Allopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity

Giamanco, Nicole; Cunningham, Bethany S.; Klein, Laura S.; Parekh, Dina S.; Warwick, Anne B.; Lieuw, Kenneth

doi:10.1097/mph.0000000000000499

Cited by 21 publications

(32 citation statements)

References 27 publications

(34 reference statements)

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“…Both morning dosing and split dosing of 6‐MP led to a reduction in his 6‐MMP levels, but with a commensurate drop in the 6‐TGN levels (Figure A) with continued episodic hypoglycemia. After several weeks without substantial improvement, a trial of allopurinol was initiated, based on data suggesting that this could result in a more significant drop in 6‐MMP levels and reduction in associated symptoms . His 6‐MP dose was reduced to 25 mg/m 2 /day and allopurinol was started at 50 mg/m 2 /day daily.…”

Section: Resultsmentioning

confidence: 99%

“…Allopurinol when given with oral 6-MP inhibits first pass metabolism leading to a three-to fivefold increase in peak plasma concentration and plasma area under the curve 10 and can alter the metabolism of 6-MP, favoring the production of 6-TGN over 6-MMP. 6,11 Small series of leukemia patients have shown that the combination of allopurinol and reduced dose 6-MP is an effective strategy for the management of 6-MP-associated pancreatits 7 and hepatotoxicity. [5][6][7] Here, we employed this strategy for the man- In conclusion, this case series contributes to the scant existing literature regarding 6-MP-associated hypoglycemia in patients with ALL.…”

Section: Discussionmentioning

confidence: 99%

“…Some patients preferentially metabolize 6‐MP to 6‐MMP. Adding allopurinol has been shown to reduce 6‐MMP levels while maintaining therapeutic 6‐TGN levels in patients with ALL . Reducing 6‐MMP levels by adding allopurinol may be an effective, previously unreported, strategy to alleviate 6‐MP‐associated hypoglycemia.…”

Section: Introductionmentioning

confidence: 99%

“…After several weeks without substantial improvement, a trial of allopurinol was initiated, based on data suggesting that this could result in a more significant drop in 6-MMP levels and reduction in associated symptoms. [5][6][7] His 6-MP dose was reduced to 25 mg/m 2 /day and allopurinol was started at 50 mg/m 2 /day daily. This led to significant reduction in 6-MMP level and increase in 6-TGN levels despite the 6-MP dose reduction ( Figure 1A (Table 1).…”

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confidence: 99%

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

Miller

Brackett

Schafer

et al. 2018

Pediatric Blood & Cancer

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Miller

Brackett

Schafer

et al. 2018

Pediatric Blood & Cancer

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“…In addition to modifying ROS levels, XOD is involved in the metabolism of several drugs. Recent reports suggest the utility of allopurinol to reduce chemotherapy toxicity in leukaemia patients [ 205 ]. An ongoing clinical trial is testing the feasibility of allopurinol to improve 6-mercaptopurine regimen in paediatric ALL treatment (NCT03022747, phase II).…”

Section: The Use Of Ros As a Therapeutic Target In Haematological Malmentioning

confidence: 99%

Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side

Prieto-Bermejo

Romo-González

Pérez-Fernández

et al. 2018

J Exp Clin Cancer Res

102

115

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Oxidative stress is related to ageing and degenerative diseases, including cancer. However, a moderate amount of reactive oxygen species (ROS) is required for the regulation of cellular signalling and gene expression. A low level of ROS is important for maintaining quiescence and the differentiation potential of haematopoietic stem cells (HSCs), whereas the level of ROS increases during haematopoietic differentiation; thus, suggesting the importance of redox signalling in haematopoiesis. Here, we will analyse the importance of ROS for haematopoiesis and include evidence showing that cells from leukaemia patients live under oxidative stress. The potential sources of ROS will be described. Finally, the level of oxidative stress in leukaemic cells can also be harnessed for therapeutic purposes. In this regard, the reliance of front-line anti-leukaemia chemotherapeutics on increased levels of ROS for their mechanism of action, as well as the active search for novel compounds that modulate the redox state of leukaemic cells, will be analysed.

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Assessment on the use of allopurinol to improve safety and efficacy of mercaptopurine in pediatric patients with Acute Lymphoblastic Leukemia and Lymphoma during maintenance therapy

Barone,

Dandekar,

McKeone

et al. 2024

Cancer Reports

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BackgroundMercaptopurine is an important component of acute lymphoblastic leukemia (ALL) and lymphoma (LLy) maintenance therapy. The 6‐thioguanine nucleosides (6‐TGN) are believed to be the primary contributor to myelosuppression and immunosuppressive effects, while 6‐methylmercaptopurine (6‐MMPN) is believed to be responsible for several toxicities including hepatotoxicity, pancreatitis, and hypoglycemia. Previous reports suggest the addition of allopurinol may reduce these toxicities.AimsTo assess the use of allopurinol to improve both safety and efficacy of mercaptopurine in pediatric patients with ALL and LLy during maintenance therapy. Secondary objectives included evaluating patient tolerability and skewed metabolism. In addition, we also analyzed mercaptopurine daily dose reduction upon allopurinol initiation.Methods and ResultsThe primary endpoint was time within goal ANC prior to and after initiation of allopurinol. Secondary endpoints included; improvement in selective toxicities (hepatotoxicity, pancreatitis, and hypoglycemia) and 6‐MMPN to 6‐TGN ratio prior to and after allopurinol initiation. In addition, an exploratory endpoint assessing mercaptopurine daily dose reduction prior to and after allopurinol initiation was included. Sixteen patients met inclusion criteria and 15 (94%) of which were included in this study. Median percent of maintenance days within goal ANC prior to and after initiation of allopurinol was 27.8 (IQR 22.6–44.9) and 41.6 (IQR 20.2–58.2) respectively. All patients experienced selective toxicities; 15 (100%) hepatotoxicity, 1 (7%) pancreatitis, and 3 (20%) hypoglycemia. Improvement of toxicities was seen in 13/15 (87%), 1/1 (100%), and 2/3 (67%) respectively. Average 6‐MMPN:6‐TGN ratio prior to allopurinol initiation was 304:1 and after, allopurinol initiation improved to 15:1, resulting in a 95% reduction. Average mercaptopurine dose prior to and after allopurinol initiation decreased by about 56% (63 to 28 mg/m2/day).ConclusionResults suggest that the use of allopurinol in pediatric patients with ALL and LLy receiving mercaptopurine during maintenance therapy is both safe and effective.

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Allopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity

Cited by 21 publications

References 27 publications

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

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

Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side

Assessment on the use of allopurinol to improve safety and efficacy of mercaptopurine in pediatric patients with Acute Lymphoblastic Leukemia and Lymphoma during maintenance therapy

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