Frontline Ibrutinib/Rituximab Produced Meaningful Response Rates in Indolent MCL

Mantle Cell Lymphoma

The combination of ibrutinib (Imbruvica) plus rituximab (Rituxan) generated a high rate of complete response (CR) and undetectable minimal residual disease (MRD) when used in the frontline treatment of patients with indolent clinical forms of mantle cell lymphoma (MCL), allowing for treatment interruption in most responders, according to data from the phase 2 IMCL-2015 trial (NCT02682641) published in the Journal of Clinical Oncology.¹

Results showed that after 12 cycles of treatment with the combination, the overall response rate (ORR) of 84% (95% CI, 74%-94%) in evaluable patients with MCL (n = 50), with 80% of patients achieving a CR (95% CI, 69%-91%), meeting the primary end point of the trial. No clinical or biologic variables, including MCL International Prognostic Index (MIPI), β2-microglobulin, molecular subtypes, TP53 mutational status, or high genomic complexity, predicted CR achievement at 12 months.

Additionally, 87% (95% CI, 77%-97%) of 46 evaluable patients achieved undetectable MRD in the peripheral blood, and 65% (95% CI, 51%-78%) of 43 evaluable patients achieved it in the bone marrow. Among the 40 patients who achieved a CR with the combination, MRD was found to be undetectable in the peripheral blood in 93% (95% CI, 86%-100%) of 40 patients, and undetectable in the bone marrow in 70% (95% CI, 55%-85%) of 85 patients.

Notably, at 2 years, 24 of 35 evaluable patients (69%) were able to discontinue ibrutinib because response with sustained undetectable MRD was observed after cycle 24.

“The IMCL-2015 study has shown the high activity, in terms of CR and undetectable MRD, of the up-front ibrutinib/rituximab combination in indolent clinical forms of MCL following a MRD-driven approach to limit the extent of treatment,” lead study author Eva Giné, MD, of Hospital Clínic de Barcelona, Barcelona, Spain, and colleagues, wrote. “The duration of molecular and clinical responses after ibrutinib discontinuation will be a key aspect to define the final role of such individualized approaches. Some patients, particularly those with a TP53mutation, may not be good candidates for treatment discontinuation, even in the case of molecular response.”

Although MCL is typically an aggressive lymphoid neoplasm, some patients with indolent disease can experience long survival times even without intensive therapy.2 Leukemic non-nodal is mainly characterized by splenomegaly and leukemic involvement without a significant enlargement of lymph nodes. There is currently no consensus on how to define those with indolent disease, nor how to optimally manage them.3Chemotherapy-free options are under extensive exploration in both the frontline and later-line settings. Because MRD has been shown to have encouraging prognostic value in trials evaluating chemoimmunotherapy regimens, there is a need to explore this marker in relation to targeted therapies for MCL.

To this end, IMCL-2015 trial investigators sought to examine the combination of ibrutinib and rituximab as a frontline treatment in patients with indolent MCL and leverage a MRD-driven strategy to limit treatment duration.

For the trial, the Spanish Lymphoma Group (GELTAMO [Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea]) identified and enrolled patients who were 18 years of age or older who had a confirmed MCL diagnosis according to World Health Organization diagnosis, excluding blastoid variants and/or a Ki-67 greater than 30%, who were asymptomatic, and who had an ECOG performance status of 0 or 1.

Other eligibility criteria included having leukemic non-nodal forms, but also other clinical presentations, if the largest diameter of the lymph nodes did not exceed 3 cm. Stable disease for at least 3 months with no signs of disease progression or immediate need was also required.

Study participants received 4 weekly doses of intravenous (IV) rituximab at 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, followed by 4 more doses on day 1 of cycles 3, 5, 7, and 9, for a total of 8 doses. Oral ibrutinib was administered at a fixed continuous dose of 560 mg once daily; the agent was discontinued at 2 years of treatment if undetectable MRD was sustained for at least 6 months at 2 consecutive determinations. Otherwise, ibrutinib was continued until disease progression or intolerable toxicity.

The primary end point of the trial was CR rate at 12 months of treatment, following the completion of cycle 12, per Lugano criteria in the intention-to-treat population. Key secondary end points included safety and tolerability, ORR and the rate of detectable MRD, progression-free survival (PFS), duration of response (DOR), and overall survival (OS).

The median age of enrolled patients was 65 (range, 40-85), 66% were male, and all had an ECOG performance status of 0 or 1. The median spleen size was 13 cm (range, 9-29), and the median longest diameter of lymph node size was 21 mm (range, 13-43), although 22% of patients had no enlargement. Furthermore, 88% of patients had bone marrow involvement, 94% had Ann Arbor stage III or IV disease, 90% had peripheral blood involvement by flow cytometry, 6% had hemoglobin of less than 100 g/L, 8% had a platelet count of less than 100 x 109/L, 8% had serum lactate dehydrogenase above the upper limit of normal (ULN), and 49% had serum B2-microglobulin above the ULN. Additionally, 38% of patients were high risk, 38% were intermediate risk, and 24% were low risk.

Additional data showed that in patients with TP53 wild-type MCL (n = 35), the ORR was 89% with a CR rate of 83%. Additionally, 8% had stable disease, and 0% had disease progression. Furthermore, those with TP53-mutant disease (n = 6) had an ORR of 83% with a CR rate of 83%. None of those patients had stable disease, and 17% had disease progression.

At a median follow-up of 36 months in surviving patients, the PFS rate was 93% (95% CI, 86%-100%), and the 36-month OS rate was 92% (95% CI, 84%-100%). Notably, only MIPI and TP53 mutational status was shown to have a significant impact on PFS and OS.

Clinical progression was observed in 3 patients with TP53 mutations, with a median PFS of 38.5 months (95% CI, 37-39) vs not reached (NR) for TP53 wild-type cases; P = .0001). Three TP53-mutated patients died, including 2 due to disease progression and 1 from SARS-CoV-2 infection, though that patient had detectable MRD. The median OS of 38.5 months (95% CI, 37 to 39) for patients with TP53-mutated MCL was significantly lower than what was seen in patients with TP53 wild-type disease, which was not reached (P = .0002).

The most common treatment-related adverse effects (AEs) were diarrhea (38%), neutropenia (36%), fatigue (32%), upper respiratory infection (24%), nausea (22%), and arterial hypertension (20%). The most common grade 3 or 4 AEs were hematologic toxicities (22%), including neutropenia (grade 3, 16%; grade 4, 6%) and thrombocytopenia (grade 4, 2%). No grade 4 or higher nonhematologic AEs were observed, and grade 3 AEs of hypertension, arthralgia, skin infection, alanine aminotransferase increase, and abdominal pain were all experienced in 2% of patients each.

Four patients had early discontinuation between 1.6 and 5.5 months of ongoing treatment because of severe aplastic anemia, accidental vertebral fractures, skin rash, and withdrawal of consent because of treatment intolerance. Additionally, 37 patients reached 24 cycles of ibrutinib. Two additional patients discontinued the trial because of disease progression and pancreatic adenocarcinoma, respectively, and seven had not yet reached 24 cycles of therapy.

“Future randomized studies are guaranteed to explore the final role of targeted therapies in the frontline treatment of patients with MCL,” the study authors concluded.

References

1. Giné E, de la Cruz F, Ubieto AJ, 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. Published online January 14, 2022. doi:10.1200/JCO.21.02321
2. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the world health organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–2390. doi:10.1182/blood-2016-01-643569
3. Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009;27(8):1209-1213. doi:10.1200/JCO.2008.19.6121