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. Author manuscript; available in PMC: 2014 Nov 1.
Published in final edited form as: Leuk Res. 2013 Sep 8;37(11):1502–1508. doi: 10.1016/j.leukres.2013.09.003

A phase I study using bortezomib with weekly idarubicin for treatment of elderly patients with acute myeloid leukemia

Dianna S Howard 1, Jane Liesveld 2, Gordon L Phillips II 2, John Hayslip 1, Heidi Weiss 1, Craig T Jordan 2, Monica L Guzman 3
PMCID: PMC4025941  NIHMSID: NIHMS528031  PMID: 24075534

Abstract

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.

Keywords: bortezomib, idarubicin, acute myeloid leukemia, elderly

Introduction

Acute myeloid leukemia (AML) is a hematologic cancer with median age at diagnosis of 65 years [1]. Although primarily a disorder of older adults, such patients have been largely excluded from advances in AML therapy. This is due to host-related factors that limit older patients’ tolerance of intensive therapies, as well as the frequent occurrence of myelodysplasia (MDS), unfavorable karyotypes, and overexpression of multidrug-resistance gene MDR1 at diagnosis, which contribute to a poor response to standard cytotoxic chemotherapy. Patients 60 years and older experience nearly half the rate of remission success compared to younger cohorts and are twice as likely to die during induction [2-17]. Age remains one of the most important adverse prognostic factors in AML and the optimal therapy for patients over age 60 is undefined. Regardless of age, at the time of relapse there is no widely accepted standard of care. In patients for whom a hematopoietic stem cell transplant is not an option, durable remissions after relapse are infrequent.

In recent years numerous studies have described the biologic relevance and cellular and molecular properties of normal human hematopoietic stem cells [18-21]. Furthermore, progress has been made in the characterization of malignant stem cells. Multiple groups have identified and characterized a leukemic stem cell (LSC) in patients with AML [22-26]. Prospective identification and isolation of enriched LSCs have allowed investigators to define biologic characteristics of normal versus leukemic stem cells, presenting an opportunity for targeted leukemia therapy [27]. Chemotherapeutic agents effectively ablate leukemia blast cells, but may not effectively target LSC due to the generally quiescent state of LSCs. It is plausible that the failure of standard chemotherapy to sustain durable remission in most patients with AML is related to the survival of LSC. Data from our laboratory has shown that nuclear factor kappa B (NF-kB) is constitutively activated in primary AML specimens, including the relatively quiescent LSC population. In addition, molecular genetic studies using a dominant negative allele of an inhibitor of NF-kB (IkBa) demonstrated that inhibition of NF-kB contributes to apoptosis in AML cells [28]. One action of proteasome inhibition is to block the degradation of IkBa, the NF-kB regulator, resulting in loss of NF-kB activity [29, 30]. Moreover, the apoptosis obseyrved when the proteasome inhibitor, bortezomib, is combined with idarubicin appears to be greater than bortezomib alone. This targeted therapy holds significant promise as a low-toxicity treatment in selected groups of AML patients who would otherwise have few treatment options [31, 32]. Based on the encouraging results of our preclinical studies with this combination, we initiated a phase I study translating our observations from the laboratory into the clinical setting.

Patients and methods

Patient eligibility

Eligible patients were treated at either the University of Kentucky or the University of Rochester and provided written informed consent according to the respective Institutional Review Board guidelines and in agreement with the Declaration of Helsinki. Eligibility criteria included: diagnosis of AML as defined by the World Health Organization classification [33] and meeting one of two entry criteria: 1) newly diagnosed and age ≥60 years unsuitable for intensive chemotherapy induction – antecedent hematologic disorders, pre-existing MDS, unfavorable cytogenetics, or unacceptable comorbidities; or, 2) age ≥18 with relapsed disease occurring after at least one successful complete remission. Other requirements included Karnofsky performance status >60, cardiac ejection fraction >40% by multiple-gate acquisition scan, and no symptomatic cardiac disease. Exclusion criteria included: prior induction chemotherapy for newly diagnosed AML with the exception of hydroxyurea within the preceding 14 days; prior anthracycline dose of ≥150 mg/m2 of doxorubicin or >36 mg/m2 of idarubicin [34, 35]; AML-M3; active central nervous system leukemia; or uncontrolled bacterial, fungal, or viral (including HIV) infections.

Treatment

This trial was conducted under the supervision of the University of Kentucky General Clinical Research Center funded by the National Institutes of Health, National Center for Research Resources (M01 RR02602). The combination of idarubicin and bortezomib was administered once as a remission induction regimen. Idarubicin was commercially available and was given weekly at a dose of 8-12 mg/m2 in 50 ml of normal saline as a 15-minute infusion (days 1, 8, 15, and 22)[36]. Idarubicin at 10 mg/m2 is associated with peak plasma levels around 9 ng/ml, comparable to the in vitro concentrations used in our experiments. Bortezomib was provided by Millennium Pharmaceuticals and was administered twice weekly as an intravenous push over 3 to 5 seconds on days 1, 4, 8, 11, 15, 18, 22, and 25 at least two hours after the idarubicin dose when given on the same day. This dosing schema was implemented to optimize the potential interaction between bortezomib and idarubicin. Given two hours after idarubicin, bortezomib inhibits NF-kB upregulation induced by idarubicin, thwarting an attempt at cell survival and increasing cytotoxicity of idarubicin. The dose escalation schema (Table 1) was based on doses from prior phase I studies of bortezomib [37]. Idarubicin 8 mg/m2 in a modified dose escalation schema (Table 2) was implemented after review by the Data Safety Monitoring Committee (DSMC) of initial dose-limiting toxicity on dose level one. Selected doses of bortezomib were associated with levels of proteasome inhibition that corresponded to dose-dependent inhibition of tumor growth [37-39]. This schedule of administration was designed to accomplish two important goals: 1) the administration of a tolerable outpatient regimen; and, 2) a schedule that allowed for maximal overlap of bortezomib and idarubicin, optimizing the potential for proteasome inhibition to suppress cellular attempts to resist the toxic effects of idarubicin [40, 41]. A bone marrow biopsy and aspirate was obtained on day 18; patients with aplasia (<5% cellularity) did not receive days 22 and 25 of treatment. The International Working Group criteria were used to determine response in AML [42, 43].

Table 1.

Dosing schema

Dose Level Bortezomib (mg/m2) Idarubicin (mg/m2)
I 0.8 10
II 1.0 10
III 1.2 10
IV 1.2 12
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Table 2.

Modified dosing schema. After two dose-limiting toxicities in the first cohort, the dose of idarubicin was reduced and dose escalation followed a modified strategy.

Modified Dose Level Bortezomib (mg/m2) Idarubicin (mg/m2)
I-M 0.8 8
II-M 1.0 8
III-M 1.2 8
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Study design

Study design was a standard modified Fibonacci, 3+3 design looking at four dose levels of bortezomib in combination with idarubicin. A minimum of three and a maximum of six patients were entered at each dose level. If toxicities exceeded what was defined as tolerable in one of the first three patients, the cohort was expanded to six. Evaluation of toxicity in each cohort was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0. Drug-related dose-limiting toxicity was defined as any grade 4 hematologic toxicity attributable to treatment and lasting >28 days after the last day of therapy, or any non-hematologic toxicity attributable to treatment of grade 4 or greater except for nausea/vomiting (which may be grade 4). The FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 was administered weekly to specifically assess neurotoxicity. A DSMC was established to review all adverse events semi-annually. Unacceptable toxicities in two of six patients defined the maximum tolerated dose (MTD) as one dose level lower. Once the MTD was established the study enrolled three additional patients at the established MTD.

Correlative endpoints

We sought to confirm our preclinical observation that demonstrated leukemia-specific induction of apoptosis, including in LSC, with bortezomib and idarubicin in human subjects. Patients had samples collected from peripheral blood before and after initial drug treatment to assess apoptosis in the AML cells using standard fluorescence-activated cell sorting (FACS) assays; samples were also collected for NF-kB electrophoretic mobility shift assay (EMSA). In combination with the FACS assays, we attempted to correlate Nf-kB activity with ablation of AML blasts and LSC.

Statistical considerations

Based on a 3+3 design, a maximum of 24 patients could be potentially enrolled across the four dose levels. Descriptive statistics were calculated to summarize patient characteristics, frequencies were tabulated to summarize adverse event data and clinical outcomes such as tumor response. The Kaplan-Meier curve was utilized to estimate overall survival among patients enrolled in the trial. Correlative endpoints including white blood count and absolute blast counts were displayed graphically and comparison of change from day 1 to last time point of follow-up was performed using non-parametric paired test statistics.

Results

Patients

From January 2005 through July 2008 a total of 20 eligible and consented patients were treated (Table 3). Thirteen of the 20 patients were newly diagnosed, previously untreated AML (median age 68, range 61-83); the remaining seven patients were relapsed (median age 58, range 40-77). Only 5/20 patients were <60 years (all relapsed patients); six were age 70 or older. More than half of treated patients on this study had prior MDS: 10/13 (77%) newly diagnosed and 1/7 (14%) relapsed. Patients were considered to have MDS prior to AML if a frank diagnosis of MDS was established >3 months prior to diagnosis of AML (9 patients) or had an antecedent hematologic disorder of >6 months (1 patient). One patient had FAB-M6 disease with multilineage dysplasia, presuming prior MDS. Of the three newly diagnosed patients without prior MDS, one was FAB M6, one was FAB M7, and the other had dyspoietic morphology. Cytogenetic information was available for all patients: per CALGB criteria [44], eight (40%) had high-risk, seven of those with complex karyotype. All but three patients accrued to this study were poor risk due to relapsed disease, high-risk karyotype, and/or an antecedent hematologic disorder.

Table 3.

Patient characteristics

Number of patients 20
Male / Female 15 / 5
Median age (range) 65 (40-83)
Relapsed 7
Median age (range) 58 (40-77)
Previously untreated 13
Median age (range) 68 (61-83)
Prior AHD/MDS 11
Unfavorable cytogenetics 8
Complex 7
Intermediate cytogenetics 12
Relapsed/M6/M7 6
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AHD, antecedent hematologic disease; MHS, myelodysplastic syndrome

Dose escalation and dose limiting toxicities (DLT)

Seven patients were enrolled on dose level 1 (Table 4). One patient rapidly progressed and was replaced per protocol. One DLT occurred in each cohort of three at dose level 1 (bortezomib 0.8 mg/m2 and idarubicin 10 mg/m2). The first DLT was grade 4 creatine-phosphokinase elevation in the setting of an antibiotic drug reaction and rhabdomyolysis with possible attribution to study drug. The second DLT was a death due to disseminated aspergillus that rapidly progressed at the point of bone marrow aplasia following treatment. After two unacceptable toxicities at the first dose level and at the recommendation of the DSMC, the dose of idarubicin was reduced to 8 mg/m2 and a modified dose schema was implemented, capping the dose of idarubicin at 8 mg/m2. Four patients were enrolled at the modified dose level 1 (1-M) and three patients at modified dose level 2 (2-M) – 2 patients enrolled simultaneously on level 1-M. After three patients were treated at dose level 3 (3-M), the cohort was expanded per protocol for further toxicity assessment. No further DLTs related to treatment were observed.

Table 4.

Patient summary

# Age Cytogenetic risk strata Dose Level Diagnosis Outcome at Day 50
1 61 Intermediate 1 MDS→AML Complete remission
2 69 Intermediate 1 AML with dys Complete remission
3 59 High-complex 1 Relapsed 3 Progressed – taken off study
4 49 Intermediate 1 Relapsed 1 Persistent AML
5 46 Intermediate 1 Relapsed 1 Persistent AML
6 58 High-complex 1 Relapsed 4 Toxic death
7 64 High-complex 1 MDS→AML Persistent AML
8 67 High-complex 1-M MDS→AML (M6) Death due to AML
9 68 Intermediate 1-M MDS→AML Persistent AML
10 40 Intermediate 1-M Relapsed 1 Persistent AML
11 72 High-complex 1-M AML with AHD Death due to AML
12 70 High-complex 2-M MDS→AML Persistent AML
13 67 Intermediate 2-M CMMoL→AML Partial remission - CMMoL
14 65 Intermediate 2-M AML (M6) Persistent AML
15 80 Intermediate 3-M MDS→AML Persistent AML
16 65 High t(6;9) 3-M Relapsed 1 Persistent AML
17 77 Intermediate 3-M Relapsed 1 (M6) Death due to AML
18 83 Intermediate 3-M MDS→AML Complete remission
19 65 High-complex 3-M MDS→AML Death due to AML
20 71 Intermediate 3-M AML (M7) Complete remission
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AHD, antecedent hematologic disease; AML, acute myeloid leukemia; CMMoL, chronic myelomonocytic leukemia; dys, dyspoiesis; MDS, myelodysplastic syndrome

Adverse events

The most commonly observed events were hematologic and neutropenic fever with or without documented infection (Table 5). Since these events are expected in this population, they were not considered dose-limiting toxicities. Hematologic events were not tallied unless they met criteria for DLT and none did. All but two patients experienced one or more episodes of grade 1-3 neutropenic fever or documented infections. One grade 5 infection was observed – death from invasive fungal pneumonia at post-treatment nadir as described above. Eighteen episodes of febrile neutropenia occurred in fifteen patients. Commonly reported non-infection adverse events included constitutional symptoms – fatigue, anorexia, sweats, myalgias, and generalized weakness. Three patients experienced grade 1 or 2 mucositis. No patient experienced symptoms of neuropathy, nor any neurotoxicity greater than grade 2. There was one grade 4 non-hematologic, non-infection toxicity: one patient developed grade 4 creatinephosphokinase elevation – a DLT, which resolved completely. Few pulmonary, cardiac, or renal serious adverse events above grade 3 were observed. These events occurred uniformly in patients with refractory AML irrespective of the treatment dose-level and were not attributed to treatment. One treatment related death occurred on study; four patients died on study (before day 50) from refractory AML.

Table 5.

Adverse events attributable to treatment

Toxicity Gr 1 Gr 2 Gr 3 Gr 4 Gr 5
Infection: Documented infection including bacteremia and pneumonia 1 6 16 1
Febrile Neutropenia: Requiring admission (3 patients with 2 episodes) 17
Respiratory: Pulmonary events - ARDS; shortness of air; pleural effusion; pleuritic chest pain; hypoxia 1 5
Mucositis: Oral mucositis / sore mouth or throat 2 1
Constitutional: Sweats, myalgias, weakness, fatigue, anorexia, dizziness 6 12 1
Skin: Rash/skin integrity 1 3
Pain: Swollen knee; swollen elbow; shoulder 1 2
Gastrointestinal: Constipation; abdominal pain; diarrhea; nausea/vomiting 1 5 2
Cardiac: Left ventricular dysfunction; atrial fibrillation; hypotension; syncope 2 5
Metabolic: Creatinine phosphokinase, amylase, lipase, transaminases 1 2 1 1
Renal insufficiency 2 1 1
Neurologic: Dysphagia; headache; depression; intracranial hemorrhage 1 3
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Clinical response

Most patients (15/20) demonstrated a hematologic response to treatment evidenced by a decrease in circulating blasts (Figure 1); four patients did not have circulating blasts to evaluate. One patient with a high white blood count and blast count had no response and was taken off study due to rapid progression and leukocytosis (Table 6). Four patients developed progressive disease before day 50 analysis of response and died from AML – three of them were initially responsive to treatment. There was one treatment related death on study. One patient met criteria for partial remission (reverted to CMML-1) – for our study, PR was defined as >50% reduction in blasts. An additional nine patients did not achieve remission with this induction regimen but survived beyond the day 50 analysis of response, suggesting potential benefit from treatment not reflected in CR status. Of these, two went on to have allogeneic bone marrow transplant. The median length of survival for those nine patients was 4.7 months (Figure 2). Four of 20 treated patients achieved a complete remission – two at dose level 1 and two at dose level 3-M. The first patient treated on this study is still alive, in remission for >7 years; another patient who achieved CR had a remission of more than 6 months. The median survival for this entire group of very high-risk group of treated patients was 3.83 months (Figure 3).

Figure 1.

Figure 1

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Patients with circulating blasts demonstrated a biologic effect by decreased absolute blast counts.

Table 6.

Outcomes

Outcome Number of Patients (n=20)
Complete remission 4
Partial remission 1
Progressive disease – progressed on or after day 50 9
Progressive disease – died before day 50 due to AML 4
Progressive disease – came off study 1
Treatment related mortality 1
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Figure 2.

Figure 2

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Subgroup survival – patients who did not achieve remission, survived beyond 50 days; potential benefit from treatment not reflected as complete remission.

Figure 3.

Figure 3

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Overall group survival.

Correlative studies

All patients had samples collected for correlative studies following administration of bortezomib and idarubicin. The kinetics of cell death in the AML cells obtained from peripheral blood specimens were carefully monitored post-treatment by standard FACS assays for immunophenotype and Annexin V/7AAD labeling to determine cell viability. Our pre-clinical studies had shown that NF-kB activity was closely correlated with the efficacy of AML cell ablation. There was a statistically significant (p=0.0017) decrease in blast count from day 1 to day 25 among patients enrolled in the trial. This was also demonstrated (p=0.0039) for a subgroup of patients with measureable peripheral blood blast counts above 100. Patients 2, 4, 5, 8, 9, 10, 11, 12, 15, and 20 showed a steep decrease in peripheral blood blasts by FACS analysis (see Figure 1). Electrophoretic mobility shift (EMSA) assays and immunoblots were performed for patients where mononuclear cells were able to be collected. We observed that for patients 1 and 2 NF-kB activity decreased after drug exposure (Figure 4A). Both of these patients achieved CR. In contrast, patient 3 (displayed disease progression) NF-kB activity was not affected by treatment. We have previously shown that activation of p53 is observed in vitro after treatment with bortezomib and idarubicin [45]. Thus, we evaluated phosphorylation of p53 by immunoblots for phospho-p53. We observed that patients 1 and 2 showed an increased activation of p53 (Figure 4B). Our data suggests that inhibition of NF-kB and activation of p53 are associated with the activity of bortezomib and idarubicin in AML blasts. However, due to the difficulty of collecting sufficient mononuclear cells for all patients enrolled in the study, significance cannot be evaluated.

Figure 4.

Figure 4

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Patients with a biologic effect demonstrated decreased NF-kB activity and activation of p53 post-treatment. (A) Electrophoretic mobility shift (EMSA) assays for NF-kB in mononuclear cells. (B) immunoblots for phospho-p53 and β-actin.

Discussion

In this study we treated both newly diagnosed elderly patients and relapsed patients, given the poor risk associated with both groups. Inherent in both groups is an increased proportion of unfavorable cytogenetics, resistance to standard chemotherapies, suboptimal remission rates, and potential for co-morbidities that affect response to chemotherapy. This phase I study demonstrated the feasibility of the combination. The schedule of administration was designed to accomplish two important goals: 1) administration of a tolerable outpatient chemotherapy regimen in a typically advanced age population; and, 2) a dosing schedule that allowed for maximal overlap of bortezomib and idarubicin. Since in vitro data has demonstrated that the combination of the drugs produced an increase in the induction of apoptosis when compared to either agent alone, this dosing schedule was selected to promote the potential interaction of bortezomib with idarubicin in such a way that NF-kB driven cellular attempts to resist the toxic effects of idarubicin may be overcome by proteasome inhibition [40, 41]. Demonstrating the potential for efficacy in vivo of this combination represented an important therapeutic advance for this very poor-risk patient population with key implications on the applicability of this combination in the treatment of all AML patients.

Our results with this combination of drugs in the treatment of poor-risk and older adult patients with AML are encouraging. While this study was not designed to evaluate efficacy, it is noteworthy that there were 4/20 (20%) complete remissions in a cohort of very unfavorable patients (see Table 6). Eleven of the 20 patients had previously been diagnosed with MDS or as with one patient had an antecedent hematologic disorder. Eight patients had an unfavorable karyotype, with seven of them having complex cytogenetic rearrangements. Of the patients with intermediate cytogenetics, the majority were normal karyotype; however, these patients with “intermediate” cytogenetics included two with M6 and one with M7 FAB classification, one with dyspoiesis and del 20q, as well as one with chronic myelomonocytic leukemia. The four patients that achieved complete remission included a patient with an antecedent hematologic disorder for a few years, who remains in complete remission >7 years; a patient with dyspoietic features and del 20q; a secondary AML in an 83-year-old with leukemia cutis; and a patient with M7 AML and no known prior AHD or MDS. Two of six patients age 70 or older were among those that achieved complete remission with treatment. There was nothing clinically observed that set apart the responders from the non-responders.

This clinical trial established the MTD of the combination of bortezomib and idarubicin in AML. A DSMC reviewed the data and confirmed the study had met this objective. Once the MTD was established, the design of the study allowed for an expanded cohort to a predefined efficacy endpoint. However, for an efficacy evaluation there would have to be >7 complete remissions in 24 patients. From the outset, the authors recognized the potential that significant therapeutic benefit might not be demonstrated in the proposed study. It was nevertheless believed that the outcome of this study would be informative. In the 20 patients treated, four achieved complete remission; demonstrating an efficacy endpoint could not be achieved with this study. Nevertheless, in this phase I study of very poor-risk AML patients, four achieved a complete response (20%), making this combination worthy of future study.

This study allowed us to gain clinical experience and make in vivo observations with a drug regimen with a strong pre-clinical rationale. Refining dose regimen and drug use in patient populations is critical for the evolution of better therapeutic regimens for hematologic malignancy. Our preclinical work with this combination prompted the work of other investigators who have continued to explore a role for bortezomib in the treatment of AML through cooperative group clinical trials in adult and pediatric populations [46-49]. This study provided a unique opportunity to assess for the biologic effects of a targeted combination. While laboratory studies demonstrated leukemia-specific induction of apoptosis could be achieved with this combination, future studies should focus on NF-kB regulated gene analyses such as cIAP, Bcl-xL, and C-FLIP – previous analyses of primary AML cells indicate reduced expression of cIAP and/or Bcl-xL can be used as a surrogate measure of NF-kB activity (Craig Jordan, unpublished), and importantly, can be performed in specimens where cell numbers are limiting.

Acknowledgements

Funding: This study was supported by Millennium Pharmaceuticals and NIH/NCI grant R21 CA108162-01A1, neither of which were involved in the study design, collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

Abbreviations

AML

acute myeloid leukemia

DLT

dose-limiting toxicity

DSMC

Data Safety Monitoring Committee

EMSA

electrophoretic mobility shift assay

FACS

Fluorescence-activated Cell Sorting

iKBa

inhibitor of NF-kB

LSC

leukemic stem cell

MDS

myelodysplastic syndrome

MTD

maximum tolerated dose

NF-kB

nuclear factor kappa B

Footnotes

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Disclosures: The authors have no relevant conflicts of interest to disclose.

Authors' contributions: Dianna S. Howard, Jane Liesveld, Gordon L. Phillips II, John Hayslip, Heidi Weiss, Craig T. Jordan and Monica L. Guzman
  1. Conception and design of the study, or data acquisition, analysis, interpretation: DSH, JL, CTJ, MLG, HW
  2. Drafting the article or revising it critically for important intellectual content: GLP, JWH
  3. Final approval of the version to be submitted: DSH, JL, GLP, JH, HW, CTJ, MLG

Conflict of Interest: None of the authors have any financial or personal relationships with other people or organizations that could inappropriately influence (bias) their work, such as employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding.

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