Mind the gap in clinical practice guidelines—how I treat CLL patients with unmutated IGHV status

Chronic lymphocytic leukemia (CLL) is a malignancy of CD5⁺ B cells, characterized by the accumulation of small, mature-appearing neoplastic lymphocytes in the blood, bone marrow, and/or secondary lymphoid tissues. This results in lymphocytosis, leukemia cell infiltration of the marrow, lymphadenopathy, and splenomegaly [1]. CLL can be divided into two main subsets, distinguished by whether CLL cells express an unmutated or mutated immunoglobulin heavy-chain variable region gene (IGHV). These subsets differ substantially in their clinical behavior. The IGHV status reflects the stage of normal B‑cell differentiation from which they originate. Unmutated IGHV cells descend from B cells before their differentiation in the germinal centers, where somatic hypermutation during the immune response usually takes place. IGHV mutated CLL cells originate from the post-germinal center B cell, having already undergone somatic hypermutation as in normal B cells in an antigen-dependent immune response. Patients harboring CLL cells with unmutated IGHV status have always shown more aggressive disease compared with patients who have mutated IGHV in the chemotherapy era [2‐4].

For a long time, the presence of an unmutated IGHV status was considered a significant risk factor for patients with CLL, which had a prognostic influence on progression-free survival (PFS) and overall survival (OS; [2‐4]). With the introduction of numerous new targeted therapies, the situation has changed. This review focuses on the outcome data of patients with unmutated IGHV status under the treatment algorithms currently in use.

The recent onkopedia guidelines distinguish between three risk groups of CLL patients eligible for treatment [5]. Patients with unmutated IGHV status without the presence of a 17p deletion or a TP53 mutation represent an intermediate category. The presence of a high-risk trait (deletion 17p, TP53 mutation, or complex karyotype) overrides the IGHV status and categorizes patients into the high-risk cohort [1].

For the group with intermediate genetic risk, continuous therapy with a Bruton tyrosine kinase inhibitor (BTKi) or alternatively a temporary therapy in the form of venetoclax–Obinutuzumab or ibrutinib–venetoclax can be recommended with equal priority according to current knowledge. Individual patient characteristics (concomitant diseases, co-medication, patient wishes, etc.) are decisive for the specific selection. The choice of chemotherapy-free treatment options is generally based on existing comorbidities (especially renal or cardiac) or potential organ toxicities as well as possible interactions with drugs already prescribed independently of CLL.

Limited therapy has the advantage of reduced toxicity due to the time-limited use of medication. The lower probability of resistance developing with the subsequent possibility of re-treatment also speaks in favor of this therapeutic approach. The combination of venetoclax (Ven) and the anti-CD20 antibody obinutuzumab (Obi) is based on the long-observed courses of the CLL14 and CLL13 studies [6, 7]. In CLL14, older, comorbid patients in the control arm received chlorambucil and obinutuzumab. The 6‑year PFS data (i.e., 5 years from the end of therapy) showed continued PFS for 53% of patients in the experimental arm vs. 22% in the control arm. Patients with unmutated IGHV status had a significantly shorter PFS than patients with mutated IGHV status, both in the Ven-Obi arm (median PFS in patients with mutated IGHV status, not reached; hazard ratio [HR]: 2.66; 95% CI: 1.63–4.34) and in the Clb-Obi arm (median PFS in patients with mutated-IGHV status, 62.2 months; HR: 3.07; 95% CI: 2.15–4.38). Patients with an unmutated IGHV status benefit from Ven-Obi, showing significantly longer PFS than those with Clb-Obi (median PFS: 64.8 vs. 26.9 months; HR: 0.30; 95% CI: 0.22–0.42; [6]).

The CLL13 or GAIA study proved the advantage of venetoclax-based combination therapies even for younger, fitter patients, as published by Barbara Eichhorst in The New England Journal of Medicine [7]. This finally seals the end of chemoimmunotherapy (CIT), which has actually not played a role in the treatment algorithm for years. The use of CIT in the control arm excluded patients with del17p/TP53 mutations. More than 900 patients received either CIT or a venetoclax-based combination (Ven-Obi, Ven-rituximab, Ven-Obi-ibrutinib) in four treatment arms. The 4‑year PFS with Ven-Obi (81.8%) or Ven-Obi-ibrutinib (85.5%) was significantly superior to the control with CIT (62%); Ven-rituximab was not convincing (70.1%; [8]). In the Ven-Obi arms, more than 90% of patients had no further need for therapy after 4 years, a clear gain in quality of life for the patients. An exploratory subgroup analysis showed that unmutated IGHV was associated with shorter PFS across all treatment groups than was mutated IGHV. Nevertheless, this means an impressive gain in therapy-free time for patients. An increased rate of grade 3 and 4 infections with CIT and the triple combination also favors the use of the Ven-Obi dual combination. The subgroup of patients with unmutated IGHV appears to benefit most from the triple combination but with a significant increase in adverse events.

One option for limited, purely oral therapy is the combination of ibrutinib and venetoclax (I + V). The treatment concept of the published studies is similar [9‐11]: initial ibrutinib for usually 3 months to minimize the risk of TLS, followed by at least 12 cycles of combination therapy [9, 10] and, in some cases, MRD-guided maintenance [11]. Excellent response rates (88% complete remission and 61% MRD-negative remission) were already published in 2019 for older and high-risk patients, achieved after only 12 cycles of combination therapy [12]. The CAPTIVATE study, which is investigating both fixed-dose and MRD-guided therapy, also scores highly with promising response rates and the advantage of purely peroral therapy [10, 13]. The ibrutinib initiation phase showed a significant reduction in the risk of TLS, defined by the lymphocyte count and tumor mass: This means that the rate of hospitalizations required to initiate therapy can also be reduced from 40% (47%) to 18% (18%). Interestingly, the CR rate was higher in patients with unmutated vs. mutated IGHV (62% vs. 47%). The 36-month PFS rates were 92% (95% CI: 85–97) for patients with unmutated IGHV vs. 88% (95% CI: 88–99) for patients with mutated IGHV [14].

In the GLOW study, the combination I + V for older, comorbid patients was also convincing, with a PFS and even OS advantage, but this was associated with an increased rate of cardiac toxicities [15]. A recently published 4‑year update shows an influence on PFS, particularly for the unmutated IGHV status in the univariable and multivariable analysis. Of note, six of seven treatment-emergent pre-progression deaths in the ibrutinib–venetoclax group occurred in patients with unmutated IGHV [9]. In the latest ASH update, with a median follow-up of 67 months, the impact of IGHV status was confirmed with reduced 60-month PFS (82.5% vs. 52.2%; [16]).

The use of MRD measurements can maximize success for patients, as was impressively demonstrated in the FLAIR study [11]. By individually adjusting the dosage depending on whether MRD negativity was achieved (time of dosage until MRD negativity × 2), a 4-year PFS of 93.5% was achieved for the I + V combination, giving the majority of patients a long treatment-free period. An update, presented at ASH 2024, identified unmutated IGHV as a predictor for early MRD attainment (mutated vs. unmutated OR: 0.44; 95% CI: 0.25–0.75; p = 0.0026; [17]). On the other hand, patients with unmutated IGHV also showed a faster relapse, which calls into question the concept of MRD-driven duration of therapy.

Data from the AMPLIFY study, which investigated acalabrutinib and venetoclax ± obinutuzumab versus chemoimmunotherapy (FCR/BR), were presented at the last ASH [17]. The doublet and triplet combination therapy achieved a clear superiority in IRC-assessed PFS (AV vs. FCR/BR, HR: 0.65; 95% CI: 0.49–0.87; p = 0.0038; AVO vs. FCR/BR, HR: 0.42; 95% CI: 0.30–0.59; p < 0.0001) with a particular benefit for patients with unmutated IGHV status. Here, the PFS benefit extended to 82.8% 36-month PFS in the AVO arm versus 68.9% in the AV arm and only 56.8% in the FCR/BR arm. Nevertheless, there was no improvement in OS due to a high proportion of COVID-19-related deaths, especially in the therapy subgroup with the CD20 antibody [18].

In contrast to the temporary use of the aforementioned combinations, BTKIs are an essential component of CLL therapy in long-term therapy alone or in combination with anti-CD20 antibodies. Due to the long use of ibrutinib, experience with this substance class has been gained not only in studies but also in the real world. The 8‑year data from the RESONATE study showed a sustained benefit in terms of response for CLL patients, and 42% of patients were still on ongoing ibrutinib therapy. At 7 years, PFS rates were higher for ibrutinib vs. chlorambucil for patients with unmutated IGHV (58% vs. 2%) or with mutated IGHV (68% vs. 17%). Importantly, PFS was similar in ibrutinib-randomized patients with mutated vs. unmutated IGHV (HR: 0.858; 95% CI: 0.437–1.686). However, there were increasing warnings due to existing off-target effects, particularly in the cardiac area [19]. For example, numerous patients showed a significant increase in the incidence and severity of arterial hypertension with a consecutively increased risk of serious cardiac events [20].

The next generation of BTKIs is already available as a successor. Both acalabrutinib and zanubrutinib proved their efficacy in the first line compared to CIT [21, 22]. Acalabrutinib was convincing as a single agent or in combination with obinutuzumab compared to Obi-Clb, with 62% (mono) and 78% (combination) 6‑year PFS (vs. 17% for Obi-Clb), regardless of IGHV mutation status. IGHV status affects PFS for patients treated with Obi-Clb but not with acalabrutinib regimens [23]. The incidence of cardiac events was low, and the overall discontinuation rate was rather low despite the long duration of treatment.

Extended follow-up data are now also available for zanubrutinib. The efficiency compared to CIT, in this case bendamustine rituximab (BR), was shown in the SEQUOIA study [22].

Median 5-year follow-up data confirmed the superiority of zanubrutinib, and similar PFS rates were observed in zanubrutinib-treated patients with either mutated or unmutated IGHV genes (HR: 1.35; 95% CI: 0.76–2.40). Among patients with mutated IGHV genes, PFS was prolonged in zanubrutinib- vs. BR-treated patients (HR: 0.40; 95% CI: 0.23–0.69;p = 0.0003). Among patients with unmutated IGHV genes, median PFS was not reached in the zanubrutinib arm and was 33.6 months in the BR arm (HR: 0.21; 95% CI: 0.14–0.33; p < 0.0001; [24]). The side effects were also within the tolerable range.