BTK Inhibitor Failure Signals Unmet Need for a Standard of Care in Relapsed/Refractory MCL

Georg Hess, MD

Improved mantle cell lymphoma (MCL) treatments are necessary for patients who have relapsed on or are refractory to BTK inhibitors, according to findings from SCHOLAR-2, a multicenter, retrospective chart review of European patients with MCL who relapsed following or were intolerant to BTK inhibitors.

In the overall patient cohort (n = 240), the median overall survival (OS) from the initiation of BTK inhibitors was 14.6 months (95% CI, 11.6-20.0). Specifically, the median OS was 5.5 months (95% CI, 3.9-8.2) in the 91 patients who did not receive post–BTK inhibitor therapy and 23.8 months (95% CI, 18.9-30.1) in the 149 patients who did receive post­­–BTK inhibitor therapy. After a median follow-up of 27.3 months, the median OS from the initiation of post–BTK inhibitor therapy was 9.7 months (95% CI, 6.3-12.7), and the 1- and 2-year estimated OS rates were 43.4% and 27.2%, respectively.

“These results provide a benchmark for survival in patients with relapsed/refractory MCL receiving salvage therapy after BTK inhibitor failure,” lead study author, Georg Hess, MD, of the Johannes Gutenberg University in Mainz, Germany, and colleagues, wrote.

This observational, international chart review collected data from patients at least 18 years of age with relapsed/refractory MCL who were treated with BTK inhibitor–based therapy between July 2012 and July 2018 and progressed while on the therapy or discontinued the therapy because of intolerance. Patients with a history of or current central nervous system manifestation were excluded, as were those who had received a genetically modified T-cell therapy such as CAR T-cell therapy.

The primary end point of this study was OS. Key secondary end points were patient demographics, disease characteristics, and treatment patterns.

The investigators summarized patient characteristics at initial MCL diagnosis for the 226 patients with an available diagnosis date. Of this population, the median age was 68 years (range, 39-92), 74.8% were male, 81.5% had stage IV disease, 88.3% had an ECOG performance status (PS) of 0 or 1, 11.7% had an ECOG PS of 2 or higher, 72.6% had bone marrow involvement, and 92.2% had cyclin D1 or translocation (11;14) overexpression. Additionally, 25.2% had blastoid morphology, 28.5% had B symptoms, 58.5% had Ki-67 proliferation over 30%, 35.1% had Ki-67 proliferation over 50%, 8.4% had bulky disease of at least 10 cm, 44.1% had splenic involvement, and 27.4% had extranodal disease.

At the initiation of post–BTK inhibitor therapy, a higher proportion of the patients in this cohort had an ECOG PS of 2 or higher (35.2%), blastoid morphology (37.0%), Ki-67 proliferation of over 30% (77.3%) and over 50% (59.1%) and bulky disease (19.0%) vs the overall population at initial MCL diagnosis. This population also had a lower proportion of patients with stage IV disease (70.3%) and bone marrow involvement (45.0%) than the overall population at initial diagnosis. The median age of these patients was 71.0 years (range, 43.0-91.0).

In total, 33.6% of patients (n = 50) had prior autologous or allogeneic stem cell transplantation. The median number of prior lines of therapy including a BTK inhibitor was 3 (range, 1-11), and the median duration of prior BTK inhibitor therapy was 7.1 months (range, 0.4-53.7). Common reasons for BTK inhibitor discontinuation were disease progression while on therapy (85.2%; n = 127) and intolerance (14.8%; n = 22).

The cohort of patients who received post–BTK inhibitor therapy had a median of 1 line (range, 1-7) of this therapy. The most common subsequent treatments following BTK inhibitor discontinuation were lenalidomide (Revlimid)–containing regimens (17.4%) and bendamustine plus rituximab (BR; 16.8%).

At the time of data collection, patients had received a median of 4 lines of MCL therapy (range, 2-12), with 85.4%, 60.8%, and 39.2% receiving further treatments in the third, fourth, and fifth or later lines, respectively. In total, 97.1% of patients received first-line chemotherapy with or without antibodies. Additionally, prior to the BTK inhibitor, 38.1% had received BR, 51.7% had received cytarabine-containing regimens, and 58.9% had received other chemotherapy with or without antibodies.

In total, 93.8% received 1 line of a BTK inhibitor, 5.8% received 2 lines, and 1 patient received 3 lines. Of these, 1.7% received a BTK inhibitor in the first line, and 35.4% and 28.3% received their first BTK inhibitor in the second and third lines, respectively. Additionally, 16.7%, 12.1%, and 5.8% received their first BTK inhibitor in the fourth, fifth, or later lines, respectively. These first BTK inhibitor regimens included ibrutinib (Imbruvica) monotherapy (87.1%), ibrutinib combinations (10.4%), and acalabrutinib (Calquence) monotherapy (2.5%).

The best objective response rate to BTK inhibitors was 34.6% (n = 46/133), including 16 complete and 30 partial responses in evaluable patients.

After stopping BTK inhibitors, 37.9% of patients (n = 91) who had received their first BTK inhibitor in the second (36.3%), third (26.4%), and later (37.4%) lines received no further systemic anti-lymphoma therapy.

In the subgroup of patients who did not receive post–BTK inhibitor therapy, 73.6% had discontinued BTK inhibitors because of disease progression, and 26.4% had discontinued BTK inhibitors because of intolerance, after a median treatment duration of 3.8 months (range, 0.1-55.2).

Of the patients who received further systemic anti-lymphoma therapy, 2.7%, 34.9%, 29.5%, and 32.9% had received their first BTK inhibitor in the first, second, third, or later lines, respectively. In total, 61.7%, 16.8%, and 14.8% of these patients received 1, 2, and 3 post–BTK inhibitor treatments, respectively.

At the time of data collection, 80.0% of patients (n = 192) in the overall cohort had died, including 71.1% (n = 106) of those who had received post–BTK inhibitor treatments. Of the patients with an initial MCL diagnosis date, the median OS from initial diagnosis was 64.5 months (95% CI, 51.7-78.5). At 1, 2, and 5 years after diagnosis, the estimated OS rates were 93.3%, 78.3%, and 53.8%, respectively.

The estimated OS rates at 1 year from the start of BTK inhibitors were 69.1% in the patients who received post­–BTK inhibitor therapy and 34.4% in those who did not. The estimated OS rates at 2 years were 50.0% and 17.2%, respectively.

The median OS from the discontinuation of the first BTK inhibitor was 4.0 months (95% CI, 2.8-7.4; n = 238), 0.4 months (95% CI, 0.2-0.7; n = 90), and 11.4 months (95% CI, 7.9-14.7; n = 148) in the overall cohort, the subgroup without post–BTK inhibitor therapy, and the subgroup with post–BTK inhibitor therapy, respectively.

Of the patients who received post–BTK inhibitor therapy, the median OS in patients with 1 to 2, 3, or 4 or more prior lines of therapy was 12.3 months (95% CI, 7.4-17.6), 10.3 months (95% CI, 3.8-15.8), and 7.7 months (95% CI, 4.3-11.7), respectively.

The investigators conducted a landmark OS analysis from first BTK inhibitor discontinuation to account for potential immortal time bias. The landmark time was 11 days, which represented the median time from BTK inhibitor discontinuation to the initiation of post–BTK inhibitor therapy. Any patients who died prior to this time or were lost to follow-up were excluded. In this analysis, the median OS among patients who did not receive post–BTK inhibitor therapy increased to 1.3 months, and the median survival among patients who did receive post–BTK inhibitor therapy changed to 11.1 months.

“This cohort of BKT inhibitor–treated patients with relapsed/refractory MCL across multiple European centers confirms the urgent unmet need for new treatment options that can improve survival in patients with relapsed/refractory MCL who relapse after receiving BTK inhibitors or who are intolerant to BTK inhibitor therapies,” the study authors concluded.

Reference

1. Hess G, Dreyling M, Oberic L, et al. Real-world experience among patients with relapsed/refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor failure in Europe: the SCHOLAR-2 retrospective chart review study. Br J Haematol. Published online October 18, 2022. doi:10.1111/bjh.18519