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1.  Activity of the Multikinase Inhibitor Sorafenib in Combination With Cytarabine in Acute Myeloid Leukemia 
Acute myeloid leukemia (AML) is a genetically heterogeneous cancer that frequently exhibits aberrant kinase signaling. We investigated a treatment strategy combining sorafenib, a multikinase inhibitor with limited single-agent activity in AML, and cytarabine, a key component of AML chemotherapy.
Using 10 human AML cell lines, we determined the effects of sorafenib (10 μM) on antileukemic activity by measuring cell viability, proliferation, ERK1/2 signaling, and apoptosis. We also investigated the effects of sorafenib treatment on the accumulation of cytarabine and phosphorylated metabolites in vitro. A human equivalent dose of sorafenib in nontumor-bearing NOD-SCID-IL2Rγnull mice was determined by pharmacokinetic studies using high performance liquid chromatography with tandem mass spectrometric detection, and steady-state concentrations were estimated by the fit of a one-compartment pharmacokinetic model to concentration–time data. The antitumor activity of sorafenib alone (60 mg/kg) twice daily, cytarabine alone (6.25 mg/kg administered intraperitoneally), or sorafenib once or twice daily plus cytarabine was evaluated in NOD-SCID-IL2Rγnull mice bearing AML xenografts.
Sorafenib at 10 μM inhibited cell viability, proliferation and ERK1/2 signaling, and induced apoptosis in all cell lines studied. Sorafenib also increased the cellular accumulation of cytarabine and metabolites resulting in additive to synergistic antileukemic activity. A dose of 60 mg/kg in mice produced a human equivalent sorafenib steady-state plasma exposure of 10 μM. The more dose-intensive twice-daily sorafenib plus cytarabine (n = 15) statistically significantly prolonged median survival in an AML xenograft model compared with sorafenib once daily plus cytarabine (n = 12), cytarabine alone (n = 26), or controls (n = 27) (sorafenib twice daily plus cytarabine, median survival = 46 days; sorafenib once daily plus cytarabine, median survival = 40 days; cytarabine alone, median survival = 36 days; control, median survival = 19 days; P < .001 for combination twice daily vs all other treatments listed).
Sorafenib in combination with cytarabine resulted in strong anti-AML activity in vitro and in vivo. These results warrant clinical evaluation of sorafenib with cytarabine-based regimens in molecularly heterogeneous AML.
PMCID: PMC3110171  PMID: 21487100
2.  Clofarabine Combinations as Acute Myeloid Leukemia Salvage Therapy 
Cancer  2008;113(8):2090-2096.
Outcome of patients with relapsed acute myeloid leukemia (AML) remains unsatisfactory. Clofarabine is a nucleoside analog with activity in adult AML. Combinations with cytarabine in AML are feasible and effective. Idarubicin is another active AML drug, which has not yet been tested with clofarabine.
The authors therefore designed a phase I study of clofarabine ± cytarabine, plus idarubicin. Patients with primary refractory or first-relapse AML were assigned to either clofarabine plus idarubicin (CI) if previously exposed to cytarabine with a response lasting <12 months, or clofarabine and idarubicin plus cytarabine (CIA) for responses ≥12 months, or if never exposed to cytarabine. A standard “3 + 3” phase 1 design was followed to define maximum tolerated dose (MTD). Forty-four patients were treated (23 CI; 21 CIA).
Dose-limiting toxicities were hyperbilirubinemia and hepatic transaminase elevations for CI-treated patients in addition to mucositis and diarrhea for CIA-treated patients. MTD for CI was clofarabine 22.5 mg/m2 intravenously daily × 5 and idarubicin 10 mg/m2 intravenously daily × 3. MTD for CIA was clofarabine 22.5 mg/m2 intravenously × 5, idarubicin 6 mg/m2 intravenously × 3, and cytarabine 0.75 g/m2 intravenously × 5 days.
A phase 2 randomized trial is in process to compare activity between treatment arms.
PMCID: PMC4163782  PMID: 18756533
nucleoside analogs; clofarabine; acute myeloid leukemia; salvage
3.  Clofarabine Does Not Negatively Impact the Outcomes of Patients With Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation 
We evaluated whether clofarabine-containing chemotherapy predisposed patients to hepatic toxicity (particularly venoocclusive disease [VOD]) after allogeneic stem cell transplantation (allo-SCT). In the group who received clofarabine and subsequent transplantation, there were no cases of VOD, and liver toxicity was comparable to a control group who received standard acute myeloid leukemia (AML) chemotherapy. Other transplant-specific outcomes, including overall survival (OS), were also similar when compared with the control group.
Clofarabine is actively being investigated as a component of frontline chemotherapy for acute myeloid leukemia (AML). Hepatotoxicity is 1 of the primary adverse events associated with clofarabine and can occasionally can include severe venoocclusive disease (VOD).
Patients and Methods
Many patients with AML undergo allogeneic stem cell transplantation (allo-SCT), a procedure that is also associated with hepatotoxicity. We identified AML patients undergoing allo-SCT and stratified them according to whether they received clofarabine-containing (clofarabine, idarubicin, and cytarabine [CIA]) or non–clofarabine-containing cytarabine-based induction/consolidation chemotherapy (idarubicin and cytarabine [ara-C] [IA]). We compared both groups for differences in posttransplantation hepatotoxicity, VOD, and other transplantation outcomes. Forty-two patients were identified (20 receiving CIA and 22 receiving IA). Patient and transplant characteristics were similar. All patients receiving clofarabine-based treatment received CIA within 2.5 months of their allo-SCT.
There was no difference in the incidence of VOD in the 30 days after transplantation (0 CIA, 1 IA; P = 1.0). Rates of grade 3/4 hepatotoxicity also did not differ between groups. Acute graft-versus-host disease (GVHD), early relapse, and survival were also not significantly different.
We conclude that clofarabine-containing chemotherapy does not adversely impact the outcome of allo-SCT. Specifically, it does not predispose patients to an increased risk of hepatotoxicity, VOD, GVHD, or relapse.
PMCID: PMC4114759  PMID: 23276886
Acute myeloid leukemia; Allogeneic stem cell transplantation; Clofarabine; Hepatotoxicity; Venoocclusive disease
4.  Daunorubicin Versus Mitoxantrone Versus Idarubicin As Induction and Consolidation Chemotherapy for Adults With Acute Myeloid Leukemia: The EORTC and GIMEMA Groups Study AML-10 
Journal of Clinical Oncology  2009;27(32):5397-5403.
To compare the antitumor efficacy of three different anthracyclines in combination with cytarabine and etoposide in adult patients with newly diagnosed acute myeloid leukemia (AML).
Patients and Methods
We randomly assigned 2,157 patients (age range, 15 to 60 years) to receive intensive induction-consolidation chemotherapy containing either daunorubicin, idarubicin, or mitoxantrone. After achieving complete remission (CR), patients were assigned to undergo either allogeneic or autologous stem-cell transplantation (SCT), depending on the availability of a sibling donor.
The overall CR rate (69%) was similar in the three groups. Autologous SCT was performed in 37% of cases in the daunorubicin arm versus only 29% and 31% in mitoxantrone and idarubicin, respectively (P < .001). However, the disease-free survival (DFS) and survival from CR were significantly shorter in the daunorubicin arm: the 5-year DFS was 29% versus 37% and 37% in mitoxantrone and idarubicin, respectively. The proportion of patients who underwent allogeneic SCT (22%) was equivalent in the three treatment groups, and the outcome was similar as well: the 5-year overall survival rates were 34%, 34%, and 31%, respectively.
In adult patients with AML who do not receive an allogeneic SCT, the use of mitoxantrone or idarubicin instead of daunorubicin enhances the long-term efficacy of chemotherapy.
PMCID: PMC2773224  PMID: 19826132
5.  Outcome of refractory and relapsed acute myeloid leukemia in children treated during 2005–2011 – experience of the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) 
Contemporary Oncology  2014;18(1):48-53.
Aim of the study
Recent studies showed relatively better outcome for children with refractory (refAML) and relapsed acute myeloid leukemia (relAML). Treatment of these patients has not been unified within Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) so far. The goal of this study is to analyze the results of this therapy performed between 2005–2011.
Material and methods
The outcome data of 16 patients with refAML and 62 with relAML were analyzed retrospectively. Reinduction was usually based on idarubicine, fludarabine and cytarabine with allogenic hematopoietic stem cell transplant (alloHSCT) in 5 refAML and 30 relAML children.
Seventy seven percent relAML patients entered second complete remission (CR2). Five-year OS and disease-free survival (DFS) were estimated at 16% and 30%. The outcome for patients after alloHSCT in CR2 (63%) was better than that of those not transplanted (36%) with 5-year OS of 34% vs. 2-year of 7% and 5-year DFS of 40% vs. 12.5%. Second complete remission achievement and alloHSCT were the most significant predictors of better prognosis (p = 0.000 and p = 0.024). The outcome of refAML children was significantly worse than relAML with first remission (CR1) rate of 33%, OS and DFS of 25% at 3 years and 53% at 2 years, respectively. All survivors of refAML were treated with alloHSCT after CR1.
The uniform reinduction regimen of the documented efficacy and subsequent alloHSCT in remission is needed to improve the outcome for ref/relAML children treated within PPLLSG. The focus should be on the future risk-directed both front and second line AML therapy.
PMCID: PMC4037997  PMID: 24876821
acute myeloid leukemia; relapse; stem cell transplantation; children
6.  Inhibition of Histone Deacetylases 1 and 6 Enhances Cytarabine-Induced Apoptosis in Pediatric Acute Myeloid Leukemia Cells 
PLoS ONE  2011;6(2):e17138.
Pediatric acute myeloid leukemia (AML) remains a challenging disease to treat even with intensified cytarabine-based chemotherapy. Histone deacetylases (HDACs) have been reported to be promising therapeutic targets for treating AML. However, HDAC family members that are involved in chemotherapy sensitivities remain unknown. In this study, we sought to identify members of the HDAC family that are involved in cytarabine sensitivities, and to select the optimal HDACI that is most efficacious when combined with cytarabine for treating children with AML.
Expression profiles of classes I, II, and IV HDACs in 4 pediatric AML cell lines were determined by Western blotting. Inhibition of class I HDACs by different HDACIs was measured post immnunoprecipitation. Individual down-regulation of HDACs in pediatric AML cells was performed with lentiviral shRNA. The effects of cytarabine and HDACIs on apoptosis were determined by flow cytometry analysis.
Treatments with structurally diverse HDACIs and HDAC shRNA knockdown experiments revealed that down-regulation of both HDACs 1 and 6 is critical in enhancing cytarabine-induced apoptosis in pediatric AML, at least partly mediated by Bim. However, down-regulation of HDAC2 may negatively impact cytarabine sensitivities in the disease. At clinically achievable concentrations, HDACIs that simultaneously inhibited both HDACs 1 and 6 showed the best anti-leukemic activities and significantly enhanced cytarabine-induced apoptosis.
Our results further confirm that HDACs are bona fide therapeutic targets for treating pediatric AML and suggest that pan-HDACIs may be more beneficial than isoform-specific drugs.
PMCID: PMC3040224  PMID: 21359182
7.  A single dose of pegfilgrastim compared with daily filgrastim for supporting neutrophil recovery in patients treated for low-to-intermediate risk acute myeloid leukemia: results from a randomized, double-blind, phase 2 trial 
BMC Cancer  2008;8:195.
Patients with acute myeloid leukemia (AML) are often neutropenic as a result of their disease. Furthermore, these patients typically experience profound neutropenia following induction and/or consolidation chemotherapy and this may result in serious, potentially life-threatening, infection. This randomized, double-blind, phase 2 clinical trial compared the efficacy and tolerability of pegfilgrastim with filgrastim for assisting neutrophil recovery following induction and consolidation chemotherapy for de novo AML in patients with low-to-intermediate risk cytogenetics.
Patients (n = 84) received one or two courses of standard induction chemotherapy (idarubicin + cytarabine), followed by one course of consolidation therapy (high-dose cytarabine) if complete remission was achieved. They were randomized to receive either single-dose pegfilgrastim 6 mg or daily filgrastim 5 μg/kg, beginning 24 hours after induction and consolidation chemotherapy.
The median time to recovery from severe neutropenia was 22.0 days for both pegfilgrastim (n = 42) and filgrastim (n = 41) groups during Induction 1 (difference 0.0 days; 95% CI: -1.9 to 1.9). During Consolidation, recovery occurred after a median of 17.0 days for pegfilgrastim versus 16.5 days for filgrastim (difference 0.5 days; 95% CI: -1.1 to 2.1). Therapeutic pegfilgrastim serum concentrations were maintained throughout neutropenia. Pegfilgrastim was well tolerated, with an adverse event profile similar to that of filgrastim.
These data suggest no clinically meaningful difference between a single dose of pegfilgrastim and multiple daily doses of filgrastim for shortening the duration of severe neutropenia following chemotherapy in de novo AML patients with low-to-intermediate risk cytogenetics.
Trial registration NCT00114764
PMCID: PMC2483721  PMID: 18616811
8.  A 78-Year-Old Man with Acute Myeloid Leukemia (AML) and Acute Renal Failure 
Patient: Male, 78
Final Diagnosis: Acute myeloid leukemia (AML)
Symptoms: Dyspnea • fatigue
Medication: Idarubicin followed by cytarabine
Clinical Procedure: Chemotherapy
Specialty: Hematology
Unusual clinical course
Renal failure is a common presentation of acute myelomonocytic and monocytic leukemia. It is usually the result of a combined glomerular and tubular dysfunction and is associated with a poor prognosis. No guidelines exist for treatment.
Case Report:
We herein describe the case of a 78-year-old Caucasian man who presented with acute myeloid leukemia M5, leukostasis with a white count of 340 000/ml, and acute renal failure with a creatinine of 7.7/dL. The patient was initially treated with leukapheresis and 3 days of idarubicin in the setting of continuous renal replacement therapy that resulted in rapid reversal of his renal failure. He then received 7 days of continuous infusion cytarabine and went into a complete remission.
Renal failure may complicate the presentation of AML but can be reversible with treatment. Dose adjustment of the chemotherapy is not needed and the treatment can be greatly facilitated with the use of continuous renal replacement therapy, as indicated in our case report. In addition, we emphasize that organ dysfunction, even in elderly patients, is not necessarily a contraindication to aggressive treatment if it is felt to be disease-related and reversible.
PMCID: PMC4159241  PMID: 25184701
Acute Kidney Injury; Cytarabine; Hemofiltration; Idarubicin; Leukemia, Myeloid, Acute; Leukostasis
9.  Feasibility of Azacitidine Added to Standard Chemotherapy in Older Patients with Acute Myeloid Leukemia — A Randomised SAL Pilot Study 
PLoS ONE  2012;7(12):e52695.
Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML.
Trial Design
Prospective, randomised, open, phase II trial with parallel group design and fixed sample size.
Patients and Methods
Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of <20,000/µl at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint.
Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days.
The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm.
Trial Registration
This trial is registered at clinical (identifier: NCT00915252).
PMCID: PMC3534078  PMID: 23300745
10.  Phase I/II Study of Combination Therapy With Sorafenib, Idarubicin, and Cytarabine in Younger Patients With Acute Myeloid Leukemia 
Journal of Clinical Oncology  2010;28(11):1856-1862.
To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years.
Patients and Methods
In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m2 by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m2 IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days.
Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity.
Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.
PMCID: PMC2930809  PMID: 20212254
11.  A Phase 1-2 Study of a Farnesyltransferase Inhibitor, Tipifarnib, Combined With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome 
Cancer  2010;117(6):1236-1244.
The authors conducted a phase 1/2 study of tipifarnib in combination with idarubicin and cytarabine (IA) in 95 patients with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome.
Induction consisted of idarubicin 12 mg/m2 a day on days 1-3, cytarabine 1.5 g/m2 intravenously continuously daily on days 1-4 (days 1-3 if age ≥60 years), and tipifarnib, with the first cohort (n = 6) receiving 200 mg orally twice a day and all others receiving 300 mg twice a day for 21 days every 28 days. Consolidation consisted of 5 courses of idarubicin 8 mg/m2 a day on days 1-2, cytarabine 0.75 g/m2 a day on days 1-3, and tipifarnib 300 mg twice a day for 14 days every 4-6 weeks. Maintenance with tipifarnib 300 mg twice a day for 21 days every 4-6 weeks was continued for 6 months.
With a median follow-up of 33 months, 61 patients achieved complete remission (CR) (64%), and 9 achieved complete remission with incomplete platelet recovery (CRp) (9%). The median duration of CR was not reached. Median overall survival was 17 months. The most common grade 3 adverse events were gastrointestinal toxicities, liver dysfunction, and skin rash. Compared with historical IA, IA and tipifarnib showed a better CR duration (P = .04) and a trend toward a higher CR rate in patients with chromosome 5/7 abnormalities.
The combination of IA and tipifarnib is safe and active. Further studies exploring different dosages and schedules are warranted, particularly in patients with poor-risk AML.
PMCID: PMC4061136  PMID: 20960519
acute myeloid leukemia; tipifarnib; combination; myelodysplastic syndrome; farnesyl transferase inhibitor
12.  Safety and Pharmacokinetics of the Antisense Oligonucleotide (ASO) LY2181308 as a Single-Agent or in Combination with Idarubicin and Cytarabine in Patients with Refractory or Relapsed Acute Myeloid Leukemia (AML) 
Investigational new drugs  2013;31(4):1023-1034.
Survivin is expressed in tumor cells, including acute myeloid leukemia (AML), regulates mitosis, and prevents tumor cell death. The antisense oligonucleotide sodium LY2181308 (LY2181308) inhibits survivin expression and may cause cell cycle arrest and restore apoptosis in AML.
In this study, the safety, pharmacokinetics, and pharmacodynamics/efficacy of LY2181308 was examined in AML patients, first in a cohort with monotherapy (n=8) and then post-amendment in a cohort with the combination of cytarabine and idarubicin treatment (n=16). LY2181308 was administered with a loading dosage of 3 consecutive daily infusions of 750 mg followed by weekly intravenous (IV) maintenance doses of 750 mg. Cytarabine 1.5 g/m2 was administered as a 4-hour IV infusion on Days 3, 4, and 5 of Cycle 1, and idarubicin 12 mg/m2 was administered as a 30-minute IV infusion on Days 3, 4, and 5 of Cycle 1. Cytarabine and idarubicin were administered on Days 1, 2, and 3 of each subsequent 28-day cycle. Reduction of survivin was evaluated in peripheral blasts and bone marrow.
Single-agent LY2181308 was well tolerated and survivin was reduced only in patients with a high survivin expression. In combination with chemotherapy, 4/16 patients had complete responses, 1/16 patients had incomplete responses, and 4/16 patients had cytoreduction. Nine patients died on study: 6 (monotherapy), 3 (combination).
LY2181308 alone is well tolerated in patients with AML. In combination with cytarabine and idarubicin, LY2181308 does not appear to cause additional toxicity, and has shown some clinical benefit needing confirmation in future clinical trials.
PMCID: PMC4167763  PMID: 23397500
antisense; acute myeloid leukemia; idarubicin; cytarabine
13.  A Case of Acute Myeloid Leukemia with a Previously Unreported Translocation (14; 15) (q32; q13) 
Case Reports in Genetics  2014;2014:921240.
Background. We hereby describe what we believe to be the first reported case of t (14; 15) (q32; q13) associated with acute myeloid leukemia (AML). Methods. PubMed, Embase, and OVID search engines were used to review the related literature and similar published cases. Case. A47-year-old female presented in December 2011 with AML (acute myelomonocytic leukemia) with normal cytogenetics; molecular testing revealed FLT-3 internal tandem duplication (ITD) mutation, while no mutations involving FLT3 D385/I836, NPM1 exon 12, or KIT exons 8 and 17 were detected. She was induced with 7 + 3 (cytarabine + idarubicin) and achieved complete remission after a second induction with high-dose cytarabine (HiDAC) followed by uneventful consolidation. She presented 19 months after diagnosis with relapsed disease. Of note, at relapse cytogenetic analysis revealed t (14; 15) (q32; q13), while FLT-3 analysis showed a codon D835 mutation (no ITD mutation was detected). She proved refractory to the initial clofarabine-based regimen, so FLAG-idarubicin then was used. She continued to have persistent disease, and she was discharged on best supportive care. Conclusion. Based on this single case of AML with t (14; 15) (q32; q13), this newly reported translocation may be associated with refractory disease.
PMCID: PMC4243475  PMID: 25436161
14.  Bortezomib Added to Daunorubicin and Cytarabine During Induction Therapy and to Intermediate-Dose Cytarabine for Consolidation in Patients With Previously Untreated Acute Myeloid Leukemia Age 60 to 75 Years: CALGB (Alliance) Study 10502 
Journal of Clinical Oncology  2012;31(7):923-929.
The purpose of this study was to determine remission induction frequency when bortezomib was combined with daunorubicin and cytarabine in previously untreated older adults with acute myeloid leukemia (AML) and safety of bortezomib in combination with consolidation chemotherapy consisting of intermediate-dose cytarabine (Int-DAC).
Patients and Methods
Ninety-five adults (age 60 to 75 years; median, 67 years) with previously untreated AML (including therapy-related and previous myelodysplastic syndrome) received bortezomib 1.3 mg/m2 intravenously (IV) on days 1, 4, 8, and 11 with daunorubicin 60 mg/m2 on days 1 through 3 and cytarabine 100 mg/m2 by continuous IV infusion on days 1 through 7. Patients who achieved complete remission (CR) received up to two courses of consolidation chemotherapy with cytarabine 2 gm/m2 on days 1 through 5 with bortezomib. Three cohorts with escalating dose levels of bortezomib were tested (0.7, 1.0, and 1.3 mg/m2). Dose-limiting toxicities were assessed during the first cycle of consolidation. The relationship between cell surface expression of CD74 and clinical outcome was assessed.
Frequency of CR was 65% (62 of 95), and 4% of patients (four of 95) achieved CR with incomplete platelet recovery (CRp). Eleven patients developed grade 3 sensory neuropathy. Bortezomib plus Int-DAC proved tolerable at the highest dose tested. Lower CD74 expression was associated with CR/CRp (P = .04) but not with disease-free or overall survival.
The addition of bortezomib to standard 3 + 7 daunorubicin and cytarabine induction chemotherapy for AML resulted in an encouraging remission rate. The maximum tested dose of bortezomib administered in combination with Int-DAC for remission consolidation was 1.3 mg/m2 and proved tolerable. Further testing of this regimen is planned.
PMCID: PMC3577952  PMID: 23129738
15.  Patients With Acute Myeloid Leukemia and RAS Mutations Benefit Most From Postremission High-Dose Cytarabine: A Cancer and Leukemia Group B Study 
Journal of Clinical Oncology  2008;26(28):4603-4609.
RAS mutations occur in 12% to 27% of patients with acute myeloid leukemia (AML) and enhance sensitivity to cytarabine in vitro. We examined whether RAS mutations impact response to cytarabine in vivo.
Patients and Methods
One hundred eighty-five patients with AML achieving complete remission on Cancer and Leukemia Group B study 8525 and randomly assigned to one of three doses of cytarabine postremission were screened for RAS mutations. We assessed the impact of cytarabine dose on cumulative incidence of relapse (CIR) of patients with (mutRAS) and without (wild-type; wtRAS) RAS mutations.
Thirty-four patients (18%) had RAS mutations. With 12.9 years median follow-up, the 10-year CIR was similar for mutRAS and wtRAS patients (65% v 73%; P = .31). However, mutRAS patients receiving high-dose cytarabine consolidation (HDAC; 3 g/m2 every 12 hours on days 1, 3, and 5 or 400 mg/m2/d × 5 days) had the lowest 10-year CIR, 45%, compared with 68% for wtRAS patients receiving HDAC and 80% and 100%, respectively, for wtRAS and mutRAS patients receiving low-dose cytarabine (LDAC; 100 mg/m2/d × 5 days; overall comparison, P < .001). Multivariable analysis revealed an interaction of cytarabine dose and RAS status (P = .06). After adjusting for this interaction and cytogenetics (core binding factor [CBF] AML v non-CBF AML), wtRAS patients receiving HDAC had lower relapse risk than wtRAS patients receiving LDAC (hazard ratio [HR] = 0.67; P = .04); however, mutRAS patients receiving HDAC had greater reduction in relapse risk (HR = 0.28; P = .002) compared with mutRAS patients treated with LDAC.
AML patients carrying mutRAS benefit from higher cytarabine doses more than wtRAS patients. This seems to be the first example of an activating oncogene mutation favorably modifying response to higher drug doses in AML.
PMCID: PMC2653132  PMID: 18559876
16.  Minimal Residual Disease-Directed Therapy for Childhood Acute Myeloid Leukemia: Results of the AML02 Multicenter Trial 
The lancet oncology  2010;11(6):543-552.
We sought to improve outcome of childhood acute myeloid leukemia (AML) by applying risk-directed therapy based on the genetic abnormalities of the leukemic cells and measurements of minimal residual disease (MRD) as determined by flow cytometry during treatment.
From October 13, 2002 to June 19, 2008, 232 patients with de novo AML (n=206), therapy- or myelodysplasia-related AML (n=12), or mixed-lineage leukemia (n=14) were enrolled at eight centers. Block, nonblinded randomization, stratified by cytogenetic or morphologic subtype, assigned patients to high-dose (18 g/m2, n=113) or low-dose (2 g/m2, n=117) cytarabine (A), given together with daunorubicin (D) and etoposide (E) (Induction I); achievement of MRD negative status was the primary endpoint. Induction II consisted of ADE with or without gemtuzumab ozogamicin (GO); consolidation therapy included three additional courses of chemotherapy or hematopoietic stem cell transplantation (HSCT). Levels of MRD were used to allocate GO and determine the timing of Induction II; both MRD and genetic abnormalities at diagnosis were used to determine final risk classification. Low-risk patients (n=68) received 5 courses of chemotherapy, whereas high-risk patients (n=79), as well as standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (performed in 48 high and 8 standard-risk patients). All randomized patients (n=230) were analyzed for the primary endpoint. The other analyses were limited to the 216 patients with AML, excluding mixed-lineage leukemia. This trial, closed to accrual, is registered with, number NCT00136084.
The complete remission rates were 80% (173 of the 216) after Induction I and 94% (203 of 216) after Induction II. Induction failures included two toxic deaths and 10 cases of resistant leukemia. The introduction of high-dose cytarabine did not significantly lower the rate of MRD positivity after Induction I therapy (34% vs. 42%, P=0.17). The cumulative incidences of grade 3 or greater infection were 79.3% ± 4.0% and 75.5% ± 4.2% for patients treated on the high-dose or low-dose arms. The 3-year estimates (± SE) of event-free and overall survival were 63.0% ± 4.1% and 71.1% ± 3.8%, respectively. Achievement of MRD < 0.1% after Induction II identified a large group of patients (80%) with a cumulative incidence of relapse of only 17% ± 3%. Post-Induction I MRD ≥ 1% was the only independent adverse prognostic factor that was statistically significant (P < 0.05) for both event-free (HR, 2.41; CI 1.36–4.26; P=0.003) and overall survival (HR, 2.11; CI 1.09–4.11; P=0.028).
Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve the outcome of childhood AML.
PMCID: PMC3171799  PMID: 20451454
17.  Therapy-Related Acute Myeloid Leukemia in A Primary Pulmonary Leiomyosarcoma Patient with Skin Metastasis 
Primary pulmonary leiomyosarcoma (LMS) is a very unusual tumor. Although LMS has well-known metastatic potential, cutaneous metastasis is a remarkably uncommon. Exposure to cytotoxic agents could lead to “therapy-related myeloid neoplasm” (t-MN). Starting from 2008, the World Health Organization (WHO) has adopted the term to cover the spectrum of malignant diseases previously known as therapy-related acute myeloid leukemia (t-AML), therapy-related myelodysplastic syndrome (t-MDS) and therapy-related myelodysplastic/myelo- proliferative neoplasm (t-MDS/MPN). We described the onset of t-MDS and progression to t-AML in one case diagnosed as primary pulmonary LMS with cutaneous metastasis. This patient achieved complete remission (CR) after three courses of IA regimen chemotherapy (idarubicin 5 mg/d, d 1-3; cytarabine 100 mg/d, d 1-5) and 1 course of HA chemotherapy regimen (homoharringtonine 3 mg/d, d 1-3; cytarabine 100 mg/d, d 1-7). This case presents the natural course of therapy-related neoplasm and provides therapeutic experience for t-AML.
PMCID: PMC3587555  PMID: 23467305
Therapy-related myelodysplastic syndrome; Therapy-related acute myeloid leukemia; Leiomyosarcoma; Metastasis; Skin
18.  The combination of valproic acid, all-trans retinoic acid and low-dose cytarabine as disease-stabilizing treatment in acute myeloid leukemia 
Clinical Epigenetics  2013;5(1):13.
A large proportion of patients with acute myeloid leukemia (AML) are not fit for intensive and potentially curative therapy due to advanced age or comorbidity. Previous studies have demonstrated that a subset of these patients can benefit from disease-stabilizing therapy based on all-trans retinoic acid (ATRA) and valproic acid. Even though complete hematological remission is only achieved for exceptional patients, a relatively large subset of patients respond to this treatment with stabilization of normal peripheral blood cell counts.
In this clinical study we investigated the efficiency and safety of combining (i) continuous administration of valproic acid with (ii) intermittent oral ATRA treatment (21.5 mg/m2 twice daily) for 14 days and low-dose cytarabine (10 mg/m2 daily) for 10 days administered subcutaneously. If cytarabine could not control hyperleukocytosis it was replaced by hydroxyurea or 6-mercaptopurin to keep the peripheral blood blast count below 50 × 109/L.
The study included 36 AML patients (median age 77 years, range 48 to 90 years) unfit for conventional intensive chemotherapy; 11 patients responded to the treatment according to the myelodysplastic syndrome (MDS) response criteria and two of these responders achieved complete hematological remission. The most common response to treatment was increased and stabilized platelet counts. The responder patients had a median survival of 171 days (range 102 to > 574 days) and they could spend most of this time outside hospital, whereas the nonresponders had a median survival of 33 days (range 8 to 149 days). The valproic acid serum levels did not differ between responder and nonresponder patients and the treatment was associated with a decrease in the level of circulating regulatory T cells.
Treatment with continuous valproic acid and intermittent ATRA plus low-dose cytarabine has a low frequency of side effects and complete hematological remission is seen for a small minority of patients. However, disease stabilization is seen for a subset of AML patients unfit for conventional intensive chemotherapy.
PMCID: PMC3765924  PMID: 23915396
To determine the possibility of synergistic anti-leukemic activity and the underlying molecular mechanisms associated with cytarabine combined with valproic acid (VPA) [a histone deacetylase inhibitor (HDACI) and an FDA-licensed drug for treating both children and adults with epilepsy] in pediatric acute myeloid leukemia (AML).
Experimental Design
The type and extent of anti-leukemic interactions between cytarabine and VPA in clinically relevant pediatric AML cell lines and diagnostic blasts from children with AML were determined by MTT assays and standard isobologram analyses. The effects of cytarabine and VPA on apoptosis and cell cycle distributions were determined by flow cytometry analysis and caspase enzymatic assays. The effects of the two agents on DNA damage and Bcl-2 family proteins were determined by Western blotting.
We demonstrated synergistic antileukemic activities between cytarabine and VPA in 4 pediatric AML cell lines and 9 diagnostic AML blast samples. t(8;21) AML blasts were significantly more sensitive to VPA and showed far greater sensitivities to combined cytarabine and VPA than non-t(8;21) AML cases. Cytarabine and VPA cooperatively induced DNA double strand breaks, reflected in induction of γH2AX and apoptosis, accompanied by activation of caspases 9 and 3. Further, VPA induced Bim expression and shRNA knockdown of Bim resulted in significantly decreased apoptosis induced by cytarabine, and by cytarabine plus VPA.
Our results establish global synergistic antileukemic activity of combined VPA and cytarabine in pediatric AML and provide compelling evidence to support the use of VPA in the treatment of children with this deadly disease.
PMCID: PMC3018695  PMID: 20889917
20.  Clofarabine, Idarubicin, and Cytarabine (CIA) as Frontline Therapy for Patients ≤60 Years with Newly Diagnosed Acute Myeloid Leukemia (AML) 
American journal of hematology  2013;88(11):961-966.
To explore the combination of clofarabine, cytarabine, and idarubicin (CIA) in patients with newly diagnosed acute myeloid leukemia (AML)
Patients and Methods
Patients ≥18-60 years with AML and adequate organ functions were candidates. Induction therapy consisted of clofarabine (C) 22.5 mg/m2 IV daily (days 1-5), idarubicin (I) 6 mg/m2 IV daily (days 1-3), and cytarabine (A) 0.75 g/m2 IV daily (days 1-5). Patients in remission received up to 6 consolidation cycles (C 22.5 mg/m2 × 3, I 6 mg/m2 × 2, and A 0.75 g/m2 × 3).
Fifty-seven patients were evaluable. The overall response rate was 79%. With a median follow up of 10.9 months (range, 1.6 - 23.1), the median overall survival (OS) was not reached, the median event-free survival (EFS) was 13.5 months, and the median relapse free survival was not reached. Most toxicities were ≤ grade 2. Four week mortality was 2%. In subgroup analysis, patients ≤ 40 years had better OS (P = 0.04) and EFS (P = 0.04) compared to patients > 40 years.
Compared to historical patients treated with IA combination, the OS and EFS were significantly higher (P = 0.005, 0.0001, respectively) for CIA treated patients. In multivariate analysis, CIA retained its superior impact on OS and EFS compared to IA.
CIA is an effective combination for patients
PMCID: PMC4110914  PMID: 23877926
AML; frontline therapy; clofarabine; idarubicin; cytarabine
Cancer  2010;116(24):5659-5666.
Nausea and vomiting in patients with acute myelogenous leukemia (AML) can be from various causes, including the use of high-dose cytarabine.
The authors compared 2 schedules of palonosetron versus ondansetron in the treatment of chemotherapy-induced nausea and vomiting (CINV) in patients with AML receiving high-dose cytarabine. Patients were randomized to: 1) ondansetron, 8 mg intravenously (IV), followed by 24 mg continuous infusion 30 minutes before high-dose cytarabine and until 12 hours after the high-dose cytarabine infusion ended; 2) palonosetron, 0.25 mg IV 30 minutes before chemotherapy, daily from Day 1 of high-dose cytarabine up to Day 5; or 3) palonosetron, 0.25 mg IV 30 minutes before high-dose cytarabine on Days 1, 3, and 5.
Forty-seven patients on ondansetron and 48 patients on each of the palonosetron arms were evaluable for efficacy. Patients in the palonosetron arms achieved higher complete response rates (no emetic episodes plus no rescue medication), but the difference was not statistically significant (ondansetron, 21%; palonosetron on Days 1–5, 31%; palonosetron on Days 1, 3, and 5, 35%; P = .32). Greater than 77% of patients in each arm were free of nausea on Day 1; however, on Days 2 through 5, the proportion of patients without nausea declined similarly in all 3 groups. On Days 6 and 7, significantly more patients receiving palonosetron on Days 1 to 5 were free of nausea (P = .001 and P = .0247, respectively).
The daily assessments of emesis did not show significant differences between the study arms. Patients receiving palonosetron on Days 1 to 5 had significantly less severe nausea and experienced significantly less impact of CINV on daily activities on Days 6 and 7.
PMCID: PMC4185295  PMID: 21218459
nausea and vomiting; palonosetron; cytosine arabinoside; ondansetron
Because cladribine can increase cytarabine triphosphate levels, we tested a cladribine—cytarabine combination in the St. Jude AML97, trial in which this combination was administered before standard chemotherapy to 96 children with acute myeloid leukemia (AML) or myelodysplastic syndrome. Patients received a 5-day course of cladribine (9 mg/m2/dose) and cytarabine either as daily 2-hour infusions (500 mg/m2/dose) (arm A) or a continuous infusion (500 mg/m2/day) (arm B). Ara-CTP levels and inhibition of DNA synthesis increased from day 1 to day 2, but were not different between the two arms. In addition, the median blast percentages at day 15 did not differ between arms A and B, but patients treated in arm A had shorter intervals between the initiation of the first and second courses of therapy. Thus, although there were trends towards better CR rates and overall survival for patients treated in arm B, the reduced efficacy of arm A may have been partially compensated by more intense timing of therapy for that group. For all patients, 5-yr event-free survival and overall survival estimates were 44.1% ± 5.4 % and 50.0% ± 5.5%. Our results suggest that cladribine in combination with continuous-infusion cytarabine is effective therapy for childhood AML.
PMCID: PMC2726271  PMID: 19242495
AML; cladribine; childhood
Journal of Clinical Oncology  2011;29(24):3293-3300.
To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia.
Patients and Methods
Twelve patients with acute leukemia (11 with acute myeloid leukemia [AML]) received sorafenib on days 1 to 7 and then concurrently with cytarabine (1 g/m2) and clofarabine (stratum one: 40 mg/m2, n = 10; stratum two [recent transplantation or fungal infection]: 20 mg/m2, n = 2) on days 8 to 12. Sorafenib was continued until day 28 if tolerated. Two sorafenib dose levels (200 mg/m2 and 150 mg/m2 twice daily) were planned. Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8.
At sorafenib 200 mg/m2, two of four patients in stratum one and one of two patients in stratum two had grade 3 hand-foot skin reaction and/or rash as dose-limiting toxicities (DLTs). No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m2. Sorafenib inhibited the phosphorylation of AKT, S6 ribosomal protein, and 4E-BP1 in leukemia cells. The rate of sorafenib conversion to its metabolite sorafenib N-oxide was high (mean, 33%; range, 17% to 69%). In vitro, the N-oxide potently inhibited FLT3–internal tandem duplication (ITD; binding constant, 70 nmol/L) and the viability of five AML cell lines. On day 8, sorafenib decreased blast percentages in 10 of 12 patients (median, 66%; range, 9% to 95%). After combination chemotherapy, six patients (three FLT3-ITD and three FLT3 wild-type AML) achieved complete remission, two (both FLT3-ITD AML) had complete remission with incomplete blood count recovery, and one (FLT3 wild-type AML) had partial remission.
Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML.
PMCID: PMC3158600  PMID: 21768474
Journal of Korean Medical Science  2009;24(3):498-503.
A refractory and resistant disease to conventional induction chemotherapy and relapsed disease are considered as the most important adverse prognostic factors for acute myeloid leukemia (AML). Sixty-one patients (median age, 33.6 yr) with relapsed or refractory AML were treated with the FLAG regimen that consisted of fludarabine (30 mg/m2, days 1-5), cytarabine (2.0 g/m2, days 1-5) and granulocyte colony-stimulating factor. Of the treated patients 29 patients (47.5%) achieved complete remission (CR). Higher CR rates were observed for patients with a first or second relapse as compared to patients with a primary refractory response or relapse after stem cell transplantation (HSCT). There was a significant difference in the response rates according to the duration of leukemia-free survival (pre-LFS) before chemotherapy (P=0.05). The recovery time of both neutrophils (≥500/µL) and platelets (≥20,000/µL) required a median of 21 and 18 days, respectively. Treatment-related mortality (TRM) occurred in seven patients (11.4%), of which 71.4% of TRM was caused by an invasive aspergillosis infection. After achieving CR, 18 patients underwent consolidation chemotherapy and six patients underwent allogeneic HSCT. In conclusion, FLAG chemotherapy without idarubicin is a relatively effective and well-tolerated regimen for relapsed or refractory AML and the use of FLAG chemotherapy has allowed intensive post-remission therapy including HSCT.
PMCID: PMC2698199  PMID: 19543516
Leukemia, Myeloid, Acute; FLAG Chemotherapy; Toxicity
Chonnam Medical Journal  2011;47(2):80-84.
The sensitization of leukemia cells with hematopoietic growth factors can enhance the cytotoxicity of chemotherapy in acute myeloid leukemia (AML). Therefore, the current trial attempted to evaluate the efficacy of granulocyte colony-stimulating factor (G-CSF) priming in remission induction chemotherapy with an intensified dose of Ara-C for newly diagnosed AML. Patients with newly diagnosed AML were randomly assigned to receive idarubicin (12 mg/m2/24 hr, days 1-3) plus Ara-C (500 mg/m2/12 hr, days 4-8) with G-CSF (250 µg/m2/d, days 3-7) (IAG group) or standard idarubicin (12 mg/m2/24 hr, days 1-3) plus Ara-C (100 mg/m2/12 hr, days 1-7) without G-CSF (IA group). There were no significant differences in sex, age, subtype, or cytogenetic risk between the two groups. Complete remission was achieved in 15 patients (88.2%) from the IAG group and in 14 patients (82.4%) from the IA group (p=0.31). The median time to complete remission was 26 vs. 31 days (p=0.779) for the IA and IAG groups, respectively. The median time to neutrophil recovery (>1×109/L) and platelet recovery (>20×109/L) did not differ significantly between the two groups (26 vs. 26 days, p=0.338; 21 vs. 16 days, p=0.190, respectively). After a median follow-up of 682 days, the 3-year overall survival rate for the IA group was 64.7%, whereas that for the IAG group was 45.6% (p=0.984). No improved clinical outcomes were observed for the AML patients subjected to intensified remission induction with G-CSF priming when compared with standard induction chemotherapy.
PMCID: PMC3214872  PMID: 22111065
Acute myeloid leukemia; Cytarabine; Granulocyte colony-stimulating factor; Induction of remission

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