Treatment of children with newly diagnosed acute promyelocytic leukemia with arsenic trioxide: a single center experience

A total of 11 children (five males and six females) with hypergranular type of acute promyelocytic leukemia (APML) were treated with intravenous arsenic trioxide (As2O3) between December 1998 and October 2003. Eight cycles of As2O3 (0.15 mg/kg/day) were administered (induction, consolidation and six cycles of maintenance) over a period of 12 months. The median WBC count at diagnosis was 3400/mm3 (range: 800-9800). In all, 10 patients (91%) achieved hematological remission at a mean duration of 48 days (range: 41-60) with all 10 patients achieving molecular remission at a median duration of 81 days (range: 64-109). Toxicity was minimal with leukocytosis in six patients, ichthyosis and hyperpigmentation of skin in five and mild peripheral neuropathy in one patient. One patient who relapsed 6 months after completing therapy achieved a second hematological and molecular remission with As2O3. With a median follow-up of 30 months (range: 4-62), the overall (OS) survival is 91% with a relapse-free survival (RFS) of 81%. As2O3 achieves hematological and molecular remission in majority of newly diagnosed children with APML with minimal toxicity, but long-term follow-up is required to evaluate late effects of As2O3 and study the minimum dose and duration required for a sustained remission

Pharmacokinetics of oral busulphan in children with beta thalassaemia major undergoing allogeneic bone marrow transplantation

The pharmacokinetics of busulphan were studied in 23 thalassaemic children undergoing BMT. Patients received busulphan at a dose of either 16 mg/kg with cyclophosphamide and ATG (Group A) or 600 mg/m2 (with cyclophosphamide alone) (Group B) in 16 divided doses every 6 h over 4 days. Busulphan levels were analyzed by a modified GC-MS method. The dose of busulphan/kg for patients in group B was 64% (range 56-71%) higher than that for patients in group A. The mean AUC, Css, Cmax and MRV were significantly higher in group B as compared with group A for both doses 1 and 13. There was no significant difference in Vd/F, T1/2 and Kel between the two groups. A significant decrease in AUC and Css was found between 1st and 13th doses in group B, but not in group A. The Cl/F values in group A were significantly higher than those in group B after dose 1, but not after dose 13. No increase in toxicity due to the higher dose of busulphan was noted. We conclude that busulphan at 600 mg/m2 results in much higher systemic exposure to the drug as compared to 16 mg/kg, without increase in toxicity in children with beta thalassaemia major

Aplastic anemia associated with interferon alpha 2a in a patient with chronic hepatitis C virus infection: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hepatitis-associated aplastic anemia is a common syndrome in patients with bone marrow failure. However, hepatitis-associated aplastic anemia is an immune-mediated disease that does not appear to be caused by any of the known hepatitis viruses including hepatitis C virus. In addition, to the best of our knowledge there are no reported cases of patients with chronic hepatitis C virus infection developing aplastic anemia associated with pegylated interferon alpha 2a treatment.</p> <p>Case presentation</p> <p>We report the case of a 46-year-old Greek man who developed severe aplastic anemia during treatment with pegylated interferon alpha 2a for chronic hepatitis C virus infection. He presented with generalized purpura and bruising, as well as pallor of the skin and mucous membranes. His blood tests showed pancytopenia. He underwent allogeneic bone marrow transplantation after completing two courses of immunosuppressive therapy with antithymocyte globulin and cyclosporin A.</p> <p>Conclusions</p> <p>The combination of a specific environmental precipitant represented by the hepatitis C virus infection, an altered metabolic detoxification pathway due to treatment with pegylated interferon alpha 2a and a facilitating genetic background such as polymorphism in metabolic detoxification pathways and specific human leukocyte antigen genes possibly conspired synergistically in the development of aplastic anemia in this patient. Our case clearly shows that the causative role of pegylated interferon alpha 2a in the development of aplastic anemia must not be ignored.</p

Association between CYP1A2 gene single nucleotide polymorphisms and clinical responses to clozapine in patients with treatment-resistant schizophrenia

OBJECTIVES: Despite clozapine's superior clinical efficacy in treatment-resistant schizophrenia (TRS), its adverse effects, need for periodic leukocyte monitoring, cost and variable clinical outcomes mandate a clinical need to predict its treatment response. Although cytochrome P450 1A2 (CYP1A2) is the principal determinant of metabolism of clozapine, the role of CYP1A2 gene in the clinical response to clozapine is uncertain. Hence, we investigated its association with treatment responses and adverse events of clozapine in TRS.METHODS: We evaluated four single nucleotide polymorphisms (SNP) in the CYP1A2 gene, clinical responses and serum clozapine levels in 101 consecutive patients with TRS on stable doses of clozapine. We defined clozapine response a priori and investigated allelic and genotypic associations. We assessed the socio-demographic and clinical profiles, premorbid adjustment, traumatic life events, cognition and disability of the participants, using standard assessment schedules for appropriate multivariate analyses.RESULTS: Our results revealed that CYP1A2 gene SNP (*1C, *1D, *1E and *1F) were not associated with clozapine treatment response, adverse effects, serum clozapine levels or with disability (p values &gt; 0.10).CONCLUSION: As CYP1A2 gene SNP do not help to predict the clinical response to clozapine, routine screening for them prior to start clozapine is currently unwarranted. We suggest future longitudinal genome-wide association studies investigating clinical and pharmacogenetic variables together.</p

Clinical predictors of response to clozapine in patients with Treatment Resistant Schizophrenia

Objectives: Despite clozapine's superior clinical efficacy in Treatment Resistant Schizophrenia (TRS), its adverse effects, need for periodic leukocyte monitoring, cost and variable clinical outcomes make the therapeutic decision making process difficult and mandate a clinical need to predict its treatment response. Hence, we investigated various clinical variables associated with treatment responses and adverse events of clozapine in TRS. Experimental Design: We assessed socio-demographic and clinical profiles, premorbid adjustment, traumatic life events, cognition, disability, psychopathology and serum clozapine levels of 101 patients with TRS on stable dose of clozapine using the following instruments: Brief Psychiatric Rating Scale, Abnormal Involuntary Movements Scale, Addenbrooke's Cognitive Examination-Revised, WHO Disability Assessment Scale-II, Childhood and Recent Traumatic Events Scale, and Premorbid Assessment Scale. We defined clozapine response a priori, adopted a casecontrol design framework and employed appropriate multivariate analyses. Principal Observations: Past history of catatonia (p= 0.005), smoking more than one pack/day (p = 0.008), hyper-somnolence (p = 0.03) and cognitive dysfunction (p = 0.007) were associated with non-response to clozapine. Outcome definitions of non-response to clozapine influenced its association with clinical predictors. Conclusions: Clinical variables are useful to predict response to clozapine. Smoking can be a potentially modifiable risk factor. Future longitudinal studies, investigating clinical and pharmacogenetic variables together, are desired.</p