mercaptopurine and Hypoglycemia

Mercaptopurine (6MP) and methotrexate are the cornerstones of maintenance therapy in pediatric patients with acute lymphoblastic leukemia. However, although bone marrow suppression and liver dysfunction are common side effects of these antimetabolites, 6MP-induced hypoglycemia during the maintenance phase is rare. Guidelines and international protocols are well established for the management of bone marrow suppression and liver dysfunction, but promptly identifying 6MP-induced hypoglycemia is the key to its control. Here we report 2 cases of leukemia that developed hypoglycemia during the maintenance phase. Both patients were boys younger than 6 years of age and both suffered symptomatic morning hypoglycemia induced by 6MP (which was diagnosed after excluding all other possible causes). Successful management included changing the time of 6MP administration from evening to morning. Other management options are also discussed.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Child; Female; Humans; Hypoglycemia; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Hypoglycemia has been observed in children receiving acute lymphoblastic leukemia (ALL) therapy, and it can negatively affect patient outcomes. We documented a 4%-6% prevalence of hypoglycemia among patients in the two clinics in this study. We aim to reduce morning hypoglycemia in children on chemotherapy for ALL at two community pediatric oncology clinics (A and B) by 50% in 9 months.. We used the Institute for Healthcare Improvement (IHI) Model for Improvement as the framework. Prolonged hours of fasting for procedural sedation, gaps in the caregivers' knowledge of hypoglycemia risk, and a lack of awareness of the new mercaptopurine administration guidelines were the most likely contributing factors for hypoglycemia. We developed a hypoglycemia prevention educational program for staff and caregivers followed by a knowledge assessment tool.. Each month, the average number of patients seen in both clinics was 43. The monthly average of blood glucose tests in these patients was 94. After implementing the intervention, the percentage of caregivers who received hypoglycemia education reached 88%. Of those, 78% scored ≥ 75% in the knowledge reassessment resurvey. The combined average hypoglycemic episodes in the two clinics decreased by 46%. A higher reduction in hypoglycemic episodes was observed in clinic A (75%) compared with clinic B (17%).. Implementing hypoglycemia education led to a significant drop in hypoglycemic episodes among children on ALL therapy. Despite using a similar approach, one of the two clinics showed a more than fourfold improvement compared with the other.

Topics: Acute Disease; Child; Fasting; Humans; Hypoglycemia; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

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.

Topics: Acidosis; Child; Female; Humans; Hypoglycemia; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Severity of Illness Index

Fasting hypoglycemia is a known complication of mercaptopurine (6MP) maintenance therapy for acute lymphoblastic leukemia (ALL). It is associated with high levels of the methylated metabolite 6-methyl-mercaptopurine (6MMP). Symptoms of hypoglycemia include morning tremulousness, nausea and vomiting. We have previously shown that switching 6MP dosing from evening to morning resolved hypoglycemia by reducing 6MMP; however, the reduction of 6MMP was only transient, potentially resulting in return of hypoglycemia. In children and adults with Crohn's disease, co-prescribing allopurinol with 6MP blocks the activity of thiopurine methytransferase (TPMT), reducing 6MMP and improving its tolerance. As a consequence of inhibiting TPMT, 6MP is shunted toward the production of 6-thioguanine nucleotide (6TGN), which will result in pancytopenia if the dose of 6MP is not reduced. We demonstrate that allopurinol with a reduced dose of 6MP in two patients with ALL and 6MMP-associated hypoglycemia resulted in a complete and sustained suppression of 6MMP and rapid reversal of hypoglycemia and its symptoms.

Topics: Allopurinol; Antimetabolites, Antineoplastic; Blood Glucose; Blood Glucose Self-Monitoring; Child; Child, Preschool; Enzyme Inhibitors; Female; Humans; Hypoglycemia; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Skewing of mercaptopurine (6-MP) metabolism preferentially toward the 6-methylmercaptopurine (6-MMP) metabolite over the antileukemic metabolite 6-thioguanine (6-TGN) is associated with 6-MP-related hepatotoxocity. Allopurinol when coadministered with 6-MP can reduce this skewing and ameliorate the associated adverse effects. The cases we report here demonstrate that aberrant overproduction of 6-MMP is also associated with profound 6-MP-associated hypoglycemia, which can be reversed by administration of allopurinol. This case series contributes to the scant literature on 6-MP-induced hypoglycemia and provides evidence that addition of allopurinol to reduced dose 6-MP can successfully manage this severe toxicity.

Topics: Allopurinol; Child; Female; Humans; Hypoglycemia; Male; Mercaptopurine; Thioguanine

Symptomatic fasting hypoglycemia has been reported as an unusual side effect in patients with acute lymphoblastic leukemia (ALL) on maintenance therapy. We evaluated the relation of the red cell 6-mercaptopurine (6-MP) metabolite 6-methyl-mercaptopurine (6MMP) with hypoglycemia.. We retrospectively reviewed charts of three patients with ALL and symptomatic hypoglycemia while fasting who were noted to have high levels of 6MMP. All patients had an empiric trial of switching from evening to morning 6-MP administration, and two patients were subsequently switched to twice daily dosing. Patients also received complex carbohydrates at bedtime.. Switching 6-MP from evening to morning administration reduced 6MMP levels yet preserved adequate levels of the active metabolite red cell 6-thioguanine nucleotide (6TGN). All patients had decreased hypoglycemic events when changed from evening to morning dosing. Two patients showed a rebound in 6MMP levels with return of hypoglycemic symptoms. Both were then switched to twice daily 6-MP dosing with one having a decrease in 6MMP and hypoglycemic symptoms.. High levels of 6MMP are associated with symptomatic hypoglycemia which may be mitigated by switching to morning or twice daily 6-MP dose administration.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Blood Glucose; Child; Child, Preschool; Dexamethasone; Dietary Carbohydrates; Drug Administration Schedule; Fasting; Female; Guanine Nucleotides; Humans; Hyperglycemia; Hypoglycemia; Hypoxanthine Phosphoribosyltransferase; Infant; Liver Glycogen; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Methylation; Methyltransferases; Polymorphism, Genetic; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Retrospective Studies; Thionucleotides

Acute lymphoblastic leukemia (ALL) maintenance therapy (MT) has been occasionally associated with symptomatic hypoglycemia (SH), attributed to purine analog (mercaptopurine [6-MP]). This hypoglycemia has been hypothesized to affect substrate utilization of gluconeogenic precursor alanine in the liver.. An overweight 5-year-old boy with ALL was evaluated for SH (lethargy and vomiting) that occurred 8-10 h after fasting while receiving daily 6-MP. Hypoglycemic episodes (>20 episodes per month) occurred predominantly around midmorning but not during the 5-day dexamethasone pulse. The adrenocorticotropic hormone test yielded a normal cortisol response, which ruled out pituitary adrenal suppression. A 12-h overnight fasting glucose was 49 mg/dL, with suppressed insulin response <2 IU/mL, low C-peptide of 0.5 ng/mL, high insulin-like growth factor-binding protein >160 ng/mL, high free fatty acid of 2.64 mmol/L, and negative glucagon stimulation test (change in blood glucose [BG] <5 mg/dL). These results ruled out hyperinsulinism. The patient was placed on cornstarch therapy 5 h prior to dosing with 6-MP. This treatment reduced the SH events to fewer than two episodes per month. To study the efficacy of cornstarch, the patient was fitted with the iPro™ professional continuous glucose monitoring system (CGMS) (Medtronic MiniMed, Northridge, CA) with a preset low alarm at 70 mg/dL, which was worn for a period of 5 days while the patient was on cornstarch. With 1,000 sensor reading the BG range was 65-158 mg/dL, and the percentage mean absolute difference between sensor and finger-stick BG readings (the parent monitored his BG four times a day) was 9.4%. There were no hypoglycemic episodes detected by the CGMS while the patient was on cornstarch. After the cessation of chemotherapy, a 15-h fasting study was performed, and the CGMS was placed. Results showed resolution of hypoglycemia.. The CGMS helped us devise an effective management plan for our patient. CGMS proved useful as an adjunct to characterize the pattern of hypoglycemia and to validate the benefit of cornstarch in hypoglycemia associated with 6-MP treatment of ALL.

Topics: Antimetabolites, Antineoplastic; Blood Glucose; Blood Glucose Self-Monitoring; Child, Preschool; Fasting; Humans; Hypoglycemia; Male; Mercaptopurine; Monitoring, Ambulatory; Precursor Cell Lymphoblastic Leukemia-Lymphoma

A 4-year-old boy with acute lymphoblastic leukemia who was receiving 6-mercaptopurine during the maintenance chemotherapy experienced prolonged generalized tonic nocturnal seizures because of severe hypoglycemia after his evening dose by a 12-hour period of fasting. Investigations ruled out all causes of these seizures other than the 6-mercaptopurine-induced severe hypoglycemia.

Topics: Anti-Infective Agents; Antimetabolites, Antineoplastic; Child, Preschool; Humans; Hypoglycemia; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Seizures; Trimethoprim, Sulfamethoxazole Drug Combination

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.

Topics: Administration, Oral; Child, Preschool; Follow-Up Studies; Humans; Hypoglycemia; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Treatment Outcome

Antimetabolite-based continuation therapy is commonly used for childhood acute lymphoblastic leukemia (ALL) and hypoglycemia after prolonged fasting has been recently reported. We have found that spontaneous, symptomatic hypoglycemia (SH) may also occur in such patients.. Between 1995 and 1999, patients treated according to the AIEOP-ALL-95 study received BFM-type intensive chemotherapy; mercaptopurine (6-MP) was given (60 mg/m(2)/days, orally for 14 days) during the second part of induction and during consolidation therapy (25 mg/m(2)/day, orally for 8 weeks); thioguanine (6-TG) was given during reinduction therapy with protocol II (60 mg/m(2)/day, orally for 14 days); continuation therapy consisted of a combination of 6-MP (50 mg/m(2)/day orally) and methotrexate (MTX, 20 mg/m(2)/weekly, i.m.). We reviewed the charts of all patients treated for childhood ALL at our two centers. This was done to assess the incidence and the characteristics of all episodes of SH: sweating, pallor, nausea, abdominal pain with or without transient alterations of alertness, in the presence of blood glucose level of under 60 mg/dl.. Six of 86 patients (6.9%) developed 18 episodes of SH. Five were male, none was older than 5 years, and four were only 3 years old. SH episodes occurred during consolidation (n = 2), reinduction (n = 7), and continuation (n = 9) phases.. SH is a rare complication associated with administration of the purine analogues, mercaptopurine and thioguanine to children with reduced fat storage and young age.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Blood Glucose; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Hypoglycemia; Italy; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Purines; Retrospective Studies; Time Factors; Vincristine

Nineteen of 35 children (54%) with acute lymphoblastic leukemia receiving maintenance therapy consisting of daily oral 6-mercaptopurine and weekly oral methotrexate developed hypoglycemia (blood glucose level <2.7 mmol/L [50 mg/dL] or <2.9 mmol/L [54 mg/dL] with symptoms) during 16 hours of overnight fasting. In 15 of 15 re-studied children, fasting tolerance had improved, and in 67% (10/15), it had become normal a few months after cessation of therapy.

Topics: Adolescent; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; Child; Child, Preschool; Fasting; Female; Finland; Humans; Hypoglycemia; Infant; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Statistics, Nonparametric