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[Title] The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy.

Acute myeloid leukemia (AML) in Down syndrome (DS) children has several unique features including a predominance of the acute megakaryocytic leukemia (AMkL) phenotype, higher event-free survivals compared to non-DS children using cytosine arabinoside (ara-C)/anthracycline-based protocols and a uniform presence of somatic mutations in the X-linked transcription factor gene, GATA1.

ETS2 transcripts measured by real-time RT-PCR were 1.8- and 4.1-fold, respectively, higher in DS and non-DS megakaryoblasts than those in non-DS myeloblasts.

In a doxycycline-inducible erythroleukemia cell line, K562pTet-on/ETS2, induction of ETS2 resulted in an erythroid to megakaryocytic phenotypic switch independent of GATA1 levels.

Microarray analysis of doxycycline-induced and doxycycline-uninduced cells revealed an upregulation by ETS2 of cytokines (for example, interleukin 1 and CSF2) and transcription factors (for example, TAL1), which are key regulators of megakaryocytic differentiation.

These results suggest that ETS2 expression is linked to the biology of AMkL in both DS and non-DS children, and that ETS2 acts by regulating expression of hematopoietic lineage and transcription factor genes involved in erythropoiesis and megakaryopoiesis, and in chemotherapy sensitivities.

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(PMID = 18094719.001).

[ISSN] 1476-5551

[Journal-full-title] Leukemia

[ISO-abbreviation] Leukemia

[Language] ENG

[Grant] United States / NCI NIH HHS / CA / R01 CA092308; United States / NCI NIH HHS / CA / R01 CA92308; United States / NIEHS NIH HHS / ES / P30 ES06639; United States / NIEHS NIH HHS / ES / P30 ES006639; United States / NCI NIH HHS / CA / T32 CA009531; United States / NCI NIH HHS / CA / R01 CA120772

[Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

[Publication-country] England

[Chemical-registry-number] 0 / ETS2 protein, human; 0 / GATA1 Transcription Factor; 0 / GATA1 protein, human; 0 / Neoplasm Proteins; 0 / Proto-Oncogene Protein c-ets-2; 04079A1RDZ / Cytarabine; ZS7284E0ZP / Daunorubicin

[Other-IDs] NLM/ NIHMS505525; NLM/ PMC3809919

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemotherapy sensitivity in acute megakaryocytic leukemia.

RUNX1 (AML1) encodes the core binding factor alpha subunit of a heterodimeric transcription factor complex which plays critical roles in normal hematopoiesis.

Translocations or down-regulation of RUNX1 have been linked to favorable clinical outcomes in acute leukemias, suggesting that RUNX1 may also play critical roles in chemotherapy responses in acute leukemias; however, the molecular mechanisms remain unclear.

The median level of RUNX1b transcripts in Down syndrome (DS) children with acute megakaryocytic leukemia (AMkL) were 4.4-fold (P < .001) lower than that in non-DS AMkL cases.

Short hairpin RNA knockdown of RUNX1 in a non-DS AMkL cell line, Meg-01, resulted in significantly increased sensitivity to cytosine arabinoside, accompanied by significantly decreased expression of PIK3CD, which encodes the delta catalytic subunit of the survival kinase, phosphoinositide 3 (PI3)-kinase.

Thus, the treatment of AMkL may be improved by integrating PI3-kinase or Akt inhibitors into the chemotherapy of this disease.

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(PMID = 19638627.001).

[ISSN] 1528-0020

[Journal-full-title] Blood

[ISO-abbreviation] Blood

[Language] ENG

[Grant] United States / NIEHS NIH HHS / ES / P30 ES006639; United States / NCI NIH HHS / CA / R01 CA120772; United States / NCI NIH HHS / CA / CA120772; United States / NIEHS NIH HHS / ES / P30 ES06639

[Publication-type] Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

[Publication-country] United States

[Chemical-registry-number] 0 / Core Binding Factor Alpha 2 Subunit; 0 / RNA, Small Interfering; 0 / RUNX1 protein, human; 04079A1RDZ / Cytarabine; EC 2.7.1.- / Phosphatidylinositol 3-Kinases; EC 2.7.1.137 / Class I Phosphatidylinositol 3-Kinases; EC 2.7.1.137 / PIK3CD protein, human; EC 2.7.11.1 / Oncogene Protein v-akt

[Other-IDs] NLM/ PMC2756129

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] HOX deregulation in acute myeloid leukemia.

The deregulation of homeobox (HOX) genes in acute myeloid leukemia (AML) and the potential for these master regulators to perturb normal hematopoiesis is well established.

To date, overexpression of HOX genes in AML has been attributed to specific chromosomal aberrations and abnormalities involving mixed-lineage leukemia (MLL), an upstream regulator of HOX genes.

The finding reported in this issue of the JCI by Scholl et al. that caudal-type homeobox transcription factor 2 (CDX2), which is capable of affecting HOX gene expression during embryogenesis, is overexpressed in 90% of patients with AML and induces a transplantable AML in murine models provides an alternative mechanism for HOX-induced leukemogenesis and yields important insights into the hierarchy of HOX gene regulation in AML (see the related article beginning on page 1037).

[MeSH-major] Gene Expression Regulation, Neoplastic. Homeodomain Proteins / genetics. Leukemia, Myeloid / genetics. Leukemia, Myeloid, Acute / genetics

[MeSH-minor] Animals. Disease Models, Animal. Genes, Homeobox. Humans. Mice. Transcription Factors / genetics

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(PMID = 17404613.001).

[ISSN] 0021-9738

[Journal-full-title] The Journal of clinical investigation

[ISO-abbreviation] J. Clin. Invest.

[Language] eng

[Publication-type] Comment; Journal Article

[Publication-country] United States

[Chemical-registry-number] 0 / CDX2 protein, human; 0 / Cdx2 protein, mouse; 0 / Homeodomain Proteins; 0 / Transcription Factors

[Other-IDs] NLM/ PMC1838955

   

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[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Weight is a risk factor for treatment mortality in AML.

: Underweight or overweight children with acute myeloid leukaemia (AML) are more likely to succumb to treatment-related complications than their normal weight counterparts.

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(PMID = 28091019.001).

[ISSN] 2047-9018

[Journal-full-title] Nursing standard (Royal College of Nursing (Great Britain) : 1987)

[ISO-abbreviation] Nurs Stand

[Language] eng

[Publication-type] Journal Article

[Publication-country] England

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The significance of the present diffusion decay study lies in the combination of three novel procedures to provide a better characterization of the diffusion decay: i) the acquisition of a large number of b-values (96 b-values up to 10,000 s/mm² ), ii) the application of a noise correction technique (3) to the acquired data, and iii) the use of a Non Negative Least Squares (NNLS) fitting algorithm to evaluate the diffusion coefficients.

The NNLS algorithm is used to fit the corrected data instead of the more commonly used Levenberg-Marquardt algorithm since the NNLS algorithm does not require the number of components to be specified, nor does it need initial estimates of the fitting parameters as input; thus giving it more versatility as a fitting tool for the diffusion decay.

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[Copyright] © 2008 American Association of Physicists in Medicine.

(PMID = 28512828.001).

[ISSN] 2473-4209

[Journal-full-title] Medical physics

[ISO-abbreviation] Med Phys

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

[Keywords] NOTNLM ; Brain / Diffusion / Medical imaging / Medical magnetic resonance imaging / Neural information

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Age and acute myeloid leukemia.

We conducted a retrospective analysis of 968 adults with acute myeloid leukemia (AML) on 5 recent Southwest Oncology Group trials to understand how the nature of AML changes with age.

Older study patients with AML presented with poorer performance status, lower white blood cell counts, and a lower percentage of marrow blasts.

Multidrug resistance was found in 33% of AMLs in patients younger than age 56 compared with 57% in patients older than 75.

Finally, the combination of a poor performance status and advanced age identified a group of patients with a very high likelihood of dying within 30 days of initiating induction therapy.

The distinct biology and clinical responses seen argue for age-specific assessments when evaluating therapies for AML.

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(PMID = 16455952.001).

[ISSN] 0006-4971

[Journal-full-title] Blood

[ISO-abbreviation] Blood

[Language] ENG

[Grant] United States / NCI NIH HHS / CA / CA12213; United States / NCI NIH HHS / CA / CA20319; United States / NCI NIH HHS / CA / CA46282; United States / NCI NIH HHS / CA / CA46368; United States / NCI NIH HHS / CA / CA32102; United States / NCI NIH HHS / CA / CA38926

[Publication-type] Clinical Trial; Journal Article; Research Support, N.I.H., Extramural

[Publication-country] United States

[Other-IDs] NLM/ PMC1895766

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Gefitinib induces myeloid differentiation of acute myeloid leukemia.

Cure rates for patients with acute myeloid leukemia (AML) remain low despite ever-increasing dose intensity of cytotoxic therapy.

In an effort to identify novel approaches to AML therapy, we recently reported a new method of chemical screening based on the modulation of a gene expression signature of interest.

We applied this approach to the discovery of AML-differentiation-promoting compounds.

Here we report that the Food and Drug Administration (FDA)-approved EGFR inhibitor gefitinib similarly promotes the differentiation of AML cell lines and primary patient-derived AML blasts in vitro.

Gefitinib induced differentiation based on morphologic assessment, nitro-blue tetrazolium reduction, cell-surface markers, genome-wide patterns of gene expression, and inhibition of proliferation at clinically achievable doses.

Importantly, EGFR expression was not detected in AML cells, indicating that gefitinib functions through a previously unrecognized EGFR-independent mechanism.

These studies indicate that clinical trials testing the efficacy of gefitinib in patients with AML are warranted.

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[Cites] J Clin Oncol. 2004 Feb 15;22(4):624-33 [14726504.001]

[Cites] Clin Cancer Res. 2004 Feb 15;10(4):1212-8 [14977817.001]

[Cites] Cancer Res. 1986 May;46(5):2314-9 [2870796.001]

(PMID = 15998836.001).

[ISSN] 0006-4971

[Journal-full-title] Blood

[ISO-abbreviation] Blood

[Language] ENG

[Grant] United States / NCI NIH HHS / CA / 5K08 CA098444-03

[Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.

[Publication-country] United States

[Chemical-registry-number] 0 / Biomarkers, Tumor; 0 / Quinazolines; EC 2.7.10.1 / Receptor, Epidermal Growth Factor; S65743JHBS / gefitinib

[Other-IDs] NLM/ PMC1895296

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Immunotherapy of acute myeloid leukemia: current approaches.

Following standard therapy that consists of chemotherapy with or without stem cell transplantation, both relapsed and refractory disease shorten the survival of acute myeloid leukemia (AML) patients.

Therefore, additional treatment options are urgently needed, especially to fight residual AML cells.

The identification of leukemia-associated antigens and the observation that administration of allogeneic T cells can mediate a graft-versus-leukemia effect paved the way to the development of active and passive immunotherapy strategies, respectively.

The aim of these strategies is the eradication of AML cells by the immune system.

In this review, an overview is provided of both active and passive immunotherapy strategies that are under investigation or in use for the treatment of AML.

[MeSH-major] Immunotherapy / methods. Leukemia, Myeloid / therapy

[MeSH-minor] Acute Disease. Humans

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(PMID = 19289488.001).

[ISSN] 1549-490X

[Journal-full-title] The oncologist

[ISO-abbreviation] Oncologist

[Language] eng

[Publication-type] Journal Article; Review

[Publication-country] United States

[Number-of-references] 135

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Therapy-related acute leukaemia with Mitoxantrone: what is the risk and can we minimise it?

BACKGROUND: Therapy-related acute leukaemia (TRAL) is a concern for neurologists and patients when considering treatment with Mitoxantrone for multiple sclerosis (MS).

Acute Myelocytic Leukaemia and Acute Promyelocytic Leukaemia represented 46.4% each of the leukaemia subtypes.

[MeSH-major] Antineoplastic Agents / adverse effects. Leukemia, Myeloid, Acute / chemically induced. Leukemia, Myeloid, Acute / epidemiology. Mitoxantrone / adverse effects. Multiple Sclerosis / drug therapy. Multiple Sclerosis / epidemiology

[MeSH-minor] Acute Disease. Adult. Databases, Factual. Female. Humans. Leukemia, Promyelocytic, Acute / chemically induced. Leukemia, Promyelocytic, Acute / epidemiology. Male. Middle Aged. Risk Factors

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(PMID = 19251838.001).

[ISSN] 1352-4585

[Journal-full-title] Multiple sclerosis (Houndmills, Basingstoke, England)

[ISO-abbreviation] Mult. Scler.

[Language] eng

[Publication-type] Journal Article

[Publication-country] England

[Chemical-registry-number] 0 / Antineoplastic Agents; BZ114NVM5P / Mitoxantrone

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

BACKGROUND & OBJECTIVE: Myelodysplastic syndromes (MDS) are a heterogenous group of haematopoietic stem cell disorders that are multifactorial in their aetiology.

Unique genetic alterations in combinations or in isolation account for a small fraction of MDS suggesting the epigenetic hypermethylation as a possible leading cause for MDS and its transformation to acute myelocytic leukaemia (AML).

Therefore, in this study, promoter hypermethylation status of key cell cycle regulators was assessed as markers in MDS patients and association of hypermethylation with clinical progression of disease was also studied.

METHODS: Promoter hypermethylation analysis of five tumour associated genes namely p16, p15, MGMT, hMLH1 and E-cadherin were done for 41 MDS patient samples with its various subtype.

MGMT gene showed a low 5 per cent (2/41) methylation whereas hMLH1 gene was not methylated in any one of the samples analysed.

All the samples analysed showed the absence of a methylator phenotype in MDS.

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(PMID = 18316853.001).

[ISSN] 0971-5916

[Journal-full-title] The Indian journal of medical research

[ISO-abbreviation] Indian J. Med. Res.

[Language] eng

[Publication-type] Journal Article; Research Support, Non-U.S. Gov't

[Publication-country] India

[Chemical-registry-number] 0 / Adaptor Proteins, Signal Transducing; 0 / MLH1 protein, human; 0 / Nuclear Proteins; 0 / Tumor Suppressor Proteins; EC 2.1.1.- / DNA Modification Methylases; EC 2.1.1.63 / MGMT protein, human; EC 6.5.1.- / DNA Repair Enzymes

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Evaluation of Polo-like Kinase 1 inhibition on the G2/M checkpoint in Acute Myelocytic Leukaemia.

Polo-Kinase 1 (PLK1) is a key cell cycle regulator that is necessary for checkpoint recovery after DNA damage-induced G2 arrest.

We have examined the effects of PLK inhibition in Acute Myelocytic Leukaemia (AML) cells, whose resistance to genotoxic agents is thought to be associated with checkpoint reinforcement.

We report that in U937 AML cells, PLK1 participates in checkpoint recovery, and that inhibition of PLK by the GW843682X compound results in mitotic accumulation and apoptosis.

Finally, we found that treatment with GW843682X slightly reduced genotoxic-induced inhibition of colony formation efficiency of primary leukaemia cells (CFU-L) from AML patients.

[MeSH-major] Benzimidazoles / pharmacology. Cell Cycle Proteins / antagonists & inhibitors. Leukemia, Myeloid, Acute / metabolism. Protein-Serine-Threonine Kinases / antagonists & inhibitors. Proto-Oncogene Proteins / antagonists & inhibitors. Thiophenes / pharmacology

[MeSH-minor] Antineoplastic Agents, Phytogenic / pharmacology. Cell Division / drug effects. Etoposide / pharmacology. G2 Phase / drug effects. Humans. Mitosis / drug effects. U937 Cells

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(PMID = 18616938.001).

[ISSN] 0014-2999

[Journal-full-title] European journal of pharmacology

[ISO-abbreviation] Eur. J. Pharmacol.

[Language] eng

[Publication-type] Journal Article; Research Support, Non-U.S. Gov't

[Publication-country] Netherlands

[Chemical-registry-number] 0 / 5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-((2-(trifluoromethyl)benzyl)oxy)thiophene-2-carboxamide; 0 / Antineoplastic Agents, Phytogenic; 0 / Benzimidazoles; 0 / Cell Cycle Proteins; 0 / Proto-Oncogene Proteins; 0 / Thiophenes; 6PLQ3CP4P3 / Etoposide; EC 2.7.11.1 / Protein-Serine-Threonine Kinases; EC 2.7.11.1 / polo-like kinase 1

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Therapy of acute myeloid leukemia (AML) for medically non-fit patients].

[Transliterated title] Die Therapie der akuten myeloischen Leukämie (AML) bei ''medically non-fit'' Patienten.

Acute myeloid leukemia (AML) has an increasing incidence with higher age, which is about 15 per 100,000 for patients > 65 years.

Many older AML patients show functional restrictions and have a high comorbidity status, so that they do not seem to be qualified for a curatively intended chemotherapy.

Decisive for the low cure rate of older AML patients are both patient-dependent and disease-dependent reasons such as secondary or therapy-related leukemia or adverse cytogenetics with complex chromosomal abnormalities, which are poor prognostic factors and are responsible for the low probability to achieve long-lasting complete remissions.

Prognostic scores are developed for identifying "medically non-fit" patients as objectively as possible.

In the future, these patients should not only be offered best supportive care but also well-tolerable concepts of therapy, which are feasible on an ambulatory basis.

[MeSH-major] Health Status. Leukemia, Myeloid, Acute / drug therapy

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(PMID = 17426936.001).

[ISSN] 0723-5003

[Journal-full-title] Medizinische Klinik (Munich, Germany : 1983)

[ISO-abbreviation] Med. Klin. (Munich)

[Language] ger

[Publication-type] English Abstract; Journal Article; Review

[Publication-country] Germany

[Number-of-references] 17

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Immunohistochemical demonstration of mutant nucleophosmin in acute myeloid leukemia: biological and clinical features related to NPMc expression].

[Transliterated title] Mutáns nucleophosmin fehérje kimutatása akut myeloid leukaemiában: az NPMc+ AML biológiai és klinikai jellemzôi.

The mutation of the nucleophosmin gene (NPM1) is the most frequently occurring genetic aberration in acute myeloid leukemia (AML).

Due to the high frequency and the obvious impact on disease outcome, the current WHO classification also defines the new (tentative) entity of "AML with NPM mutation".

The present study focused on further biological and clinical characterization of NPMc+ AML determined by histological and cytological preparations of the bone marrow.

41 adult AML cases were investigated in our center between 2005 and 2008, 6/41 cases were presented with cytoplasmic NPM immunostaining (14.6%).

All but one were female patients, and were diagnosed as de novo AML with no recurrent cytogenetic aberrations (6/23, 26.1%).

The NPMc+ group displayed M2 or M4 morphology, low CD34, c-kit and HLA-DR expression making a clear phenotypic distinction from the unaffected cases possible.

In conclusion, immunohistochemistry is well applicable for the identification of NPM mutated AML in the daily hematopathology practice.

[MeSH-major] Biomarkers, Tumor / analysis. Biomarkers, Tumor / genetics. Bone Marrow / chemistry. Leukemia, Myeloid, Acute / metabolism. Mutation. Nuclear Proteins / analysis. Nuclear Proteins / genetics

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(PMID = 19465351.001).

[ISSN] 0030-6002

[Journal-full-title] Orvosi hetilap

[ISO-abbreviation] Orv Hetil

[Language] hun

[Publication-type] English Abstract; Journal Article

[Publication-country] Hungary

[Chemical-registry-number] 0 / Biomarkers, Tumor; 0 / Nuclear Proteins; 117896-08-9 / nucleophosmin

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [How I treat... Acute myeloid leukemia in older patients with good performance status].

[Transliterated title] Comment je traite...La leucémie myéloblastique aiguë (LMA) du sujet âgé en bon état général.

This article describes the treatment of acute myeloid leukemia in older patients with good performance status, and then discusses briefly some future therapeutic perspectives.

[MeSH-major] Antineoplastic Agents / therapeutic use. Hematopoietic Stem Cell Transplantation. Leukemia, Myeloid, Acute / drug therapy

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(PMID = 18372541.001).

[ISSN] 0370-629X

[Journal-full-title] Revue médicale de Liège

[ISO-abbreviation] Rev Med Liege

[Language] fre

[Publication-type] English Abstract; Journal Article

[Publication-country] Belgium

[Chemical-registry-number] 0 / Antineoplastic Agents

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia.

Down syndrome children with acute megakaryocytic leukemia (AMkL) have higher cure rates than non-Down syndrome acute myeloid leukemia (AML) patients treated with cytosine arabinoside (ara-C).

Megakaryoblasts from Down syndrome AML patients are more sensitive in vitro to ara-C than cells from non-Down syndrome AML patients.

Stable transfection of wild-type GATA1 cDNA into the Down syndrome AMkL cell line CMK resulted in decreased (8- to 17-fold) ara-C sensitivity and a threefold-lower generation of the active ara-C metabolite ara-CTP compared with that for mock-transfected CMK cells.

Cytidine deaminase transcripts were a median 5.1-fold (P = .002) lower in Down syndrome megakaryoblasts (n = 16) than in blast cells from non-Down syndrome patients (n = 56).

These results suggest that GATA1 transcriptionally upregulates cytidine deaminase and that the presence or absence of GATA1 mutations in AML blasts likely confers differences in ara-C sensitivities due to effects on cytidine deaminase gene expression, which, in turn, contributes to the high cure rate of Down syndrome AMkL patients.

[MeSH-major] Cytidine Deaminase / metabolism. DNA-Binding Proteins / metabolism. Down Syndrome / complications. Down Syndrome / metabolism. Leukemia, Megakaryoblastic, Acute / metabolism. Transcription Factors / metabolism

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(PMID = 15687366.001).

[ISSN] 1460-2105

[Journal-full-title] Journal of the National Cancer Institute

[ISO-abbreviation] J. Natl. Cancer Inst.

[Language] eng

[Grant] United States / NCI NIH HHS / CA / R01 CA92308

[Publication-type] Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.

[Publication-country] United States

[Chemical-registry-number] 0 / Antimetabolites, Antineoplastic; 0 / DNA-Binding Proteins; 0 / Erythroid-Specific DNA-Binding Factors; 0 / GATA1 Transcription Factor; 0 / GATA1 protein, human; 0 / Transcription Factors; 04079A1RDZ / Cytarabine; 13191-15-6 / Arabinofuranosylcytosine Triphosphate; 3083-77-0 / Arabinofuranosyluracil; EC 3.5.4.5 / Cytidine Deaminase

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Comorbidity description using the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) in elderly de novo poor-risk AML patients (pts) treated with laromustine.

: 7050 Background: Treatment of older pts with AML is often complicated by comorbidities and pts with comorbidities are often underrepresented in clinical trials.

The HCT-CI, which was developed in pts receiving allogeneic SCT, has been applied to pts receiving induction therapy for AML in an effort to assist in therapeutic and investigational decisions (Kantarjian 2006; Etienne 2007; Giles 2007).

HCT-CI scores have been shown to be predictive of early death and survival in pts ≥ 60 years receiving induction therapy for AML, with early death rates of 3%, 11%, and 29% for pts with HCT-CI scores of 0, 1-2, and ≥ 3, respectively (Giles 2007).

METHODS: 140 pts age ≥ 60 with poor risk de novo AML from two phase II studies were scored for comorbidity by HCT-CI.

CONCLUSIONS: The majority (81%) of these older poor risk AML pts treated with laromustine had a HCT-CI score ≥ 3, confirming the poor risk nature of this patient group.

The induction death rate for pts treated with laromustine and with HCT-CI score ≥ 3 was lower than that reported for a group of pts with HCT-CI score ≥ 3 treated with standard induction chemotherapy (14% vs 29%; Giles 2007).

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(PMID = 27961414.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

OBJECTIVE: A case series of gliomas treated with alkylator-based chemotherapy who subsequently developed myelodysplastic syndrome (tMDS) or acute myelocytic leukemia (AML).

The diagnosis of tMDS was determined by bone marrow biopsy in seven patients.

Three patients were diagnosed with AML as well (in two determined by bone marrow and one at autopsy).

Interval from last chemotherapy exposure to diagnosis of tMDS/AML ranged from 3 months to 31 months (median 24 months).

Five patients have died, two as a consequence of recurrent brain tumor, one as a complication of transplantation, and due due to AML.

CONCLUSIONS: Although rare, induction of tMDS/AML following extended use of alkylator-based chemotherapy may become more relevant with the evolving practice to treat gliomas for protracted periods.

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(PMID = 27962878.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

: e22231 Background: Chromosomal abnormalities and molecular detection has potential importance for diagnosis and prognosis of MDS, although the mechanisms underlying the development of MDS and their progressive evolution to AML are still largely unknown.

Since, no studies have been reported from India on the prevalence of N-RAS, K- RAS point mutation in codon 12 and FLT3-ITD mutations in patients with MDS, we undertook this study.

PCR-RFLP and nested PCR-RFLP were used for the detection of point mutation in codon 12 of N-RAS and K-RAS.

One out of 53 patients (2%) was found positive for N-RAS and four patients were positive for K-RAS (8%) mutation.

The presence of N-RAS codon 12 mutation was associated with the poor survival.

FLT3-ITD mutation was not observed in any of our cases, which is in contrast to 3% reported from the West.

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(PMID = 27964108.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Some authors have suggested that pegfilgrastim-induced bone pain is unpredictable and refractory to analgesics (Kirshner 2007), though that impression may not be uniformly accepted.

The incidence of bone pain was determined by treatment (pegfilgrastim, filgrastim, or placebo), chemotherapy (taxane-containing or not), cycle, severity, age, and body surface area (BSA).

In studies comparing pegfilgrastim (n=74) and filgrastim (n==7) in pts with AML and NHL, 52% were female, and the mean (SD) age was 50 (15.1) years.

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(PMID = 27963898.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Five pts experienced serious AEs, and there were 2 cases of disease progression to AML: one pt in the QWSC cohort who received romiplostim for 4 weeks and one in the Q2WSC cohort who received romiplostim for 20 weeks.

For pts who completed 8 weeks treatment, 15/23 (65%) achieved a plt response, defined by IWG 2006 criteria, and 14/23 (61%) did not require a plt transfusion during this period.

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(PMID = 27961381.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

: 8528 Background: Classical Hodgkin lymphoma (cHL) is characterized by a minority of neoplastic cells surrounded by a heterogeneous background of non-neoplastic cells.

CD163 expression was assessed immunohistochemically and the degree of intratumoral LAM infiltration was scored semi-quantitatively.

All pts were homogeneously treated with either chemo-radiotherapy (localised disease) or ABVD chemotherapy (advanced disease).

The histological subtypes were: nodular sclerosis (NS)-type I, 167 cases (59 %); NS-type II, 71 (25%); mixed cellularity (MC), 44 (15 %); lymphocyte-rich, lymphocyte-depleted and cHL-NOS, each one case.

Of 253 pts with assessable International Prognostic Score (IPS), 204 had a low-risk (≤ 2) and 49 a high risk (>2) profile.

Furthermore, a high expression of CD163 strongly correlated to stage IV disease (p=0.035), presence of B-symptoms (p=0.008), lymphocytopenia (p=0.003), hypersedimentation (p=0.009).

CONCLUSIONS: In cHL, a high number of intratumoral CD163+ monocytes/macrophages correlates with adverse outcome and with clinical parameters reflecting underlying aggressive disease biology.

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(PMID = 27960903.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Among 5-yr survivors, the impact of changes in therapy on cause-specific late mortality has not been thoroughly assessed.

Cause-specific mortality was categorized as death from recurrence/progression of primary disease, external causes, and non-recurrence/non-external causes (Non-Recur/Ext) (i.e., deaths from health conditions including sequelae of cancer therapy).

No significant improvement in late mortality attributable to Non-Recur/Ext causes was seen.

Additionally, all-cause mortality was significantly lower in more recent eras for 5-year survivors of ALL, AML, Hodgkin, NHL, and CNS tumors, but not neuroblastoma and Ewing's Sarcoma where an increase in cumulative incidence of late mortality was seen in more recent eras.

CONCLUSIONS: All-cause late mortality has improved with more recent eras, attributable to reduced rates of mortality from progression of primary disease (i.e., durable remission).

Importantly, however, efforts to reduce the toxicity of more recent therapies have not produced detectable reduction in mortality attributable to other health conditions including sequelae of cancer therapy (non-Recur/Ext causes of death), which would include death from second malignancy, cardiac and pulmonary conditions.

Worsening late mortality for 5-year survivors of neuroblastoma and Ewing's sarcoma may be due to improved use of salvage therapies that delay, but do not ultimately prevent death.

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(PMID = 27962548.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

: 10043 Background: We previously identified the importance of intact apoptosis signaling for treatment response in pediatric ALL and AML by analyzing two key apoptogenic events, caspase-3 activation and cytochrome c release.

Using a NOD/SCID mouse model for pediatric BCP-ALL we found that short time from transplant to overt leukemia in the recipient mice (short time to leukemia, TTLshort) determines poor patient outcome.

METHODS: In this study we investigated the importance of deficient apoptosis signaling for leukemia engraftment in this model.

CONCLUSIONS: Our finding in the NOD/SCID/huALL model matches our results in pediatric ALL and AML to conclude that the functional integrity of a downstream apoptotic checkpoint is an important feature regulating leukemia biology.

Thus, deficient apoptosis signaling appears to determine rapid engraftment of leukemia cells in the NOD/SCID model in vivo and consequently poor patient outcome.

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(PMID = 27962469.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Incidence of therapy-related leukemia following chemoradiotherapy for esophageal cancer.

METHODS: From July 2000 to March 2008, 348 patients with esophageal squamous cell carcinoma underwent CRT.

RESULTS: Four patients, who achieved CR after CRT, developed leukemia.

Case1, 60-yo-male, developed overt acute myeloid leukemia (AML) from myelodysplastic syndrome 48 months after CRT.

Case2, 64-yo-male, developed AML M0 with t(9;22)(q34;q11) 44 months after CRT.

Case3, 72-yo-male, developed Burkitt leukemia with t(8;14)(q24;q32) 19 months after CRT.

Case4, 65-yo-male, developed myeloid crisis of chronic myelogenous leukemia with complicated abnormalities including t(9;22)(q34;q11) 48 months after CRT.

Case 1 and 3 had localized disease and received single course of neoadjuvant CRT.

Case 2 and 4 had advance disease and received 2 courses of CRT.

All patients eventually died of leukemia.

To this end, atypical cytogenetic abnormalities seen in the present cases give a new insight into the biology of therapy-related leukemia.

Notably, this is the first report presenting the incidence of secondary leukemia by nedaplatin.

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(PMID = 27962759.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia (AML).

: 7015 Background: Mutations of the FLT3 gene (in special internal tandem duplication -ITD) are common in normal karyotype AML (NK-AML) and are associated with shorter relapse free and overall survival (OS).

METHODS: The records of patients (pts) with newly diagnosed AML (from 2003 to 2007) were reviewed.

A Cox model was fit for OS, and non-significant variables were eliminated in a step-down fashion with a p- value cut-off of p = .10.

No difference was found in median OS between FLT3-mutated and FLT3- wild type pts in the good risk group (not reached (NR) vs NR, P = 0.57) nor in the poor risk group (55 vs 24 weeks, P = 0.44).

In intermediate risk, OS was worse in FLT3-ITD positive pts (33 vs 89 weeks, P < 0.0001) but not in FLT3-TKD positive pts (77 vs 70 weeks, P = 0.89).

CONCLUSIONS: In our cohort of pts, FLT3 mutations did not have a prognostic impact in AML with good and poor risk karyotype.

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(PMID = 27961388.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Recently, our group have reported that patients with acute myeloid leukaemia have defective interactions receptor -ligand in NK cells due to a decreasing expression of Natural Cytotoxicity Receptors and it could be used as a evasion mechanism by leukaemia cells.

In ADPC and AIPC NK cells, the expression of NKRi and other NKRa did not differ from healthy donors.

In LPC NK cells, the expression of NKRi and NKRa did not differ from healthy donors.

Is it hormonal therapy or extension of the disease that is responsible of NK cells alterations?

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(PMID = 27963371.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Phase I/II study of idarubicin (Ida), high-dose ara-C, and sorafenib (S) in patients (pts) younger than 65 years with acute myeloid leukemia (AML).

It selectively induces apoptosis in FLT3-mutant human AML cell lines at nM concentrations.

METHODS: Objectives of this study are to determine the tolerability and efficacy of combination of S with chemotherapy.

In the phase I part, pts with relapsed AML were treated with escalating doses of S (400 mg qod, 400 mg daily, 400 mg bid) for 7 days during induction, and 400 mg bid was established as safe.

RESULTS: 10 pts (median age 34, range 21-58) with relapsed AML (median prior therapy 2, range 1-6) were treated in the phase I .

5 pts have relapsed; median CR duration has not been reached, (range; 0.2+ - 10.6+ mo).

CONCLUSIONS: S can be safely combined with IA; it has a high CR rate in frontline therapy of younger pts with AML, in particular those with FLT3 mutations.

Correlative studies confirm potent activity of S against FLT3 signaling.

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(PMID = 27961390.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Phase II study of vorinostat (V) in combination with idarubicin and high-dose cytarabine (IA) as front-line therapy in patients (pts) with high-risk myelodyplsatic syndrome (MDS) or acute myeloid leukemia (AML).

: 7004 Background: Standard induction therapy for pts with AML has not changed over the last 2 decades nor has the outcome of these pts.

We designed a phase II study of V with IA as front-line therapy for MDS/AML.

METHODS: Pts with untreated int-2/high-risk MDS or AML ages 15-65 with adequate liver and renal functions and PS, and EF ≥ 50% were eligible.

3 pts with relapsed/refractory AML were treated in the run-in phase.

8 (47%) had secondary disease.

The median PFS has not been reached.

CONCLUSIONS: The combination of IA and V is safe and active in AML/MDS.

Results will be compared with those of a parallel IA study at MDACC.

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(PMID = 27961376.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A comparative study of single-dose pegfilgrastim versus daily filgrastim in patients with acute myeloid leukemia.

It can be used during induction and consolidation chemotherapy in acute myeloid leukemia (AML).

Few studies addressed the use of pegylated filgrasim in AML.

Safety profile and complete remission status did not differ between the two groups.

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(PMID = 27964003.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Data from each clinical trial supporting overall improvement, duration of improvement, time to AML or death, progression-free survival (PFS), and transfusion independence was assessed.

RESULTS: Patients had IPSS classification scores of intermediate-2 or high-risk (D-0007, 70%; EORTC-06011, 93%; ID03-0180, 66%; DACO-020, 46%) and de novo MDS (D-0007, 87%; EORTC-06011, 88%; ID03-0180, 70%; DACO-020, 89%).

Comparable overall improvement (complete response [CR] + partial response [PR] + hematologic improvement [HI]), time to AML or death, and PFS was observed across all trials (Table).

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(PMID = 27961372.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A randomized trial of anthracycline dose intensification during induction of younger patients with acute myeloid leukemia: Results of Eastern Cooperative Oncology Group study E1900.

: 7003 Background: In younger adults with newly diagnosed acute myeloid leukemia (AML), anthracycline dose intensification during induction may improve complete remission (CR) rates; however, an improvement in overall survival (OS) in a randomized trial has not been demonstrated.

METHODS: Adult patients with previously untreated AML were randomized to receive either SDD (45 mg/m²/d) or HDD (90 mg/m²/d) each for 3days combined with standard-dose cytarabine (100 mg/m²/d) for 7 days by continuous intravenous infusion.

Those achieving a CR were allocated to allogeneic hematopoietic stem cell transplantation (HSCT) or high-dose cytarabine (with or without a single dose of gemtuzumab ozogamicin) prior to autologous HSCT.

There were no differences in patient demographics or disease characteristics between the two groups at presentation.

In younger AML patients a higher dose of anthracycline in induction should be considered the new standard of care.

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(PMID = 27961375.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Improving the molecular risk classification for younger (<60 years) de novo cytogenetically normal acute myeloid leukemia (CN AML) patients (pts).

: 7002 Background: CN AML pts are currently stratified into Low-risk [FLT3-ITD negative (neg)/NPM1 mutated (mut)] and High-risk [FLT3-ITD positive (pos) or NPM1 wild type (wt)] groups (FLT3-ITD/NPM1-only classification).

Here, we assess if adding CEBPA and WT1 mutation and ERG expression testing improves the currently used CN AML molecular risk classification.

METHODS: FLT3, NPM1, CEBPA and WT1 mutations and ERG and BAALC expression were tested at diagnosis in 143 CN AML adults enrolled on CALGB treatment protocols 9621 and 19808.

RESULTS: CALGB Group I (n=56) v Group II (n=87) had more complete remissions (CRs) (P=.005; 96% v 79%), and longer disease-free (DFS; P<.0001; 5 year (y) 69% v 21%) and overall (OS; P<.0001; 5 y 70% v 31%) survival [median follow-up for pts alive 6 y].

In contrast, for the same cohort of pts grouped by the FLT3-ITD/NPM1-only classification, CRs were 94% v 82% and 5 y DFS 59% v 32% and OS 67% v 36% in the Low- v High-risk groups.

CONCLUSIONS: Prognostic classification of younger de novo CN AML pts is improved by adding CEBPA and WT1 mutation and ERG expression testing.

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(PMID = 27961374.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Randomized phase II trial of the nucleolin targeting aptamer AS1411 combined with high-dose cytarabine in relapsed/refractory acute myeloid leukemia (AML).

AS1411 has synergistic effects in combination with cytarabine on AML cell lines in vitro and in vivo.

METHODS: This open-label randomized phase II trial compared AS1411 plus high-dose cytarabine (HiDAC) with HiDAC alone in patients with primary refractory or relapsed AML who had received up to 3 previous lines of chemotherapy.

CONCLUSIONS: Data from this first phase II trial of an aptamer in oncology are encouraging.

The combination of AS1411 at 10 or 40 mg/kg/day with HiDAC appears well tolerated and shows promising signs of activity in patients with relapsed/refractory AML.

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(PMID = 27961391.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Acute myeloid leukemia or myelodysplastic syndrome (AML/MDS) and overall mortality with chemotherapy (CT) and granulocyte colony-stimulating factor (G-CSF): A meta-analysis of randomized controlled trials (RCTs).

: 9524 Background: To evaluate the risk of AML/MDS and overall mortality in patients receiving CT ± G-CSF, a meta-analysis of RCTs were conducted.

Eligibility included RCTs of solid tumor or lymphoma patients randomized to CT ± primary G-CSF support, ≥2 years follow-up and reporting AML/MDS or all second malignancies.

Pre-specified study categories included: a)same dose/schedule, b)dose-dense or c)dose-escalated CT.

Primary outcomes were AML/MDS and mortality.

RR for AML/MDS with CT+G-CSF compared to control was 1.92 [P=.006] with ARD increase of 0.4% [P=.008].

RR for AML/MDS in study categories to receive the same, dose-dense or dose-escalated CT+G-CSF were 1.95 [P=.346], 1.20 [P=.666] and 2.47 [P=.006], respectively.

No differences in estimates of AML/MDS or mortality were observed between industry and non-industry-funded studies.

CONCLUSIONS: Risk of AML/MDS is increased with dose escalated CT+G-CSF.

Dose-dense regimens are associated with the greatest RR reduction in mortality and lowest risk of AML/MDS.

Further research is needed to differentiate any impact of G-CSF on the risk of AML/MDS from that due to increased CT intensity.

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(PMID = 27964513.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Age-specific differences in oncogenic pathway deregulation and chemosensitivity in patients with acute myeloid leukemia: Strategies to maximize response to induction chemotherapy.

: 7013 Background: Despite all the advances made in understanding the poor prognosis of acute myeloid leukemia (AML) in the elderly, the underlying biology at a molecular signaling pathway level has yet to be defined.

METHODS: Clinically annotated, microarray data from 425 patients with newly diagnosed AML from two publicly available datasets GSE1159 and GSE12417 were analyzed.

Standard Kaplan-Meier survival curves were generated using the two-sided log-rank test and individual differences in the probability of oncogenic pathway deregulation between young vs. elderly were analyzed via the non-parametric Mann-Whitney U test and a one-sided p-value ≤ 0.05 was considered statistically significant.

RESULTS: Elderly AML patients had worse OS (median 8.8 months vs. 24.1 months in younger patients; p = 0.001) and EFS (median 7.1 months vs. 15.3 months in younger patients; p < 0.0001).

Older patients were also less sensitive to anthracycline compared to younger AML patients, p < 0.0001.

Unsupervised hierarchical clustering of younger AML patients revealed two clusters and clinically better survival for cluster 1 compared to cluster 2 (high Ras, Src, TNF pathway activation) and the latter were in turn less sensitive to adriamycin.

However, in elderly patients those in cluster 2 also had high Ras, Src, TNF but this did not translate into differences in survival or chemotherapy sensitivity.

CONCLUSIONS: AML arising in the elderly represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that contributes to poor survival and resistance to adriamycin.

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(PMID = 27961386.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] The pharmacokinetics of azacitidine following subcutaneous treatment in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML).

: 7087 Background: 5-azacitidine (AZA), through its effects on DNA metabolism, gene expression, and cell differentiation, has proven beneficial in treatment of MDS and AML and AZA therapy significantly increases survival in higher-risk MDS and AML compared to conventional care.

Few studies have evaluated the pharmacokinetics (PK) of AZA and the renal elimination of AZA has not been previously published to our knowledge.

METHODS: Adult patients with MDS or AML and ECOG status 0-2 were treated with 7 consecutive daily SC doses of 75 mg/m² AZA during their first treatment cycle.

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(PMID = 27961481.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Importance of genetic heterogeneity in curing adult acute leukemia (AL).

Publication of the French-American-British classification 34 years ago resulted in acceptance that morphology and cytochemistry separated AL into two different diseases, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), that required separate treatment.

During the next 15-20 years the importance of cytogenetics in dissecting ALL and AML into entities requiring different therapies became widely accepted, resulting in 2001 in their first incorporation into the World Health Organization (WHO) classification of AL.

The most striking example of increased curability of AL is acute promyelocytic leukemia, in which targeted therapy combined with chemotherapy has increased survival from a 2-week median to an 80% cure rate.

Recognition of increased sensitivity of a genetic subtype of AML to high-dose cytarabine (HiDAC) has increased the cure rate of core-binding factor (CBF) AML from <10%-25% to 55%-60%.

Recent discovery of the adverse impact of KIT mutations in CBF AML may allow the addition of tyrosine kinase inhibitors to HiDAC to substantially further increase cure.

Among adult de novo AML 40%-45% are cytogenetically normal (CN); the striking molecular heterogeneity of CN-AML is now being recognized and promises to allow individualized approaches that improve substantially upon the current cure rate of 40%.

New approaches to studying the leukemia genome and epigenome should improve our understanding of AL heterogeneity, identify new therapeutic targets, and allow the cure of most patients.

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(PMID = 27962366.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A functional procedure using fresh samples to select patients with acute myeloid leukemia prior to treatment with the novel targeted cytotoxic agent F14512.

This system can be viewed as a suitable molecular gate to deliver selectively polyamine-based molecules into cancer cells.

This study was undertaken to investigate the potential of N-methyl-spermine-NBD, a proprietary fluorescent polyamine conjugate, designed to select patients with PTS-positive leukemic cells.

METHODS: The uptake of this probe was first measured by flow cytometry in a panel of human leukemia cell lines.

RESULTS: Data showed that high level of fluorescence was detected in F14512 -sensitive cancer cell lines whereas leukemia cells responding poorly to F14512 generally exhibited very low levels of PTS.

A panel of 50 fresh human acute myeloid leukemia samples showed a larger inter-individual variation and, interestingly, incorporation of the fluorescent probe was generally higher in leukemia blasts than in lymphocytes.

CONCLUSIONS: The data show that the PTS can easily be evaluated in fresh AML blasts and provides a simple means to identify patients for future enrollment in clinical trials with F14512.

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(PMID = 27963178.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Phase I trial of laromustine in combination with infusional ara-C in elderly patients over age 60 with newly diagnosed AML or high-grade MDS.

: 7054 Background: Laromustine is a novel sulfonylhydrazine-alkylating agent with activity in acute myeloid leukemia (AML).

Laromustine in phase I and II trials shows activity in patients with relapsed/refractory leukemia (1) and elderly patients with new AML (2).

Based on this data, a phase I study to evaluate the safety and efficacy of combining escalating doses of laromustine with infusional ara-C in AML and MDS patients over 60.

METHODS: Laromustine 300 mg/m2 (cohort 1, n = 6), 400 mg/m2 (cohort 2, n = 5) and 500 mg/m2 (cohort 3) was administered by IV infusion over 1 hour on day 1 in combination with ara-C 100 mg/m2/day as a continuous infusion for 7 days.

Patients achieving CR after induction therapy were offered up to 2 cycles of consolidation therapy for a maximum cumulative laromustine dose of 1,000 mg/m2.

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(PMID = 27961420.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Cytogenetic abnormalities in mesenchymal stem cells in chronic lymphocytic leukemia (CLL) patients and normal subjects.

: e22002 Background: Mesenchymal stem cells (MSC) residing in the marrow support hematopoiesis and protect cancer cells from undergoing cell death induced by chemotherapy.

Recent reports have described clonal cytogenetic abnormalities in the MSC of acute myeloid leukemia and myelodysplastic syndrome patients.

After 3-4 non-stimulated cell culture passages, the karyotype was analyzed in 5-40 metaphase cells from each subject Abnormalities were considered clonal using the accepted convention of the same chromosomal gain or rearrangement in 2 or more cells or loss in at least 3 cells.

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(PMID = 27963169.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A phase I trial of adoptive transfer of allogeneic natural killer (NK) cells in patients (pts) with advanced non-small cell lung cancer (NSCLC).

: 3001 Background: HLA-mismatched NK cells have been found effective in acute myeloid leukemia pts.

RESULTS: Between 11/2007 and 11/2008 16 pts (performance status 0-1) were enrolled; 1 pt had rapid disease progression before treatment.

Pts characteristics: M/F 12/4; histology: adenocarcinoma/squamous cell carcinoma 13/3; stage IIIb/IV 2/14; 1^st/2^nd line treatment 13/3; median age 64 years (range, 50-71).

With a median follow-up of 6 months (range, 1-14) 3 pts with partial response and 7 pts with disease stabilization were recorded.

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(PMID = 27962051.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] NPM1 mutations as an independent prognosticator for older cytogenetically normal acute myeloid leukemia (CN AML).

: 7000 Background: In younger CN AML without FLT3-ITD, NPM1 mutations predict favorable outcome.

METHODS: Pretreatment marrow was studied in 189 older CN AML pts [median age 69 y (60 - 83 y); 162 de novo & 27 secondary (s; prior hematologic disorders) cases] enrolled on CALGB 9720 (n=106) & 10201 (n=83).

RESULTS: In de novo CN AML, NPM1 mutated (NPM1mut) pts (54%) had more CRs (85% v 45%, P<.0001) & longer relapse-free (RFS) (P=.02; 3 y rates 23% v 10%) & overall survival (OS) (P<.0001; 3 y 34% v 7%) than NPM1 wild-type (NPM1wt) pts.

CONCLUSIONS: NPM1 mutations independently predict better outcome in older CN AML.

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(PMID = 27963957.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Updated remission duration and survival results of single-agent clofarabine in previously untreated older adult patients with acute myelogenous leukemia (AML) unlikely to benefit from standard induction chemotherapy due to unfavorable baseline risk factor(s).

We now report updated duration of remission (DOR), disease-free survival (DFS), and overall survival (OS).

METHODS: Single arm, multi-center, phase II, open-label, 2-stage study of patients with untreated AML, ≥60 years old, and at least one adverse prognostic factor: age ≥70 years, antecedent hematologic disorder (AHD), PS = 2, and/or intermediate/unfavorable risk karyotype.

Clofarabine (CLO) administered days 1-5 at 30 mg/m² during induction and 20 mg/m² during re-induction/consolidation for maximum 6 cycles.

Median DOR (censored at alternative therapy) for CR/CRp was 56 weeks (95% CI, 33 weeks - not yet estimable [n/e]) and for CR 65 weeks (95% CI, 41 weeks - n/e).

Median DFS (not censored at alternative therapy) for CR/CRp was 34 weeks (95% CI, 24 - 65 weeks).

CONCLUSIONS: These data expand on the previously reported efficacy and safety data of single agent CLO in adult AML.

These results suggest that single agent CLO is an effective and tolerable treatment option for older adult patients with untreated AML and 1 or more unfavorable baseline prognostic factor(s).

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(PMID = 27961436.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Phase I dose escalation trial of sorafenib as a single agent for adults with relapsed and refractory acute leukemias.

Based on preclinical activity in FLT3 mutant AML, sorafenib was studied in refractory acute leukemia.

METHODS: The primary objective was to determine the safety and tolerability of sorafenib in refractory acute leukemias.

RESULTS: Fifteen patients (13 = AML, 2 = ALL) were enrolled (ages 37-85) and treated on three dosing schedules (400 mg BID x 14 d, 400 mg BID x 21 days, 600 mg BID x 21days) of single agent sorafenib.

No patients met criteria for complete or partial response, but 11 of 15 (73%) patients experienced stable disease as best response, with 6 showing a reduction in bone marrow blasts after only one cycle, half of who experienced a >50% reduction in bone marrow blasts.

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(PMID = 27961441.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Here we report the results of a CTEP-sponsored phase I trial of SJG-136 administered on a daily x 5 schedule in pts with relapsed or refractory (R/R) leukemias.

METHODS: Previously treated pts with R/R acute leukemias (AML, ALL, high risk MDS, CML blast phase) or R/R CLL with adequate organ function and ECOG performance status of ≤ 2 were eligible for the study.

Thirteen (81%) pts had R/R AML, and 3 (19%) had R/R ALL of which 5 (31%) had diploid and 6 (38%) had adverse cytogenetics.

Other non-dose limiting toxicities included nausea, dyspnea, fatigue, bloating, and insomnia.

One pt had a PR, 8 pts had stable disease, and 6 had progression.

CONCLUSIONS: SJG-136 is safe and active in patients with advanced leukemias.

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(PMID = 27961262.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Amplification of RUNX1 gene in two new cases of childhood B-cell precursor acute lymphoblastic leukemia: A case report.

: e21000 Background: Chromosome abnormalities of leukemia cells have important prognostic significance in childhood acute lymphoblastic leukemia (ALL).

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) ETV6/RUNX1 (alias TEL/AML1) is most frequent i.e.

We report two new cases with Pre B- cell ALL without ETV6/RUNX1 rearrangement, showing amplification of AML1 gene detected by FISH analysis.

RESULTS: In first case a 3-year girl with four copies of AML (RUNX1) gene were observed in 95% of the cell with normal two copies of TEL (ETV6) gene in both interphase and metaphase FISH.

In second case, a 4-year male we observed four copies of AML and two copies of TEL gene in more than 80% of cells.

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(PMID = 27960689.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Promoter DNA methylation of CD10 in infant acute lymphoblastic leukemia with MLL/AF4 fusion gene.

While CD10 negativity reflects an earlier stage of B-cell development, complete IgH gene rearrangements (VDJ_H) show more mature IgH status.

METHODS: CD10-negative infant ALL with MLL/AF4, CD10-positive infant ALL with germ-line MLL, CD10-positive pre-B ALL cell line, infant AML (M5) with MLL/AF9 and pediatric AML (M2) with AML1/ETO were analyzed for VDJ_H status and methylation of CD10 gene promoters.

In contrast, none or a few of the CpG dinucleotides were methylated in the CD10-positive ALL, AML (M5) with MLL/AF9 or AML (M2) with AML1/ETO.

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(PMID = 27962471.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A phase I study of the anti-natural killer inhibitory receptor (KIR) monoclonal antibody (1-7F9, IPH2101) in elderly patients with acute myeloid leukemia (AML).

: 3015 Background: The outcome of the majority of patients with AML remains poor, especially in the oldest patients.

Allogeneic SCT is a curative approach for AML.

In some models, it has been shown that KIR mismatch is important for the anti-leukemic effect of the graft, most probably through unleashed NK cells towards AML blasts, as suggested by enhanced in vitro NK lytic activity of KIR-HLA mismatched donor NK against recipient blasts.

We present the results of the first-in-human phase I trial of this agent in patients with AML in complete remission (CR).

METHODS: Patients aged 60-80 years with non promyelocytic AML in first CR following induction and 1-6 cycles of consolidation chemotherapy, normal renal, and hepatic functions, KIR-expression on patient NK-cells and who signed informed consent were eligible.Dose escalation (0.0003, 0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg) was studied using a 3+3 scheme.

As expected for an IgG4, NK cell numbers were unaffected by the treatment.

Upregulation of CD69 on NK cells and concomitant increases in TNF and MIP1b circulating cytokines were observed in some patients at the highest doses (0.075, 0.1, 0.3 mg/kg) but a dose dependency has not been reached yet.

At the 0.3mg/kg dose, MTD has not been reached, but a one week receptor blockade and signs of NK activation were observed.

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(PMID = 27962059.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A phase II study of voreloxin as single agent therapy for elderly patients (pts) with newly diagnosed acute myeloid leukemia (AML).

Interim results of REVEAL-1, a phase II study of single agent voreloxin in newly diagnosed elderly AML pts, are reported.

Eligibility: newly diagnosed AML (de novo or secondary AML), pts age ≥ 60 and ≥ 1 additional adverse risk factor (age ≥ 70, secondary AML, intermediate or unfavorable cytogenetics, or PS 2).

Median duration of remission has not been reached.

Voreloxin PK were similar to those in an earlier single agent phase I study in relapsed/refractory AML.

Ex-vivo sensitivity did not predict clinical response.

CONCLUSIONS: In REVEAL-1, voreloxin demonstrates clinical activity with 2 dosing schedules in previously untreated elderly (age ≥ 60) patients with AML who are unlikely to benefit from standard chemotherapy.

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(PMID = 27961427.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Clinical activity has been observed in ovarian cancer and AML.

METHODS: Pts may have received ≤ 3 prior platinum regimens plus one additional non-platinum regimen.

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(PMID = 27962535.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

METHODS: Between January 1990 and December 2006, 94 children (53 male, 41 female) with a median age of 13 (5-16) years and a histopathologic diagnosis of osteosarcoma were treated with an institutional chemotherapy regimen comprising of 6 courses (3 pre-, 3 postoperatively) of epirubicin (90 mg/m2), cisplatin(100 mg/m2), and ifosfamide(2 g/m2 × 3 days) every 3 weeks.

26 patients died; 20 of disease, 5 of toxicity, and 1 of second malignancy (acute myeloid leukemia).

5 and 10 year EFS for nonmetastatic patients was superior to those with metastatic disease [62.4 % (95% CI 49.9-79.9 %) vs. 6.9 % (95% CI 0-19.9 %)) (p<0.001).

10 year OS for 18 patients (11 metastatic at diagnosis) who progressed during preoperative chemotherapy was 13 % vs. 75 % for those who didnot have progressive disease (p< 0.001).

Histologic response (<90 percent necrosis vs ≥90 percent) significantly correlated with 5 year EFS (31 % vs 67.6 %, p=0.023) but not with OS (57.7 % vs 76.5 %, p=0.13).

CONCLUSIONS: The presence of metastases at diagnosis was the most significant characteristic influencing outcome.

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(PMID = 27962466.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Phase I study of pemetrexed in patients with relapsed or refractory acute leukemia or lymphoid blast phase chronic myelogenous leukemia.

The purpose of this phase I trial was to define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of pemetrexed given with vitamin supplementation to patients with relapsed or refractory leukemia.

METHODS: Patients ≥15 years of age were enrolled with relapsed or refractory leukemia, Eastern Cooperative Oncology Group performance status ≤2, adequate renal and hepatic function, and life expectancy of ≥6 weeks.

RESULTS: Twenty-two patients entered the trial; median age was 50 years (range: 18-75); 15 patients had acute myeloid leukemia and 7 patients had acute lymphocytic leukemia (ALL).

Two patients were ineligible and did not receive study drug.

At the 1,200 and 1,500 mg/m² dose levels, 1 patient per level developed grade (G) 3-4 liver enzyme and bilirubin elevations attributed to sepsis.

At the 3,600 mg/m² dose level, 1 patient had a G3 liver enzyme elevation and 2 added patients also had G3 liver toxicity.

In addition, 2 patients in the 3,600 mg/m² cohort developed G2 liver abnormalities.

Based on liver toxicities, the DLT dose level was established at 3,600 mg/m².

Two patients died during the study due to disease progression and 1 patient discontinued due to a subdural hematoma of unknown cause.

PK and PD data were not available for this report.

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(PMID = 27961463.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Age at diagnosis does not adversely affect outcome in patients with Hodgkin's Disease (HD) after autologous transplantation.

: e19507 Background: Age at diagnosis is a poor prognostic factor for overall survival after standard therapy for HD.

Whether older age is a prognostic factor for outcome after autologous transplantation is not known.

We sought to evaluate the effect of older age at diagnosis on transplant outcome.

Seventy two patients (29%) were older than 40 years of age at the time of initial diagnosis.

At transplantation, 63 (25%) were in complete remission (CR); 148 (60%) were in partial remission (PR); and 37 (15%) had stable (SD) or progressive disease (PD).

Peripheral blood stem cells were used as stem cell source in 241 (97%) patients.

The cumulative incidence of non-relapse mortality at 1 year was 1.6%.

The cumulative incidence of secondary MDS or AML was 8%.

In univariate analysis, disease status (p<0.001) and number of prior chemotherapy regimens (p=0.007) were the only factors significantly predicting OS.

Disease status was the only factor significant (p<0.01) in a multivariate analysis with a hazard ratio of 2.7 (1.1-6.9) and 9.2 (3.4-25) for patients in PR, and SD/PD respectively (CR reference group).

Age at diagnosis was not a significant factor (see table ).

CONCLUSIONS: High-dose chemotherapy and autologous transplantation abrogate the adverse impact of age at diagnosis in patients with HD.

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(PMID = 27960864.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Febrile neutropenia during acute myeloid leukemia therapy: Single institution experience from a developing country.

: e18000 Background: Febrile neutropenia poses a major challenge during treatment of acute myeloid leukaemia (AML).

METHODS: Episodes of febrile neutropenia in 104 consecutive patients of AML admitted to the medical oncology ward between May 2001 and December 2006 were studied.

RESULTS: 402 febrile episodes including 363 episodes of febrile neutropenia (180 in induction, 183 in consolidation) and 39 non-neutropenic episodes (18 in induction, 21 in consolidation) occurred.

Prompt and proper institution of antibiotics and antifungals besides considering alternative diagnosis peculiar to the region (e.g. tuberculosis, malaria) may aid in better management.

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(PMID = 27964014.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

: 7066 Background: There continues to be no effective second-line therapy for refractory AML or ALL and the cure rate with current therapy has not significantly improved in decades.

The first-line therapy for adult AML has remained the same 7 + 3 that it was a generation ago.

The MTD was determined to be 150 mg/m2/day for 3 days.

We are now testing it in a phase I study in children and young adults with refractory ALL or AML.

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(PMID = 27961442.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Clinical, pharmacokinetic (PK), and pharmacodynamic findings from a phase I trial of an Eg5 inhibitor (AZD4877) in patients with refractory acute myeloid leukemia (AML).

Eg5 inhibition is thus specific for dividing cells, resulting in monoastral mitotic spindles (monoasters) and apoptotic cell death.

Preclinically, hematologic tumor cell lines were generally more sensitive to AZD4877 than those derived from solid tumors.

The T_1/2 of AZD4877 ranged from 26 to 42 hr; PK were linear and drug levels non-cumulative.

Myelosuppression, the dose limiting toxicity (DLT) in solid tumor studies, was not considered a DLT in this trial.

Preliminary results suggest possible clinical activity in AML.

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(PMID = 27961757.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Outpatient versus inpatient autologous stem cell transplantation for malignant hematologic disorders.

: 7042 Background: High-dose chemotherapy with autologous stem cell support is utilized for the treatment of a variety of malignancies including Hodgkin/non-Hodgkins lymphoma and acute leukemias.

The aim of this study was to compare the time of engraftment and mortality rate and cost of neutropenic treatment in outpatient versus inpatient autologous stem cell transplantation (SCT).

METHODS: 9 outpatients (5 HL, 2 NHL, and 2 AML) were compared with 32 inpatients (15 HL, 8 NHL, and 9 AML; for whom the outpatient facilities were not ready) from May 2008 to December 2008.

They received conditioning regimen (CEAM for NHL and HL, busulfan and etoposide for AML) and stem cell infusion in hospital.

The day after SCT, outpatient group were discharged and followed by outpatient SCT team, and to be re-hospitalized in case of febrile neutropenia, after sepsis workup and performing chest x-ray, they were received the first dose of antibiotic in hospital and treatment continued in home.

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(PMID = 27961405.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Prognostic significance of leukopenia at the time of diagnosis in acute myeloid leukemia (AML).

: 7070 Background: In contrast to the poor prognosis associated with hyperleukocytosis, the prognostic significance of leukopenia at the time of diagnosis of AML is unknown.

METHODS: Single institution retrospective analysis of 225 consecutive, newly diagnosed AML patients (pts), homogeneously treated between July 1996 and February 2005; and divided into 2 groups based on presenting WBC: < 2,000/uL (30) and > 2,000/uL (195).

Simultaneously obtained peripheral blood and marrow blasts were analyzed for cell surface expression of CD34, cKit, CXCR4, PCAM, VLA-2, VLA-3, VLA-4, VLA-5, and FLT3 using flow cytometry.

RESULTS: Patients' characteristics (gender, secondary vs. de novo, and cytogenetic [CTG] risk) were comparable between the 2 groups.

Leukopenic AML pts were older (median 56 vs. 53 years, p = 0.02), and had lower induction complete remission [CR] rates: 63% vs. 81% (p = 0.03) by univariate analysis.

Induction mortality was 0% for leukopenic and 5% for non-leukopenic pts.

In primary refractory pts, median survival was longer for leukopenic (11) vs. non-leukopenic (34) pts: 137 vs. 81 d (p = 0.026).

Event-free (EFS), disease-free (DFS), and overall survivals (OS) were lower in the leukopenic group: 12 vs. 14; 14 vs. 17; and 17 vs. 19 mos, respectively; but did not reach statistical significance.

The level of expression of cell surface adhesion molecules on blood and marrow blasts was comparable for the 2 groups.

CONCLUSIONS: AML pts presenting with leukopenia have comparable outcomes to those presenting with normal or high WBC despite a lower likelihood of achieving remission.

Leukopenic AML did not have over-expression of cell surface adhesion molecules.

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(PMID = 27961453.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

METHODS: Between January 2007 and December 2008, bone marrow samples for morphologic analysis, FISH and classical cytogenetics were obtained from 49 pts. (30 male; 19 female, mean age 62) with unresectable or metastatic GIST before and during treatment with 400 mg/d of imatinib.

For pts. with progressive disease (15 pts.) or exon 9 mutant disease (5 pts.

All pathologic material was reviewed to identify pts. with MDS or AML according to the WHO classification.

One patient developed a RAEB-1 with monosomy 7 which rapidly transformed into AML.

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(PMID = 27963910.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The PI3K p110δ isoform is highly expressed in cells of hematopoietic origin and plays a key role in B cell maturation and function.

In vitro studies of 0.1 to 10 μM CAL-101 showed inhibition of pAKT expression and/or apoptotic effects against primary chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) cells and against a range of leukemia and lymphoma cell lines.

METHODS: In an ongoing phase 1 dose escalation study in sequential cohorts of 3 patients with relapsed/refractory CLL or select B-cell non-Hodgkin's lymphoma, CAL-101 is administered orally twice daily for 28 days per cycle.

Two of 6 patients attained partial response and 4 have stable disease.

Partial responses were observed after 2 cycles of 50 mg in a patient with mantle cell lymphoma with 6 prior therapies, and after 1 cycle of 100 mg in a patient with follicular lymphoma with 6 prior therapies, including autologous stem cell transplant.

Disease specific cohort expansion will occur at the maximally tolerated dose, and patients with AML will be added.

CONCLUSIONS: Early results from a phase 1 study of the oral PI3K p110δ inhibitor CAL-101 show that it is well tolerated and has preliminary clinical activity in patients with B-cell malignancies.

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(PMID = 27961357.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

: 2053 Background: Secondary acute myeloid leukemia (AML) is reported to occur in 3%-10% of patients treated with alkylating agents for Hodgkin's lymphoma, non-Hodgkin's lymphoma, ovarian cancer, breast cancer, and multiple myeloma.

The incidence of secondary AML is greatest at 5-10 years after treatment, and AML often follows myelodysplastic syndrome (MDS).

Among these patients, we identified 140 cases that we labeled as major hematologic adverse events: agranulocytosis (8 cases), aplasia (42), aplastic anemia (52), leukemia (26), MDS (6), and lymphoma (6).

Risk of leukemia/MDS from our review may also be significant, but length of follow-up is insufficient and the real risk is likely still unknown.

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(PMID = 27964671.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

METHODS: We investigated the outcomes of pts with RI and MDS, chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML) receiving therapy with HA.

We used the International Working Group criteria to evaluate the response rates.

RESULTS: Forty-two pts with sCr ≥ 1.5 mg/dL (including 17 with MDS, 16 with AML, and 9 with CMML) were treated with DAC or 5AZA alone or in combination with other agents (primarily histone deacetylase inhibitors).

The incidence of complications, DA, and the response rate were not significantly different for pts with sCr > 2.0 mg/dL.

CONCLUSIONS: The use of HA is well tolerated in pts with MDS and AML and RI who achieved comparable OR rates to those without RI.

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(PMID = 27961273.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Pretransplant comorbidity as an outcome predictor in adult patients younger than 60 years of age receiving standard induction chemotherapy for de novo acute myeloid leukemia.

: 7055 Background: Comorbidity has been evaluated as an outcome predictor in elderly patients receiving induction chemotherapy for acute myeloid leukemia (AML) as well as in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for various hematologic disorders.

In this single-institute retrospective study, we investigated the prognostic significance of comorbidity in younger AML patients.

METHODS: A total of 276 patients, aged 14 to 59 years, who received standard induction chemotherapy consisting of cytarabine plus daunorubicin or idarubicin for de novo AML excluding M3 subtype between 2000 and 2007 were included.

Pre-treatment comorbidity score, assessed by the HCT specific comorbidity index (HCT-CI), was calculated using clinico- pathologic data, which were retrieved from Asan Medical Center Leukemia Registry Database.

RESULTS: In the univariate analyses, the HCT-CI score was not a significant prognostic factor for induction of complete remission (CR), whereas survival outcomes such as overall survival (OS), relapse-free survival (RFS) and event-free survival (EFS) were significantly different according to the HCT-CI scores (Table).

The multivariate models showed that the HCT-CI score was an independent prognostic factor for EFS (P=0.044), but not for OS (P=0.301) and RFS (P=0.119).

CONCLUSIONS: Pre-treatment comorbidity may provide additional prognostic information over established prognostic factors in patients younger than 60 years of age receiving standard induction chemotherapy for de novo AML.

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(PMID = 27961421.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A randomized phase II study of sapacitabine, an oral nucleoside analogue, in elderly patients with AML previously untreated or in first relapse or previously treated MDS.

: 7021 Background: Sapacitabine is a novel nucleoside analogue with a unique ability to cause irreparable single-strand DNA breaks and induce G2 cell cycle arrest.

It is orally administered and has demonstrated promising anti-leukemic activity against relapsed or refractory AML and MDS in a phase 1 trial.

METHODS: Eligible patients must be ≥70 years with AML previously untreated or in first relapse or ≥60 years with MDS previously treated with hypomethylating agents.

The planned sample size is 60 AML patients and 60 MDS patients.

RESULTS: As of December 2008, 60 AML and 13 MDS patients were enrolled and had ≥ 30 days of follow-up.

Preliminary efficacy data were available for the AML stratum.

Eight deaths of all causes occurred within 30 days of randomization and all were in the AML stratum (13%).

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(PMID = 27961383.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] MicroRNA 181a (miR-181a) expression as a prognosticator in cytogenetically normal acute myeloid leukemia (CN AML).

: 7001 Background: We showed recently that CEBPA mutations (mut) in CN AML are associated with better outcome and a unique microRNA expression profile, including miR-181a upregulation.

METHODS: We analyzed 187 de novo CN AML adult patients (pts) aged <60 years (y; median 45) similarly treated on CALGB 9621 and 19808.

Of these, 122 had molecular high risk [FLT3-ITD or NPM1 wild type (wt)] and 65 low risk (no FLT3-ITD, NPM1 mut) CN AML.

The mean of 2 miR-181a probe log intensities was used as a continuous variable for analyses.

RESULTS: Higher miR-181a levels (miR-181a↑) were associated with CEBPA mut, NPM1 wt, no FLT3-TKD, lower ERG expression, higher %FAB M1/M2, lower WBC and age, higher blood blasts, and lower % gum hypertrophy. miR-181a↑ tended to associate with more complete remissions (CRs; p = .07) and significantly associated with longer disease-free (DFS; p = .05) and overall (OS; p = .01) survival (median follow-up 6.5 y for pts alive).

CONCLUSIONS: miR-181a expression is a prognostic marker in CN AML, mainly in the molecular high risk group, where it predicts outcome independently of other variables including CEBPA mutations.

As miR-181a↑ confer better treatment response, novel approaches increasing miR-181a levels might benefit not only CN but also other AML pts.

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(PMID = 27961373.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A phase II study with CP-4055 in patients with second salvage AML.

: 7047 Background: CP-4055 (cytarabine 5'-elaidic acid ester) is a novel derivative of cytarabine, independent of nucleoside transporters to enter the cell.

The aim of this study was to assess efficacy and safety of CP-4055 when given as second salvage therapy to patients (pts) with acute myeloid leukemia (AML).

METHODS: Adult pts who received two previous chemotherapy regimens and who had refractory/relapsed AML (CR after first salvage therapy lasting less than 6 months) were enrolled.

6 pts had previous transplant, the majority of the pts had previous ara-C based therapy, 12 pts had not obtained CR1 or CR2.

Only 1 pt did not receive d1-5 dosing.

Most frequently reported related AE ≥ grade 3 (CTCAE v3.0) were myelosuppression, abdominal pain, colitis, diarrhoea, nausea, fatigue, liver function test (LFT) elevation.

Clinical activity (IWG criteria for AML), 2 CR (1 with no CR1 or CR2), and 1 CRp (CR rate 15%), were reported.

CONCLUSIONS: CP-4055 given as second salvage therapy to AML pts show manageable toxicity when administered at 2,000 mg/m²/d, 24 h CIV, in a d1-5 q3w schedule.

Clinical activity (2 CR and 1 CRp) has been reported among the first 20 late stage AML pts.

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(PMID = 27961426.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

CONCLUSIONS: Despite reduced induction chemotherapy prior to and CONS after tandem melphalan (200mg/m2)-based autotransplants from 4 in TT2 to 2 in TT3, overall and persistent MDS-CA increased significantly in TT3.

Clinical MDS and AML were rarely observed and a full account of hematopathologic findings will be presented.

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(PMID = 27962291.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Interim results of protracted low doses of temozolomide in high-risk acute myeloid leukemia.

: 7052 Background: High treatment-related mortality and low response rates often discourage elderly patients with acute myeloid leukemia from receiving treatment.

METHODS: Phase II clinical trial of tailored temozolomide therapy to high-risk AML patients according to AGAT methylation promoter status.

Patients demonstrating evidence of AGAT promoter methylation were stratified to conventional doses of temozolomide at 200 mg/m2 orally x 7 days.

Patients demonstrating lack of AGAT promoter methylation (unmethylated) received protracted doses of temozolomide (100 mg/m2 orally x 14 days) followed by conventional doses of temozolomide.

De novo AML was diagnosed in eight patients and five patients had s-AML.

Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias.

Seven patients have died from disease progression, while two patients died of neutropenic sepsis (early deaths).

CONCLUSIONS: These preliminary results suggest that temozolomide therapy may be individually tailored to elderly patients with AML according to AGAT promoter status.

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(PMID = 27961417.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Phase Ib/II pharmacokinetic/pharmacodynamic (PK/PD) study of combination voreloxin and cytarabine in relapsed or refractory AML patients.

Clinical activity is observed in ovarian cancer and AML.

Interim results from a phase Ib/II study in relapsed or refractory AML are reported.

METHODS: Dose-escalation in relapsed/refractory AML patients (pts) with ≤ 3 prior induction regimens; phase II expansion in first-relapse pts (CR1 ≥ 3 months) at MTD.

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(PMID = 27961377.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Disease distribution included ALL(80%), AML(5%), NHL(5%), neuroblastoma (5%) and RMS (5%).

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(PMID = 27962033.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Etoposide and mitoxantrone in newly diagnosed acute myeloid leukemia patients with persistent leukemia after a course of induction therapy with cytarabine and idarubicin.

: 7073 Background: The goal of induction chemotherapy in acute myeloid leukemia (AML) is complete remission with restoration of normal bone marrow.

If residual leukemia is present after the first course of induction therapy, patients receive a second course identical to the first or receive a non-cross resistant antileukemic regimen.

METHODS: In a retrospective study of adult patients with newly-diagnosed AML treated at the University of Pittsburgh Cancer Institute between December 2002 and May 2008, we evaluated the efficacy and toxicity of mitoxantrone (10 mg/m²/d) and etoposide (100 mg/m²/d), both administered intravenously within 5 days as second course therapy of patients not responding to first-course induction therapy with cytarabine and idarubicin.

RESULTS: 74 AML patients (mean age 56 years, range: 18-73 years) completed treatment with etoposide and mitoxantrone; 29 (39%) achieved CR.

Lower CR rate was associated with unfavorable cytogenetic risk status at diagnosis and higher percent blasts prior to treatment with mitoxantrone and etoposide.

CONCLUSIONS: Our study suggests that the combination of etoposide and mitoxantorne is an active and well-tolerated regimen as second-course therapy in newly diagnosed AML patients who have persistent leukemia after a first course of induction therapy with cytarabine and idarubicin.

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(PMID = 27961456.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Inclusion criteria were diagnosis of hematolymphoid malignancy, neutropenic febrile episode secondary to chemotherapy or during induction therapy of acute leukemia and more than 18 years of age All patients were risk stratified, hospitalized and treated with broad-spectrum, empiric, intravenous antibiotic therapy until recovery or outcome of the event.

We subsequently analyzed the subset of Acute Myeloid Leukemia (AML) patients as they were the majority comprising of 62/81 episodes.

The subset of AML patients risk stratified according to MASCC risk index showed sensitivity, specificity, PPV, NPV and accuracy of 71%, 25.5%, 11%, 87.5%, 31% respectively.

This trend is also seen in the subset analysis of AML patients.

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(PMID = 27961676.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Effect of bexarotene on platelet counts in patients undergoing cancer treatment: An analysis of clinical trials in lung cancer and leukemia.

: e20533 Background: Bexarotene (Bex) is an oral retinoid X receptor agonist with activity against cutaneous T cell lymphoma and currently under investigation for other malignancies.

In patients receiving this agent for acute myeloid leukemia (AML), we noted increases in platelet counts.

METHODS: We analyzed platelet count data from 3 Bex clinical trials encompassing non-small cell lung cancer (NSCLC) and AML.

Similar findings were seen in a phase I monotherapy trial in AML where 5/18 (28%) patients achieved platelet transfusion independence with peak platelet counts of 40-91 K/uL.

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(PMID = 27960979.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Population pharmacokinetic (PK) analysis of ABT-869 in solid tumors and acute myelogenous leukemia (AML) patients.

The objectives of this analysis were to understand the population pharmacokinetics of ABT-869 and explore the effect of several demographic/disease state covariates influencing ABT-869 disposition.

METHODS: A population PK analysis of 181 patients (pts) enrolled in two phase 1 (multiple types of solid tumors and AML) and three phase 2 monotherapy studies (non-small cell lung cancer, hepatocellular carcinoma [HCC] and renal cell carcinoma) was conducted.

Available plasma concentrations obtained after intensive and sparse pre-dose PK sampling were analyzed by population PK using the non linear mixed effects modeling (NONMEM) approach.

Potential covariates including body weight, body surface area (BSA), age, sex, creatinine clearance (CrCL) and disease state (HCC vs. non-HCC pts) were tested.

Oral clearance (CL/F) was not affected by body weight (range 35-177 kg); however, apparent volume of distribution (V/F) increased by 6L per 0.1 mg/m² increase in BSA.

CrCL (39.9-290.3 ml/min) was not a significant covariate on V/F and CL/F suggesting renally impaired pts do not require a different dose/dosing regimen.

Race and impaired renal function does not appear to alter PK.

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(PMID = 27961681.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A medical decision tree for the prophylaxis (P) and treatment (T) of tumor lysis syndrome (TLS): An international TLS consensus panel.

METHODS: We convened an international panel (N = 17) of experts in pediatric and adult hematological malignancies and solid tumors (ST) to develop a medical decision tree for the P and T of TLS based on the risk classification (low, medium, high) and management recommendations of Coiffier et al (J Clin Oncol.

2008) Results: Patients without evidence of LTLS were assigned to either low-risk disease (LRD), medium-risk (MRD), or high-risk (HRD).

Risk factors included pathological classification stage, bulk, disease burden (WBC/LDH) and renal impairment/involvement.

HRD was assigned to patients with either B-ALL, ALL/AML ≥100K/mm³, BL/LL stage III/IV, and/or high LDH, DLBCL/PTCL/MCL/ATL with bulky and elevated LDH and patients with MRD with renal impairment/involvement.

MRD consisted of ALL ≤100K/mm³, AML 25-100K/mm³, BL/LL stage I/II and low LDH, childhood ALCL, DLBCL/PTCL/MCL/ATL non-bulky but elevated LDH, CLL treated with targeted therapy, and LRD with renal impairment/involvement.

LRD consisted of ST (except bulky sensitive to cytotoxic therapy [MRD]), CML, MM, HL, other NHL and AML <25K/mm³.

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(PMID = 27963935.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Midostaurin: Review of pharmacokinetics (PK) and PK/pharmacodynamic (PD) relationship in AML/MDS patients.

: e14540 Background: Midostaurin is a multi-tyrosine-kinases inhibitor targeting class III tyrosine-protein-kinases, including Fms-like tyrosine kinase-3 (FLT3), involved in hematopoiesis and leukemia.

METHODS: The two studies presented here involved patients with wild-type or FLT3-mutated de novo (phase Ib) or relapsed (phase II) AML or MDS.

However, evaluation of available bone marrow blast (BM) response data revealed that a much higher midostaurin plasma would be needed for a satisfactory BM response.

These results support the ongoing phase III AML study in AML FLT3-mutated patients with midostaurin given in combination with chemotherapy.

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(PMID = 27963644.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A safety and schedule seeking trial of Bcl-2 inhibitor obatoclax in previously untreated older patients with acute myeloid leukemia (AML).

: 3579 Background: Obatoclax (Ob) is a small-molecule inhibitor of all Bcl-2 prosurvival proteins.

In a previous study a 70 year old patient with untreated AML had a cytogenetic CR 8 days after receiving 20 mg/m² of Ob over 24 hrs.

This study evaluated the single-agent response rate in older patients with previously untreated AML.

Eligibility criteria included age ≥ 70, untreated AML (1 prior Rx allowed in Safety phase), ECOG PS ≤2, adequate renal and hepatic function.

Efficacy data after C2 show that 3 patients in the 20 mg 3-hr infusion cohort in the Safety phase and 1 at the same dose & schedule in the Schedule Seeking phase had ≥50% decrease in BM blasts after C2, which was not seen in the 60 mg 24-hr infusion cohort.

CONCLUSIONS: MTD for Ob as a 3-hr infusion administered in older patients with AML on 3 consecutive days is 20 mg/day, and both this regimen and 60 mg as a 24-hr infusion x 3 days were well tolerated.

Evidence of biological activity was seen with the 3-hr infusion schedule but not with the 24-hr infusion schedule, suggesting that efficacy may be improved with the 3-hr infusion schedule and may be related to PK differences.

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(PMID = 27961704.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States

   

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Long-term outcomes of high-dose therapy using busulfan, etoposide, and cyclophosphamide followed by allogeneic hematopoietic cell transplantation for patients with high-risk or advanced stages of myeloid malignancies.

: 7033 Patients (pts) with high risk (HR) or advanced myeloid malignancies have limited effective treatment options.

These include high-dose therapy followed by allogeneic hematopoietic cell transplantation (HCT).

All pts were treated with a uniform preparatory regimen: busulfan 16.0 mg/kg (d-8 to-5), etoposide 60mg/kg (d-4), cyclophosphamide 60mg/kg (d-2), and graft-versus-host-disease (GVHD) prophylaxis of cyclosporine and prednisone.

Disease status at transplantation was induction failure (IF) acute myeloid leukemia (AML) (n = 10), HR AML in 1st complete remission (CR1) n = 11, in CR2 (n = 5), in CR3 (n = 2), relapsed refractory (RR) AML (n = 14), chronic myeloid leukemia (CML) in second chronic phase (n = 6), blast crisis (n = 2), myelofibrosis (n = 6), myeloproliferative disorders (n = 2), and MDS (n = 38).

Non-relapse mortality (NRM) was 29 % (95% CI 20%5-38%) at day 100 and 39% (95% CI 29%-49%) at one yr.

Cumulative incidence of acute (grade 3-4) and chronic GVHD was 28% (95% CI 19%-37%) and 38% (95% CI 24%-52%), respectively.

There was no statistically significant difference in OS; 31% versus 32% (p = 0.89) or FFP 71% versus 60% (p = 0.29) for recipients of BM versus PBMC with similar results in IF and RR AML.

These results confirm that pts with high-risk or advanced myeloid malignancies can achieve long-term survival following myeloablative allogeneic HCT with aggressive conditioning.

Relapse and acute GVHD remain significant causes of mortality.

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(PMID = 27961395.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[ISO-abbreviation] J. Clin. Oncol.

[Language] eng

[Publication-type] Journal Article

[Publication-country] United States