Selecting from the Red Book CHS: What's New in This Year's Recommendations for the Diagnosis and Treatment of CLL?

1st Line Treatment for Patients Without TP53 Deletion/Mutation

The main treatment regimen for patients without TP53 deletion/mutation in good condition remains FCR (fludarabine, cyclophosphamide, rituximab), which, unlike the regimens venetoclax + obinutuzumab, ibrutinib + venetoclax, acalabrutinib + obinutuzumab, ibrutinib, and zanubrutinib, is covered by public health insurance (PHI) and does not require a reviewer's approval.

For patients with significant comorbidities (according to the Cumulative Illness Rating Scale /CIRS/ > 6) or with kidney function impairment, the main covered regimen is venetoclax + obinutuzumab. Based on the results of the randomized study CLL13, this regimen can also be used for patients without significant comorbidities (CIRS ≤ 6), but it currently does not have coverage. A highly effective therapeutic alternative is the combination of ibrutinib + venetoclax, which also currently lacks coverage conditions.

Another covered treatment option is obinutuzumab + chlorambucil, especially in the case of IGHV mutation. Non-covered regimens mentioned above: acalabrutinib + obinutuzumab, ibrutinib, zanubrutinib, ibrutinib + venetoclax can also be utilized.

1st Line Treatment for Patients with 17p Deletion/TP53 Mutation

For patients with 17p deletion and/or TP53 mutation, continuous administration of a Bruton tyrosine kinase inhibitor (BTKi) − ibrutinib, acalabrutinib or zanubrutinib is recommended. In the case of higher cardiovascular risk, the latter two are preferred.

In addition to BTKi, these patients can use the venetoclax + obinutuzumab regimen, or ibrutinib + venetoclax (without PHI coverage).

Treatment of Relapsed or Refractory CLL

The choice of a suitable regimen for patients with relapsed CLL depends on many factors:

• overall condition
• comorbidities
• age
• presence of 17p deletion or TP53 mutation
• previous therapy
• treatment response and its duration

For patients with late relapse (treatment response > 3 years), the same regimen can be repeated. For venetoclax-based regimens, the minimum duration of the treatment response is not currently clearly defined, but it is assumed to be at least 1−2 years. If the response was shorter or progression occurred during venetoclax therapy, or if the therapy had to be discontinued due to toxicity, BTK inhibitors are the main option.

For BTKi regimens, it depends on the reason for discontinuation. If it was for side effects, an alternative BTKi regimen can be used. If it was due to progression during therapy, the main treatment option is the venetoclax + rituximab regimen. Alternatively, continuous administration of venetoclax (currently without PHI coverage) can be considered.

If we are deciding for a patient with 17p deletion and/or TP53 mutation, the preferred option is continuous BTKi administration, if not previously treated with it, or the venetoclax + rituximab combination. This has several advantages for 2nd-line treatment in relapsed or refractory patients to chemoimmunotherapy: it has high efficacy in achieving undetectable minimal residual disease (MRD). Additionally, venetoclax treatment is limited to 2 years compared to BTKi, where long-term continuous administration until progression (or unacceptable toxicity) is required, increasing the risk of side effects, a decline in therapy compliance, and the selection of a resistant clone.

Continuous venetoclax administration in monotherapy can be considered for patients who fail BTKi, especially in the presence of 17p deletion and/or TP53 mutation.

If BTKi or venetoclax is not suitable, the idelalisib + rituximab regimen can be used, in some cases also the RCD regimen (rituximab, cyclophosphamide, dexamethasone), especially with concurrent autoimmune cytopenia, or alemtuzumab (available in the Czech Republic only within a specific treatment program).

Prognostic Examinations

Recommendations for prognostic examinations remain largely unchanged. Newly, clinical relevance has been found for minor clones with TP53 mutations detectable by next-generation sequencing (NGS). NGS should be preferred over classical Sanger sequencing.

What Do the New Findings from Clinical Studies Say?

Recently published results from the CLL14 and MURANO studies support the role of venetoclax in the treatment of CLL. While the multicenter randomized CLL14 study evaluated the venetoclax + obinutuzumab (Ven+O) regimen compared to obinutuzumab + chlorambucil in 1st-line treatment, the randomized MURANO study focused on comparing venetoclax + rituximab (Ven+R) versus bendamustine + rituximab (BR) regimens in relapsed or refractory disease; both cases involved fixed-duration venetoclax administration.

In the CLL14 study, 53.1% of patients were in remission 5 years after completing Ven+O treatment, and 65.2% did not require starting another line of therapy. In patients with relapsed or refractory CLL, the MURANO study demonstrated longer overall survival with the Ven+R regimen compared to the BR regimen. In cases where the Ven+R regimen needed to be repeated upon relapse, this therapy showed a high overall response rate with the possibility of achieving undetectable MRD.

(jala)

Sources:
1. Špaček M., Šimkovič M., Pospíšilová Š. et al. Chapter 7: Chronic Lymphocytic Leukemia. In: Red Book. Treatment Procedures in Hematology 2023. Czech Hematological Society ČLS JEP, October 23, 2023. Available at: www.hematology.cz/wp-content/uploads/2023/10/07-Chronicka_lymfocytarni_leukemie-verze-01-2023.pdf
2. Móciková H. Long-term results of venetoclax administration with anti-CD20 antibody for limited treatment duration. Acta Medicinae 2023; 12 (11−13): 111−114.