A retrospective study of the clinical and pathological features of peripheral T-cell lymphomas in a Spanish population

Subclassifying T-cell lymphomas (TCLs) is difficult due to the heterogeneity and broad morphological spectrum of this group of lymphoid diseases. A study by Socorro Maria Rodriguez-Pinilla et al, Hospital Universitario Fundación Jiménez Díaz, Madrid, ES, published in the British Journal of Haematology, retrospectively investigated the characteristics of patients with peripheral TCL (PTCL) from 13 sites across Spain. The group analyzed relevant clinical antecedents, CD30 expression and staining patterns, prognostic indices using the International Prognostic Index (IPI) and the Intergruppo Italiano Linfomi system¹, treatments, and clinical outcomes, and commented on diagnostic differences present between initial pathological assessment and secondary central review of samples.

Patients and methods

Medical records from 13 centers in Spain were searched for patients with PTCL who were diagnosed between January 2008 and December 2013. Inclusion criteria included biopsy specimens used from the initial diagnosis and histologically confirmed PTCL according to the WHO 2008 guidelines², including extranodal natural killer (NK) TCL nasal type, enteropathy-associated TCL (EATCL), hepatosplenic TCL, PTCL not-otherwise-specified (PTCL-NOS), angioimmunoblastic TCL (AITL), anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL), or ALK-negative ALCL (ALK− ALCL). A total of 198 patients were identified, with 175 patients meeting the eligibility criteria for this study. The central review involved updating the classification into six distinct subtypes using the WHO 2016 guidelines³:

1. PTCL-NOS
2. AITL plus nodal PTCL with a T follicular helper (TFH) phenotype
3. ALK+ ALCL
4. ALK− ALCL
5. Extranodal NK/TCL (including Epstein Barr virus-associated TCLs)
6. Intestinal TCL (including patients diagnosed with EATCL and those with monomorphic epitheliotropic intestinal TCL)

CD30 expression was considered positive with ≥ 15% tumor cells (no expression, negative > 0–14%), while intensity of staining was estimated visually and scored as no expression (negative), weak, moderate, and strong. Expression of p53 was also included and classified into negative, positive (0–50%), and very positive (> 50%). The International Non-Hodgkin Lymphoma Prognostic Factors Project system⁴ and the Intergruppo Italiano Linfomi system¹ were used to calculate the IPI and the Prognostic Index for TCL (PIT), respectively.

Key findings

Baseline characteristics

Characteristics of patients included in this study are listed in Table 1 and the key clinical features of PTCL are shown in Table 2. A notable association between PTCL and a history of immune related disorders was identified with 16% of patients having had autoimmune diseases, 17% viral infections, and 19% had chemo/radiotherapy-treated carcinomas.

 Table 1. Baseline patient characteristics⁵

The median follow-up times were:

• All patients: 12.4 months (range 0.1−92.3)
• Surviving patients:
  • 42.3 months (0.5−92.3; censoring times)
  • 53.0 months (42.4−63.7; by reverse censoring)

Table 2. Clinical features of PTCL⁵

In total, 158 patients received curative treatments while three received only palliative care. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens were mostly commonly used (69.7%).

Central review

No change in classification or update referring to the WHO 2016 classification were required in 67.4% of patients. Diagnosis of PTCL-NOS changed from 30.9% to 12% after expert review. The remaining cases were reclassified into new subtypes with nodal PTCL with TFH (n = 23) and monomorphic epitheliotropic intestinal TCL (n = 5) being the most common. There was an increase in incidence of AITL + TFH being reported after expert review (30.9% vs 44.6%, respectively).

Treatments

Best response to treatment was observed after a median of 4 months (range 0−65.2).

Response to first-line therapy:

• Complete response (CR): 34.9% (n = 61)
• Partial response (PR): 22.9% (n = 40)
• Stable disease (SD): 9
• Disease progression (DP): 41 patients

The median duration between first-line treatment and DP or relapse was 6 months (range: 0.2−77.3).

Salvage therapy was required by 90 patients due to no CR or relapse; of these, 38% received platinum-based regimens. In 41 patients, salvage therapy demonstrated clinical benefit with 21 reaching CR, 20 achieving PR, and a further 15, SD.

In terms of first-line therapy, autologous stem cell transplant (SCT) was used in 21 patients, with four undergoing this procedure for salvage treatment. Allogeneic SCT was used in five patients for first-line therapy and two patients following salvage treatment.

Beyond second-line, 40 patients received further treatment, with 27 requiring third-line treatment, and nine requiring fourth.

Progression-free survival (PFS) and overall survival (OS)

Patients achieving a CR after first-line treatment had a significantly better median PFS (62.6 months; 95% CI, 20.2–105.1; p < 0.001) compared with those only reaching PR (7.1 months; 95% CI, 5.8–8.4) or SD (6.3 months; 95% CI, 1.1–11.4; p < 0.001). OS after achieving CR with first-line treatment was 67.0 months (95% CI, 58.2–75.9; p < 0.01) compared with a median of 7.3 months (95% CI, 5.9–8.8; p < 0.001) in patients who did not achieve a CR.

Median OS for all patients was 15.8 months (95% CI, 10.2–21.3). The most common causes of death (n = 114) was DP (65.8%), and infections (18.4%).

When the different subtypes of PTCL were compared, patients with ALK+ ALCL had a significantly better PFS, demonstrating a PFS of 22.7 months compared with other subtypes (p < 0.001). Intestinal forms of PTCL had much poorer outcomes, with a median PFS of 2.6 months.

The univariate and multivariate testing of the PFS results, shown above and in Table 3, demonstrate that when PIT and IPI were excluded, reaching CR was associated with a lower risk of DP, Ann Arbor stages I-II, and an ECOG PS of 0–2. In terms of OS, low/intermediate IPI risk and low/normal lactate dehydrogenase were predictive factors along with reaching CR after first-line treatment.

Table 3. Prognostic factors for OS and PFS with the results of the univariate and multivariate analysis⁵

Prognostic factors for CR to first-line treatment

Significant differences were found using univariate analysis between the number of patients achieving CR and the non-CR patients, especially when comparing different PTCL subtypes. However, when examined with multivariate analysis only the ALK+ ALCL subtype was significantly associated with a high probability of achieving CR (p < 0.015).

CD30 expression

CD30 was expressed in all subtypes and the authors indicated that it may be useful to allow the distinction of PTCL-NOS from ALK− ALCL. CD30 expression was decreased in all high-risk groups; however, the difference was not statistically significant.

Conclusion

This study provides an epidemiological update of the incidence of PTCL in Spain and highlights the clinical features that characterize the various subtypes.

The value of PIT and IPI as prognostic indicators of patients at high-risk of DP or death was confirmed.

The identification of an association of PTCL with immune-related disorders indicates that a further study into the accompanying immunosuppressive factors along with relevant genetic studies is required.

CD30 may be a target for treatment but the data of the current study do not currently support its use as a prognostic indicator.