Outcomes of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia after Ibrutinib Discontinuation Outside Clinical Trials: A Single Institution Experience
Authors: Sandoval-Sus Jose D , Chavez Julio C , Dalia Samir , Bello Celeste M. , Shah Bijal D. , Ho Viet Q. , Nodzon Lisa , Kharfan-Dabaja Mohamed A. , Sotomayor Eduardo M. , Sokol Lubomir , Pinilla-Ibarz Javier 
Published: October 2019

BACKGROUND:

The B-cell receptor (BCR) signaling pathway plays a pivotal pathogenic role in chronic lymphocytic leukemia (CLL). Ibrutinib is an irreversible Bruton's tyrosine kinase (BTK) inhibitor that effectively treats patients with CLL, including those harboring poor-risk mutations such as del17p. Here we present the outcomes of CLL patients (pts) who discontinued ibrutinib while being treated outside clinical trials.

METHODS:

The primary objective was to describe the clinical characteristics, reasons for of discontinuation and outcomes after stopping Ibrutinib. Using the Moffitt Cancer Center, Total Cancer Care and pharmacy registry, we identified and reviewed the charts of all CLL pts that had been treated with ibrutinib from January 2013 to July 2015. Pts were evaluated for time to discontinuation, reason for discontinuation and overall survival (OS) after discontinuation. Survival outcomes were estimated using the Kaplan-Meier method and the log-rank test. All analyses were done using SPSS version 19.0.

RESULTS:

We identified 54 relapsed/refractory (R/R) CLL pts treated with ibrutinib. The median age was 62 (36-80) and female/male ratio 0.1. The median number of prior therapies was 2 (1-6), 60% had unmutated IgVH, 36% had del17p and 14% had complex karyotype. Eighty percent received and failed fludarabine-based regimens (Table 1). After a median follow up of 9.1 months (0.5-23.3) for survivors, there were 22 (41%) CLL pts who discontinued ibrutinib; 7 due to disease progression (PD), 8 due to toxicity and 7 due to proceeding with hematopoietic stem cell transplantation (HSCT). The most common side effects that lead to ibrutinib discontinuation were: major bleeding events (3), atrial fibrillation (2), grade 3 constipation (1) and grade 2 recurrent skin rashes (1). The median duration of ibrutinib therapy was 3.7 (0.9 - 10.9) months. The median OS for CLL pts with PD after ibrutinib and HSCT was 5.5 and 10.8 months, respectively. In pts who discontinued ibrutinib due to toxicity, the median OS was not reached. Of the seven patients who underwent HSCT, 71% had unmutated IgVH, 43% had del17p, one had complex karyotype and all of them had a clinical response to ibrutinib (PR= 1 and SD =6) prior to HSCT. Four patients developed RichterÕs transformation (RT) upon progression with median OS of 3 months; 3 had del17p/complex karyotype. By univariate analysis RT was associated with inferior OS.

CONCLUSION:

R/R CLL patients that are treated with ibrutinib and experience disease progression have a dismal prognosis, especially in those who develop RT that appears to be the most important prognostic factor for OS in this group.

In addition, ibrutinib appears to be an effective therapy for CLL pts as a bridge for allogeneic HSCT and in general for patients with R/R CLL.

Table 1. Main characteristics of CLL patients that discontinued Ibrutinib outside clinical trials Patients characteristics Patients (N=22) Age at discontinuation* 62 (36-80) Unmutated IgVH 13 (60%) Del17p# 8 (36 %) Complex karyotype 3 (14%) Number of prior therapies* 2 (1-5) Clinical responseá Stable disease (SD)á Partial response (PR)á Progressive disease (PD) 12 (52%) 3 (13%) 2 (9%) *Median; #one patient had both del17p and TP53 mutation.

Disclosures

Shah: Acetylon: Membership on an entity's Board of Directors or advisory committees; Rosetta Genomics: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria; Pharmacyclics: Speakers Bureau; PLexus Communications: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding. Sokol:Spectrum: Consultancy; Seatle Genetics: Research Funding; Celgene: Consultancy. Pinilla-Ibarz:BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Speakers Bureau; Pfizer: Consultancy, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau; Novartis: Consultancy, Other: Consulting & Advisory Role, Research Funding; ARIAD Pharmaceuticals, Inc.: Consultancy, Other: Consulting & Advisory Role, Research Funding; Teva: Consultancy, Speakers Bureau.