History and initial presentation
A 66-year-old female presented with bilateral cervical lymphadenopathy in January 2022. She had type 2 diabetes mellitus, hypertension and hyperlipidaemia. Blood tests showed haemoglobin (Hb) level of 12.6 g/dL, white blood cell (WBC) count of 75.2 x 109/L, lymphocyte count of 67.6 x 109/L, and platelet count of 214 x 109/L. She was asymptomatic with a baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0.
On 30 March 2022, a cervical lymph node (LN) excisional biopsy confirmed chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL).
On 8 April 2022, a PET-CT scan showed generalized lymphadenopathy, with the largest LNs measuring approximately 3 cm in the common, external and internal iliac regions, with no organomegaly.
On 6 May 2022, a bone marrow examination showed extensive disease involvement by CLL, and cytogenetic findings revealed the presence of 13q14.3 deletion without 17p deletion. Next-generation sequencing showed unmutated immunoglobulin heavy-chain variable (IGHV) gene. Beta-2 microglobulin was elevated at >3.5 mg/dL. She was assessed to have Rai stage I and Binet stage B CLL. These findings corresponded to a CLL International Prognostic Index (IPI) score of 6.1 Since the patient was asymptomatic, a watch-and-wait approach was adopted with no treatment given.2
In December 2023, disease progression was noted based on progressive lymphocytosis and anaemia. (Figure 1) She also developed multiple palpable LNs measuring up to 3 cm in the bilateral cervical and submandibular regions.
Treatment and response
In view of disease progression, the patient was started on treatment with the oral next-generation Bruton tyrosine-kinase (BTK) inhibitor, acalabrutinib, at 100mg BID, on 26 February 2024. Her blood counts were monitored weekly. During the first few weeks of treatment, she reported self-limiting palpitations with no associated chest pain, syncope or arrhythmia.
On 26 March 2024, lymphocytosis worsened (lymphocyte count, 269.3 x 109/L; WBC count, 286 x 109/L). On 9 April 2024, anaemia also worsened (Hb level, 7.6 g/dL). (Figure 1) However, her lymphadenopathy had improved, with no palpable LNs noted on 10 April 2024.
In May 2024, the patient developed a self-limiting, nonspecific rash over her arms and legs. These promptly resolved after using a prescribed topical cream.
On 18 June 2024, blood tests showed gradual improvement in leucocytosis and anaemia. (Figure 1)
The patient was hospitalized due to COVID-19 pneumonia on 27 September 2024. Acalabrutinib treatment was temporarily withheld, and she was treated with remdesivir, dexamethasone and meropenem. She was discharged on 19 October 2024, resuming acalabrutinib therapy after recovery.
On 7 October 2024, a PET-CT scan showed complete resolution of lymphadenopathies. By 12 December 2024, the patient’s blood counts had almost normalized. (Figure 1)
Except for the temporary treatment interruption due to COVID-19, the patient continued acalabrutinib treatment without any dose adjustments. As of 13 December 2024, she remained asymptomatic and was tolerating therapy well, with an ECOG PS of 0.
Discussion
CLL is a clinically heterogeneous disease, displaying a variety of molecular abnormalities that are responsible for disease pathogenesis, progression, and transformation. Molecular studies in CLL have identified biomarkers for precision management, which entails individually tailored treatment of the disease on the basis of genetic characteristics and the patient’s clinical profile. These predictors allow optimization of treatment strategies, including the use of innovative drugs, for personalized medicine in CLL management.3
In particular, TP53 and IGHV mutation status are predictive biomarkers crucial for CLL risk stratification and prognostication, and should be determined especially in treatment-naïve CLL patients to guide the choice of therapy at treatment initiation. TP53 mutations indicate high-risk disease with poor prognosis and reduced chemotherapy response. Unmutated IGHV is associated with adverse outcomes and poor chemo-immunotherapy (CIT) response, but these patients may benefit from BTK inhibitors, such as acalabrutinib.3
Since our patient did not have a strong preference on choice of treatment, did not have complex karyotype or bulky disease in need of rapid debulking, and had unmutated IGHV, acalabrutinib – the preferred first-line treatment for patients with CLL/SLL without del(17p)/TP53 mutation – was selected.2,4 Even with the high-risk genomic feature of unmutated IGHV, the patient still had a positive experience with first-line acalabrutinib, which aligns with results of the randomized, open-label, phase III ELEVATE-TN trial.5
ELEVATE-TN investigated the efficacy and safety of acalabrutinib with or without the anti-CD20 monoclonal antibody, obinutuzumab, vs CIT with chlorambucil and obinutuzumab in 535 patients with treatment-naïve CLL. After a median follow-up of 28.3 months, median progression-free survival (PFS) was longer in acalabrutinib-treated vs CIT-treated patients (median PFS, not reached for both acalabrutinib-containing arms vs 22.6 months with obinutuzumab; p<0.0001 for both comparisons).5
After a 6-year follow-up, survival benefits remained in favour of acalabrutinib-containing arms. Median PFS was not reached for acalabrutinib-obinutuzumab and acalabrutinib monotherapy vs 27.8 months for CIT (hazard ratios [HRs] vs CIT, 0.14 and 0.24, respectively; both p<0.0001).6,7 (Figure 2)
Results remained consistent in patients with high-risk genomic features, namely, del(17p) and/or TP53 mutation, unmutated IGHV, or complex karyotypes.5-7 In particular, median PFS in patients with unmutated IGHV was also not reached in acalabrutinib-containing arms vs 22.2 months in the CIT arm.6
Acalabrutinib’s safety profile in ELEVATE-TN was consistent with previously reported findings, with low incidence of grade ≥3 adverse events (AEs) typically associated with BTK inhibitors.5-7 The phase III ELEVATE-RR study showed that in patients with previously treated CLL, acalabrutinib was associated with significantly lower rates of all-grade atrial fibrillation/atrial flutter vs ibrutinib.8 Similar findings have also been demonstrated in a real-world study.9
ELEVATE-TN showed a potential PFS benefit with acalabrutinib-obinutuzumab vs acalabrutinib monotherapy (6-year HR, 0.58; p=0.0229). However, this was a post hoc analysis, and the study was not powered for this comparison. Results also showed that adding obinutuzumab increased grade ≥3 AEs, including neutropenia, thrombocytopenia, diarrhoea and second primary malignancies. Due to these findings, acalabrutinib monotherapy was deemed a safer option for our patient with cardiovascular comorbidities.6,7
As long-term efficacy and safety data are still limited, the author is of the opinion that at present, the combination of obinutuzumab with acalabrutinib should be reserved for patients with minimal comorbidities with high-risk CLL features (such as TP53 mutation and unmutated IGHV) who are likely to benefit the most from this treatment.
As experienced by our patient, BTK inhibitor use in CLL may cause initial lymphocytosis.4 However, this represents lymphocyte egress from nodal compartments rather than disease progression, and typically resolves within 8 months in most cases.10-12 (Figure 1) Importantly, prolonged lymphocytosis does not negatively impact PFS or indicate early relapse.10-12
In summary, our patient’s positive experience with first-line acalabrutinib monotherapy aligns with the current efficacy and safety data and treatment recommendations for patients with CLL/SLL with unmutated IGHV and without del(17p)/TP53 mutation.
