Methotrexate concentrations and associated variability factors in high dose therapy of children with acute lymphoblastic leukemia and non-Hodgkin lymphoma.

Monitoring and optimization procedures improved high dose methotrexate (HDMTX) treatment outcomes. However, there are still some concerns regarding unexplained concentration variability. The objective of this study was to evaluate drug concentrations and associated variability factors in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) on HDMTX. Fifty patients (aged 1-18 years), receiving in total 184 HDMTX cycles of 3 or 5 g/m2/24 h infusion, were included in the study. Comparisons of MTX concentrations and concentrations to dose ratio between two dosing groups were conducted by Mann-Whitney U test. Regression analysis was performed with transformed data to assess relationship between MTX concentration to dose ratio and patient characteristics, biochemical analysis and therapy data. Statistically significant difference in concentrations between 3 and 5 g/m2 dosing groups was detected only at 24 h after the start of infusion (p < 0.001), but not at 48 and 72 h (p > 0.05). There was no difference between dose-normalized concentrations. Regression analysis showed that 73.9% of variability in dependent variable can be explained by included variables: time since dose, creatinine clearance (CrCl), hemoglobin and certain concomitant therapy. Our results highlight the importance of not only renal function and concomitant therapy, but also hemoglobin in reducing the variation in MTX concentrations. Therefore, monitoring of aforementioned biochemical parameters during HDMTX is important not only to assess toxicity, but also in predicting their impact on drug level.

Central nervous system involvement in hemophagocytic lymphohistiocytosis: a single-center experience.

BACKGROUND: Hemophagocytic lymphohistiocytosis is a rare multisystem disorder characterized by proliferation and diffuse infiltration multiple organs with histiocytes, including the central nervous system. PATIENTS AND METHODS: Thirty children diagnosed with hemophagocytic lymphohistiocytosis between 1997 and 2010 were reviewed and analyzed. Central nervous system disease involvement was defined as the presence of neurological symptoms and signs or elevated values of cerebrospinal fluid cells and/or proteins. RESULTS: Among the 30 patients, 17 (56%) had central nervous system involvement. Fourteen patients (46%) presented with neurological symptoms including seizures, irritability, bulging fontanelle, cranial nerve palsy, or disturbance of consciousness, whereas the remaining three patients developed central nervous system symptoms during the course of the disease. Seventeen patients (56%) had cerebrospinal fluid abnormalities. Neuroradiological studies were performed in nine patients. The most common findings were edema, atrophy, subcortical necrosis, and high signal intensity on T2-weighted magnetic resonance imaging. All patients were treated according to the Hemophagocytic Lymphohistiocytosis-94 and Hemophagocytic Lymphohistiocytosis-2004 protocols. Patients with central nervous system involvement had greater mortality. In prediction of the outcome, the cutoff value for cerebrospinal fluid protein was 470 mg/L. The most common neurological sequela was psychomotor delay. CONCLUSION: Central nervous system involvement in hemophagocytic lymphohistiocytosis is common and is associated with poor outcome.

Severe transient left ventricular pseudohypertrophy during treatment of hemophagocytic lymphohistiocytosis: a case report.

BACKGROUND: An association between hemophagocytic lymphohistiocytosis (HLH) and severe transient left ventricular (LV) hypertrophy has not been described to date. Possible explanations, including etoposide toxicity, are discussed. OBSERVATION: A 2-month-old male infant with HLH was treated according to the HLH-2004 protocol. Initial cardiac evaluation was within normal limits. During the second month of therapy, a heart murmur was discovered; electrocardiogram demonstrated signs of LV hypertrophy, and echocardiogram confirmed the presence of thickness of LV walls. This complication was transient: clinical findings, echocardiogram, and electrocardiogram recorded 6 months afterward were all within normal limits. CONCLUSIONS: The case suggests the need for close echocardiographic monitoring during HLH treatment.

Successful treatment of hodgkin lymphoma in nijmegen breakage syndrome.

Nijmegen breakage syndrome (NBS) is a rare DNA repair disorder characterized by microcephaly, immunodeficiency, and predisposition to malignancy. We report on a 5-year-old patient with NBS who presented with nodular sclerosing type of Hodgkin disease stage IVB. Chemotherapy consisting of COPP/ABV regimen with reduction at 75% of full doses was employed. During this treatment, no major toxic or infectious complications were observed. Complete remission was achieved lasting now for 20 months. In DNA repair disorders, prognosis of Hodgkin disease is poor as opposed to excellent overall prognosis in general pediatric population. Better survival may be achieved both with adopted, disease-specific regimens, and individualized approach considering patient's clinical condition. Also, better recognition and treatment of infections during chemotherapy may reduce early deaths in patients with DNA repair disorders.