Patient outcomes following ibrutinib discontinuation for CLL in a real-world setting

On 24 April, Paul Hampel from Mayo Clinic, Rochester, MN, USA, and colleagues, published in Leukemia & Lymphoma a systematic outcome evaluation following ibrutinib discontinuation in patients with chronic lymphocytic leukemia (CLL), outside the clinical trial setting.

Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that has been approved by Food and Drug Administration (FDA) for the treatment of both relapsed/refractory and naïve CLL. Ibrutinib has shown great efficacy in CLL. Nevertheless, the clinical management and outcomes of patients who discontinue ibrutinib requires further investigation. Thus, the authors sought to identify the main reasons for ibrutinib discontinuation and the subsequent patient outcomes in patients with CLL, who received treatment in a real-world setting.

Study design & baseline characteristics

• N = 202 patients with CLL treated outside clinical trials from the Mayo Clinic database (11/2013−06/2017). Ibrutinib discontinuation should have lasted for more than 60 days
• Median follow-up from ibrutinib start to last unknown status: 2.1 years
• Median patient age at ibrutinib start (range): 69 (41–93) years
• Male patients: 69%
• Genetic characteristics:
  • Patients with TP53 abnormalities (del17p or TP53 mutation): 26% (n = 46)
  • Patients with unmutated immunoglobulin heavy-chain variable (IGVH) gene: 75% (n = 129)
  • Patients with normal fluorescence in situ hybridization (FISH): 14% (n = 25)
• Patients treated with ibrutinib as frontline: 20% (n = 40)
• Median number of prior lines (range): 2 (0–15)
• Patients who discontinued ibrutinib: 26%
  • Median follow-up from ibrutinib start to discontinuation: not reached
• Rapid progression after ibrutinib discontinuation was defined when at least two of the following criteria were present:
  • Clinical symptoms (fever, worsening, fatigue, lymph node enlargement-related symptoms, malaise)
  • Exam and/or radiographic evidence of rapidly worsening splenomegaly or lymphadenopathy
  • Laboratory changes (increasing absolute lymphocyte count or lactate dehydrogenase) within four weeks after discontinuation

Key findings

• Estimated risk of ibrutinib discontinuation:
  • One-year risk: 18%
  • Two-year risk: 28%
• Main reasons for ibrutinib discontinuation (n = 52):

Toxicity	56% (n = 29)
CLL progression	17% (n = 9)
Richter’s transformation (RT)	15% (n = 8)
Second malignancy: Lung adenocarcinoma Invasive non-melanoma skin cancer Merkel cell carcinoma	6% (n = 3) n = 1 n = 1 n = 1
Other: Financial issues Patient choice	6% (n = 3) n = 2 n = 1

• Most common toxicities resulting in ibrutinib discontinuation:

Infection	n = 6
Bleeding	n = 4
Arrhythmia	n = 3
Gastrointestinal symptoms	n = 3
Neutropenia	n = 3

• Patients who received subsequent therapy after ibrutinib discontinuation: n = 37
  • Anti-CD20 monoclonal antibodies ± steroids: n = 13
    • Rituximab: n = 5
    • Obinutuzumab: n = 6
    • Ofatumumab: n = 2
  • Retreatment with ibrutinib: n = 8
  • Venetoclax: n = 6
  • Chemoimmunotherapy: n = 5
  • Pembrolizumab: n = 4
  • Idelalisib: n = 1
• Median time to next therapy:
  • All patients who discontinued ibrutinib: 2.7 months
  • Patients who stopped ibrutinib due to toxicity: 6.5 months
  • Patients who stopped ibrutinib due to CLL or RT progression: 0.3 months
  • Comparison: P < 0.0001
• After ibrutinib discontinuation:

Median overall survival (OS)	Months	P value
In patients who stopped due to toxicity	27.8 months	0.04
In patients who stopped due to CLL or RT progression	11.5 months

• The only variable that seemed to significantly affect median OS in patients who had discontinued ibrutinib was older age at ibrutinib initiation (HR = 1.06; [95% CI, 1.02–1.10; P = 0.004)
• Rapid disease progression was observed in 25% of patients (n = 9/36)
• Among these patients:
  • Three patients received subsequent therapy the day after ibrutinib discontinuation:
    • Received idelalisib: n = 2
    • Received anti-CD20 monoclonal antibody + steroids: n = 1
  • One patient did not receive subsequent therapy
  • Four patients received subsequent therapy (multi-agent chemotherapy) after a median of 5 days (range, 3–13)
• Univariate analyses revealed that rapid disease progression after ibrutinib discontinuation was not associated with age, sex, IGHV mutation status, TP53 genetic anomalies, FISH, ibrutinib treatment duration or reasons for ibrutinib discontinuation

Conclusions

The results of this real-world patient outcome analysis indicate that approximately one third of patients with CLL will discontinue ibrutinib treatment after two years. The most common reason for ibrutinib discontinuation was toxicity. Moreover, roughly 25% of the patients discontinuing ibrutinib progressed rapidly, further highlighting the medical need for such patient populations.