Betaine for Patients with Acute Lymphoblastic Leukemia Intolerant of Maintenance Chemotherapy Due Deficiency of S-Adenosyl Methionine

Background: We noted that rare patients with acute lymphoblastic leukemia (ALL) who are intolerant to oral mercaptopurine (6MP) and methotrexate (MTX) have low plasma S-adenosyl methionine (SAM) levels of less than70 nM.  SAM is the methyl donor for the metabolic detoxification of 6MP.  Betaine, an oral supplement can serve as a methyl donor for the restoration of SAM.  The purpose of this study was to document the effect of oral betaine on tolerance of oral 6MP and MTX during maintenance therapy in select children with ALL who have repeated interruptions of therapy that may compromise cure.

Procedure: The data from five patients with multiple interruptions of maintenance chemotherapy and low SAM seen over a five year period were compared before and after betaine treatment.  None of the patients were deficient in thiopurine methyltransferase.  One patient was homozygous deficient for MTHFR C667T.  These patients continued to have interruptions after switching from sulfamethoxazole-trimethoprim to pentamidine.   The following were compared before and after betaine treatment:  the percentage of days chemotherapy had to be interrupted, plasma SAM levels, mercaptopurine red cell metabolites, dose of 6MP and MTX, and variance in blood cell counts.  Betaine was started at a dose of 25 mg/kg/dose twice a day and increased weekly by 50 mg/kg/day as tolerated to keep SAM >70.  Doses up to 150 mg/kg/day have been used in patients with hyperhomocysteinemia.

Results:  Betaine treatment significantly reduced the percentage of days maintenance chemotherapy was withheld (figure right panel). There was less variability in blood cell counts and increased plasma SAM levels after betaine therapy.  Betaine altered neither the average dose of 6MP and MTX nor the red cell 6MP metabolites levels.   The figure left panel shows the effect of betaine supplementation in the index patient who had no interruptions and stable blood counts on 6MP (75 mg/m²/day) and MTX (14 mg/m²/week).

Conclusions: We concluded that betaine is effective in reducing maintenance chemotherapy interruptions in patients with intolerance due to low SAM.  An in vitro study showed SAM depletion occurs from 6MP metabolites due to inhibition of de novo protein synthesis, depleting ATP which is necessary for the conversion of methionine to SAM [Stet EH et al. Biochem. J. 1994:304:163-168].   This  may lead to alteration in gene methylation possibly resulting in another mechanism of leukemic killing by 6MP.  While this finding is concerning, non-adherence to oral 6MP is a known risk for relapse.  Betaine allows the rare patient with maintenance intolerance due to SAM deficiency to continue on stable doses of 6MP and MTX without interruption. 

Left Panel: Hemoglobin, ANC and platelet count for patient #1 before and after starting betaine on day 570.

Right Panel: Percent days oral 6MP and MTX withheld during maintenance before (left bar, blue) and after (right bar, red) betaine supplementation (p = 0.02).