[Recommendations for the perioperative use of dipyrone : Expert recommendation of the working group on acute pain of the German Pain Society, the scientific working group on pain medicine of the German Society for Anesthesiology and Intensive Care Medicine and the surgical working group on acute pain of the German Society for Surgery with participation of representatives of the Drug Commission of the German Medical Association]. / Empfehlungen zur perioperativen Anwendung von Metamizol : Expertenempfehlung des Arbeitskreises Akutschmerz der Deutschen Schmerzgesellschaft, des Wissenschaftlichen Arbeitskreises Schmerzmedizin der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin und der Chirurgischen Arbeitsgemeinschaft Akutschmerz der Deutschen Gesellschaft für Chirurgie unter Beteiligung von Vertretern der Arzneimittelkommission der deutschen Ärzteschaft.

BACKGROUND: Dipyrone (metamizole) is widely used for perioperative pain management in countries where it is marketed; however, uncertainty exists concerning the safe use of this drug, specifically considering the rare adverse event of an agranulocytosis. METHODS: As evidence from published studies was lacking, an expert panel developed recommendations for the perioperative use of dipyrone. After a formal, structured consensus process, the recommendations were approved by the involved medical societies. RESULTS: The panel agreed that blood cell counts shall not be standard for short-term perioperative use in patients unless they are at risk for neutropenia. The medical staff shall be aware of the symptoms and course of action when agranulocytosis is suspected. Patients shall be informed about the risks and benefits of dipyrone and about potential alternatives. The expert group concluded that dipyrone has a relatively positive risk-benefit ratio compared to other nonopioid analgesics. The group strongly recommended educating patients about the symptoms of agranulocytosis if they have received dipyrone over several days and/or treatment is to be continued after discharge, because agranulocytosis can occur several days after discontinuation of metamizole. Further recommendations refer to the information of the physician taking over the patient's care after discharge and the avoidance of re-exposure in patients having previously suffered from dipyrone-induced agranulocytosis. CONCLUSION: The group's recommendations shall be communicated in order to raise medical staff's and patients' awareness of the appropriate use of dipyrone in the perioperative period.

Agranulocytosis-Protective Olanzapine-Loaded Nanostructured Lipid Carriers Engineered for CNS Delivery: Optimization and Hematological Toxicity Studies.

Potential risk of agranulocytosis is one of the drug-induced adverse effects of the second-generation antipsychotic agents. The present investigation aimed to formulate and investigate olanzapine (OLZ)-loaded nanostructured lipid carriers (OLZ-NLCs) via intranasal (i.n.) route. The NLC was prepared by melt emulsification method and optimized by Box-Behnken design. Mucoadhesive NLC was prepared by using 0.4% Carbopol 974P (OLZ-MNLC (C)) and the combination of 17% poloxamer 407 and 0.3% of HPMC K4M (OLZ-MNLC (P+H)). The particle size, zeta potential, and entrapment efficiency were found to be 88.95 nm ± 1.7 nm, - 22.62 mV ± 1.9 mV, and 88.94% ± 3.9%, respectively. Ex vivo permeation of OLZ-NLC, OLZ-MNLC (P+H), and OLZ-MNLC (C) was found to be 545.12 µg/cm2 ± 12.8 µg/cm2, 940.02 µg/cm2 ± 15.5 µg/cm2, and 820.10 µg/cm2 ± 11.3 µg/cm2, respectively, whereas the OLZ-MNLC (P+H) formulation showed rapid drug permeation than the OLZ-NLC and OLZ-MNLC (C) formulations. The OLZ-MNLC (P+H) formulation was shown to have 13.57- and 27.64-fold more Jss than the OLZ-MNLC (C) and OLZ-NLC formulations. The OLZ nanoformulations showed sustained release of up to 8 h. Finally, the brain Cmax of technetium-99m (99mTc)-OLZ-MNLC (i.n.) and 99mTc-OLZ-NLC (i.v.) was found to be 936 ng and 235 ng, respectively, whereas the Cmax of i.n. administration was increased 3.98-fold more than the Cmax of i.v. administration. The in vivo hematological study of OLZ-MNLC (P+H) confirmed that the i.n. formulation did not reflect any variation in leukocyte, RBC and platelet counts. Hence, it can be concluded that the nose-to-brain delivery of OLZ-MNLC (P+H) can be considered as an effective and safe delivery for CNS disorders.

Metamizole (Dipyrone) as an Alternative Agent in Postoperative Analgesia in Patients with Contraindications for Nonsteroidal Anti-Inflammatory Drugs.

PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) play an important role in multimodal pain management. In patients with a contraindication for NSAIDs, pain management is challenging. A recent Dutch anesthesiology guideline propagates the use of metamizole (dipyrone) in these patients. Metamizole is a controversial drug, its use being previously discouraged because of the risk for agranulocytosis. We discuss whether metamizole could be an alternative to classical NSAIDs and opioids in postoperative pain management despite this drawback. METHOD: Literature review and pharmacovigilance research based on World Health Organization adverse effect registrations. RESULTS: Metamizole causes fewer gastric and duodenal ulcers than other nonselective NSAIDs, and the risk for bleeding is limited. It is unknown whether it is safer than a nonselective NSAID combined with a proton pump inhibitor. Although the drug appears to be safe for renal function in healthy volunteers, data in high-risk patients (eg, those with heart or renal failure) are lacking. The incidence of metamizole-induced agranulocytosis is controversial, but the risk is likely to be limited with short-term postoperative use in this selected group of patients. CONCLUSION: Although firm evidence is lacking, metamizole may be safer for the upper intestinal tract and kidneys than other NSAIDs, and could alternatively be used in patients with an increased risk for stomach or renal problems. Hereby, improved postoperative pain relief can potentially be achieved. The risk for metamizole-induced agranulocytosis is judged to be acceptable.

Deviating from safety guidelines during deferiprone therapy in clinical practice may not be associated with higher risk of agranulocytosis.

BACKGROUND: A risk associated with the iron chelator deferiprone is the development of neutropenia or agranulocytosis. Accordingly, the product label recommends weekly blood monitoring and immediate interruption of treatment upon detection of an absolute neutrophil count (ANC) <1.5 × 10(9)/L, out of concern that continued therapy might lead to a more severe drop. However, it is uncertain how these recommendations are followed under real-life conditions and, if they are not followed, whether continuation of therapy results in increased incidence of agranulocytosis. PROCEDURE: This non-interventional surveillance program assessed the monitoring of deferiprone therapy in clinical practice. A total of 294 patients with transfusion-dependent anemias received deferiprone, as monotherapy or with another chelator, for up to 1 year. The participating physicians were not given any instructions about treatment and monitoring beyond being referred to the information in the package insert. RESULTS: ANC monitoring was conducted at an average interval of 5 ± 4 weeks, and deferiprone was not always interrupted upon detection of neutropenia. One patient (0.3%) experienced agranulocytosis, and nine others (3%) experienced a total of 11 episodes of neutropenia. All neutropenia episodes resolved; median time to resolution was similar whether or not treatment was interrupted; and no case of neutropenia progressed to agranulocytosis. CONCLUSIONS: These data indicate that less frequent ANC monitoring and continuation of deferiprone therapy during neutropenia are not associated with prolonged neutropenia or with progression to agranulocytosis.

Does switching to another antipsychotic in patients with clozapine-associated granulocytopenia solve the problem? Case series of 18 patients.

UNLABELLED: Clozapine is a well-known drug that is used in treatment-resistant schizophrenia, but granulocytopenia, which may lead to a potentially fatal condition such as agranulocytosis, limit its use. The question about which antipsychotic should be used after a diagnosis of clozapine-associated granulocytopenia is difficult to answer, because antipsychotics other than clozapine may also have hematologic toxicity, or they may prolong clozapine-associated granulocytopenia. In this study, we aimed to find out the incidence of clozapine-associated granulocytopenia in our treatment sample and discuss suitable antipsychotic drug options in terms of hematologic toxicity, for management of clozapine-associated granulocytopenia. SUBJECTS: One thousand five hundred twenty-four schizophrenia patients, treated with clozapine, were included in the study. METHODS: Patients' white blood cell counts were monitored closely. Should granulocytopenia related to clozapine be diagnosed, clozapine was stopped immediately, and a new antipsychotic that the patient did not have a history of use was begun, according to the clinical profile of the patient. Persistent low white blood cell count after the 10th day of cessation of clozapine was accepted as prolongation effect. RESULTS: Of the 1524 schizophrenia patients, 18 were diagnosed to have granulocytopenia, which means that 1.18% of the clozapine users developed granulocytopenia related to clozapine. Six of the patients were treated with olanzapine, 5 patients were treated with quetiapine, 1 patient was treated with risperidone, and 6 patients were treated with amisulpride after clozapine is stopped. None of the patients treated with risperidone or amisulpride showed prolonged low white blood cell count. Two of the patients treated with olanzapine (33.3%) and 2 of the patients treated with quetiapine (40.0%) showed prolonged leukopenia. DISCUSSION: It is noteworthy that 33.3% of the patients treated with olanzapine and 40.0% of the patients treated with quetiapine showed prolonged leukopenia. This finding is also consistent with the literature that declares higher numbers of cases about prolongation of clozapine-associated granulocytopenia for olanzapine and quetiapine than risperidone and amisulpride. After switching to another antipsychotic drug, close monitoring of white blood cell count on a daily basis for the first 2 weeks should be continued until white blood cell counts are stabilized. Quetiapine and olanzapine especially need attention after clozapine-associated granulocytopenia. Further studies with larger series and longer follow-up should be carried out.

Severe agranulocytosis as a rare side effect of pegylated interferon therapy for chronic hepatitis B.

We report on a 19-year-old male patient with chronic HBeAg-positive hepatitis B-infection and agranulocytosis as a severe side effect of pegylated interferon alpha therapy. Within the first six months of therapy the hepatitis B virus DNA became undetectable in parallel with a significant decrease of the HBsAg serum concentration. After a six-month course of therapy the patient was admitted to our emergency unit. He appeared significantly ill and reported that he had fever for two days, painful oral mucosa, throat pain and general fatigue and discomfort. A complete blood cell count was performed and revealed a complete agranulocytosis with no detectable neutrophilic granulocytes in the blood smear. Antiviral therapy was immediately stopped and he was admitted to our clinic where a supportive therapy and an empirical course of broadband antibiotics were initiated. A few days later an additional treatment with intravenous prednisolone was started. Within the next week the agranulocytosis resolved and the neutrophil count was completely restored. In parallel, the clinical status improved quickly. This case demonstrates the need for our awareness of agranulocytosis as a rare but severe and potentially life-threatening side effect of interferon alpha therapy.

[Risk minimization evolution of agranulocytosis caused by the administration of pharmaceutical products containing Clozapine in Argentina]. / Evolución de la minimización del riesgo de producir agranulocitosis por la administración de especialidades medicinales que contienen clozapina en Argentina.

Clozapine is an antipsychotic medication used in the treatment of schizophrenia. Compared to other drugs, Clozapine has shown remarkable advantages. However, its use entails a serious risk of causing hematologic alterations (including granulocytopenia/agranulocytosis). Such alterations may result in death if they are not detected early. Clozapine was recalled from the worldwide market and it was reintroduced some years later, but a mandatory hematologic monitoring program was implemented. The program was established in Argentina by ANMAT's regulation 935/00. It helped to monitor of the use of the drug. Currently, the incidence of agranulocytosis in our country is lower than the international incidence rates.

Can we prevent blood dyscrasia (leucopenia, thrombocytopenia) and epileptic seizures induced by clozapine.

Clozapine is associated with various haematological adverse effects, including leukopenia, neutropenia, agarnulocytosis, leukocytosis, anaemia, eosinophilia, thrombocytopenia and thrombocythaemia. Recognition and treatment of clozapine-related seizures also will become increasingly important as clozapine use grows in the 1990s. The decision to stop clozapine as a result of haematological adverse effects or seizures is a frustrating one for the clinician, and frequently disastrous for the patient. Cessation of treatment results in relapse. In case that patient is unresponsive to other antipsychotic, restarting clozapine should be consider, despite the risk involved. As the risk of a second agranulocytosis is much higher in those patients, various methods of militating against repeat blood dyscrasias have been treated, including granulocyte colony-stimulating factor and lithium. The decision to restart clozapine should be taken on case-by-case basis and should take into account the likely risks and benefits of restarting. Prior response to clozapine and magnitude of patient deterioration on stopping treatment are important factors to take into this consideration. Clozapine-related seizures did not preclude successful treatment with clozapine. A strategy that has been proposed to reduce the occurrence of seizures is the addition of an anticonvulsant agent. However, clozapine does induce a variety of adverse effects, most of which are of limited duration and either preventable or manageable if a number of simple clinical procedures are followed. With careful haematologyc control, the risk of agranulocytosis can be minimized and in case of clozapine related seizures recommendations include dose reduction, electroencephalogram (EEG), plasma-level monitoring and prophylactic antiepileptic treatment. Re-exposure to clozapine may rarely be attempted where there are facilities for very close and frequent monitoring.

Failure of filgrastim to prevent severe clozapine-induced agranulocytosis.

Although a highly effective medication, the usage of clozapine is limited mostly by its 2.7% incidence of neutropenia. It is often a treatment of last resort for patients with severe psychiatric illnesses, and therefore often the only medication to which a patient has responded. There has thus been a great deal of interest in ways to continue the medication in spite of emergent blood dyscrasias. There have been several reports documenting the successful continuation of clozapine in spite of neutropenia by adding granulocyte colony-stimulating factors such as filgrastim. This strategy was unsuccessful for a 63-year-old man, resulting in severe, prolonged agranulocytosis. Although a promising strategy for such refractory patients, its inherent dangers should not be underestimated.

Myeloprotective effects of C-type natriuretic peptide on cisplatin-induced bone marrow granulocytopenia in mice.

PURPOSE: Cisplatin is an effective chemotherapeutic agent used to treat a variety of malignant tumors. The major toxicity associated with cisplatin treatment is granulocytopenia. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, protects against toxicity in many organs, including the heart, blood vessels, lung, and kidney. The objective of this study was to investigate the myeloprotective effects of CNP in a mouse model of cisplatin-induced granulocytopenia. METHODS: The mice were divided into two groups: cisplatin with vehicle and cisplatin with CNP. CNP (2.5 µg/kg/min via osmotic pump, subcutaneously) or vehicle administration was started two day before cisplatin injection, and continued until the mice were killed. At 0, 2, 4, 8, and 14 days after cisplatin injection (16 mg/kg, intraperitoneally as a single dose), we counted total and living cells and granulocyte/macrophage colony-forming units (CFU-GM) in bone marrow. In addition, at 0, 1, 2, and 4 days after cisplatin injection, we measured mRNA levels of CXC chemokine receptor 4 (CXCR4) and chemokine CXC ligand 12 (CXCL12) in bone marrow. RESULTS: CNP significantly attenuated the reduction in bone marrow nucleated cell count and CFU-GM in bone marrow at 4 days after cisplatin injection. Four days after cisplatin injection, CNP significantly decreased the CXCR4 mRNA level in bone marrow, but had no effect on the level of CXCL12 mRNA. CONCLUSIONS: CNP exerts myeloprotective effects in cisplatin-induced granulocytopenia and decreases CXCR4 expression.

Lithium and clozapine rechallenge: a retrospective case analysis.

BACKGROUND: Clozapine is a uniquely effective antipsychotic, although its use is limited by the risk of neutropenia. Lithium is occasionally prescribed during a clozapine rechallenge, with the hope that it will prevent a second neutropenia or agranulocytosis. There are concerns, however, that lithium use will mask the onset of a neutropenia, leading to a more severe dyscrasia. The objective of this analysis was to determine the utility and safety of lithium coprescription in clozapine rechallenge. METHOD: A retrospective case analysis was performed of all patients who had experienced a previous clozapine-induced blood dyscrasia and had a clozapine rechallenge with lithium coprescribed in a tertiary referral center between September 1998 and September 2003. RESULTS: Twenty-five patients met the study criteria; 1 patient (4%) had a second episode of neutropenia or agranulocytosis while undergoing the rechallenge. This rate was significantly lower (p = .021) than the national (U.K.) rate (21.2%). Although recurrent dyscrasias were not more common, or more severe, than those seen with rechallenge in general, our single case did show some evidence that the patient's neutropenia was masked by lithium use. CONCLUSION: This study provides support for the utility of lithium in preventing neutropenias in rechallenge; extra vigilance may be required, however, to detect masked blood dyscrasias.

[Recommendation for using granulocyte and granulocyte-macrophage growth factor during anti-cancer therapy in children]. / Rekomendacje stosowania granulocytarnych i granulocytarno-makrofagowych czynników wzrostu w przebiegu leczenia przeciwnowotworowego u dzieci.

Neutropenia is the most often side effect during antineoplastic treatment. In this article current recommendations for clinical applications of granulocyte and granulocyto-macrophage hematopoietic factors and possibility of protection of neutropenia, and its serious complications in pediatric oncology are presented.

Benign Ethnic Neutropenia and Clozapine Use: A Systematic Review of the Evidence and Treatment Recommendations.

OBJECTIVE: To evaluate the epidemiology, pathobiology, and management of benign ethnic neutropenia and determine the extent to which these factors should influence measures designed to avoid clozapine-induced agranulocytosis. DATA SOURCES: A structured MEDLINE search with no language limitation was performed from database inception until March 31, 2015, using the terms clozapine and benign ethnic neutropenia. Retrieved articles were cross-checked for additional relevant studies. STUDY SELECTION: Included in the study were articles that reported on the prevalence, etiology, and complications of benign ethnic neutropenia and the hematologic outcome of clozapine treatment in patients with this condition. DATA EXTRACTION: Study results that documented the epidemiology, pathobiology, and clozapine utilization in persons of African, Arabian, and Mediterranean descent with a neutrophil count in the 1,000-1,800/mm³ range. RESULTS: The search identified 342 publications. Forty-two articles described the epidemiology, pathobiology, and management of benign ethnic neutropenia. Of these, 12 articles described patients with benign ethnic neutropenia whose neutrophil count decreased during treatment with clozapine. Persons with benign ethnic neutropenia do not have signs of impaired phagocytosis, and the frequency, severity, and outcome of their infections are similar to those observed in the general population. These features suggest that a neutrophil count > 1,000/mm³ is safe for initiating and/or resuming clozapine therapy. CONCLUSIONS: The presence of benign ethnic neutropenia should not prevent treatment with clozapine. Patients with benign ethnic neutropenia who develop a clozapine-induced decrease in the neutrophil count, but have no evidence of infection or impaired phagocytosis, may resume clozapine as soon as they have > 1,000 neutrophils/mm³.

Atrial natriuretic peptide protects against cisplatin-induced granulocytopenia.

PURPOSE: Granulocytopenia is the major toxicity associated with cisplatin treatment. Atrial natriuretic peptide (ANP) is a cardiac hormone used clinically for the treatment of acute heart failure in Japan. ANP exerts a wide range of protective effects on various organs, including the heart, blood vessels, lungs, and kidneys. This study's objective was to investigate the protective effects of ANP on cisplatin-induced granulocytopenia in mice. METHODS: The mice were divided into two groups: cisplatin with vehicle and cisplatin with ANP. ANP (1.5 µg/kg/min via osmotic pump, subcutaneously) or vehicle administration was started 1 day before cisplatin injection until the mice were killed. At 0, 2, 4, 8, and 14 days after cisplatin injection (16 mg/kg, intraperitoneally as a single dose), the white blood cell, red blood cell, and platelet counts were measured in the peripheral blood in both groups. The numbers of total and live cells and colony-forming unit-granulocyte-macrophage (CFU-GM) colonies in the bone marrow of the mice were also examined. In addition, at 0, 0.5, 1, and 2 days after cisplatin injection, serum granulocyte colony-stimulating factor (G-CSF) levels were measured. RESULTS: ANP significantly attenuated the white blood cell count decrease in the peripheral blood 2 and 4 days after cisplatin injection. ANP also attenuated the decrease in the number of live cells and CFU-GM colonies in bone marrow 2, 4, and 8 days after cisplatin injection. ANP significantly increased serum G-CSF levels 1 day after cisplatin injection. CONCLUSIONS: ANP has protective effects in cisplatin-induced granulocytopenia, with increased G-CSF production.

Phase I study of CPT-11 and etoposide in patients with refractory solid tumors.

PURPOSE: To determine the maximum-tolerated dose (MTD) and acceptable dose level of a cytotoxic regimen of CPT-11, a new camptothecin derivative, in combination with etoposide (VP-16) and to describe the principal toxicities associated with it. PATIENTS AND METHODS: Patients with refractory solid tumors received VP-16 and CPT-11 daily for 3 consecutive days (days 1 through 3) every 3 or 4 weeks. Groups entered the trial at escalating CPT-11/VP-16 dose levels of 40/60, 60/60, 60/80, and 80/60 mg/m2. Thirty-four patients entered this study, of whom 33 were assessable for toxicity and 22 for therapeutic efficacy. RESULTS: Granulocytopenia was so severe that this regimen required supportive therapy with recombinant human granulocyte colony-stimulating factor (G-CSF). The majority of the patients experienced a 5% weight loss and diarrhea was the dose-limiting toxicity. The MTDs were 60/80 and 80/60 mg/m2 administered on days 1 through 3. Five of seven previously untreated patients with non-small-cell lung cancer (NSCLC) achieved partial responses (PRs) to this therapy, as did two with NSCLC who had received prior chemotherapy, two with head and neck cancer, and one with an adenocarcinoma (primary tumor unknown). CONCLUSION: The recommended dose of CPT-11/VP-16 for this regimen with G-CSF is 60/60 mg/m2 on days 1 through 3 every 3 to 4 weeks. We suggest that the combination of topoisomerase I and II inhibitors is likely to be an effective treatment strategy. The activity of this regimen against NSCLC is particularly encouraging and should be evaluated in a phase II trial.

Phase I and pharmacokinetic study of recombinant human granulocyte-macrophage colony-stimulating factor given in combination with fluorouracil plus calcium leucovorin in metastatic gastrointestinal adenocarcinoma.

PURPOSE: To determine the toxicities and potential for dose escalation of intravenous (IV) bolus fluorouracil (5-FU) given with 500 mg/m2/d leucovorin (LCV) and granulocyte-macrophage colony-stimulating factor (GM-CSF). PATIENTS AND METHODS: Thirty-seven patients received escalating doses of 5-FU/LCV on days 1 to 5 with subcutaneous GM-CSF either 5 or 10 micrograms/kg/d starting on day 6 or 3 micrograms/kg/d starting on day 1. 5-FU was escalated from 370 mg/m2/d by 15% increments between patient cohorts and within patients according to tolerance. RESULTS: With GM-CSF starting on day 6, dose-limiting toxicity occurred during cycle no. 1 in all three patients entered at 5-FU 490 mg/m2/d. However, individual patients tolerated 5-FU doses up to 644 mg/m2/d. When all cycles were analyzed, grade 3 to 4 mucositis and grade 4 granulocytopenia complicated < or = 15% and < or = 6% of cycles with 5-FU doses < or = 560 mg/m2/d (115 cycles). With GM-CSF starting on day 1, dose-limiting granulocytopenia occurred during cycle no. 1 in five of 10 patients entered at 5-FU 490 mg/m2/d. Although the granulocyte nadirs were significantly lower at each 5-FU dose level with the concurrent GM-CSF schedule (eg, 490 mg/m2/d: median, 879/microL v3,286/microL; two-tailed P [P2] < .001), dose-limiting granulocytopenia complicated < or = 16% of cycles with 5-FU < or = 560 mg/m2/d (99 cycles); > or = grade 3 mucositis occurred in < or = 20% of cycles. Grade 3 to 4 diarrhea was unusual with either GM-CSF schedule. Most patients treated with GM-CSF > or = 5 micrograms/kg/d required dose reductions for constitutional toxicity; 3.0 to 3.8 micrograms/kg/d was better tolerated. Venous thrombosis occurred in 17% of patients (concurrent v sequential GM-CSF, 29% v 5%; P2 = .08). The median delivered 5-FU dose-intensity for GM-CSF starting either on day 6 or on day 1 was 615 and 647 mg/m2/wk (P2 = .41), respectively. Pharmacologic exposure to 5-FU increased with higher doses of 5-FU, and concurrent GM-CSF administration did not affect 5-FU clearance. CONCLUSION: A starting dose of 425 mg/m2/d of 5-FU with LCV on days 1 to 5 could be safely combined with GM-CSF starting either on day 1 or day 6, with further 5-FU dose escalation according to individual tolerance.

Recombinant human granulocyte-macrophage colony-stimulating factor reduces hematologic toxicity and widens clinical applicability of high-dose cyclophosphamide treatment in breast cancer and non-Hodgkin's lymphoma.

High-dose administration of anticancer agents is attractive both on theoretic and clinical grounds. Yet, high-dose regimens are usually used as salvage treatments, mainly as a consequence of their considerable hematologic toxicity. One pertinent example is represented by cyclophosphamide, an alkylating agent with a wide spectrum of marked antitumor activity. When used at doses up to 7 g/m2 (190 to 200 mg/kg) this drug does not cause myeloablation, but induces a severe, albeit transient, myelosuppression, which requires platelet transfusions in approximately 50% of treated patients, and is frequently complicated by infectious episodes, occasionally lethal. To accelerate hematopoietic recovery, we continuously infused for 14 consecutive days 5.5 micrograms/kg/d of the glycosylated human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) into 15 patients with breast cancer and non-Hodgkin's lymphoma treated with 7 g/m2 cyclophosphamide. This schedule was chosen having obtained the fastest hematopoietic recovery among four different options during an initial schedule-finding phase on 12 overall patients. Twenty-one comparable subjects with solid tumors served as controls. We report here that this relatively low, well-tolerated dose of rhGM-CSF reduces from 20 to 14 (median) and from 24 to 14, the number of days required to recover circulating granulocyte counts over 1,000 and 2,500/microL, respectively. The stimulatory effect was associated with a remarkable clinical benefit. In fact, treated patients experienced less infectious complications (7% v 24%) were eligible to receive chemotherapy earlier (median, by day +14 v day +20 for controls), and fewer required prophylactic platelet transfusions (13% v 43%). Our results show that even very high doses of cyclophosphamide can be administered with improved hematologic toxicity, tolerable morbidity, and reduced supportive care requirements. The increase in the therapeutic index made possible by rhGM-CSF infusion prompts the use of high-dose cyclophosphamide, and possibly of other agents with similar myelotoxic activity, early in the clinical course of chemotherapy-sensitive tumors.

Randomized trial of recombinant human granulocyte-macrophage colony-stimulating factor in pediatric patients receiving intensive myelosuppressive chemotherapy.

PURPOSE: To evaluate whether recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the hematologic toxicities and supportive care requirements of an intensive combination chemoradiotherapy regimen in pediatric and young adult sarcoma patients. PATIENTS AND METHODS: Thirty-seven newly diagnosed patients age 1 to 25 years were randomized to receive 18 cycles of chemotherapy alone or with GM-CSF beginning in cycle 3. GM-CSF (5 to 15 micrograms/kg/d subcutaneously) was begun 24 hours after the completion of chemotherapy and continued through day 19 of each cycle or until the absolute granulocyte count (AGC) was > or = 500/microliter on 2 consecutive days. RESULTS: GM-CSF reduced the median duration of grade 4 granulocytopenia from 9.0 days (range, 2 to 24) to 7.0 days (range, 1 to 21) (P < .0001), but did not significantly affect the grade of granulocyte nadir. No differences were seen in the incidence or types of infectious complications, incidence or duration of hospitalization and antimicrobial therapy, response to chemotherapy, or event-free or overall survival. GM-CSF was associated with more severe and protracted thrombocytopenia (median platelet nadir, 29,500/microliter [range, 3,000 to 288,000] v 59,000/microliter [range, 3,000 to 309,000], P < .0001; median time to recovery > 75,000/microliter, 16.0 days [range, 0 to 61] v 14.0 days [range, 0 to 38], P < .0001). CONCLUSION: GM-CSF does not produce clinically meaningful reductions in the degree or duration of severe granulocytopenia following intensive multiagent chemotherapy, but is associated with worsened thrombocytopenia. GM-CSF also does not reduce the need for hospitalization or the incidence of febrile neutropenia and infectious complications. We conclude that the costs and increased toxicities associated with the use of this agent are not justified by its minimal clinical benefit for regimens of this level of intensity.

Protective effect of partially purified human urinary colony-stimulating factor on granulocytopenia after antitumor chemotherapy.

We conducted a randomized crossover study comparing the hemopoietic effect of partially purified human urinary colony-stimulating factor (CSF-HU, an active drug) and human serum albumin (HSA, a control drug) in 24 patients with malignant lymphoma, solid tumors, or multiple myeloma who were receiving two consecutive courses of the same chemotherapeutic regimen. Patients received daily 2-4 X 10(6) units of CSF-HU or an equal amount of protein HSA for five days after the end of the courses of chemotherapy. Assignment to CSF-HU or HSA was determined by the envelope method. The average number of blood granulocytes of 24 cases on day 7 after chemotherapy was 2116 +/- 1649 in CSF-HU-infused courses, which was significantly higher than in HSA-infused courses (1520 +/- 1022) (p less than 0.05). The average time that patients had fewer than 2000 granulocytes/mm3 was 7.6 +/- 4.4 days in CSF-HU-infused courses and 10.3 +/- 5.0 days in HSA-infused courses (p less than 0.02). Fever greater than 38 degrees C was the most frequent side effect, occurring in 32% of the patients receiving CSF-HU infusions. A reduction in the neutropenic interval in CSF-HU-infused courses was observed in patients with fever, as well as in those without fever. Infusions of CSF-HU did not change the number of other hematological parameters, such as erythrocytes, platelets, monocytes, and lymphocytes. These results suggest that CSF-HU infusions may partially protect the patients from granulocytopenia after anticancer chemotherapy.

Myelosuppressive changes from single or repeated doses of radioantibody therapy: effect of bone marrow transplantation, cytokines, and hematopoietic suppression.

Myelosuppression is the dose-limiting side effect of most forms of radioimmunotherapy (RAIT). Long-term leukopenia (4-8 weeks) has been documented from a single maximum tolerated dose (MTD) in experimental mice. Several methods for alleviating RAIT-induced marrow toxicity have been evaluated preclinically, including cytokine intervention, bone marrow transplantation (BMT), and hemoregulatory peptide administration. To improve the therapeutic potential of RAIT, multiple doses of radioantibody must be delivered. Maximizing the frequency of radioantibody administration is desirable. However, little is known about the myelotoxic effects of multiple cycles of RAIT. In the studies presented here we compared the magnitude of myelosuppression, the time of nadir, and the duration of toxicity associated with one or two MTDs of 1-131-MN-14 anti-carcinoembryonic antigen immunoglobulin G (250 microCi) administered to BALB/c mice 49 days apart, the shortest interval possible without producing lethality. Studies were conducted with radioantibody alone or with cytokines (interleukin-1/granulocyte-macrophage colony-stimulating factor), BMT, or Hp5b to determine whether bone marrow became more "brittle" after the first dose. Profiles of myelosuppression and recovery were monitored weekly for 7 weeks after each dose in both granulocyte and lymphocyte populations. The results demonstrated that granulocyte suppression was greater and of longer duration after the second dose of RAIT administered alone, with cytokines, or with BMT, but less severe with Hp5b. For example, in the RAIT + BMT treatment, the second dose resulted in an 87% loss of granulocytes, whereas a 30% loss occurred after the first dose. The nadir of toxicity lasted until days 21 to 28 after the second dose and until day 14 after the first dose. Lymphocyte suppression was of greater duration after the second cycle of RAIT alone or RAIT with BMT, plateauing at <50% of untreated levels between days 28 and 49, but was of shorter duration when RAIT was given with cytokines or Hp5b. The results are discussed in terms of 1) the radiosensitivity of each subpopulation, 2) the effects on progenitors and on stromal cells, 3) the benefits of increasing dose frequency vs. increasing dose intensity, and 4) the possibility of using preclinical data to optimize the frequency of dosing in patient trials.