Publications by authors named "Eric H Kraut"

34 Publications

Considerations for Use of Hematopoietic Growth Factors in Patients With Cancer Related to the COVID-19 Pandemic.

J Natl Compr Canc Netw 2020 Sep 1:1-4. Epub 2020 Sep 1.

2Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, Washington.

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.
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http://dx.doi.org/10.6004/jnccn.2020.7610DOI Listing
September 2020

NCCN Guidelines Insights: Hematopoietic Growth Factors, Version 1.2020.

J Natl Compr Canc Netw 2020 01;18(1):12-22

National Comprehensive Cancer Network.

Management of febrile neutropenia (FN) is an integral part of supportive care for patients undergoing cancer treatment. The NCCN Guidelines for Hematopoietic Growth Factors provide suggestions for appropriate evaluation, risk determination, prophylaxis, and management of FN. These NCCN Guidelines are intended to guide clinicians in the appropriate use of growth factors for select patients undergoing treatment of nonmyeloid malignancies. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines regarding the incorporation of newly FDA-approved granulocyte-colony stimulating factor biosimilars for the prevention and treatment of FN.
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http://dx.doi.org/10.6004/jnccn.2020.0002DOI Listing
January 2020

A phase I trial of flavopiridol in relapsed multiple myeloma.

Cancer Chemother Pharmacol 2014 Feb 16;73(2):249-57. Epub 2013 Nov 16.

Division of Hematology, The Ohio State University, B321 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH, 43210, USA,

Purpose: Flavopiridol is primarily a cyclin-dependent kinase-9 inhibitor, and we performed a dose escalation trial to determine the maximum tolerated dose and safety and generate a pharmacokinetic (PK) profile.

Methods: Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus and then continuous infusion weekly for 4 weeks in a 6-week cycle.

Results: Fifteen patients were treated at three dose levels (30 mg/m(2) bolus, 30 mg/m(2) CIV to 50 mg/m(2) bolus, and 50 mg/m(2) CIV). Cytopenias were significant, and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients and grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein >50 % that did not persist. PK properties were similar to prior publications, and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response.

Conclusions: Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myeloma (ClinicalTrials.gov identifier NCT00112723).
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http://dx.doi.org/10.1007/s00280-013-2347-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946636PMC
February 2014

A phase I dose escalation and pharmacodynamic study of SU5416 (semaxanib) combined with weekly cisplatin and irinotecan in patients with advanced solid tumors.

Onkologie 2013 14;36(11):657-60. Epub 2013 Oct 14.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Medical Center, The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH, USA.

Background: This phase I study evaluated the safety of SU5416, a potent and selective inhibitor of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase Flk-1, in combination with weekly cisplatin and irinotecan in patients with advanced solid tumors.

Methods: The patients received cisplatin 30 mg/m² and irinotecan 50 mg/m² weekly from week 1 to week 4, with SU5416 at either 65 mg/m² (dose level (DL)1) or 85 mg/m² (DL2) twice weekly for 6 weeks (1 cycle). Serial ¹⁸fluorodeoxyglucose-positron emission tomography (¹⁸FDG-PET) and ¹⁵O-H₂O-PET scans were obtained.

Results: 13 patients were treated (7 on DL1, 6 on DL2); 7 patients completed at least 1 cycle of treatment. 3 patients experienced dose-limiting toxicity (DLT) at DL2 (grade 3 neutropenia and grade 3 thrombocytopenia causing treatment delay, grade 3 nausea/vomiting). No objective responses were observed at DL1, which was determined to be the maximum tolerated dose (MTD). 1 partial response (PR) was observed at DL2. ¹⁸FDG-PET responses were documented but did not predict response according to the Response Evaluation Criteria in Solid Tumors (RECIST).

Conclusions: SU5416 at 65 mg/m² twice weekly combined with cisplatin and irinotecan weekly for 4 of 6 weeks is well tolerated but without evidence of clinical activity. ¹⁸FDG-PET may be a useful pharmacodynamic marker of SU5416 bioactivity but requires additional development.
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http://dx.doi.org/10.1159/000355665DOI Listing
June 2014

Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer.

Cancer Chemother Pharmacol 2013 May 21;71(5):1183-90. Epub 2013 Feb 21.

Division of Medical Oncology, Stefanie Spielman Comprehensive Breast Center, The Ohio State University Comprehensive Cancer Center, B411 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210, USA.

Purpose: Triple negative breast cancers (TNBC) frequently have high epidermal growth factor receptor (EGFR) expression and are sensitive to DNA-damaging agents. Improved therapies are needed for this aggressive malignancy.

Patients And Methods: We performed a phase I trial of bendamustine and erlotinib, an EGFR tyrosine kinase inhibitor, in patients with metastatic TNBC, ECOG performance status ≤2, and ≤1 prior chemotherapy for metastatic disease. Each 28-day cycle included intravenous bendamustine on days 1, 2 and oral erlotinib on days 5-21 with dose escalation according to a 3 + 3 phase I study design. Dose-limiting toxicity (DLT) was determined by toxicities related to study therapy observed during cycle 1.

Results: Eleven patients were treated, 5 on dose level 1 and 6 on dose level 2. One patient had DLT on dose level 2. However, cumulative toxicities were observed, including grade 3/4 lymphopenia in 91 % (95 % CI 0.59-0.998) with progressively decreased CD4 counts and grade ≥3 infections in 36 % (95 % CI 0.11-0.69) of patients.

Conclusions: Combination therapy with bendamustine and erlotinib causes excessive toxicity with severe, prolonged lymphopenia, depressed CD4 counts, and opportunistic infections and should not be pursued further. Future trials of bendamustine combinations in TNBC patients should account for potential cumulative lymphocyte toxicity necessitating patient monitoring during and after treatment.
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http://dx.doi.org/10.1007/s00280-013-2112-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710373PMC
May 2013

Myocardial infarction in sickle cell disease: use of translational imaging to diagnose an under-recognized problem.

J Cardiovasc Transl Res 2013 Oct 21;6(5):752-61. Epub 2012 Nov 21.

Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Ave, Suite 200, Columbus, OH, 43210, USA.

Sickle cell disease (SCD) is an inherited disorder in which microvascular occlusion causes complications across multiple organ systems. The precise incidence of myocardial ischemia and infarction (MI), potentially under-recognized microvascular disease-related complications, remains unknown. The absence of typical atherosclerotic lesions seen in other patients with MI suggests a microvascular mechanism of myocardial injury. Cardiac magnetic resonance (CMR) can demonstrate microvascular disease, making it an appealing modality to assess symptomatic SCD patients. We demonstrate in several dramatic instances how CMR is uniquely able to depict cardiac microvascular obstruction in patients with SCD and chest pain, without which the possibility of myocardial injury would almost certainly be otherwise neglected. Much remains unknown regarding ischemic heart disease in patients with SCD including prevalence, detection, and management. Further work to define evaluation and management algorithms for chest pain in SCD and to develop risk assessment tools may reduce sudden cardiac death in this population.
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http://dx.doi.org/10.1007/s12265-012-9426-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594058PMC
October 2013

Cancer- and chemotherapy-induced anemia.

J Natl Compr Canc Netw 2012 May;10(5):628-53

Anemia is prevalent in 30% to 90% of patients with cancer. Anemia can be corrected through either treating the underlying cause or providing supportive care through transfusion with packed red blood cells or administration of erythropoiesis-stimulating agents (ESAs), with or without iron supplementation. Recent studies showing detrimental health effects of ESAs sparked a series of FDA label revisions and a sea change in the perception of these once commonly used agents. In light of this, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer- and Chemotherapy-Induced Anemia underwent substantial revisions this year. The purpose of these NCCN Guidelines is twofold: 1) to operationalize the evaluation and treatment of anemia in adult cancer patients, with an emphasis on those who are receiving concomitant chemotherapy, and 2) to enable patients and clinicians to individualize anemia treatment options based on patient condition.
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http://dx.doi.org/10.6004/jnccn.2012.0064DOI Listing
May 2012

Phase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein.

J Clin Oncol 2011 Sep 8;29(25):3427-34. Epub 2011 Aug 8.

The Ohio State University, Columbus, OH 43210, USA.

Purpose: Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM.

Patients And Methods: A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per week during a 28-day cycle. Pharmacokinetic data for both agents were obtained, and in vitro transport and uptake studies were conducted to evaluate potential drug-drug interactions.

Results: Twenty-one patients were treated with 15 to 25 mg lenalidomide and 15 to 20 mg CCI-779. The maximum-tolerated dose (MTD) was determined to be 25 mg lenalidomide with 15 mg CCI-779. Pharmacokinetic analysis indicated increased doses of CCI-779 resulted in statistically significant changes in clearance, maximum concentrations, and areas under the concentration-time curves, with constant doses of lenalidomide. Similar and significant changes for CCI-779 pharmacokinetics were also observed with increased lenalidomide doses. Detailed mechanistic interrogation of this pharmacokinetic interaction demonstrated that lenalidomide was an ABCB1 (P-glycoprotein [P-gp]) substrate.

Conclusion: The MTD of this combination regimen was 25 mg lenalidomide with 15 mg CCI-779, with toxicities of fatigue, neutropenia, and electrolyte wasting. Pharmacokinetic and clinical interactions between lenalidomide and CCI-779 seemed to occur, with in vitro data indicating lenalidomide was an ABCB1 (P-gp) substrate. To our knowledge, this is the first report of a clinically significant P-gp-based drug-drug interaction with lenalidomide.
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http://dx.doi.org/10.1200/JCO.2010.32.4962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164245PMC
September 2011

A phase I study of topotecan and gemcitabine in advanced solid tumors.

Invest New Drugs 2011 Dec 25;29(6):1390-4. Epub 2010 Jun 25.

Division of Hematology and Oncology, The Ohio State University, Columbus, OH 43210, USA.

Purpose: Gemcitabine and topotecan are commonly used anti-tumor agents with a wide spectrum of activity in vitro and in vivo. A phase I trial of a combination of these two agents was initiated based on the premise that both gemcitabine and topotecan cause DNA damage and interfere with DNA repair by different mechanisms. Synergism has been demonstrated in vitro when gemcitabine and other topoisomerase I inhibitors have been combined.

Patients And Methods: Seventeen patients with advanced solid tumors signed consent and were treated on this study with at least one cycle. Treatment consisted of gemcitabine at doses of 400 to 625 mg/m(2) days 1 and 5 in combination with topotecan at doses of 0.8 to 1 mg/m(2) given on days 2 through 5 every 21 days.

Results: The dose limiting toxicities of granulocytopenia and thrombocytopenia were reached at the highest dose level of gemcitabine 625 mg/m(2) and topotecan 1 mg/m(2). A diffuse skin rash was also seen in four treated patients and responded well to treatment with steroids. One partial response and seven stable disease were seen as best response in 16 evaluable patients.

Conclusion: The combination of gemcitabine and topotecan was found to be tolerable with interesting preliminary activity. The recommended phase II dose for this combination is gemcitabine at 500 mg/m(2) on days 1 and 5 with topotecan at 0.8 mg/m(2) on days 2 to 5.
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http://dx.doi.org/10.1007/s10637-010-9480-9DOI Listing
December 2011

Phase I and pharmacokinetic study of erlotinib (OSI-774) in combination with docetaxel in squamous cell carcinoma of the head and neck (SSCHN).

Cancer Chemother Pharmacol 2011 Mar 19;67(3):579-86. Epub 2010 May 19.

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, College of Medicine and The Ohio State University Medical Center, Columbus, OH, USA.

Purpose: This phase I study determined the maximal-tolerated dose, dose-limiting toxicities, pharmacokinetics, and recommended dose of erlotinib with docetaxel.

Patients And Methods: Twenty-eight patients with head and neck cancer were enrolled. Patients were orally given erlotinib (50 mg) daily plus 35 mg/m² of docetaxel intravenously weekly × 3 every 4 weeks. Dose escalation of erlotinib was in 50-mg increments until toxicity. Pharmacokinetics were studied with LC-MS/MS, standard, and population pharmacokinetic methods.

Results: Ninety-five courses were successfully given (median 3, range 1-6). The most frequent side effects were diarrhea, fatigue, skin rash, anemia, and hypoalbuminemia. Dose de-escalation for both erlotinib and docetaxel was due to skin rash, neutropenia and/or severe infection with docetaxel to 25 mg/m² and erlotinib to starting dose of 50 mg and re-escalation of docetaxel to 35 mg/m². Responses were observed in 4/26 evaluable patients (100 mg erlotinib). In 24 patients, the mean Cmax and AUC erlotinib values increased with dose and following cumulative dosing (days 7 and 8 vs. day 1, p < 0.05). The CL/F (~7 L/h), V/F (~140 L), and t1/2 (~20 h) for erlotinib were similar to the reported. The mean AUC ratio of metabolite OSI-420 to erlotinib following repetitive dosing at 100 mg (+ or - docetaxel) showed a ~50% increase (p < 0.02), possibly suggesting self-enzyme induction. Population pharmacokinetic studies showed no significant covariate affecting erlotinib pharmacokinetics.

Conclusions: The combination of erlotinib and docetaxel was associated with significant toxicity, which limited the amount of administered erlotinib. Dosing for phase II trials was docetaxel 35 mg/m² and erlotinib 50 mg. The reason for excessive toxicity is not clear, but not due to change in pharmacokinetics.
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http://dx.doi.org/10.1007/s00280-010-1332-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828747PMC
March 2011

Flavopiridol, fludarabine, and rituximab in mantle cell lymphoma and indolent B-cell lymphoproliferative disorders.

J Clin Oncol 2010 Jan 14;28(3):418-23. Epub 2009 Dec 14.

Division of Hematology and Oncology, The Ohio State University, Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA.

Purpose: Flavopiridol downmodulates antiapoptotic proteins associated with resistance to fludarabine and rituximab and is effective against p53-mutated chronic lymphocytic leukemia (CLL). We conducted a phase I study of flavopiridol, fludarabine, and rituximab (FFR) in patients with mantle-cell lymphoma (MCL), indolent B-cell non-Hodgkin's lymphomas (B-NHL), and CLL to determine the activity of FFR.

Patients And Methods: Therapy included fludarabine 25 mg/m(2) intravenously (IV) days 1 to 5 and rituximab 375 mg/m(2) day 1 every 28 days for 6 cycles. We administered flavopiridol 50 mg/m(2) by 1-hour IV bolus (IVB) day 1 (n = 15); day 1 to 2 (n = 6); 20 mg/m(2) 30-minute IVB + 20 mg/m(2) 4-hour IV infusion (n = 3); or 30 mg/m(2) + 30 mg/m(2) (n = 14).

Results: Thirty-eight patients (median age, 62 years) with MCL (n = 10); indolent B-NHL including follicular (n = 9), marginal zone (n = 4), lymphoplasmacytic (n = 1), or small lymphocytic lymphoma (n = 3); and CLL (n = 11), were enrolled. Twenty-two patients were previously untreated; 16 had received one to two prior therapies. Two patients in cohort 2 developed grade 3 dose-limiting toxicity (seizures, renal insufficiency). The median number of treatment cycles was 4, with cytopenias (n = 10) and fatigue (n = 3) the most common reasons for early discontinuation. Overall response rate was 82% (complete response, 50%; unconfirmed complete response, 5%; partial response, 26%), including 80% of patients with MCL (median age, 68; seven complete responses, one partial response). Median progression-free survival (PFS) was 25.6 months. Median PFS of patients with nonblastoid variant MCL (n = 8) was 35.9 months.

Conclusion: FFR was active in MCL, indolent B-NHL, and CLL and should be studied for older patients with MCL who are not candidates for aggressive chemotherapy.
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http://dx.doi.org/10.1200/JCO.2009.24.1570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815704PMC
January 2010

Extended use of intravenous bisphosphonate therapy for the prevention of skeletal complications in patients with cancer.

Cancer Invest 2009 Dec;27(10):984-8

Department of Pharmacy, The Ohio State University Medical Center, 410 West 10th Avenue, Columbus, OH 43235, USA.

Purpose: To evaluate the incidence of skeletal complications in patients with multiple myeloma, and metastatic breast, prostate, or lung cancers, when therapy with intravenous bisphosphonates is continued for longer than 21 months.

Methods: The primary outcome was the diagnosis of at least one skeletal-related event (SRE) after 21 months of therapy. The secondary outcome was the incidence of osteonecrosis of the jaws (ONJ).

Results: The primary outcome was 30%. The secondary outcome was 3%, while six patients (5%) were referred to a dentist for suspected ONJ.

Conclusion: There appears to be a continued benefit when intravenous bisphosphonates are given for longer than 21 months.
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http://dx.doi.org/10.3109/07357900902783203DOI Listing
December 2009

Phase II trial of pyrazoloacridine (NSC#366140) in patients with metastatic breast cancer.

Invest New Drugs 2011 Apr 21;29(2):347-51. Epub 2009 Oct 21.

Division of Hematology and Oncology, Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH 43210, USA.

Purpose: Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases 1 and 2. We conducted a phase II clinical study to determine the efficacy and toxicities of PZA in patients with metastatic breast cancer (MBC).

Experimental Design: In this phase II multicenter study, patients who were treated with no more than one prior chemotherapy for MBC were treated with 750 mg/m² of PZA given as a 3-hour intravenous infusion every 3 weeks. Treatment cycles were continued until disease progression or unacceptable toxicities. The study was designed to distinguish between a response rate of < 15% vs > 30% (alpha = 0.10, beta = 0.10) using Simons optimal 2-stage design. At least 2 responses were required in the first 12 patients in the 1st stage and 6 of 35 in the 2nd stage to recommend the agent for further study.

Results: Two patients in the first stage had a response allowing accrual to second stage. A total of 15 patients (out of 35 planned) were treated on the study prior to premature closure. Three patients had a partial response (20%) lasting 4.5-6 months. Two patients had stable disease for 3 and 5 months. The dose limiting toxicity was granulocytopenia with ten patients requiring dose reduction or dose delay for grade 4 neutropenia. Other grade 3 and 4 toxicities include vomiting (n = 2), nausea (n = 2), neurotoxicity (n = 1), fatigue (n = 1), anemia (n = 1), dyspnea 9n = 1) and renal (n = 1).

Conclusions: Pyrazoloacridine demonstrated modest activity in patients with metastatic breast cancer.
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http://dx.doi.org/10.1007/s10637-009-9338-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486428PMC
April 2011

Demographic and ADAMTS13 biomarker data as predictors of early recurrences of idiopathic thrombotic thrombocytopenic purpura.

Eur J Haematol 2009 Dec 10;83(6):559-64. Epub 2009 Aug 10.

Department of Medicine, Columbus, OH, USA.

Objective: Approximately 40% of idiopathic thrombotic thrombocytopenic purpura (TTP) patients will suffer an exacerbation (recurrence of TTP within 30 d after their last plasma exchange (PE) procedure), but there are no data to predict who is at greater risk. We studied the clinical utility of demographic and ADAMTS13 biomarker data to predict the risk for exacerbation.

Patients: Forty-four acute episodes of idiopathic TTP from 26 patients were studied.

Methods: PE was performed plus either prednisone (1 mg/kg/d) or cyclosporin (2-3 mg/kg/d) as adjuncts. PE was continued daily until response (platelet count >150 000/microL and normalized lactate dehydrogenase) and tapered uniformly in all patients. ADAMTS13 biomarkers were studied prior to PE and after achieving a response, but within 7 d of the last PE.

Results: African American race (AA) was associated with an increased risk for exacerbation (P = 0.046). ADAMTS13 at presentation was also significantly lower in patients experiencing an exacerbation (P = 0.0364). After adjusting for the race effect, ADAMTS13 remained marginally significant (P = 0.0569).

Conclusions: AA is significantly associated with an increased risk for exacerbations of TTP. These data also suggest that decreasing pretreatment ADAMTS13 activity was associated with an increased risk for exacerbation, even after accounting for the effect of race.
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http://dx.doi.org/10.1111/j.1600-0609.2009.01331.xDOI Listing
December 2009

Intersecting guidelines: administering erythropoiesis-stimulating agents to chronic kidney disease patients with cancer.

Semin Dial 2009 Jan-Feb;22(1):1-4. Epub 2008 Dec 5.

There has been a dramatic sea change in the use of erythropoiesis-stimulating agents (ESAs) for anemic persons with chronic kidney disease (CKD) or cancer patients undergoing chemotherapy. An important area that has not been addressed previously is a CKD patient who also has a malignancy. Clinical guidelines exist that outline recommended treatments for each disease, but the intersection of the two disease processes presents difficult decisions for patients and physicians. Herein, we review the background underlying recent revisions in clinical alerts and guidelines for ESAs, and provide guidance for treating anemia among CKD patients who are receiving no therapy, chemotherapy with curative intent, or chemotherapy with palliative intent. The guiding principle is that comprehensive assessment of risks and benefits in the relevant clinical setting is imperative.
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http://dx.doi.org/10.1111/j.1525-139X.2008.00524.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296236PMC
August 2009

Effect of prophylactic cyclosporine therapy on ADAMTS13 biomarkers in patients with idiopathic thrombotic thrombocytopenic purpura.

Am J Hematol 2008 Dec;83(12):911-5

Division of Hematology/Oncology, Department of Internal Medicine, Ohio State University, College of Medicine and Public Health, Columbus, Ohio 43210, USA.

Several reports have been published regarding the use of cyclosporine (CSA) in the treatment of idiopathic thrombotic thrombocytopenic purpura (TTP). We hypothesized that prophylactic CSA therapy may prevent recurrences in patients with a history of multiple relapses of TTP. Nineteen patients with idiopathic TTP were enrolled on prospective studies at Ohio State University between September 2003 and May 2007. Patients achieving remission remained on CSA therapy for 6 months, allowing us to evaluate the efficacy of CSA as prophylactic therapy. CSA was administered orally at a dose of 2-3 mg/kg in twice a day divided dose in all patients and continued for a total of 6 months. Long-term clinical follow-up with serial analysis of ADAMTS13 biomarkers during and after CSA therapy were performed to evaluate the efficacy of CSA as a prophylactic therapy. 17/19(89%) patients completed 6 months of CSA therapy in a continuous remission. Two patients relapsed during therapy with CSA and seven patients relapsed after discontinuing CSA therapy. Ten patients have maintained a continuous remission a median of 21 months (range, 5-46) after discontinuing CSA. The ADAMTS13 data suggest that CSA resulted in a significant increase in the ADAMTS13 activity during therapy with CSA. 8/9(89%) relapsing patients had severely deficient ADAMTS13 activity (<5%) suggesting this is a significant risk factor for relapse of TTP. These data support the hypothesis that prophylactic CSA improves the ADAMTS13 activity and may be effective at preventing relapses in patients at risk for recurrences of TTP.
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http://dx.doi.org/10.1002/ajh.21281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824143PMC
December 2008

A phase I and pharmacokinetic study of weekly oxaliplatin followed by paclitaxel in patients with solid tumors.

Clin Cancer Res 2008 Jun;14(11):3434-40

Division of Hematology and Oncology, The Ohio State University, A434B Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210, USA.

Purpose: Oxaliplatin and paclitaxel are widely used in treating solid tumors. We designed a phase I study with the purpose of determining the maximal tolerated dose and pharmacokinetic properties of weekly oxaliplatin followed by paclitaxel based on evidence suggesting that weekly administration of both drugs allows equivalent dose intensity with less neurotoxicity.

Experimental Design: Twenty-three patients with advanced solid tumors were treated. Starting doses were 35 mg/m2 oxaliplatin followed by 45 mg/m2 paclitaxel weekly for 4 weeks every 6 weeks. Dose was escalated as follows: 45 mg/m2 oxaliplatin and 45 mg/m2 paclitaxel, 60 mg/m2 oxaliplatin and 45 mg/m2 paclitaxel, and 60 mg/m2 oxaliplatin and 60 mg/m2 paclitaxel. Pharmacokinetic studies were evaluated during the first course of therapy for oxaliplatin using population kinetics approach.

Results: A total of 49 courses were administered. The dose-limiting toxicity was peripheral neuropathy with oxaliplatin and paclitaxel both at 60 mg/m2. There were three partial responses. There was evidence of pharmacokinetic interaction with a significant amount of total platinum (46.2-49.5%/24 h) eliminated in the urine in this group of patients, consistent with published data from others. The total body clearance values of plasma platinum and ultrafiltrable platinum were higher in this combination compared with corresponding values from our previous study with oxaliplatin only (P < 0.001).

Conclusions: The recommended phase II dose of this combination is 60 mg/m2 oxaliplatin followed by 45 mg/m2 paclitaxel. Evidence of antitumor activity and acceptable toxicity with this combination and schedule warrants further investigation. We have obtained more definitive pharmacokinetic properties of oxaliplatin and confirmed its drug interaction with paclitaxel in the current sequence.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-4903DOI Listing
June 2008

Review: isolated skeletal involvement in hairy cell leukemia.

Clin Adv Hematol Oncol 2008 Apr;6(4):294-6

Department of Hematology and Oncology, Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.

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April 2008

Cyclosporin and plasma exchange in thrombotic thrombocytopenic purpura: long-term follow-up with serial analysis of ADAMTS13 activity.

Br J Haematol 2007 Nov;139(3):486-93

Division of Hematology/Oncology, Department of Internal Medicine, Ohio State University, Columbus, OH 43210, USA.

We hypothesized that cyclosporin (CSA) as adjunct to plasma exchange (PE) improves the efficacy of PE in idiopathic thrombotic thrombocytopenic purpura (TTP) via suppression of the antibody inhibitor of ADAMTS13. Our preliminary findings with CSA and PE as the upfront treatment of TTP suggested that the addition of CSA to PE significantly decreased the exacerbation (disease recurrence within 30 d of the last PE) rates compared to a cohort that received corticosteroids and PE as their upfront therapy of TTP. We present an updated analysis with long-term follow-up of 18 patients with idiopathic TTP treated with concurrent CSA and PE with analysis of serial measurements of ADAMTS13 activity, antigen and inhibitor concentration in the context of clinical outcome data. Overall, 16/18 (89%) patients achieved remission, similar to historical remission rates in idiopathic TTP with PE with only one patient suffering an exacerbation. Clinical responses correlated with improvements in ADAMTS13 activity and suppression of the antibody inhibitor of ADAMTS13. These data suggest that the efficacy of CSA is at least in part related to its suppression of the antibody inhibitor of ADAMTS13 and a subsequent improvement in ADAMTS13 activity and antigen.
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http://dx.doi.org/10.1111/j.1365-2141.2007.06819.xDOI Listing
November 2007

An evaluation of cyclosporin and corticosteroids individually as adjuncts to plasma exchange in the treatment of thrombotic thrombocytopenic purpura.

Br J Haematol 2007 Jan 27;136(1):146-9. Epub 2006 Oct 27.

Division of Hematology/Oncology, Department of Internal Medicine, Ohio state University, Columbus, OH 43210, USA.

We present the results of two consecutively performed cohort studies that evaluated the clinical effects of corticosteroids or cyclosporin as an adjunct to plasma exchange (PE) for the treatment of an acute episode of thrombotic thrombocytopenic purpura (TTP). In comparing 12 corticosteroid-treated patients with eight cyclosporin-treated patients, none of the cyclosporin-treated patients suffered an exacerbation or recurrence of TTP in the first 30 d after discontinuing PE compared with 6/10 (60%) of the corticosteroid-treated patients (P = 0.042). These data suggest that cyclosporin may have advantages over corticosteroids as an adjunct to PE therapy in the initial treatment of idiopathic TTP.
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http://dx.doi.org/10.1111/j.1365-2141.2006.06384.xDOI Listing
January 2007

Myocardial ischemia and right ventricular dysfunction in adult patients with sickle cell disease.

Haematologica 2006 Oct;91(10):1329-35

Division of Cardiovascular Medicine, The Ohio State University 473 W. 12th Avenue, Suite 200, Columbus, OH 43210, USA.

Background And Objectives: Patients with sickle cell disease (SCD) have multi-organ manifestations of microvascular disease, though cardiac manifestations have been poorly characterized in vivo. This study sought to characterize myocardial characteristics in adult patients with SCD.

Design And Methods: Twenty-two consecutive outpatients and 11 age-matched controls underwent magnetic resonance imaging to assess myocardial perfusion reserve as well as left and right ventricular size and function and myocardial iron. Computed tomography of the coronary arteries was performed to assess epicardial coronary stenosis.

Results: Three of 22 outpatients with clinically stable SCD and no controls had abnormal myocardial perfusion reserve limited to the subendocardium, consistent with microvascular disease. Coronary arteries were free of disease as detectable by computed tomography angiography. Myocardial T2* was normal in all subjects (29 +/- 5 ms, median 29 ms), consistent with absence of cardiac iron deposition despite a high prevalence of hepatic iron overload (liver T2* 14 +/- 9 ms, median 12.0 ms). SCD patients had right ventricular enlargement and dysfunction (right ventricular ejection fraction 45 +/- 15 in SCD patients vs. 58 +/- 5% in controls, p=0.001) even in the absence of overt pulmonary hypertension.

Interpretation And Conclusions: A subset of adult SCD patients may have myocardial ischemia in the absence of infarcted myocardium, myocardial iron overload, or coronary artery disease. Right ventricular dysfunction is present in stable SCD patients, despite normal resting pulmonary artery pressures. These findings could represent under-recognized mechanisms for chest pain and mortality in this population, and warrant further investigation in SCD crises.
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October 2006

A phase II study of chloroquinoxaline sulfonamide (CQS) in patients with metastatic colorectal carcinoma (MCRC).

Invest New Drugs 2006 Jul;24(4):343-6

Division of Hematology and Oncology, Department of Medicine, The Ohio State University-James Cancer Hospital, Columbus, OH, USA.

Purpose: Phase II multicenter study investigated the efficacy and toxicity of the novel halogenated derivative of sulfaquixonaline Chloroquinoxaline Sulfonamide (CQS) in metastatic colorectal cancer.

Experimental Design: Eligible patients with metastatic or recurrent colorectal cancer received CQS at a dose schedule of 2000 mg/m2 over an hour weekly for 4 weeks every 42 days. Treatment was continued until unexpected toxicity or disease progression.

Results: A total of seventeen patients were enrolled on this study. 94% of all patients enrolled had prior treatment. Sixteen patients were evaluable for response with fifteen patients showing evidence of disease progression and one patient with prolonged stable disease. One patient had non-evaluable disease. Following this interim analysis, the drug was considered ineffective and the study was terminated early. The most frequent adverse event was anemia. No patients discontinued the treatment because of toxicity.

Conclusion: CQS, when given at a dose of 2000 mg/m2 weekly for 4 weeks every 42 days to patients with metastatic colorectal cancer, does not result in significant tumor regression.
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http://dx.doi.org/10.1007/s10637-005-4827-3DOI Listing
July 2006

Pentostatin in the treatment of hairy-cell leukemia.

Best Pract Res Clin Haematol 2003 Mar;16(1):91-9

Department of Internal Medicine, Ohio State University, Room 215, Means Hall 1654, Upham Drive, Columbus, OH 43210, USA.

Pentostatin (2'-deoxycoformycin; Nipent), a potent inhibitor of adenosine deaminase, is a purine nucleoside analogue that is highly effective in the treatment of hairy-cell leukemia. This agent is capable of inducing durable complete remissions in the majority of patients, and is capable of re-inducing a complete remission in many of the patients who have relapsed. Pentostatin appears to have changed the natural history of this disease. Long-term follow-up studies suggest that patients with hairy-cell leukemia who are induced into complete remission have a projected survival comparable to age-matched controls. While purine nucleoside analogues induce profound T-cell dysfunction and longstanding immunosuppression, the incidence of secondary malignancies is apparently not increased. Infections still pose a threat to these patients, and effective strategies for treating this disease that do not further compromise the immune system are needed. Patients with this disease should be encouraged to participate in ongoing clinical trials to better define the optimal treatment regimen. New studies should explore the combination of pentostatin and rituxan in treating the typical form of hairy-cell leukemia, and the incorporation of new agents for those with the rare variant form of this disease.
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http://dx.doi.org/10.1016/s1521-6926(03)00002-1DOI Listing
March 2003

Clinical manifestations and infectious complications of hairy-cell leukaemia.

Authors:
Eric H Kraut

Best Pract Res Clin Haematol 2003 Mar;16(1):33-40

Division of Hematology-Oncology, The Ohio State University, 320 W 10th Avenue, Columbus, OH 43210, USA.

Hairy-cell leukaemia is an indolent lymphoproliferative malignancy characterized by infiltration of the bone marrow, liver, spleen, and occasionally lymph nodes with a malignant B cell with hair-like cytoplasmic projections. This involvement leads to splenomegaly with secondary consumption of red cells, platelets and neutrophils as well as other complications of an enlarged spleen, including infarction-or-rarely rupture. The common haematological complications of anaemia, neutropenia and thrombocytopenia are due not only to the enlarged spleen but probably also to hairy cells in the bone marrow inducing cytokine-mediated suppression of haematopoiesis. Hepatic involvement, although frequent, only occasionally leads to liver dysfunction. Infections are a major cause of morbidity and mortality in patients with hairy-cell leukaemia, presumably owing to neutropenia and monocytopenia in these patients. The infections seen may be due to unusual pathogens, including Mycobacterium and Listeria. Autoimmune disease, including polyarthitis and vasculitis, occurs frequently and does not correlate with the severity of the disease. Other rare complications include bone involvement, meningitis and ascites. A wide range of secondary malignancies have been reported in patients with hairy-cell leukaemia, but it is still unclear whether the incidence is increased and whether they are related to the disease or treatment.
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http://dx.doi.org/10.1016/s1521-6926(02)00085-3DOI Listing
March 2003

Dosing sequence-dependent pharmacokinetic interaction of oxaliplatin with paclitaxel in the rat.

Cancer Chemother Pharmacol 2002 Dec 16;50(6):445-53. Epub 2002 Oct 16.

College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

Background: In a phase I clinical trial of oxaliplatin (OPT) in combination with paclitaxel (PXL), a pharmacokinetic interaction was observed when OPT was given as a 2-h i.v. infusion followed by a 1-h i.v. infusion of PXL. The purpose of this study was to use a rat model to evaluate whether the pharmacokinetic interaction between OPT and PXL is dosing sequence-dependent.

Methods: One group of rats was given OPT as a 2-h i.v. infusion followed by a 1-h i.v. infusion of PXL formulated in 50% Cremophor EL (CrEL)/50% ethanol (OPT-->fPXL), similar to the current phase I clinical protocol. In a second group of rats, the fPXL was infused first to reach a quasi-steady-state plasma level of PXL, followed by an i.v. bolus dose of OPT (CIfPXL-->OPT). In a third group of rats, fPXL was replaced with the formulation vehicle, CrEL, which was infused in the same manner as in the second group. Each combination was accompanied with a control of either OPT alone or with replacement of PXL with dextrose 5% in water (CID5W-->OPT). The total platinum (Pt) levels in plasma and plasma ultrafiltrate were measured by a validated inductively coupled plasma mass spectrometry (ICPMS) method. The protein binding, red blood cell (RBC) uptake and urinary elimination of Pt were also examined in each group of rats.

Results: The concentration-time profiles of plasma Pt and ultrafiltrable Pt followed triexponential decays in all groups of rats. In the rat receiving OPT-->fPXL, the terminal elimination rate constant (gamma) of plasma Pt increased, with essentially no change in the total body clearance (CL) and the AUC value, when compared to those without PXL infusion (CID5W-->OPT). The steady-state volume of distribution (V(ss)) of the ultrafiltrable Pt also showed an increase in the combination group receiving OPT-->fPXL ( P<0.01). These results were similar to those from the clinical trial, although the magnitude of change was less. However, in the CIfPXL-->OPT group, both CL and V(ss) of Pt in plasma and plasma ultrafiltrate decreased, with corresponding increases in AUCs ( P<0.01). The 24-h urinary elimination of total Pt increased in both combination groups, irrespective of the dosing sequence. No difference in protein binding of Pt was observed among the groups. There was a decrease in RBC uptake in the presence of steady-state level of fPXL, but the same was not observed in the OPT-->fPXL group. Additionally, similar results were observed with OPT in combination with CrEL alone.

Conclusions: These results suggest that alterations in the pharmacokinetics of OPT by fPXL are dosing sequence-dependent and mainly caused by the formulation vehicle CrEL. It is suggested that the dosing sequence of fPXL followed by OPT would be more clinically favorable because it would prolong the residence of OPT in systemic circulation. It is further recommended that the use of other formulations of PXL without CrEL or docetaxel would avoid the complication effect of CrEL.
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http://dx.doi.org/10.1007/s00280-002-0531-6DOI Listing
December 2002

Phase II study of dolastatin-10 as first-line treatment for advanced colorectal cancer.

Am J Clin Oncol 2002 Oct;25(5):451-3

Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Dolastatin-10 is a potent inhibitor of microtubule assembly derived from the sea hare, which displayed significant antitumor activity in preclinical models. We conducted a phase II study of dolastatin-10 in patients with advanced colorectal cancer and no prior chemotherapy for metastatic disease. Fourteen patients received doses ranging from 300 microg/m(2) to 450 microg/m(2) as an intravenous push every 21 days. There were no major objective responses. Toxicity was mainly hematologic, with grade III or IV granulocytopenia occurring in 9 of 42 treatment courses. Other toxic effects were generally mild. Dolastatin-10 lacks clinically significant activity in advanced colorectal cancer when used in this dose and schedule.
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http://dx.doi.org/10.1097/00000421-200210000-00005DOI Listing
October 2002