Ibrutinib Demonstrates Real-world ORR Benefit in Relapsed/Refractory MCL

Ales Obr, MD, PhD

Ibrutinib (Imbruvica) therapy remains an effective treatment, particularly in the second line, in patients with relapsed/refractory mantle cell lymphoma (MCL), according to findings from a retrospective analysis conducted as part of the Observational Epidemiological and Clinical Study (NCT03199066).

After a median follow-up of 14.0 months (range, 1.3-92.0), ibrutinib elicited an overall response rate (ORR) of 66% (n = 47), with 31% (n = 22), 35% (n = 25), and 35% (n = 25) of patients achieving a complete metabolic remission (CMR), partial metabolic remission (PMR), or stable/partial disease, respectively, on PET/CT.

“We confirmed good efficacy of ibrutinib in unselected, heavily pretreated [patients with] MCL,” lead study author, Ales Obr, MD, PhD, of Palacky University and University Hospital in Olomouc, Czech Republic, and colleagues, wrote.

Patients were eligible for inclusion in this study if they were at least 18 years at diagnosis, had an ECOG performance status of 0 to 2, had received at least 1 prior systemic anti-lymphoma therapy in the form of immunotherapy plus chemotherapy, had received ibrutinib for at least 1 day, and began ibrutinib treatment by July 2020.

This real-world analysis evaluated 77 patients from 5 university centers in the Czech Republic who were diagnosed with relapsed/refractory MCL between November 1997 and December 2019 and had received ibrutinib and at least 1 prior systemic anti-lymphoma therapy. Of these patients, 11 were treated in the phase 3 RAY (NCT01646021) and SYMPATICO (NCT03112174) trials.

The median age at diagnosis was 68 years (range, 40-81), and the median age at the initiation of ibrutinib treatment was 70 years (range, 42-82). In total, 78% (n = 60) of patients were male.

All but 2 patients received rituximab (Rituxan)–containing regimens in the first line. First-line treatments included CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens (54%; n = 42), high-dose cytarabine regimens (33%; n = 25), non-anthracycline regimens (13%; n = 10); autologous stem cell transplant (25%; n = 19), and rituximab maintenance (53%; n = 41). Patients received a median of 2 lines of therapy (range, 1-8) prior to ibrutinib. The investigators evaluated ibrutinib response at a median of 3 months (range, 1.3-28.2) from therapy initiation.

Of the 73 patients with available data, 66% (n = 48) had bone marrow involvement at the time of diagnosis. Of those 48 patients, 56% (n = 27) had bone marrow involvement at ibrutinib initiation. A total of 20 patients with detectable bone marrow involvement before ibrutinib initiation who achieved CMR (n = 13) or PMR (n = 7) had bone marrow reassessment on ibrutinib.

No patients achieved MCL remission in the bone marrow. In total, 30% of patients with bone marrow involvement (n = 6) had reduced MCL load in the bone marrow, 35% (n = 7) had stable bone marrow involvement, and 35% had a significantly increased MCL load in the bone marrow while achieving CMR or PMR. Additionally, 2 patients with no detectable bone marrow involvement before ibrutinib initiation had isolated progressed in the bone marrow while achieving CMR. One of these patients subsequently received rituximab added to ibrutinib, which eradicated the MCL cells in their bone marrow within 4 weekly doses of rituximab.

After median follow-up, 56 patients had relapsed or progressed on ibrutinib, and 45 had died. The median progression-free survival (PFS) and overall survival (OS) was 10.3 months (range, 1.2-66.0) and 23.1 months (range, 1.2-82.5), respectively. The median OS was 28.8 months (95% CI, 24.2-45.2) in the patients who responded vs 8.3 months (95% CI, 4.3-11.2) in the patients who did not respond (P < .005). The median OS of the patients who did not relapse on ibrutinib was not reached, and the median OS of the patients who relapsed or progressed on ibrutinib was 12.6 months (95% CI, 8.7-24.2; P < .005).

Univariate and multivariate analyses found that at 12, 24, and 36 months after MCL diagnosis, disease progression negatively correlated with OS (HR, 2.99, 2.87, and 2.08, respectively; P < .05). Disease progression at these time points did not correlate with survival at 12, 24, and 36 months, after ibrutinib initiation (HR, 1.53, 1,42, and 0.99, respectively).

These analyses also found that Ki67 proliferation of at least 30% (68%; n = 27) was associated with shorter OS from ibrutinib initiation, at 12.0 months (95% CI, 4.8-12.6) vs 58.1 months (95% CI, 26.8-58.1) in patients with Ki67 proliferation less than 30% (HR, 2.20; 95% CI, 1.00-4.82; P = .04). Additionally, patients who received 1 line of therapy prior to ibrutinib had a significantly longer OS than those with 2 or more prior lines, at 36.1 months (95% CI, 32.3-52.5) vs 12.6 months (95% CI, 8.7-24.2; P = .03). Female gender also correlated with longer OS from ibrutinib initiation, at 52.5 months (95% CI, 12.0-64.2) vs 18.2 months (95% CI, 9.6-26.4) in males, although this finding was not statistically significant (HR, 0.53; 95% CI, 0.29-0.98; P = .076).

Before the database lock, 73% of patients (n = 56) discontinued ibrutinib because of progression or relapse, 4 discontinued because of toxicity, 1 discontinued at their own request, and 1 discontinued for unknown reasons.

The median PFS in patients who relapsed or progressed on ibrutinib after achieving CMR or PMR was 4.9 months (range, 1.2-54.5), and the median OS from ibrutinib failure was 3.7 months (range, 0-5.8). A total of 42 patients received best supportive or palliative therapy, including bortezomib (Velcade), lenalidomide (Revlimid), temsirolimus (Torisel), or immunotherapy plus chemotherapy and succumbed to refractory MCL. Of the 11 patients who relapsed or progressed on ibrutinib and were still alive at the database lock, 5 received R-BAC500 (rituximab, bendamustine, and cytarabine), 2 received venetoclax (Venclexta) monotherapy, and 1 each received bortezomib plus rituximab, single-agent lenalidomide, bendamustine plus rituximab, and palliative immunotherapy plus chemotherapy. Two patients were prepared for allogeneic stem cell transplantation, which 1 patient successfully received.

“Prognosis of the patients after ibrutinib failure was extremely poor regardless of the number of previous lines of therapy,” the study authors concluded. “[However,] our findings support the use of a combination of ibrutinib and rituximab in patients with bone marrow involvement.”

Reference

Obr A, Benesova K, Janikova A, et al. Ibrutinib in mantle cell lymphoma: a real-world retrospective multi-center analysis of 77 patients treated in the Czech Republic. Ann Hematol. Published online November 11, 2022. doi:10.1007/s00277-022-05023-2