Ibrutinib or R-BAC Prolong PFS2 in Relapsed/Refractory Mantle Cell Lymphoma

Patients with mantle cell lymphoma treated with second-line ibrutinib or the R-BAC regimen experienced improvement in progression-free survival 2 compared with treatment on rituximab and bendamustine and other regimens, according to findings from the international, retrospective MANTLE-FIRST study.

Patients with mantle cell lymphoma (MCL) treated with second-line ibrutinib (Imbruvica) or the R-BAC regimen (rituximab [Rituxan], bendamustine, and cytarabine) experienced improvement in progression-free survival 2 (PFS2) compared with treatment on rituximab and bendamustine (R-B) and other regimens, according to findings from the international, retrospective MANTLE-FIRST study published in Leukemia.

Characterization of clinical outcomes and subsequent patterns of care following second-line therapy appears to be more defined for elderly patients with MCL compared with younger patients. MANTLE-FIRST aimed to fill the gap in research by enrolling younger patients with MCL who had progressive disease or a first relapse when treated with high-dose cytarabine in the frontline setting followed by autologous stem cell transplant (ASCT).

Data were retrospectively analyzed from patients with MCL treated in 32 centers in Italy, Spain, and the United Kingdom. Patients in the cohort had been diagnosed with MCL between January 1, 2008, and June 30, 2018. The cohort was followed for relapsed, re-treatment, and death through July 1, 2019. At data cutoff, the medical records were reviewed.

To decipher the data for outcomes, investigators led by Carlo Visco, MD, of the University of Verona, in Verona, Italy estimated response rates, overall survival (OS), and PFS2 from the time of treatment initiation to salvage therapy. Kaplan-Meir analyses we carried out to determine the 2 time-to-event outcomes: OS2 and PFS2.

Overall, 261 patients with MCL were evaluated in the study, and of those patients, 76 received R-BAC, 54 received R-B, 50 were given ibrutinib, and 81 received other therapies in the second-line setting. Across the treatment arms, patients were a median age of 58 years (range, 19-70 years). Baseline characteristics also showed that 36% of the patient population had a high Mantle Cell Lymphoma International Prognostic Index score, 24% had blastoid or pleomorphic histology, 49% had early progression of disease (POD), and 14% were refractory to their induction therapy. Prior treatment included the following:

  • 24% of patients received rituximab in combination with cyclophosphamide, vincristine, adriamycin, and dexamethasone plus methotrexate and cytarabine;
  • 33% received the R-CHOP regimen (rituximab, cyclophosphamide doxorubicin, vincristine sulfate, and prednisone) plus the R-DHAP regimen (rituximab, dexamethasone, cytarabine, and cisplatin) plus ASCT; and
  • 43% received rituximab plus alternating cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (Maxi-CHOP) and high-dose cytarabine plus rituximab combined with high-dose sequential chemotherapy.

On all second-line treatments, the ORR observed in the study subjects was 59% (range, 37%-73%) with patients who received R-BAC having higher response rates compared with those treated with other regimens. The complete response (CR) rate for all patients treated in the second-line setting ranged from 30% to 60%. Notably, CR rates were significantly higher among patients treated with R-BAC (63%) compared with 43% for those treated with R-B (odds ratio [OR], 0.43; 95 CI, 0.20%-0.93%, = .033). R-BAC also yielded a higher CR rate compared with the 38% rate observed with ibrutinib (OR, 0.36; 95% CI, 0.16%-0.81%; = .013), and the 30% observed with other regimens (OR, 0.27; 95% CI, 0.13%-0.56%; P < .0001).

Differences in responses were also assessed in patients who had POD at baseline. Among those with early POD, the CR rate was 31% with ibrutinib and 32% with R-BAC. Among those with late POD, treatment with R-BAC led to a higher CR rate of 85% compared with 63% for patients who received R-B, 45% for those who received ibrutinib, and 41% for those who received other regimens.

In terms of time-to-event outcomes, the results showed that R-BAC achieved a median PFS2 of 24 months (95% CI, 10 to not reached [NR]), and ibrutinib achieved a median PFS2 of 25 months (95% CI, 8-47). Treatment with R-B and other regimens has a shorter median PFS2 of 13 months (95% CI, 3-26) and 12 months (95% CI, 2-12), respectively.

For OS2, the treatment arms had similar results. But patients who received other treatment regimens had a median OS2 of 2.3 months (95% CI, 13.3-37.8). When Visco et al assessed time-to-event outcomes based on baseline late or early POD, patients showed worse outcomes compared with the rest of the population. Looking specifically at those treated with other second-line regimens versus those treated with ibrutinib, the difference in the median OS2 was (HR, 2.07; 95% CI 1.14-3.74, P = .016) in the late POD group and (HR, 2.74; 95% CI 1.92-3.92, P < .001) in the early POD group.

OS2 outcomes were also analyzed in the 37 patients with refractory disease at baseline. In all treatment groups combined, the patients had a median PFS2 of 3.5 months (95% CI, 2.1-9.3), and median OS2 was 7.9 months (95% CI, 4.4-15.7). A Better PFS2 was observed in the 8 patients who were treated with ibrutinib at 9.3 months (95% CI, 2.1 to NR) compared with all other regimens, but the difference was not considered to be significant. Patients treated with ibrutinib also demonstrated a longer median OS2 of 15.7 months (95% CI, 13.9-15.9), which was also not statically significant.

“MANTLE-FIRST is the first patient-level analysis of outcomes of relapsed/refractory MCL failing cytarabine containing induction regimens. Overall, R-BAC was associated with similar PFS2 to ibrutinib. Ibrutinib was the best per-former in early-POD patients. Bendamustine-based regimens demonstrated similar activity to ibrutinib in late-POD, but longer follow-up is needed to confirm this observation. Biological aspects related to refractoriness require further clarification,” wrote Visco et al.


Visco C, Rocco AD, Evangelista A, et al. Outcomesin first relapsed-refractory younger patients with mantle cell lymphoma: results from the MANTLE-FIRST study. Leukemia. 2021; 35(3), 787-797. doi: 10.1038/s41375-020-01013-3