Up to five sequential dose cohorts will enroll a maximum of 6 patients each. Escalation of the pralatrexate dose, after CHOP administration (Fol-CHOP), will continue in a traditional 3+3 design, until determination of the MTD. If the MTD is not reached, the Maximum Administered Dose (MAD) of pralatrexate in combination with CHOP will be 30 mg/m2 IV on Days 1 and 8 of each 21-day cycle for up to 6 cycles.