|Year : 2015 | Volume
| Issue : 2 | Page : 411-414
Toxic complications of treatment with 6-mercaptopurine in pediatric acute lymphoblastic leukemia
Farida H Rashidy1, Seham M Ragab1, Ashraf A Dawood2, Shaymaa A Temraz MSc 3
1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Medical Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Shebin Elkom Fever Hospital, Shebin Elkom, Egypt
|Date of Submission||15-Apr-2014|
|Date of Acceptance||07-Jun-2014|
|Date of Web Publication||31-Aug-2015|
Shaymaa A Temraz
Ganzour-Berket El Sabaa, Menoufia
Source of Support: None, Conflict of Interest: None
The aim of this work was to study the complications of 6-mercaptopurine (6-MP) drug therapy developed during the course of chemotherapy in children with acute lymphoblastic leukemia (ALL).
Mercaptopurine is an anticancer drug used in the routine treatment of pediatric patients with ALL, which is administered daily during maintenance phases of chemotherapy. The principal and potentially serious toxic effects of 6-MP are bone marrow toxicity and hepatotoxicity.
Patients and methods
Twenty-five children with ALL were included in the present study. Initially, complete blood count, liver function tests (alanine aminotransferase, aspartate aminotransferase), bone marrow examination, immunophenotyping, and cytochemical analysis were performed. Markers for hepatitis B and C using PCR were applied/determined. Data on toxicity were traced during the maintenance phase.
During the maintenance phase, 16.0% of patients were seen to have febrile neutropenia grade 2 (ANC < 1.5 to >1.0 × 109/l), 56.0% to have febrile neutropenia grade 3 (ANC < 1.0 to >0.5 × 109/l), and 28.0% to have febrile neutropenia grade 4 (ANC < 0.5 × 109/l). Sixteen percent of patients had mildly elevated levels of liver enzymes up to 200 IU/l, 32.0% had elevated levels of liver enzymes more than 200 IU/l, and 52.0% of patients had normal levels of liver enzymes. Eight percent of patients did not need drug interruption, 24.0% needed interruption for up to 1 week, and 68.0% of patients had to discontinue 6-MP for more than 1 week. An overall 16.0% of patients required 6-MP dose modification by 25-50% reduction of total dose, 4.0% needed 6-MP dose modification by less than 50% reduction of total dose, and 80.0% did not need dose modification throughout the maintenance course. The total number of mortality cases was 10 (40.0%) of 25 patients.
6-MP could induce hematological toxicity and several forms of hepatotoxicity. 6-MP dose reductions should be performed throughout the maintenance phase according to the protocol.
Keywords: febrile neutropenia, hepatotoxicity, leukemia, mercaptopurine
|How to cite this article:|
Rashidy FH, Ragab SM, Dawood AA, Temraz SA. Toxic complications of treatment with 6-mercaptopurine in pediatric acute lymphoblastic leukemia. Menoufia Med J 2015;28:411-4
|How to cite this URL:|
Rashidy FH, Ragab SM, Dawood AA, Temraz SA. Toxic complications of treatment with 6-mercaptopurine in pediatric acute lymphoblastic leukemia. Menoufia Med J [serial online] 2015 [cited 2020 Feb 27];28:411-4. Available from: http://www.mmj.eg.net/text.asp?2015/28/2/411/163930
| Introduction|| |
Mercaptopurine is indicated for the maintenance therapy of acute lymphoblastic leukemia (ALL) as part of a combination regimen. The response to this agent depends upon the particular subclassification of ALL and the age of the patient  .
Mercaptopurine is administered orally at a dose of 75-100 mg/m2/day with upward or downward dose adjustments based on the degree of myelosuppression. Ensuring that patients are receiving their maximum tolerated dose of mercaptopurine appears to be an important factor in the outcome for children with ALL  .
The principal and potentially serious toxic effects of mercaptopurine are bone marrow toxicity and hepatotoxicity. Patients receiving mercaptopurine for leukemia often show transient and asymptomatic elevations in serum aminotransferase or alkaline phosphatase levels, and a proportion of these patients develop jaundice, particularly when it is given at high doses  .
| Patients and methods|| |
This study was carried out at the Department of Pediatrics, Hematology and Oncology Unit, Menoufia University Hospital, Egypt. This study was approved by the ethical committee, and informed consent was obtained from caregivers of the included children. This study included 25 ALL patients (10 boys and 15 girls) with an age range of 1-14 years and a median of 6 years and were designed to receive St Jude Total XV Chemotherapy Protocol  .
Diagnosis was made on the basis of standard clinical and laboratory investigations.
Complete blood count was performed using the AC920 Autocounter (Boule Medical AB, Domnarvsgatan, Sweden).
The bone marrow was aspirated and classified as follows:
Morphological classification was carried out on the basis of the French-American-British.
Cytochemical classification was carried out using enzymatic (peroxidase, esterase) and nonenzymatic cytochemical stains (Sudan Black, Periodic acid Schiff).
Immunophenotypic classification was made using flow cytometry.
Determination of alanine aminotransferase and aspartate aminotransferase levels was carried out using the IFCC method without pyridoxal phosphate  .
Hepatitis B surface antigen was determined using commercially available enzyme immunoassays, and the presence of anti-hepatitis C virus antibody was determined using a third-generation enzyme immunoassay.
Determination of urea was carried out using the enzymatic method  and that of creatinine using the Jaffe method  . Electrolyte and uric acid concentrations were evaluated. Risk stratification was performed using the criteria of St Jude Total XV Therapy Protocol.
- Patients with ALL.
- Patients on St Jude Total Fifteen Chemotherapy Protocol (Total XV).
- Age of patients: 1-18 years.
- Patients who were not on St Jude Total XV Chemotherapy Protocol.
- Patients who had positive hepatitis C virus infection on PCR.
Once the diagnosis of ALL was established, clinical follow-up, documentation of events, and 6-mercaptopurine (6-MP) dose reductions were performed throughout the maintenance phase according to the protocol.
Using Microsoft Excel 2010 and SPSS v.20 (SPSS Inc., Chicago, IL, USA) for Microsoft Windows 7, the clinical and laboratory data were statistically analyzed. The data were represented in a descriptive manner. Mean ± SD and range were used for the continuous variables, whereas numbers and percentages were used for categorical variables.
| Results|| |
The age of the patients ranged from 1.0 to 14.0 years, with mean ± SD of 6.4 ± 4.0 years. There were 10 (40.0%) boys and 15 (60.0%) girls. The most frequent clinical presentation was fever in 25 (100.0%) patients and pallor in 25 (100.0%), followed by hepatosplenomegaly in 15 (60.0%), lymph node enlargement in six (24.0%), and bleeding in the form of epistaxis in seven (28.0%) patients [Table 1].
|Table 1 Demographic and clinical data (at diagnosis) of the studied patients|
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Twelve (48.0%) patients were classified as low risk (received 48 infusions of HDMTX 2.5 g/m2), whereas 13 (52.0%) were classified as standard risk (received 56 infusions of HDMTX 5 g/m2) on the basis of the criteria of St Jude Total XV Protocol for risk stratification [Table 2].
|Table 2 Laboratory investigations and risk stratification of the studied patients at presentation|
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Four (16.0%) patients were seen to have febrile neutropenia grade 2 (ANC between 1.5 and 1.0 × 109/l), 14 (56.0%) patients to have febrile neutropenia grade 3 (ANC between 1.0 and 0.5 × 109/l), and seven (28.0%) patients to have febrile neutropenia grade 4 (ANC<0.5 × 109/l). The liver enzyme levels were mildly elevated (200 IU/l) in four (16.0%) patients, more than 200 IU/l in eight (32.0%) patients, and were normal in 13 (52.0%) patients [Table 3].
Only two (8.0%) patients did not require drug interruption; six (24.0%) patients required interruption for up to 1 week, whereas 17 (68.0%) patients had to discontinue 6-MP for more than 1 week. Four (16.0%) patients needed dose modification by a reduction of 25-50% of total dose, one (4.0%) patient needed less than 50% reduction of total dose, and 20 (80.0%) patients had no dose modification [Table 3]. The total number of mortality cases was 10 (40.0%) of 25 patients.
|Table 3 Complications of 6-mercaptopurine therapy developed during the maintenance course of chemotherapy|
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| Discussion|| |
The traditional approach to dosing anticancer drugs is to administer a standard starting dose, which is normalized to the body surface area, and then to adjust or individualize subsequent doses on the basis of the severity of drug toxicity. For mercaptopurine, which is used to maintain remission in childhood ALL, the standard starting dose is 75 mg/m2/day orally, and subsequent dose adjustments are primarily based on the degree of suppression of the neutrophil count  .
The objective of this study was to study the complications of 6-MP during the maintenance phase. This study included 25 pediatric patients with ALL who received Total Therapy XV Protocol at St Jude Children Research Hospital.
As regards 6-MP toxicity in this study, febrile neutropenia was reported in 25 (100%) patients during the course of the treatment: grade 2 in four (16.0%) patients, grade 3 in 14 (56.0%) patients, and grade 4 in seven (28.0%) patients. The attacks of febrile neutropenia ranged from one to 12 attacks with the longest duration of 2 weeks due to the presence of infection - for example, fungal infection and septicemia [six (24%) patients] - to the shortest duration of 1 week [19 (76%) patients]. After each attack we did not need bone marrow aspiration.
Marshall  reported that thiopurine induced hematological toxicity and bone marrow suppression; this may be manifested by leukopenia, thrombocytopenia, or any combination of these.
The second common toxicity was hepatotoxicity: four (16.0%) patients had elevated liver enzyme levels up to 200 IU (five-fold), eight (32.0%) patients had more than 200 IU, and 13 (13.0%) patients had liver enzyme levels less than 200 IU. The mean alanine aminotransferase was (200-300 IU). The longest duration was 2 weeks and the shortest was 1 week.
DeLeve  reported that mercaptopurine is associated with several forms of hepatotoxicity and often leads to transient and asymptomatic elevations in serum aminotransferase or alkaline phosphatase.
Among the 25 studied ALL patients, 23 (92%) patients needed drug interruption during maintenance, whereas two (8.0%) patients did not require drug interruption. This drug interruption was due to febrile neutropenia, hepatotoxicity, or infection.
Among the 25 studied ALL patients, four (16%) patients needed 25-50% dose reduction, one (4.0%) patient needed less than 50% dose reduction of total dose, whereas 20 (80%) patients required no dose reduction according to the used protocol.
Aboul Naga et al.  reported that, of the 52 studied patients, 12 (23.1%) required 6-MP dose reduction by 30% (70% of the original dose was given). The other 40 (76.9%) patients required no dose reduction.
| Conclusion|| |
6-MP could induce hematological toxicity and several forms of hepatotoxicity and often leads to transient and asymptomatic elevations in serum aminotransferase. 6-MP dose reductions were performed throughout the maintenance phase according to the protocol.
| Acknowledgements|| |
The authors thank all the workers and the participants who generously agreed to participate in the study.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Relling MV, Hancock HL, Rivera GK. Intolerance to mercaptopurine therapy related to heterozygosity at the thiopurine methyltransferase gene locus. J Natl Cancer Inst 2008; 91
Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. New Engl J Med 2006; 354
DeLeve LD. In: Kaplowitz N, DeLeve LD, editors. Thiopurines. Cancer chemotherapy. Drug-induced liver disease 3rd ed. Amsterdam: Elsevier; 2011
Pui CH, Sandlund JT, Pei D. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 2004; 104
Moss D, Henderson R. In: Burtis CA, Ashwood ER, editors. Clinical enzymology. Tietz textbook of clinical chemistry. Philadelphia, PA, USA: WB Saunders; 1999
Patton CJ, Crouch SR. Determination of serum urea. Anal Chem 1977; 49
Lamb E, Newman DJ, Price CP. Burtis, CA, Ashwood ER, Bruns DE, editors. Saunders. Kidney function tests in Tietz textbook of clinical chemistry and molecular diagnostics 4th ed. Philadelphia: Elsevier Inc.; 2006. 24
Bhatia S, Landier W, Shangguan M. Non adherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children's oncology group. J Clin Oncol 2012; 30
Marshall E. Preventing toxicity with a gene test. Science. 2003; 302
Aboul Naga A, Ebid T, Fahm M. Effects of thiopurine S-methyltransferase genetic polymorphism on mercaptopurine therapy in pediatric ALL. J Am Sci 2011; 7
:337-346. ISSN: 1545-1003.
[Table 1], [Table 2], [Table 3]