Early use of a BTK inhibitor in an elderly patient with high-risk CLL and multiple comorbidities

History and presentation
A 77-year-old male presented with an incidental finding of lymphocytosis (absolute lymphocyte count [ALc], 9 x 10⁹/L) in November 2018.

Medical history revealed recovered hepatitis B virus (HBV) infection (HBV DNA, negative; hepatitis B surface antigen [HbsAg], negative; hepatitis core antibody [HbcAb], positive; hepatitis surface antibody [HbsAb], positive), comorbid ulcerative colitis and immune thrombocytopenia, which were controlled with medications. Additionally, the patient had paroxysmal atrial fibrillation (pAF) and sick sinus syndrome, which required permanent pacemaker implantation, apixaban 2.5 mg BID (reduced dose due to risk of gastrointestinal bleeding), and metoprolol 25 mg BID.

Apart from lymphocytosis, the patient had no B symptoms, palpable lymph node (LN) or splenomegaly, and results of blood tests (haemoglobin [Hb], 13.6 g/dL; platelet, 208 x 10⁹/L) were unremarkable. This was suggestive of a diagnosis of Binet stage A, Rai stage 0 chronic lymphocytic leukaemia (CLL). As the patient was asymptomatic without active disease, a watch-and-wait approach was taken.

Treatment and response
In May 2020, 1.5 years after diagnosis, the patient developed significant weight loss (-4 kg) and shotty cervical lymph nodes, but no other palpable LN or hepatosplenomegaly were detected. Blood tests showed anaemia (Hb, 9.4 g/dL) and a rapidly rising trend of ALc (to 140 x 10⁹/L), with a lymphocyte doubling time of <6 months. Fluorescence in situ hybridization (FISH) test showed trisomy 12 and TP53 mutation, as well as deletions (del) of 17p and 13q14, indicating high-risk CLL with poor prognosis.¹

As the patient was reluctant to receive intravenous treatment and had financial concerns about oral Bruton’s tyrosine kinase (BTK) inhibitors or B-cell lymphoma 2 (BCL2) inhibitor, he was started on chlorambucil (10 mg QD) plus prednisolone (30 mg QD) in May 2020, but disease progression occurred after approximately 1 month of treatment.

Consequently, the patient’s treatment was switched to a BTK inhibitor, ibrutinib (420 mg QD), in August 2020.² During treatment, he experienced grade 3 oral ulcers in September 2020, increased pAF episodes since January 2021, and HBV reactivation (HBV DNA, 6 log IU/mL; HbsAg, positive; hepatitis B e-antigen [HbeAg], positive) in November 2021, which resolved with ibrutinib dose interruption and reductions as well as addition of flecainide 50 mg BID as antiarrhythmic agent and entecavir 0.5 mg QD as antiviral agent after consultation with our cardiology and hepatology teams.

In July 2021, the patient achieved complete remission with ibrutinib treatment (280 mg QD). Apart from ALc and Hb normalization in July 2021, he also gained weight (+5 kg) and had improved Eastern Cooperative Oncology Group performance status (from 1 to 0), which may be attributed to resolution of B symptoms.

As of April 2023, the patient remained asymptomatic without disease progression after 2.5 years of ibrutinib treatment. The treatment will continue until disease progression or unacceptable toxicity.

Discussion
High-risk genomic features (eg, TP53 mutation, del17p) in CLL predict inferior treatment response and survival with traditional chemoimmunotherapy.^1,3 In our patient’s case, disease progression was rapid, occurring after approximately 1 month of frontline chlorambucil-based treatment.

Guidelines of the European Society for Medical Oncology (ESMO) recommend novel agents including BTK inhibitor (eg, ibrutinib) as treatment for CLL patients with del17p or TP53 mutation based on survival results of the phase III RESONATE (relapsed/refractory CLL or small lymphocytic lymphoma [R/R CLL/SLL]) and RESONATE-2 (previously untreated CLL or SLL) trials.^3-5

RESONATE was a randomized phase III study comparing ibrutinib with ofatumumab in patients with R/R CLL/SLL who were unsuitable for purine analogue–based treatment. With up to 6 years of follow-up, ibrutinib monotherapy significantly prolonged median progression-free survival (PFS; hazard ratio [HR], 0.148; 95 percent confidence interval [CI], 0.113–0.196; p<0.001) and improved overall survival (OS; HR, 0.639; 95 percent CI, 0.418–0.975) vs ofatumumab. The PFS benefit attained with ibrutinib was preserved in high-risk patients with del17p, del11q, TP53 mutation, and/or unmutated IGHV status (HR, 0.110; 95 percent CI, 0.080–0.152), which represented 82 percent of the overall population.⁴

Notably, long-term follow-up data of RESONATE-2 demonstrated an unprecedented 7-year OS rate of 78 percent (HR vs chlorambucil, 0.453; 95 percent CI, 0.276–0.743) and superior PFS (HR vs chlorambucil, 0.154; 95 percent CI, 0.108–0.220) in previously untreated CLL/SLL. (Figure) The OS and PFS benefits of frontline ibrutinib were consistent in the high-risk population with del11q, TP53 mutation, and/or unmutated IGHV status.⁵

 

As observed in this case, HBV reactivation may occur with ibrutinib therapy in patients with recovered HBV infection. Therefore, antiviral prophylaxis should be considered before starting ibrutinib or else close monitoring for potential HBV reactivation will be needed.^6,7

Generally, ibrutinib treatment is well tolerated. Even in our elderly CLL patient with multiple comorbidities, including pre-existing pAF, and high risk of bleeding due to anticoagulation and underlying ulcerative colitis, ibrutinib’s adverse events (AEs) could be managed with dose interruptions or reductions and a multidisciplinary approach.^4,5,8

Furthermore, the safety profile of ibrutinib was extensively studied in its pivotal trials. Long-term data of RESONATE and RESONATE-2 showed no new safety signals and a low discontinuation rate due to AEs. The prevalence rates of most grade ≥3 AEs decreased over time, except for hypertension, which showed a relatively stable prevalence.^4,5

With a favourable benefit-risk profile (eg, OS benefit in both untreated and R/R CLL), convenient once-daily oral administration, and dosing flexibility for AE management, early treatment with ibrutinib should be considered in patients with CLL, especially in those with high genomic risk.^2,4,5