Induction therapy with ibrutinib and rituximab is safe and effective in young patients with newly diagnosed MCL: the WINDOW-1 study

Treatment of mantle cell lymphoma (MCL) has evolved from combination chemotherapy regimens to chemotherapy-free targeted therapies such as Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalatinib, zanubrutinib Ni et al.
), veneclax, and CD19-targeted chimeric antigen receptor (CAR)-T cell therapy
.

For younger (<65 years) patients, intensive chemotherapy plus rituximab immunotherapy with or without autologous hematopoietic stem cell transplantation (ASCT) and rituximab maintenance therapy is the standard first-line treatment
.

Based on the existing standard treatment, despite the high complete remission (CR) rate and durable remission rate, and the 3-year progression-free survival (PFS) rate of 60%-75%, based on intensive immunochemotherapy and ASCT and the patient's bone marrow Suppression, death, infection, and secondary leukemia are associated with secondary second tumors
.

Based on the previous efficacy of the combination of ibrutinib and rituximab in patients with relapsed MCL, the investigators designed the WINDOW-1 study to determine induction therapy with ibrutinib-rituximab followed by shortening of R- Efficacy and safety of HCVAD/MA consolidation therapy
.

Study Methods WINDOW-1 is an investigator-initiated, single-center, single-arm, Phase II clinical trial conducted at the University of Texas MD Anderson Cancer Center
.

Key inclusion criteria included previously untreated MCL, age ≤65 years, serum bilirubin <1.
5 mg/dL, creatinine clearance ≥30 mL/min, ECOG performance status ≤2, and cardiac ejection fraction ≥2 on echocardiography 50%
.

The study was divided into two parts (Figure 1).
In Part A (induction), ibrutinib was co-administered with rituximab; patients received induction therapy with ibrutinib-rituximab for up to 12 cycles, or until CR, plateau of remission, disease progression, intolerable toxicity, or withdrawal of informed consent
.

Responses are assessed every 2 cycles, and patients who achieve CR in Part A begin Part B (consisting of a short course of R-HCVAD/MA)
.

Response assessments were performed every 2 cycles for the first 12 months
.

CT scans were repeated at cycles 3, 5, and 7, and then every 3 cycles until disease progression
.

18F-FDG PET scans were performed at baseline, and CT-achieved CR was confirmed using the Deauville score
.

Multiparametric flow cytometry using bone marrow aspirate to assess minimal residual disease (MRD) in evaluable patients
.

Safety assessments are performed every 2 cycles in Part A and before each cycle in Part
B.

Figure 1: WINDOW-1 Study Treatment Plan Study Results Patient characteristics and distribution From June 12, 2015 to December 6, 2018, a total of 131 patients were enrolled in the study
.

According to the biological MIPI score, 47 (36%) patients were in the high-risk group, 43 (33%) in the intermediate-risk group, and 41 (31%) in the low-risk group (Table 1); other characteristics included among the 117 patients 58 (50%) had Ki-67 hyperproliferation (≥30%), 15 of 127 (11%) had aggressive MCL (blastoid or pleomorphic), and 11 of 34 (32 %) with TP53 mutation
.

Table 1: Baseline Characteristics of Patients in the WINDOW-1 Study Patient Short-Term Response Patients received a median of 7 cycles of treatment in Part A and 4 cycles in Part
B.

Eleven patients did not receive Part B treatment
.

For patients treated with Part A (ibrutinib-rituximab), the 16-week overall response rate (ORR) was 89% (95%CI 83-94%) and the CR rate was 14% (95%CI) 8-21%)
.

Among all 131 patients studied, patients had an ORR of 98% (95% CI 95-100%), a CR rate of 87% (95% CI 80-92%), and a partial response (PR) rate of 11% ( 95% CI 7-18%), meeting the primary endpoint of this study
.

The median time to CR for Part A patients alone was 5 months
.

In post hoc analyses, among evaluable patients with available data, Ki-67 high-risk (≥30%) and low-risk (<30%) patients, and patients with blastoid or pleomorphic MCL versus typical MCL, Part A alone Both ORR and CR rates were similar after treatment
.

The best ORR of patients after Part B treatment was 90% (95% CI 84-95%), and the CR rate was 89% (95% CI 83-94) (Table 2); according to investigator assessment, 118 patients in Part B Ninety-nine percent of evaluable patients achieved CR, and of the 117 patients who achieved CR in Part B, 107 (91%) had achieved CR during Part
A.

Of the 15 patients who achieved a PR in part A, 10 (66%) achieved a CR in part
B.

At the last (study period) follow-up, 85% of the 131 patients sustained a CR
.

Table 2: Short-term efficacy of patients in WINDOW-1 study Long-term efficacy of patients After a median follow-up of 42 months, 24 patients progressed and 6 died (5 died of progression, 1 unknown)
.

Of the 6 patients who died, only 1 patient developed central nervous system (CNS) recurrence; the median PFS was not reached, nor was the median overall survival (OS)
.

Patients had a 3-year PFS rate of 79% (95% CI 70-85%) and a 3-year OS rate of 95% (95% CI 89-98%; Figure 2)
.

There was no difference in OS between the high and low Ki-67 proliferative index subgroups when the 30% cutoff (P=0.
64) and 50% cutoff (P=0.
28) were used
.

With the exception of patients with complex karyotypes, OS in other high-risk categories was similar to that in low-risk categories
.

There were no significant differences in PFS and OS between patients who did not receive Part B and who received less than 4 cycles of Part B and those who received 4 cycles of Part
B.

Figure 3: The incidence of adverse events in patients with PFS and OS in WINDOW-1 patients at a median follow-up of 42 months.
Most adverse events (AEs) in patients in this study were grade 1 or 2 (Table 3)
.

The most common grade 3-4 hematologic AE in Part A was lymphopenia (14%)
.

The most common grade 3-4 non-hematologic AEs were rash (12%), infection (8%), and fatigue (8%)
.

No patients in Part A discontinued treatment due to AEs
.

Ibrutinib dose was reduced in 33% of 131 patients due to grade 3-4 AEs (thrombocytopenia and anemia, fatigue and rash, hypertension)
.

Grade 3 hypertension occurred in 6% of the 131 patients, 4 of whom had new-onset hypertension requiring antihypertensive medication
.

Part A AF or flutter occurred in 4% of patients, 3 of which were new (no grade 3 or higher)
.

No patients developed ibrutinib-related grade ≥3 bleeding or atrial fibrillation
.

Part A There was 1 death after cycle 1, unrelated to treatment
.

Table 3: AEs in patients in the WINDOW-1 Study Conclusions This study shows that short-course consolidation chemotherapy with R-HyperCVAD/MA after induction therapy with ibrutinib-rituximab without chemotherapy is a viable first-line treatment option for young MCL patients
.

References Michael L Wang , Preetesh Jain , Shuangtao Zhao, et al.
Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial.
Lancet Oncol.
2022 Jan 21;S1470-2045(21)00638-0.
Reviewer: Quinta Typesetting: Quinta pokes "read the original text", we will make progress together