-
Clinical Pharmacology and Therapeutics May 2019Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme...
Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmacologic effects of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org).
Topics: Antimetabolites, Antineoplastic; Azathioprine; Dose-Response Relationship, Drug; Drug Dosage Calculations; Humans; Inactivation, Metabolic; Mercaptopurine; Methyltransferases; Pharmacogenetics; Pharmacogenomic Testing; Pyrophosphatases; Thioguanine
PubMed: 30447069
DOI: 10.1002/cpt.1304 -
Boletin Medico Del Hospital Infantil de... 2017In parallel to the human genome sequencing project, several technological platforms have been developed that let us gain insight into the genome structure of human... (Review)
Review
In parallel to the human genome sequencing project, several technological platforms have been developed that let us gain insight into the genome structure of human entities, as well as evaluate their usefulness in the clinical approach of the patient. Thus, in acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, genomic tools promise to be useful to detect patients at high risk of relapse, either at diagnosis or during treatment (minimal residual disease), and they also increase the possibility to identify cases at risk of adverse reactions to chemotherapy. Therefore, the physician could offer patient-tailored therapeutic schemes. A clear example of the useful genomic tools is the identification of single nucleotide polymorphisms (SNPs) in the thiopurine methyl transferase (TPMT) gene, where the presence of two null alleles (homozygous or compound heterozygous) indicates the need to reduce the dose of mercaptopurine by up to 90% to avoid toxic effects which could lead to the death of the patient. In this review, we provide an overview of the genomic perspective of ALL, describing some strategies that contribute to the identification of biomarkers with potential clinical application.
Topics: Antimetabolites, Antineoplastic; Biomarkers, Tumor; Child; Genomics; Humans; Mercaptopurine; Methyltransferases; Neoplasm, Residual; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence
PubMed: 29364809
DOI: 10.1016/j.bmhimx.2016.07.007 -
Pediatric Blood & Cancer Feb 2021This pilot study explored the feasibility and acceptability of implementing text-based assessments of oral chemotherapy adherence in adolescents and young adults (AYA)...
BACKGROUND
This pilot study explored the feasibility and acceptability of implementing text-based assessments of oral chemotherapy adherence in adolescents and young adults (AYA) with leukemia.
METHODS
AYA prescribed maintenance 6-mercaptopurine (6MP) received daily text message surveys and utilized an electronic pill bottle for 28 days. Text surveys assessed 6MP adherence and contextual associates (eg, mood). Feasibility was defined by recruitment/retention rates, survey completion rates, cost, and technical issues. After the 28-day period, AYA completed an acceptability survey. Secondary analyses compared text survey and electronic pill bottle adherence rates, and explored the daily associations between contextual factors and 6MP nonadherence.
RESULTS
Eighteen AYA enrolled (M age = 18, range 15-22) and completed study procedures (100% recruitment and retention rates). Adherence survey completion rates were high (M = 88.9%), the technology cost was $204.00, and there were few technical issues. AYA reported high satisfaction with the surveys and perceived them as a helpful medication reminder. While not significantly correlated, survey and electronic pill bottle adherence data converged on the majority of days (>90%). Exploratory analyses showed that AYA were more likely to miss a dose of 6MP on weekends (OR = 2.33, P = .048) and on days when their adherence motivation (OR = 0.28, P = .047) and negative affect (OR = 3.92, P = .02) worsened from their own typical functioning.
CONCLUSIONS
For AYA with leukemia, daily text-based surveys are a feasible and acceptable method for delivering medication adherence assessments, and may operate as a short-term intervention. To develop personalized mobile health interventions, findings also highlighted the need to study time-varying predictors of 6MP nonadherence.
Topics: Adolescent; Antimetabolites, Antineoplastic; Female; Humans; Leukemia; Male; Medication Adherence; Mercaptopurine; Motivation; Pilot Projects; Reminder Systems; Surveys and Questionnaires; Text Messaging; Young Adult
PubMed: 33073479
DOI: 10.1002/pbc.28767 -
JAMA Network Open Aug 2020Suboptimal adherence to oral mercaptopurine treatment in children with acute lymphoblastic leukemia (ALL) increases the risk of relapse. A frequently expressed barrier... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of a Daily Text Messaging and Directly Supervised Therapy Intervention on Oral Mercaptopurine Adherence in Children With Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.
IMPORTANCE
Suboptimal adherence to oral mercaptopurine treatment in children with acute lymphoblastic leukemia (ALL) increases the risk of relapse. A frequently expressed barrier to adherence is forgetfulness, which is often overcome by parental vigilance.
OBJECTIVE
To determine whether a multicomponent intervention, compared with education alone, will result in a higher proportion of patients with ALL who have mercaptopurine adherence rates 95% or higher, for all study participants and among patients younger than 12 years and vs those aged 12 years and older.
DESIGN, SETTING, AND PARTICIPANTS
The adherence intervention trial was an investigator-initiated, multi-institutional, parallel-group, unblinded, randomized clinical trial conducted between July 16, 2012, and August 8, 2018, at 59 Children's Oncology Group institutions in the US, enrolling patients with ALL diagnosed through age 21 years and receiving mercaptopurine for maintenance. The date of final follow-up was January 2, 2019. Data analysis was performed from February to October 2019.
INTERVENTIONS
Patients were randomized 1:1 to education alone or the intervention package, which consisted of education and personalized text message reminders daily to prompt directly supervised therapy. Four weeks of baseline adherence monitoring were followed with a 16-week intervention.
MAIN OUTCOMES AND MEASURES
The primary end point was the proportion of patients with adherence rates 95% or higher over the duration of the intervention for all study participants, and for those younger than 12 years vs those aged 12 years and older.
RESULTS
There were 444 evaluable patients (median age, 8.1 years; interquartile range, 5.3-14.3 years), including 230 in the intervention group and 214 in the education group. Three hundred two patients (68.0%) were boys, 180 (40.5%) were non-Hispanic White, 170 (38.3%) were Hispanic, 43 (9.7%) were African American, and 51 (11.5%) were Asian or of mixed race/ethnicity. The proportion of patients with adherence rates 95% or higher did not differ between the intervention vs education groups (65% vs 59%; odds ratio, 1.33; 95% CI, 1.0-2.0; P = .08). Exploratory analyses showed that among patients aged 12 years and older, those in the intervention group had higher mean (SE) adherence rates than those in the education group (93.1% [1.1%] vs 90.0% [1.3%]; difference, 3.1%; 95% CI, 0.1%-6.0%; P = .04). In particular, among patients aged 12 years and older with baseline adherence less than 90%, those in the intervention group had higher mean (SE) adherence rates than those in the education group (83.4% [2.5%] vs 74.6% [3.4%]; difference, 8.8%; 95% CI, 2.2%-15.4%; P = .008). No safety concerns were identified.
CONCLUSIONS AND RELEVANCE
Although this multicomponent intervention did not result in an increase in the proportion of patients with ALL who had mercaptopurine adherence rates 95% or higher, it did identify a high-risk subpopulation to target for future adherence intervention strategies: adolescents with low baseline adherence.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01503632.
Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Directly Observed Therapy; Female; Humans; Male; Medication Adherence; Mercaptopurine; Patient Education as Topic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Text Messaging
PubMed: 32852553
DOI: 10.1001/jamanetworkopen.2020.14205 -
Journal of Crohn's & Colitis Jul 2023Scepticism about the efficacy of thiopurines for ulcerative colitis [UC] is rising. This study aimed to evaluate mercaptopurine treatment for UC. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
Scepticism about the efficacy of thiopurines for ulcerative colitis [UC] is rising. This study aimed to evaluate mercaptopurine treatment for UC.
METHODS
In this prospective, randomized, double-blind, placebo-controlled trial, patients with active UC, despite treatment with 5-aminosalicylates [5-ASA], were randomized for therapeutic drug monitoring [TDM]-guided mercaptopurine treatment or placebo for 52 weeks. Corticosteroids were given in the first 8 weeks and 5-ASA was continued. Proactive metabolite-based mercaptopurine and placebo dose adjustments were applied from week 6 onwards by unblinded clinicians. The primary endpoint was corticosteroid-free clinical remission and endoscopic improvement [total Mayo score ≤2 points and no item >1] at week 52 in an intention-to-treat analysis.
RESULTS
Between December 2016 and April 2021, 70 patients were screened and 59 were randomized at six centres. In the mercaptopurine group, 16/29 [55.2%] patients completed the 52-week study, compared to 13/30 [43.3%] on placebo. The primary endpoint was achieved by 14/29 [48.3%] patients on mercaptopurine and 3/30 [10%] receiving placebo (Δ = 38.3%, 95% confidence interval [CI] 17.1-59.4, p = 0.002). Adverse events occurred more frequently with mercaptopurine [808.8 per 100 patient-years] compared to placebo [501.4 per 100 patient-years]. Five serious adverse events occurred, four on mercaptopurine and one on placebo. TDM-based dose adjustments were executed in 22/29 [75.9%] patients, leading to lower mercaptopurine doses at week 52 compared to baseline.
CONCLUSIONS
Optimized mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at 1 year following corticosteroid induction treatment in UC patients. More adverse events occurred in the mercaptopurine group.
Topics: Humans; Colitis, Ulcerative; Mercaptopurine; Prospective Studies; Mesalamine; Remission Induction
PubMed: 36847130
DOI: 10.1093/ecco-jcc/jjad022 -
Saudi Journal of Gastroenterology :... 2022Methotrexate is an antineoplastic agent that is also used at lower doses for anti-inflammatory properties. Along with thiopurines (azathioprine and 6-mercaptopurine), it... (Review)
Review
Methotrexate is an antineoplastic agent that is also used at lower doses for anti-inflammatory properties. Along with thiopurines (azathioprine and 6-mercaptopurine), it has historically been an important part of pharmacological treatment for patients with inflammatory bowel disease. Despite an increase in therapeutic options, these immunomodulators continue to play important roles in the management of inflammatory bowel disease, used either as a monotherapy in mild to moderate cases or in combination with monoclonal antibodies to prevent immunogenicity and maintain efficacy. In light of data linking the use of thiopurines with the risk of malignancies, methotrexate has regained attention as a potential alternative. In this article, we review data on the pharmacology, safety, and efficacy of methotrexate and discuss options for the positioning of methotrexate alone, or in combination, in therapeutic algorithms for Crohn's disease and ulcerative colitis.
Topics: Azathioprine; Colitis, Ulcerative; Gastroenterologists; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate
PubMed: 35042318
DOI: 10.4103/sjg.sjg_496_21 -
The Cochrane Database of Systematic... May 2016Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial.
OBJECTIVES
To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis.
SEARCH METHODS
The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to 30 July 2015. Both full randomized controlled trials and associated abstracts were included.
SELECTION CRITERIA
Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes.
MAIN RESULTS
Seven studies including 302 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalazine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). One very small study compared azathioprine with cyclosporin and found that there was no significant difference between patients failing remission on azathioprine (50%, 4/8) or cyclosporin (62.5%, 5/8) (1 study, 16 patients, RR 0.80 95% CI 0.33 to 1.92). When placebo-controlled studies were pooled with aminosalicylate-comparator studies to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases, plus 1 case on cyclosporin) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported.
AUTHORS' CONCLUSIONS
Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (September 2012).
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Azathioprine; Colitis, Ulcerative; Humans; Maintenance Chemotherapy; Mercaptopurine; Mesalamine; Randomized Controlled Trials as Topic; Secondary Prevention; Sulfasalazine
PubMed: 27192092
DOI: 10.1002/14651858.CD000478.pub4 -
Bosnian Journal of Basic Medical... Aug 2018The main role of therapy in Crohn's disease (CD) is to achieve long-term clinical remission, and to allow for normal growth and development of children. The... (Review)
Review
The main role of therapy in Crohn's disease (CD) is to achieve long-term clinical remission, and to allow for normal growth and development of children. The immunomodulatory drugs used for the maintenance of remission in CD include thiopurines (azathioprine and 6-mercaptopurine) and methotrexate (MTX). Development of hepatosplenic T-cell lymphoma in some patients with inflammatory bowel disease, treated with thiopurines only or in combination with anti-tumor necrosis factor agents, resulted in a growing interest in the therapeutic application of MTX in children suffering from CD. This review summarizes the literature on the therapeutic role of MTX in children with CD. MTX is often administered as a second-line immunomodulator, and 1-year clinical remission was reported in 25-69% of children with CD after excluding for the use of thiopurines. Initial data on MTX effectiveness in mucosal healing, and as a first-line immunomodulator in pediatric patients with CD, are promising. A definite conclusion, however, may only be made on the basis of additional research with a larger number of subjects.
Topics: Adolescent; Azathioprine; Child; Crohn Disease; Drug Administration Schedule; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate; Patient Safety; Remission Induction; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 29338679
DOI: 10.17305/bjbms.2018.2792 -
The Cochrane Database of Systematic... Oct 2016The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease have been... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease have been conflicting and controversial. An updated meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease.
OBJECTIVES
The primary objective was to determine the efficacy and safety of azathioprine and 6-mercaptopurine for induction of remission in active Crohn's disease.
SEARCH METHODS
We searched MEDLINE, EMBASE and the Cochrane Library from inception to 30 October 2015. Review articles and conference proceedings were also searched to identify additional studies.
SELECTION CRITERIA
Randomized controlled trials (RCTs) of oral azathioprine or 6-mercaptopurine compared to placebo or active therapy involving adult patients with active Crohn's disease were selected for inclusion.
DATA COLLECTION AND ANALYSIS
Data were extracted by two independent observers based on the intention-to-treat principle. Outcomes of interest included: clinical remission, clinical improvement, fistula improvement or healing, steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. We calculated the pooled relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria.
MAIN RESULTS
Thirteen RCTs (n = 1211 patients) of azathioprine and 6-mercaptopurine therapy in adult patients were identified: nine included placebo comparators and six included active comparators. The majority of included studies were rated as low risk of bias. There was no statistically significant difference in clinical remission rates between azathioprine or 6-mercaptopurine and placebo. Forty-eight per cent (95/197) of patients receiving antimetabolites achieved remission compared to 37% (68/183) of placebo patients (5 studies, 380 patients; RR 1.23, 95% CI 0.97 to 1.55). There was no statistically significant difference in clinical improvement rates between azathioprine or 6-mercaptopurine and placebo. Forty-eight per cent (107/225) of patients receiving antimetabolites achieved clinical improvement or remission compared to 36% (75/209) of placebo patients (8 studies, 434 patients; RR 1.26, 95% CI 0.98 to 1.62). There was a statistically significant difference in steroid sparing (defined as prednisone dose < 10 mg/day while maintaining remission) between azathioprine and placebo. Sixty-four per cent (47/163) of azathioprine patients were able to reduce their prednisone dose to < 10 mg/day compared to 46% (32/70) of placebo patients (RR 1.34, 95% CI 1.02 to 1.77). GRADE analyses rated the overall quality of the evidence for the outcomes clinical remission, clinical improvement and steroid sparing as moderate due to sparse data. There was no statistically significant difference in withdrawals due to adverse events or serious adverse events between antimetabolites and placebo. Ten percent of patients in the antimetabolite group withdrew due to adverse events compared to 5% of placebo patients (8 studies, 510 patients; RR 1.70, 95% CI 0.94 to 3.08). Serious adverse events were reported in 14% of patients receiving azathioprine compared to 4% of placebo patients (2 studies, 216 patients; RR 2.57, 95% CI 0.92 to 7.13). Common adverse events reported in the placebo controlled studies included: allergic reactions. leukopenia, pancreatitis and nausea. Azathioprine was significantly inferior to infliximab for induction of steroid-free clinical remission. Thirty per cent (51/170) of azathioprine patients achieved steroid-free remission compared to 44% (75/169) of infliximab patients (1 study, 339 patients; RR 0.68, 95% CI 0.51 to 0.90). The combination of azathioprine and infliximab was significantly superior to infliximab alone for induction of steroid-free clinical remission. Sixty per cent (116/194) of patients in the combined azathioprine and infliximab group achieved steroid-free remission compared to 48% (91/189) of infliximab patients (2 studies, 383 patients; RR 1.23, 95% CI 1.02 to 1.47). Azathioprine or 6-mercaptopurine therapy was found to be no better at inducing steroid free clinical remission compared to methotrexate (RR 1.13, 95% CI 0.85 to 1.49) and 5-aminosalicylate or sulfasalazine (RR 1.24, 95% CI 0.80 to 1.91). There were no statistically significant differences in withdrawals due to adverse events between azathioprine or 6-mercaptopurine and methotrexate (RR 0.78, 95% CI 0.23 to 2.71); between azathioprine or 6-mercaptopurine and 5-aminosalicylate or sulfasalazine (RR 0.98, 95% CI 0.38 to 2.54); between azathioprine and infliximab (RR 1.47, 95% CI 0.96 to 2.23); or between the combination of azathioprine and infliximab and infliximab (RR 1.16, 95% CI 0.75 to 1.80). Common adverse events in the active comparator trials included nausea, abdominal pain, pyrexia and headache.
AUTHORS' CONCLUSIONS
Azathioprine and 6-mercaptopurine offer no advantage over placebo for induction of remission or clinical improvement in active Crohn's disease. Antimetaboilte therapy may allow patients to reduce steroid consumption. Adverse events were more common in patients receiving antimetabolites although differences with placebo were not statistically significant. Azathioprine therapy is inferior to infliximab for induction of steroid-free remission. However, the combination of azathioprine and infliximab was superior to infliximab alone for induction of steroid-free remission.
Topics: Adult; Antimetabolites; Azathioprine; Crohn Disease; Glucocorticoids; Humans; Immunosuppressive Agents; Induction Chemotherapy; Infliximab; Mercaptopurine; Mesalamine; Prednisone; Randomized Controlled Trials as Topic; Sulfasalazine; Withholding Treatment
PubMed: 27783843
DOI: 10.1002/14651858.CD000545.pub5 -
Zhongguo Dang Dai Er Ke Za Zhi =... Sep 2017Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and... (Review)
Review
Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. It may cause severe adverse effects such as myelosuppression, which may result in the interruption of treatment or complications including infection or even threaten patients' lives. However, the adverse effects of mercaptopurine show significant racial and individual differences, which reveal the important role of genetic diversity. Recent research advances in pharmacogenomics have gradually revealed the genetic nature of such differences. This article reviews the recent research advances in the pharmacogenomics and individualized application of mercaptopurine.
Topics: Antimetabolites, Antineoplastic; Humans; Mercaptopurine; Methyltransferases; Pharmacogenetics; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases
PubMed: 28899477
DOI: 10.7499/j.issn.1008-8830.2017.09.019