Second-line treatment with a next-generation BTK inhibitor in a patient with relapsed CLL

History and presentation
An 80-year-old female on antihypertensive treatment was initially referred to the clinic in 2018 due to high lymphocyte count. She had 1 year’s history of fatigue, reduced appetite and mild weight loss, but no fever or night sweats. At presentation, her white blood cell (WBC) count, haemoglobin level and platelet count were 84 x 10⁹/L, 9.1 g/dL and 162 x 10⁹/L, respectively.

Imaging at presentation showed enlarged lymph nodes (LNs) in the neck, abdomen and pelvic regions, including mesenteric and iliac LNs. Further investigations, including bone marrow test, confirmed Binet stage C chronic lymphocytic leukaemia (CLL). Chromosome analysis detected trisomy 12, but neither del(17p) nor TP53 mutation was present. Immunoglobulin heavy-chain variable (IGHV) gene mutation status was not evaluated due to lack of access to the test. Treatment was required as the patient had anaemia upon presentation.

Initial treatment
In September 2018, the patient was started on chemoimmunotherapy (CIT) with obinutuzumab and chlorambucil. She received six cycles of the standard-dose regimen and tolerated the treatment well apart from experiencing neutropenia, which required granulocyte colony–stimulating factor support, and transient renal impairment. She completed the last treatment cycle in March 2019. By then, her enlarged LNs had resolved, and haemoglobin and WBC count had normalized.

In 2021, the patient’s lymphocyte count started to increase, but she remained asymptomatic. She was monitored until early 2023, when she presented with lymphadenopathy, weight loss, worsening fatigue, and elevated WBC (120 x 10⁹/L) and lymphocyte (105 x 10⁹/L) counts, while her haemoglobin level was 11.1 g/dL and platelet level was normal. This prompted the decision to start second-line treatment. At this time, the patient’s Eastern Cooperative Oncology Group performance status (ECOG PS) was 1.

Second-line treatment and response
At 85 years of age, the patient was deemed unfit for further CIT. Thus, in March 2023, she was started on acalabrutinib, a next-generation Bruton tyrosine kinase (BTK) inhibitor available through public hospitals’ safety net. The standard dose of acalabrutinib 100 mg BID for 3 months resulted in good control of CLL symptoms, including improvement in WBC count and shrinkage of LNs. However, the patient experienced fatigue and persistent loss of appetite. The dosage of acalabrutinib was thus reduced to 100 mg QD, and the patient remained on the reduced dose for the past 3 months between July and September (the time of writing) 2023 with improved appetite, reduced fatigue and sustained disease control.

The most recent laboratory tests in August 2023 showed normal levels of WBC, haemoglobin and platelets. During 6 months of acalabrutinib treatment, the patient enjoyed good quality of life with stable ECOG PS.

Discussion
The choice of second-line treatment for CLL depends on several factors, including patients’ age, fitness, presence or absence of del(17p) or TP53 mutation, and prior treatment and response. For relapsed/refractory (R/R) CLL without TP53 mutation or del(17p) abnormality, second-line treatment options recommended by international guidelines include BTK inhibitor monotherapy (acalabrutinib, zanubrutinib, or ibrutinib), venetoclax + rituximab, idelalisib + rituximab (IR), or bendamustine + rituximab (BR).^1,2

The choice of acalabrutinib as second-line therapy in our patient was based on efficacy results of the ASCEND and ELEVATE-RR trials as well as acalabrutinib’s safety profile.^3,4

The randomized, open-label, phase III ASCEND trial compared acalabrutinib monotherapy with investigator’s choice of IR or BR in 310 patients with R/R CLL. After a median follow-up of 16.1 months, progression-free survival (PFS) was significantly longer with acalabrutinib vs IR or BR (median, not reached vs 16.5 months; hazard ratio [HR], 0.31; 95 percent confidence interval [CI], 0.20–0.49; p<0.0001).³ The PFS benefit associated with acalabrutinib was evident even in patients with high-risk genomic features, such as del(17p) plus TP53 mutation or unmutated IGHV. Furthermore, acalabrutinib demonstrated a better safety profile vs IR, with serious adverse events (AEs) occurring in 29 percent vs 56 percent of patients.³

ELEVATE-RR was a randomized, open-label, noninferiority, phase III trial (n=533) that compared acalabrutinib with ibrutinib in patients with previously treated CLL. After a median follow-up of 40.9 months, acalabrutinib was found to be noninferior to ibrutinib, with a median PFS of 38.4 months in both arms (HR, 1.00; 95 percent CI, 0.79–1.27).⁴ Acalabrutinib was associated with a significantly lower incidence of any-grade atrial fibrillation/flutter vs ibrutinib (9.4 percent vs 16.0 percent; p=0.02), as well as lower rates of bleeding events (38.0 percent vs 51.3 percent; p<0.05 [descriptive and numerical difference only]) and hypertension (9.4 percent vs 23.2 percent; p<0.001 [descriptive and numerical difference only]).⁴ (Figure)

Acalabrutinib’s lower rates of bleeding and CV AEs vs ibrutinib can be attributed to its increased selectivity for BTK occupancy and reduced activity against off-target kinases, while ibrutinib is known to inhibit other kinases, which possibly contributes to its less favourable safety profile.⁵ One of the risks associated with ibrutinib use is atrial fibrillation, which can be challenging to manage because of the bleeding risk associated with prophylactic anticoagulation medication.⁴

Consistent with findings from ELEVATE-RR, our patient had no evidence of bleeding, arrhythmia or worsening of hypertension during acalabrutinib treatment. The main AEs she experienced were loss of appetite and fatigue, which resolved following dose reduction. Whilst on acalabrutinib, patients should be monitored for symptoms of arrythmia, headache, musculoskeletal pain, hypertension, and bleeding. Coadministration of acalabrutinib with proton pump inhibitors should be avoided due to potential drug-drug interactions.⁶

In Hong Kong’s public hospitals, acalabrutinib use in R/R CLL is covered by a safety net with capping programmes. Once the cap is reached, free drug is subsequently provided through designated community pharmacies for as long as the patient needs treatment (ie, until disease progression or unacceptable toxicity).

Tolerability and long-term safety are crucial components of continuous BTK inhibitor therapy. Acalabrutinib’s lower rates of bleeding and CV AEs vs ibrutinib make it a preferred chemotherapy-free second-line treatment option for R/R CLL patients, especially the elderly or those with CV risk factors.⁴