Correlation Between Baseline Methylmalonic Acid Status and Mucositis Severity in the PROPEL Study: Implications for Vitamin Prophylaxis.

The rationally designed antifolate, pralatrexate, has high affinity for reduced folate carrier-1 (RFC-1) and was designed to be retained longer within cancer cells due to efficient polyglutamation by folylpolyglutamyl synthetase (FPGS). Prophylactic vitamin supplementation with folic acid and vitamin B₁₂ is often used by physicians to minimize toxicities seen with antifolate chemotherapy (Scagliotti GV, JCO 2003; 21:1556). Nutritional status is a concern for cancer patients in general, and particularly for patients with aggressive disease that have been treated previously. In the PROPEL study, a pivotal international multi-center Phase 2 study of pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), patients were treated with pralatrexate and received folic acid and vitamin B₁₂ supplementation. Patients in PROPEL had been treated with a median of three prior regimens, and an overall response rate of 28% by independent central review was observed. The most common grade 3-4 toxicities were thrombocytopenia (32%) and mucositis (22%). This report includes analyses of baseline MMA, Hcy, and RBC folate levels and their association with thrombocytopenia or mucositis in the PROPEL trial.

Patients received pralatrexate 30 mg/m² IV weekly for 6 weeks in 7-week cycles and supplementation with vitamin B₁₂ (1 mg IM q8-10 wks) and folic acid (1.0-1.25 mg PO daily). Eligibility criteria included histologically confirmed PTCL, disease progression after ≥ 1 prior treatment, and ECOG performance status £ 2. MMA, Hcy and RBC folate levels were measured at baseline, prior to vitamin initiation. A linear model was used to estimate the relationship (slope) between each of these baseline values and the maximum grade of mucositis and thrombocytopenia.

Of the 115 patients enrolled, 111 were evaluable for safety and 109 were evaluable for response. Eighty-nine had baseline MMA levels, 91 had baseline Hcy levels, and 75 had baseline RBC folate levels before initiation of vitamin supplementation. Baseline values are summarized by the highest grade of thrombocytopenia or mucositis in the Table. The linear relationship between maximum mucositis grade on study (0 vs 1-2 vs 3-4) and baseline MMA was statistically significant (slope estimate = 43.3 nmol/L, p = 0.039). In addition, there was a trend for increasing MMA and increasing severity of thrombocytopenia that did not meet statistical significance (slope estimate = 17.6 μmol/L, p = 0.267). No other significant relationships were noted.

In the subset of relapsed or refractory PTCL patients tested for MMA levels in the PROPEL study, higher levels of baseline MMA were associated with increased severity of mucositis. There was an association between MMA and severity of thrombocytopenia that did not reach statistical significance. RBC folate and Hcy were not predictive of the severity of mucositis and thrombocytopenia in this analysis. Because patients with relapsed or refractory PTCL may have poor nutritional status, all patients treated with pralatrexate, including those with elevated MMA, should be supplemented with vitamins. Additional studies may be warranted to define the relationship between MMA levels and the development of mucositis and thrombocytopenia among patients treated with pralatrexate.

Pro:Allos Therapeutics, Inc: Research Funding. Horwitz:Allos Therapeutics, Inc: Consultancy, Research Funding. Boyd:Allos Therapeutics, Inc.: Employment. Fruchtman:Allos Therapeutics, Inc.: Employment.