PETAL: a global view on R/R T-/NK-lymphoma treatment reality

In this issue of Blood Advances, Han et al¹ report outcomes and prognoses for relapsed/refractory (R/R) mature T-cell lymphoma (MTCL) and mature natural killer (NK)–cell lymphoma (MNKCL) from 13 institutions in 10 countries around the globe. This international retrospective cohort study, the Peripheral T-Cell Lymphoma (PETAL) consortium, analyzed 925 patients with R/R MTCL and MNKCL, to address the pertinent lack of robust strata that would explain the heterogeneous second-line treatment responses and that would aid in decisions on subset-specific therapeutic choices. Given the often poor prognosis of this heterogeneous group of rare lymphomas in light of only few efficient treatment options, such an effort is to be applauded. PETAL profits from several incorporated valuable initiatives of systematic data collections (ie, T-cell lymphoma registries).

The frontline treatment for MTCL and MNKCL subsets is usually more uniform, mostly anthracycline based, than the landscape of applied approaches in the R/R setting. Historically, platinum-, ifosfamide-, and gemcitabine-based cytotoxic chemotherapy (CC) has been applied as such second-line strategies.^2,3 More recent, mostly phase 2 trial data, on targeted single-agent (SA) treatments exist and show encouraging activity, but there is hardly any comparative data on the efficacy of SAs vs CC in R/R MTCL and MNKCL. Generally, the overall response rate of second-line CC or SA approaches lies between 20% and 60%.^2,3 Moreover, existing prognostic indices for subsets of MTCL and MNKCL are validated for the CC-based first-line setting, but there are no scores for guiding our management of R/R MTCL and MNKCL.

The PETAL consortium¹ addressed this void and also tackles the global geographic heterogeneities of subtype incidences as well as variances in access to drugs and clinical practices. Common forms of MTCL and MNKCL include peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma (AITL), anaplastic large-cell lymphoma (ALCL), and cutaneous T-cell lymphomas, most frequently found in Western populations.⁴ Extranodal NK-/T-cell lymphoma is more prevalent in Asian countries.⁵ Also, the roles for autologous and allogeneic hematopoietic stem cell transplantation as primary consolidating measures or salvage strategies are not firmly established^6,7 and the global patterns of their inclusion into the approach to R/R MTCL and MNKCL likely also influence reported outcomes.

As already implicated by a Dutch registry,⁸ the PETAL data¹ suggest that treatment with SAs is linked to a significant improvement in progression-free survival, regardless of transplantation status. The authors also observed a higher 3-year overall survival (OS) in patients with R/R AITL and anaplastic lymphoma kinase–negative ALCL treated with SA vs CC.¹ These significant observations suggest that SA therapies may offer a more effective and less toxic alternative to traditional multi–agent chemotherapy regimens. The OS advantage noted in R/R AITL treated with small-molecule inhibitors instead of CC is particularly compelling. Primary chemotherapy insensitivity is a major challenge in the treatment of MTCL and MNKCL; expectedly, patient who are primary refractory showed an inferior outcome as compared with those with relapsed disease.¹ 

These encouraging results highlight the need for further research to confirm the efficacy of targeted SA therapies, for example, in larger, prospective comparative trials. This should also include efforts to better understand the mechanisms of resistance, or particular vulnerabilities, in specific MTCL and MNKCL subtypes. Hopefully these multiple efforts of data collections involved in the PETAL consortium include systematic banking of biomaterial from R/R MTCL and MNKCL.

Another central aspect of PETAL is the development of a novel prognostic index for R/R TCL (PIRT).¹ There are several indices available for newly diagnosed patients with different MTCL/MNKCL subtypes, such as the international prognostic index, prognostic index for T-cell lymphoma, modified PIT, international peripheral T-cell lymphoma project, and prognostic index for NK-cell lymphoma scores. However, no risk score has been established for R/R settings. Additionally, there is a lack of clinical scores that are cross validated between Western and Asian populations. In the presented study, the authors divided the global cohort of 763 patients into a training set (80%) and a test set (20%) and systematically evaluated 21 clinically relevant and easy-to-use features in a real-world data set.¹ Finally, 248 best-annotated cases were included for the calculation of the PIRT. The univariable analysis identified 11 nontreatment factors to be associated with an inferior OS from the start of the second-line therapy (P ≤ .3). Based on a multivariable Cox regression analysis and clinical considerations, 6 risk factors were incorporated for calculation of the PIRT, including age of >60 years, primary refractory, not AITL subtype, >1 extranodal site involvement, Ki67 of ≥40%, and absolute lymphocyte count lower than the lower limit of normal, with a score of 1 assigned to each of such unfavorable features. Patients were then categorized into 3 final risk groups: low (0-1), intermediate (2-3), and high (4-6), which were associated with 3-year OS of 57.14% (95% confidence interval [CI], 17.1-83.7), 23.3% (95% CI, 8.7-41.9), and 7% (95% CI, 0.4-26.9), respectively. This is, to our knowledge, the first report of a prognostic score to estimate survival outcomes for patients with R/R MTCL and MNKCL.

Given the persistent challenges in MTCL/MNKCL, particularly in R/R disease, the new prognostic model might be of use to medical professionals in real-time scenarios across the globe. It should be verified in future well-designed cohort studies and prospective trials, potentially with additional members welcomed to the PETAL effort.

One limitation of the PETAL data¹ is their retrospective nature, which inherently introduces the risk of selection bias and confounding factors that could affect outcomes. Another limitation is the heterogeneity of treatments applied in the study cohort. A wide range of options from various centers and countries is included, with many treatments administered to only a single patient. This variability imposes difficulties to draw clear conclusions about the effectiveness of specific therapies and highlights the importance of prospective controlled trials to validate these findings.

In conclusion, the presented PETAL consortium data¹ provide a comprehensive analysis of the global outcomes and prognostic factors for R/R MTCL and MNKCL, highlighting the challenges and disparities in managing these problematic tumors. The findings underscore the need for continued international collaborations and innovation in the development of predictive tools and therapeutic modalities for R/R MTCL and MNKCL. As such, this global collaboration will hopefully serve as a precipitator for a long-term platform of multinational studies and data collection.

Conflict-of-interest disclosure: The authors declare no competing financial interests.