“Real world” study – median OS after ibrutinib failure is poor in R/R MCL patients and ibrutinib represents a potential bridge to allo-HCT

Last month, Narendranath Epperla from the Medical College of Wisconsin, Milwaukee, WI, USA, and colleagues published results in Hematological Oncology of a “real world” study investigating outcomes and prognostic indicators for ibrutinib treatment in patients with R/R MCL.

This retrospective study analyzed data from 97 R/R MCL patients treated with single-agent ibrutinib from November 2013 to December 2015 from 8 US academic centers.

Key Highlights:

Response to ibrutinib

• Ibrutinib responders: CR = 32 pts (33%); PR = 31 pts (32%)
• Ibrutinib non-responders: PD = 24 pts (25%); SD = 10 pts (10%)
• Median (m) DoR = 17 months
• Response Rate (RR) in pts with no, auto-, & allo-HCT = 65%, 66%, & 64% (P=0.99)
• mDoR in pts with no, auto-, & allo-HCT = 12, 14, & 6 months (P=0.57)
• Lack of primary refractory disease was predictive of response to ibrutinib (P=0.03)

Survival

• Whole group: median OS = 22 months; median PFS = 15 months
• mOS in pts with no, auto-, & allo-HCT = 22 months, not reached, & 27 months (P=0.81)
• mPFS in pts with no, auto-, & allo-HCT = 15, 18, & 6 months (P=0.28)
• mOS in ibrutinib responders vs non-responders = not reached vs 12 months (P<0.0001)
• mPFS in ibrutinib responders vs non-responders = 17 vs 3 months (P<0.0001)
• Predictors of good PFS: ibrutinib response (HR = 0.09; CI = 0.03–0.22), low MIPI (HR = 0.29; CI = 0.13–0.65), & lack of primary refractory disease (HR = 0.16; CI = 0.06–0.42)
• Predictors of good OS: ibrutinib response (HR = 0.09; CI = 0.03–0.27) & ECOG performance status ≤1 (HR = 0.16; CI = 0.06–0.43)
• mOS after ibrutinib failure (non-responders plus pts who experienced initial response then disease progression) = 2.5 months (range, 0.1–18 months)
• mOS after ibrutinib failure in initial responders versus non-responders = 5 months (range, 1–18 months) vs 1 month (range, 0.1–13 months)

Therapies after ibrutinib failure

• Twenty-nine pts were administered therapies after ibrutinib failure
• Two patients underwent allo-HCT; both in CR at 6 and 14 months post-allo-HCT
• Bortezomib based therapy most common after ibrutinib failure (n = 9, 31%)
• ORR of whole group for first therapy after ibrutinib failure = 42% (12/29); mDOR = 3 months (range, 1–12.8)
• RR to bortezomib, lenalidomide, and bendamustine as first therapy after ibrutinib failure = 33%, 50%, and 50%
• mDOR to bortezomib, lenalidomide, and bendamustine as first therapy after ibrutinib failure = 3 (2–12.8), 5.5 (1.5–6), and 3 (1–8) months
• mOS of pts administered bortezomib, lenalidomide, and bendamustine containing regimens after ibrutinib failure = 7 (1–13), 6 (1–13), and 4.5 (1–18) months

Limitations of this analysis included the fact that it was retrospective and information on BTK mutations of patients who progressed on ibrutinib was missing. However, strengths of the study were that it included patients from eight different centers, representative of a “real world” population.

The authors stated that the results of their “real world” study are in agreement with the previously reported high ORR and DoR that can be achieved with ibrutinib in patients with R/R MCL. They found that lack of primary refractory disease was predictive of response to ibrutinib, and previous HCT does not have an adverse effect on ibrutinib efficacy.

Expectedly, mOS and mPFS were longer in ibrutinib responders compared to non-responders; however, the mOS after ibrutinib failure was poor (2.5 months). Based on this poor outcome in patients who experience ibrutinib failure, and the authors suggested that transplant eligible patients should be considered for allo-HCT and that ibrutinib represents a potential bridge to allo-HCT in R/R MCL. The authors also stated that finding more effective therapies for patients who fail ibrutinib signifies a pressing area of unmet need.

It was concluded that, based on the encouraging ORR and DoR reported, lenalidomide based therapy represents a potential first treatment following ibrutinib failure, however this approach needs validating in larger clinical trials. Finally, the mechanisms of resistance to ibrutinib need to be identified in order to allow strategies to overcome resistance to be designed and implemented.

Abstract:

Ibrutinib has demonstrated significant activity in relapsed/refractory mantle cell lymphoma (MCL) in clinical trials. However, the impact of hematopoietic cell transplantation on the outcomes of ibrutinib and the predictive factors for ibrutinib response has not been well studied. Hence, we conducted a multicenter retrospective study of MCL patients who received ibrutinib to (1) determine the overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of ibrutinib in routine clinical practice, (2) examine characteristics predictive of response to ibrutinib therapy, and (3) describe the outcomes of patients failing ibrutinib. Ninety-seven patients met the eligibility criteria. Overall response rate and median DOR to ibrutinib were 65% and 17 months, respectively. Only lack of primary refractory disease was predictive of ibrutinib response on multivariate analysis. Twenty-nine patients received postibrutinib therapies, with an ORR of 48% and a median DOR of 3 months. The median OS and PFS for the entire group (n = 97) was 22 and 15 months, respectively. On multivariate analysis, ibrutinib response, low MCL international prognostic index, and absence of primary refractory disease were predictors of better PFS, while ibrutinib response and Eastern Cooperative Oncology Group performance status ≤1 were predictors of better OS. The median OS postibrutinib failure was 2.5 months. Our results confirm the high ORR and DOR of ibrutinib in MCL and that prior hematopoietic cell transplantation does not negatively influence ibrutinib outcomes. Survival following ibrutinib failure is poor with no specific subsequent therapy showing superior activity in this setting. As a result, for select (transplant eligible) patients, allogeneic transplant should be strongly considered soon after ibrutinib response is documented to provide durable responses.