International T-cell Project: a subgroup analysis of patients with extranodal natural killer T-cell lymphoma

Extranodal natural killer (NK) T-cell lymphoma (ENKTL) is a rare and aggressive disease. Radiotherapy is effective in early-stage disease¹, but most patients with advanced stage or extranasal disease have poor outcomes. This aggressive lymphoma is resistant to anthracycline-based chemotherapy², and recent studies support the treatment with non-anthracycline-based chemoradiotherapy for localized disease³, and incorporating L-asparaginase into non-anthracycline -based regimens for advanced-stage and relapsed or refractory ENKTL.^4-5

A recent study, published by Christopher Fox et al. in Lancet Haematology, analyzed data on a cohort of patients with ENKTL from the T-cell Project (NCT01142674), exploring the clinical characteristics and outcomes of patients with ENKTL.⁶

Study design and patient characteristics

• Of the 1,695 patients, aged > 18 years old with mature T-cell or NK lymphomas, registered in the T-Cell Project cohort⁶
  • 1,553 were eligible for analysis
  • Of these, 166 patients were diagnosed with ENKTL
    • nasal-type, n = 98
    • extranasal-type, n = 68
• According to the prognostic index of NK lymphoma (PINK),⁷ considering four risk factors (age ˃ 60 years, stage III or IV, distant lymph-node involvement, non-nasal type disease), patients were stratified as low (0 factors), intermediate (1 factor), and high risk (≥ 2 factors)
• Primary outcome: 5-year overall survival (OS)
• Secondary endpoints:
  • 5-year progression free survival (PFS)
  • 3-year OS and PFS
• In the entire population, median age was 53 years, the majority of patients were male (65%) and had received first-line treatment of chemo alone (33%), radiotherapy alone (4%), combination of chemotherapy and radiotherapy (56%), or chemotherapy and consolidation high-dose treatment (11%)
• Patients with extranasal disease had more adverse clinical conditions than those with nasal disease such as, involvement of ˃ 1 extranodal site, and high serum lactate dehydrogenase

Results⁶

OS and PFS were estimated after a median follow-up of 44 months (IQR 20–61) and data are reported in Table 1.

• In patients with stage I-II vs patients with stage III-IV ENKTL:  median PFS, 46 months (11–81) vs 15 months (9–20; HR 7.2, 95% CI, 5.4–19.9; p = 0.021), and median OS 59 months (not estimable–not estimable) vs 19 months (4–34; p = 0.042), respectively

Based on PINK score, patients (n = 144 with available data) were classified as:

• Low-risk (n = 34)
• intermediate-risk (n = 41)
• high-risk (n = 69)

In low-risk vs intermediate-risk vs high-risk:

• 5-year OS 54% vs 51% vs 35% (p = 0.0021)
• 5- year PFS 56% vs 34% vs 28% (p = 0.0082)

Outcomes based on treatment were evaluated in 130 patients (75 nasal disease, 55 extranasal) and data are reported in Table 2. The most used regimen incorporating L-asparaginase was the SMILE protocol (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide), administered in 23 patients.

Relative to the chemotherapeutic regimen used, outcomes in patients receiving L-asparaginase based regimen vs those receiving an anthracycline-based regimen vs those not receiving either drug, were:

• 5-year PFS: 42% vs 26% vs 59%
• 5-year OS: 50% vs 31% vs 66%

Of 130 patients, 93 responded to first-line therapy:

• Complete response (CR): 84 (nasal disease, 54; extranasal disease, 30)
• Partial response (PR): 9 (nasal disease, two; extranasal disease, seven)

In patients achieving CR, 5-year OS was 63% and 5-year PFS was 61%. In patients achieving only PR, 5-year OS was 32% and 5-year PFS was not estimable.

CR was also evaluated by treatment group:

• In patients with stage I–II disease (n = 60), CR in chemotherapy alone vs radiotherapy alone vs chemotherapy plus radiotherapy, was 13% vs 25% vs 79%, respectively
• In patients with stage III–IV disease (n = 60), treated with L-asparaginase-based vs anthracycline-based vs non- anthracycline /non-asparaginase protocols, was 67% vs 30% vs 1%, respectively

Conclusions⁶

• The T-cell project is a global study involving 74 hospitals in 13 countries. Results from this subgroup analysis highlighted the importance of using radiation therapy together with chemotherapy in the management of ENKTL with an improved OS and PFS in patients treated with this combined therapy
• Patients with advanced stage disease, treated with L-asparaginase-based regimen showed a better response compared to patients treated with anthracycline-based or non- anthracycline /non-asparaginase regimens
• Patients with extranasal disease, high-risk PINK score had poor prognosis and investigational therapies are warranted