Ibrutinib May Thwart PFS Decline in R/R Mantle Cell Lymphoma

Simon Rule, MD, PhD

In patients with relapsed mantle cell lymphoma (MCL), treatment with ibrutinib (Imbruvica) might mitigated a historical trend toward decreased progression-free survival (PFS) with succeeding lines of therapy, according to long-term follow-up data from a prospective trial presented at the 2019 ASH Annual Meeting.

“This pooled analysis of ibrutinib in relapsed/refractory MCL with extended follow-up to 7.5 years indicates a late plateau in the PFS curve with a notable number of patients experiencing remissions greater than 5 years,” Simon Rule, MD, of Plymouth University Medical School in England, and colleagues concluded in a poster presentation. “Patients with only 1 prior line of therapy and those achieving a complete response continued to have the best outcomes with ibrutinib.”

Investigators reported updated pooled data from 3 clinical trials—SPARK (MCL2001; NCT01599949), RAY (MCL3001; NCT01646021), and PCYC-1104 (NCT01236391)—of ibrutinib in relapsed/refractory MCL. All patients enrolled (N = 370) in the 3 trials received ibrutinib 560 mg once daily until disease progression or development of unacceptable toxicities. Patients who continued to benefit at end of study could enroll in a long-term access study.

The median PFS was 12.5 months (range, 9.8-16.6) with ibrutinib as compared with an estimated 10.9 months with a patient’s more recent prior regimen. More than half of 370 patients had a longer PFS with ibrutinib than with the prior regimen, and 27% had a PFS ≥1 year longer than the prior regimens estimated PFS.¹

Patient age and number of prior lines of therapy did not significantly affect PFS with ibrutinib, although patients with a single prior line of therapy had the best PFS, along with those who attained a complete remission (CR).

“Ibrutinib represents a significant advance in MCL and should be considered standard of care in second line, regardless of a patient’s initial response to frontline therapy,” the authors added.

The study originated with the recognition that PFS in MCL declines with each successive line of chemoimmunotherapy, regardless of patient age.² Additionally, patients who progress within 24 months of frontline treatment have a shorter PFS and overall survival (OS) than those who progress later.³ As a result, second-line therapies that reverse or mitigate the historical tends would fulfill an unmet need, the authors noted. Ibrutinib has an approved indication for relapsed/refractory MCL, and Rule and colleagues previously reported improved outcomes with earlier use of ibrutinib.⁴

Investigators defined PFS with the most recent prior regimen as the time from first dose of the regimen to the first dose of ibrutinib. They further defined disease progression on frontline therapy as occurring within 24 months (POD24) or later (POD≥24).

The study population comprised 99 patients with one prior line of therapy and 271 with more than 1 line (median of 2). Investigators reported that 44% of the patients with 1 prior line of therapy were ≥70, 26% had high-risk simplified MIPI score, 6% had blastoid variant, and 43% had POD24.

Median exposure to ibrutinib for all patients was 11.1 months. Almost a third of the patients continued treatment for at least 2 years, and half of that group remained on treatment for 4 years or more.

With follow-up for as long as 92 months (median 41), 11.9% of patients discontinued ibrutinib because of adverse events (AEs). The estimated 5-year OS for the entire cohort was 41%.

The objective response rate was 69.7%, including a complete response rate of 27.6%. The subgroup with 1 prior line of therapy had a response rate of 77.8%, including complete responses in 37.4%, a median PFS of 25.4 months, and median OS of 61.6 months. Patients who attained complete response had a median response duration of 65.6 months. The responses were durable, regardless of the number of prior lines of therapy.

In the subgroup with known blastoid and/or TP53-mutated disease (n = 61), a third had a longer PFS with ibrutinib versus the prior regimen. The median duration of PFS 5.4 months in the blastoid group and 4.0 months in patients with TP53-mutated disease.

Among the 27% of patients whose PFS with ibrutinib was ≥1 year longer than with their prior regimen, 66% attained complete response, as compared with 14% of patients who did not have ≥1-year improvement in median PFS.

Patients whose PFS was longer with ibrutinib as compared with the prior regimen were less likely to have high-risk MIPI (38.8% vs 61.2%), bulky disease (44.4% vs 55.6%), blastoid variant (37.2% vs 62.8%) and TP53-mutated disease (20.0% vs 80.0%).

In the subgroup of patients who received ibrutinib in second line, PFS and response duration were longer with POD≥24 versus POD24. PFS with second-line ibrutinib was similar to the estimated PFS with a patient’s frontline regimen, regardless of age. Median PFS for patients with POD24 was similar with ibrutinib and frontline therapy but was 15 months longer with ibrutinib for patients with POD≥24.

With additional follow-up, no late unexpected toxicity emerged in patients treated with ibrutinib. The most common grade ≥3 treatment-emergent AEs were neutropenia (17%), pneumonia (13.5%), and thrombocytopenia (12.4%). The most frequently reported serious AEs were pneumonia (13.2%), atrial fibrillation (5.7%), and dyspnea (4.3%). Secondary malignancies occurred in 11.4% of patients, primarily nonmelanoma skin cancer.

References

1. Rule S, Dreyling MH, Goy A, et al. Presented at: 2019 ASH Annual Meeting; December 7 to 10, 2019; Orlando, FL. Abstract 1538. bit.ly/2LzEfFU.
2. Kumar A, Sha F, Toure A, et al. Patterns of survival in patients with recurrent mantle cell lymphoma in the modern era: progressive shortening in response duration and survival after each relapse. Blood Cancer J. 2019;9(6):50. doi: 10.1038/s41408-019-0209-5.
3. Visco C, Tisi MC, Evangelista A, et al; Fondazione Italiana Linfomi and the Mantle Cell Lymphoma Network. Time to progression of mantle cell lymphoma after high-dose cytarabine-based regimens defines patients risk for death. Br J Haematol. 2019;185(5):940-944. doi: 10.1111/bjh.15643.
4. Rule S, Dreyling MH, Goy A, et al. Ibrutinib for the treatment of relapsed/refractory mantle cell lymphoma: extended 3.5-year follow up from a pooled analysis. Haematologica. 2019;104(5):e211-e214. doi: 10.3324/haematol.2018.205229.

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