Ibrutinib-Based Combination Therapy Displays Superior Efficacy Vs Monotherapy in MCL

Ibrutinib-based combination therapy demonstrated a higher overall response rate and longer progression-free survival compared with ibrutinib alone in patients with relapsed/refractory mantle cell lymphoma.

Ibrutinib (Imbruvica)-based combination therapy demonstrated a higher overall response rate (ORR) and longer progression-free survival (PFS) compared with ibrutinib alone in patients with relapsed/refractory mantle cell lymphoma (MCL), according to data from a retrospective review published in Cancer Medicine.

At a median follow-up of 20.5 months, the ORR was 84.9% in patients who received ibrutinib combination therapy compared with 60.3% in patients who received ibrutinib alone (P = .003). The median PFS was 30.8 months (95% CI, 23.5-not reached) in the combination therapy arm compared with 18.5 months (95% CI, 12.1-21.8) in the monotherapy arm (HR, 0.53; 95% CI, 0.30-0.93; P = .025). Additionally, 43.4% of patients who received the combination therapy achieved complete remission (CR) compared with 16.2% of patients who received the monotherapy (P < .001).

Ibrutinib as a single agent or in combination with other agents has previously been shown to be an important treatment option for patients with relapsed/refractory MCL. Prospective phase 2 and 3 clinical trials have evaluated the efficacy of ibrutinib monotherapy, and several retrospective studies have confirmed these favorable results in patients with MCL in the United States, Europe, and South Korea. However, less is known about the efficacy of ibrutinib in Chinese patients with MCL.

This nationwide, multicenter, retrospective analysis examined the treatment patterns, efficacy, and toxicity of ibrutinib monotherapy and ibrutinib-based combination therapy in a real-world setting in Chinese patients with relapsed/refractory MCL.

This analysis included a total of 121 adult patients from 13 medical centers in China who began ibrutinib monotherapy or ibrutinib-based combination therapy between August 2017 and December 2020. Eligible patients had pathologically confirmed relapsed/refractory MCL and were at least 18 years of age.

Patients were excluded if they had been previously treated with BTK inhibitors, had participated in clinical trials related to MCL or ibrutinib, or if they were missing a response assessment after their ibrutinib treatment.

Patients were retrospectively divided into 2 groups based on the treatment they had received. Sixty-eight patients were studied in the ibrutinib-alone group, and 53 patients were studied in the ibrutinib combination group.

In the monotherapy group, patients received ibrutinib until disease progression or unacceptable activity, or until they or their physicians chose to discontinue treatment.

In the combination group, patients received ibrutinib-based combination therapy for 4 to 8 cycles and received either maintenance therapy upon achieving stable disease (SD), or next-line treatment upon experiencing disease progression. A total of 84.9% (n = 45) of patients in this group received a chemotherapy-free ibrutinib-based regimen. The most common combination therapy was ibrutinib plus rituximab (Rituxan), which 60.4% (n = 32) of this group received. The second most common combination therapy was ibrutinib plus rituximab plus lenalidomide (Revlimid), which 18.9% (n = 10) of this group received.

Of these 53 patients, 45 achieved at least SD, and 41 received subsequent maintenance therapy, including ibrutinib monotherapy (n = 29), ibrutinib plus rituximab (n = 10), rituximab (n = 1), and rituximab plus lenalidomide (n = 1).

This analysis looked at data on ORR, PFS, CR rate, time to response (TTR), duration of response (DOR), overall survival (OS), reasons for treatment discontinuation, and incidence of treatment-emergent adverse effects (TEAEs).

Of all 121 patients, the ORR was 71.1% (n = 86), the CR rate was 28.1% (n = 34), and the partial remission (PR) rate was 43.0% (n = 52).

Additional results showed 9.4% of patients in the combination group achieved SD compared with 30.9% in the monotherapy group (P = .004). Of patients from the combination group who received chemotherapy-free regimens, the ORR was 84.4%, and the CR rate was 44.4%.

The median TTR for the monotherapy group was 6.3 months (95% CI, 4.6-8.1) compared with 2.6 months (95% CI, 2.4-3.5) in the combination group. Of the 86 patients across both groups who responded to treatment, the median DOR was 14.8 months (95% CI, 11.2-22.7) in the monotherapy group; the median DOR was not reached in the combination group.

Regarding survival outcomes, the median PFS for the entire group was 21.7 months (95% CI, 15.2-26.6). The median OS was 37.6 months (25.4 months-not estimable [NE]).

PFS benefit was evaluated in various subgroups, and statistically significant benefit was observed in patients of male gender without refractory disease and a Ki67 score of less than 30% who had received 1 previous line of therapy, had a non-blastoid subtype, and had less than 2 extranodal sites involved.

Although the combination group displayed a superior PFS compared with the monotherapy group, no OS benefit was observed in the combination group. The median OS for the combination group was not reached (95% CI, 20.6-NE) vs 28.2 months (21.5-NE) in the monotherapy group (HR, 0.77; 95% CI, 0.39-1.55; P = .430).

At the last follow-up, 67 patients across both cohorts had discontinued ibrutinib. The most common reason for discontinuation was disease progression (n = 50), followed by adverse effects (AEs), which included pulmonary infection (n = 2), bleeding (n = 3), second malignancies (n = 3), and ventricular premature contractions and palpitations (n = 1). Physician or patient decision led to 4 patients discontinuing treatment, 3 patients discontinued for unknown reasons, and 1 MCL-unrelated death occurred.

Treatment-emergent AEs were investigated in 105 patients. The combination group had a higher incidence of all-grade neutropenia than the monotherapy group (32.0% vs 12.7%; P = .017), although this AE was manageable and not a cause for treatment discontinuation. The 2 groups showed no other significant differences in all-grade or grade 3 or 4 TEAEs.

Most patients experienced mild to moderate AEs, and no new safety signals arose in this study from ibrutinib treatment. A total of 4 patients experienced major bleeding events, including central nervous system hemorrhage (n = 2), grade 3 subcutaneous hemorrhage (n = 1), and grade 3 gastrointestinal hemorrhage (n = 1).

After ibrutinib treatment, 2 patients from each group experienced newly diagnosed secondary malignancies, including acute myeloid leukemia, nasopharyngeal carcinoma, colorectal carcinoma, and myelodysplastic syndrome. All 4 of these patients had received cyclophosphamide, anthracycline, vincristine, and prednisone-based chemotherapy before beginning ibrutinib treatment. Those who received a secondary diagnosis of nasopharyngeal carcinoma had previously received autologous stem cell transplantation (ASCT).

Further research is needed to determine whether the clinical efficacy of ibrutinib differs across patients of various ethnicities, as MCL disease characteristics vary widely in patients from different regions and ethnic backgrounds. Future investigation may also consider whether medical center-related factors such as economic level, supportive care availability, toxicity surveillance, and patients’ medical compliance affects ibrutinib efficacy levels.


Zhang Y, Liu P, Cai J, et al. Ibrutinib as monotherapy versus combination therapy in Chinese patients with relapsed/refractory mantle cell lymphoma: a multicenter study. Cancer Med. Published online April 19, 2022. doi:10.1002/cam4.4765

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