Real-World Results on Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Data from 97 Swedish Patients Treated in a Compassionate Use Program
Authors: Hansson Lotta , Winqvist Maria , Asklid Anna , Andersson P-O , Karlsson Karin , Karlsson Claes , Lauri Birgitta , Lundin Jeanette , Mattsson Mattias , Norin Stefan , Sandstedt Anna , Österborg Anders 
Published: October 2019

Abstract
Background: Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and those with del 17p CLL have a poor prognosis. Ibrutinib (ImbruvicaTM) is a first-in-class Bruton´s tyrosine kinase (BTK) inhibitor that has recently been approved for previously treated patients with CLL or those with del 17p after having demonstrated convincing effects in pivotal clinical studies. However, there is often a discrepancy between data from patients strictly included in clinical trials and those later obtained in routine health care. We report here the first Real-World results on ibrutinib in 97 consecutive Swedish patients with poor-prognosis CLL who received their treatment in a compassionate use program (CUP).
Methods: Patients with CLL were eligible for the CUP if they a) had a confirmed diagnosis of CLL or small lymphocytic lymphoma (SLL) b) had relapsed after or were refractory to conventional CLL therapy or had del 17p / TP53 disruption in any disease phase c) had a treatment indication for CLL d) had no contraindication for ibrutinib such as receiving a strong CYP3A inhibitor or warfarin treatment e) had a neutrophil count of at least 0.5x109/L and a platelet count above 30x109/L.
Patients received 420 mg oral ibrutinib once daily until progression. Endpoints were overall response rate (ORR) with or without persistent lymphocytosis, complete remission (CR) rate with or without (CRi) complete blood count recovery, duration of response (DOR), progression-free survival (PFS), overall survival and safety of ibrutinib. The IWCLL response criteria were applied.
Results: Fourenrolled patients were excluded as they died or were diagnosed with Richter transformation (RT) and never received ibrutinib. Ninety-seven patients (95 with CLL, 2 with SLL) were included between May 15, 2014 and May 31, 2015. The median age was 69 years (24% were 75 years or older). FISH or TP53 mutation test was performed in 82 patients and 61% had del 17p / TP53 disruption. Del 11q was present in 17%. Baseline characteristics included 65% of patients with Rai Stage III or IV, 48% with at least one lymph node >5 cm and 25% had performance status grade 2 or 3. A median of 3 prior therapies (range 0-10) were reported. At the time of writing, 81 patients (86%) had been enrolled for least 2 months and were included in the preliminary efficacy analysis. All patients who had received at least one dose of ibrutinib (n=92) at the time of writing were included in the safety analysis. The median treatment duration at analysis was 6.8+ months (range 0-12.7+ months) and 78 patients (85%) remain on continuous ibrutinib therapy. Investigator-assessed ORR was 80% including 25% PR with lymphocytosis (PR-L). No CR or CRi were reported. At a median follow-up time of 6.8+ months (range 0.5-12.7+ months) the median PFS and DOR had not been reached.
Ninety- two patients were evaluable for toxicity. Twenty-five patients (27%) were hospitalized due to grade 3 or worse infection. Neutropenia grade 4 occurred in 16% of the patients. Diarrhea of any grade was reported in 17% (4% were grade 3, none was grade 4). Arthralgia or muscle pain was reported in 15% (all but one were grade 1-2) and any hemorrhage occurred in 30 patients (33%). Atrial fibrillation occurred in 3%. Three patients had a secondary tumor during ibrutinib treatment. Ibrutinib was permanently stopped in 13 patients for the following reasons: CLL progression (n=1), RT (n=4, after a median time of 7.6 months, range 3.7-10.3), cutaneous adverse event (n=2), congestive heart failure (n=1), infections (n=3) or other malignancy (n=2). Twelve patients have died. The reasons were progression (n=3), RT (n=2), congestive heart failure (n=1), infection (n=3), secondary tumor (n=2) or unknown (n=1).
Conclusions: This is the first Real-World analysis on ibrutinib treatment of poor prognosis CLL patients from a well-defined geographical region. The efficacy of ibrutinib was similar to that of a previous pivotal clinical trial (Byrd et al NEJM 2013) and with a similar adverse event profile as previously reported (Byrd et al, NEJM 2014) despite that our patients were older, had a lower performance status and with a majority having del 17p / TP53 disruption. The median PFS has not yet been reached and most patients remain on continuous ibrutinib therapy. Updated results will be presented at the meeting.

Disclosures
Hansson: Jansse Cilag: Research Funding. Winqvist:Janssen Cilag: Research Funding. Asklid:Janssen Cilag: Research Funding. Lundin:Janssen: Research Funding; Novartis: Research Funding. Mattsson:Janssen: Consultancy. Österborg:Janssen, Pharmacyclics, Gilead: Consultancy, Research Funding; Novartis: Research Funding.