Maintenance Treatment With Low‐Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine‐Induced Pancreatitis

Mercaptopurine (6‐mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy.     

Symptomatic hypoglycemia: an unusual side effect of oral purine analogues for treatment of ALL

Symptomatic hypoglycemia is an unusual complication in children receiving oral purine analogues for treatment of childhood acute lymphoblastic leukemia (ALL). The exact mechanism of the hypoglycemic effect of the antimetabolic therapy remains unclear. Reduced hepatic glycogen stores or impaired hepatic glyconeogenesis may partly explain the hypoglycemia. To prevent hypoglycemia, food containing complex carbohydrates is recommended before sleep. In severe cases of hypoglycemia due to 6-mercaptopurine (6-MP), the dose can be given in the morning and if this fails 6-MP can be discontinued for a short period of time. We report a 3-year-old child who developed severe early morning hypoglycemia episodes that resolved after decreasing 6-MP while receiving non-high risk ALL therapy.     

Severe mercaptopurine-induced hypoglycemia in acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia maintenance chemotherapy includes mercaptopurine, a purine analog with uncommon side effects, that can be life-threatening. We describe a 7-year-old female patient with ALL that presented with altered state of consciousness after maintenance chemotherapy with methotrexate and 6-mercaptopurine, due to severe hypoglycemia with metabolic acidosis. She initiated metabolic corrections with rapid resolution of symptoms. Hypoglycemia secondary to 6-mercaptopurine is a rare and transient side effect. The cause effect relation is difficult to establish, leading to underdiagnosis. Hypoglycemia is preventable without compromising maintenance therapy efficacy.     

Erythrocyte concentrations of metabolites or cumulative doses of 6-mercaptopurine and methotrexate do not predict liver changes in children treated for acute lymphoblastic leukemia

BACKGROUND: During therapy consisting of 6MP and MTX, metabolites accumulate in the erythrocytes. The erythrocyte levels of metabolites reflect the intensity of therapy. Whether they are associated with hepatotoxicity manifested as histological liver changes is not known. We studied the association of the metabolites and cumulative doses of 6MP and MTX with histological liver disease. METHODS: Serial measurements of E-TGN, E-MTX, and ALT during maintenance therapy were performed and cumulative doses of 6MP and MTX were calculated as g/m2 in 16 children with ALL. Each subject underwent a percutaneous liver biopsy at the end of therapy to screen for histological liver disease. RESULTS: No differences in E-TGN, E-MTX, or cumulative doses of 6MP or MTX were detected in the children with ALL with liver fibrosis compared to those without fibrosis, or in the children with less liver fatty change compared to those with more fatty change. Serum median ALT levels correlated significantly positively with cumulative doses of 6MP during therapy (rS = 0.527, P = 0.036), but not with cumulative doses of MTX, or E-TGN, or E-MTX. CONCLUSIONS: Erythrocyte levels of the metabolites or the cumulative doses of 6MP and MTX do not predict histological liver disease in children treated for ALL.     

Monitoring of inosine monophosphate dehydrogenase activity in mononuclear cells of children with acute lymphoblastic leukemia: enzymological and clinical aspects

BACKGROUND: Inosine 5'-monophosphate dehydrogenase (IMPDH; EC1.1.1.205) catalyzes the rate-limiting step in guanine nucleotide biosynthesis, and may play an important role in treatment of patients with antipurines. METHODS: We used an HPLC method to measure the IMPDH activity in peripheral blood and bone marrow mononuclear cells (MNC). IMPDH activities were determined in children who were diagnosed with and treated for acute lymphoblastic leukemia (ALL), and in a group of control children. RESULTS: The median IMPDH activity for control children was 350 pmol/10(6) pMNC/hr (range 97-896; n = 47). No gender or age differences were observed. IMPDH activity at diagnosis of ALL was correlated with the percentage of peripheral blood lymphoblasts (r = 0.474; P < 0.001; n = 71). The median IMPDH activity at diagnosis was 410 pmol/10(6) pMNC/hr (range 40-2009; n = 76), significantly higher than for controls (P = 0.012). IMPDH activity significantly decreased after induction treatment, and during treatment with methotrexate (MTX) infusions (median 174 pmol/10(6) pMNC/hr; range 52-516; n = 21). The activity remained low during maintenance treatment with 6-mercaptopurine (6MP) and MTX, at a significantly lower level than for controls (P < 0.004). One year after cessation of treatment IMPDH activity returned to normal values. CONCLUSION: The decrease of IMPDH activity at remission of ALL seems to be at least partly due to the eradication of lymphoblasts with the type 2 isoform of the enzyme.     

Polymyxin‐direct hemoperfusion for sepsis‐induced multiple organ failure

We report a case of multiple organ failure caused by the Bacillus cereus infection during acute lymphoblastic leukemia therapy, who was treated successfully. A 15‐year‐old male developed (B. cereus) sepsis on the 19th day after chemotherapy initiation. Polymyxin‐direct hemoperfusion for septic shock was started, followed by continuous hemodiafiltration. His condition improved after starting the hemoperfusion. At the onset of sepsis, elevated levels of serum inflammatory cytokines, anti‐inflammatory cytokines, and plasminogen‐activator inhibitor complex‐1 were observed. Serum levels of these cytokines and bioactive substances decreased after blood purification therapy, which correlated with the improvement of clinical symptoms. Pediatr Blood Cancer 2010;55:202–205. © 2010 Wiley‐Liss, Inc.     

Toxic ingestion of 6-mercaptopurine by young siblings of pediatric oncology patients

We report two cases of accidental ingestion of large quantities of 6-mercaptopurine (6-MP) in siblings of patients with acute lymphoblastic leukemia (ALL). These cases reinforce the need for thorough anticipatory guidance to families in order to prevent the incidence of potentially life-threatening accidental ingestions.     

Characterization of the anti‐CD22 targeted therapy,moxetumomab pasudotox,for B‐cell precursor acute lymphoblastic leukemia

Moxetumomab pasudotox is a second‐generation recombinant immunotoxin against CD22 on B‐cell lineages. Antileukemic activity has been demonstrated in children with chemotherapy‐refractory B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL), with variable responses. Here, we report in vitro and in vivo evaluation of moxetumomab pasudotox treatment of human cell lines and patient‐derived cells as a preliminary study to understand characteristics of sensitivity to treatment. Binding, internalization, and apoptosis were evaluated using fluorescently tagged moxetumomab pasudotox. Studies in NOD‐scid IL2Rg^null mice showed a modest survival benefit in mice engrafted with 697 cells but not in NALM6 or the two patient‐derived xenograft models.