The prospect of new drug treatment is promising - the treatment progress of peripheral T-cell lymphoma

There is still a lot of unmet need for the treatment of relapsed/refractory peripheral T-cell lymphoma (PTCL), and the prognosis for patients with PTCL is very poor
due to the lack of effective salvage therapies.
Therefore, PTCL treatment needs to be updated and better
.
This review reviews data from three classes of drugs currently being evaluated in clinical trials: the PI3K inhibitors duvelisib and linperlisib, the JAK1 inhibitor golidocitinib (DZD4205), and the EZH1/EZH2 inhibitor valemtostat
.

1PI3K inhibitors

Duvelisib is a PI3K γ/δ inhibitor
.
The Phase 2 PRIMO trial, which explored the efficacy of duvelisib in relapsed/refractory PTCL, included an initial dose optimization phase and a dose expansion phase
.
The initial dose optimization phase consists of cohort 1 and cohort 2, cohort 1 with duvelisib 25 mg 2 times/day, and cohort 2 with 75 mg twice daily; The dose expansion phase duvelisib was administered 2 times / day for 2 previous cycles of 75 mg 2 times / day, followed by 25 mg 2 times / day
.
Patients in cohorts 1 and 2 had overall response rates (ORRs) of 35% and 54%, respectively, with complete response (CR) rates of 25% and 31%,
respectively.
In the dose expansion phase, the 78 patients included had a median number of previously received treatment lines of 3 and an ORR of 50%, of which 32% were CR and 18% were partial response (PR).

The median to response time was 53 days and the median duration of response (DOR) was 233 days
.
Discontinued due to disease progression in 44% of patients and discontinued due to adverse events
in 18% of patients.
Abnormal liver function, neutropenia, infection, and maculopapular rash are common grade 3 to 4 drug-related adverse events
.
6% of patients successfully bridge autologous or allogeneic hematopoietic stem cell transplantation
.
In addition, in a cohort of 55 patients with relapsed/refractory PTCL, duvelisib combined with romidepsin resulted in an ORR of 55% of patients, of which 34% were CR; Median progression-free survival (PFS) was 7 months; Bridging transplantation
is possible in 28% of patients.

Linperlisib is an orally highly selective PI3K δ inhibitor
.
An ongoing Phase Ib clinical trial evaluated the drug's efficacy in PTCL; Patients included were relapsed/refractory PTCLs
who had received at least one systemic therapy.
In 30 evaluable patients, Linperlisib achieved an ORR of 70%, with a CR rate of 33%; In addition, PTCL non-specific and angioimmunoblastic T-cell lymphoma are the most responsive subtypes
.
Most remissions occur within the second month of treatment; Median PFS, OS, and DOR have not yet been reached
.
The drug is generally well tolerated; Neutropenia is a significant grade 3 adverse event, occurring in nearly 11% of patients
.

2JAK inhibitors

The JAK/STAT pathway plays an important role in the development and development of PTCL, JAK mutation is present in anaplastic large cell lymphoma, and STAT3 mutation is expressed in all subtypes of PTCL as high as 40%.

Therefore, inhibition of the JAK/STAT pathway has a good theoretical basis
in the treatment of relapsed/refractory PTCL.
golidocitinib (DZD4205) is an orally selective JAK1 inhibitor currently being evaluated
in a phase I/II clinical trial.
golidocitinib achieved an ORR of 48% in 42 previously treated patients with relapsed/refractory PTCL, with CR and PR rates of 19% and PR rates, respectively; Disease is stable
in 14% of patients.
Survival data is not yet mature
.
Neutropenia, thrombocytopenia, and pulmonary infections are common grade 3 to 4 drug-related adverse events
.

3EZH1/EZH2 inhibitors

EZH1 and EZH2 are epigenetic regulators of histone methyltransferase activity on lysine (H3K27), position 27 on histone H3
.
EZH2 is highly expressed in PTCL, which is associated
with higher tumor proliferation rates and poor prognosis.
Valemetostat is a potent dual inhibitor of EZH1 and EZH2, which can change gene expression patterns by preventing trimethylation of H3K27, thereby reducing the proliferation potential
of tumor cells.
In a phase I study, 44 patients with PTCL received a median of 2 prior treatment lines, and valemetostat resulted in an ORR of 55% of the patients, of which 28% were CR; PTCL non-specific and angioimmunoblastic T-cell lymphoma have better response rates
.
The onset of action is about 8 weeks after administration; The median DOR was 56 weeks and the median PFS was 52 weeks
.
Grade 3 to 4 neutropenia, anaemia, and thrombocytopenia are common drug-related adverse events
.

4brief summary

In conclusion, new drugs being evaluated in clinical trials, including novel PI3K inhibitors, JAK1 inhibitors and EZH1/EZH2 inhibitors, are expected to bring new dawn
to patients with relapsed/refractory PTCL.

References: Alessandro Broccoli and Pier Luigi Zinzani.
2022 SOHO.
EXABS-224-NQ.

Reviewed by Quinta

Typesetting: Quinta

Execution: Quarterly year

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