Prevention of mercaptopurine‐induced hypoglycemia using allopurinol to reduce methylated thiopurine metabolites

Miller, Michelle; Brackett, Julienne; Schafer, Eric S.; Rau, Rachel E.

doi:10.1002/pbc.27577

Cited by 13 publications

(17 citation statements)

References 11 publications

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“…Thus far, these methods have only been reported in patients experiencing hypoglycemia. Two cases demonstrated complete reversal of symptoms with changes in timing of 6-MP administration plus a carbohydrate-enriched diet, whereas these methods failed to resolve hypoglycemic episodes in two other reports (25)(26)(27)(28). A fifth case required 6-MP dose reduction in addition to morning administration to achieve the desired response (29).…”

Section: Clinical Use Of Allopurinol To Mitigate 6-mp Toxicity Duringmentioning

confidence: 97%

“…Both patients had previously developed pancreatitis following asparaginase while simultaneously taking 6-MP in pre-maintenance phases, perhaps increasing the likelihood of recurrence with 6-MP alone. Two case reports including four total patients have also been published using combination therapy for 6-MP associated hypoglycemia (27,28). All four patients experienced complete resolution of symptoms along with lower 6-MMP levels and lower 6-MMP:6-TGN ratio.…”

Section: Clinical Use Of Allopurinol To Mitigate 6-mp Toxicity Duringmentioning

confidence: 99%

“…A report of an adult case where 6-MP and allopurinol were prescribed independently for different disorders resulted in profound neutropenia and infection (33). While the exact dose in pediatrics is not standardized, 6-MP doses have generally been reduced by 50-75% when allopurinol is initiated (19,27,30,32). IBD studies err on the lower side with 75% dose reduction followed by dose escalation until therapeutic response or dose-limiting side effects occur (8,34,35).…”

Section: Clinical Use Of Allopurinol To Mitigate 6-mp Toxicity Duringmentioning

confidence: 99%

“…Eighty-nine percent of patients underwent subsequent dose escalations due to elevated neutrophil counts, though only 47% of these patients maintained this higher dose whereas 53% later required dose reduction due to recurrent neutropenia. Allopurinol dosing has also not been standardized, with some reports using a fixed dose such a 50 mg once or twice daily, whereas others use 50 mg/m 2 /day (19,27,31,32). A majority of case reports maintain the same dose of allopurinol throughout therapy for each patient, though in some cases allopurinol is also titrated to the desired response.…”

Section: Clinical Use Of Allopurinol To Mitigate 6-mp Toxicity Duringmentioning

confidence: 99%

“…In ALL, the most common side effects were fever and neutropenia or other cytopenias, with nearly half of patients requiring subsequent holds in 6-MP therapy. Of course, these side effects can also be seen with 6-MP use alone (19,27,32). A distinct difference between IBD and ALL use of allopurinol is that neutropenia is a desired effect and target of ALL therapy, whereas this is not the case for IBD, and thus IBD patients may achieve desired therapeutic responses without as much risk for neutropenia.…”

Section: Clinical Use Of Allopurinol To Mitigate 6-mp Toxicity Duringmentioning

confidence: 99%

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Use of Allopurinol to Mitigate 6-Mercaptopurine Associated Gastrointestinal Toxicity in Acute Lymphoblastic Leukemia

2020

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An essential component of acute lymphoblastic leukemia (ALL) therapy is the prolonged maintenance phase with daily 6-mercaptopurine (6-MP) as the cornerstone. While 6-MP is generally well-tolerated, some patients suffer from significant side effects such as gastrointestinal (GI) toxicity, including hepatitis, hypoglycemia, nausea, and pancreatitis, which can substantially limit the tolerated dose of 6-MP. These toxicities are thought to result from skewed metabolism of 6-MP leading to an accumulation of the 6-methylmercaptopurine (6-MMP) metabolite. Here, we describe current knowledge behind the use of allopurinol to modify 6-MP metabolism and improve tolerance to therapy. This method has been successfully used in adults with inflammatory bowel disease refractory to purine therapy and has been modified for use in children with GI toxicities related to 6-MP in maintenance therapy for ALL. Use of allopurinol for 6-MP related toxicities should be reserved for patients in which an alternative cause of signs or symptoms has been excluded and for whom non-pharmacologic measures have failed. When allopurinol is used, simultaneous dose reduction of 6-MP is required to avoid severe myelosuppression and related side effects, though overall combination therapy appears to be well-tolerated and effective when instituted appropriately.

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Section: Clinical Use Of Allopurinol To Mitigate 6-mp Toxicity Duringmentioning

confidence: 97%

Section: Clinical Use Of Allopurinol To Mitigate 6-mp Toxicity Duringmentioning

confidence: 99%

Section: Clinical Use Of Allopurinol To Mitigate 6-mp Toxicity Duringmentioning

confidence: 99%

Section: Clinical Use Of Allopurinol To Mitigate 6-mp Toxicity Duringmentioning

confidence: 99%

Section: Clinical Use Of Allopurinol To Mitigate 6-mp Toxicity Duringmentioning

confidence: 99%

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Use of Allopurinol to Mitigate 6-Mercaptopurine Associated Gastrointestinal Toxicity in Acute Lymphoblastic Leukemia

2020

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Allopurinol use during pediatric acute lymphoblastic leukemia maintenance therapy safely corrects skewed 6‐mercaptopurine metabolism, improving inadequate myelosuppression and reducing gastrointestinal toxicity

Cohen

Cooper

Sison

et al. 2020

Pediatric Blood & Cancer

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Background: Inadequate myelosuppression during maintenance therapy for acute lymphoblastic leukemia (ALL) is associated with an increased risk of relapse. One mechanism is skewed metabolism of 6-mercaptopurine (6MP), a major component of maintenance therapy, which results in preferential formation of the hepatotoxic metabolite (6-methyl mercaptopurine [6MMP]) with low levels of the antileukemic metabolite, 6-thioguanine nucleotides (6TGN). Allopurinol can modify 6MP metabolism to favor 6TGN production and reduce 6MMP. Methods: Patients in maintenance were considered for allopurinol treatment who had the following features: (a) Grade ≥3 hepatotoxicity; (b) Grade ≥2 nonhepatic gastrointestinal (GI) toxicity; or (c) persistently elevated absolute neutrophil count (ANC) despite >150% protocol dosing of oral chemotherapy. Results: From 2013 to 2017, 13 ALL patients received allopurinol: nine for hepatotoxicity, five for inadequate myelosuppression, and three for nonhepatic GI toxicity (four met multiple criteria). Allopurinol was well tolerated, without significant adverse events. Allopurinol resulted in a significant decrease in the average 6MMP/6TGN ratio (mean reduction 89.1, P = .0001), with a significant increase in 6TGN (mean 550.4, P = .0008) and a significant decrease in 6MMP (mean 13 755, P = .0013). Patients with hepatotoxicity had a significant decrease in transaminase elevation after starting allopurinol (alanine transaminase [ALT] mean decrease 22.1%, P = .02), and all with nonhepatic GI toxicity had improved symptoms. Those with inadequate myelosuppression had a significant increase in the time with ANC in goal (mean increase 26.4%, P = .0004). Conclusions: Allopurinol during ALL maintenance chemotherapy is a safe, feasible, and effective intervention for those who have altered metabolism of 6MP causing toxicity or inadequate myelosuppression.

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Incidence and risk factors for hypoglycemia during maintenance chemotherapy in pediatric acute lymphoblastic leukemia

Rosenfeld

Getz

Miller

et al. 2021

Pediatric Blood & Cancer

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Background Fasting hypoglycemia is a recognized occurrence among pediatric patients with acute lymphoblastic leukemia (ALL) during maintenance therapy. Existing publications describing this finding are limited to small studies and case reports. Our objective was to determine the incidence of hypoglycemia during maintenance chemotherapy and to investigate the association of age, as well as other potential risk factors, with this outcome in pediatric patients with ALL. Procedure This retrospective cohort study included individuals 1 to 21 years of age with ALL treated with antimetabolite‐containing maintenance chemotherapy at a large children's hospital between January 2011 and December 2014. The primary endpoint was time to first documented episode of hypoglycemia during maintenance therapy, defined as single measurement of plasma glucose <60 mg/dL. Cox regression was used to evaluate the association with age and identify other potential risk factors. Results We identified 126 eligible patients, of whom 63% were documented as White, non‐Hispanic, 28% as non‐White, non‐Hispanic, and 9% as Hispanic. Twenty‐eight children (22%) had documented hypoglycemia during maintenance therapy. Younger age at the start of maintenance and hepatotoxicity documented during chemotherapy prior to maintenance initiation were associated with hypoglycemia (adjusted HR age = 0.88; 95% CI, 0.78‐0.99; adjusted HR prior hepatotoxicity = 3.50; 95% CI, 1.47‐8.36). Conclusions Nearly one quarter of children in our cohort had hypoglycemia documented during maintenance chemotherapy. Younger age at maintenance initiation and hepatotoxicity during chemotherapy prior to maintenance initiation emerged as risk factors. These findings highlight the importance of counseling about the risk of, and monitoring for, hypoglycemia, particularly in young children.

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Prevention of mercaptopurine‐induced hypoglycemia using allopurinol to reduce methylated thiopurine metabolites

Cited by 13 publications

References 11 publications

Use of Allopurinol to Mitigate 6-Mercaptopurine Associated Gastrointestinal Toxicity in Acute Lymphoblastic Leukemia

Use of Allopurinol to Mitigate 6-Mercaptopurine Associated Gastrointestinal Toxicity in Acute Lymphoblastic Leukemia

Allopurinol use during pediatric acute lymphoblastic leukemia maintenance therapy safely corrects skewed 6‐mercaptopurine metabolism, improving inadequate myelosuppression and reducing gastrointestinal toxicity

Incidence and risk factors for hypoglycemia during maintenance chemotherapy in pediatric acute lymphoblastic leukemia

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