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Current standard of care regimens to treat peripheral T-cell lymphoma (PTCL) fall short in terms of complete response rates and long-term overall survival. A phase II clinical trial recently published by Cai et al.1 in Genome Medicine investigated the efficacy and safety of alternating regimens of cyclophosphamide, epirubicin, vincristine, prednisolone (CEOP), ifosfamide, epirubicin, etoposide (IVE), and gemcitabine, cisplatin, dexamethasone (GDP; CEOP/IVE/GDP) compared with CEOP alone, in newly diagnosed PTCL patients. Tumors and peripheral blood from this cohort of patients were further analyzed for the presence of mutations that could be used as prognostic biomarkers of responsiveness to treatment, and progression free survival (PFS) using whole-exosome sequencing.
Table 1. Randomization and dosing schedules (21-day treatment cycles)1
CEOP, cyclophosphamide, epirubicin, vincristine, prednisolone; GDP, gemcitabine, cisplatin, dexamethasone; IVE, ifosfamide, epirubicin, etoposide |
|||
CEOP |
Day 1 Cyclophosphamide 750 mg/m2 Epirubicin 70 mg/m2 Vincristine 1.4 mg/m2 (maximum 2 mg) |
Day 1–5 (Cycles 1 and 4): Prednisone 60 mg/m2 (maximum of 100 mg) |
— |
IVE |
Days 1–3 Ifosfamide 2,000 mg/m2 Epirubicin 70 mg/m2 |
Days 1–3 (Cycles 2 and 5): Etoposide 100 mg/m2 |
— |
GDP |
Days 1–8 Gemcitabine 1,000 mg/m2
|
Days 1–3: Cisplatin 25 mg/m2
|
Days 1–4 (Cycles 3 and 6): Dexamethasone 40 mg
|
Table 2. Treatment response outcomes1
CEOP, cyclophosphamide, epirubicin, vincristine, prednisolone; GDP, gemcitabine, cisplatin, dexamethasone; IVE, ifosfamide, epirubicin, etoposide; OS, overall survival; PFS, progression-free survival Statistically significant p values of < 0.05 are shown in bold |
|||
Outcome |
CEOP (N = 51)
|
CEOP/IVE/GDP (N = 51) |
p value |
---|---|---|---|
Interim response rates, % |
|
|
|
Overall response |
60.8 |
84.3 |
0.008 |
Complete response |
35.3 |
33.3 |
0.834 |
Partial response |
25.5 |
51.0 |
0.008 |
End of treatment response rates, % |
|
|
|
Overall response |
49.0 |
72.5 |
0.015 |
Complete response |
31.4 |
37.3 |
0.532 |
Partial response |
17.6 |
35.3 |
0.042 |
Median PFS, months |
9.2 |
15.4 |
0.122 |
2-year PFS, % |
25.4 |
25.0 |
— |
Median OS, months |
21.9 |
24.3 |
0.178 |
2-year OS, % |
47.1 |
49.2 |
— |
Table 3. Incidence of adverse events1
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CEOP, cyclophosphamide, epirubicin, vincristine, prednisolone; GDP, gemcitabine, cisplatin, dexamethasone; IVE, ifosfamide, epirubicin, etoposide |
||||||
Adverse event |
CEOP (N = 51)
|
CEOP/IVE/GDP (N = 51) |
||||
---|---|---|---|---|---|---|
|
Grade 1–2 |
Grade 3 |
Grade 4 |
Grade 1–2 |
Grade 3 |
Grade 4 |
Hematological events (%) |
||||||
Neutropenia |
24 |
18 |
45 |
22 |
18 |
43 |
Thrombocytopenia |
20 |
2 |
6 |
24 |
4 |
4 |
Anemia |
61 |
10 |
0 |
67 |
8 |
2 |
Non-hematological events (%) |
||||||
Infection |
20 |
12 |
2 |
18 |
8 |
4 |
Nausea or vomiting |
37 |
2 |
0 |
29 |
4 |
0 |
Fatigue |
67 |
2 |
0 |
73 |
2 |
0 |
Headache |
10 |
2 |
0 |
25 |
2 |
0 |
Mucositis |
29 |
2 |
0 |
25 |
0 |
0 |
ALT or AST increase |
16 |
2 |
0 |
18 |
4 |
0 |
Table 4. Most common mutations identified in PTCL tumors1
EOT, end-of-treatment; JAK, Janus kinase; OS, overall survival; PFS, progression-free survival; PTCL, peripheral T-cell lymphoma; STAT, signal transducer and activator of transcription |
||||
Class of genes |
Most common mutations (% incidence) |
Mutations associated with fewer EOT responses |
Mutations associated with poor/inferior PFS |
Mutations associated with poor/inferior OS |
---|---|---|---|---|
Histone modification
|
KMT2D (22.6) EP300 (8.1) CREBBP (4.8) KMT2A (3.2) SETD2 (1.6) |
KMT2D CREBBP |
KMT2D CREBBP |
CREBBP |
DNA methylation |
TET2 (22.6) DNMT3A (11.3) IDH2 (4.8) TET1 (1.6) |
IDH2 |
IDH2 |
IDH2 |
Chromatin remodeling |
ARID1B (14.5) ARID1A (9.7) ARID2 (1.8) CHD8 (1.8) |
— |
ARID1B |
— |
Tumor suppressors |
TP53 (6.5) ATM (4.8) MGA (3.2) NF1 (1.6) |
— |
— |
— |
JAK-STAT pathway |
SOCS1 (4.8) JAK3 (1.6) STAT3 (1.6) |
— |
— |
— |
Transcription regulation |
ASXL3 (1.6) PRDM1 (1.6) |
— |
— |
— |
Others |
RHOA (11.3) NOTCH1 (1.6) |
— |
— |
— |
The results from this phase II clinical trial indicate that there is no survival or CRR advantage to the addition of IVE/GDP to CEOP regimens in newly diagnosed PTCL patients. However, this study did identify several mutations associated with PTCL that predicted clinical outcomes. In particular, KMT2D, CREBBP, IDH2, and ARID1B, which are associated with histone modification, DNA methylation, and chromatin remodeling, were found in patients with fewer end of treatment responses and inferior to poor PFS. Mutations in this subset of genes have also been correlated with poor prognosis in other lymphomas. Further validation of these results might facilitate the use of these mutations as biomarkers for clinical prognosis of PTCL in newly diagnosed patients.
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