Pushing the boundaries further in the management of CLL

Treatment-naïve disease

Interim analysis of the AMPLIFY trial

In patients with treatment-naïve chronic lymphocytic leukemia (CLL), the multicenter, open-label, randomized, phase III AMPLIFY trial was initiated to evaluate fixed-duration treatment with acalabrutinib plus venetoclax ± obinutuzumab compared to investigator’s choice of chemoimmunotherapy (CIT). The second-generation BTK inhibitor acalabrutinib was selected for this trial as it shows improved safety and tolerability compared to the first-generation BTK inhibitor ibrutinib [1]. At 133 sites in 27 countries, fit untreated patients without del(17p) or TP53 mutations were randomized to either acalabrutinib plus venetoclax (AV) for 14 cycles (n = 291), acalabrutinib plus venetoclax and obinutuzumab (AVO) for 14 cycles (n = 286), or CIT with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR) for 6 cycles (n = 290). Almost half of patients across the arms had Rai stage III/IV. Unmutated IGHV was identified in approximately 60 %, and approximately 15 % showed a complex karyotype with ≥ 3 aberrations.

Progression-free survival (PFS) for AV vs. FCR/BR according to independent review committee (IRC) was defined as the primary endpoint. Secondary endpoints including PFS for AVO vs. FCR/BR, undetectable minimal residual disease (uMRD) and overall survival (OS) were tested in a fixed sequential hierarchy. AMPLIFY provides the first phase III evidence of fixed-duration therapy combining a second-generation BTK inhibitor with venetoclax (with or without anti-CD20 therapy) in treatment-naïve CLL. At ASH 2024, Brown et al. presented the prespecified interim analysis of the trial after a median follow-up of 40.8 months [2].

Superior results for AV and AVO

Indeed, IRC-PFS was significantly longer for AV than for FCR/BR (HR, 0.65; p = 0.0038), with 36-month PFS rates of 76.5 % vs. 66.5 %. The first key secondary endpoint, which was IRC-PFS for AVO vs. CIT, showed an even greater difference (HR, 0.42; p < 0.0001); the 36-month PFS rate in the AVO arm was 83.1 %. Median PFS had not been reached for AV and AVO, and was 47.6 months for FCR/BR. Similar results for the three arms emerged in the subgroup with unmutated IGHV, whereas no differences were noted in the mutated cohort. Patients with both mutated and unmutated IGHV showed 36-month PFS rates of approximately 83 % for AVO. Moreover, PFS censored for COVID-19 deaths, which was a prespecified analysis, revealed findings consistent with the primary analysis (AV vs. FCR/BR: HR, 0.71; p = 0.0356; AVO vs. FCR/BR: HR, 0.26; p < 0.0001).

The uMRD rates in the peripheral blood were highest for AVO across the ITT and evaluable populations (Figure 1). In the subgroups that had achieved uMRD, PFS at the end of treatment was prolonged across all three arms, although AV was still superior vs. FCR/BR (HR, 0.43), as was AVO vs. FCR/BR (HR, 0.27). In the subgroups with detectable MRD, the PFS benefit for AV vs. CIT was preserved (HR, 0.44), whereas the AVO arm was hardly assessable due to very few patients with detectable MRD. AV treatment improved OS compared to FCR/BR (HR, 0.33). After censoring of COVID-19 deaths, both AV and AVO showed OS benefits (HRs, 0.27 and 0.47, respectively).

The most common adverse event (AE) overall was neutropenia, although the rates of febrile neutropenia were low. Grade ≥ 3 neutropenia emerged in 32.3 %, 46.1 % and 43.2 % with AV, AVO and CIT, respectively. Grade ≥ 3 infections occurred in 12.4 %, 23.6 % and 10.0 %, respectively. Any-grade cardiac events were observed in 9.3 %, 12.0 % and 3.5 %, respectively, with low rates of atrial fibrillation of 0.7 %, 2.1 %, and 0.8 %, respectively. Hypertension was reported in 4.1 %, 3.9 % and 2.7 %, respectively. Tumor lysis syndrome developed in one patient each on AV and AVO treatment vs. eight patients receiving CIT.

Figure 1: uMRD rates for acalabrutinib plus venetoclax ± obinutuzumab vs. chemoimmunotherapy

AVO in patients with TP53 aberrations

Data are lacking on the efficacy and safety of AVO in patients with CLL harboring TP53 aberrations. An open-label, single-arm, phase II study including a small subgroup with TP53 aberration has already demonstrated activity and tolerability of frontline AVO treatment [3]. This phase II study was expanded to enroll additional patients with TP53 aberration. Davids et al. presented the primary endpoint evaluation for the entire study (n = 72) at ASH 2024, with a focus on the outcomes in the TP53-mutated population (n = 45) [4].

Acalabrutinib and venetoclax were started in cycles 1 and 4, respectively, while obinutuzumab was administered through cycles 2-6. On day 1 of cycle 16, the primary endpoint was assessed, which was the complete response (CR) rate with uMR D in the bone marrow. Patients who achieved CR plus uMRD discontinued treatment thereafter, whereas those who did not or only obtained partial response continued acalabrutinib/venetoclax for 9 cycles. After another MRD assessment on day 1 of cycle 25, patients either discontinued treatment or continued acalabrutinib and venetoclax until progression depending on their uMRD status.

AVO therapy with MRD-guided treatment duration demonstrated high tolerability and efficacy. The primary endpoint evaluation showed that 42 % of patients in the overall population and 42 % of those with TP53 aberration achieved CR with uMRD in the bone marrow at the start of cycle 16. In patients with TP53 aberration, the 4-year PFS and OS rates were 70 % and 88 %, respectively. In those without, these were 96 % and 100 %, respectively.

Thirty-five patients (51 %) had MRD recurrence after a median of 32.2 months, and ten experienced clinical progression. Five individuals were retreated with AV due to CLL progression (n = 3) or recurrent MRD without CLL progression (n = 2). Three of them responded to retreatment, while one patient progressed and another one had not been evaluated with respect to their best response yet. To date, three patients have died. According to these data, AVO is a potential frontline option for patients with TP53-altered CLL.

Pirtobrutinib-based triplet

The time-limited triplet combination therapy of the non-covalent BTK inhibitor pirtobrutinib plus venetoclax and obinutuzumab was evaluated in untreated patients with CLL in an investigator-initiated, single-arm, single-center phase II trial reported by Jain et al. [5]. Patients received pirtobrutinib from cycle 1 to 13 and venetoclax from cycle 2 to 13. Obinutuzumab was administered for the first 6 cycles. At the end of cycle 7, uMRD was assessed with 10-6 sensitivity based on bone marrow and peripheral blood (primary endpoint) in addition to imaging studies. Patients who were still MRD-positive at ≥ 10-5 in either blood or marrow at the end of cycle 13 could continue pirtobrutinib plus venetoclax for an additional 12 cycles. Eighty patients were enrolled. In this group, 79 % had unmutated IGHV, and del(17p)/TP53 mutation was present in 13 %.

After one cycle of pirtobrutinib and obinutuzumab, the majority of patients showed low risk of tumor lysis syndrome (TLS). Ninety percent and 86 % with high and medium risk, respectively, had experienced downgrading of their TLS risk category. The efficacy data presented after a median follow-up of 11.9 months yielded high uMRD4 rates in the bone marrow of 91 % and 98 % at the end of cycles 7 and 13, respectively (Figure 2). As the authors noted, these uMRD rates are numerically higher than those observed in their previous first-line trial investigating ibrutinib plus venetoclax [6]. No patient had developed progression or died during the observation period.

The AE profile was similar to that observed in prior first-line studies with doublet and triplet combination therapies. Grade 3/4 neutropenia and thrombocytopenia occurred in 60 % and 14 %, respectively. Fifty-eight percent of patients required G-CSF treatment. Pirtobrutinib and venetoclax dose reductions were performed in 21 % and 31 %, respectively, with neutropenia being the most common reason. Two patients developed atrial fibrillation, including one in the setting of COVID-19 infection. The patient population will be followed up in the off-therapy phase to determine long-term remission duration.

Figure 2: MRD at serial timepoints in blood and bone marrow in patients treated with pirtobrutinib plus venetoclax and obinutuzumab

Sustained benefit in SEQUOIA at 5 years

The next-generation BTK inhibitor zanubrutinib has been compared to BR in the registrational open-label, randomized, phase III SEQUOIA study. Patients with treatment-naïve CLL/small lymphocytic lymphoma (SLL) without del(17p) received either continuous zanubrutinib until disease progression (n = 241) or BR for a maximum of 6 cycles (n = 238). At a median follow-up of 26.2 months, zanubrutinib has demonstrated statistically significant and clinically meaningful PFS superiority over BR [7, 8]. Shadman et al. reported the 5-year update of SEQUOIA after a median follow-up of 61.2 months [9]. At that time, 59 patients (24.8 %) had crossed over from the BR arm to receive zanubrutinib after disease progression.

The significant PFS benefit for zanubrutinib was sustained even after the prolonged observation period, resulting in a 71 % risk reduction (median PFS, not reached vs. 44.1 months; HR, 0.29; p < 0.0001). After adjustment for COVID-19 impact, there was a 75 % risk reduction (HR, 0.25; p < 0.0001) with 60-month PFS rates of 78.7 % % vs. 40.6 % (Figure 3). Zanubrutinib showed consistent PFS benefit irrespective of the IGHV mutation status, whereas PFS with BR was considerably shorter in patients with unmutated IGHV. Together with data from cohort 2 in SEQUOIA that had del(17p)/TP53 mutation and showed a 42-month PFS rate similar to rates of patients without this high-risk feature, these findings suggest that treatment with zanubrutinib might overcome negative prognostic factors [10]. Overall, 97.5 % and 88.7 % of patients responded to zanubrutinib and BR treatment, respectively. CR plus CR with incomplete bone marrow recovery (CRi) resulted in 20.7 % vs. 23.5 %. The authors pointed out that the 20.7 % CR/CRi rate obtained with zanubrutinib, which increased over the course of the study, is the highest reported with BTK inhibitor monotherapy. The COVID-19–adjusted OS rates at 60 months were 89.4 % vs. 86.8 % for the two regimens.

Even over the extended treatment period, zanubrutinib was well tolerated, with low rates of infections and AEs that limit daily living activities, such as gastrointestinal toxicities. The cumulative incidences of hypertension (0.50 vs. 0.38) and atrial fibrillation/flutter (0.13 vs. 0.09) remained low and were comparable to those in the BR arm. Taken together, the results of this follow-up of the SEQUOIA study support the use of zanubrutinib as a first-line option for CLL patients regardless of disease risk status.

Figure 3: Progression-free survival with zanubrutinib vs. bendamustine/rituximab after COVID-19 adjustment in the SEQUOIA study

Five-year data for the BOVen regimen

An MRD-driven first-line approach has been tested by the multicenter phase II BOVen study that evaluated zanubrutinib plus venetoclax and obinutuzumab (BOVen). Zanubrutinib and obinutuzumab were started in cycle 1 and venetoclax in cycle 3. Obinutuzumab was administered for 8 cycles. After a minimum of 8 cycles and a maximum of 24 cycles, venetoclax and zanubrutinib were discontinued in patients showing uMRD in their peripheral blood and bone marrow. Retreatment with zanubrutinib and venetoclax was possible upon CLL relapse. The BOVen regimen appeared well tolerated and achieved frequent uMRD [11].

According to the long-term follow-up presented at ASH 2024 after a median of 57 months, the best end-of-treatment uMRD4 (MRD < 10-4) rates were 96 % and 92 % in the peripheral blood and bone marrow, respectively [12]. All 46 patients with bone marrow uMRD met the prespecified treatment discontinuation criterion and stopped therapy after a median of 10 months. Their median MRD4-free survival was estimated at 34 months. No additional safety signals occurred in the course of the extended observation period.

Moreover, the scientists demonstrated that the decrease in MRD in the peripheral blood on day 1 of cycle 5 (ΔMRD400) predicted uMRD4 in the bone marrow within 8 months, with a 400-fold reduction identified as the optimal cutoff. Twenty-one patients who achieved ΔMRD400 had an MRD4-free survival of 51 months, which was significantly longer than that of 13 patients who failed ΔMRD400 (23 months; p < 0.001), even though their treatment duration was significantly shorter (8 vs. 13 months; p < 0.001). ΔMRD400 did not appear to track with traditional risk factors such as TP53 mutation or unmutated IGHV. wW

Retreatment with zanubrutinib and venetoclax was started in 16 patients. The overall response rate (ORR) in this group was 92 %, with 46 % showing uMRD4 in the peripheral blood. Patients who had achieved ΔMRD400 with the initial BOVen therapy appeared more likely to obtain peripheral blood uMRD with retreatment than those who had not (75 % vs. 29 %). A phase II study investigating ΔMRD400-directed administration of BOVen for 24 vs. 10 months is currently ongoing in treatment-naïve patients with CLL. This is based on the hypothesis that longer duration of therapy for patients who did not achieve ΔMRD400 will further improve uMRD duration.

Survival with fixed-duration ibrutinib plus venetoclax

Ghia et al. conducted an analysis to explore whether the OS rates obtained in patients receiving fixed-duration ibrutinib plus venetoclax are comparable to those of an age-matched general European population [13]. For this purpose, data from patients with treatment-naïve CLL from the GLOW study and the fixed-duration cohort of the CAPTIVATE trial were pooled, which yielded a total of 265 patients. This population had a balanced distribution of younger and older individuals. Median age at randomization was 65 years.

After a follow-up of 55.7 months, the OS estimates were indeed comparable between the pooled ibrutinib/venetoclax-treated cohort and the age-matched population (HR, 0.999; p = 0.998). This applied to both older and younger subgroups (≥ 65 years: HR, 0.828; p = 0.582; < 65 years: HR, 1.636; p = 0.377). At 60 months, 88 % of patients aged ≥ 65 years and 93 % of those aged < 65 years were alive. Likewise, patients with unmutated IGHV showed OS estimates comparable to the general population (HR, 1.182; p = 0.633), while the OS estimate in those with mutated IGHV favored ibrutinib/venetoclax, although not significantly so (HR, 0.396; p = 0.171). Overall, first-line fixed-duration ibrutinib/venetoclax was shown to provide patients with a life expectancy approximating that of an age-matched general European population regardless of age and IGHV mutation status.

GAIA/CLL13: patient-reported QoL

Time-limited first-line treatment with venetoclax-based regimens was assessed in fit patients in the phase III GAIA/CLL13 trial. Venetoclax plus obinutuzumab (GV) for 12 months and venetoclax plus obinutuzumab and ibrutinib (GIV) for 12-36 months were compared with CIT and venetoclax plus rituximab (RV) for 12 months. After > 4 years of follow-up, GV and GIV were shown to significantly improve PFS compared with both CIT and RV [14]. An exploratory analysis presented at ASH 2024 assessed patient-reported quality of life outcomes from the GAIA/CLL13 study. These were measured using the EORTC QLQ-C30 and QLQ-CLL16 questionnaires until month 60 after the start of treatment.

According to these results, global health status/quality of life improved rapid­ly after treatment initiation with GV and RV, with the benefit lasting throughout the study, while improvements beyond the minimal important difference were reported later for GIV and CIT [15]. Similar dynamics emerged with respect to physical, role and social functioning as well as fatigue/physical condition. This difference in the timing of improvement between GIV and the GV/RV doublets appeared to be driven by a higher symptom burden during treatment with the triplet. While the symptom burden slightly increased with GIV over the first half year before decreasing, there was a sharp reduction with GV and RV directly after treatment initiation and a slower decrease with CIT (Figure 4).

Time until the first deterioration of diarrhea was significantly shorter with GIV than with all other treatments and significantly longer with CIT compared to all other treatments. For nausea and vomiting, time until the first deterioration was significantly shorter with GIV vs. CIT and RV. The authors emphasized that these differences in patient-reported outcomes should be considered when comparing efficacy outcomes of different venetoclax combinations in CLL.

Figure 4: Reduction in symptom burden in the context of treatment according to EORTC QLQ-CLL16 in the GAIA/CLL13 study. MID, minimal important difference

Next-generation Bcl-2 and BTK inhibition

The ongoing global phase I/IB BGB-11417-101 study is evaluating the next-generation Bcl-2 inhibitor sonrotoclax as monotherapy or combined with zanu­brutinib and/or obinutuzumab in patients with various B-cell malignancies. Compared to venetoclax, sonrotoclax is more selective and potent, with shorter half-life and no drug accumulation [16, 17]. Sonrotoclax 160 mg and 320 mg have been selected for expansion. At ASH 2024, Soumerai et al. reported updated expansion data for the cohort of patients with untreated CLL/SLL who received sonrotoclax plus zanubrutinib [18]. The study treatment consisted of 8-12 weeks of zanubrutinib lead-in followed by the combination until disease progression or intolerance. While 51 patients received sonrotoclax 160 mg plus zanubrutinib, 86 were treated with sonrotoclax 320 mg plus zanubrutinib. TP53 mutation and del(17p) was present in 31 % of the total population, almost 60 % had unmutated IGHV, and 29 % showed a high tumor bulk at baseline.

After a median follow-up of 19.4 months, sonrotoclax plus zanubrutinib demonstrated substantial antitumor activity in this all-comer population, including in patients with high-risk features. The depth of responses increased over time, with CR/CRi rates reaching 40 % and 42 % in the sonrotoclax 160 mg and 320 mg groups, respectively, at week 48. The ORR was 100 % for both dose groups. High uMRD4 rates in the peripheral blood occurred early on in both dose cohorts and increased over time (Figure 5). Sonrotoclax 320 mg gave rise to higher uMRD4 rates compared to sonrotoclax 160 mg. As of the data cutoff date, no patients had switched from uMRD to detectable MRD4. Only one primary PFS event, which was Richter transformation, occurred during the observation period in a patient from the 320 mg dose cohort.

At a median relative dose intensity of 99 % across dose cohorts, sonrotoclax 160 mg or 320 mg plus zanubrutinib was well tolerated. The frequency of AEs including grade ≥ 3 AEs and serious AEs was similar across groups. Most treatment-emergent AEs (TEAEs) were low-grade. Neutropenia as the most common any-grade and grade ≥ 3 TEAE in both dose groups was transient and did not lead to higher rates of grade ≥ 3 infections. No laboratory or clinical TLS events were reported, and none of the patients died due to TEAEs. Also, no complicated COVID-19 cases or deaths occurred. Treatment discontinuation rates for zanubrutinib and sonrotoclax were low at 3.6 % and 2.2 %, respectively. The authors concluded that with longer follow-up, the combination continued to demonstrate compelling safety and efficacy in the setting of treatment-naïve CLL. Sonrotoclax 320 mg plus zanubrutinib is being evaluated in untreated patients with CLL in the phase III CELESTIAL-TNCLL study (NCT06073821).

Figure 5: uMRD rates in the peripheral blood on treatment with sonrotoclax plus zanubrutinib

Relapsed/refractory disease

Final analysis of BRUIN ­CLL-321

There is an increasing medical need in the treatment of patients with CLL/SLL as the use of covalent BTK inhibitors is growing in the first- and second-line settings and patients experience poor outcomes after progression on these drugs [19]. The highly selective, non-covalent BTK inhibitor pirtobrutinib has been approved in several countries for the treatment of patients with CLL/SLL after ≥ 2 prior lines of therapy including a BTK inhibitor and a Bcl-2 inhibitor. BRUIN CLL-321 investigated pirtobrutinib monotherapy compared to idelalisib plus rituximab (IdelaR) or bendamustine/rituximab (BR) in patients with CLL/SLL previously treated with covalent BTK inhibitors. There was no limit on prior lines of therapy. A history of atrial fibrillation was allowed. PFS by IRC constituted the primary endpoint of the study. BRUIN CLL-321 is the first prospective, randomized phase III clinical trial to assess treatment regimens entirely in CLL/SLL patients pretreated with covalent BTK inhibitors.

Sharman et al. presented the final results from BRUIN CLL-321 for 119 patients in each treatment arm after a median follow-up of 17.2 months [20]. The median number of prior lines of therapy was 3, with one third of subjects having received ≥ 4 lines. Approximately 15 % of patients had been treated with ≥ 1 covalent BTK inhibitor. Bcl-2 inhibition had been administered in half of patients. The reason for any BTK inhibitor discontinuation was disease progression in 71 % and 73 % in the pirtobrutinib and IdelaR/BR arms, respectively. High-risk molecular features were prevalent; more than half of patients had del(17p) and/or TP53 mutation, and 93 % and 80 %, respectively, showed unmutated IGHV. Complex karyotype was present in 72 % and 59 %, respectively.

Delaying the next treatment by 2 years

Pirtobrutinib, as compared to IdelaR/BR, reduced the risk of progression or death by 46 % according to IRC. Median PFS was 14.0 vs. 8.7 months (HR, 0.54; p = 0.0002). Subgroup analyses showed consistent PFS benefits of pirtobrutinib across clinically relevant cohorts, which also applied to genetic risk feature subgroups. The event-free survival was improved by 61 % (median, 14.1 vs. 7.6 months; HR, 0.39; p < 0.0001). As this endpoint also captures discontinuations due to toxicity, it reflects the additional impact of the favorable tolerability profile of pirtobrutinib compared to IdelaR/BR.

The risk of starting next treatment or death was reduced by 63 %, with a median time to next treatment (TTNT) of 24.0 vs. 10.9 months (HR, 0.37; p < 0.0001). This delay of approximately two years highlights the potential benefit of the BTK inhibitor in treatment sequencing. Pirtobrutinib-associated risk reductions regarding TTNT were similar in venetoclax-naïve and venetoclax-treated patients (HRs, 0.36 and 0.37, respectively). In the venetoclax-naïve cohort, subsequent treatment was delayed by 29.5 months (vs. 12.5 months with IdelaR/BR; p = 0.0001; Figure 6). BRUIN CLL-321 was not powered to detect an OS difference across the arms. In addition, this analysis was confounded by the substantial crossover rate of 76 %. Sensitivity analyses with adjustment for crossover demonstrated numerical OS improvement in the experimental arm.

Pirtobrutinib treatment was well tolerated. After adjustment for exposure, the incidence rate of TEAEs was lower with pirtobrutinib than with IdelaR/BR. Treatment-related AEs (TRAEs) necessitated discontinuation in the experimental arm in 5.2 % vs. 21.1 % in the control arm. The overall rates of AEs of special interest for pirtobrutinib were comparable to those observed in the phase I/II BRUIN study [21]. Cumulative event rates of atrial fibrillation/flutter remained low (any grade, 2.6 %; grade ≥ 3, 1.7 %). The authors concluded that pirtobrutinib is an effective, well-tolerated agent for patients with difficult-to-treat CLL/SLL and provides a clinically meaningful way to sustained BTK inhibition.

Figure 6: Time to next treatment or death in the venetoclax-naïve cohort included in the BRUIN CLL-321 study

Fixed-duration zanubrutinib/venetoclax

Ahn et al. initiated a non-randomized phase II study to evaluate the efficacy of the combination of zanubrutinib and venetoclax in the setting of relapsed/refractory CLL, particularly in patients who had been exposed to or progressed on targeted agents. In this trial, patients were assigned to three cohorts based on prior treatment history. Cohort A comprises BTK- and Bcl-2-inhibitor-naïve patients. Cohorts B and C have been exposed to BTK and/or Bcl-2 inhibitors. While Cohort B patients have stopped their previous treatment due to reasons other than disease progression, progression on a covalent BTK inhibitor without BTK C481 mutation was the reason for treatment discontinuation in Cohort C. Venetoclax administration started in cycle 4 in Cohorts A and B, and in cycle 2 in Cohort C. Treatment was stopped after 15 cycles. Retreatment with 12 cycles of the combination is possible in case of clinical disease progression accompanied by MRD at the end of treatment (EoT), or MRD recurrence after uMRD. The rate of bone marrow uMRD4 at EoT has been defined as the primary endpoint.

At ASH 2024, results were presented for 13 patients in Cohort A, 12 in Cohort B and one in Cohort C [22]. Nine had completed 15 cycles of zanubrutinib plus venetoclax, including one patient who began retreatment per protocol due to disease progression after EoT. Seventeen were on active initial treatment. In the group of 22 patients evaluable for response, the ORR was 95 %, with no differences across cohorts after a median follow-up of 8 months. Cohort A responded in 91 % and Cohorts B/C in 100 %. CR resulted in 18 % in all cohorts. One of six patients who reached the EoT timepoint achieved uMRD in the peripheral blood and bone marrow. Thrombocytopenia and neutropenia were reported in 38.5 % and 34.6 %, respectively. Neutropenia was the most common grade ≥ 3 AE (19 %); however, febrile neutropenia and sepsis were uncommon (4 % each). Among non-hematologic toxicities, bruising occurred most commonly (57.7 %), followed by diarrhea (42.3 %). Two patients (8 %) developed atrial fibrillation. No TLS event occurred. The AEs did not require any dose reductions on study.

In their conclusion, the authors noted that fixed-duration combination therapy with zanubrutinib and venetoclax is effective and well-tolerated in the setting of relapsed/refractory CLL, including in patients previously exposed to targeted agents. A larger number of patients and longer follow-up will provide further insights into the potential benefits of this regimen.

BTK degradation: (pre)clinical data on NX-5948

Targeted protein degradation is a novel therapeutic approach that is being evaluated in clinical trials. Degraders are small molecules that have potential benefits over BTK inhibitors as they eliminate both the catalytic (i.e. kinase activity) and the non-catalytic (scaffolding) functions of BTK. Huynh et al. demonstrated that the cereblon-recruiting BTK degraders NX-2127 and NX-5948 induce degradation of BTK in primary CLL cells without interfering with T cell activation or survival in vitro [23]. These findings provided a strong rationale for the continued investigation of these compounds in CLL and lymphoid malignancies.

An ongoing phase IA/B study is assessing NX-5948 in patients with relapsed/refractory B-cell malignancies. At ASH 2024, Shah et al. reported results for 60 patients from the CLL/SLL cohort that received NX-5948 200 mg or 600 mg OD after ≥ 2 prior lines of therapy [24]. Pretreatment included BTK inhibitor therapy in almost all patients, Bcl-2 inhibition in 83.3 %, and both in 81.7 %. Chemotherapy or CIT had previously been administered in 72 % of patients. Forty percent were carriers of TP53 mutations, 38.6 % had BTK mutations and 12.3 % PLCG2 mutations. Patients with CNS involvement were allowed to participate; this applied to five individuals (8.3 %).

In vitro findings showed that NX-5948 rapidly degrades gatekeeper, kinase-proficient and kinase-dead BTK mutations. The clinical profile of the drug in this heavily pretreated population was encouraging. At the time of the primary ORR analysis at week 8 after ≥ 1 response assessment, the ORR was 75.5 % for both doses (n = 49; Table 1). This increased to 84.2 % at 16 weeks at the time of the exploratory analysis after ≥ 2 response assessments (n = 38). Clinical activity was observed in patients including those with baseline mutations and CNS involvement. Regardless of prior therapy, NX-5948 induced durable responses, with median duration of response not having been reached; 13 patients (26.5 %) showed duration of response > 6 months, and five remained on treatment beyond one year.

NX-5948 was well tolerated across B-cell malignancies. No additional safety signals emerged with longer duration on study or increased dose. Few grade ≥ 3 AEs occurred, with cytopenias representing the majority of cases. The phase IB dose expansion is underway, and pivotal assessment of NX-5948 therapy will start in 2025.

Table 1

BGB-16673: CaDAnCe-101

The bivalent CNS-penetrating BTK degrader BGB-16673 works by binding specifically to BTK and the E3 ligase [25]. In preclinical models, BGB-16673 has been shown to degrade both wild-type and mutant BTK known to confer resistance to both covalent and non-covalent BTK inhibitors [25, 26]. Patients with a range of relapsed/refractory B-cell malignancies are being treated with BGB-16673 at doses of 50-500 mg in the global, open-label, phase I/II CaDAnCe-101 study. Thompson et al. presented updated efficacy and safety results for 60 patients with relapsed/refractory CLL/SLL who had received a median of four prior lines of therapy [27]. This was a high-risk population with 82.6 % of patients harboring unmutated IGHV and del(17p) and/or TP53 mutation present in 66.7 %. Half of the cohort had complex karyotype. Covalent BTK inhibitors and Bcl-2 inhibitors had been administered in 93.3 % and 83.3 %, respectively. Previous BTK inhibitor therapy had been discontinued due to disease progression in 89.3 %.

According to the analysis, BGB-16673 demonstrated significant antitumor activity. Cytopenias improved rapidly and significantly in responders, including improvement in neutrophil count, hemoglobin level, and platelet count. Responses were observed at the lowest dose level of 50 mg. Overall, 77.6 % of patients responded, with the highest ORR of 93.8 % observed in the 200 mg dose group. Two patients (4.1 %) in the total group achieved CR/CRi. Median time to first response was 2.8 months. High ORRs resulted irrespective of specific mutations such as BTK, PLCG2, or TP53 mutations and/or del(17p), as well as in the group with complex karyotype. The ORR was 86.7 % after double exposure (i.e., covalent BTK and Bcl-2 inhibition) and 58.3 % after triple exposure (i.e., covalent and non-covalent BTK inhibition as well as Bcl-2 inhibition). Responses deepened over time. Median PFS had not yet been reached after a follow-up of 10.2 months.

BGB-16673 treatment was safe and well tolerated. The maximum tolerated dose had not been reached at the time of the analysis. One dose-limiting toxicity (i.e., grade 3 maculopapular rash) was observed at the 200-mg dose level; here, the patient was able to continue on treatment after a 5-day hold. Fatigue, contusion and neutropenia constituted the most common AEs, with neutropenia showing the highest incidence among grade ≥ 3 TEAEs (21.7 %). However, the rate of febrile neutropenia was low at 1.7 %. No atrial fibrillation or pancreatitis events occurred. Major hemorrhage was observed in 3.3 %. None of the patients died due to TRAEs. In two patients (3.3), TRAEs led to treatment discontinuation.

Preliminary findings suggested promising activity also in patients with Richter transformation (n = 12). In this group, the ORR was 58.3 %, with CR in 8.3 % of cases. Five responders had been on treatment for > 6 months at the time of the analysis. A phase II cohort of patients with CLL/SLL exposed to both BTK and Bcl-2 inhibition is currently enrolling.

Extension study results for zanubrutinib ± obinutuzumab

The phase I/II AU-003 study has evaluated zanubrutinib monotherapy in patients with various B-cell malignancies including CLL/SLL, while the phase IB GA-101 study investigated zanubrutinib in combination with obinutuzumab for 6 cycles followed by continuous zanubrutinib monotherapy in patients with CLL/SLL or follicular lymphoma [28, 29]. Both trials comprised treatment-naïve and relapsed/refractory patients. Upon completion of these studies, patients could enroll in a long-term extension study for continued treatment with zanubrutinib and survival follow-up. Between January 2020 and March 2021, 117 patients treated with zanubrutinib monotherapy in AU-003 or zanubrutinib plus obinutuzumab in GA-101 rolled over to the extension study. Tam et al. reported efficacy and safety outcomes after a median follow-up of 76 months for zanubrutinib monotherapy and 88.1 months for zanubrutinib plus obinutuzumab [30].

In patients from the AU-003 study, the ORRs were 100 % and 94.2 % for treatment-naïve and relapsed/refractory individuals, respectively (Table 2). CR/CRi occurred in 36.4 % and 25.2 %, respectively. For the group that had previously received the combination, the ORRs were 100 % and 92.0 % in the treatment-naïve and relapsed/refractory cohorts, respectively; CR/CRi was reported in 60.0 % and 36.0 %, respectively. The authors pointed out that the CR/CRi rates were unprecedented for BTK inhibitor therapy of treatment-naïve patients. Moreover, zanubrutinib and zanu­brutinib/obinutuzumab led to durable responses and impressive PFS regardless of the pretreatment status. COVID-19–adjusted median PFS was 89.2 months for the AU-003 group and 83.7 months for the GAG-101 group, while COVID-19–adjusted median OS had not been reached in either group. The tolerability and safety profile of zanu­brutinib alone and in combination with obinutuzumab remained favorable. TEAEs leading to treatment discontinuation and dose reduction occurred in 13.5 % and 12.9 %, respectively. Most TEAEs of interest including cytopenias, diarrhea, and hemorrhage showed decreasing prevalence over time.

Table 2

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