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1.  Younger adults with acute myeloid leukemia in remission for ≥3 years have a high likelihood of cure: the ECOG experience in over 1200 patients 
Leukemia research  2014;38(8):901-906.
We examined 1229 younger patients with acute myeloid leukemia who achieved CR1 on Eastern Cooperative Oncology Group trials. We defined late relapse as occurring after ≥3 years of CR1. With median follow-up of 11.3 years, there were 14 late relapses (1.1% of CR1 patients; 3.3% of 3-year CR1 patients). Eight achieved second CR and median overall survival after late relapse was 3.2 years. Most patients tested (9/11) had a normal karyotype at diagnosis; none had new cytogenetic abnormalities at relapse. Late relapse is rare and nearly all 3-year CR1 patients are cured. If late relapse occurs, outcomes are relatively favorable.
doi:10.1016/j.leukres.2014.05.018
PMCID: PMC4326112  PMID: 24986381
acute myeloid leukemia; late relapse; outcomes; clinical trials; normal cytogenetics
2.  [No title available] 
PMCID: PMC3946941  PMID: 24183236
3.  A dose escalation feasibility study of lenalidomide for treatment of symptomatic, relapsed chronic lymphocytic leukemia☆ 
Leukemia research  2014;38(9):1025-1029.
Adequate dosing of lenalidomide in Chronic Lymphocytic Leukemia (CLL) remains unclear. This study determined maximum tolerated dose (MTD) in relapsed CLL patients (Cohort A) and patients achieving a partial response (PR) or better to recent therapy (Cohort B). Thirty-seven patients were enrolled. MTD was 2.5 mg followed by 5.0 mg continuous. In Cohort A, tumor flare grade 1–2 occurred in 15 patients (50%) and grade 3 in 1 patient (3%). Cohort A had 19 of 23 evaluable (83%) patients, 4 PR (17%) and 15 (65%) stable disease (SD), Cohort B had 6 of 7 patients (86%) with SD. Despite overall response rate not being high, many patients remained on therapy several months with SD.
doi:10.1016/j.leukres.2014.05.011
PMCID: PMC4312491  PMID: 25082342
Chronic Lymphocytic Leukemia; Relapse; Lenalidomide; Tumor flare; Maintenance
4.  Oxidative stress leads to increased mutation frequency in a murine model of myelodysplastic syndrome 
Leukemia research  2013;38(1):10.1016/j.leukres.2013.07.008.
The myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, dysplasia, and transformation to acute myeloid leukemia (AML). Although it has been suggested that additional mutations lead to progression of MDS to AML, the causative agent(s) for such mutations remains unclear. Oxidative stress is a potential cause, therefore, we evaluated levels of reactive oxygen species (ROS) in NUP98-HOXD13 (NHD13) transgenic mice, a murine model for MDS. Increased levels of ROS were detected in bone marrow nucleated cells (BMNC) that express CD71, a marker for cell proliferation, as well as immature, lineage negative bone marrow nucleated cells from NHD13 mice. In addition to the increase in ROS, increased DNA double strand breaks and activation of a G2/M phase cell cycle checkpoint were noted in NHD13 BMNC. Finally, using an in vivo assay for mutation frequency, we detected an increased mutation frequency in NHD13 BMNC. These results suggest that oxidative stress may contribute to disease progression of MDS to AML through ineffective repair of DNA damage and acquisition of oncogenic mutations.
doi:10.1016/j.leukres.2013.07.008
PMCID: PMC3872269  PMID: 23958061
MDS; AML; ROS; Mutation; NHD13; Big Blue® mice
5.  Developing an in vitro model of T cell type of large granular lymphocyte leukemia 
Leukemia research  2013;37(12):10.1016/j.leukres.2013.10.002.
We developed a strategy that can prolong in vitro growth of T cell type of large granular lymphocyte (T-LGL) leukemia cells. Primary CD8+ lymphocytes from T-LGL leukemia patients were stably transduced with the retroviral tax gene derived from human T cell leukemia virus type 2. Expression of Tax overrode replicative senescence and promoted clonal expansion of the leukemic CD8+ T cells. These cells exhibit features characteristic of leukemic LGL, including resistance to FasL-mediated apoptosis, sensitivity to the inhibitors of sphingosine-1-phosphate receptor and IκB kinases as well as expression of cytotoxic gene products such as granzyme B, perforin and IFNγ. Collectively, these results indicate that this leukemia cell model can duplicate the main phenotype and pathophysiological characteristics of the clinical isolates of T-LGL leukemia. This model should be useful for investigating molecular pathogenesis of the disease and for developing new therapeutics targeting T-LGL leukemia.
doi:10.1016/j.leukres.2013.10.002
PMCID: PMC3865428  PMID: 24183305
T-LGLL; Stat3; NF-κB; retroviral Tax oncoprotein
6.  Interaction with RXR is Necessary for NPM-RAR-Induced Myeloid Differentiation Blockade 
Leukemia research  2013;37(12):10.1016/j.leukres.2013.09.024.
The t(5;17)(q35;q21) APL variant results in expression of a fusion protein linking the N-terminus of nucleophosmin (NPM) to the C-terminus of the retinoic acid receptor alpha (RAR). We have previously shown that NPM-RAR is capable of binding to DNA either as a homodimer or heterodimer with RXR. To determine the biological significance of NPM-RAR/RXR interaction, we developed two mutants of NPM-RAR that showed markedly diminished ability to bind RXR. U937 subclones expressing the NPM-RAR mutants showed significantly less inhibition of vitamin D3/TGFbeta-induced differentiation, compared with NPM-RAR. These results support the hypothesis that RXR interaction is necessary for NPM-RAR-mediated myeloid maturation arrest.
doi:10.1016/j.leukres.2013.09.024
PMCID: PMC3876950  PMID: 24183235
acute promyelocytic leukemia; NPM-RAR; RXR; differentiation
7.  The fusion partner specifies the oncogenic potential of NUP98 fusion proteins 
Leukemia research  2013;37(12):10.1016/j.leukres.2013.09.013.
NUP98 is among the most promiscuously translocated genes in hematological diseases. Among the 28 known fusion partners, there are two categories: homeobox genes and non-homeobox genes. The homeobox fusion partners are well-studied in animal models, resulting in HoxA cluster overexpression and hematological disease. The non- homeobox fusion partners are less well studied. We created transgenic animal models for three NUP98 fusion genes (one homeobox, two non- homeobox), and show that in this system, the NUP98-homeobox fusion promotes self-renewal and aberrant gene expression to a significantly greater extent. We conclude that homeobox partners create more potent NUP98 fusion oncogenes than do non-homeobox partners.
doi:10.1016/j.leukres.2013.09.013
PMCID: PMC3883578  PMID: 24090997
NUP98; homeobox; HOX; leukemia; translocation
8.  Homeostatic defects in B cells deficient in the E3 ubiquitin ligase ARF-BP1 are restored by enhanced expression of MYC 
Leukemia research  2013;37(12):1680-1689.
The E3 ligase ARF-BP1 governs the balance of life and death decisions by directing the degradation of p53 and enhancing the transcriptional activity of MYC. We find B cells selectively deficient in ARF-BP1 have many defects in developing and mature B cells associated with increased expression of p53 and reduced expression of Myc. Overexpression of Myc results in suppression of p53 and complete reversal of defects induced by ARF-BP1 deficiency. These findings indicate that the dynamic balance between MYC and p53 required for normal B cell maturation and function is finely tuned and critically dependent on the activities of ARF-BP1.
doi:10.1016/j.leukres.2013.09.009
PMCID: PMC4077183  PMID: 24199708
ARF-BP1; MYC; p53; B cell development
9.  Modest Activity of Pomalidomide in Patients with Myelofibrosis and Significant Anemia 
Leukemia research  2013;37(11):1440-1444.
We evaluated single agent pomalidomide for myelofibrosis-associated anemia. First, 21 patients received pomalidomide 3.0mg/day on 21-day-on/7-day-off schedule. Due to poor tolerance the study was quickly suspended. Second, 29 patients received pomalidomide 0.5mg/day continuously. Three patients (10%) experienced clinical improvement in hemoglobin per International-Working-Group criteria (median time to response 1.6 months; median response duration 6.7 months). Ten patients were RBC-transfusion-dependent per Delphi criteria; 2 (20%) achieved RBC-transfusion-independence (time to response 0.9 months in both; response duration of 8.3 and 15 months). One grade 3/4 toxicity (neutropenia) occurred. Pomalidomide at low dose is well tolerated but has modest clinical activity in myelofibrosis.
doi:10.1016/j.leukres.2013.07.007
PMCID: PMC4232180  PMID: 23890523
pomalidomide; myelofibrosis; anemia
10.  Differential Activities of Thalidomide and Isoprenoid Biosynthetic Pathway Inhibitors in Multiple Myeloma Cells 
Leukemia research  2009;34(3):344-351.
Thalidomide has emerged as an effective agent for treating multiple myeloma, however the precise mechanism of action remains unknown. Agents known to target the isoprenoid biosynthetic pathway (IBP) can have cytotoxic effects in myeloma cells. The interactions between thalidomide and IBP inhibitors in human multiple myeloma cells were evaluated. Enhanced cytotoxicity and induction of apoptosis was observed in RPMI-8226 cells. Examination of intracellular levels of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) revealed a wide variance in basal levels and response to IBP inhibitors. These findings provide a mechanism for the differential sensitivity of myeloma cells to pharmacologic manipulation of the IBP.
doi:10.1016/j.leukres.2009.06.035
PMCID: PMC4228479  PMID: 19646757
Myeloma; isoprenoid; lovastatin; thalidomide; zoledronic acid; farnesyl pyrophosphate; geranylgeranyl pyrophosphate
11.  Methylation of the DPH1 promoter causes immunotoxin resistance in acute lymphoblastic leukemia cell line KOPN-8 
Leukemia research  2013;37(11):10.1016/j.leukres.2013.08.005.
Moxetumomab pasudotox (HA22) is an immunotoxin with an anti-CD22 Fv fused to a portion of Pseudomonas exotoxin A that kills CD22 expressing ALL cells. HA22 produced significant responses in some cases of ALL. To understand how to increase response rate, we isolated HA22-resistant KOPN-8 cells and found that HA22 cannot inactivate elongation factor-2 (EF2) due to low levels of DPH1 RNA and protein. Resistance was associated with methylation of the CpG island in the DPH1 promoter. 5-azacytidine prevented resistance and methylation of the CpG residues and merits evaluation to determine if it can increase the efficacy of HA22 in ALL.
doi:10.1016/j.leukres.2013.08.005
PMCID: PMC3818433  PMID: 24070652
DNA methylation; Drug resistance; ADP-ribosylation; Diphthamide synthesis; Epigenetic regulation
12.  Phase II trial of clofarabine and daunorubicin as induction therapy for acute myeloid leukemia patients greater than or equal to 60 years of age 
Leukemia research  2013;37(11):10.1016/j.leukres.2013.07.036.
We designed a phase II study evaluating the upfront combination of clofarabine and daunorubicin in acute myeloid leukemia (AML) patients ≥60 years old. The median age of the 21 patients was 69 (range 60–85) years. Fourteen patients (67%) had unfavorable risk features. The principal toxicities were grade ≥3 infections and prolonged myelosuppression. Three (14%) deaths occurred from infectious complications. Six (28.6%) patients achieved complete remission including three (21.4%) of 14 patients with unfavorable AML. The median disease-free survival was 6.8 months and the median overall survival was 11.2 months.
doi:10.1016/j.leukres.2013.07.036
PMCID: PMC3818466  PMID: 24011826
elderly; AML; clofarabine; daunorubicin; clinical trial
13.  Role of microRNA deregulation in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) 
Leukemia research  2013;37(11):10.1016/j.leukres.2013.08.020.
MicroRNAs (miRNAs) are small endogenous RNA molecules that regulate gene expression at the post-transcriptional level through its sequence complementation with target mRNAs. An individual miRNA species can simultaneously influence the expression of multiple genes and conversely, several miRNAs can synchronously control expression of specific gene product mRNA levels. Thus, miRNAs expression in cells has to be precisely regulated and alterations in miRNA levels may cause an aberrant expression of genes involved in oncogenic pathways and consequently result in cancer development. Indeed, miRNA expression is often deregulated in many cancers, including B-cell lymphomas. Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas with different genetic backgrounds, morphologic features, and responses to therapy. Over the past decade, miRNAs emerged as a new tool for understanding DLBCL biology, and promising candidate molecular markers in DLBCL classification and treatment. In this review, we will focus on miRNAs aberrantly expressed in DLBCL and discuss the putative mechanisms of this deregulation. Additionally, we will summarize miRNAs’ involvement in the identification of DLBCL subgroups, and their potential role as diagnostic/prognostic biomarkers as well as specific therapeutic targets for DLBCL.
doi:10.1016/j.leukres.2013.08.020
PMCID: PMC3856880  PMID: 24054860
microRNA; DLBCL; lymphoma
14.  Patients with Polycythemia Vera and Essential Thrombocythemia with Prior Malignancy Do Not Have Significantly Worse Outcome 
Leukemia research  2013;37(11):10.1016/j.leukres.2013.08.002.
The clinical relevance of prior malignancy (PM) in patients with essential thrombocythemia (ET) and polycythemia vera (PV) is largely unknown. We retrospectively evaluated 437 patients (ET, n=263; PV, n=174) treated at MD Anderson between 1960 and 2010. Forty-four patients had PM (ET, 10%; PV, 11%), with median time to diagnosis of 66 months. PM was not associated with abnormal cytogenetics, JAK2-mutation frequency, blood-cell counts or progression to acute leukemia or myelofibrosis. In multivariate analysis, only older age and high LDH levels were associated with worse OS. In conclusion, PM does not predict worse outcomes for patients with ET and PV.
doi:10.1016/j.leukres.2013.08.002
PMCID: PMC3818458  PMID: 23993426
myeloproliferative disorders; polycythemia vera; essential thrombocythemia; prior malignancy; transformation to acute leukemia; transformation to myelofibrosis
15.  A phase I study using bortezomib with weekly idarubicin for treatment of elderly patients with acute myeloid leukemia 
Leukemia research  2013;37(11):1502-1508.
We report the results of a phase I study with four dose levels of bortezomib in combination with idarubicin. Eligible patients were newly diagnosed with acute myeloid leukemia (AML) age ≥60 years, or any adult with relapsed AML. Bortezomib was given twice weekly at 0.8, 1.0, or 1.2 mg/m2 with once weekly idarubicin 10 mg/m2 for four weeks. Twenty patients were treated: 13 newly diagnosed (median age 68, range 61-83) and 7 relapsed (median age 58, range 40-77). Prior myelodysplastic syndrome (MDS) was documented in 10/13 (77%) newly diagnosed and 1/7 (14%) relapsed patients; the three newly diagnosed patients without prior MDS had dyspoietic morphology. Two dose-limiting toxicities occurred at the initial dose level (bortezomib 0.8 mg/m2 and idarubicin 10 mg/m2); idarubicin was reduced to 8 mg/m2 without observing subsequent dose-limiting toxicities. The maximum tolerated dose in this study was bortezomib 1.2 mg/m2 and idarubicin 8 mg/m2. Common adverse events included: neutropenic fever, infections, constitutional symptoms, and gastrointestinal symptoms. No subjects experienced neurotoxicity. Most patients demonstrated hematologic response as evidenced by decreased circulating blasts. Four patients (20%) achieved complete remission. There was one treatment-related death. The combination of bortezomib and idarubicin in this mostly poor-risk, older AML group was well tolerated and did not result in high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00382954.
doi:10.1016/j.leukres.2013.09.003
PMCID: PMC4025941  PMID: 24075534
bortezomib; idarubicin; acute myeloid leukemia; elderly
16.  Phase I Clinical, Pharmacokinetic, and Pharmacodynamic Study of the Akt-Inhibitor Triciribine Phosphate Monohydrate in Patients with Advanced Hematologic Malignancies 
Leukemia research  2013;37(11):1461-1467.
Akt, a serine/threonine protein kinase, is constitutively phosphorylated and hyperactivated in multiple cancers, including acute myeloid leukemia. High levels are linked to poor survival and inferior responses to chemotherapy, making Akt inhibition an attractive therapeutic target. In this phase I/II study of TCN-PM, a small-molecule Akt inhibitor, TCN-PM therapy was well tolerated in patients with advanced hematological malignancies, and reduced levels of phosphorylation of Akt and its substrate Bad were shown, consistent with inhibition of this survival pathway and induction of cell death. Further investigation of TCN-PM alone or in combination in patients with high Akt levels is warranted.
doi:10.1016/j.leukres.2013.07.034
PMCID: PMC4205589  PMID: 23993427
Akt; nucleoside analog; Triciribine; AML; phase I clinical trial
17.  PHASE II STUDY OF IMATINIB MESYLATE AS THERAPY FOR PATIENTS WITH SYSTEMIC MASTOCYTOSIS 
Leukemia research  2009;33(11):1481-1484.
Gain-of-function D816V point mutation within the kinase domain of the transmembrane receptor KIT is found in the great majority of patients with systemic mastocytosis (SM) and is attractive therapeutic target. Twenty patients with SM were enrolled during 2003–2005 in phase II clinical trial with imatinib mesylate (400mg daily), a KIT inhibitor. Median time on therapy was 9 months (range, 0.5 – 44+). Only 1 patient, with D816V KIT mutation-negative FIP1L1-PDGFRα-negative SM-HES, achieved complete remission (now lasting for 44 months). Six other patients reported symptomatic improvement, including 2 with D816V KIT mutation-positive SM (one reported improvement in diarrhea and the other in fatigue). Other patients had no benefit. Imatinib was relatively well tolerated. Our study confirms that imatinib therapy does not result in appreciable clinical activity in patients with D816V mutation-positive SM, but may result in a significant benefit in occasional patient with D816V mutation-negative SM.
doi:10.1016/j.leukres.2008.12.020
PMCID: PMC4184059  PMID: 19193436
18.  Blood counts at time of complete remission provide additional independent prognostic information in acute myeloid leukemia 
Leukemia research  2008;32(10):1505-1509.
Prognostic relevance of blood counts at complete remission (CR) in acute myeloid leukemia (AML) is not clear. To address this issue, we analyzed 891 AML patients in first CR. From the data of randomly selected 446 patients (training set), we first established optimal cutoffs for neutrophil and platelet counts and hemoglobin level at CR in terms of relapse-free survival (RFS). Patients whose counts were higher than each optimal cutoff were shown to have significantly better RFS (p < 0.01 for neutrophil and platelets, and p = 0.02 for hemoglobin). Then we tested whether these cutoffs were, after accounting for better known prognostic covariates, also predictive of RFS in the remaining 445 patients (validation set). Our data revealed that higher neutrophil count was independently predictive of longer RFS in the validation set (hazard ratio 1.38, p = 0.02), as was higher platelet count (hazard ratio 1.35, p = 0.04). These findings suggest that blood counts at CR, information readily available, are useful in prognostication in AML.
doi:10.1016/j.leukres.2008.03.002
PMCID: PMC4182927  PMID: 18405972
Acute myeloid leukemia; Blood counts; Complete remission; Relapse-free survival; Prognostication
19.  Hydrogen sulfide-releasing aspirin inhibits the growth of leukemic Jurkat cells and modulates β-catenin expression 
Leukemia research  2013;37(10):1302-1308.
Hydrogen sulfide-releasing aspirin (HS-ASA) is a novel compound with potential against cancer. It inhibited the growth of Jurkat T-leukemia cells with an IC50 of 1.9 ± 0.2 µM whereas that of ASA was >5000 µM. It dose-dependently inhibited proliferation and induced apoptosis in these cells, causing a G0/G1 cell cycle arrest. HS-ASA down-regulated β-catenin protein levels and reduced mRNA and protein expression of β-catenin/TCF downstream target genes cyclinD1 and c-myc. Aspirin up to 5 mM had no effect on β-catenin expression. HS-ASA also increased caspase-3 protein levels and dose-dependently increased its activity. These effects were substantially blocked by z-VAD-fmk, a pan-caspase inhibitor.
doi:10.1016/j.leukres.2013.07.004
PMCID: PMC3769470  PMID: 23896061
Leukemia; β-catenin; caspase-3; hydrogen sulfide; apoptosis; proliferation; cell cycle
20.  Interleukin-6 and JAK2/STAT3 signaling mediate the reversion of dexamethasone resistance after dexamethasone withdrawal in 7TD1 multiple myeloma cells 
Leukemia research  2013;37(10):1322-1328.
We previously reported the establishment and characteristics of a DXM-resistant cell line (7TD1-DXM) generated from the IL6-dependent mouse B cell hybridoma, 7TD1 cell line. After withdrawing DXM from 7TD1-DXM cells over 90 days, DXM significantly inhibited the cell growth and induced apoptosis in the cells (7TD1-WD) compared with 7TD1-DXM cells. Additionally, IL-6 reversed while IL-6 antibody and AG490 enhanced the effects of growth inhibition and apoptosis induced by DXM in 7TD1-WD cells. Our study demonstrates that 7TD1-DXM cells become resensitized to DXM after DXM withdrawal, and IL-6 and JAK2/STAT3 pathways may regulate the phenomenon.
doi:10.1016/j.leukres.2013.06.026
PMCID: PMC3769515  PMID: 23871159
multiple myeloma; dexamethasone resistance; dexamethasone withdrawal; interleukin-6; AG490; JAK2/STAT3 signaling pathway
21.  Low NK cell counts in peripheral blood are associated with inferior overall survival in patients with follicular lymphoma 
Leukemia research  2013;37(10):1213-1215.
Host immune responses influence follicular lymphoma (FL) outcomes. To test our hypothesis that immune cells in blood reflect that response, we assessed by peripheral blood flow cytometry in 75 untreated FL patients the absolute counts of: lymphocytes (ALC), CD4+T (ACD4C), CD8+T (ACD8C) and natural killer (ANKC) cells. Low ANKC was the only parameter associated with inferior overall survival by univariate analysis (p= 0.02), and trended to significance in multivariable analysis with ACD4C (p= 0.08). Five (24%) patients with low initial ANKC died, while none with normal/high ANKC have died Conclusions: Evaluation of blood ANKC may be a useful indicator of outcome in previously untreated FL patients.
doi:10.1016/j.leukres.2013.07.038
PMCID: PMC3976217  PMID: 23968916
Follicular lymphoma; immunology; lymphocyte subsets; NK cells; prognosis
22.  All-trans retinoic acid and late relapses in acute promyelocytic leukemia: Very long-term follow-up of the North American Intergroup Study I0129 
Leukemia research  2013;37(7):795-801.
We report a long-term follow-up (median 11.8 years) of the First North American Intergroup Study. 379 patients were randomized to induction with ATRA or to chemotherapy. All complete responders (CR) received consolidation chemotherapy, then randomized to 1 year ATRA or observation. 245 patients received ATRA sometime during the study: 195 (80%) achieved a CR. Nine (4.6%) relapsed late (>3 years from CR), the last occurred after 4.6 years; 7 of them were still alive after 5.5–15 years. In APL patients, late relapses are uncommon, and those who sustain CR >5 years can be considered cured.
doi:10.1016/j.leukres.2013.03.001
PMCID: PMC4174301  PMID: 23528262
Acute promyelocytic leukemia; All-trans retinoic acid; Late relapse
23.  Arsenic trioxide and Ascorbic Acid Demonstrates Promising Activity against Primary Human CLL Cells in Vitro 
Leukemia research  2010;34(7):925-931.
The compromised antioxidant defense system in chronic lymphocytic leukemia (CLL) suggested a potential use for Reactive Oxygen Species (ROS) generating Arsenic Trioxide (ATO) and Ascorbic Acid. While both ATO and ascorbic acid mediated cytotoxicity in CLL B cells as single agents, the efficacy of ATO is enhanced by ascorbic acid. This effect is dependent on increased ROS accumulation, as pretreatment of B-CLL cells with a glutathione reducing buthionine sulfoximine or catalase inhibiting aminotriazole, enhanced ATO/ascorbic acid mediated cytotoxicity. Petreatment with reducing agents such as catalase, or thiol anti-oxidant, N-acetyl cysteine or GSH also abrogated ATO/ascorbic acid mediated cytotoxicity. Furthermore, Hu1D10 mediated cell death was enhanced with ATO and ascorbic acid, thus justifying potential combination of ATO/arsenic trioxide therapy with antibodies such as Hu1D10 that also cause accumulation of ROS.
doi:10.1016/j.leukres.2010.01.020
PMCID: PMC4164821  PMID: 20171736
CLL; Arsenic trioxide; ascorbic acid
24.  Circulating heat shock protein 70 and progression in patients with chronic myeloid leukemia 
Leukemia research  2008;33(2):212-217.
We evaluated the association of circulating levels of heat shock protein 70 (Hsp70) in plasma with clinical behavior and progression in 139 chronic myeloid leukemia (CML) patients. Circulating Hsp70 levels did not differ significantly between CML patients in the chronic phase (n = 93; median 33.24 ng/mL, range 3.89–128.2 ng/mL) and those in the accelerated/blast phase (n = 46; median 26.57 ng/mL, range 4.5–114.7 ng/mL). However, overall CML patients had significantly higher levels of Hsp70 than healthy subjects (n = 95, median 4.17 ng/mL, range 1.75–24.7 ng/mL) (P < 0.001). In chronic phase CML patients, Hsp70 levels above the median were associated with a higher rate of progression to the accelerated/blast phase and a tendency toward shorter survival. Plasma Hsp70 thus could be a potential marker for predicting disease progression in patients with chronic phase CML.
doi:10.1016/j.leukres.2008.07.012
PMCID: PMC4163801  PMID: 18715642
Circulating heat shock protein; Chronic myeloid leukemia; Imatinib resistance
25.  THERAPY WITH THE HISTONE DEACETYLASE INHIBITOR PRACINOSTAT FOR PATIENTS WITH MYELOFIBROSIS 
Leukemia research  2012;36(9):1124-1127.
Approximately half of the patients with myelofibrosis (MF) carry mutant JAK2V617F proteins. JAK2V617F has been recently shown to translocate to the nucleus and modify specific histones, thus regulating transcription. We report on a phase II study testing the activity and tolerability of the histone deacetylase inhibitor pracinostat given at 60mg every other day for three weeks per month in 22 patients with intermediate or high risk MF. Eight (36%) patients experienced clinical benefit, with 6 (27%) experiencing reductions in splenomegaly (median 3cm, range 1–4cm). According to International Working Group criteria, 2 (9%) patients had clinical improvement (anemia response in both cases). The most frequent side effect associated to pracinostat therapy was fatigue, which occurred in 20 (91%) patients (grade 2 in 3 patients). Grade 3–4 neutropenia, anemia, and thrombocytopenia occurred in 13%, 0%, and 21%, respectively. Twenty-one patients permanently discontinued pracinostat, mainly due to lack of efficacy. In conclusion, pracinostat at the dose tested is reasonably tolerated and has modest activity in patients with MF.
doi:10.1016/j.leukres.2012.03.003
PMCID: PMC4152772  PMID: 22475363
myelofibrosis; pracinostat; SB939; histone deacetylase inhibitor; JAK2

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