreeva SV, Drozdova VD
Chromosomal abnormalities of bone marrow cells in dynamic chronic myeloid leukemia (CML) with bcr-abl-tyrosinkinase inhibitor (400 mg/m2) in 34 children and adolescent were estimated. Appearence of additional chromosomal abnormalities such as del(16)(q22), del(11)(q23), del(6) (q23), del(21)(q12), trisomy chromosome 8, additional neartetraploid clones were evidence about tumor cells resistence to therapy in children and adolescent.
PMID: 24908961 [PubMed - indexed for MEDLINE]
Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in chronic myeloid leukemia: an Egyptian study.
Med Oncol. 2014 Jan;31(1):794
Authors: Khorshied MM, Shaheen IA, Abu Khalil RE, Sheir RE
Methylenetetrahydrofolate reductase (MTHFR) gene plays a pivotal role in folate metabolism. Several genetic variations in MTHFR gene as MTHFR-C677T and MTHFR-A1298C result in decreased MTHFR activity, which could influence efficient DNA methylation and explain susceptibility to different cancers. The etiology of chronic myeloid leukemia (CML) is obscure and little is known about individual’s susceptibility to CML. In order to assess the influence of these genetic polymorphisms on the susceptibility to CML and its effect on the course of the disease among Egyptians, we performed an age-gender-ethnic matched case-control study. The study included 97 CML patients and 130 healthy controls. Genotyping of MTHFR-C677T and -A1298C was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The results showed no statistical difference in the distribution of MTHFR-C677T and -A1298C polymorphic genotypes between CML patients and controls. The frequency of MTHFR 677-TT homozygous variant was significantly higher in patients with accelerated/blastic transformation phase when compared to those in the chronic phase of the disease. In conclusion, our study revealed that MTHFR-C677T and -A1298C polymorphisms could not be considered as genetic risk factors for CML in Egyptians. However, MTHFR 677-TT homozygous variant might be considered as a molecular predictor for disease progression.
PMID: 24338216 [PubMed - indexed for MEDLINE]
Functional polymorphism of CYP2B6 G15631T is associated with hematologic and cytogenetic response in chronic myeloid leukemia patients treated with imatinib.
Med Oncol. 2014 Jan;31(1):782
Authors: Kassogue Y, Quachouh M, Dehbi H, Quessar A, Benchekroun S, Nadifi S
In the spite of the impressive results achieved with imatinib in chronic myeloid leukemia (CML) patients, differences in patient’s response are observed, which may be explained by interindividual genetic variability. It is known that cytochrome P450 enzymes play a major role in the metabolism of imatinib. The present study aimed to understand the functional impact of CYP2B6 15631G>T polymorphism on the response of imatinib in CML patients and its relation to CML susceptibility. We have genotyped CYP2B6 G15631T in 48 CML patients and 64 controls by PCR-RFLP. CYP2B6 15631G>T was not found to be a risk factor for CML (OR 95 % CI, 1.12, 0.6-2, p > 0.05). Hematologic response loss was higher in patients with 15631GG/TT genotype when compared with 15631GT (36.8 vs. 13.8 %; X (2) = 3.542, p = 0.063). Complete cytogenetic response was higher in 15631GG/GT genotype groups when compared with 15631TT (X (2) = 3.298, p = 0.024). Primary cytogenetic resistance was higher in patients carrying 15631GG/TT genotype when compared with 15631GT carriers (52.6 vs. 17.2 %; X (2) = 6.692, p = 0.010). Furthermore, side effects were more common for patients carrying 15631GG genotypes when compared with GT/TT carriers (36 vs. 13.8 %; X (2) = 8.3, p = 0.004). In light of our results, identification of 15631G>T polymorphism in CML patients might be helpful to predict therapeutic response to imatinib.
PMID: 24293093 [PubMed - indexed for MEDLINE]
Eyelid Myeloid Sarcoma: Ominous Presentation of Acute Myelogenous Leukemia.
Orbit. 2014 Jul 24;:1-3
Authors: Phelps PO, Marcet MM, Hong AR, Nichols JW
Abstract A 19 year-old African American man presented to our clinic for a second opinion about a right upper eyelid mass which had been recalcitrant to treatment for nonspecific orbital inflammation by an outside facility. Examination for systemic causes of the patients eyelid lesion led to a diagnosis of acute myelogenous leukemia (AML) FAB subtype M1. A subsequent biopsy of the eyelid tumor confirmed the diagnosis of a myeloid sarcoma. The patient succumbed to complications from his leukemia within 13 months of presentation. This case report is the first, to our knowledge, of an eyelid myeloid sarcoma as the presenting sign of AML and demonstrates the poor prognosis of this lesion.
PMID: 25058666 [PubMed - as supplied by publisher]
Unusual T-lymphoblastic blast phase of chronic myelogenous leukemia.
Case Rep Hematol. 2014;2014:304359
Authors: Xu J, Li S
T-lymphoblastic leukemia/lymphoma (T-ALL) presenting as blast phase of chronic myelogenous leukemia (CML-BP) is rare. In patients without history of CML, it is difficult to differentiate between CML-BP or de novo T-ALL. Here we reported 2 unusual cases of T-ALL presenting as CML-BP. Case 1 was a 24-year-old female with leukocytosis. Besides T-lymphoblasts (32%), her marrow exhibited some morphologic features of CML. Multiple remission or relapsing marrow had never demonstrated morphologic features of CML. Despite of imatinib treatment and stem cell transplant, she died 2.5 years later. Case 2, a 66-year-old male with diffuse lymphadenopathy, showed T-ALL in a lymph node and concurrent CML chronic phase (CML-CP) in his marrow. Same BCR-ABL1 fusion transcript with minor breakpoint was present in both the lymph node and marrow specimens. Although both cases did not have a history of CML, both cases represented T-lymphoblastic CML-BP with unusual features: Case 1 is unusual in that it presented as T-ALL with some CML morphologic feature but never showed CML-CP in her subsequent marrows biopsies; Case 2 is the first reported case of T-lymphoblastic CML-BP harboring BCR-ABL1 transcript with a minor breakpoint.
PMID: 25057418 [PubMed]
Moving towards patient-centered decision-making in chronic myeloid leukemia: assessment of quality of life and symptom burden.
Haematologica. 2014 Feb;99(2):205-8
Authors: Baccarani M, Efficace F, Rosti G
PMID: 24497557 [PubMed - indexed for MEDLINE]
Allogeneic T cells: maestro in the co-ordination of the immune response after hematopoietic stem cell transplantation.
Haematologica. 2014 Feb;99(2):203-5
Authors: Saudemont A, Madrigal JA
PMID: 24497556 [PubMed - indexed for MEDLINE]
Chronic myeloid leukemia (CML): association of treatment satisfaction, negative medication experience and treatment restrictions with health outcomes, from the patient’s perspective.
Health Qual Life Outcomes. 2013;11:167
Authors: Hirji I, Gupta S, Goren A, Chirovsky DR, Moadel AB, Olavarria E, Victor TW, Davis CC
BACKGROUND: The availability of the tyrosine-kinase inhibitor (TKI), imatinib, and later introduction of second generation TKIs, dasatinib and nilotinib, have not only improved clinical outcomes of patients with chronic myeloid leukemia (CML), but also provide multiple therapeutic options for CML patients. Despite the widespread use of these oral therapies, little is known about the impact of different treatment regimens on patient-reported outcomes (PROs) among CML patients. The objective of this study was to assess the impact of patient-reported treatment restrictions and negative medication experiences (NMEs) on satisfaction and other health outcomes among patients with CML treated with oral TKIs.
METHODS: Participants recruited from survey panels and patient networks in the United States (US) and Europe completed an online questionnaire. Respondents included adults (? 18 years) with chronic-phase CML currently on TKI treatment. Study variables included treatment difficulty (i.e., difficulty in following treatment regimens), CML dietary/dosing requirements, NMEs, and validated PROs assessing treatment satisfaction, health-related quality of life (HRQoL), activity impairment, and non-adherence. Structural equation models assessed associations among variables, controlling for covariates.
RESULTS: 303 patients with CML (US n=152; Europe n=151; mean age 51.5 years; 46.2% male) completed the questionnaire. Approximately 30% of patients reported treatment difficulties; treatment difficulty was higher among nilotinib (63.3%) than among dasatinib (2.6%) or imatinib (19.2%) treated patients (p<0.0001). Non-adherence was generally low; however, patients on nilotinib vs. imatinib reported missing doses more often (p<0.05). Treatment satisfaction was associated with significantly increased HRQoL (p<0.05) and lower activity impairment (p<0.01). NMEs were associated with decreased treatment satisfaction (p<0.01) and HRQoL (p<0.05), and greater activity impairment (p<0.01). Higher overall treatment restrictions were associated with greater treatment difficulty (p<0.001), which correlated with non-adherence (p<0.01).
CONCLUSIONS: Treatment satisfaction and NMEs are important factors associated with HRQoL among patients with CML. Increased treatment restrictions and associated difficulty may affect adherence with TKIs. Choosing a CML treatment regimen that is simple and conveniently adaptable in patients’ normal routine can be an important determinant of HRQoL and adherence.
PMID: 24099272 [PubMed - indexed for MEDLINE]
Development of a coordinated allo T cell and auto B cell response against autosomal PTK2B after allogeneic hematopoietic stem cell transplantation.
Haematologica. 2014 Feb;99(2):365-9
Authors: Kremer AN, van der Griendt JC, van der Meijden ED, Honders MW, Ayoglu B, Schwenk JM, Nilsson P, Falkenburg JH, Griffioen M
It is well known that allo-reactive T cells play a crucial role in graft-versus-leukemia and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (alloSCT). Allo-reactive CD4(+) T cells can mediate direct cytolysis, but may also stimulate production of IgG antibodies as helper cells. Immune complexes may subsequently be processed and presented by professional antigen presenting cells and stimulate induction of specific CD8(+) T cells. As such, proteins targeted in coordinated T- and B-cell responses may represent a class of immunodominant antigens in clinical responses after alloSCT. We previously identified LB-PTK2B-1T as HLA class II restricted polymorphic antigen in a patient treated with donor lymphocyte infusion for relapsed chronic myeloid leukemia after HLA-matched alloSCT. Since PTK2B has also been described as antibody target, we here investigated whether a coordinated T- and B-cell response against PTK2B was induced. Patient serum before and after alloSCT and donor lymphocyte infusion (DLI) was screened for antibodies, and we indeed observed development of a humoral immune response against PTK2B. Antibodies against PTK2B were only found after DLI and, in contrast to the CD4(+) T cells, recognized a monomorphic region of the protein. To our knowledge, this is the first description of a coordinated allo-reactive CD4(+) T-cell and auto-reactive antibody response against an autosomal antigen.
PMID: 24097630 [PubMed - indexed for MEDLINE]
The impact of molecular biology techniques on the management of newly diagnosed chronic myeloid leukemia patients in chronic phase. A review.
Transfus Apher Sci. 2013 Oct;49(2):116-9
Authors: Lewalle P, Martiat P
Since the introduction of tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML), the management of this disease has completely changed. The aim has been first to bring to the patient a maximal response and to identify at different time-points what could be considered an optimal response (which is to render the progression free survival as important as possible). To achieve this, new molecular tools were needed, the most important being the real time quantitative PCR (RT-qPCR), to measure the number of remaining transcripts after several period of treatment. The second important tool was the sequencing of the BCR-ABL kinase domain to identify potential mutations giving rise to resistance to imatinib first and next to second generation TKIs. This technique, much more sensitive than cytogenetics, has allowed the definition of important levels of transcripts (the major molecular response i.e. a three log reduction and the complete molecular response i.e. a 4.5 log reduction) the first ensuring a long term PFS on treatment, the second allowing the birth of studies looking at whether it would be possible to discontinue the treatment in this group of patients.
PMID: 24007867 [PubMed - indexed for MEDLINE]
Veterans and Agent Orange: Update 2002
Authors: Institute of Medicine (US) Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fourth Biennial Update)
This report concentrates on the evidence published after the completion of work on Veterans and Agent Orange: Update 2000 (IOM, 2001) and Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans (IOM, 2002). For each health outcome, the new evidence is reviewed in detail. Conclusions, however, are based on the totality of accumulated evidence, not just on recently published studies. That is, new evidence is interpreted not alone but in the context of evidence addressed in previous reports.
Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans
Authors: Institute of Medicine (US) Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Third Biennial Update)
This report begins with a brief overview of the study methodology and the considerations underlying the assessment of research reviewed. This is followed by an evaluation of the epidemiologic evidence, which includes background on the scientific data reviewed in VAO, Update 1996, Update 1998, and Update 2000 and a more thorough discussion of the new information and their interpretation. The reader is referred to relevant sections of the previous reports for additional detail and explanation.