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© 2001 American Society for Clinical Oncology Preponderance of Thiopurine S-Methyltransferase Deficiency and Heterozygosity Among Patients Intolerant to Mercaptopurine or AzathioprineFrom the St Jude Children’s Research Hospital and University of Tennessee, Memphis; Vanderbilt University Medical Center, Nashville; East Tennessee State University, Johnson City, TN; Baylor College of Medicine, Houston; Cook Children’s Medical Center, Fort Worth; University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Stanford University, Stanford; Children’s Hospital of Los Angeles, Los Angeles; Children’s Hospital of San Diego, San Diego, CA; University of New Mexico, Albuquerque, NM; West Virginia University, Morgantown, WV; Miami Children’s Hospital, Miami, FL; Children’s Hospital of Michigan, Detroit, MI; and Ospedale Pediatrics Meyer, Florence, Italy. Address reprint requests to William E. Evans, PharmD, St Jude Children’s Research Hospital, 332 N Lauderdale, PO Box 318, Memphis, TN 38101-0318; email: william.evans{at}stjude.org
PURPOSE: To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management. PATIENTS AND METHODS: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography.
RESULTS: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P < .001, CONCLUSION: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.
THIOPURINE methyltransferase (TPMT) is a cytosolic enzyme that catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds, including mercaptopurine (MP), thioguanine (TG), and azathioprine (AZA). The human TPMT gene exhibits genetic polymorphism, and TPMT activity is inherited as an autosomal codominant trait.1,2 This polymorphism causes approximately 90% of whites and African-Americans to inherit high TPMT activity, 10% intermediate activity, and one in 300 low TPMT activity.1,3 The molecular genetic basis for the TPMT polymorphism has now been elucidated,4,5 and methods have been established for the molecular diagnosis of TPMT deficiency on the basis of genotype.6 Genetic polymorphism of TPMT is evident in all populations studied to date, including whites, Asians, African-Americans, and Africans.6-11 TPMT*3A, TPMT*3C, and TPMT*2 are the most prevalent mutant alleles in whites, Asians, and African-Americans, comprising approximately 95% of TPMT mutant alleles in these populations. TPMT*2 contains a single nucleotide transversion in exon 5 (G238C), TPMT*3C contains a single transition mutation in exon 10 (A719G), and TPMT*3A contains two transition mutations, one in exon 7 (G460A) and the other in exon 10 (A719G), each of which causes an amino acid change. Each of these mutant alleles has been shown to encode TPMT proteins that undergo rapid proteolysis, thereby causing the deficiency.12,13 TPMT*3A is the most prevalent mutant allele in whites,6,7,9 whereas TPMT*3C is the predominant TPMT mutant allele in Asian,14 African,9 and African-American8 populations.15 Polymerase chain reaction (PCR)–based methods have been developed to detect the three signature mutations in these mutant alleles and can be used to identify TPMT-deficient and heterozygous patients on the basis of their genotype.6 Thiopurines are primarily used as antineoplastic and immunosuppressive agents. MP is a component of essentially all modern treatment protocols for childhood acute lymphoblastic leukemia (ALL), TG is commonly used for acute myeloid leukemia and in some ALL protocols, and AZA is largely used as an immunosuppressant in autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus, and in solid organ transplant recipients to prevent graft rejection. AZA is a prodrug of MP, which is converted to thioinosine 5'-monophosphate (TIMP) by hypoxanthine phosphoribosyltransferase, and further metabolized to thioguanosine mono-, di-, and triphosphates (collectively known as TG nucleotides, TGN). Alternatively, MP and TG are inactivated by xanthine oxidase and TPMT; TPMT also catalyzes the methylation of their nucleotide metabolites including TIMP and thioguanosine 5'-monophosphate.16 The methylated parent drugs are inactive because they are not substrates for hypoxanthine phosphoribosyltransferase. TPMT plays an important role in the clinical pharmacology of thiopurines, because TPMT activity determines how much MP, AZA, or TG is inactivated to methylated metabolites or remains available for activation to TGN. There is an inverse relationship between TPMT activity and the level of TGN accumulation in erythrocytes17,18 and presumably other hematopoietic tissues, because these cells have negligible xanthine oxidase activity, leaving TPMT methylation as the only inactivation pathway. TGN are the principal active metabolites of thiopurines, and their concentrations have been associated with the efficacy and toxicity of these medications.17,19,20 In one study, children with ALL who had TGN concentrations less than the population median had worse relapse-free survival than those with TGN concentrations greater than the median, when treated with an antimetabolite-based chemotherapy regimen.21 There have been numerous reports of severe hematopoietic toxicity when conventional doses of thiopurines are given to TPMT-deficient patients,19,22-25 including fatal toxicity in a TPMT-deficient heart transplant recipient treated with conventional doses of AZA.26 Essentially all TPMT-deficient patients will develop dose-limiting hematopoietic toxicity when treated with conventional doses of thiopurines,10,17,27-29 whereas most,10,17 but not all,29 studies have found that those with a heterozygous TPMT phenotype (ie, intermediate activity) have intermediate intolerance to thiopurine therapy. The current analysis was performed to assess TPMT phenotype and genotype among patients who were referred to St Jude Children’s Research Hospital because of intolerance to therapy that included a thiopurine medication. This revealed a six-fold higher prevalence of TPMT-deficient and heterozygous individuals among thiopurine-intolerant patients, when compared with the general population or with the total population of children with ALL.
Patient Analysis Data were obtained from all patients who were referred between 1994 and 1999 to St Jude Children’s Research Hospital for evaluation of toxicity associated with drug therapy that included a thiopurine medication. None were patients at St Jude Children’s Research Hospital, nor have any of these patients been reported previously. Written informed consent was obtained from each patient (or his or her guardian) enrolled onto an investigational protocol, each of which had been approved by the local institutional review board. Erythrocyte (RBC) TPMT activity, TGN, and methyl-TIMP concentrations were measured, and TPMT genotype was determined when genomic DNA was available. Recommendations for subsequent thiopurine therapy were based on these results. The patient’s primary physician provided data on the demographics, disease state, toxicity profile, therapeutic intervention after toxicity, drug therapy, and clinical outcomes. Thiopurine intolerance was defined as the occurrence of hematopoietic toxicity, hepatotoxicity, mucositis, and/or other toxicities that resulted in dose reductions or delays in subsequent chemotherapy. Hematologic toxicity was defined as an absolute neutrophil count (ANC) less than 500 x 106/L and hepatic toxicity as a greater than two-fold increase in serum bilirubin and liver transaminases (AST, ALT). The time for development of toxicity was defined as the weeks of thiopurine therapy at full protocol dosage before dose-limiting toxicity occurred. The time to recover from toxicity was defined as the weeks elapsed until ANC greater than 500 x 106/L or the weeks elapsed until chemotherapy could be restarted. Hematopoietic toxicity was further evaluated on the basis of WBC nadir, RBC nadir, platelet nadir, ANC, hemoglobin, and hematocrit. Therapeutic interventions to treat toxicity were assessed by the units of packed RBCs (pRBCs) and platelets transfused, hospitalization, and use of antibiotics and granulocyte colony-stimulating factor. Thiopurine tolerance was assessed by the thiopurine dosage at the onset of toxicity, the final tolerable dosage, thiopurine dosage reduction, and the amount of thiopurines taken 1 month before and after the initial blood sample was taken. Concurrent use of other medications was also assessed. Clinical outcomes were assessed by the dosages (full or reduced) of other protocol chemotherapeutic agents that could be given after thiopurine dose adjustments were made and by the patient’s current ALL disease status (ie, complete remission or relapse).
TPMT Phenotype and Genotype Patients were classified into three different groups (TPMT phenotypes) on the basis of their TPMT activity, using previously reported criteria.17 Where multiple samples were obtained, the lowest TPMT activity was used to assign phenotype. When there had been infusion of allogeneic erythrocytes within 100 days of the blood sample, only samples obtained more than 90 days after the RBC transfusion were used to assign TPMT phenotype. Homozygous-mutant phenotype was defined as TPMT activity less than 5 U/mL of pRBCs. Patients with an intermediate TPMT activity (5 to 13.5 U/mL of pRBCs while on thiopurine therapy) were considered TPMT heterozygotes, and those with high TPMT activity (> 13.5 U/mL of pRBCs) were defined as homozygous-wildtype phenotype.17
Erythrocyte Thiopurine Concentrations At the time of initial referral and blood collection, dose-limiting toxicity had occurred and the thiopurine dose had been reduced or discontinued. RBC TGN and MeTIMP concentrations were included in the analysis only if patients had taken a thiopurine medication within 6 weeks of the initial RBC sample. Likewise, thiopurine metabolite concentrations in the follow-up samples were included in the analysis only for patients who were restarted on thiopurines.
Statistical Analysis
Patients Between 1994 and 1999, clinical data and blood samples from twenty-four patients who experienced excessive toxicity while receiving thiopurine medications were referred to St Jude Children’s Research Hospital for evaluation. For this analysis, detailed clinical outcome data were provided by the referring physician for 23 of these patients. Table 1 summarizes the demographic characteristics of these patients. The great majority (21 of 23) of these patients had a primary diagnosis of ALL; their treatment protocol and TPMT phenotypes are summarized in Table 1. MP and/or TG were prescribed in all treatment protocols for patients with ALL. Nineteen of these children received MP, one received TG, and one received both MP and TG on separate occasions. AZA was given to the two patients with autoimmune diseases; one had Crohn’s disease and the other polyarthritis nodosa.
TPMT Phenotype and Genotype TPMT phenotype was determined in all patients (n = 23), and genomic DNA was available to determine TPMT genotype in twenty. Table 2 summarizes the TPMT phenotype and genotype, and Fig 1 compares the frequency of TPMT phenotypes in the thiopurine-intolerant patients and the general population (which is the same as the entire population of childhood ALL patients).3 Six patients had TPMT activity indicative of a mutant/mutant TPMT genotype (TPMT activity, 0 to 2.3 U/mL of pRBCs). All six of these TPMT-deficient patients had a TPMT*3A/TPMT*3A genotype. Nine patients had intermediate TPMT activity (6.7 to 12.5 U/mL of pRBCs), indicative of a heterozygous genotype; two had a TPMT*1/TPMT*3A genotype, one a TPMT*1/TPMT*3C genotype, five did not have any of the three point mutations detected by the genotyping method, and genotype was not tested in one patient (DNA not available). The remaining eight patients had high TPMT activity (14 to 25.8 U/mL of pRBCs), which was indicative of a homozygous-wildtype genotype, and TPMT mutations were not found in any of these patients (Table 2).
Erythrocyte Thiopurine Metabolite Concentrations The median TGN concentration in the initial blood sample obtained at the time of referral was 200 pmol/8 x108 RBCs (4.2 to 687 pmol/8 x108 RBCs, n = 5) in the homozygous-mutant, 89.5 pmol/8 x108 RBCs (34.6 to 447 pmol/8 x108 RBCs, n = 6) in the heterozygotes, and 87 pmol/8 x108 RBCs (4.2 to 147 pmol/8x108 RBCs, n = 5) in the homozygous-wildtype patients. One homozygous-wildtype patient was excluded from the above comparison, because TG (and not MP) was being prescribed at the time of the sample. Because thiopurine therapy had been discontinued for 1 to 43 days (median, 7 days) before obtaining the initial blood sample (median, 24 days in homozygous-mutant, 4 days in heterozygotes, and 3 days in homozygous-wildtype patients), the TGN concentrations do not reflect their maximum or steady-state levels at the time of toxicity. As anticipated, a greater median MeTIMP/TGN ratio was found in the TPMT homozygous-wildtype patients (46.9, n = 5) when compared with the TPMT heterozygotes (7.5, n = 6) or TPMT-deficient (homozygous-mutant) patients (0.03, n = 5; P = .003, Kruskal-Wallis 3-way comparison).
Toxicity Profile
Table 3 summarizes the nature of toxicity in patients with each of the three TPMT phenotypes. Two homozygous-wildtype patients did not develop hematologic abnormalities, having been referred only because of hepatotoxicity. One of these patients had pre-existing liver disease, and results from liver function tests worsened during thiopurine therapy. Conversely, hepatotoxicity was not detected in any of the homozygous-mutant patients. The occurrence of mucositis and other adverse effects did not differ among patients with the three TPMT phenotypes (Pearson  2; P = .128 for hematopoietic toxicity, P = .234 for hepatic toxicity, P = .486 for mucositis, and P = .931 for other toxicities). There were no significant differences in the time to onset of dose-limiting toxicity in the three TPMT phenotypes. A median of 3.5 weeks (range, 0.29 to 30 weeks; n = 22) of full-dose thiopurine therapy had been given before dose-limiting toxicity was evident. The one heterozygous patient who received 30 weeks of prolonged therapy before the onset of toxicity had been treated with TG. The prolonged period of TG tolerance may be related to the decreased dependence of TG on methylation for inactivation relative to MP’s dependence on methylation. One additional patient had received thiopurine therapy for 77 weeks before the onset of toxicity, but it was determined that this patient was likely noncompliant with thiopurine therapy. Thiopurine administration was discontinued in all patients at the onset of toxicity. A median of 3 weeks (range, 1 to 8 weeks; n = 20) was required for the ANC to recover (> 500/µL), and there was a median of 3 weeks (range, 1 to 23 weeks; n = 19) before chemotherapy could be restarted in all patients, with no difference observed among the three TPMT phenotypes.
Therapeutic Management of Toxicity
Adjustment of Thiopurine Dosages At the time of referral for evaluation of toxicity and TPMT phenotype, the median dosage for patients with homozygous-deficient phenotype was 350 mg/m2/wk (range, 280 to 410.2 mg/m2/wk; n = 5), 525 mg/m2/wk (range, 350 to 889 mg/m2/wk; n = 8) for heterozygotes, and 350 mg/m2/wk (range, 175 to 525 mg/m2/wk; n = 8) for homozygous-wildtype patients (P = .0162, Kruskal-Wallis). After dosage adjustments, the final tolerable dosages for homozygous-mutant, heterozygous, and wildtype patients, respectively, were as follows: 32 mg/m2/wk (range, 20 to 140 mg/m2/wk; n = 5), 175 mg/m2/wk (range, 30 to 420 mg/m2/wk; n = 7), and 280 mg/m2/wk (range, 30 to 420 mg/m2/wk; n = 8) (P = .043, Kruskal-Wallis). A median 90.8% (range, 50% to 94.3%; n = 5) reduction in thiopurine dosage was required for the homozygous-deficient patients, which was significantly greater than the decrease required for the heterozygotes (median, 66.7%; range, 0% to 92.9%; n = 7) and wildtype patients (median, 8.3%; range, -20% to 91.4%; n = 8) (P = .033, Kruskal-Wallis) ( Fig 2). Because AZA was given in a different dosage unit (mg/kg) from thiopurines given to children with ALL (mg/m2), patients treated with AZA were excluded from the above comparison. AZA was not restarted in the two patients who had autoimmune diseases.
Clinical Outcomes The total number of doses of scheduled chemotherapy that had to be withheld because of thiopurine toxicity, before individualization of thiopurine doses, tended to be higher in the homozygous-mutant and heterozygous patients, with a median number of missed doses of 91 (range, 30 to 164; n = 3) in the TPMT-deficient patients and 49 (range, 25 to 126; n = 3) in heterozygotes, compared with 7.0 (range, 0 to 182; n = 5) in the wildtype patients (P = .144, Kruskal-Wallis). After thiopurine dosage adjustments, a similar proportion (50% to 62%) of ALL patients with each TPMT phenotype was subsequently treated with full protocol doses of their other chemotherapy. Twelve (57.1%) were given full doses of other chemotherapy, and nine (42.9%) were empirically treated with a lower dose of their other chemotherapy. Among the 17 children with ALL in first remission, 15 remained in continuous complete remission after a median of 2.6 years (range, 1.42 to 5.0 years, as of June 2000). One ALL patient who relapsed after first remission was homozygous wildtype for TPMT, and the other was heterozygous for TPMT.
It is now well recognized that patients who inherit TPMT deficiency are at great risk for developing severe and potentially life-threatening hematopoietic toxicity when treated with conventional (full) doses of thiopurine medications (MP, TG, and AZA).17,19,23,25,26,29-32 More recently, it has been shown that patients who inherit intermediate TPMT activity resulting from heterozygosity at the TPMT gene locus are also at higher risk of thiopurine hematopoietic toxicity,10,17 although the frequency and severity of toxicity in heterozygotes are less than those of TPMT-deficient patients.17 However, intolerance among TPMT heterozygotes has not been observed in every study, likely because of the intensity of other chemotherapy being administered concomitantly.29 The current analysis was undertaken to assess TPMT phenotypes and genotypes among a series of patients referred for evaluation of thiopurine toxicity, revealing a large overrepresentation (> six-fold) of TPMT-deficient and heterozygous individuals among thiopurine-intolerant patients treated on widely used ALL protocols from the Pediatric Oncology Group, Children’s Cancer Group, and Berlin-Frankfurt-Munster group. The majority of these patients (21 of 23, 91.3%) presented with hematopoietic toxicity, either alone or in combination with other toxicities. Because hematopoietic tissues have low or undetectable xanthine oxidase activity, TPMT is the only remaining inactivation pathway for thiopurines in these tissues. Thus, one would anticipate that hematopoietic toxicity would be the principal dose-limiting toxicity in TPMT-deficient and heterozygous patients, as was the case in the current series. If one includes only those presenting with hematopoietic toxicity in the current study, the overrepresentation of TPMT-deficiency and heterozygosity is even greater (15 of 21, 71%), when compared with the general population of ALL patients (8% to 10% are TPMT-deficient or heterozygotes). Both patients in the current series who presented with hepatic toxicity as the only dose-limiting toxicity had a homozygous-wildtype TPMT phenotype. It has been suggested previously that the methylated metabolites of thiopurines (eg, methyl-TIMP) contribute to hepatoxicity,31-33 and there has been a report of greater TPMT activity among patients who developed hepatic toxicity associated with thiopurine therapy.34 The current findings are consistent with these earlier observations, although a definitive causal relationship remains to be established.
Once TPMT deficiency or heterozygosity was diagnosed in these patients, it was possible to reinitiate thiopurine therapy at a lower dosage, without acute dose-limiting toxicity. The median dose reduction required for TPMT-deficient patients was 90.8% (range, 50% to 94%), compared with a median 67% dose reduction in TPMT heterozygotes (range, 0% to 93%). The median final tolerable dosage in TPMT-deficient ALL patients was 32 mg/m2/wk, compared with 175 mg/m2/wk in the TPMT heterozygotes, both of which are substantially lower than the conventional dose of 350 to 525 mg/m2/wk. The final tolerable thiopurine dosage in the current study, from a group of patients treated on a variety of ALL protocols at 14 different institutions, is consistent with our recently reported findings in a group of ALL patients treated on a common treatment protocol at a single institution.17 In our prior experience,17,19 the thiopurine dosage had to be reduced in all TPMT-deficient patients, by an average of approximately 90%. Our prior experience in heterozygotes is that they require a thiopurine dose reduction more often than homozygous-wildtype patients but that the dose often need be reduced only 15% to 30%.17 The greater average decrease in heterozygotes in the current series may be because these patients were referred because of hematopoietic toxicity and thus represent the most sensitive subset of heterozygous patients. They may have had lower bone marrow reserve or additional predisposing factors that decreased their ability to tolerate thiopurines. Importantly, when TPMT deficiency was diagnosed and appropriate thiopurine dose reductions were made, it was possible to resume therapy with full doses of all other chemotherapy. The ability to reinitiate full doses of other chemotherapy likely enhances the probability of curative therapy for ALL, by enhancing treatment intensity with all effective agents.35,36 It has been shown previously that these lower thiopurine doses in TPMT-deficient and heterozygous patients are able to maintain RBC TGN levels at or greater than those achieved by full doses in homozygous-wildtype patients.17 RBC TGN levels in samples obtained from three TPMT-deficient and two heterozygous patients after restarting chemotherapy in the current study ranged from 285 to 2,064 pmol/8 x108 RBCs. These levels are in or greater than the range of 280 to 400 pmol/8 x108 RBCs for homozygous-wildtype patients receiving MP doses of 75 mg/m2/d,17 and greater than the value ( In the current study, there was 100% concordance between TPMT genotype and phenotype in the TPMT-deficient patients and among the homozygous-wildtype patients, whereas five of nine patients with heterozygous phenotypes did not have one of the three coding region mutations that define the most common TPMT mutant alleles. Complete sequencing of the TPMT coding region in three of these discordant patients did not reveal any mutations, suggesting that these patients either have mutations outside the coding region (eg, TPMT promoter region) or their intermediate TPMT activity is not a result of heterozygosity at the TPMT gene locus. This latter possibility cannot be excluded, because the measured TPMT activity in four of the five discordant patients was in the range of 10.4 to 10.7, a value slightly above the activity used to discriminate homozygous-wildtype and heterozygous individuals among patients who are not taking thiopurine containing chemotherapy.1,3 However, when patients are taking thiopurines, it is well recognized that TPMT activity increases (median increase of 35%)3,18 and that the cut point for discriminating homozygous-wildtype and heterozygous individuals increases to values in the range of 13 to 14.17 For this reason, a value of 13.5 was used to discriminate homozygous-wildtype and heterozygous individuals in the present study, because all were receiving thiopurine therapy and the patients in question were clearly below this cut point. Nonetheless, it will be important to conduct additional molecular analyses of these patients, to determine whether there are indeed TPMT mutations outside the coding region that caused these patients to have a heterozygous phenotype. In summary, an inherited deficiency of TPMT should be considered as a likely etiology for severe hematopoietic toxicity in patients who are being treated with chemotherapy regimens containing thiopurines (MP, TG, AZA), whether for ALL or nonmalignant diseases for which these medications are prescribed. The current study indicates that the likelihood that such patients are TPMT-deficient or heterozygotes is substantially greater than the general population of ALL patients. In contrast, hepatic toxicity in the absence of hematopoietic toxicity was not associated with TPMT-deficiency in the current series. The reason it is important to make a definitive diagnosis of TPMT deficiency in such patients is that it is possible to restart all other chemotherapy at full protocol dosages, but only after a 90% dose reduction in thiopurine therapy in the TPMT-deficient patients. Unless a definitive molecular or biochemical diagnosis of TPMT deficiency is made, it is likely that modest dose reductions (eg, 25%) will be made in all cytotoxic chemotherapy, instead of a 90% dose reduction in only the toxic thiopurine medication. The St Jude experience is that TPMT-deficient patients have an excellent event-free survival if their MP dose is adjusted,17,36 and they do not receive thiopurines concomitantly with cranial irradiation37 or leukemogenic therapy.38 Furthermore, the TPMT genetic polymorphism illustrates the potential utility of pharmacogenomics to optimize ALL therapy on the basis of each patient’s inherited ability to metabolize and respond to antileukemic agents.39
Supported in part by grants no. R37 CA36401 and R01 CA78224 from the National Institutes of Health, Bethesda, MD, Cancer Center support grant no. CA21765, a Center of Excellence grant from the State of Tennessee, and American Lebanese Syrian Associated Charities. We thank the following: our clinical colleagues for contributions to the treatment of these patients; Yaqin Chu, Emily Melton, Sheree Johns, Eve Su, Kathryn Brown, Leigh Graham, Natasha Lenchik, and May Chung for their excellent technical assistance; and the patients and parents who participated in these protocols.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
290 pmol/8 x108 RBCs) associated with a more favorable outcome in patients with ALL.
