Infusion-related Side Effects Research Articles

Strategies in the Management of Alemtuzumab-Related Side Effects

B-cell chronic lymphocytic leukemia has traditionally been treated with alkylating agents and purine analogues. The introduction of alemtuzumab, a CD52 monoclonal antibody with significant clinical activity in chemotherapy refractory B-cell chronic lymphocytic leukemia, is accompanied by a side effect profile different from that resulting from chemotherapy. The intravenous administration of alemtuzumab is usually accompanied by transient infusion-related side effects manifesting primarily as flu-like symptoms. These reactions can be reduced by use of corticosteroid prophylaxis, and will subside gradually during continued treatment. Alternatively, administration of alemtuzumab subcutaneously may markedly reduce the occurrence of general side effects but results in limited transient local skin reactions in most patients. Neutropenia (grade 4) may occur in approximately 20% of patients, but is usually transient and/or responds promptly to colony stimulating factor therapy; episodes of febrile neutropenia are infrequent. The major side effect of alemtuzumab is T-cell depletion, leading to an increased risk of infection, in particular reactivation of cytomegalovirus. This event typically occurs 3 to 8 weeks after initiation of therapy, coinciding with the T-cell nadir. With vigilance and early detection, these infections are usually manageable and do not cause organ failure. Preliminary data indicate that other infections following alemtuzumab therapy do not seem to occur at a frequency that is higher than expected, probably because of the general prophylactic use of cotrimoxazole (trimethoprim and sulfamethoxazole) and valacyclovir in combination with clinical tumor regressions. The overall safety profile of alemtuzumab appears to be beneficial in relation to disease severity and prognosis in patients with fludarabine-refractory B-cell chronic lymphocytic leukemia.

Rituximab in the Treatment of Factor VIII Inhibitor.

Rituximab is a monoclonal antibody directed against the CD20 antigen found on both malignant and normal B lymphocytes. It was given FDA approval in 1997 for relapsed or refractory, low grade or follicular, CD20+ non-Hodgkin's lymphoma. We report the use of selective B-cell depletion with Rituximab on a fifty-nine year old male with acquired Factor VIII inhibitor who failed to respond to convential therapy. The patient presented with compartment syndrome of the left calf due to spontaneous severe hematoma, and was subsequently hospitalized. The patient was found to have a PTT of 86, Factor VIII <3%, and Factor VIII inhibitor 108 b.u. The patient had completed forty-eight weeks of interferon and ribavirin for Hepatitis C one month prior to admission. The PTT was normal nineteen months prior when liver biopsies were obtained. The patient was subsequently diagnosed with acquired Factor VIII deficiency, thought to be secondary to either the Hepatitis C infection or the interferon therapy. He improved with Factor VIII concentrate therapy, but did not spontaneously recover from the inhibitor. He had minimal response to IVIG. Rituxin was subsequently started (intravenously at 375mg/m2) once a week for eight consecutive weeks, and repeated every six months. After four cycles, a consistent response was documented by increased Factor VIII activity (as high as 62%), and decreased Factor VIII inhibitor (stable at <0.5%). The treatment was well tolerated, and no infusion related side effects were observed. The patient did well with no bleeding on maintenance therapy for approximately twenty-one months. Unfortunately, two weeks after completion of the fourth cycle the patient suffered a ruptured AAA, and upon surgical intervention became unresponsive and a right cerebral infarct was identified. The patient's family subsequently discontinued life support and the patient died. This experience suggests that further investigation of Rituximab therapy in this defined population might benefit similar patients.

Rituximab Monotherapy Is an Effective Treatment for Splenic Marginal Zone B-Cell Lymphomas (SMZL).

Splenectomy has traditionally been considered as standard treatment for SMZL conferring a survival advantage over chemotherapy. However it carries significant complications, especially in elderly patients. The purpose of the present study is to evaluate the safety and efficacy of Rituximab for the treatment of SMZL. Fourteen patients with SMZL, diagnosed in our Department were treated with Rituximab. Diagnosis was established using standard criteria. Twelve received Rituximab as first line treatment at a median time of 2 months (1–120) after diagnosis. The remaining two received Rituximab after splenectomy. Four patients were symptomatic. Patients' median age was 68 yrs (range 50–78) and four were male. All non-splenectomized patients had palpable splenomegaly before treatment. The median size of the spleen was 10 cm blcm (3–20 cm). 12/14 patients had anemia, 6/14 leukocytosis, 9/14 lymphocytosis, 4/14 leukopenia and 5/14 thrombocytopenia prior to treatment initiation. Rituximab was administered for six weekly cycles of 375mg/m2. 6/13 patients received maintenance treatment, starting at a median time of four months (range 2–7) after the completion of the six cycles. Maintenance was given as 375mg/m2 every two months. Complete clinical response was defined as disappearance of palpable splenomegaly. Complete hematologic response was defined as the restoration of all hematologic parameters to normal values and partial hematologic response as an improvement of abnormal values without complete normalization. Molecular remission was defined as PCR negativity for IgH rearrangement in patients with negative bone marrow biopsy. 11 of 11 non-splenectomized patients achieved a complete clinical response (the 12th patient is still under treatment and response cannot be evaluated). Symptomatic patients had resolution of disease/splenomegaly related symptoms. 8/13 (62%) patients achieved a complete hematologic response, including the two previously splenectomized patients and 5/13 (38%) a partial hematologic response. Anemia was resolved in 8/11 patients, leukocytosis in 6/6, leukopenia in 1/3 and thrombocytopenia in 4/4 patients. Bone marrow biopsy after treatment disclosed persistent but reduced infiltration in 6/10, disappearance of lymphomatous infiltration in 3/10 and remained unchanged in a single patient. 2/3 patients with negative bone marrow biopsy were in molecular remission, while one patient remained PCR positive after treatment. He subsequently received a second course of four weekly cycles and became PCR negative. No patient presented infectious complications after Rituximab administration. Infusion related side effects were easily treated with steroids, antihistamines and paracetamol. Two patients, who did not receive maintenance treatment progressed with reappearance of splenomegaly both at 7 months after completion of treatment and were retreated with six cycles of Rituximab. One of them had a second response and the other remained with stable disease. All patients are alive. Median follow up after treatment initiation is 16 months (range 1–22) and median response duration has not been reached. In conclusion, Rituximab is a safe and effective treatment for SMZL and can be considered an alternative to splenectomy as first line therapy. Maintenance may be important for consolidation of response.

Effect of Treatment with Rituximab in Patients with Refractory Autoimmune Cytopenias.

The autoimmune cytopenias encompass the disorders of immune thrombocytopenia purpura (ITP), autoimmune haemolytic anaemia (AIHA), autoimmune neutropenia (AIN), pure red cell aplasia (PRCA) and various combinations of these conditions. We describe 34 patients with severe autoimmune cytopenias resistant to standard immunosuppression treated with the anti-CD20 monoclonal antibody Rituximab. 17 patients had ITP, 6 AIN, 2 AIHA, 2 PRCA, 4 AIHA and ITP (Evan's syndrome), 1 AIHA and AIN, 1 PRCA and ITP, and 1 AIN and ITP. 28 patients had primary autoimmune cytopenias and in 6 patients, the cytopenia was secondary to an underlying disorder (3 B-NHL, 1 T-NHL, 1 B-CLL and 1 SLE).Rituximab was administered intravenously at a dose of 375mg/m2 weekly for 4 weeks. 33 of 34 patients completed treatment. In one patient treatment was discontinued after 3 infusions due to a hypotensive syncopal episode. No other major infusion related side effects were observed. Responses were seen in 9/17 patients with ITP, 2/2 patients with AIHA and 4/4 patients with AIHA and ITP. Responses were sustained in 8/9 ITP patients with median follow up of 25.8months (range 4–66 months). We observed a complete response in 5 of 7 ITP patients who were previously splenectomised.In contrast, there was no response in 5/6 patients with AIN and in 3/3 patients with PRCA.In two patients we observed severe neutropenia at 3 months post Rituximab which was associated with fatal infection in both patients, namely pnemocystis pneumoniae infection and acute exacerbation of bronchiectasis. Apart from these 2 cases no other infections were seen.In conclusion, Rituximab appears to be a an alternative and safe option in the treatment of patients with ITP, AIHA and Evan's syndrome inducing sustained clinical remissions in patients who have failed to respond to conventional immunosuppression and/or splenectomy. In contrast Rituximab does not seem to be effective in AIN and PRCA and this may reflect a different pathogenesis for these conditions.

An Applicational Observation of Low-Dose Rituximab in Elderly Patients with Nodal Marginal Zone Lymphomas.

Background: Single-agent rituximab was shown to prolong overall response rate (ORR) in marginal zone lymphomas. However, despite the confirmed activity of this immuno-biologic agent a significant number of adverse events were reported in this commonly considered indolent lymphoma entity.Methods: To reduce the impact of rituximab toxicity we investigated the activity of low-dose rituximab infusions in 3 consecutive elderly patients (over 70 years) with nodal marginal zone lymphomas. All patients (Ann Arbor stage IV with bone marrow (BM) involvement, age range from 71 to 84 years, normal LDH and WHO performance status = 0) were treated with weekly low-dose rituximab (75 mg/m2) administred for 6 consecutive weeks.Results: All patients complleted the treatment program. No complete response were observed. All patients confirmed a partial response (PR) with reduction of symptoms and disease related BM involvement. The median response duration was 14 months. At a median follow-up of 18 months, 2 patients relapsed and one patient (chemiotherapy naive) is still responding. The 3 patients did not experienced any adverse events and depsite the older age of patients, no expected infusion-related side effects were recorded.Conclusion: This investigative report demostrated the efficacy and the well tolerability of low-dose rituximab (75 mg/m2 administreted weekly for 6 consecutive weeks) in elderly patients with well defined diagnosis of nodal marginal zone lymphoma. These observations can lead to the hypothesis that the dose and the schedule of rituximab should be redefined in this lymphoma entity.

Rituximab for the Treatment of Adults with ITP: A Systematic Review.

Background: Rituximab, a monoclonal anti-CD20 antibody, is a promising therapeutic agent for adults with idiopathic immune thrombocytopenic purpura (ITP).Objective: To determine the estimate of effect and to describe the safety of rituximab in adults with ITP.Methods: Systematic review of the world literature and meta-analysis. We searched MEDLINE, EMBASE, the Cochrane Registry for Controlled trials, abstracts of the American Society of Hematology annual meetings from 1997 to 2004 and bibliographies of relevant articles. In duplicate and independently, studies were assessed for eligibility using the apriori inclusion criteria of idiopathic ITP and adults 16 years of age or older. All study designs and all languages were included. Agreement on study selection was good (k=0.87) and discrepancies were resolved by consensus in all cases. Data extraction was performed in duplicate. A random effects model was used to pool the estimates of the proportions for overall response, defined as a platelet count of 50 x109/L or greater, and complete response, defined as a platelet count of 100 x109/L or greater. Funnel plots were examined for evidence of publication bias.Results: 39 studies enrolling a total of 365 patients were included. Studies were case reports, case series or single-arm cohorts; there were no comparative trials of either a randomized or non-randomized design. Small studies showing a large treatment effect were overrepresented. The median age of patients in all studies was 50 years (range 4 – 98) including one study of adults and children which did not report adult data separately. Prior to receiving rituximab, nearly all patients had failed treatment with steroids; 195/365 (53.4%) had failed splenectomy and 100/365 (27.4%) had failed treatment with danazol, immunosuppressives and/or cytotoxic agents. In most studies, rituximab was administered as a weekly infusion of 375mg/m2 for 4 consecutive doses. Among 17 studies of 5 or more patients, the pooled estimate of the proportion for overall response was 61.2% (95% CI: 49.8%, 72.6%) and for complete response was 48.3% (95% CI: 36.1%, 60.4%). The median duration of response was 7 months (range 0.5 – 41) as reported in 31 of 39 studies. Infusion-related side effects occurred in 52 patients. Severe toxicities were reported in 15 patients and included bronchospasm, anaphylactoid reaction, serum sickness, interstitial pneumonitis, pulmonary embolism (PE), retinal artery thrombosis and infection. There were 8 deaths temporally related to rituximab including 3 fatal bleeds and 1 postoperative fatal PE.Conclusions: Pooling results of the published literature demonstrates that rituximab achieves a platelet count response in 61.2% of adults with ITP, however without appropriate controls, improved outcome compared with standard therapy remains uncertain. In addition, heterogeneity of patient pre-treatment status, poor follow up data and publication bias limit the results. Significant morbidity and a high number of deaths complicated this treatment. Our results confirm the need for prospective randomized data before widespread use of this potentially toxic therapy can be recommended.

Continuous infusion of amphotericin B: preliminary experience at Faculdade de Medicina da Fundação ABC

Intravenous amphotericin B deoxycholate (AmB-D) infusions, usually given over 4 hours, frequently induce nephrotoxicity and undesirable infusion-related side effects such as rigors and chills. There is evidence in the literature that the use of AmB-D in the form of continuous 24-hour infusion is less toxic than the usual four-hour infusion of this drug. Our objective was to evaluate the efficacy and safety of continuous infusion of AmB-D for the treatment of persistent fever in neutropenic patients with hematological malignancies after chemotherapy. Observational retrospective analysis of our experience with continuous infusion of AmB-D, at Faculdade de Medicina da Fundação ABC and Hospital Estadual Mário Covas in Santo André. From October 2003 to May 2004, 12 patients with hematological malignancies and chemotherapy-induced neutropenia received 13 cycles of continuous infusion of AmB-D. The median dose of AmB-D was 0.84 mg/kg/day (0.33 to 2.30 mg/kg/day). Concomitant use of nephrotoxic medications occurred in 92% of the cycles. Nephrotoxicity occurred in 30.76% of the cycles, hypokalemia in 16.67%, hepatotoxicity in 30% and adverse infusion-related events in 23%. All patients survived for at least seven days after starting continuous infusion of AmB-D, and clinical resolution occurred in 76% of the cycles. Continuous infusion of AmB-D can be used in our Institution as an alternative to the more toxic four-hour infusion of AmB-D and possibly also as an alternative to the more expensive liposomal formulations of the drug.

Effects of hydration with salt repletion on renal toxicity of conventional amphotericin B empirical therapy: a prospective study in patients with hematological malignancies

Several studies have suggested that hydration and sodium load might reduce nephrotoxicity related to amphotericin B-deoxycholate (AmB-d). However, a schedule of these nephroprotective measures has not been standardized until now. A protocol of hydration and electrolyte supplementation was used prospectively in patients with hematological malignancies receiving empirical AmB-d treatment to evaluate its effect on AmB-d-related renal toxicity. A total of 77 consecutive patients received AmB-d (1 mg/kg per day) in association with an initial intravenous hydration of at least 1 l/m2 body surface, containing at least 1 l of 0.9% saline daily. Hydration was increased when serum creatinine levels showed a 20% increase from baseline. Serum electrolytes were replaced when indicated. The median duration of AmB-d therapy was 14 days. The mean intravenous hydration and the mean diuresis were 1530 and 1970 ml/m2 of body surface per day, respectively. Overall, 55 patients (71.4%) received a mean of 18.5 days of therapy without dose-limiting adverse events. Despite significant increases in mean creatinine serum levels and decreases in mean creatinine clearance observed early in the whole population, in only six patients (7.8%) was therapy discontinued due to renal failure, which always recovered after treatment discontinuation. In eight patients (10.4%) therapy was stopped due to infusion-related side effects. Seven patients died while under antifungal therapy without relevant signs of AmB-d-associated toxicity. Our prospective experience confirms that adequate hydration (about 1500 ml/m2 of body surface) and careful electrolyte supplementation are simple measures able to contain nephrotoxicity and to permit adequate antifungal therapy at least in the empirical setting.

Efficacy of caspofungin in prophylaxis and treatment of an adult leukemic patient with invasive pulmonary aspergillosis in allogeneic stem cell transplantation

Summary Invasive aspergillosis is a major problem in the management of immunocompromised patients, its prevalence is rising and it is still a major cause of death in this group. The clinical success rate with classical drugs is far away from expectations. New drugs are needed in the treatment of this complication. Belonging to the new class of echinocandins, caspofungin is a newly introduced and promising drug in this fatal situation. We report a patient with acute myeloid leukemia who had invasive pulmonary aspergillosis during induction therapy being treated with amphotericin B in first step and afterwards with caspofungin. The patient received consolidation therapy and allogeneic stem cell transplantation while using caspofungin, and did not experience any adverse effect related to drug. Many side effects, e.g. derangements in liver and kidney functions, hypokalemia, infusion-related side effects and especially thrombocytopenia, which are common with amphotericin B treatment are no longer problem with caspofungin. The efficacy of caspofungin in terms of regression of pulmonary lesions and control of fever is quite successful. The optimal therapies for opportunistic fungal infections are still debated, and further evaluation is needed.

EVALUATION OF A PRE-EMPTIVE GANCICLOVIR THERAPY BASED ON THE USE OF CMV PP67 NASBA IN HIGH-RISK (R-/D+) PEDIATRIC KIDNEY TRANSPLANTED PATIENTS FOR THE PREVENTION OF CYTOMEGALOVIRUS DISEASE.

P814 Aims: Despite considerable progress in laboratory diagnosis of cytomegalovirus (CMV) infection and despite more active anti-viral agents, CMV infection remains an important source of morbidity, especially in high-risk CMV seronegative recipients (R-) of CMV seropositive organs (D+). Because of the high incidence of R- recipients in the pediatric population and the increasing rate of D+ donors, prophylactic ganciclovir administration is often advocated. We elected to use a different strategy: prophylactic administration of intravenous CMV immune globulin (CMV-IG) for high-risk (R-/D+) recipients over the first four months and pre-emptive use of intravenous ganciclovir therapy, guided by monitoring CMV pp67 mRNA in whole blood by the qualitative nucleic acid sequence-based amplification assay (NASBA). We would like to report our initial results. Methods: A retrospective study was conducted in 20 consecutive children (9 boys, 11 girls, aged 14.8 ± 2.6 years) who underwent successful renal transplantation (graft survival ≥ 6months) between April 2000 to June 2003. PCR NASBA monitoring was performed at the time of transplantatation, then every week until day 90, and bi-monthly during the second trimester. Intravenous ganciclovir (5 mg/kg twice a day) was initiated on first positive NASBA results and stopped after two consecutive weekly negative PCR results. CMV disease was defined according to standard criteria. Results: In children R-/D-, the NASBA assay was negative in all (0/9). It became positive post transplantation in 72% (8/11) R-/D+ children. The first positive PCR NASBA occurred between 25-115 days (mean: 56 days) post transplant. Two of the 11 (18%) high-risk children developed CMV disease (pneumonia in one child and thrombocytopenia in the other), simultaneously with the first positive PCR, as PCRs were negative one week before the onset of CMV disease. Of note, these two children were the only high-risk subjects who did not receive the complete CMV- IG treatment, because of infusion related side effects. In addition, one of them had been treated for acute rejection 15 days prior to CMV infection. Intravenous ganciclovir was administered for a mean duration of 20 days. Four patients experiencing CMV infection relapses, detected by the NASBA assay, received another course of antiviral therapy. Conclusion: Although CMV seroconversion in R-/D+ is common (72%) after renal transplantation, CMV disease is not (18%) when pre-emptive ganciclovir is used. PCR NASBA monitoring failed to predict the development of CMV disease in 2/11 D+/R- patients. Pp67 NASBA-based pre-emptive ganciclovir therapy, combined with prophylactic administration of CMV-IG in high-risk patients leads to a low rate of CMV disease, when CMV-IG prophylaxis treatment is completed. These results could be optimized by the addition of intravenous ganciclovir, as a targeted prophylaxis strategy, during the treatment of acute rejection in high-risk populations.

Selective B-cell depletion with rituximab for the treatment of patients with acquired hemophilia

AbstractThe activity and safety profile of selective B-cell depletion with rituximab, an anti-CD20 monoclonal antibody, were evaluated in 10 patients with acquired hemophilia. Rituximab was given intravenously at the dose of 375 mg/m2 once weekly for 4 consecutive weeks. Infusion-related side effects were observed in 3 patients but were of mild intensity and did not require discontinuation of treatment. Eight patients with Factor VIII (FVIII) inhibitor titers between 4 and 96 Bethesda units per milliliter (BU/mL) achieved a complete remission, which was defined as a return to normal FVIII activity and undetectable FVIII inhibitor titers. Two more patients with inhibitor levels greater than 100 BU/mL experienced only a partial transient decrease of the inhibitor after rituximab alone, but they achieved a complete response after being challenged with a combination of rituximab plus pulse intravenous cyclophosphamide. With a median follow-up of 28.5 months (range, 12-41 months), 3 patients have thus far relapsed. Retreatment with the monoclonal antibody at the same dose and schedule resulted in a new sustained response in all these patients. In conclusion, rituximab appears an effective and well-tolerated treatment for patients with acquired hemophilia and low inhibitor titers. A reinforcement of therapy with other agents seems to be required to achieve a full and durable response in those patients with high inhibitor levels. (Blood. 2004;103:4424-4428)

History of the development of azole derivatives

Until the 1940s, relatively few agents were available for the treatment of systemic fungal infections. The development of the polyene antifungals represented a major advance in medical mycology. Although amphotericin B quickly became the mainstay of therapy for serious infections, its use was associated with infusion-related side-effects and dose-limiting nephrotoxicity. The continued search for new and less toxic antifungals led to the discovery of the azoles several decades later. Ketoconazole, the first available compound for the oral treatment of systemic fungal infections, was released in the early 1980s. For almost a decade, ketoconazole was regarded as the drug of choice in nonlife-threatening endemic mycoses. The introduction of the first-generation triazoles represented a second major advance in the treatment of fungal infections. Both fluconazole and itraconazole displayed a broader spectrum of antifungal activity than the imidazoles and had a markedly improved safety profile compared with amphotericin B and ketoconazole. Despite widespread use, however, these agents became subject to a number of clinically important limitations related to their suboptimal spectrum of activity, the development of resistance, the induction of hazardous drug–drug interactions, their less than optimal pharmacokinetic profile (itraconazole capsules), and toxicity. In order to overcome these limitations, several analogues have been developed. These so-called ‘second-generation’ triazoles, including voriconazole, posaconazole and ravuconazole, have greater potency and possess increased activity against resistant and emerging pathogens, in particular against Aspergillus spp. If the toxicity profile of these agents is comparable to or better than that of the first-generation triazoles and drug interactions remain manageable, then these compounds represent a true expansion of our antifungal arsenal.

Alemtuzumab therapy in B-cell lymphoproliferative disorders

Alemtuzumab (Campath-1H, Ilex Pharmaceuticals, San Antonio, TX) is a humanized monoclonal antibody that recognizes the CD52 antigen expressed on malignant and normal B lymphocytes. It has come to be used therapeutically in B-cell malignancies. Responses are seen in non-Hodgkin’s lymphoma (NHL), and alemtuzumab can induce molecular remissions in relapsed chronic lymphocytic leukaemia (CLL), even when refractory to purine analogues. Most studies reveal the responses to be superior in the absence of bulky disease. Infusion-related side effects such as rigors, hypotension, and nausea are reduced by using the subcutaneous route of administration. Infectious complications are the most important toxicity seen and are related to the depletion of normal lymphocytes. The clinical efficacy in combination with both fludarabine and rituximab is under investigation.

Factors affecting purification of CD34(+) peripheral blood stem cells using the Baxter Isolex 300i.

A total of 201 patients with breast cancer, ovarian cancer, or hematological malignancies underwent mobilization of peripheral blood stem cells (PBSC) using chemotherapy and granulocyte-colony stimulating factor (G-CSF). Stem cell products were collected using the Baxter CS3000 pheresis machine. The Baxter Isolex 300i was used to perform 240 CD34(+) cell separations on the apheresis products. Factors affecting yield and purity of the CD34(+) cells were analyzed. Overall yield was 55% and overall purity was 91.7%. T cell contamination was limited to 0.43% of total cells. Variables including red blood cells (RBC) concentration, platelet concentration, CD34(+) cell concentration, total WBCs selected, and time until processing had little effect on yields and purities. Installation of version 2.5 of the software in the Isolex 300i showed a modest improvement in yield and purity. Patients were reinfused with the cryopreserved CD34(+) selected cells following high-dose chemotherapy. No infusion-related side effects were noted. Analysis of engraftment data using the CD34(+)-selected cells revealed an increased risk of delayed or failed platelet engraftment when <5.0 x 10(6) CD34(+) cells per kilogram were transplanted. The Baxter Isolex 300i provides reproducible CD34(+) cell purification over a wide range of starting conditions. To provide prompt engraftment, >5.0 x 10(6) CD34(+) cells per kilogram should be infused for transplantation.

Amphotericin B and its lipid formulations

More than 40 years after its approval, Amphotericin B is still the gold standard in the treatment of invasive fungal infections due to Candida and Aspergillus spp. Three different lipid formulations of Amphotericin B have been available for over 10 years, with only one of them, i.e. liposomal Amphotericin B (Ambisome), approved in Germany. Liposomal Amphotericin B is superior to conventional Amphotericin B due to its reduced nephrotoxicity, the option of a higher initial loading-dose, and fewer infusion-related side-effects, all this with identical or even higher efficacy.

Overview of the lipid formulations of amphotericin B.

Invasive fungal infections have been increasingly recognized as a major cause of morbidity and mortality in the immunocompromised host. Amphotericin B has a broad spectrum and has remained the drug of choice for life-threatening invasive fungal infections. However, adverse events, particularly renal insufficiency, are limiting factors in achieving an effective dose: the prescription of amphotericin B is a compromise between toxicity and efficacy. Lipid formulations offer a better therapeutic index by circumscribing amphotericin B toxicity. Three lipid formulations are available in most countries: AmBisome, the only true liposome; Abelcet, with a ribbon-like structure; and Amphocil/Amphotec, composed of disc-like structures. All these formulations contain amphotericin B, but they differ in shape, size, reticuloendothelial clearance, C(max), AUC and visceral diffusion. The impact of these differences in pharmacokinetics and pharmacodynamics on clinical efficacy is still unclear. Efficacy has been shown in neutropenic patients with fever of unknown origin, systemic candidosis, invasive aspergillosis, cryptococcal meningitis and a variety of other difficult-to-treat mycoses, such as Fusarium or Zygomycetes infections. The effective dose may vary from one formulation to the other and is c. 3-5 mg/kg/day. All formulations are less nephrotoxic than amphotericin B. In one randomized double-blind study, AmBisome 3 or 5 mg/kg/day was less nephrotoxic and gave fewer infusion-related events than Abelcet 5 mg/kg/day. Abelcet induces fewer infusion-related side effects than Amphocil. All formulations seem at least as effective as amphotericin B. In some patients with life-threatening mycosis who failed treatment with, or were intolerant to, amphotericin B, the lipid formulations were effective. Further studies with comparable selected high-risk patients are warranted to clarify the usefulness and the indications of each of the formulations. Cost is a factor limiting prescription in many institutions, where use is often restricted to patients intolerant of, or refractory to, amphotericin B.

Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura

The role of rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, in the treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP) has not been determined. The effectiveness and side effects of this therapeutic modality were investigated in a cohort of 25 individuals with chronic ITP. All patients had ITP that had been resistant to between 2 and 5 different therapeutic regimens, including 8 patients who had already failed splenectomy. Patients were scheduled to receive intravenous rituximab at the dose of 375 mg/m(2) once weekly for 4 weeks. Rituximab infusion-related side effects were observed in 18 patients, but were of modest intensity and did not require discontinuation of treatment. A complete response (platelet count greater than 100 x 10(9)/L) was observed in 5 cases, a partial response (platelet count between 50 and 100 x 10(9)/L) in 5 cases, and a minor response (platelet count below 50 x 10(9)/L, with no need for continued treatment) in 3 cases, with an overall response rate of 52%. In 7 cases, responses were sustained (6 months or longer). In 2 patients with relapsed disease, repeat challenge with rituximab induced a new response. In patients with a complete or partial response, a significant rise in platelet concentrations was observed early during the course of treatment, usually 1 week after the first rituximab infusion. No clinical or laboratory parameter was found to predict treatment outcome, although there was a suggestion that women and younger patients have a better chance of response. In conclusion, rituximab therapy has a limited but valuable effect in patients with chronic ITP. In view of its mild toxicity and the lack of effective alternative treatments, its use in the setting of chronic refractory ITP is warranted. (Blood. 2001;98:952-957)

Two Lipid Formulations of Amphotericin B Compared

Amphotericin B, still the best drug for many systemic mycoses, is limited in its usefulness by infusion-related side effects and organ toxicity. Lipid

Amphotericin B colloidal dispersion (Amphocil) vs fluconazole for the prevention of fungal infections in neutropenic patients: data of a prematurely stopped clinical trial

We conducted an open label, randomised clinical trial to compare amphotericin B colloidal dispersion (ABCD, Amphocil) 2 mg/kg/day intravenously with fluconazole 200 mg/day orally, for the prevention of fungal disease in neutropenic patients with haematological malignancies. In the event of unresolved fever after 4 days of empirical antibacterial therapy, patients in both treatment groups were to receive ABCD, 4 mg/kg/day. However, the study had to be stopped in an early phase, due to severe side-effects of ABCD. A total of 24 patients were enrolled, 12 patients were randomly assigned to receive prophylactic ABCD, which was administered for a mean of 13.9 days. Fluconazole prophylaxis was given to 12 patients for a mean of 21.2 days. Therapeutic ABCD, 4 mg/kg, was initiated in four patients because of suspected fungal infection, all of whom had initially received fluconazole. A high rate of infusion-related toxicity of ABCD was observed. Chills occurred in 15/16 ABCD recipients (94%), accompanied by a temperature rise of >/=2 degrees C in 4/16 patients and of >/=1 degrees C but <2 degrees C in 10/16 patients. Other ABCD-related adverse events were hypotension (4/16), nausea with vomiting (5/16), tachycardia (7/16), headache (3/16) and dyspnoea (3/16). For premedication patients received: antihistamines (12/16), hydrocortisone (9/16) and/or morphine (6/16). ABCD was discontinued in 8/16 patients (50%) due to side-effects, which ultimately dictated early termination of the study. We conclude that ABCD is not suitable for antifungal prophylaxis in neutropenic patients due to severe infusion-related side-effects. Subject numbers were too low for conclusions on variables of antifungal efficacy.

Rituximab: a new monoclonal antibody therapy for non-Hodgkin's lymphoma.

To review the use of monoclonal antibodies (MAbs), specifically rituximab, in the treatment of non-Hodgkin's lymphoma (NHL) and to describe the nursing management of patients receiving rituximab. Published articles, abstracts, book chapters, drug manufacturer, lectures, and personal experience with rituximab. NHL ranks sixth among malignancies in incidence and mortality in the United States. The most common subtype, low-grade follicular lymphoma, is considered incurable. Lack of specificity may limit the usefulness of chemotherapy for low-grade follicular NHL. However, MAb therapy may deliver a cytotoxic effect specifically to the targeted cancer cell. Rituximab is the first MAb approved for cancer therapy. Clinical trials indicate that rituximab is efficacious and safe for recurrent or chemotherapy-resistant, B-cell, low-grade NHL. Infusion-related side effects are the most common and can be managed effectively by following the infusion rate recommendations. Monoclonal antibody therapy is an effective and safe treatment modality for cancer. Infusion-related side effects are managed effectively by following infusion rate recommendations. Nurses need to be knowledgeable about MAb therapy to educate patients and families regarding the mechanism of action and side-effect profiles of these agents, which often differ from those of chemotherapy or radiation therapy. Nurses should be familiar with the unique side effects of rituximab and also specific infusion-rate instructions, measures to reduce the incidence of side effects, and criteria for stopping the infusion when necessary.