A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) Alternating with Pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial

Abstract

Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti-folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL, provided a rationale to incorporate it into the front-line setting. This phase 2 study evaluated a novel front-line combination whereby cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate (CEOP-P) in PTCL. Patients achieving a complete or partial remission (CR/PR) were eligible for consolidative stem cell transplantation (SCT) after 4 cycles. Thirty-three stage II-IV PTCL patients were treated: 21 PTCL-not otherwise specified (64%), 8 angioimmunoblastic T cell lymphoma (24%) and 4 anaplastic large cell lymphoma (12%). The majority (61%) had stage IV disease and 46% were International Prognostic Index high/intermediate or high risk. Grade 3-4 toxicities included anaemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). Seventeen patients (52%) achieved a CR. The 2-year progression-free survival and overall survival, were 39% (95% confidence interval 21-57) and 60% (95% confidence interval 39-76), respectively. Fifteen patients (45%) (12 CR) received SCT and all remained in CR at a median follow-up of 21·5 months. CEOP-P did not improve outcomes compared to historical data using CHOP. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need.

Keywords: T-cell lymphoma; clinical trials; therapy.

Conflict of interest statement

Conflicts of interest

RHA has reported research funding from Seattle Genetics and Allos Therapeutics. MJL has reported research funding from Allos Therapeutics, Celgene, Seattle Genetics and Millennium; consultancy for Millennium, Allos Therapeutics and Seattle Genetics. AB has reported GlaxoSmithKline (GSK) stock and family member is an employee of GSK; research funding from Spectrum Pharmaceuticals; speakers board for Celgene and Seattle Genetics. KC has reported research funding and honoraria from Spectrum Pharmaceuticals. FF has reported research funding from Merck, Spectrum Pharmaceuticals, Celgene and Seattle Genetics; membership on Board of Directors or advisory committees for Eisai and Millennium; honoraria received from Celgene and Millennium. SH has reported research funding from Celgene, Spectrum Pharamaceuticals, Genzyme, Seattle Genetics, Janssen and Millennium; Consultancy for Spectrum Pharamaceuticals, Celgene, Seattle Genetics, Kyowa Hakko Kirn Pharma, Infinity Pharmaceuticals and Millennium. BP has reported honoraria from Spectrum Pharmaceuticals. LPB has reported consultancy/honoraria from Spectrum Pharmaceuticals. SMS has reported consultancy for Allos Therapeutics, Celgene, Seattle Genetics, Onyx, Genentech, Micromet and Gilead; speakers bureau for Janssen. AS has reported research funding from Celgene; consultancy honoraria from Celgene and Spectrum Pharamaceuticals. KJS has reported research funding from Spectrum Pharmaceuticals. JV has reported research funding from Spectrum Pharmaceuticals. All remaining authors have declared no conflicts of interest.

© 2015 John Wiley & Sons Ltd.

Figures

Figure 1. CEOP-P Treatment Schema

Cycle A: cyclophosphamide 750 mg/m2 day 1 IV; etoposide 100 mg/m2 days 1–3 IV (etoposide may be given PO on days 2 and 3 at double dose of 100 mg/m2 BID); vincristine 1.4 mg/m2 (capped at 2 mg) day 1 IV; prednisone 100 mg PO days 1–5; optional, per institutional standards, pegfilgrastim 6 mg day 4 of Week 1 of each course SQ. Cycle B: pralatrexate 30 mg/m2 day 1 IV q week x 3; optional, per institutional standards, filgrastim (granulocyte colony-stimulating factor) 300 μg day 30 of each course SQ. Patients achieving stable disease after 4 courses (1,2,3,4) received 2 additional courses (5,6) and were then re-evaluated for response post-course 6. PD, progressive disease; CR, complete response; PR, partial remission; HDT/SCR; High Dose Therapy/Stem Cell Rescue

Figure 2. Progression-free survival and overall survival

A. Kaplan–Meier curves for estimated 1- and 2-year progression-free survival: 48% (95% confidence interval [CI] 31–64) and 39% (95% CI 21–57) respectively. B. Kaplan–Meier curves for estimated 1- and 2-year overall survival: 67% (95% CI 48–80) and 60% (95% CI 39–76) respectively.

Figure 2. Progression-free survival and overall survival

A. Kaplan–Meier curves for estimated 1- and 2-year progression-free survival: 48% (95% confidence interval [CI] 31–64) and 39% (95% CI 21–57) respectively. B. Kaplan–Meier curves for estimated 1- and 2-year overall survival: 67% (95% CI 48–80) and 60% (95% CI 39–76) respectively.

Figure 3. Progression-free survival and overall survival in patients who received HDT/SCT compared to those who did not

A. Kaplan–Meier curves at 24 months for patients treated with high dose therapy and stem cell transplantation (HDT/SCT) (n=15) and without HDT/SCT (n=18): progression-free survival with HDT/SCT: 63% (95% confidence interval [CI] 25–86) and without HDT/SCT: 17% (95% CI 4–36) log rank p-value = 0.0002. B. Kaplan–Meier curves at 24 months for patients treated with high dose therapy and stem cell transplantation (HDT/SCT) (n=15) and without HDT/SCT (n=18): Overall survival with HDT/SCT: 80% (95% CI 37–95) and without HDT/SCT: 44% (95% CI 22–65) log rank p-value = 0.007.

Figure 3. Progression-free survival and overall survival in patients who received HDT/SCT compared to those who did not

A. Kaplan–Meier curves at 24 months for patients treated with high dose therapy and stem cell transplantation (HDT/SCT) (n=15) and without HDT/SCT (n=18): progression-free survival with HDT/SCT: 63% (95% confidence interval [CI] 25–86) and without HDT/SCT: 17% (95% CI 4–36) log rank p-value = 0.0002. B. Kaplan–Meier curves at 24 months for patients treated with high dose therapy and stem cell transplantation (HDT/SCT) (n=15) and without HDT/SCT (n=18): Overall survival with HDT/SCT: 80% (95% CI 37–95) and without HDT/SCT: 44% (95% CI 22–65) log rank p-value = 0.007.