Application of JAK1 Inhibitors in Peripheral T-cell Lymphoma: Highlights from the 15th Chinese Medical Association Hematology Academic Conference and the First Rare Blood Disease Academic Conference

From March 23rd to 24th, 2024, the 15th Chinese Medical Association Hematology Academic Conference and the First Rare Blood Disease Academic Conference, hosted by the Chinese Medical Association and the Hematology Branch of the Chinese Medical Association, and co-organized by the First Affiliated Hospital of Soochow University, was successfully held in Suzhou, Jiangsu Province, China. Numerous hematological experts and scholars from China and abroad engaged in academic exchanges on experimental diagnosis in the field of hematological diseases and the latest developments in rare blood diseases through academic presentations and thematic discussions.During the conference, Professor Bing Xiang from West China Hospital of Sichuan University delivered an insightful presentation titled “Application of JAK1 Inhibitors in Peripheral T-cell Lymphoma.” In this article, we summarize the main points of the presentation for the benefit of our readers.

JAK kinase (Janus kinase, JAK) is a non-receptor tyrosine kinase family with seven structural domains inside the cell, transmitting cytokine signals through the JAK-STAT signaling pathway. The JAK-STAT signaling pathway plays a crucial role in multifaceted systems, including programming and functional responses of immune reactions, particularly T lymphocyte polarization, hematopoietic control, inflammatory responses, lipid synthesis, and cell growth.

With the deepening research on JAK inhibition in oncology, increasing evidence suggests that JAK mutations and aberrant JAK/STAT signaling pathway activation are associated with the occurrence, development, and drug resistance of various malignant tumors. Among the JAK family kinases, JAK1 has been proven to be the main driving factor for STAT3 phosphorylation and signal transduction. Selective JAK1 inhibitors can reduce toxicity to hematopoietic pathways while maintaining a high level of target coverage of the JAK1-STAT3 signaling pathway.

The pathogenesis of PTCL is complex and closely associated with the JAK-STAT signaling pathway

The pathogenesis of Peripheral T-cell Lymphoma (PTCL) is complex, involving molecular biological abnormalities such as multiple signaling pathways, cellular genetic mutations, and epigenetic mutations. Among them, the sustained activation of the γc-JAK1/3-STAT3/5 pathway is closely related to the occurrence and development of PTCL. (1) Under physiological conditions, common γ chain-dependent cytokines (such as IL-2/7/15) mediate T cell proliferation and differentiation through downstream JAK1/JAK3 dimerization; (2) In a carcinogenic state, abnormal signals from JAK1/JAK3-STAT3/5 promote the formation of T cell leukemia and lymphoma.

Selective inhibition of the JAK1-STAT pathway is a potentially efficient and safe way to treat PTCL. Studies have shown that almost all malignant T-cell tumors have abnormalities in the JAK-STAT pathway. The JAK1-STAT3 pathway is an important pathway for the pathogenesis of PTCL, and its abnormal activation can lead to the occurrence of lymphocyte tumors. JAK1 inhibitors selectively inhibit the JAK1/3-STAT3/5 pathway without inhibiting the JAK2-STAT5 pathway, thereby avoiding occurrences such as anemia, thrombocytopenia, and neutropenia.

Several mechanisms influence the sustained activation of the PTCL-associated γc-JAK-STAT signaling pathway aberrations, including: (1) Dysregulation and genetic mutations in the JAK/STAT signaling pathway. Multiple studies have shown the presence of JAK/STAT pathway-related gene mutations in PTCL, with the main mutated genes being JAK1, JAK3, STAT3, and STAT5. (2) Increased expression of γ chain-dependent cytokines. In addition to gene mutations in the JAK-STAT pathway, PTCL also exhibits increased expression of selective γ chain-dependent cytokines, further enhancing JAK-STAT signal transduction. (3) Abnormal positive and negative regulatory effects of the JAK/STAT signaling.

Relapsed/refractory (R/R) PTCL has a poor prognosis. The 2018 EHA Prospective International T-cell Project study showed that the median overall survival (OS) of PTCL patients who failed first-line treatment was only 5.8 months. The median survival for refractory and relapsed patients was 5 months and 11 months, respectively, with a median follow-up of 38 months, and 70% of patients died. Newly approved drugs have not been effective for all subtypes of R/R PTCL, highlighting the urgent need for more effective medications.

Highly Selective JAK1 Inhibitors: Novel Mechanistic Drugs for PTCL Treatment

Due to the high homology in structure among JAK family members (48%), achieving subtype specificity of JAK is challenging. Furthermore, even with attempted specificity, considering the broad and complex roles of JAK and the interdependence of many cytokine receptors, the resulting effects can be multifaceted.

However, the new generation JAK1 inhibitor, Golidocitinib, achieves high selectivity for JAK1 due to its unique molecular structure advantages. The high selectivity of Golidocitinib for JAK1 significantly enhances treatment tolerability and efficacy. (1) Effective inhibition of PTCL by highly selective JAK1 inhibitors can also reduce toxic side effects caused by targeting other family members, greatly improving clinical treatment safety. (2) By avoiding tolerance issues caused by inhibiting JAK2, the treatment dose of Golidocitinib can be increased to 150 mg/d, thereby better exerting its anti-tumor effects.

Global Multicenter Phase II Registered Clinical Study — JACKPOT8 PARTB Data

The global multicenter phase II clinical study of Golidocitinib (JACKPOT8 PARTB) was selected for oral presentation at the 2023 ASH conference and simultaneously published in The Lancet Oncology. The study included 104 patients with relapsed or refractory/chemotherapy-resistant disease after initial treatment. Key inclusion criteria were: (1) Previous failure of ≥1 line of systemic treatment for PTCL relapsed or refractory/intolerance; in CD30-positive anaplastic large cell lymphoma (ALCL) patients, previous systemic treatment should include CD30-targeted therapy; (2) Histopathologically confirmed PTCL; (3) Evaluable disease status; (4) Age ≥18 years; (5) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤2; (6) Normal bone marrow hematopoietic function and organ function.

Dosage regimen: Golidocitinib 150 mg, orally once daily, every 21 days a cycle, continued treatment until disease progression or intolerance. On Day 1 of the 3rd cycle, and then assessed every 3 cycles until disease progression, intolerance, or withdrawal from the study. The primary endpoint: Objective Response Rate (ORR) confirmed by an Independent Review Committee (IRC) based on CT and the 2014 Lugano assessment criteria. Secondary endpoints included: Complete Response Rate (CRR), Duration of Response (DOR), Progression-Free Survival (PFS), and Time to Response (TTR).

Subjects included in the analysis must meet the following criteria: Received at least one dose of Golidocitinib; centrally confirmed as PTCL by pathological review; had at least one measurable lesion at baseline confirmed by IRC review; if the above conditions are met, subjects who did not undergo any post-baseline assessments could still be included in the efficacy assessment. A total of 88 patients were included, among whom 100% had previously received chemotherapy, with 50% receiving HDAC inhibitors. The largest proportion of included patients had Peripheral T-cell Lymphoma, not otherwise specified (PTCL-NOS), followed by Angioimmunoblastic T-cell Lymphoma (AITL) and ALCL. See below for baseline characteristics of enrolled patients in JACKPOT8 PARTB:

Baseline Characteristics of Enrolled Patients in JACKPOT8 PARTB: Essential Response Disease Population Characteristics

Note: PTCL, NOS = Peripheral T-cell Lymphoma, not otherwise specified; AITL = Angioimmunoblastic T-cell Lymphoma; ALCL = Anaplastic Large Cell Lymphoma; NK/TCL = NK/T-cell Lymphoma; T-PLL = T-cell Prolymphocytic Leukemia

In the evaluable 88 patients, Golidocitinib monotherapy for R/R PTCL achieved an ORR of up to 44.3%, with a complete response (CR) rate of 23.9%. Tumor shrinkage in target lesions was observed in 70% of patients after treatment.

Golidocitinib monotherapy achieved high remission rates in various subtypes of PTCL, with complete remission achieved in 33.3% of NK/TCL patients, 25% of AITL patients, and 28% of PTCL-NOS patients.

Golidocitinib monotherapy demonstrated prolonged remission duration in R/R PTCL. As of the last follow-up on August 31, 2023, the median Duration of Response (DOR) was 20.7 months (with 53.8% of patients still in continuous remission), the median Progression-Free Survival (PFS) was 5.6 months, and the median Overall Survival (OS) was 19.4 months.

In addition to the JACKPOT8 Phase II study, several other studies involving Golidocitinib in the field of PTCL are currently underway. These include Phase III studies targeting PTCL patients who have relapsed or are refractory/chemotherapy-resistant after initial treatment, Phase II studies for maintenance therapy after initial treatment in newly diagnosed PTCL patients, and studies focusing on Cutaneous T-cell Lymphoma (CTCL) in patients who have relapsed or are refractory after initial treatment. With the continuous publication of results from these studies, it is believed that Golidocitinib will bring more benefits to patients with PTCL.