Incidence Of Severe Neutropenia Research Articles

Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in non-small cell lung cancer patients treated with irinotecan and cisplatin

13121 Purpose: To determine whether UGT1A1, UGT1A7, and UGT1A9 polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of Korean patients with advanced non-small cell lung cancer (NSCLC). Methods: Eighty-one patients with advanced NSCLC were treated with irinotecan and cisplatin chemotherapy. Genomic DNA was extracted from peripheral blood and genotyped using direct sequencing. We analyzed the association of UGT1A genotypes with irinotecan PK and clinical outcomes. Results: In genotype-PK association analysis, UGT1A1*6/*6 (n = 6), UGT1A7*3/*3 (n = 6) and UGT1A9–118(dT)9/9 (n = 11) were associated with significantly lower AUCSN-38G/AUCSN-38 ratio (P = 0.002, 0.009and 0.001, respectively). In linkage disequilibrium (LD) analysis, the UGT1A7 variants were highly linked with UGT1A1*6 (D` = 0.85, r2 = 0.63) and UGT1A9*22 (D` = 0.95, r2 = 0.88), which was substantiated in haplotype analysis. Patients with UGT1A1*6/*6 had lower tumor response and higher incidence of severe neutropenia. UGT1A9–118(dT)9/9 also showed a trend for high incidence of severe diarrhea, but not tumor response. In survival analysis, patients with UGT1A1*6/*6 had significantly shorter progression-free survival (P = 0.001) and overall survival (P = 0.017). Conclusions: These findings suggest that UGT1A1*6 and UGT1A9*22 genotypes may be important for SN-38 glucuronidation and associated with irinotecan-related severe toxicity. Specifically, UGT1A1*6 might be useful for predicting tumor response and survival outcome of Korean patients with NSCLC treated with irinotecan-based chemotherapy. (Supported in part by NCC Grant 0210130 and 0510080 from National Cancer Center, Korea). No significant financial relationships to disclose.

Phase I and Pharmacokinetic Study of Sequences of the Rebeccamycin Analogue NSC 655649 and Cisplatin in Patients with Advanced Solid Tumors

To evaluate the feasibility of administering NSC 655649, a water-soluble rebeccamycin analogue that inhibits both topoisomerases I and II, in combination with cisplatin (CDDP) in adults with solid malignancies. Major toxicologic and pharmacologic differences between the two sequences of drug administration were also assessed. NSC 655649 was administered as a 60-minute i.v. infusion; CDDP was given i.v. before or after NSC 655649 on day 1. Each patient was treated with alternating drug sequences every 3 weeks; doses of each drug were escalated in separate cohorts of new patients. Sequential dose escalation of NSC 655649 or CDDP resulted in three dosage permutations of NSC 655649/CDDP: 440/50, 550/50, and 440/75 mg/m2. After the maximum tolerated dose level was determined, the feasibility of using granulocyte colony-stimulating factor to permit further dose escalation was explored. Twenty patients were treated with 70 courses of NSC 655649/CDDP. Myelosuppression was the principal toxicity. The incidence of severe neutropenia, often associated with severe thrombocytopenia, was unacceptably high in minimally pretreated patients at the NSC 655649/CDDP dose level of 550/50 mg/m2 without and with granulocyte colony-stimulating factor. Major pharmacokinetic interactions between NSC 655649 and CDDP were not apparent. No relevant sequence-dependent differences in toxicity or pharmacokinetic variables occurred. Three patients had partial responses. NSC 655649 and CDDP were well tolerated by minimally pretreated subjects at 440 and 50 mg/m2, respectively. Neither pharmacokinetic interactions between the agents nor sequence-dependent toxicologic or pharmacokinetic effects were apparent. The tolerance and preliminary activity observed with this combination suggest that disease-directed evaluations of the regimen are warranted.

Are prophylactic haematopoietic growth factors of value in the management of patients with aggressive non-Hodgkin's lymphoma?

Combination chemotherapy used to treat patients with aggressive non-Hodgkin's lymphoma is associated with neutropenia and subsequent infection, hospital admission and treatment delays. Haematopoietic growth factors (HGF) can prevent neutropenia and improve quality of life. We undertook a meta-analysis of six randomised and one nonrandomised trials to quantify the effect in previously untreated patients, and a simple cost-effectiveness analysis. The trials compared HGF plus chemotherapy with chemotherapy alone. In total, there were 779 patients aged between 15 and 82 years. Haematopoietic growth factors was associated with a statistically significant 44% reduction in the incidence of severe neutropenia (neutrophil count <0.5 × 109 l−1), a 60% reduction in the number of hospital admissions due to infection, an 80% reduction in the number of patients who had a treatment delay due to neutropenia and a 50% reduction in hospital stay. These data together with UK G-CSF drug costs were combined to develop a simple cost-effectiveness model, based on direct costs. Given the current cost of G-CSF, it would only be cost-effective among patients in which high rates of hospital stay due to neutropenia or infection are expected. Alternatively, if the cost could be reduced then all patients may be able to obtain the benefits. However, the evidence that prophylactic HGFs are clinically worthwhile is clear.

Low-dose oral fludarabine plus cyclophosphamide in elderly patients with chronic lymphoproliferative disorders

A synergistic effect of fludarabine (FLU) and cyclophosphamide (CY) has been extensively demonstrated in the treatment of chronic lymphoproliferative disorders (CLD), although a high incidence of severe neutropenia and infectious complications, particularly in elderly patients, have been reported. Based on a previous clinical experience in elderly CLD patients treated with a combination of low-dose intravenous (i.v.) FLU and CY in whom we obtained good response rates and negligible toxicity, we tested efficacy and safety of the new oral formulation of FLU combined with CY at low doses. A total of 28 elderly patients with relapsed/refractory or untreated CLD were treated with oral FLU and CY (25 and 150 mg/m2 respectively, both for 4 days every 4 weeks). The treatment design consisted in four consecutive courses and the median value of courses per patient was 3. Overall, 25 out of 28 evaluable patients were responsive to the treatment (six CR and 19 PR; ORR 89%), while the remaining three patients did not show any appreciable response (two progressive and one stable disease). Hematological toxicity was low in the majority of patients (grade 2-3 neutropenia/anemia in 8/28 cases); however, two fatal infections occurred and one additional patient died because of disease progression. Extra-hematological toxicity was generally mild. This preliminary report suggests that oral combination of FLU and CY at low dose is effective as the i.v. formulation and standard doses, since it may induce rapid responses in about 90% of elderly patients with CLD, with an acceptable toxicity.

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Hemolytic Uremic Syndrome Associated With Clopidogrel

Clopidogrel and ticlopidine are antiplatelet agents used in the treatment of patients with cerebrovascular and peripheral vascular disease and to reduce the risk for thrombosis in patients undergoing coronary artery stenting. Ticlopidine has been reported to have major hematologic adverse effects, including neutropenia and thrombotic thrombocytopenic purpura or hemolytic uremic syndrome (HUS). Clopidogrel, an analogue of ticlopidine, was developed because it did not show bone marrow toxic effects in either tissue culture or animal models. In human studies, to date, clopidogrel has been associated with a low incidence of severe neutropenia and no reported cases of thrombotic thrombocytopenic purpura or HUS. For these reasons, clopidogrel has been increasingly used in place of ticlopidine after coronary artery stenting. We report a case of clopidogrel-associated HUS. This observation implicates clopidogrel as a possible causative agent in HUS.

Therapeutic management of hematological malignancies in elderly patients. Biological and clinical considerations. Part II: Non-Hodgkin lymphomas and Hodgkin's disease.

Increased knowledge of the nature and biology of lymphoid cells has provided more rational classification schemes, and has improved therapeutic strategies. However, non-Hodgkin lymphomas (NHL) as well as Hodgkin's disease (HD) show a less favorable outcome in elderly compared to young patients. The poorer outcome in elderly patients with NHL is largely due to chemotherapy-related issues, although other age-related factors may contribute to determine a poor prognosis, such as the presence of more aggressive pathological subtypes and an increase in extranodal vs nodal presentations. Similarly, HD patients older than 50 years have higher rates of advanced disease, B symptoms, and histological types associated with poor prognosis at presentation. The poor prognosis in lymphoid malignancies also appears to be attributable to inadequate treatment. However, the inability to administer full therapy may be real, due to the high percentages of deaths caused by severe infections and intercurrent disease (cardiac, renal, lung) related to diminished organ function. The availability of growth factors may help to reduce the incidence of severe neutropenia and other related septic conditions.

IMPACT OF PROPHYLACTIC USE OF COLONY STIMULATING FACTORS ON THE PATTERN OF NEUTROPENIA AND INFECTIONS IN MODERATELY INTENSIVE CHEMOTHERAPY

In this study, colony stimulating factors (CSF) were used to prevent neutropenia during moderately intensive chemotherapy in 26 episodes of chemotherapy (12 of acute lymphoblastic leukaemia (ALL) and 14 patients with other malignancies). CSF was administered in doses of 5 µg/kg of body weight within 24 hours of completion of chemotherapy for 7 days in 6 patients and for 10 days in others. Twenty six age and sex matched patients of ALL were included as controls. In the CSF group, incidence of severe neutropenia (grades 3 and 4) reduced significantly by 42.3 per cent though overall incidence of neutropenia did not differ much. Mean duration of neutropenia reduced by 4 days. Nadir total leucocyte count and absolute neutrophil count were significantly higher. There was no difference in the incidence of anaemia, thrombocytopenia and requirement of blood transfusions. Overall infections were less and incidence of severe infections reduced by 42.3 per cent. The duration of infection and of fever was shortened. Requirement of antibiotics was also reduced. All patients in CSF group recovered from infection, while 1 patient died in the control group. Mean duration of delay in chemotherapy was reduced from 10 days in control group to 3 days in CSF group. CSF administration resulted in an escalation of the cost by 112.24 per cent. However shortened duration of antibiotics, hospitalisation, reduced laboratory expenses compensated it by 66.94 per cent Our study indicates that the prophylactic use of CSF is beneficial and cost effective in moderately intensive chemotherapy with a high incidence of febrile neutropenia. Administration for 10 days appears to be more beneficial than 7 days.

Placebo-Controlled phase III Study of lenograstim (Glycosylated recombinant human granulocyte colony-Stimulating factor) in Aggressive non-Hodgkin's lymphoma: Factors influencing chemotherapy administration

The purpose of this study was to, assess the efficacy of glycosylated recombinant human granulocyte colony-stimulating factor (lenograstim) in the prevention of neutropenia and infection in patients receiving dose-intensive chemotherapy for non-Hodgkin's lymphoma (NHL). A second objective was to determine clinical predicators of delay to cytotoxic chemotherapy administration. One hundred-sixty two patients with intermediate- or high-grade NHL and at least one poor prognostic factor received a total of 4 cycles of the LNH-84 regimen every 2 weeks, with an open randomization to treatment with anthracyclines. Patients were randomized to receive subcutaneous lenograstim 5 μg/kg/day (n = 82) or placebo (n = 80) from day 6 to day 13 of each cycle.The incidence of severe neutropenia (absolute neutrophil count (ANC) < 0.5 × 109/L) was reduced in the lenograstim group compared with placebo (52% vs 75%). A significant reduction (p < 0.001) in the median duration of ANC < 0.5 × 109/L was also observed in patients treated with lenograstim during each cycle of chemotherapy (0–1 day vs 2–4 days in placebo recipients). Fever occurred in 66 patients in each treatment group. Thirty-four percent of placebo recipients had documented infections during ANC < 1.0 × 109/L compared with 18.5% of lenograstim-treated patients (p < 0.05). Infections of ≥grade 2 severity were significantly less frequent (p = 0.001) among lenograstim recipients compared with placebo (25 vs 49). The most common adverse events among lenograstim recipients were headache, mild bone pain and injection site reactions. Although lenograstim significantly increased (p = 0.0001) relative dose intensity compared with placebo (93% vs 80%), no difference in CR rate (67% vs 71%) or 3-year survival (63% vs 55%) was observed.The results of this study suggest that patients treated with a chemotherapy regimen that induces severe neutropenia can benefit from treatment with lenograstim. Furthermore, lenograstim permits treatment to be delivered at full dose intensity at 2 week intervals, even in patients with bone marrow involvement, and may permit further dose escalation of the chemotherapeutic regimen used.