H Jean Khoury

Emory University, Atlanta, Georgia, United States

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Publications (156)1032.52 Total impact

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    ABSTRACT: How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a reactive oxygen species scavenging enzyme glutathione peroxidase 1. Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer Cell 02/2015; 27(2):257-70. DOI:10.1016/j.ccell.2014.12.006 · 23.89 Impact Factor
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    ABSTRACT: Survival has increased dramatically for patients with chronic phase chronic myeloid leukemia (CP-CML) using BCR-ABL targeted tyrosine kinase inhibitors, such that life expectancy is expected to approximate that of patients without CP-CML. Randomized controlled trials (RCTs) and observational studies provide valuable insights into the management of chronic diseases such as CP-CML. RCTs are undoubtedly the backbone of clinical research, and the 'gold standard' for evaluating the efficacy and safety of new therapies. However, many questions surrounding the optimal management of patients with CML remain unanswered, and it is widely accepted that these questions will be best answered by evaluating the use of available therapies in clinical practice. Observational studies can extend the knowledge base beyond the clinical trial setting and thus capture a more accurate picture of everyday clinical practice, particularly patients' experiences of long-term CML treatment. There is therefore growing interest in and appreciation of the value of observational research. This review article will examine the relative merits of RCTs and observational studies in the setting of CML, highlighting those factors - such as the advancing age of the CML patient population and growing importance of patient-reported outcomes - that mean that observational studies should play an important role in shaping clinical practice. This article also provides an overview of what observational studies have told us thus far about the optimal management of patients with CML, outlines some of the key remaining unanswered clinical questions in CML, and summarizes ongoing observational studies designed to provide answers to these key questions.
    02/2015; 6(1):3-14. DOI:10.1177/2040620714560305
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    ABSTRACT: Omacetaxine, a protein synthesis inhibitor, is indicated in the United States for the treatment of patients with chronic-phase (CP) or accelerated-phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors. The final analysis, with 24 months of follow-up, included additional efficacy and safety analyses to assess the benefit of long-term omacetaxine administration (1.25 mg/m(2) twice daily for 14 days every 28 days followed by 7 days every 28 days) in CP-CML and AP-CML patients receiving >3 cycles. Eighteen percent of CP-CML patients achieved a major cytogenetic response (MCyR) with a median duration of 12.5 months (95% confidence interval [CI], 3.5 months to not reached [NR]); responses were maintained for ≥12 months in 3 of 14 responders, and the median overall survival (OS) was 40.3 months (95% CI, 23.8 months to NR). Among patients with AP-CML, 14% achieved or maintained a major hematologic response for a median of 4.7 months (95% CI, 3.6 months to NR); MCyR was not achieved, and the median OS was 14.3 months (95% CI, 6.7-18.7 months). In patients with CP-CML and patients with AP-CML who received >3 cycles of treatment (n = 50 and n = 14, respectively), the median OS was 49.3 months (95% CI, 23.8 months to NR) and 24.6 months (95% CI, 12-37.2 months), respectively. Grade 3 or higher hematologic toxicities were the major side effects (79% and 73% for CP-CML and AP-CML, respectively), with discontinuation due to toxicity in 10% of CP patients and in 5% of AP patients. These results suggest that the long-term administration of omacetaxine is feasible with dose adjustments to manage toxicities and that omacetaxine provides a durable benefit for some patients. Cancer 2015. © 2015 American Cancer Society. © 2015 American Cancer Society.
    Cancer 01/2015; DOI:10.1002/cncr.29240 · 5.20 Impact Factor
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    ABSTRACT: Abstract Quantitative detection of BCR-ABL1 transcript is essential in monitoring residual disease of Philadelphia chromosome positive B lymphoblastic leukemia (Ph+ B-LL). We studied the kinetics of BCR-ABL1 transcript in 41 Ph+ B-LL patients in correlation with their clinical outcome. Twenty three patients achieved complete molecular remission at 6 months post-treatment. This was associated with a lower relapse risk and better overall survival. Likewise, sustainable complete molecular remission in 27 patients was associated with superior clinical outcome. Sporadic low level BCR-ABL1 was detected in 12 of 27 patients who had attained complete molecular remission. The relapse rate was significantly higher in non-transplant patients with persistent positive BCR-ABL1 than patients transplanted when BCR-ABL1 was detectable. All 8 patients harboring ABL1 kinase domain mutations died of disease or were transferred to hospice care. We concluded that monitoring the level of BCR-ABL1 transcript after hematologic remission has predictive value to the long term outcome.
    Leukemia and Lymphoma 01/2015; DOI:10.3109/10428194.2014.1003059 · 2.61 Impact Factor
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    ABSTRACT: Cyclophosphamide in combination with busulfan (Bu) or total body irradiation (TBI) are the most commonly used myeloablative conditioning regimens in patients with Chronic Myeloid Leukemia (CML). We used data from the Center for International Bone Marrow Transplantation Research to compare outcomes in adults who underwent hematopoietic cell transplantation for CML in first chronic phase following myeloablative conditioning with cyclophosphamide (Cy) in combination with TBI, oral Bu or intravenous (IV) Bu. Four hundred thirty-eight adults received human leukocyte antigen (HLA)-matched sibling grafts and 235 received well-matched grafts from unrelated donors from 2000 through 2006. Important differences existed between the groups in distribution of donor relation, exposure to tyrosine kinase inhibitors and year of transplantation. In multivariate analysis, relapse occurred less frequently among patients receiving IV Bu compared to TBI (RR=0.36; P=0.022) or oral Bu (RR=0.39; P=0.028), but non-relapse mortality and survival were similar. A significant interaction was detected between donor relation and the main effect in leukemia-free survival (LFS). Among recipients of HLA-identical sibling grafts, but not URD grafts, LFS was better in patients receiving IV (RR=0.53; P=0.025) or oral Bu (RR=0.64; P=0.017) compared to TBI. In CML in first chronic phase, Cy in combination with IV Bu was associated with less relapse than TBI or oral Bu. LFS was better following IV or oral Bu compared to TBI. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2014; DOI:10.1016/j.bbmt.2014.12.010 · 3.15 Impact Factor
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    ABSTRACT: Purpose: Data suggest that activity of p38 MAPK and Tie2 kinase are dysregulated in MDS and may be targets for novel therapies. A Phase 1 study of ARRY 614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by IWG 2006 criteria. Experimental Design: Forty-five patients received ARRY-614 either QD or BID in dose escalation (400, 600, 900 or 1200 mg QD; 200 or 300 mg BID) or expansion cohorts. Results: The 300 mg BID schedule was not tolerated, and a maximum tolerated dose was not reached for QD dosing. Treatment-related adverse events were primarily grade 1-2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Inter-patient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 RBC transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI. Conclusions: ARRY-614 was well tolerated with sufficient activity to warrant further evaluation in this patient population. We recommend 1200 mg QD as the optimal dose for further study. This study was registered at http://www.clinicaltrials.gov as NCT00916227. Copyright © 2014, American Association for Cancer Research.
    Clinical Cancer Research 12/2014; DOI:10.1158/1078-0432.CCR-14-1765 · 8.19 Impact Factor
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    ABSTRACT: BACKGROUND Flow cytometry (FC) is a commonly requested test in the workup of leukocytosis in community practices. The role of FC in chronic-phase chronic myeloid leukemia (CP-CML) is unknown. We hypothesized that finding aberrant cells with FC in CP-CML may predict early blast-phase (BP) transformation.METHODS Results for FC performed at the time of diagnosis for adult and pediatric patients with CP-CML who were referred to our institution were reviewed, and they were correlated with outcomes.RESULTSFC was performed at the time of diagnosis for 110 of 233 patients (47%) with CP-CML. Aberrant populations, representing a median of 2% (range, 0.3%-15%), were detected with FC in 30% of patients (33 of 110): 2 of these 33 patients expressed lymphoid markers, and 31 expressed aberrant myeloid markers. Patients received imatinib (85%), dasatinib (12%), or nilotinib (3%) as their first-line treatment. With a median follow-up of 43 months (range, 2-113 months), chronic myeloid leukemia transformed to BP in 5 of the 33 patients. The 2 patients with lymphoid markers and the 3 of 31 patients with aberrant myeloid markers experienced a transformation to lymphoid BP at a median of 11 months (range, 4-72 months) after the initiation of tyrosine kinase inhibitor therapy. Although both cases with detectable lymphoid markers rapidly progressed to lymphoid BP, the positive predictive value of BP transformation by the detection of myeloid aberrant cells with FC was only 10% (3 of 31).CONCLUSIONS In contrast to aberrant myeloid markers, the detection of lymphoid markers by FC at the time of the diagnosis of CP-CML appears to be associated with early progression to lymphoid BP. Cancer 2014. © 2014 American Cancer Society.
    Cancer 11/2014; DOI:10.1002/cncr.29142 · 5.20 Impact Factor
  • Ann Q Shen, Mihaela Munteanu, Hanna Jean Khoury
    The Oncologist 10/2014; DOI:10.1634/theoncologist.2014-0230 · 4.54 Impact Factor
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    ABSTRACT: Resistance to the BCR-ABL inhibitor imatinib mesylate (IM) poses a major problem for the treatment of chronic myeloid leukemia (CML). IM resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, in many instances, there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent IM resistance remains to be elucidated. To gain insight into BCR-ABL-independent IM resistance mechanisms, we performed a large-scale RNA interference screen and identified IM-sensitizing genes (IMSGs) whose knockdown renders BCR-ABL(+) cells IM-resistant. In these IMSG knockdown cells, RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling is sustained after IM treatment because of up-regulation of PRKCH, which encodes the protein kinase C (PKC) family member PKCη, an activator of CRAF. PRKCH is also up-regulated in samples from CML patients with BCR-ABL-independent IM resistance. Combined treatment with IM and trametinib, a U.S. Food and Drug Administration-approved MEK inhibitor, synergistically kills BCR-ABL(+) IMSG knockdown cells and prolongs survival in mouse models of BCR-ABL-independent IM-resistant CML. Finally, we showed that CML stem cells contain high levels of PRKCH, and this contributes to their intrinsic IM resistance. Combined treatment with IM and trametinib synergistically kills CML stem cells with negligible effect on normal hematopoietic stem cells. Collectively, our results identify a therapeutically targetable mechanism of BCR-ABL-independent IM resistance in CML and CML stem cells.
    Science translational medicine 09/2014; 6(252):252ra121. DOI:10.1126/scitranslmed.3009073 · 14.41 Impact Factor
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    ABSTRACT: BACKGROUND. Anemia, or low blood hemoglobin (Hgb) levels, afflicts 2 billion people worldwide. Currently, Hgb levels are typically measured from blood samples using hematology analyzers, which are housed in hospitals, clinics, or commercial laboratories and require skilled technicians to operate. A reliable, inexpensive point-of-care (POC) Hgb test would enable cost-effective anemia screening and chronically anemic patients to self-monitor their disease. We present a rapid, stand-alone, and disposable POC anemia test that, via a single drop of blood, outputs color-based visual results that correlate with Hgb levels. METHODS. We tested blood from 238 pediatric and adult patients with anemia of varying degrees and etiologies and compared hematology analyzer Hgb levels with POC Hgb levels, which were estimated via visual interpretation using a color scale and an optional smartphone app for automated analysis. RESULTS. POC Hgb levels correlated with hematology analyzer Hgb levels (r = 0.864 and r = 0.856 for visual interpretation and smartphone app, respectively), and both POC test methods yielded comparable sensitivity and specificity for detecting any anemia (n = 178) (<11 g/dl) (sensitivity: 90.2% and 91.1%, specificity: 83.7% and 79.2%, respectively) and severe anemia (n = 10) (<7 g/dl) (sensitivity: 90.0% and 100%, specificity: 94.6% and 93.9%, respectively). CONCLUSIONS. These results demonstrate the feasibility of this POC color-based diagnostic test for self-screening/self-monitoring of anemia. TRIAL REGISTRATION. Not applicable. FUNDING. This work was funded by the FDA-funded Atlantic Pediatric Device Consortium, the Georgia Research Alliance, Children's Healthcare of Atlanta, the Georgia Center of Innovation for Manufacturing, and the InVenture Prize and Ideas to Serve competitions at the Georgia Institute of Technology.
    Journal of Clinical Investigation 08/2014; 124(10). DOI:10.1172/JCI76666 · 13.77 Impact Factor
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    ABSTRACT: Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph+) leukemia, including the recalcitrant BCR-ABL1T315I mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph+ leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.
    Cancer Cell 08/2014; 26(3). DOI:10.1016/j.ccr.2014.07.006. · 23.89 Impact Factor
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    ABSTRACT: The mitochondrial pyruvate dehydrogenase complex (PDC) plays a crucial role in regulation of glucose homoeostasis in mammalian cells. PDC flux depends on catalytic activity of the most important enzyme component pyruvate dehydrogenase (PDH). PDH kinase (PDK) inactivates PDC by phosphorylating PDH at specific serine residues including S293, while dephosphorylation of PDH by PDH phosphatase (PDP) restores PDC activity. The current understanding suggests that S293 phosphorylation of PDH impedes active site accessibility to its substrate pyruvate. Here we report that phosphorylation of a tyrosine residue Y301 also inhibits PDHA1 by blocking pyruvate binding through an independent mechanism in addition to S293 phosphorylation. In addition, we found that multiple oncogenic tyrosine kinases directly phosphorylate PDHA1 at Y301, and Y301 phosphorylation of PDHA1 is common in EGF-stimulated cells as well as diverse human cancer cells and primary leukemia cells from human patients. Moreover, expression of a phosphorylation-deficient PDHA1 Y301F mutant in cancer cells resulted in increased oxidative phosphorylation, decreased cell proliferation under hypoxia, and reduced tumor growth in mice. Together, our findings suggest that phosphorylation at distinct serine and tyrosine residues inhibits PDHA1 through distinct mechanisms to impact active site accessibility, which act in concert to regulate PDC activity and promote the Warburg effect.
    Journal of Biological Chemistry 08/2014; 289(38). DOI:10.1074/jbc.M114.593970 · 4.60 Impact Factor
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    ABSTRACT: We investigated an apparent increase in acute lymphoblastic leukemia (ALL) referrals from northern Georgia to a tertiary care center located in Atlanta.
    Southern Medical Journal 08/2014; 107(8):497-500. DOI:10.14423/SMJ.0000000000000146 · 1.12 Impact Factor
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    ABSTRACT: Although the oxidative pentose phosphate pathway is important for tumor growth, how 6-phosphogluconate dehydrogenase (6PGD) in this pathway is upregulated in human cancers is unknown. We found that 6PGD is commonly activated in EGF-stimulated cells and human cancer cells by lysine acetylation. Acetylation at K76 and K294 of 6PGD promotes NADP(+) binding to 6PGD and formation of active 6PGD dimers, respectively. Moreover, we identified DLAT and ACAT2 as upstream acetyltransferases of K76 and K294, respectively, and HDAC4 as the deacetylase of both sites. Expressing acetyl-deficient mutants of 6PGD in cancer cells significantly attenuated cell proliferation and tumor growth. This is due in part to reduced levels of 6PGD products ribulose-5-phosphate and NADPH, which led to reduced RNA and lipid biosynthesis as well as elevated ROS. Furthermore, 6PGD activity is upregulated with increased lysine acetylation in primary leukemia cells from human patients, providing mechanistic insights into 6PGD upregulation in cancer cells.
    Molecular Cell 07/2014; 55(4). DOI:10.1016/j.molcel.2014.06.020 · 14.46 Impact Factor
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    ABSTRACT: Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor for treatment of chronic myeloid leukemia (CML) following resistance/intolerance to prior therapy. Here we report the data from the 2-year follow-up of a phase 1/2 open-label study evaluating the efficacy and safety of bosutinib as second-line therapy in 288 patients with chronic phase CML resistant (n = 200) or intolerant (n = 88) to imatinib. The cumulative response rates to bosutinib were as follows: 85% achieved/maintained complete hematologic response, 59% achieved/maintained major cytogenetic response (including 48% with complete cytogenetic response), and 35% achieved major molecular response. Responses were durable, with 2-year estimates of retaining response >70%. Two-year probabilities of progression-free survival and overall survival were 81% and 91%, respectively. The most common toxicities were primarily gastrointestinal adverse events (diarrhea [84%], nausea [45%], vomiting [37%]), which were primarily mild to moderate, typically transient, and first occurred early during treatment. Thrombocytopenia was the most common grade 3/4 hematologic laboratory abnormality (24%). Outcomes were generally similar among imatinib-resistant and imatinib-intolerant patients and did not differ with age. The longer-term results of the present analysis confirm that bosutinib is an effective and tolerable second-line therapy for patients with imatinib-resistant or imatinib-intolerant chronic phase CML.
    American Journal of Hematology 07/2014; 89(7). DOI:10.1002/ajh.23728 · 3.48 Impact Factor
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    ABSTRACT: Many cancer cells rely more on aerobic glycolysis (the Warburg effect) than mitochondrial oxidative phosphorylation and catabolize glucose at a high rate. Such a metabolic switch is suggested to be due in part to functional attenuation of mitochondria in cancer cells. However, how oncogenic signals attenuate mitochondrial function and promote the switch to glycolysis remains unclear. We previously reported that tyrosine phosphorylation activates and inhibits mitochondrial pyruvate dehydrogenase kinase (PDK) and phosphatase (PDP), respectively, leading to enhanced inhibitory serine phosphorylation of pyruvate dehydrogenase (PDH) and consequently inhibition of pyruvate dehydrogenase complex (PDC) in cancer cells. In particular, Y381 phosphorylation of PDP1 dissociates deacetylase SIRT3 and recruits acetyltransferase ACAT1 to PDC, resulting in increased inhibitory lysine acetylation of PDHA1 and PDP1. Here we report that phosphorylation at another tyrosine residue, Y94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyl-transferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Y94, and Y94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients. Moreover, expression of a phosphorylation-deficient PDP1 Y94F mutant in cancer cells resulted in increased oxidative phosphorylation, decreased cell proliferation under hypoxia, and reduced tumor growth in mice. Together, our findings suggest that phosphorylation at different tyrosine residues inhibits PDP1 through independent mechanisms, which act in concert to regulate PDC activity and promote the Warburg effect.
    Journal of Biological Chemistry 06/2014; 289(31). DOI:10.1074/jbc.M114.581124 · 4.60 Impact Factor
  • Journal of Clinical Oncology 06/2014; DOI:10.1200/JCO.2013.50.1221 · 17.88 Impact Factor
  • H Jean Khoury, Dale L. Bixby
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    ABSTRACT: ABSTRACT The therapeutic landscape of chronic-phase chronic myeloid leukemia (CP-CML) has truly been revolutionized with the advent of BCR-ABL1 tyrosine-kinase inhibitor (TKI) therapy. First-line therapy with the TKI imatinib has produced high rates of remissions among treatment-naive patients, as well as patients previously treated with interferon. However, imatinib resistance and intolerance remain significant clinical challenges. Dasatinib, nilotinib, bosutinib, and ponatinib are more recently developed TKIs that have been shown to be very effective as second- or later-line treatment for CML after imatinib failure. Dasatinib and nilotinib are also approved for use in newly diagnosed patients with CP-CML, and produce faster responses when compared with first-line imatinib. Resistance or intolerance can occur with any of the currently available TKIs, necessitating a change to an alternate TKI or consideration of allogeneic hematopoietic stem cell transplant. Treatment options and outcomes for patients whose first-line therapy has failed are reviewed in depth in this article.
    Leukemia and Lymphoma 06/2014; DOI:10.3109/10428194.2014.918969 · 2.61 Impact Factor
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    ABSTRACT: Purpose Hematopoietic stem cell transplantation (HSCT) is the mainstay of treatment for adults with acute leukemia. Total body irradiation (TBI) remains an important part of the conditioning regimen for HCST. For those patients unable to tolerate myeloablative TBI (mTBI), reduced intensity TBI (riTBI) is commonly used. In this study we compared outcomes of patients undergoing mTBI with those of patients undergoing riTBI in our institution. Methods and Materials We performed a retrospective review of all patients with acute leukemia who underwent TBI-based conditioning, using a prospectively acquired database of HSCT patients treated at our institution. Patient data including details of the transplantation procedure, disease status, Karnofsky performance status (KPS), response rates, toxicity, survival time, and time to progression were extracted. Patient outcomes for various radiation therapy regimens were examined. Descriptive statistical analysis was performed. Results Between June 1985 and July 2012, 226 patients with acute leukemia underwent TBI as conditioning for HSCT. Of those patients, 180 had full radiation therapy data available; 83 had acute lymphoblastic leukemia and 94 had acute myelogenous leukemia; 45 patients received riTBI, and 135 received mTBI. Median overall survival (OS) was 13.7 months. Median relapse-free survival (RFS) for all patients was 10.2 months. Controlling for age, sex, KPS, disease status, and diagnosis, there were no significant differences in OS or RFS between patients who underwent riTBI and those who underwent mTBI (P=.402, P=.499, respectively). Median length of hospital stay was shorter for patients who received riTBI than for those who received mTBI (16 days vs 23 days, respectively; P<.001), and intensive care unit admissions were less frequent following riTBI than mTBI (2.22% vs 12.69%, respectively, P=.043). Nonrelapse survival rates were also similar (P=.186). Conclusions No differences in OS or RFS were seen between all patients undergoing riTBI and those undergoing mTBI, despite older age and potential increased comorbidity of riTBI patients. riTBI regimens were associated with shorter length of hospital stay, fewer intensive care unit admissions, and similar rates of nonrelapse survival, which may reflect reduced toxicity. Prospective trials comparing riTBI and mTBI are warranted.
    International journal of radiation oncology, biology, physics 06/2014; 89(2):360–369. DOI:10.1016/j.ijrobp.2014.02.032 · 4.59 Impact Factor
  • Brittany G Hill, Vamsi K Kota, Hanna Jean Khoury
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    ABSTRACT: Bosutinib is an oral tyrosine kinase inhibitor (TKI) with very potent dual inhibitory activity against SRC and abelson gene. Bosutinib was approved in 2012 for the treatment of resistant Philadelphia chromosome positive chronic myeloid leukemia (CML). Bosutinib is a very effective TKI against all phases of intolerant or resistant CML regardless of the presence or absence of an abelson gene domain mutation, except for cases with detectable T315I or V299L. Bosutinib is overall well tolerated and associated with a unique, but manageable toxicity profile. Factors that influence the prescribing pattern of this drug are complex and include physicians', and increasingly patients and families' preference, patients' comorbid conditions, schedule of administration, as well as financial factors. This paper provides an overview of CML, the TKI market, pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of bosutinib.
    Expert Review of Anticancer Therapy 05/2014; DOI:10.1586/14737140.2014.924400 · 3.22 Impact Factor

Publication Stats

3k Citations
1,032.52 Total Impact Points


  • 2005–2015
    • Emory University
      • • Department of Hematology and Medical Oncology
      • • Winship Cancer Institute
      Atlanta, Georgia, United States
  • 2006–2014
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
    • University of Washington Seattle
      Seattle, Washington, United States
    • Barnes Jewish Hospital
      San Luis, Missouri, United States
    • Medical College of Wisconsin
      • Center for International Blood & Marrow Transplant Research
      Milwaukee, WI, United States
  • 2013
    • University of Wales
      Cardiff, Wales, United Kingdom
  • 2012
    • The Nebraska Medical Center
      Omaha, Nebraska, United States
  • 2010
    • University Hospitals Bristol NHS Foundation Trust
      Bristol, England, United Kingdom
    • New York Blood Center
      New York City, New York, United States
    • University of Toronto
      Toronto, Ontario, Canada
  • 2007
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 1998–2007
    • Washington University in St. Louis
      • • Division of Oncology
      • • Department of Medicine
      San Luis, Missouri, United States
  • 2000
    • University of Rochester
      • Division of Hematology/Oncology
      Rochester, New York, United States