Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial

Abstract

The Children's Cancer Group 1952 (CCG-1952) clinical trial studied the substitution of oral 6-thioguanine (TG) for 6-mercaptopurine (MP) and triple intrathecal therapy (ITT) for intrathecal methotrexate (IT-MTX) in the treatment of standard-risk acute lymphoblastic leukemia. After remission induction, 2027 patients were randomized to receive MP (n = 1010) or TG (n = 1017) and IT-MTX (n = 1018) or ITT (n = 1009). The results of the thiopurine comparison are as follows. The estimated 7-year event-free survival (EFS) for subjects randomized to TG was 84.1% (+/- 1.8%) and to MP was 79.0% (+/- 2.1%; P = .004 log rank), although overall survival was 91.9% (+/- 1.4%) and 91.2% (+/- 1.5%), respectively (P = .6 log rank). The TG starting dose was reduced from 60 to 50 mg/m(2) per day after recognition of hepatic veno-occlusive disease (VOD). A total of 257 patients on TG (25%) developed VOD or disproportionate thrombocytopenia and switched to MP. Once portal hypertension occurred, all subjects on TG were changed to MP. The benefit of randomization to TG over MP, as measured by EFS, was evident primarily in boys who began TG at 60 mg/m(2) (relative hazard rate [RHR] 0.65, P = .002). The toxicities of TG preclude its protracted use as given in this study. This study is registered at https://ichgcp.net/clinical-trials-registry/NCT00002744" title="See in ClinicalTrials.gov">NCT00002744.

Figures

Figure 1

Thiopurine conversion to active nucleotides and methylated compounds. MP is converted to thioguanine nucleotides (TGNs) via 3 enzymatic steps and TG via 1 step. Both MP and TG undergo S-methylation by thiopurine methyltransferase (TPMT) to methyl-mercaptopurine (meMP) and methyl-thioguanine (meTG), respectively. TPMT competes with hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the first enzymatic step in conversion of thiopurines to TGNs. Thioinosine monophosphate (TIMP), thioxanthene monophosphate (TXMP), and thioguanylate (TGMP) are also S-methylated by TPMT. Methyl-6-thioinosine monophosphate (meTIMP), a product of MP but not TG metabolism, is a potent inhibitor of de novo purine synthesis. meTXMP indicates methyl-thioxanthene monophosphate; IMP, inosine monophosphate; and meTGMP, methyl-thioguanylate.

Figure 2

Study schema for CCG-1952. Randomization was performed at the completion of standard induction. Patients with M1 marrow status at day 7 did not require a day-14 sample.

Figure 3

Switch from TG to MP. A total of 2027 eligible children were randomized to TG (1017) or MP (1010) and are included in this intent-to-treat analysis. The first 414 subjects randomized to TG began consolidation with TG at 60 mg/m2; the last 603 began at 50 mg/m2. During the course of treatment, 581 patients switched from TG to MP. Of the 1017 subjects, 436 (43%) received TG throughout treatment: 294 in cohort 1 and 142 in cohort 2.

Figure 4

Outcome according to randomized thiopurine regimen, TG versus MP. (A) EFS and (B) OS by intent-to-treat analysis.

Figure 5

EFS comparison of TG versus MP by cohort. (A) Cohort 1 and (B) cohort 2.

Figure 6

EFS comparison of boys on TG versus MP.

Figure 7

EFS comparison of all 4 randomized treatment regimens.