This is a Phase 1/2a, non-randomized, open-label, multi-center study designed to determine the Maximum Tolerated Dose (MTD) of Pralatrexate Injection and Gemcitabine with vitamin B12 and folic acid supplementation to patients with relapsed or refractory lymphoproliferative malignancies.

• Drug: Pralatrexate Injection
• Drug: Gemcitabine hydrochloride (HCl)

Inclusion Criteria:

• Diagnosis per the REAL WHO disease classification.
• Phase 1: Histologically/cytologically confirmed lymphoproliferative malignancy. Patients with Hodgkin's disease or non-Hodgkin's lymphoma are eligible, with the exceptions per exclusion criterion #1.
• Phase 2a: Histologically/cytologically confirmed PTCL or B-cell lymphoma, with the exceptions per exclusion criterion #1.
• Documented disease progression after at least 1 prior treatment, and progression after last prior treatment. Any number of prior therapies is allowed. Patient has recovered from the toxic effects of prior therapy. Patients treated with an FDA-approved monoclonal antibody therapy may be enrolled any time the therapy if they have progression of disease.
• ECOG Performance Status ≤ 2.
• At least 18 years of age.
• Adequate hematological, hepatic, and renal function, including: MMA < 200 nmol/L and Hcy < 10 μmol/L, or receipt of 1 mg oral folic acid daily for at least 10 days prior to planned start of pralatrexate & 1 mg intramuscular vitamin B12 within 10 weeks of the planned start of pralatrexate.
• Women of childbearing potential must agree to practice a medically acceptable contraceptive regimen from study treatment start until at least 30 days after the last administration of pralatrexate and must have a negative serum pregnancy test within 14 days prior to the first day of study treatment.
• Men who are not surgically sterile must agree to practice a medically acceptable contraceptive regimen from study treatment start until at least 90 days after the last administration of pralatrexate.
• Given written informed consent.

Exclusion Criteria:

• Phase 1, B-cell:

  • Lymphoplasmacytic lymphoma (± Waldenström's macroglobulinemia)
  • Plasma cell myeloma/plasmacytoma
  • Hairy cell leukemia

• Phase 2a, PTCL:

  • Precursor T/NK neoplasms, except blastic NK lymphoma
  • T-cell prolymphocytic leukemia
  • T-cell large granular lymphocytic leukemia
  • Mycosis fungoides, except transformed mycosis fungoides
  • Sézary syndrome
  • Primary cutaneous CD30+ disorders: Anaplastic large cell lymphoma and lymphomatoid papulosis

• Phase 2a, B-cell:

  • Lymphoplasmacytic lymphoma (± Waldenström's macroglobulinemia)
  • Plasma cell myeloma/plasmacytoma
  • Hairy cell leukemia
• Relapsed Hodgkin's disease or diffuse large B-cell lymphoma patients who are candidates for high dose therapy and autologous stem cell transplantation and for whom it is a standard curative option.
• Active concurrent malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix). If there is a history of prior malignancy, must be disease-free for ≥ 5 years.
• NYHA Functional Classification congestive heart failure Class III/IV.
• Uncontrolled hypertension.
• HIV-positive diagnosis and is receiving combination anti-retroviral therapy.
• Central nervous system disease.
• Undergone allogeneic stem cell transplant.
• Relapsed < 100 days from time of an autologous stem cell transplant.
• Patients with disease refractory to peripheral blood stem cell transplant or who have relapsed < 100 days after transplant.
• Active uncontrolled infection or underlying medical condition including unstable cardiac disease, or other serious illness impairing the ability to receive protocol treatment.
• Major surgery within 2 weeks of planned start of treatment.
• Receipt of any conventional chemotherapy or radiation therapy (encompassing > 10% of bone marrow) within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study treatment or planned use during the study.
• Receipt of systemic corticosteroids within 7 days of study treatment, unless on a continuous dose of ≤ 10 mg/day of prednisone for at least 1 month.
• Use of investigational drugs, biologics, or devices within 4 weeks prior to study treatment or planned use during the study.
• Received a monoclonal antibody within 3 months without evidence of progression.
• Previous exposure to pralatrexate and/or gemcitabine if it was discontinued due to treatment-related toxicity.