A Phase 2 Multicenter Study of Pegaspargase in Combination with Gemcitabine, Etoposide, Mitoxantrone Hydrochloride Liposome, and Dexamethasone (P-GEMD) for Newly Diagnosed Early Non-Upper Aero-Digestive Tract or Advanced Stage Extranodal NK/T Cell Lymphoma

Background

Extra-nodal natural-killer (NK)/T-cell lymphoma (ENKTL) is an aggressive disease common in Asia but rare in the West. More than two-thirds of persons have stage I/II disease of the upper aero-digestive tract (UAT), which have relatively superior prognosis. However, patients of early non-UAT (NUAT) or advanced stage show an aggressive clinical course with extremely poor prognosis and low survival rates. Mitoxantrone hydrochloride liposome has reported to have efficacy in relapsed/ refractory (R/R) ENKTL in a phase II clinical trial (Hui-Qiang Huang, ASH 2020). Furthermore, patients of early NUAT or advanced stage always have hemophagocytic lymphohistiocytosis (HLH) at diagnosis. Therefore, etoposide and high dose dexamethasone were also important for these patients. Based on these facts, this study evaluates the efficacy and safety of the regimen of pegaspargase, gemcitabine, etoposide, mitoxantrone hydrochloride liposome, and dexamethasone (P-GEMD) in patients of newly diagnosed early NUAT or advanced stage ENKTL.

Methods

This was a prospective, single-arm, multicenter Phase II clinical study (NCT05774028). Eligible patients (≥18 years, ECOG performance score 0-2) had histologically/cytologically confirmed newly diagnosed early NUAT and advanced stage ENKTL. The P‐GEMD regimen (pegaspargase at 3750 IU, d2; gemcitabine at 1000 mg/m², d1; etoposide at 65 mg/m², d2‒4; mitoxantrone hydrochloride liposome at 12 mg/m², d1; dexamethasone at 40 mg/d, d1‒4.) was administered intravenously every 3 weeks until disease progression (PD) or unacceptable toxicity, up to 6 cycles of therapy were planned. The primary endpoint is complete response (CR) rate. The second endpoint are overall response rate (ORR), duration of response (DOR), 1-year overall survival (OS) ,1-year progression-free survival (PFS) and safety.

Results

As of July 2024, the study had enrolled 17 patients, including 14 (82.4%) patients of advanced-stage nasal type, ENKTL, and 3 (17.6%) patietns of NUAT-NKTL. The median age of all patietns was 41 years (range 18‒75 years) and 12 (70.6%) patietns were males. All (100%) patients had advanced-stage disease with stage IV and 16 patietns (94.1%) had PINK score ≥2. Eleven patients (64.7%) had elevated plasma EBV DNA levels. Five patients experienced HLH at diagnosis. Thirteen patients completed the induction of P-GEMD regimen with the median cycles of 6 (range 4‒6).

At the data cutoff, 16 patients had undergone at least one efficacy assessment, and the best CR rate was 81.3% (13/16) and ORR was 87.5% (14/16). Furthermore, the 13 patients with CR evaluated by PET-CT were all negatively for minimal residual disease (circulating tumor DNA, ctDNA) checked by next generation sequencing (NGS) while the ctDNA burden of patient with PD was positive. With median follow-up of 6.6 months, median PFS and OS will be reported after long-term follow-up. The grade ≥3 reatment-related adverse events (TRAEs) with an incidence ≥10% were hematological toxicity, hypocalcemia (23.5%), and hyponatremia (17.6%).

Conclusion

P‐GEMD regimen has shown promising efficacy with manageable toxicities as a front‐line treatment for early NUAT or advanced stage ENKTL. Further information on long-term survival is needed for a comprehensive assessment.

No relevant conflicts of interest to declare.

Mitoxantrone hydrochloride liposome (PLM60) is an anthracycline anti-tumor drug approved by the National Medical Products Administration (NMPA) for the treatment of relapsed or refractory Peripheral T-cell Lymphoma patients who have previously undergone at least one line of therapy.