Ibrutinib combined with rituximab is expected to be an effective first-line treatment option for indolent MCL

Mantle cell lymphoma (MCL) is generally considered an aggressive lymphoma, but a rare subset of patients exhibit an indolent clinical course and prolonged survival even without intensive therapy
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In the past two decades, multiple studies have shown the existence of a subtype of leukemia rather than lymph node MCL (nnMCL)
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These patients often have specific biological characteristics
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From a clinical point of view, asymptomatic patients with indolent MCL can choose to watch and wait until disease progression before starting treatment
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However, there is no consensus on how to define these indolent MCL patients and how to manage them
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With the introduction of targeted drugs, the treatment of MCL has developed rapidly in the past few years
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Combination therapy of targeted drugs with immunochemotherapy or other targeted drugs without chemotherapy is currently being explored in patients with relapsed or refractory MCL (R/R MCL) and newly diagnosed MCL
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Based on this, we conducted the IMCL-2015 study, which aimed to limit the duration of MCL treatment through a minimal residual disease (MRD)-driven approach, to evaluate ibrutinib in combination with rituximab (IR) as indolent MCL Feasibility of upfront treatment in patients
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Study Methods We conducted an open-label, multicenter, single-arm, phase II clinical study in untreated patients with indolent MCL
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Eligible patients were screened in 12 research centers, and the key inclusion criteria were: age ≥18 years; MCL diagnosed according to WHO diagnosis, excluding embryoid variants and/or Ki-67>30%; no prior anti-MCL therapy ; No obvious symptoms, and ECOG score of 0 or 1
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Patients received rituximab 375 mg/m2 intravenously on days 1, 8, 15, and 22 of the first cycle for 2 cycles of 28 days
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Ibrutinib was administered orally at a fixed continuous dose of 560 mg once daily and discontinued after 2 years of treatment if persistently undetectable MRD (uMRD) occurred until disease progression or intolerable toxicity
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The primary endpoint was the complete response (CR) rate in the intention-to-treat population for patients who completed 12 months of standard therapy
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Secondary endpoints included safety and tolerability of IR combination therapy, overall response (ORR) and uMRD rates, progression-free survival (PFS), duration of response (DOR) and overall survival (OS)
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Findings 1 Patient Characteristics The study enrolled 50 patients with untreated indolent MCL who received IR combination therapy at 12 medical centers from June 7, 2016 to December 10, 2019
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Patient baseline characteristics are summarized in Table 1, and the median time from diagnosis to treatment was 7.
9 months
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The histological, genetic, and molecular data of the 49 available patients are detailed in Table 2
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Among patients with clinical manifestations of leukemia, with or without splenomegaly or small lymph nodes, 68% had features of nnMCL
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The patient study process is shown in Figure 1
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The data cutoff date is May 28, 2021.
The first phase of the study completed the recruitment of 15 patients in April 2017.
When 6 patients achieved CR without early discontinuation, the recruitment of 50 patients who completed the original plan continued.

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Forty-three patients received eight expected doses of rituximab, and seven patients received only four to seven doses of rituximab
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Six patients underwent ibrutinib dose reduction and 4 patients discontinued early; at 1 year, 46 patients were still receiving ibrutinib
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Table 1: Baseline profile of patients in the IMCL-2015 studyTable 2: Histological, genetic, and molecular characteristics of the 49 patients with MCL in the IMCL-2015 study for which data are availableFigure 1: The IMCL-2015 study flow chart After 12 cycles of treatment in the study patients, 46 patients were evaluable for efficacy, and the remaining 4 patients discontinued early during 1.
6 to 5.
5 months of continuous treatment
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Overall, the ORR for all patients was 84% ​​(95% CI, 74-94%) and the CR rate was 80% (95% CI, 69-91%)
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The response rates for subgroup analysis of patients according to molecular subtype and TP53 mutation status are shown in Table 3
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After 12 months of completion of standard therapy in 46 evaluable patients, the uMRD rate was 87% (95% CI, 77-97%) in PB and 65% (95% CI, 51-78%) in BM
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Table 3: Response 12 months after completion of standard therapy, according to patient molecular subtype (nnMCL or cMCL) and TP53 mutation status Detection of MRD
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After a median follow-up of 36 months in surviving patients, the estimated PFS rate at 36 months was 93% (95% CI, 86-100%; Figure 2A)
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Only MIPI and TP53 mutation status were factors affecting patients' PFS, while different molecular subtypes (nnMCL vs cMCL), genomic complexity (Figure 2B-2E), or MRD status at 12 months of completion of standard therapy had no effect on patients' PFS
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The patient event-free survival (EFS) rate at 36 months was 76% (95% CI, 64-89%; Figure 2A)
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The OS rate for patients at 36 months was 92% (95% CI, 84-100%; Figure 2A)
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MIPI and TP53 mutation status are also factors that affect patient OS
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A total of 6 patients with TP53 mutation were included in this study, 5 patients achieved CR after treatment, 4 patients achieved uMRD, and 2 patients discontinued ibrutinib according to the protocol
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All but 1 patient eventually had MRD converted to detectable; clinical disease progression was observed in 3 patients
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The median PFS in patients with and without TP53 mutation was 38.
5 months (95% CI, 37-39%) vs not achieved (P = 0.
0001; Figure 2C)
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The median OS of TP53 mutant patients was significantly lower than that of TP53 wild-type patients (P=0.
0002)
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Figure 2: Survival 4 Patient Safety in the IMCL-2015 Study The most common treatment-related adverse events (TRAEs) for patients in this study were diarrhea (38%), neutropenia (36%), fatigue (32%) %), upper respiratory tract infection (24%), nausea (22%), and arterial hypertension (20%) (see Table 4 for details)
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Grade ≥3-4 AEs were predominantly hematologic (22%)
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Table 4: Conclusions of treatment-related AEs in patients from the IMCL-2015 study This study demonstrated that, in indolent MCL, the combination of upfront IR had excellent efficacy in CR and uMRD after MRD monitoring was used to drive time-limited treatment
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References: Eva Giné, Fátima de la Cruz, Ana Jiménez Ubieto, et al.
Ibrutinib in Combination With Rituximab for Indolent Clinical Forms of Mantle Cell Lymphoma (IMCL-2015): A Multicenter, Open-Label, Single-Arm, Phase II Trial.
J Clin Oncol.
2022 Jan 14; JCO2102321.
Reviewer: Quinta Typesetting: Wenting Execution: Wenting pokes "read the original text", we make progress together