Safety and Management of Pralatrexate Treatment in Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL).

Chemotherapeutic agents may be associated with early-onset toxicities (eg, bortezomib peripheral neuropathy) or late-term/cumulative-dose toxicities (eg, doxorubicin cardiotoxicity, platinum nephrotoxicity). The rationally designed antifolate, pralatrexate, has high affinity for reduced folate carrier-1 (RFC-1) and is an efficient substrate for polyglutamation by folylpolyglutamyl synthetase, resulting in increased drug uptake and retention by cells. As with all new agents, strategies must be learned and employed to maximize efficacy and minimize toxicities. The pivotal, international, Phase 2 PROPEL study of pralatrexate in patients with relapsed or refractory PTCL showed an overall response rate of 28% (30/109) by independent central review. Patients received pralatrexate for a mean of 112 days (range, 1-558). Patients accrued to PROPEL had received a median of 3 prior therapies, and 68% had received combination chemotherapy or stem cell transplant just prior to inclusion in the study. The objectives of this analysis were to assess the safety profile of pralatrexate according to duration of treatment, to evaluate both early and late-onset toxicities, and to assess the impact of dose modification.

Eligibility criteria included histologically confirmed PTCL by central review, disease progression after ≥ 1 prior treatment, and ECOG performance status £ 2. Response was assessed centrally using the International Workshop Criteria. All patients received pralatrexate 30 mg/m² IV once weekly for 6 weeks in 7-week cycles with supplementation of vitamin B₁₂ (1 mg IM q8-10 wks) and folic acid (1.0-1.25 mg PO daily). If a patient had Grade 3 thrombocytopenia, Grade 3 neutropenia (± fever), Grade 3 non-hematologic toxicity, or Grade 2 mucositis, that week's pralatrexate dose was omitted. Pralatrexate dose was decreased to 20 mg/m² for all cycles after grade 3 non-hematologic toxicity or two occurrences of the following: Grade 4 thrombocytopenia, Grade 4 neutropenia, Grade 3 febrile neutropenia, or Grade 2 mucositis.

In the PROPEL Trial, 111 patients received pralatrexate and were evaluable for safety. Patients received pralatrexate for a mean of 112 days (range, 1-558). Nineteen patients received pralatrexate for ≥180 days, including 10 who received pralatrexate for ≥300 days. Sixty-four patients received 2 or more cycles of therapy, including 43 patients who received 3 or more cycles. The median cumulative dose of pralatrexate was 207.9 mg/m² (range, 26.7-1900). The incidence by cycle of the most common Grade 3-4 adverse events for patients who received 3 or more cycles are presented in the Table. Seventy-seven (69%) patients maintained the starting dose at 30 mg/m² without dose reduction to 20 mg/m². Of the 34 (31%) patients with a dose reduction at any time during the study, 20 had their dose reduced in cycle 1, 8 in cycle 2, and 6 in cycle 3 or later. Mucositis was the most common reason for dose reduction. In these 34 patients the frequency of Grade 2-4 mucositis before vs. after dose reduction was 28 vs. 15.

Despite pretreatment with a median of 3 prior therapies, the majority of patients with relapsed or refractory PTCL tolerated full dose pralatrexate. The most common Grade 3-4 adverse events for patients who initiated cycle 3 were observed at a similar rate in cycles 1-2 vs. cycles 3 or later, and no single adverse event increased in incidence in these patients, suggesting no cumulative-dose toxicity effects. Dose reduction to 20 mg/m² per the protocol effectively reduced the occurrence of mucositis. Adherence to pralatrexate dose modification guidelines allowed for minimization of toxicity with continued therapy.

Pinter-Brown:Allos Therapeutics, Inc.: Consultancy. Horwitz:Allos Therapeutics, Inc: Consultancy, Research Funding. Pro:Allos Therapeutics, Inc.: Research Funding. Gisselbrecht:Allos Therapeutics, Inc.: Research Funding. Fruchtman:Allos Therapeutics, Inc.: Employment.