A new study by researchers at Mass General Brigham has identified a treatment sequence that improves survival for patients with relapsed/refractory (R/R) mature T and natural killer (NK)-cell lymphomas (TNKL), a rare and aggressive blood cancer with no established treatment protocol.
R/R TNKLs are notoriously difficult to treat due to their biological heterogeneity, resistance to standard therapies, and lack of clearly effective treatment options. These lymphomas include subtypes such as angioimmunoblastic T-cell lymphoma and typically have poor prognoses. With no standard of care, clinicians are often left to choose between cytotoxic chemotherapy (CC), small molecule inhibitors (SMIs), or epigenetic modifiers (EMs) for second- and third-line therapies.
“Our robust study design, multiple stability analyses, and independent machine learning models using the PETAL global dataset, all pointed to the same conclusion: targeted therapies and epigenetic modifiers consistently showed benefit over chemotherapy for patients with relapsed/refractory T-cell/NK-cell lymphomas,” said lead author Mark Sorial, PharmD, BCOP, a researcher in the Mass General Cancer Center.
Published in the British Journal of Haematology, the new study used data from the international Peripheral T-cell Lymphoma (PETAL) Consortium to evaluate the survival impact of various sequential treatment regimens. Researchers conducted a retrospective, multiple intervention ‘target-trial’ including 540 patients who received second-line therapies and 290 who received third-line treatments. Each patient had first been treated with frontline cytotoxic chemotherapy.
The researchers compared 12 possible treatment paths involving CC, SMI, and EM as second- and third-line therapies. Results indicated that the sequence of a second-line SMI followed by a third-line EM offered the greatest survival benefit. This sequence was significantly more effective than repeated chemotherapy (CC–CC), with an adjusted hazard ratio (aHR) of 0.29 (95% CI: 0.11–0.74; p = 0.010).
“2L SMI then 3L EM improved OS (adjusted hazard ratio [aHR]: 0.29, 95% confidence interval [CI]: 0.11–0.74; p = 0.010) versus 2L–3L CC–CC, and consistently across most other sequential strategies,” the researchers wrote.
Treatment benefits were particularly pronounced in patients with angioimmunoblastic T-cell lymphoma, where second-line SMI yielded an aHR of 0.23 (95% CI: 0.10–0.4; p
“This research builds on earlier investigations that evaluated the individual effects of epigenetic and small molecule agents,” said senior author Salvia Jain, MD, a founding member of the PETAL Consortium. Previous studies had shown promise for drugs like duvelisib, a targeted signaling inhibitor, but had not established their optimal timing or sequencing in therapy.
“These results support the earlier use of these novel therapies, prioritize further research of these drug classes, and provide a framework for examining survival effects with sequential treatments in other cancers,” said Sorial. “They also highlight that targeted signaling inhibitors like duvelisib warrant ongoing clinical investigation in this patient population with limited treatment options.”
The study’s strengths include its large and globally diverse dataset, robust statistical methods, and clear findings across multiple analytical models. The researchers incorporated adjustments for age, disease subtype, primary refractory status, PIT score, response to second-line therapy, and transplant consolidation—factors known to influence outcomes in TNKL.
The limitations of the study include its retrospective design, which limited the ability to establish causality, and the sample sizes for some treatment sequences were relatively small. While the researchers acknowledged these limitations, they said that the consistency of findings across some models increases confidence in the observed associations.
Future work will involve prospective validation of these findings and clinical trials to assess the timing, safety, and efficacy of SMIs and EMs in specific TNKL subgroups. Researchers also aim to investigate the biological mechanisms that may explain the enhanced effectiveness of this treatment sequence.
