ABSTRACT
The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.
Subject(s)
Anemia , Antineoplastic Agents , Neoplasms , Adult , Anemia/chemically induced , Anemia/drug therapy , Antineoplastic Agents/adverse effects , Hematopoietic Cell Growth Factors/therapeutic use , Humans , Neoplasms/drug therapyABSTRACT
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.
ABSTRACT
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.
Subject(s)
Biosimilar Pharmaceuticals/therapeutic use , Chemotherapy-Induced Febrile Neutropenia/drug therapy , Hematopoietic Cell Growth Factors/therapeutic use , Neoplasms/drug therapy , Practice Guidelines as Topic , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biosimilar Pharmaceuticals/economics , Biosimilar Pharmaceuticals/standards , Chemotherapy-Induced Febrile Neutropenia/etiology , Drug Approval , Drug Costs , Education, Medical, Continuing , Hematopoietic Cell Growth Factors/economics , Hematopoietic Cell Growth Factors/standards , Humans , Medical Oncology/education , Medical Oncology/standards , Neoplasms/blood , Oncologists/education , Organizations, Nonprofit/standards , Risk Factors , United States , United States Food and Drug Administration/legislation & jurisprudenceABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Chemotherapy-Induced Febrile Neutropenia/etiology , Nausea/chemically induced , Neoplasms/drug therapy , Neoplasms/metabolism , Thrombocytopenia/etiology , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Camptothecin/pharmacokinetics , Chemotherapy-Induced Febrile Neutropenia/diagnosis , Cisplatin/administration & dosage , Cisplatin/adverse effects , Cisplatin/pharmacokinetics , Dose-Response Relationship, Drug , Female , Humans , Indoles/administration & dosage , Indoles/adverse effects , Indoles/pharmacokinetics , Irinotecan , Male , Middle Aged , Nausea/diagnosis , Neoplasms/complications , Pyrroles/administration & dosage , Pyrroles/adverse effects , Pyrroles/pharmacokinetics , Thrombocytopenia/diagnosis , Treatment OutcomeABSTRACT
BackgroundStorage pool deficiency (SPD) is a rare bleeding disorder characterized by reduction in the number of delta granules within platelets, interfering with hemostasis. Current literature lacks well-designed studies from which to draw concrete conclusions regarding pre-procedural management of bleeding complications. Objective: The purpose of this study is to describe bleeding and safety outcomes of SPD patients receiving either pre-procedural platelet transfusions or platelet-sparing regimens. Methods: An exploratory retrospective cohort study was conducted among SPD patients, comparing major bleeding events between those who received platelet transfusion and those who received desmopressin, tranexamic acid, and/or aminocaproic acid within 24 hours prior to procedure. Results: Rates of major bleeding were not found to be higher among patients who received a platelet-sparing regimen [platelet-sparing: 2/25 (8%); platelet transfusion: 2/29 (6.9%); P = .99]. Incidence of non-major bleeding was higher in the platelet transfusion group, but this was not statistically significant [platelet-sparing: 0/25 (0%); platelet transfusion: 3/29 (10.3%); P = .24]. Treatment-related adverse effects were observed following 8 of 54 procedures (14.8%). Conclusion: Use of a platelet-sparing regimen was not associated with a significantly higher incidence of major or non-major bleeding events. Future prospective trials are recommended to compare outcomes between therapies.
Subject(s)
Hemostatics , Platelet Storage Pool Deficiency , Humans , Platelet Transfusion/adverse effects , Platelet Transfusion/methods , Hemostatics/therapeutic use , Retrospective Studies , Platelet Storage Pool Deficiency/complications , Platelet Storage Pool Deficiency/drug therapy , Hemostasis , Hemorrhage/drug therapyABSTRACT
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.
Subject(s)
Anemia/etiology , Antineoplastic Agents/adverse effects , Medical Oncology/methods , Medical Oncology/standards , Neoplasms/blood , Neoplasms/drug therapy , Anemia/chemically induced , Anemia/therapy , Antineoplastic Agents/therapeutic use , Blood Transfusion/methods , Hematinics/adverse effects , Hematinics/therapeutic use , Humans , Risk Factors , Transfusion ReactionABSTRACT
Myoclonus-dystonia syndrome (MDS) is an autosomal dominant disorder due to a mutated epsilon-sarcoglycan gene (SGCE) at the dystonia 11 (DYT11) locus on chromosome 7q21-31. ε-sarcoglycan has been identified in vascular smooth muscle and has been suggested to stabilize the capillary system. This report describes two siblings with MDS treated with bilateral globus pallidus interna deep brain stimulation. One patient had a history of bleeding following dental procedures, menorrhagia, and DBS placement complicated by intraoperative bleeding during cannula insertion. The other sibling endorsed frequent epistaxis. Subsequent procedures were typically treated perioperatively with platelet or tranexamic acid transfusion. Hematologic workup showed chronic borderline thrombocytopenia but did not elucidate a cause-specific platelet dysfunction or underlying coagulopathy. The bleeding history and thrombocytopenia observed suggest a potential link between MDS and platelet dysfunction. Mutated ε-sarcoglycan may destabilize the capillary system, thus impairing vasoconstriction and leading to suboptimal platelet aggregation.
Subject(s)
Dystonia , Dystonic Disorders , Sarcoglycans , Dystonia/blood , Dystonia/genetics , Dystonic Disorders/blood , Dystonic Disorders/genetics , Female , Humans , Mutation , Sarcoglycans/blood , Sarcoglycans/genetics , SiblingsABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Dose-Response Relationship, Drug , Drug Synergism , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/pathology , Topotecan/administration & dosage , Treatment Outcome , GemcitabineABSTRACT
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.
Subject(s)
Acridines/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Pyrazoles/therapeutic use , Acridines/adverse effects , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Demography , Female , Humans , Middle Aged , Neoplasm Metastasis , Pyrazoles/adverse effects , Treatment OutcomeABSTRACT
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.
Subject(s)
Bone Density Conservation Agents/administration & dosage , Bone Neoplasms/drug therapy , Diphosphonates/administration & dosage , Fractures, Bone/prevention & control , Imidazoles/administration & dosage , Spinal Cord Compression/prevention & control , Adult , Aged , Aged, 80 and over , Bone Density Conservation Agents/adverse effects , Bone Neoplasms/secondary , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Diphosphonates/adverse effects , Drug Administration Schedule , Female , Fractures, Bone/etiology , Humans , Imidazoles/adverse effects , Jaw Diseases/chemically induced , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Male , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Osteonecrosis/chemically induced , Pamidronate , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Retrospective Studies , Spinal Cord Compression/etiology , Time Factors , Treatment Outcome , Zoledronic AcidABSTRACT
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.
Subject(s)
ADAM Proteins/blood , Autoantigens/blood , Black or African American/statistics & numerical data , Purpura, Thrombotic Thrombocytopenic/epidemiology , ADAM Proteins/immunology , ADAMTS13 Protein , Adult , Autoantibodies/blood , Autoantigens/immunology , Biomarkers , Female , Humans , Male , Middle Aged , Plasma Exchange , Purpura, Thrombotic Thrombocytopenic/immunology , Purpura, Thrombotic Thrombocytopenic/therapy , Recurrence , Reproducibility of Results , Risk , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
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.
Subject(s)
Anemia/drug therapy , Hematinics/administration & dosage , Kidney Failure, Chronic/complications , Neoplasms/complications , Practice Guidelines as Topic , Anemia/etiology , Antineoplastic Agents/therapeutic use , Drug Therapy, Combination , Humans , Kidney Failure, Chronic/drug therapy , Neoplasms/drug therapy , Treatment OutcomeABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Neoplasms/drug therapy , Adult , Aged , Area Under Curve , Drug Administration Schedule , Female , History, 17th Century , Humans , Male , Maximum Tolerated Dose , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Oxaliplatin , Paclitaxel/administration & dosage , Paclitaxel/adverse effectsABSTRACT
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.
Subject(s)
ADAM Proteins/blood , Cyclosporine/administration & dosage , Immunosuppressive Agents/administration & dosage , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Purpura, Thrombotic Thrombocytopenic/drug therapy , ADAM Proteins/immunology , ADAMTS13 Protein , Adult , Autoantibodies/blood , Biomarkers/blood , Drug Administration Schedule , Female , Humans , Longitudinal Studies , Male , Middle Aged , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombotic Thrombocytopenic/blood , Remission Induction , Secondary Prevention , Young AdultABSTRACT
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.
Subject(s)
Anemia, Sickle Cell/physiopathology , Myocardial Ischemia/physiopathology , Ventricular Dysfunction, Right/physiopathology , Adult , Anemia, Sickle Cell/complications , Female , Humans , Male , Middle Aged , Myocardial Ischemia/complications , Prospective Studies , Ventricular Dysfunction, Right/complicationsABSTRACT
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.
Subject(s)
Leukemia, Hairy Cell/complications , Leukemia, Hairy Cell/pathology , Anemia, Hemolytic, Autoimmune/complications , Autoimmune Diseases/etiology , Hepatomegaly/etiology , Humans , Infections/etiology , Neoplasms, Second Primary/etiology , Splenomegaly/etiologyABSTRACT
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.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Leukemia, Hairy Cell/drug therapy , Pentostatin/therapeutic use , Clinical Trials, Phase II as Topic/methods , Clinical Trials, Phase III as Topic/methods , Dose-Response Relationship, Drug , Follow-Up Studies , HumansABSTRACT
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.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Glycerol/analogs & derivatives , Organoplatinum Compounds/pharmacokinetics , Paclitaxel/pharmacokinetics , Animals , Area Under Curve , Biological Availability , Chromatography, High Pressure Liquid , Drug Interactions , Glycerol/pharmacology , In Vitro Techniques , Infusions, Intravenous , Leukocytes/chemistry , Male , Oxaliplatin , Rats , Rats, Sprague-Dawley , Tissue DistributionABSTRACT
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.
Subject(s)
Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/drug therapy , Oligopeptides/therapeutic use , Aged , Antineoplastic Agents/administration & dosage , Depsipeptides , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Oligopeptides/administration & dosageABSTRACT
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).