Retrospective Data Show BTK Inhibitors May Be Optimal Second-Line Approach in Late-Relapse Mantle Cell Lymphoma

Data from the retrospective LATE-POD trial showed that patients with mantle cell lymphoma (MCL) with late progression of disease (POD) more than 24 months removed from diagnosis derived more benefit from a BTK inhibitor–based regimen in the second line compared with chemoimmunotherapy.

The findings, which were published in Blood, revealed that patients treated with a BTK inhibitor after late POD (n = 114) experienced a median time to second progression (PFS2) that was not reached (NR) compared with 26 months (95% CI, 20-35) for those treated with chemoimmunotherapy (n = 271; P = .0003). Additionally, the median overall survival from the initiation of second-line therapy (OS2) was NR in the BTK inhibitor arm vs 56 months (95% CI, 43-69) for the chemoimmunotherapy arm (P = .04).

Notably, the median follow-up for the chemoimmunotherapy arm was 64 months (range, 3-144) compared with 34 months (range, 1-85) for the BTK inhibitor arm (P = .001), which lead study author Chiara Malinverni, MD, and colleagues, explained reflected a recent shift toward the use of BTK inhibitors in MCL. Malinverni is a member of the Department of Engineering for Innovation Medicine in the Section of Hematology at the University of Verona in Italy.

“To our knowledge, this study represents the first report comparing chemoimmunotherapy with targeted therapy in patients with MCL experiencing late first relapse,” the study authors wrote. “The hypothesis formulated by the study was met, with BTK inhibitors proving superior to chemoimmunotherapy as second-line therapy in patients with late POD, thus confirming the observations already reported in [patients with] early POD.”

In the multicenter, historical cohort, mixed-design LATE-POD study, investigators gathered data on patients with relapsed/refractory MCL who experienced late POD and received treatment at 30 centers affiliated with Fondazione Italiana Linfomi, along with 9 more cancer centers in the European MCL Network. The study included patients diagnosed between January 2008 and June 2019 who experienced first disease recurrence at least 24 months after initial diagnosis; received up-front intensive therapy; and were treated at the time of relapse with at least 1 cycle of chemoimmunotherapy, a BTK inhibitor, or alternative drug combinations. Patients were only included if they were not observed for more than 3 months after initial diagnosis to avoid cases of indolent clinical behavior. Patients who received a BTK inhibitor in the first-line setting or had central nervous system involvement were excluded.

All patients included in the retrospective study had received first-line treatment with regimens containing rituximab (Rituxan) and high-dose cytarabine. Patients were then divided into groups based on the type of second-line therapy they received: a BTK inhibitor or chemoimmunotherapy. In the BTK inhibitor group, 99% of patients received second-line ibrutinib (Imbruvica). Patients in the chemoimmunotherapy group were administered bendamustine plus rituximab (BR; n = 101), BR plus cytarabine (n = 70), and other rituximab-based treatments (n = 100).

The study’s primary end point was PFS2, and OS2 served as a secondary end point.

In the BTK inhibitor and chemoimmunotherapy populations, the median age was 57 years (range, 19-70) and 59 years (range, 35-70), respectively. The majority of patients in the respective arms were male (75%; 76%) and from Italy (54%; 51%). Patients in the BTK inhibitor arm had a MCL International Prognostic Index score of low (42%), intermediate (39%), or high (19%); these respective rates were 39%, 25%, and 26% in the chemoimmunotherapy arm. In the BTK inhibitor arm, 11% of patients had blastoid/pleomorphic histology, 38% had a Ki-67 level of at least 30%, and 17% harbored TP53 mutations; these rates were 12%, 47%, and 14%, respectively, in the chemoimmunotherapy arm.

The median time to POD in the first-line setting was 48 months (range, 24-145) in the BTK inhibitor arm and 48 months (range, 24-165) in the chemoimmunotherapy arm. Frontline treatment regimens included RHyperCVAD/MTXHDAC (fractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone alternated with high-dose methotrexate and cytarabine; BTK inhibitor arm, 13%; chemoimmunotherapy arm, 24%), R-CHOP/DHAP+ (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone alternated with cisplatin, cytarabine, and dexamethasone) and autologous stem cell transplant (ASCT; 36%; 14%), and Nordic/R-HDS (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone alternated with rituximab and high-dose cytarabine, followed by ASCT; 51%; 62%).

Six percent of all patients included in the study underwent ASCT consolidation, and 19% of patients received allogeneic stem cell transplant at second (n = 60) or later (n = 12) remissions.

“Given that this was not a randomized study, clinical or pathological differences in distribution of patients between the chemoimmunotherapy and the BTK inhibitor groups were expected, but…[no differences] were statistically significant,” study authors noted.

Findings for the whole study population, irrespective of second-line therapy, showed that a median follow-up of 53 months (range, 1-144), the median PFS2 was 33 months (95% CI, 26-36), and the median OS2 was 60 months (95% CI, 51-72).

Additional findings showed that second-line BTK inhibitors and BR plus cytarabine were associated with similar PFS2 and OS2 outcomes; however, BR alone and other chemoimmunotherapy regimens were associated with significantly worse PFS2 (P = .0003) and OS2 (P =.018).

Data from a multivariate analysis demonstrated that advanced age (HR for PFS2, 1.04 [95% CI, 1.02-1.06]; HR for OS2, 1.03 [95% CI, 1.02-1.06]) and blastoid morphology (HR for PFS2, 1.57 [95% CI, 1.02-2.48]; HR for OS2, 2.20 [95% CI, 1.42-3.41]) were independent predictive factors associated with impaired survival. However, a longer time to POD (HR for PFS2, 0.99 [95% CI, 0.98-0.99]; HR for OS2, 0.98 [95% CI, 0.97-0.99]) and second-line BTK inhibitor use (HR for PFS2, 0.44; HR for OS2, 0.59) were independently associated with superior survival. Male patients had significantly worse PFS2 (HR, 1.84; 1.25-2.72). Moreover, BR plus cytarabine was linked with improved PFS2 (HR, 0.51; 95% CI, 0.33-0.77) but not OS2 (HR, 0.68; 95% CI, 0.43-1.06).

Since time to POD was found to be an independent predictor of both PFS2 and OS2, investigators also delved into the effect of longer POD on OS2. A POD of 36 months (P < .0001) and 48 months (P = .02) both remained prognostic; however, a POD of 60 months was not prognostic (P = .51). For patients treated with second-line BTK inhibitors, the 36-month POD cutoff remained prognostic for OS2 (P = .04), but no differences were observed for a POD of 48 or 60 months.

OS from time of second relapse (OS3) was also examined in evaluable patients (n = 206). In this population, third-line treatment included a BTK inhibitor (40%), BR (10%), BR plus cytarabine (10%), and other therapies (40%). An OS3 benefit was observed with BTK inhibitors vs chemoimmunotherapy (P = .004).

“[The OS3] effect was identified when [a] BTK inhibitor was administered as third-line treatment, confirming the importance of BTK inhibitors in the treatment journey of patients with MCL,” study authors wrote.

The authors concluded by noting that the study may have been limited by a lack of central pathological review to address tumor morphology. They added that the retrospective format could have created selection and treatment bias in patient enrollment from different centers and countries.

Reference

Malinverni C, Bernardelli A, Glimelius I, et al. Outcomes of younger patients with mantle cell lymphoma experiencing late relapse (>24 months): the LATE-POD study. Blood. 2024;144(9):1001-1009. doi:10.1182/blood.2023023525