Thiopurines In The Treatment Of Childhood Acute Lymphoblastic Leukemia

The thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were synthesized by Elion and Hitchings in the 1950s, and they play an important part in treatment protocols for leukemia (61,62,63,64). For no other than historical reasons, 6-MP is used in ALL while 6-TG is mainly used in acute myeloid leukemia (AML) or relapsed ALL. First-line treatment for childhood ALL usually includes several cycles of 6-MP at doses of 50-75 mg/m2/d, starting as early as in consolidation/early intensification treatment until up to 36 months after diagnosis (1,2,3).

To elucidate the extensive administration of thiopurines in the treatment of childhood ALL, using the ALL-BFM 95 trial as an example, the elements containing either 6-MP or 6-TG are indicated (57); see Fig. 1. After induction of remission, thiopurines are used almost throughout the entire therapy. The most extensive application of thiopurines occurs during the maintenance phase. Maintenance treatment aims at a further stabilization of remission by suppressing the re-emergence of a drug-resistant clone through consistently reducing the pool of residual leukemic cells. The current standard of maintenance therapy consists of up to 2-3 years of treatment (from initial time of diagnosis) with daily oral 6-MP and weekly oral methotrexate (1,2,3). The combination of 6-MP with methotrexate acts synergistically as methotrexate inhibits purine de novo synthesis, leading to a higher intracellular availability and increased incorporation of phosphorylated thiopurines in DNA and RNA (65,66,67,68). Several studies in childhood ALL compared parental to intravenous 6-MP application with none of them proving advantageous for parental administration (69,70,71).

In contrast to administration in earlier treatment elements applied in childhood ALL protocols (e.g., consolidation or extra-compartment therapy) where thiopurines are given at fixed doses, in maintenance both 6-MP and methotrexate doses are adjusted according to absolute leukocyte or neutrophil and platelet counts. Current BFM dose modification guidelines for maintenance treatment in childhood ALL call for an absolute leukocyte count in a target range of 2-3 x 109/L (2, 57). Minimal requirements for starting maintenance treatment are an absolute leukocyte count of > 1 x 109/L with at least 0.2 x 109/L neutrophils and 50 x 109/L thrombocytes (counts not decreasing).

The starting dose as well as dose adjustment in therapy are made according to guidelines fixed in the treatment protocols. For pneumocystis carinii pneumonia prophylaxis, trimethoprim-sulfamethoxazole is administered on three consecutive days per week, with the largest possible interval in reference to the weekly methotrexate application. This is done to account for the theoretical enhancement of the antifolic activity of methotrexate by co-administered trimethoprim-sulfamethoxazole (72,73). Because several reports have suggested an improved outcome with bedtime administration, 6-MP is commonly administered in the evening hours (74, 75). Also, 6-MP should not be given in combination with milk because the xanthine oxidase (XO) activity contained in milk decreases the bioavailability of 6-MP (76,77,78).

Relling and colleagues at St Jude Childrens' Research Hospital have demonstrated that maintaining the highest tolerable dose of daily 6-MP in maintenance therapy is an important prognostic factor in childhood ALL (79). However, when results are compared on efficacy and toxicity of thiopurines from clinical trials of different study groups, it must be considered that recommendations on the exact schedule of 6-MP, methotrexate, and other thiopurine- and/or methotrexate-interacting medications regularly administered during maintenance (e.g., trimethoprim-sulfamethoxazole for pneumocystis carinii pneumonia prophylaxis) may differ (72, 73,80,81).

Of particular importance, dose modification guidelines may differ between clinical trials and study groups. In some childhood ALL treatment protocols, other cytotoxic chemotherapeutic drugs may be administered during the maintenance phase as well, such as pulsed applications of vincristine and a glucocorticoid (8284). The reduction of maintenance below two years (from the date of initial diagnosis) was associated with an increased frequency of leukemic relapses (82,85).

Although it has been proven disadvantageous to shorten maintenance treatment, whether or not extended maintenance of up to 3 years is offering any beneficial effect in the context of different treatment strategies remains to be evaluated, particularly in males patients. Other issues that must be resolved in the future include differences in requirements for maintenance therapy in specific childhood ALL patient subsets (e.g., those defined immunophenotypically or genetically). These questions are still under investigation.

With regard to the debate about the better thiopurine, there are three published randomized studies comparing the toxicity and efficacy of 6-TG with 6-MP in interim maintenance and maintenance therapy of childhood ALL. The first published trial randomized 474 patients with childhood ALL to either 6-TG or 6-MP in maintenance and was conducted by the German COALL study group (86). The COALL-92 trial results showed no difference in the primary outcomes, but observed a tendency of higher CNS relapse (3.4% vs. 0.8%,p = 0.053) and prolonged myelosuppression with marked thrombocytopenia in the 6-TG treatment arm. In this trial, the incidence of thrombocytopenia (< 100 x 109/L) without evidence of leukocytopenia (< 1 x 109/L) was 7.5-fold higher in the 6-TG compared with the 6-MP arm. Treatment interruptions occurred at a 1.7-fold higher rate in the 6-TG arm (4.7% of maintenance treatment weeks vs. 2.8% for 6-MP).

A recent British trial, UK MRC ALL 97, randomized 1498 children to receive either 6-TG or 6-MP (87). After a median follow-up of 6 years, no differences in event-free survival were detected between the two treatment arms. A large reduction of isolated disease recurrence in the CNS by 6-TG [odds ratio (OR) = 0.53, 95% confidence interval

(CI) = 0.30 - 0.92] was offset by an increased risk of death in remission (OR = 2.22, 95% CI = 1.20 - 4.14), mainly due to infections. Strikingly, 11% of patients in the 6-TG arm compared to less than 2% in the 6-MP arm developed non-fatal hepatic toxicity with features of veno-occlusive disease (VOD) characterized by symptoms including tender hepatomegaly, hyperbilirubinaemia with elevated aminotransferases, thrombocytopenia out of proportion to neutropenia, and portal hypertension. In 85% of affected 6-TG recipients, these symptoms were observed during maintenance or interim maintenance. Of interest, in patients randomized to 6-MP, hepatic toxicity was associated with intensification elements in which both treatment arms received exclusively 6-TG.

A third, not yet completely published study randomizing 6-TG and 6-MP in childhood ALL, is the U.S. trial CCG-1952 including more than 2000patients with lower-risk features at diagnosis (NCI standard-risk ALL) (88). This trial suggests for the 6-TG arm a significantly better event-free survival (85.1% vs. 77.1% at 5 years, p = 0.02), less CNS and also bone marrow and testicular relapses without differences in remission deaths between the arms. Of importance, 6-TG administration led to hepatic VOD-like symptoms in approximately 20% of patients.

Looking at 6-TG-related efficacy and toxicity in the three trials, it is obvious that the CCG-1952 trial shows the greatest benefit for the 6-TG arm at the highest rate of hepatotoxic side effects. This trial also used the highest starting dose of 6-TG in maintenance (60mg/m2/d, reduced to 50mg/m2/d after noting 6-TG-related hepatotoxicity). The above-mentioned British trial used a starting dose of 40 mg/m2/d; the COALL-92 trial initially used 50 mg/m2/d which was reduced to 40 mg/m2/d upon recognition of marked thrombocytopenia. Although the latter two trials used comparable starting doses, differences between COALL-92 and UK MRC ALL 97 with regard to risk of CNS relapse and toxicity can be identified. As a possible explanation, it may be speculated that either different treatment-adjustment procedures may have led to different 6-TG doses, or different background treatments in the trials may have contributed differently to the development of hepatotoxic side effects associated with 6-TG.

Of importance, data from patients with inflammatory bowel disease suggest a critical threshold dose for development TG-related hepatotoxicity (89). Unfortunately, for UK MRC ALL 97, 6-TG doses and information on treatment interruptions are not available for an adequate comparison with the COALL-92 trial. Thus, this discussion remains speculative until detailed information on 6-TG doses, dose adjustment procedures, and pharmacologically relevant parameters (e.g., 6-thioguanine nucleotide [6-TGN] levels, thiopurine S-methyltransferase [TPMT]) is available in association with well-defined clinical endpoints. The latter will also require a consensus agreement on diagnostic procedures for measuring hepatotoxic side effects. When these goals are met, carefully designed randomized controlled trials aimed at identifying the best thiopurine for childhood ALL, with adaptation to the underlying causes, will become even more informative.

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