Chronic Lymphocytic Leukemia (CLL)

Treatment options for first-line therapy are currently changing and expanding. The following are currently considered genetic risk factors:

• del(17p13) or TP53 mutation

• IGHV unmutated status (IGHV_unmut )

Various treatment options are available, particularly for patients without a high-risk genetic profile (without del(17p13) or TP53 mutation). The selection of these options—which are generally chemotherapy-free—is primarily guided by existing comorbidities or potential organ toxicity (particularly renal or cardiac) as well as possible interactions with medications already prescribed independently of CLL. The relevant results from treatment studies can be summarized as follows:

The choice of relapse therapy depends on several individual factors. In addition to the patient’s age and comorbidities, these primarily include clinical parameters such as the type of primary therapy, the duration of remission achieved, and any changes in the biological characteristics of CLL since the initial diagnosis in the context of clonal evolution (e.g., acquisition of a del(17p13) or TP53 mutation). Furthermore, after continuous therapy with BTK or BCL2 inhibitors, specific resistance mutations (including those in BTK, PLCγ2, or BCL2) may arise; detection of these mutations makes repeating the corresponding therapy appear inadvisable. Resistance testing can be particularly informative when using the non-cytotoxic BTK inhibitor (ncBTKi) pirtobrutinib following failure on acalabrutinib or zanubrutinib, as cross-resistance may occur. Testing for resistance mutations is also recommended in the reverse scenario—that is, prior to initiating a cytotoxic BTK inhibitor (cBTKi) following failure of the ncBTKi pirtobrutinib. However, the clinical significance of not all variants is clear. As a general rule, given the clear superiority of the new agents (particularly BTK and BCL2 inhibitors) over various chemoimmunotherapies in terms of overall survival (OS), the latter should now only be used in very select, exceptional cases of relapse (patient preference, pre-existing combined cardiac/renal conditions, etc.). If a patient has received chemoimmunotherapy as primary therapy, in the event of relapse — even with a long remission duration (>24 months) — repeat chemoimmunotherapy is not recommended due to the demonstrated survival benefit (e.g., the MURANO study) and the risk of secondary malignancies (including tMDS); instead, therapy with new agents is preferred. An algorithm is shown in Figure 3. Whenever possible, treatment should be conducted within the framework of clinical trials.

Patients who are refractory to current therapy or who achieve a remission duration of less than 3 years, as well as patients with relapsed disease who test positive for a del(17p13) or a TP53 mutation, have a poor prognosis. Before the introduction of the new agents, their median overall survival was 1–2 years, calculated from the start of salvage therapy. In these studies, achieving “stable disease” in patients requiring treatment, as defined by the 2018 IWCLL criteria, was also classified as treatment failure [15].

Meanwhile, the following agents are available: the covalent BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib; the non-covalently binding BTK inhibitor pirtobrutinib; the BCL2 inhibitor venetoclax (plus rituximab); and the PI3K-delta inhibitor idelalisib (plus rituximab). The registration trials primarily enrolled patients with relapse following chemoimmunotherapy; consequently, the data available on the use of these new agents in patients who have previously received BTK inhibitors or venetoclax-based regimens are limited.

The most important current study data can be summarized as follows, although it should be noted that in these studies, prior treatments were mostly based on chemoimmunotherapy, so the interpretive value regarding relapse therapy following targeted therapies is limited.

• The BTK inhibitor acalabrutinib resulted in a significant prolongation of progression-free survival (HR 0.31) in patients who had received at least one prior therapy, compared with a treatment regimen chosen by the treating physician (idelalisib/rituximab or bendamustine/rituximab) (ASCEND study) [42].

• The BTK inhibitor zanubrutinib resulted in a higher remission rate (80.4% vs. 72.9%, p=0.0264) and better 3-year PFS (64.9% vs. 54.8%) in patients with relapsed CLL compared with ibrutinib (ALPINE trial) [27]. In the subgroup of patients with TP53 aberrations, PFS was significantly better compared with ibrutinib (HR 0.53) [27].

• The non-covalently binding BTK inhibitor pirtobrutinib was specifically tested in the BRUIN-321 study in patients who had all been pretreated with a covalent BTK inhibitor and, in half of the cases, also with venetoclax. Compared with relapse therapy using bendamustine/rituximab or idelalisib plus rituximab, pirtobrutinib demonstrated significantly better PFS (14 months vs. 8.2 months and 8.8 months, respectively). The time to next treatment (TTNT) was also significantly prolonged with pirtobrutinib (24 months vs. 10.9 months) [43].

• The BCL2 inhibitor venetoclax, in combination with rituximab, resulted in prolonged PFS (HR 0.16; median not reached) and OS (HR 0.50; median not reached), an increase in the rate of hematologic remissions, and an increase in MRD negativity (MURANO study) [44, 45]. Venetoclax monotherapy resulted in a 79% remission rate in patients with relapsed or refractory CLL with evidence of del(17p13) or a TP53 mutation and following prior treatment with a BCR signaling pathway inhibitor (single-arm study) [46, 47].

The treatment recommendation for disease recurrence (see Figure 3) depends largely on the prior therapy:

For patients who have received first-line treatment with chemoimmunotherapy, BTK inhibitors are available as an alternative to the venetoclax/rituximab combination for second-line therapy. Results from direct comparative studies between venetoclax/rituximab and ibrutinib, acalabrutinib, or zanubrutinib are not available. Even though direct data from studies for this patient group are lacking, if a TP53 aberration is detected — even in the relapse — continuous therapy with a BTKi would, in principle, be preferred over a time-limited BCL2i-based treatment (VenR); conversely, in cases of mutated IGHV, there would be a preference for time-limited therapy with venetoclax/rituximab.

For patients who have received prior BTKi treatment, the combination of venetoclax and rituximab (VenR) represents the preferred standard of care starting with second-line therapy, regardless of risk classification or performance status, due to its high efficacy and limited treatment duration (2 years for VenR). Due to the clear superiority of VenObi over VenR in the first-line setting (see the DCLLSG’s CLL13 study), the VenObi regimen (as in the CLL14 study) can and should also be considered. Based on the EMA approval, pirtobrutinib may be administered regardless of prior therapies and, therefore, also in cases of relapse, regardless of whether prior therapy included a BTKi or venetoclax. For this specific treatment situation in particular, there is a stronger evidence base based on the BRUIN-321 study, which included 100% BTKIs-pretreated patients (in contrast to 3% BTKIs pretreatment in MURANO). Overall, even in the relapsed setting, the advantages and disadvantages of a time-limited regimen versus a continuous regimen — similar to first-line therapy — must be weighed and discussed with the patient.

Conversely, in patients who have previously been treated with venetoclax plus obinutuzumab, BTK inhibitors (cBTKi, ncBTKi) demonstrate very good efficacy. Following prior treatment with venetoclax plus obinutuzumab, re-treatment with venetoclax (plus rituximab, in accordance with the current approval) may be effective, particularly in cases of prolonged remission (over 2 to 3 years). Re-exposure to VenObi in relapse is currently being tested as part of the ReVenG study. However, there are currently insufficient data on how long the remission duration should be for re-treatment with the BCL2 inhibitor to be appropriate.

For patients who relapse after or during primary therapy based on ibrutinib plus venetoclax (I+V) or acalabrutinib plus venetoclax (AV, AVO), preliminary data are available on re-treatment with a BTKi or venetoclax-based therapy. In principle, therefore, only a preliminary recommendation can currently be made for relapse therapy based on BTK inhibitor monotherapy (including pirtobrutinib), venetoclax monotherapy, or venetoclax/rituximab.

In summary, following prior treatment with venetoclax/obinutuzumab and I+V, venetoclax-based therapy or a switch to a BTK inhibitor is possible. Conversely, following treatment failure—defined as disease progression—while on a covalent BTK inhibitor, therapy with venetoclax (+/- rituximab) or with the non-covalent BTK inhibitor pirtobrutinib may be initiated. If intolerance is the cause of first-line treatment failure, a switch to a different BTKi may be possible. When using BTK inhibitors, second-generation BTK inhibitors (acalabrutinib, zanubrutinib) and the non-covalent BTK inhibitor pirtobrutinib are preferred over first-generation BTK inhibitors ( ; zanubrutinib, see the ALPINE study) due to their more favorable side effect profile and, in some cases, greater efficacy; ibrutinib remains available as an alternative therapy. No definitive data on the optimal sequence are currently available.

The availability of highly effective molecular therapies, along with the resulting improvement in prognosis, has significantly diminished the importance of allogeneic stem cell transplantation (allo-SCT) in CLL. However, it remains an option in situations associated with a relatively poor prognosis even with modern treatment options. Its efficacy has been demonstrated even after prior exposure to signaling pathway inhibitors, including in double-refractory patients [56], although it remains unclear at this time whether the latter benefit as much as patients responsive to signaling pathway inhibitors [55]. Allogeneic stem cell transplantation (allo-SCT) is generally worth considering when patients with TP53 alterations or a highly complex karyotype have become refractory to covalent BTK inhibitors or venetoclax, or when, regardless of TP53 status, both classes of agents have failed in cases of “double-refractory CLL” [57].

The indication, timing, and execution of a transplant—including donor selection—should be clarified in close collaboration with a transplant center before initiating salvage therapy. An important prognostic factor for achieving long-term disease control is the presence of remission at the time of allogeneic transplantation. Whenever possible, the transplant should be performed within the context of clinical trials.

High-dose therapy with autologous blood stem cell transplantation can no longer be recommended for the treatment of CLL.

Although CLL was the first condition in which CAR-T cells were successfully used in adults, efficacy data for CLL have not kept pace with those for established B-cell NHL indications, particularly with regard to complete response rates. Based on the CLL004 study, in which an overall response rate of 47% and a rate of durable complete remissions (CRs) of 18% were achieved in double-refractory patients [58], Lisocel has been approved by the FDA for this patient population. However, the Lisocel manufacturer did not pursue EMA approval. In contrast to the CLL004 study and also the ZUMA-8 study with Brexucel, which primarily included patients with large tumor masses [41], the Heidelberg HD-CAR-1 study followed the concept of consolidative CAR-T therapy. Although 5 out of 7 patients treated with an effective dose of the CD19 product Heidagen lecleucel achieved an MRD-negative CR, the majority did not achieve sustained disease control (median PFS 12 months, 2-year PFS 40%) [55, 59]. Based on these data, Heidagen lecleucel received marketing authorization from the Paul Ehrlich Institute under Section 4b of the German Medicines Act (AMG) (Hospital Exemption) and is thus available in Germany for the treatment of double-refractory patients even outside of clinical trials.

The clinical significance of CAR-T therapy cannot yet be conclusively assessed; however, with the currently available products, a curative effect is likely to be achievable—if at all—only in a small proportion of double-refractory patients, in contrast to allogeneic stem cell transplantation (allo-SZT). Nevertheless, it represents a comparatively effective and well-tolerated addition to the previously inadequate therapeutic arsenal for double-refractory patients. CAR T-cell therapy should be administered within the framework of clinical trials whenever possible,

In patients with Richter transformation, retrospective, multicenter analyses have shown evidence of efficacy for the CAR T-cell products Axi-cel, Tisa-cel, and Liso-cel, which are approved for LBCL. However, with 2-year PFS rates of around 30%, the results appear to be somewhat poorer than those for de novo LBCL [60, 61]. Nevertheless, commercial CAR-T therapy may be considered as a potentially curative option in individual cases of relapse even outside of clinical trials, particularly if a response to salvage therapy can be achieved and allogeneic stem cell transplantation is not an option. The same applies to BiTEs (including epcoritamab) in refractory situations.

New data on bispecific antibodies (particularly epcoritamab) suggest high efficacy even in multi- (double/triple)-refractory patients. Preliminary analyses report high response rates with low CRS and ICANS frequencies, both as monotherapy (EPCORE-CLL1) [62] and in combination with venetoclax (AETHER Trial) [63].

In addition to CARs and BiTEs, so-called BTK degraders—a new class of drugs for CLL—are currently being tested in clinical trials and are showing, in some cases, high response rates exceeding 90% in refractory CLL study populations [64].

CLL patients frequently experience infectious complications over the course of the disease, which are exacerbated by the decline in immunoglobulin concentrations and other mechanisms of acquired immunodeficiency; see Onkopedia’s entry on secondary immunodeficiencies (in German only). Particularly careful monitoring with intensive general internal medicine treatment—e.g., for chronic or recurrent bronchitis—is indicated. Prophylactic immunoglobulin replacement therapy reduces the risk of severe infections but has no significant effect on mortality. In June 2018, the EMA updated its guideline in the form of a Summary of Product Characteristics and established the following criteria for immunoglobulin replacement therapy in patients with secondary immunodeficiency [65]:

• Severe or recurrent infections

• Ineffective antimicrobial therapy

• And evidence of a lack of specific antibody production (following vaccination) or serum IgG levels <4 g/L.

Age-appropriate vaccinations are recommended (see Onkopedia – Vaccinations (in German only)), although the production of specific antibodies may be reduced, and vaccinations should be administered whenever possible before initiating therapy. Travel vaccinations should only be administered after consultation with the treating specialist, as live vaccines, among other things, could pose a risk to the patient.

Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) are common concomitant conditions in CLL [66]. AIHA is typically Coombs-positive. Cold agglutinins with detectable IgM antibodies are the exception. Coombs-negative hemolytic anemias have been described following prior therapy with purine analogs. Patients should be made aware of the particularly high risk of crises in the context of infections. Pure red cell aplasia (PRCA) is rarely observed. If AIHA or ITP occurs in isolation without other symptoms of CLL requiring treatment (see above), therapy with corticosteroids is indicated. Otherwise, treatment according to the algorithms mentioned above (see Tables 1 and 2), with a preference for anti-CD20-containing therapies (VenObi, Acalabrutinib-Obi, Venetoclax/Rituximab), is recommended, although there is also limited data on the use of targeted agents in patients with autoimmune phenomena [67].

Acalabrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor. This kinase plays a central role in the development, differentiation, signal transduction, and survival of B lymphocytes. In the pivotal trial, acalabrutinib—either alone or in combination with obinutuzumab—significantly prolonged progression-free survival compared with chlorambucil/obinutuzumab in patients >65 years of age and in patients <65 years of age with comorbidities who had untreated CLL (acalabrutinib HR 0.2; acalabrutinib/obinutuzumab HR 0.1) [23]. Acalabrutinib in combination with obinutuzumab also led to an improvement in overall survival compared with chlorambucil/obinutuzumab (HR 0.55, p=0.0474) [68]. Patients with a confirmed del(17p13) or TP53 mutation benefit from acalabrutinib to nearly the same extent as patients without this risk factor; however, the addition of obinutuzumab does not improve outcomes compared with monotherapy.

Severe adverse events (CTCAE Grade 3/4) associated with acalabrutinib monotherapy in the ELEVATE-TN trial [23] included neutropenia (10%), anemia (7%), thrombocytopenia (3%), and pneumonia (2%). Diarrhea of all severities occurred in 35% of patients. Arrhythmias may occur with acalabrutinib, most commonly atrial fibrillation in 3–4% of patients. Diarrhea that occurs early in treatment is often self-limiting. Treatment with acalabrutinib may initially lead to lymphocytosis due to the flushing out of leukemia cells from lymphatic compartments. Other clinically relevant side effects include mild bleeding (43%), particularly from bruises (24%), and the development or worsening of hypertension, with 3% of cases classified as CTCAE Grade 3. Acalabrutinib is administered orally.

Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor. This kinase plays a central role in the development, differentiation, signal transduction, and survival of B lymphocytes. In the pivotal trial, ibrutinib resulted in a significant prolongation of progression-free survival (hazard ratio 0.22) and overall survival (hazard ratio 0.43) in patients with relapsed or refractory CLL [69]. Patients with a confirmed del(17p13) or TP53 mutation benefit to nearly the same extent as patients without this risk factor. In untreated patients aged ≥65 years, ibrutinib is superior to chlorambucil monotherapy. Furthermore, ibrutinib-based therapy demonstrated superiority over both bendamustine/rituximab [22] and a combination of chlorambucil/obinutuzumab [70] in first-line therapy for older or less fit patients. Ibrutinib monotherapy was not inferior to the combination of ibrutinib and rituximab [22]. In the context of the E1912 study, the superiority of ibrutinib/rituximab over FCR in first-line therapy for young/fit CLL patients was also documented [21]; see Chronic Lymphocytic Leukemia – Study Results.

Severe adverse effects of ibrutinib monotherapy (CTCAE Grade 3/4) in the RESONATE studies [71] and the ALLIANCE study [22] included neutropenia (10–16%), anemia (4–12%), thrombocytopenia (2–7%), pneumonia (4–7%), and diarrhea (4%). Arrhythmias may occur with ibrutinib; the most common is atrial fibrillation, occurring in 5–8% of patients. Patients with severe arrhythmias (ventricular tachycardia, high-degree block) were excluded from the studies. Isolated cases of sudden death and invasive aspergillosis have been reported. Diarrhea that occurs early in treatment is often self-limiting. Treatment with ibrutinib initially leads to lymphocytosis due to the flushing out of leukemia cells from lymphatic compartments. Other clinically relevant side effects include skin hemorrhages (approximately 40%) and the development or worsening of arterial hypertension. The rate of worsening hypertension is reported to be 78% when a threshold of 130/90 mmHg is used, in accordance with the criteria of the American College of Cardiology. Based on the threshold of the European Society of Cardiology (ESC), this rate is calculated at 44% [72]. Ibrutinib is administered orally.

Idelalisib is a selective inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ). This kinase plays an important role in B-cell receptor-induced signal transduction in mature B lymphocytes and in the pathogenesis of CLL. When combined with an anti-CD20 antibody (ofatumumab or rituximab), idelalisib leads to an increase in remission rates to 70–85%, a significant prolongation of progression-free survival (hazard ratio 0.2), and overall survival (hazard ratio 0.34–0.75) [73, 74]. Severe adverse effects of the combination therapy of idelalisib + rituximab (CTCAE Grade 3/4) included neutropenia (34%), thrombocytopenia (10%), anemia (5%), elevated transaminases (5%), diarrhea (4%), fever (3%), fatigue (3%), and chills (2%). In the spring of 2016, interim results from three ongoing studies on first-line therapy showed an increased number of infection-related deaths in the treatment arm receiving idelalisib. The report by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recommends antibiotic prophylaxis for Pneumocystis jirovecii and regular monitoring for signs of infection, particularly signs of CMV infection. Idelalisib is administered orally. The company will discontinue the distribution of idelalisib as of March 1, 2027, meaning that this medication will no longer be available for the treatment of CLL in the future.

On March 15, 2024, Liso-cel was approved by the FDA in the United States for patients with BTKi- and BCL2-i-refractory CLL, based on the CLL004 study [58]. However, approval in Germany is still pending. Based on 49 patients who received a higher dose of CAR-T cells (100 ^{× 10⁶}, dose level 2), the CLL004 study ( ) showed that 18% of patients achieved complete remission. Based on 117 patients, severe cytokine release syndrome (CRS) was observed in 9% of patients, and severe neurological events in 19%. A fatal case of macrophage activation syndrome was reported in one patient in this study.

Obinutuzumab is an anti-CD20 antibody with altered glycosylation. In treatment-naive patients with comorbidities, it led to a significant prolongation of progression-free survival (hazard ratio 0.39; median 11.5 months) when used in combination with chlorambucil compared to chlorambucil-rituximab therapy [75] and, in a later analysis, also in terms of overall survival (hazard ratio 0.76; median not reached) [76]. Severe adverse effects of combination therapy with chlorambucil (CTCAE Grade 3/4) included infusion-related reactions (21%), neutropenia (35%), thrombocytopenia (11%), and anemia (5%). Obinutuzumab is administered intravenously.

Pirtobrutinib is a selective, non-covalently binding BTK inhibitor that was evaluated in a Phase I/II trial in patients with relapsed/refractory CLL/SLL (BRUIN). Among patients, the majority of whom (78%) had received a BTKi and some of whom had also received venetoclax (40.5%) as prior therapy, a response rate of 73.3% was observed with a median PFS of 19.6 months [77]. The most common adverse effects reported were infections (71%), bleeding (42.6%), and neutropenia (32.5%). In addition, the following adverse events occurred in this study with pirtobrutinib: hypertension (14.2%), atrial fibrillation/flutter (3.8%), and severe hemorrhages (2.2%). The so-called BRUIN-321 study, which randomly compared the use of pirtobrutinib against idelalisib/rituximab or bendamustine/rituximab, was relevant for regulatory approval. Based on 238 patients, a significantly better median PFS was observed with pirtobrutinib (14 months) compared to the standard-of-care arm (8.7 months). The time to next treatment (TTNT) was also significantly improved with pirtobrutinib, at 24 months (24 months vs. 10.9 months) [43]. The drug was approved by the FDA on December 1, 2023, for patients with double-refractory (BTKi, BCL2i) CLL. On March 31, 2025, the EMA granted approval, with pirtobrutinib already approved for patients who had previously been treated with a covalent BTK inhibitor alone; thus, patients do not necessarily have to be double-refractory. Pirtobrutinib was also recently tested as a first-line therapy in two randomized Phase III trials: In the BRUIN-313 trial, pirtobrutinib demonstrated a significant prolongation of progression-free survival (PFS) and a substantial reduction in risk compared with the standard therapy of bendamustine/rituximab [28]. The BRUIN-314 study further demonstrated the non-inferiority of pirtobrutinib compared to ibrutinib in terms of overall response rate, while also exhibiting a more favorable safety profile and fewer cardiac side effects [29]. On June 26, 2026, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive recommendation to expand the marketing authorization for pirtobrutinib to include first-line treatment of CLL, based on these two studies.

Rituximab is a chimeric anti-CD20 antibody. It was first approved for the treatment of patients with indolent lymphomas. Rituximab is effective as monotherapy for CLL; the effect is dose-dependent. In combination with fludarabine and cyclophosphamide (FCR), rituximab was the first agent to result in a significant prolongation of overall survival. The most common side effects of rituximab are immediately infusion-related and include fever, chills, nausea, and general malaise. Cytokine release syndrome can lead to severe hypotension with high fever, hypoxia, and the need for intensive care. The occurrence of cytokine release syndrome correlates with tumor burden and depends on the rituximab dosage. Side effects of FCR combination therapy classified as CTCAE Grade 3/4 include cytokine release syndrome, neutropenia (34%), infections (25%), thrombocytopenia (7%), and anemia (4%). Rituximab can be administered intravenously or subcutaneously. Currently, only intravenous administration is approved for CLL.

Venetoclax blocks the anti-apoptotic B-cell lymphoma-2 protein (BCL2), thereby inducing programmed cell death. In one of the two non-randomized registration studies, venetoclax resulted in partial or complete remission in 75% of pretreated patients with a del17p or TP53 mutation. Among patients without a del17p or TP53 mutation but who had previously been treated with a BCR signaling pathway inhibitor (ibrutinib or idelalisib), 67% achieved partial or complete remission. Furthermore, venetoclax demonstrates clinical activity in patients who have received prior treatment with chemoimmunotherapy and a BCR inhibitor, regardless of TP53 aberration status [44, 46]. Furthermore, data from a randomized trial comparing venetoclax to bendamustine were published as part of the MURANO study; response rates—including the MRD-negativity rate—and progression-free survival were significantly improved in favor of the venetoclax/rituximab combination (time-limited therapy over a total of 2 years), regardless of TP53 status [46]. Venetoclax is approved as monotherapy for first-line treatment of patients with 17p or TP53 mutations, provided the patient is not eligible for ibrutinib therapy. The combination of venetoclax and obinutuzumab (limited to a total treatment duration of approximately 10.5 months, corresponding to 12 cycles of venetoclax) was approved by the FDA and EMA in 2020 based on data from the CLL14 study [31]; for national regulations.

The most common side effects of venetoclax are neutropenia, diarrhea, nausea, anemia, upper respiratory tract infections, fatigue, and elevated blood phosphate levels. Severe side effects may include febrile neutropenia, pneumonia, and initial tumor lysis syndrome. To prevent tumor lysis syndrome, a dose escalation schedule for the first few weeks has been included in the prescribing information. It starts at 20 mg and reaches the target dose of 400 mg by week 5. Venetoclax is administered orally.

Zanubrutinib is a second-generation Bruton’s tyrosine kinase (BTK) inhibitor with more specific kinase inhibition compared to ibrutinib. In the SEQUOIA study, zanubrutinib monotherapy in patients >65 years of age or in patients <65 years of age with comorbidities and untreated CLL resulted in a significant prolongation of progression-free survival compared with bendamustine/rituximab (zanubrutinib HR 0.3), but not of overall survival. Patients with a confirmed del(17p13) or TP53 mutation benefit to nearly the same extent as patients without this risk factor; the same applies to those with an unmutated IGHV status.

Severe adverse events associated with zanubrutinib monotherapy (CTCAE Grade 3/4) in the SEQUOIA study [25] included, in particular, neutropenia (11%), anemia (0.4%), thrombocytopenia (2.1%), infections (16.3%), and pneumonia (1.7%). Diarrhea of all severities occurred in 13.8% of patients. Arrhythmias may occur with zanubrutinib; the most common was atrial fibrillation, observed in 1.7% of patients. Treatment with zanubrutinib may initially lead to lymphocytosis due to the flushing out of leukemia cells from lymphatic compartments. Other clinically relevant adverse effects include mild bleeding (28.3%), primarily from contusions (24.2%), and the development or worsening of arterial hypertension, with 6.3% of cases classified as CTCAE Grade 3. Zanubrutinib is administered orally.