Frontline BTK Inhibitors Improve OS in Real-World Patients with MCL

The use of BTK inhibitors as a frontline treatment improved overall survival vs their deployment in subsequent lines of therapy in patients with mantle cell lymphoma, according to a real-world study (IRB-300004501) published in Blood Advances.

The use of BTK inhibitors as a frontline treatment improved overall survival (OS) vs their deployment in subsequent lines of therapy in patients with mantle cell lymphoma (MCL), according to a real-world study (IRB-300004501) published in Blood Advances.1 Additionally, the presence of 17p deletions or TP53 mutations did not reduce OS in patients administered BTK inhibitors.

Among 1076 analyzed patients with MCL who received BTK inhibitors, the median OS was 23 months (95% CI, 21-27). However, the use of BTK inhibitors in the frontline setting elicited a median OS of 35 months (95% CI, 27-50), compared with 24 months (95% CI, 22-30) in the second-line setting and 18 months (95% CI, 14-21) in the third-line setting or later.

The presence of 17p deletions or TP53 mutations was not associated with a lower OS in patients who received BTK inhibitors (HR, 1.17; 95% CI, 0.88-1.55). Investigators found that blastoid variant MCL was a predictor for inferior OS (HR, 1.56; 95% CI, 1.21-2.02).

“With longer OS with BTK inhibitors in the frontline setting [vs subsequent lines] and without the negative influence of 17p deletions/TP53 mutations, our study provides preliminary evidence supporting the use of BTK inhibitors in frail patients who are unable to tolerate intensive frontline chemoimmunotherapy,” lead study author Mayur Narkhede, MD, an assistant professor at the University of Alabama at Birmingham, and colleagues, wrote.

MCL is considered incurable. For patients with newly diagnosed disease, the current standard of care is chemoimmunotherapy with or without consolidative autologous stem cell transplant (ASCT).2 However, due to the heterogenous nature of MCL, outcomes vary based on different clinical and biological prognostic factors.

This real-world study aimed to analyze the treatment patterns in patients with MCL and assess the usage patterns, patient characteristics, and survival outcomes of patients with relapsed MCL treated with BTK inhibitors, alone or in combination, at predominately community-based practices.

Investigators collected patient data from the nationwide Flatiron Health electronic health record (HER)–derived, de-identified database. The majority of patients in the database originated from community oncology settings.

Investigators identified 4336 adult patients who were diagnosed with MCL from January 2011 to February 2021. Patients were required to have at least 2 HER-documented visits on or after the date of diagnosis, with at least 3 months of follow-up from the data cutoff of February 2021. Exclusion criteria for the analysis included the absence of structured activity, such as vital signs, laboratory measurement, documented office visit, or treatment administration, within 90 days of diagnosis. Overall, 4049 patients were eligible for the analysis.

Targeted agents were grouped into multiple categories: BTK inhibitors with or without chemoimmunotherapy; bortezomib (Velcade) with or without chemoimmunotherapy; lenalidomide (Revlimid) with or without chemoimmunotherapy; venetoclax (Venclexta) with or without chemoimmunotherapy; and venetoclax plus BTK inhibitors. Chemotherapy regimens included bendamustine plus rituximab (Rituxan; BR); rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); R-CHOP or rituximab in combination with dexamethasone, cytarabine and platinum chemotherapy (R-DHAP); combination chemotherapy containing cyclophosphamide, vincristine, doxorubicin, methotrexate, and cytarabine (HyperCVAD); and BR with sequential high dose cytarabine (HiDAC).

The primary end points of the study were to determine the treatment patterns in MCL during different lines of therapy and to identify usage patterns of BTK inhibitors vs other targeted agents. Secondary objectives included the influence of prognostic factors, such as blastoid variant MCL, TP53 mutations, and 17p deletions, on OS from the time of diagnosis; the time to next treatment (TTNT); and OS for BTK inhibitors stratified for lines of therapy.

Among patients analyzed, the median age at diagnosis was 69 years (interquartile range [IQR], 62-76) and 71% of patients were male. Furthermore, 85% of patients were treated at community-based practices and 70% of patients had advanced-stage disease. Investigators identified blastoid variant MCL in 7% of patients, and 5% of patients had a 17p deletion/TP53 mutation. Notably, 23% of patients with blastoid variant MCL had a 17p deletion/TP53 mutation compared with 9% in all other patients. The median duration of follow-up was 51 months (IQR, 26-35).

Of patients who received BTK inhibitors (n = 1076), the median age at the time of diagnosis was 72 years (IQR, 64-78), 72% were male, 82% were treated at a community practice, 77% were White, 75% had stage III/IV disease, and 46% had an ECOG performance status of 0 or 1. The median time to BTK initiation from the time of diagnosis was 19 months (IQR, 6-38).

Additional data showed 3771 of 4049 patients received frontline treatment, and 7% of patients did not receive any treatment documented in the database as of the last available follow-up. The most common treatments used were BR plus chemoimmunotherapy (42%), R-CHOP alone (17%), HyperCVAD (7%), and BTK inhibitors with or without chemoimmunotherapy (4%). Notably, cytarabine-based induction chemotherapy was given to 41% of patients younger than 65 years old, compared with 5% of patients 65 years or older.

Additionally, 31% of patients received consolidation therapy after frontline induction. Of those, 65% received rituximab alone compared with 35% who underwent ASCT. Of those patients who received ASCT, only one-third (n = 410) underwent rituximab maintenance.

Furthermore, 49% of all patients were administered treatment in the second line or later. In the second line (n = 1728), chemoimmunotherapy was the most common treatment (52%). Seven percent of patients received ASCT following salvage chemotherapy. Use of BTK inhibitors with or without chemoimmunotherapy was more common in the second line, with 37% of patients undergoing this treatment.

BTK inhibitors with or without chemotherapy were the most common treatments used subsequent treatment lines, with 40%, 30%, and 24% receiving the regimen in the third, fourth, and fifth line or later, respectively. Of the 1614 patients who received a second-line or later therapy after the December 2013 FDA approval of ibrutinib (Imbruvica), 57% were given a BTK inhibitor at least once. The most common BTK inhibitors administered were ibrutinib (78%), acalabrutinib (Calquence; 20%), and zanubrutinib (Brukinsa; 2%).

Notably, 105 patients received more than 1 BTK inhibitor, including 89 patients who switched from ibrutinib to acalabrutinib, 11 who moved from ibrutinib to zanubrutinib, and 5 patients who switched from acalabrutinib to zanubrutinib. Thirty-five patients received retreatment with the same BTK inhibitor in later lines of therapy.

Among patients who received a BTK inhibitor, the median TTNT was 13 months (95% CI, 11-15). The median TTNT for BTK inhibitors as frontline, second-line, and third- or later-line therapy was 17 months (95% CI, 13-24), 13 months (95% CI, 11-16), and 9 months (95% CI, 8-12, respectively.

“BTK inhibitors were the most used targeted therapies in the relapsed setting and represented 57% of all therapies received,” study authors wrote. “Even in the frontline setting, BTK inhibitors, predominantly as monotherapy, were preferred over lenalidomide or bortezomib. With multiple ongoing clinical trials incorporating BTK inhibitors in the frontline setting (NCT04566887, NCT03282396, NCT04002297), the use of BTK inhibitors in the frontline setting has also percolated into routine clinical practice for the elderly and unfit patients.”


  1. Narkhede M, Goyal G, Shea L, Mehta A, Giri S. Real-world treatment patterns and outcomes of mantle cell lymphoma. Blood Adv. Published online May 13, 2022. doi:10.1182/bloodadvances.2022007247
  2. Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377(13):1250-1260. doi:10.1056/nejmoa1701769