Jennifer Amengual, MD, Shares Updates in the Treatment of T-Cell Lymphomas

Jennifer Amengual, MD, Herbert Irving Assistant Professor of Medicine, Columbia University, New York, New York, presented updates in the treatment of T-cell lymphoma, including prognosis, epigenetic mutations, viable biomarkers, and toxicity concerns in patient outcomes during the virtual Great Debates & Updates in Hematologic Malignancies.

Dr Amengual identified T-cell lymphomas as a group of heterogenous diseases made up mostly of peripheral T-cell lymphoma (PTCL; 25.9%), angioimmunoblastic T-cell lymphoma (AITL; 18.5%), extranodal NK/T-cell lymphoma (10.4%), adult T-cell leukemia or lymphoma (ATLL; 9.6%), anaplastic large cell (ALK-ALCL; 6.6%), and more.

“Altogether T-cell lymphoma remains challenging to treat. The 3-year overall survival (OS) at initial diagnosis ranges between 50% to 88%. Recently, it was found that the median time to first relapse is 6.7 months and those who first relapse have an OS of 5.5 month. There is a dismal treatment outlook, and we really need to do better in this disease,” Dr Amengual said.

There is progress to be made toward understanding biology and biomarkers within upfront treatment strategies in both chemotherapy regimens and transplant in first remission, she said. Additionally, leverages in biologic understanding in the relapsed setting require refinement in epigenetics, PI3K, and checkpoint blockades.

Recently, regulators GATA3 and TBX21 have been found to stratify prognosis in PTCL not otherwise specified (NOS). GATA3 expression is associated with inferior OS and TBX21 demonstrates favorable OS. Clinical supports that both regulators are associated with genomic expression profiling. As of recent, these findings were validated by immunohistochemistry (IHC) and formalin-fixed paraffin-embedded (FFPE) tissue preservation.

Additionally, follicular T-helper cells of origin were found to be enriched in epigenetic mutations. These include RHOA G17V, TET2, DNMT3A, IDH2 R172, as well as KMT2D, and SETD2, amongst other mutated compounds and proteins.

Dr Amengual explained that adaptions of epigenetic abnormalities tend to poorly compare to those without chemotherapy, however, these are more sensitive to epigenetic treatment.

“ALK-ALCL associated with DUSP22 expressions were found to have a superior OS whereas those with TP63 had an inferior OS. Furthermore, the JAK/SAT pathway has been found to be activated in many nodal ALK-ALCL, which opens up potential targeted treatment opportunities,” Dr Amengual said.

In relation to upfront treatment strategies, Dr Amengual described azacitidine-cyclophosphamide, doxorubicin, and vincristine (AZA-CHOP) as a frontline therapy for PTCL during a recent American Society of Hematology (ASH) trial. Patients received AZA then CHOP chemotherapy in 6 cycles. The overall response rate (ORR) was 75%, however, patients with PTCL with a TFH phenotype had an ORR of 88%.

Further in the study, findings showed that TET2 mutations correlated with favorable progression-free survival (PFS), whereas DNMT3A mutations correlated with adverse OS.

“This is a great example of how epigenetic drugs have an enriched outcome in patients with T-cell lymphoma and how our new biomarkers may help stratify patients toward appropriate disease treatment strategies,” Dr Amengual elaborated.

In another study presented at ASH was the Ro-CHOP phase 3 study, Dr Amengual said, where patients were randomized to romidepsin plus CHOP (Ro-CHOP) chemotherapy. The 1 disease entity with an improved response were those with AITL. However, toxicities were significant overall in patients who received Ro-CHOP or CHOP with grade 3 adverse events (AEs) of anemia, nausea, and thrombocytopenia.

Autologous stem cell transplantation (ASCT) in first remission represents a general practice in patients with T-cell lymphoma, however, there is some controversy surrounding this method, she said.

Dr Amengual shared results from the International T-cell Project—the largest prospective study in AITL with 282 patients enrolled. With a median age of 64, 16% of patients received etoposide and 13% of patients underwent ASCT in CR1. The findings demonstrated that 89% of patients had a 5-year OS, which supports the idea of using transplant during CR1.

These findings correspond with the COMPLETE study, she said, with 499 patients enrolled at a median age of 64. Overall, 213 patients achieved CR and 30% underwent ASCT in CR1. There was a 2-year OS in ASCT at 88% compared with non-ASCT at 70%. These results underscore the potential use and efficacy of transplant during first remission.

Allo-transplant for PTCL was also presented at ASH 2020, Dr Amengual said. In a retrospective analysis, many patients who received allo had CR or partial remission (PR). About 7% of patients were treated with allo after CR1, then 69% at CR2. After allo-transplant, the 2-year OS was 59% (95% CI, 54-63) and the 5-year OS was 50% (95% CI, 46-55). However, the median time until relapse to death post-allo was 10 months.

Dr Amengual emphasized that it is crucial to consider if the increase in toxicities that are associated with allo-transplants will support decisions in successful patient outcomes.

For leveraging biologic understanding in relapsed settings, Dr Amengual sought to answer if enhancements could be made in HDAC inhibitor effects in PTCL.

“Romidepsin was studied in combination with lenalidomide, which is an IMID. In a relapse setting for PTCL, the ORR was 60% and the duration response rate (DOR) was 9 months. During ASCO 2021, romidepsin plus lenalidomide was presented in the frontline setting with an ORR of 75%. In AITL, the ORR was 85% with a CR rate of 30-38%,” Dr Amengual said.

This trial presents interest for patients who cannot tolerate chemotherapy in the frontline setting. Romidepsin plus lenalidomide demonstrates potentiality as a viable option for AITL.

In 2018, Dr Amengual said she presented a phase I study of romidepsin plus pralaxtrexate, resulting in an ORR of 71% and a CR rate of 29%. The PFS was 4 months with well-toleration and few AEs.

Romidepsin in combination with duvelisib was studied as a novelty PI3K inhibitor. In PTCL, the ORR was 50% with a CR rate of 19% and a PFS rate of was 8 months.

“Azacitidine is a DNA methyltransferase inhibitor that was studied with 5 groups in the setting of AITL and was found to have a 75% response rate compared to PTCL with a 15% response rate. Those with AITL had a CR of 50%. All of these patients had TET2 mutations,” continued Dr Amengual.

An additional phase II study that supported these findings evaluated oral 5-azacitidine plus romidepsin with 23 patients enrolled. The ORR was 61%, CR was 43%, and median PFS was 8 months. However, patients with T-follicular helper cells (tTFHs) had an ORR of 80%, a CR rate of 60%, and median PFS was 9 months. Patients in the frontline setting had a higher chance of CR in comparison to those with multiple relapsed refractory disease.

Dr Amengual observed that both studies showed comparative response rates, suggesting whether strategies need to pair romidepsin with azacitidine for improved patient outcomes.

The recent phase II PRIMO trial, Dr Amengual mentioned, evaluated duvelisib in patients with relapsed or refractory (R/R) PTCL treated with 25 mg BID or 75 mg BID with a CR rate ranging from 25%-31%, respectively. Patients who required further maintenance had a 52% ORR with a CR rate of 6%.

Dr Amengual discussed a checkpoint blockade for MTCL that appeared in an avelumab NK/TCL study. In all, 21 patients were enrolled with an ORR of 38% and a CR rate of 24%. Responses were significantly associated with PD-L1 expression on tumor tissue. Those with strong-positive staining also had a higher chance of CR.

“The Avail-T study used the same avelumab drug in MTCL with 34 patients enrolled, but only 16 were evaluable due to progression of disease, death, withdrawal prior to first assessment. Six patients achieved a partial remission with 27 appearances of adverse events involving fulminant liver failure, gastric perforation, and immune related colitis. We really need to account for potential toxicities when treating T-cell lymphoma,” continued Dr Amengual.

An additional study for MTCL evaluated pembrolizumab with 18 patients enrolled and 13 who were valuable. This trial was halted early for futility with an ORR of 33% and a median PFS of 3 months.

Finally, pembrolizumab in combination with romidespin was studied on 20 patients with 14 patients who reached phase 2 with an ORR of 50%. The most common AEs were nausea and vomiting, and 2 patients experienced hyperprogression. Evidently, there was a trend toward increase effect with PD-L1 expression on tumors.

Novel strategies for immune engagement were highlighted in 2 studies presented at ASH 2020, Dr Amengual said. First, AFM13 CD30/CD16A bispecific was identified as a tetravalent antibody that engages and activates NK cells. In this study, 14 patients were enrolled with CD30+ cutaneous involvement and had an ORR of 40%. In tumor tissue, responders demonstrated increase tumor infiltration with NK cells and expression of Granzyme B.

TT1-621 anti-CD47 was identified as a fusion protein of CD47 binding domain of SIRPa linked to Fc region IgG1 to enhance phagocytosis by macrophages. Parts 1 through 3 of the trial enrolled 214 patients. For 42 CTCL patients, 1 had CR, 7 had PR, and the ORR was 19%. For 22 PTCL patients, 2 had CR, 2 had PR, and the ORR was 18%. An ongoing part 4 dose optimization study resulted in 2 out of 6 patients responding at an intermediate dose.

Checkpoint blockade methods have led to mixed results and novel strategies toward engaging and activating immune function are under investigation.

Dr Amengual then highlighted the ALLIANCE Frontline PTCL study with upcoming activation, which will observe untreated non-ALCL CD30-negative PTCL and randomize patients to CC486 + CHO(E)P, duvelisib + CHO(E)P, or CHOP or CHOEP in 6 cycles. Each experimental arm will receive comparisons and refine optimization of front-line treatment.

“In conclusion, improvements continue to be made in PTCL in the upfront setting and there is interest in observing AZA-CHOP and further validation of ASCT in first remission. Novel epigenetic and PI3K combinations are under evaluation with combinations of romidespin plus lenalidomide, praxlatrexate, duvelisib, pembrolizumab, and azacitidine,” concluded Dr Amengual.—Alexa Stoia