Muheez A. Durosinmi

Multicenter Independent Assessment of Outcomes in Chronic Myeloid Leukemia Patients Treated With Imatinib

BACKGROUND Imatinib slows development of chronic myeloid leukemia (CML). However, available information on morbidity and mortality is largely based on sponsored trials, whereas independent long-term field studies are lacking. PATIENTS AND METHODS Consecutive CML patients who started imatinib treatment before 2005 and who were in complete cytogenetic remission (CCyR) after 2 years (± 3 months) were eligible for enrollment in the independent multicenter Imatinib Long-Term (Side) Effects (ILTE) study. Incidence of the first serious and nonserious adverse events and loss of CCyR were estimated according to the Kaplan-Meier method and compared with the standard log-rank test. Attainment of negative Philadelphia chromosome hematopoiesis was assessed with cytogenetics and quantitative polymerase chain reaction. Cumulative incidence of death related or unrelated to CML progression was estimated, accounting for competing risks, according to the Kalbleisch-Prentice method. Standardized incidence ratios were calculated based on population rates specific for sex and age classes. Confidence intervals were calculated by the exact method based on the χ(2) distribution. All statistical tests were two-sided. RESULTS A total of 832 patients who were treated for a median of 5.8 years were enrolled. There were 139 recorded serious adverse events, of which 19.4% were imatinib-related. A total of 830 nonserious adverse events were observed in 53% of patients; 560 (68%) were imatinib-related. The most frequent were muscle cramps, asthenia, edema, skin fragility, diarrhea, tendon, or ligament lesions. Nineteen patients (2.3%) discontinued imatinib because of drug-related toxic effects. Forty-five patients lost CCyR, at a rate of 1.4 per 100 person-years. Durable (>1 year) negative Philadelphia chromosome hematopoiesis was attained by 179 patients. Twenty deaths were observed, with a 4.8% mortality incidence rate (standardized incidence ratio = 0.7; 95% confidence interval = 0.40 to 1.10, P = .08), with only six (30%) associated with CML progression. CONCLUSIONS In this study, CML-related deaths were uncommon in CML patients who were in CCyR 2 years after starting imatinib, and survival was not statistically significantly different from that of the general population.

Lymphomas in sub-Saharan Africa--what can we learn and how can we help in improving diagnosis, managing patients and fostering translational research?

Approximately 30 000 cases of non‐Hodgkin lymphoma (NHL) occur in the equatorial belt of Africa each year. Apart from the fact that Burkitt lymphoma (BL) is very common among children and adolescents in Africa and that an epidemic of human immunodeficiency virus (HIV) infection is currently ongoing in this part of the world, very little is known about lymphomas in Africa. This review provides information regarding the current infrastructure for diagnostics in sub‐Saharan Africa. The results on the diagnostic accuracy and on the distribution of different lymphoma subsets in sub‐Saharan Africa were based on a review undertaken by a team of lymphoma experts on 159 fine needle aspirate samples and 467 histological samples during their visit to selected sub‐Saharan African centres is presented. Among children (<18 years of age), BL accounted for 82% of all NHL, and among adults, diffuse large B‐cell lymphoma accounted for 55% of all NHLs. Among adults, various lymphomas other than BL, including T‐cell lymphomas, were encountered. The review also discusses the current strategies of the International Network of Cancer Treatment and Research on improving the diagnostic standards and management of lymphoma patients and in acquiring reliable clinical and pathology data in sub‐Saharan Africa for fostering high‐quality translational research.

Treatment of Burkitt lymphoma in equatorial Africa using a simple three-drug combination followed by a salvage regimen for patients with persistent or recurrent disease

Prior to the introduction of the International Network for Cancer Treatment and Research (INCTR) protocol INCTR 03‐06, survival of patients with Burkitt lymphoma at four tertiary care centres in equatorial Africa was probably no more than 10–20%. The results reported here for 356 patients have demonstrated marked improvement in survival through the use of a uniform treatment protocol consisting of cyclophosphamide, methotrexate, vincristine, and intrathecal therapy, and the introduction of non‐cross resistant second‐line (salvage) therapy, consisting of ifosfamide, mesna, etoposide and cytarabine, when patients failed to achieve a complete response to first‐line therapy or relapsed early. Overall survival rates of 67% and 62% were observed at 1 and 2 years (relapse is rare after 1 year of remission). Of interest was the small impact of cerebrospinal fluid (CSF) and bone marrow involvement on outcome. However, the presence or absence of abdominal involvement clearly defined two prognostic groups. An additional finding was the association between CSF pleocytosis and orbital tumours, suggesting that spread of tumour cells to the central nervous system may sometimes occur via direct involvement of cranial nerves in the orbit. Survival rates may be increased in patients with abdominal involvement by combining first‐ and second‐line therapy, but verification will require a further clinical study.

Erythrocyte Cholinesterase Enzyme Activity and Hemoglobin Values in Cacao Farmers of Southwestern Nigeria as Related to Insecticide Exposure

ABSTRACT The blood of 76 cacao farmers from Southwestern Nigeria was monitored for erythrocyte cholinesterase enzyme activity (AChE) and hemoglobin values before and after insecticide application. Eight farmers had 30% to 50% baseline AChE activity, which suggests chronic organophosphate insecticide poisoning. AChE activity inhibition suggestive of occupational exposure (20% to 30%) was manifested by 28% of the farmers, whereas 30% to 50% inhibition suggestive of hazard was manifested by 11%. Significantly depressed post–insecticide application hemoglobin values were similarly recorded among the farmers. AChE activity inhibition, depression in hemoglobin values, and the years of involvement of the farmers in insecticide application on cacao, were positively correlated. Occupational exposure hazard due to organophosphate insecticides is therefore real among cacao farmers in Southwestern Nigeria. Regular biomonitoring of their blood for AChE activity and hemoglobin level is necessary.

Degrees of Kidney Disease in Nigerian Adults with Sickle-Cell Disease

Objective: To study degrees of chronic kidney disease (CKD) using creatinine clearance in adult Nigerian patients with sickle-cell disease (SCD). Methods: One hundred SCD patients, made up of 79 HbSS (homozygous haemoglobin S) patients and 21 HbSC (heterozygous haemoglobins S and C) patients, were investigated prospectively, along with 50 normal controls. Their sociodemographic data, weight and drug history were documented. Each participant underwent dipstick urinalysis, and creatinine clearance was calculated following a 24-hour urine collection and serum creatinine measurement. They were categorized into stages of CKD based on the creatinine clearance. Results: Of the 79 HbSS patients, 14 (18%), 28 (35%), 33 (42%) and 4 (5%) had stage 1, 2, 3 and 4 CKD, respectively. In the HbSC group, 3 (14%), 9 (43%) and 9 (43%) patients had stage 1, 2 and 3 CKD, respectively. Proteinuria was noted in 16 (20%) HbSS patients but not in any of the HbSC patients. Of the subjects aged ≤24 years (n = 49), 9 (18%), 18 (37%), 21 (43%) and 1 (2%) had stage 1, 2, 3 and 4 CKD, respectively. Of those aged >24 years (n = 51), 8 (16%), 19 (37%), 21 (41%) and 3 (6%) had stage 1, 2, 3 and 4 CKD, respectively. None of the subjects had stage 5 CKD. Conclusion: In this study, the adult subjects with SCD had various degrees of CKD. Adequate follow-up and active intervention are advocated to delay the onset of end-stage nephropathy.

Influence of CYP3A5*3 and ABCB1 C3435T on clinical outcomes and trough plasma concentrations of imatinib in Nigerians with chronic myeloid leukaemia.

Imatinib mesylate is the first‐line drug for the treatment of Philadelphia/bcr‐abl positive chronic myeloid leukaemia (CML). It is known to be metabolized mostly by CYP3A4 and CYP3A5 isoforms while its efflux is mediated by the transporters ABCB1 and ABCG2. Genetic polymorphism of some of these enzymes and transporters have been linked with inter‐individual variations in the pharmacokinetics of the drug. This study, therefore, investigated the influence of CYP3A5*3, ABCG2 421C>A and ABCB1 3435 C>T genetic polymorphism on the clinical outcome and steady‐state trough plasma concentration (TPC) of imatinib in Nigerians with CML.

Simple HPLC-UV Method for Pharmacokinetic Studies of Imatinib in the Presence of Common Antimalaria Agents

Imatinib mesylate is currently the drug of choice for treatment of chronic myeloid leukaemia. There is great possibility of coadministration of this drug with antimalaria agents in malaria-endemic regions of the world. The need, therefore, arises to develop a sensitive, simple, and reliable HPLC method that could determine imatinib in human plasma in the presence of these common antimalaria agents. After protein precipitation with acetonitrile and centrifugation, the sample was subjected to isocratic elution on an Agilent Zorbax SB-Cyano column with a mobile phase consisting of methanol-phosphate buffer (0.1 M, adjusted to pH 3 with perchloric acid) (60:40%, v/v) at a flow rate of 1 ml/min and monitored at 267 nm. The method was found to be specific in determining imatinib in plasma in the presence of amodiaquine, chloroquine, proguanil, quinine, artesunate, artemether, and lumefantrine. The standard curve for imatinib was linear over the concentration range of 10–2000 ng/mL (r > 0.999) with improved recovery in the range of 96.5–98.5%. The inter- and intra-day precisions, expressed as % coefficient of variation (% CV), were lower than 10% in all the concentration levels tested, whereas assay accuracy was in the range of 97.26–109.3%. The method was used to estimate pharmacokinetic parameters of imatinib in three imatinib-naïve patients.

Familial Burkitt's lymphoma in Nigerians.

Three Nigerian sib-pairs with familial Burkitts lymphoma (BL) seen between 1986 and 1996 are described. Their ages ranged from 4 to 20 years (median 9.5), and there were five males and one female. The mean age interval between each pair at presentation was 4 years (3-6) and the mean time interval 22 months (0.3-41). Two of the sib-pairs were sex-concordant, including a set of monozygotic twins. Five of the patients presented in stage C and one in stage A. Parental consanguinity was not found in any group. Space-clustering was confirmed in all three but time-clustering in only one. The occurrence of BL in multiple members of the same family, the presence of sex concordance and the relatively wide variation in the time of onset of disease between each pair suggest genetic predisposition as a possible additional aetiological factor for BL in the families affected.

Chronic Myeloid Leukemia in Nigerian Patients: Anemia is an Independent Predictor of Overall Survival:

Objectives The advent of the tyrosine kinase inhibitors has markedly changed the prognostic outlook for patients with Ph+ and/or BCR-ABL1+ chronic myeloid leukemia (CML). This study was designed to assess the overall survival (OS) of Nigerian patients with CML receiving imatinib therapy and to identify the significant predictors of OS. Methods All patients with CML receiving imatinib from July 2003 to June 2013 were studied. The clinical and hematological parameters were studied. The Kaplan-Meier technique was used to estimate the OS and median survival. P-value of <0.05 was considered as statistically significant. Results The median age of all 527 patients (male/female = 320/207) was 37 (range 10-87) years. There were 472, 47, and 7 in chronic phase (CP), accelerated phase, and blastic phase, respectively. As at June 2013, 442 patients are alive. The median survival was 105.7 months (95% confidence interval [CI], 91.5-119.9); while OS at one, two, and five years were 95%, 90%, and 75%, respectively. Multivariate Cox regression analysis revealed that OS was significantly better in patients diagnosed with CP (P = 0.001, odds ratio = 1.576, 95% CI = 1.205-2.061) or not in patients with anemia (P = 0.031, odds ratio = 1.666, 95% CI = 1.047-2.649). Combining these variables yielded three prognostic groups: CP without anemia, CP with anemia, and non-CP, with significantly different median OS of 123.3, 92.0, and 74.7 months, respectively (χ2 = 22.042, P = 0.000016). Conclusion This study has clearly shown that for Nigerian patients with CML, the clinical phase of the disease at diagnosis and the hematocrit can be used to stratify patients into low, intermediate, and high risk groups.

Population Pharmacokinetics of Imatinib in Nigerians With Chronic Myeloid Leukemia: Clinical Implications for Dosing and Resistance

Imatinib, a tyrosine kinase inhibitor, is the drug of choice for the treatment of chronic myeloid leukemia in Nigeria. Several studies have established interindividual and interpopulation variations in imatinib disposition although no pharmacokinetic study have been conducted in an African population since the introduction of the drug. This study explored a population pharmacokinetic approach to investigate the disposition of imatinib in Nigerians and examined the involvement of some covariates including genetic factors in the variability of the drug disposition with a view to optimize the use of the drug in this population. A total of 250 plasma concentrations from 126 chronic myeloid leukemia patients were quantified using a validated method. A population pharmacokinetic model was fitted to the data using NONMEM VII software, and the influences of 12 covariates were investigated. The mean population‐derived apparent steady‐state clearance, elimination half‐life, area under the concentration‐time curve over 24 hours, and volume of distribution were 17.2 ± 1.8 L/h., 12.05 ± 2.1 hours, 23.26 ± 0.6 μg·h/mL, and 299 ± 20.4 L, respectively. Whole blood count, ethnicity, CYP3A5*3, and ABCB1 C3435T were found to have significant influence on the apparent clearance, while the interindividual variability in clearance and interoccasion variability in bioavailability were 17.4% and 20.4%, respectively. There was a wide variability in apparent clearance and area under the curve compared to those reported in other populations. Thus, treatment with a standard dose of imatinib in this population may not produce the desired effect in most of the patients, whereas continuous exposure to a low drug concentration could lead to pharmacokinetic‐derived resistance. The authors suggest the need for therapeutic drug monitoring–guided dose individualization in this population.