The combined regimen of oral azacitidine and romidepsin showed better efficacy in PTCL

With the discovery of mutations in epigenetic regulatory factors such as TET2, DNMT3A, and IDH2, the view that peripheral T-cell lymphoma (PTCL) is epigeneticly regulated has gradually been supported.

Epigenetic drugs (including HDAC inhibitors vorinostat, romidepsin, belisstat, and chidamide) in PTCL show single-agent activity also indirectly confirms epigenetic regulation in the pathogenesis of PTCL The core role of this part of the drug in PTCL is about 25%, and it can bring a longer duration of remission (DOR) for PTCL patients.

 Related studies have explored the efficacy and safety of the combination of epigenetic drugs in PTCL.

The results of a previously published phase I study showed that compared with patients with B-cell lymphoma, the DNMT inhibitor oral azacitidine combined with romidepsin has a better effect in patients with PTCL (ORR: 10% vs 73%) .

The preliminary analysis of the study showed that the disease relief brought about by the combined program has nothing to do with the patient's epigenetic mutations.

A multi-center, phase II study further explored the efficacy and safety of the combined regimen in patients with PTCL.
The main results of the study are summarized below for the reference of readers.

The key point: Oral azacitidine and romidepsin combined regimen in the treatment of PTCL has a higher remission rate and prolongs the duration of remission.

Research methods: The study included patients with PTCL who were ≥18 years old and had an ECOG score ≤2 points for treatment-naïve (TN) or relapsed and refractory (R/R).

The enrolled patients were given the recommended phase 2 dose (RP2D) determined in the previous phase I study: oral azacitidine 300mg, 1-14 days of each cycle; intravenous injection of romidepsin 14mg/m2, 8th, 8th of each cycle 15.
22 days; a cycle of 35 days until the patient's disease progresses, an intolerable adverse reaction occurs, and the trial is withdrawn.

The primary endpoint of the study was ORR assessed by the investigator, and secondary endpoints included progression-free survival (PFS), DOR, overall survival (OS), and potential biomarkers related to disease remission.

Results of the study The overall situation of the patients The study included 25 patients from April 2017 to March 2019, of which 5 patients received treatment in the phase I study dose expansion cohort.

Seventeen patients (68%) had angioimmunoblastic T-cell lymphoma (AITL) or PTCL (hereinafter collectively referred to as tTFH) with a follicular helper T cell phenotype (TFH).

Thirteen patients with R/R had previously received a median of 2 lines (range: 1-6), and 10 patients had TN.

After 13.
5 months of follow-up (range: 2.
3-33.
5), the patient’s median PFS was 8.
0 months, among which the median PFS of tTFH patients was 8.
9 months, and the median PFS of patients with other PTCL subtypes was 2.
3 Month (HR: 0.
3; 95%CI: 0.
09-1.
06; P=0.
05).

Compared with R/R patients, TN patients had longer PFS (less than 8 months), but the difference was not statistically significant (HR: 0.
7; 95%CI: 0.
21-2.
45; P=0.
58).

The median DOR of the patients in the study was 20.
3 months.
Compared with R/R patients, the DOR of TN patients was longer (less than 13.
5 months), but the difference was also not statistically significant (HR: 0.
5; 95%CI: 0.
05-6.
08; P=0.
62).

The median OS of the patients in the study has not been reached, and the median OS of patients with tTFH is significantly longer than that of patients with other subtypes (not reached vs 9.
4 months; HR: 0.
2; 95%CI: 0.
03-1.
0; P=0.
03) .

The median OS of R/R patients was 20.
6 months, and the median OS of TN patients was not reached.

 Two patients were unable to evaluate the efficacy due to malignant tumors (rectal cancer) and fatal sepsis caused by immune neutropenia after rectal bleeding.

The ORR of 23 patients with evaluable efficacy was 61%, and the complete remission (CR) rate was 43%.

The ORR and CR rates of 13 R/R patients were 54% and 38%, respectively; the curative effect of 10 TN patients was relatively good, with ORR and CR rates reaching 70% and 50%, respectively.

Compared with the overall population in the study, tTFH patients have a higher remission rate, with an ORR of 80% and a CR rate of 60%.

 In the study, the tumor burden of most patients (61%) was reduced by ≥50%, and the reduction in tumor burden of these patients was not related to the previous treatment (TN or R/R).

The depth of remission in some patients increased with the passage of treatment time: 1 patient achieved partial remission (PR) after 2 courses of treatment, and reached CR after 6 courses of treatment; 1 patient received 2 courses of treatment After stable disease (SD), PR was achieved after 6 courses of treatment, and the tumor volume continued to decrease after 1 year of treatment.

In the study, 5 patients successfully received hematopoietic stem cell transplantation (4 autologous hematopoietic stem cell transplantation, 1 allogeneic hematopoietic stem cell transplantation), and 1 patient withdrew from the trial and received consolidation radiotherapy.

The adverse effects (AE) of the oral azacitidine combined with romidepsin regimen observed in the safety study are basically consistent with the results of the previous phase I study.

In the study, 7 patients were dosed down due to AE; 1 patient permanently terminated the treatment due to EBV activation, and then the disease progressed; an 83-year-old patient was admitted to the hospital due to neutropenia after the second cycle of treatment, and the patient was concurrently inhaled Pneumonia caused supraventricular tachycardia, hypotension, and autoimmune hemolytic anemia.
The patient’s nasopharyngeal disease progression was confirmed during hospitalization.

 The most common grade ≥3 AE in the study was cytopenia, mainly thrombocytopenia (48%), neutropenia (40%), and lymphopenia (32%).

The duration of other AEs is relatively short and easy to control.

Research conclusions The research results show that oral azacitidine combined with romidepsin has a better curative effect in patients with PTCL, especially in patients with tTFH and TN.

Reference: Lorenzo Falchi, Helen Ma, Sandra Klein, Jennifer K.
Lue, et al.
Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study.
Blood (2021) 137 (16): 2161–2170.
; https://doi.
org/10.
1182/blood.
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