P1089: zanubrutinib-rituximab chemo-free therapy with or without autologous stem cell transplantation in newly diagnosed mantle cell lymphoma

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Mantle cell lymphoma(MCL) is an incurable B-cell lymphoma with heterogeneous clinical presentation. Frontline intensive chemoimmunotherapy induction with or without autologous stem cell transplantation (ASCT) as consolidation is recommended for previously untreated MCL patients. However, this approach has the tendency to increase short- and long-term toxicities. Window-1 study demonstrated upfront use of ibrutinib-rituximab induction allowed minimization of chemotherapy exposure, thereby reducing adverse events. Based on favourable response rates and superior safety of zanubrutinib in relapsed/refractory(R/R) MCL patients, combination of zanubrutinib plus rituximab(ZR) might obviate the need for chemotherapy in newly diagnosed MCL patients. Aims: This study aimed to analyze the efficacy and safety of ZR chemo-free therapy with or without ASCT in previously untreated MCL patients. Methods: Patients with newly diagnosed MCL were enrolled in this ongoing, prospective, multicenter, open-label phase II study(NCT05504603). Patients received oral zanubrutinib(160 mg twice daily) and rituximab(375 mg/m2 weekly for cycle 1 and then on day 1 of cycles 2-5, 4 weeks per cycle) as induction therapy. Then, patients achieved complete remission(CR)or partial remission(PR) were followed by zanubrutinib maintainence for elderly(age>70y) or unfit patients until intolerable toxicities or relapsed, while ASCT was given to younger(age≤70y) and fit patients. The primary endpoints were overall response rate(ORR) and complete response rate(CRR) at the end of cycle 3, cycle 5 and ASCT. The secondary endpoints were 2-year overall survival(OS), 2-year progression free survival(PFS) and safety profiles. Results: Eighteen patients with a median age of 64 years were enrolled. The majority had intermediate-risk international prognostic index (77.8%), stage III/IV disease (94.4%), blastic(11.1%), and complex karyotye(22.2%). Next-generation sequencing was performed in 13(72.2%) patients to detect genetic mutations, including ATM(n=6, 46.2%), and TP53(n=3, 23.1%) mutations. 16(88.9%) patients completed ≥3 cycles of ZR and fifteen patients achieved CR and one got stable disease(SD) who was then taken off and enrolled in another clinical trial. The overall response rate(ORR) and complete response rate(CRR) for a 3-cycle response were both 93.8%. 14(77.8%) patients completed planned 5-cycle treatment with 4(22.2%) patients exposed to ASCT. Among the 14 patients, 7 patients(50%) achieved minimal residue disease(MRD) negative. During the whole treatment, no progressive disease or death was reported. By the subgroup analysis in 16 patients with efficacy available, patients with blastic type(n=2), complex karyotype(n=4) and TP53(n=3) mutations all obtained CR. Within a median follow-up of 23.3 months, the 2-year OS and PFS were both 100%, and the median overall survival and progression free survival were undefined. During ZR induction, only 1 (5.6%) case occurred grade 2 infusion-related response. During ASCT consolidation, 1(5.6%) case showed transient alaninetransaminase elevation(grade 1); 1 case showed oral mucositis(grade 2); 4(22.2%) cases showed transient and reversible leukopenia(grade 4) and thrombocytopenia(grade 4). During the whole treatment, no atrial fibrillation, infection and bleeding were observed. Summary/Conclusion: This study demonstrates a favorable efficacy and tolerable safety of chemo-free regimen ZR in patients with newly diagnosed MCL and expands therapeutic options for newly diagnosed MCL. More updated clinical data will be presented from this ongoing study. Keywords: Bruton’s tyrosine kinase inhibitor (BTKi), Autologous hematopoietic stem cell transplantation, Mantle cell lymphoma, Clinical trial