Rule S, et al. ASH 2017:151
Median 3.5-year follow-up of ibrutinib treatment in patients with relapsed/refractory mantle cell lymphoma: A pooled analysis
In relapsed/refractory (R/R) mantle cell lymphoma (MCL), time to next therapy generally decreases with each subsequent line of therapy. There is a need for treatments with higher durability of response and longer progression-free survival (PFS) to improve outcomes. Ibrutinib has previously been shown to improve PFS compared to temsirolimus in patients with R/R MCL.1 At the 2017 ASH Annual Meeting, mature follow-up of a large cohort of patients treated with ibrutinib across three studies was presented, with a median follow-up of 3.5 years.2
- Patients were enrolled in one of three studies (PCYC-1104, SPARK, or RAY) between 2011 and 2013.
- Ibrutinib 560 mg once daily was given orally until progressive disease or unacceptable toxicity.
- Patients continuing to benefit from ibrutinib at the end of the studies could enrol in CAN3001, a phase IIIb, open-label access study.
- In this study, safety reporting was limited to grade 3/4 adverse events (AEs) and serious AEs.
- Efficacy outcomes included investigator-assessed tumour response, PFS, and overall survival (OS).
- Cheson 2007 criteria3 were used, and all complete responses (CRs) were confirmed by positron emission tomography (plus bone marrow biopsy and/or endoscopy if positive at baseline).
- Multivariate analysis was conducted to assess the effect of baseline characteristics on PFS and OS.
Baseline characteristics and disposition
- A total of 370 patients were included in the pooled analysis.
- Median age was 67.5 years (range: 35–85).
- The majority of patients were male (78.1%) with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1 (93.5%).
- Bulky disease (≥5 cm) occurred in 48.9% of patients, and 11.9% of patients had the blastoid variant of MCL.
- Median duration of follow-up was 41.1 months (range: 0.2–72.1).
- Eighty-seven patients (23.5%) rolled over to the CAN3001 study.
- Treatment discontinuation occurred in 316 patients (85.4%).
- Reasons for discontinuation included AE (n = 37), disease progression (n = 218), death (n = 19), alternative access to ibrutinib (n = 1), physician decision (n = 14), withdrawal of consent (n = 24), and other reasons (n = 3).
- Approximately one-third of patients (n = 115; 31.1%) were treated with ibrutinib for ≥2 years.
- Fifty-four patients remained on ibrutinib at the time of analysis, with a median exposure of 46.3 months (range: 28.8–72.1).
- Maximum treatment exposure was 72 months.
- Median PFS was 33.6 months in patients with one prior line of therapy (95% CI: 19.4–42.1). (Figure 1)
- In the pooled intent-to-treat (ITT) population, median PFS was 13.0 months (95% CI: 8.4–16.8).
- Median OS was not reached in patients with one prior line of therapy, and was 22.5 months in patients with >1 prior line of therapy.
- In the ITT population, median OS was 26.7 months (95% CI: 22.5–38.4).
- Overall response rate (ORR) was 69.7% in the ITT population, with 26.5% achieving a CR and 43.2% achieving a partial response (PR).
- In patients with one prior line of therapy, ORR was 77.8%, CR rate was 36.4%, and PR rate was 41.4%.
- In patients with >1 prior line of therapy, ORR was 66.8%, CR rate was 22.9%, and PR rate was 43.9%.
- Median PFS was 46.2 months (95% CI: 42.1–not estimable [NE]) in patients who achieved a CR and 14.3 months (95% CI: 10.4–17.5) in patients who achieved a PR.
- Median OS was NE (95% CI: 59.9–NE) in patients who achieved a CR and 26.2 months (95% CI: 21.6–34.7) in patients who achieved a PR.
- In patients achieving a CR, median duration of response (DOR) was 4.5 years. (Table 1)
- Patients with one prior line of therapy had a DOR that was more than double that of patients with >1 prior line of therapy.
- ECOG PS, simplified MCL International Prognostic Index risk, number of prior lines of therapy, presence of bulky disease, and blastoid history were independent predictors of PFS with ibrutinib. (Figure 2)
- The most common grade ≥3 treatment-emergent AEs (TEAEs) occurring in ≥5% of patients (by ITT population, patients with one prior therapy, and patients with >1 prior lines of therapy, respectively) were as follows:
- Neutropenia (17%, 7.1%, and 20.7%);
- Thrombocytopenia (12.2%, 7.1%, and 14%);
- Pneumonia (11.9%, 7.1%, and 13.7%);
- Anemia (9.5%, 5.1%, and 11.1%);
- Atrial fibrillation (5.9%, 5.1%, and 6.3%); and
- Hypertension (5.1%, 6.1%, and 4.8%).
- Generally, grade 3/4 AEs were less common in patients with one prior line of therapy.
- Secondary malignancies occurred in 9.7% of patients and were predominantly nonmelanoma skin cancers.
- New onset grade ≥3 TEAEs generally decreased after the first year of treatment. (Figure 3)
- A similar trend was observed for atrial fibrillation and bleeding.
- New onset grade ≥3 TEAEs were generally lower in patients with one vs. >1 prior line of therapy.
- Patients with significant cardiac risk factors were enrolled in the studies, including:
- Hypertension (n = 176);
- Hyperlipidemia (n = 60);
- Atrial fibrillation/abnormal heart rhythm (n = 53);
- Diabetes (n = 48); and
- Coronary artery disease (n = 31).
- The majority of patients who entered the study with a history of atrial fibrillation or arrhythmia did not have a recurrence (70%; 37 of 53).
- Less than 2% of the 370 patients treated with ibrutinib discontinued or had a dose reduction due to grade ≥3 bleeding or atrial fibrillation. (Table 2)
- No patients discontinued ibrutinib due to grade ≥3 atrial fibrillation.
- In this mature pooled data set of 370 patients with R/R MCL from three studies:
- The median PFS was 33.6 months for patients with one prior line of therapy;
- The median PFS was 46.2 months for patients who achieved a CR; and
- The median DOR was 55 months for patients who achieved a CR.
- Clinical risk factors and number of prior lines of therapy predicted PFS with ibrutinib.
- New onset grade ≥3 AEs were most common in the first year, generally decreased over time, and were less common in patients with only one prior line of therapy.
- Less than 2% of patients had to reduce ibrutinib dose or discontinue due to atrial fibrillation or bleeding.
- Most patients with a history of atrial fibrillation did not have a recurrence (70%).
References: 1. Dreyling M, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet 2016;387(10020):770–8. 2. Rule S, Dreyling M, Goy A, et al. Median 3.5-year follow-up of ibrutinib treatment in patients with relapsed/refractory mantle cell lymphoma: a pooled analysis. ASH Annual Meeting Abstracts 2017:151. 3. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25(5):579–86.