Combination Regimens Expand CLL Treatment Paradigm

The treatment landscape of chronic lymphocytic leukemia (CLL) has expanded rapidly in recent years, with data emerging using triplet, doublet, and monotherapy approaches. In the frontline setting, the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa) has emerged as a viable treatment option both as monotherapy and as a combination component. For patients with relapsed/refractory disease, the chimeric antigen receptor (CAR) T-cell agent lisocabtagene maraleucel (liso-cel; Breyanzi) has received FDA approval, and novel BTK degraders such as NX-5948 and BGB-16673 have shown promise in early-phase clinical trials.

During an OncLive Peer Exchange filmed at the 2024 American Society of Hematology (ASH) Meeting and Exposition, expert investigators in hematology discussed exciting findings from several clinical trial updates in CLL presented during the meeting.

“The past decade has been a revolution in CLL treatment, particularly for our older [patients with CLL],” Matthew S. Davids, MD, MMSc, said. “For many of them, we have the available tools to prolong life to what their natural life span would be otherwise. The patients I still worry the most about are my younger patients; if they’re in their early 50s, we don’t know what happens over 20 or 30 years with these targeted therapies. That’s a group where additional research is needed. I’m also optimistic about modalities such as bispecific antibodies; if we use them in smart ways earlier in the treatment course, there may be curative potential there. We shouldn’t shy away from developing curative strategies for younger patients with CLL.”

Triplet and Doublet Regimens Offer Deep Responses in Frontline CLL

The most recent agent to gain FDA approval in CLL is zanubrutinib.1 In January 2023, the agent earned an indication from the FDA for the treatment of patients with CLL or small lymphocytic lymphoma (SLL). The regulatory decision was supported by findings from the phase 3 SEQUOIA (NCT03336333) trial, which compared zanubrutinib with bendamustine plus rituximab (Rituxan) in patients with previously untreated CLL or SLL.2

At a median follow-up of 61.2 months, updated findings from SEQUOIA demon- strated that the median progression-free survival (PFS) among patients who received zanubrutinib (n = 241) was not reached (NR) compared with 44.1 months (95% CI, 38.4- 55.6) in the bendamustine plus rituximab arm (n = 238; HR, 0.29; 95% CI, 0.21-0.40; P < .0001). The 54-month PFS rates were 80.1% (95% CI, 74.3%-84.7%) and 44.6% (95% CI, 37.6%-51.3%), and the 60-month rates were 75.8% (95% CI, 69.0%-81.3%) and 40.1% (95% CI, 32.7%-47.3%), respectively. The estimated 54-month overall survival (OS) rates were 87.7% (95% CI, 82.7%-91.3%) and 86.0% (95% CI, 80.6%-90.0%), and the 60-month rates were 85.8% (95% CI, 80.6%-89.7%) and 85.0% (95% CI, 79.5%-89.2%), respectively.

“The interesting aspect of SEQUOIA is not the comparator arm or even the comparison between the drugs: It’s what happened to the zanubrutinib-treated patients and their toxicity profiles over time,” Marc S. Hoffmann, MD, said. “Those data are compelling, and I have already converted to using zanubrutinib in the vast majority of my patients based on the toxicity data. [There were] continuing low rates of atrial fibrillation. It confirms a lot of the previous observations that we had with the drug, both about its excellent efficacy and the relatively high-quality safety profile.”

In a phase 2 trial (NCT03824483), investigators examined zanubrutinib as a combination component with obinutuzumab (Gazyva) and venetoclax (Venclexta; BOVen) in patients with treatment-naive CLL or SLL.3 The primary end point was minimal residual disease (MRD) negativity rate. The threshold for undetectable MRD (uMRD) was 10–4 by flow cytometry (MRD4).

At a median follow-up of 57 months (range, 4-63+), data from the trial demonstrated that patients who received the triplet and were included in the 8-month analysis (n = 49) achieved an 8-month MRD4 negativity rate of 77.6% (1 patient was confirmed positive). The best and end-of-treatment MRD4 negativity rates by peripheral blood and bone marrow analysis were 96% and 92%, respectively, in the total population (n = 50). The median MRD4-free survival was 34 months (95% CI, 23-NR), with 92% of patients reaching this threshold.

“These patients are remaining in a very deep remission, and, on average, they only had [approximately] 10 months of treatment,” Hoffmann said. “They get 10 months of treatment and then 2 years of ongoing, extremely deep MRD remissions, which is a remarkable outcome for a targeted therapy combination that is well tolerated and avoids chemotherapy. That’s extremely exciting, [but] my question with a lot of these triplets is about toxicity. When you add the third drug, you get increased toxicity, and it doesn’t bear out perfectly well in the reported abstracts.”

Another triplet regimen is being evaluated in a separate phase 2 trial (NCT05536349). Investigators are examining pirtobrutinib (Jaypirca) plus venetoclax and obinutuzumab as first-line therapy for patients with CLL or SLL.4 The primary end point is uMRD rate; secondary objectives included overall response rate (ORR), PFS, OS, and safety and tolerability.

At a median follow-up of 11.9 months (range, 2.0-21.4), among patients who completed 7 cycles of treatment (n = 66), the peripheral blood uMRD rate at a threshold of less than 10–6 (uMRD6) was 79%, with 93% achieving uMRD4 at this time point. Patients who completed 13 cycles of treatment (n = 41) achieved an uMRD4 rate of 100% and an uMRD6 rate of 85%.

“The responses are early, this is less than a year [of follow-up], but the data look very exciting. There are high response rates in both bone marrow and peripheral blood, with a 10–6 [threshold],” Nicole Lamanna, MD, said. “With this triplet, there’s more neutropenia and thrombocytopenia, but very high levels of response.”

Beyond triplet therapy, the phase 3 AMPLIFY trial (NCT03836261) is exam- ining acalabrutinib (Calquence) plus venetoclax with or without obinutuzumab vs chemoimmunotherapy in frontline CLL.5 The primary end point is PFS per blinded independent central review (BICR). Secondary end points include uMRD4 rate and OS.

“AMPLIFY compared acalabrutinib plus venetoclax [with or without obinutuzumab] given in a time-limited fashion [over] 14 cycles vs chemoimmunotherapy with investigator’s choice of fludarabine, cyclophosphamide, and rituximab, or bendamustine plus rituximab,” Brad S. Kahl, MD, said. “The findings show, not surprisingly, a big advantage for the novel agents over chemoimmunotherapy.”

Findings from the interim analysis of AMPLIFY showed that the median BICR-assessed PFS among patients who received acalabrutinib plus venetoclax (n = 291) or acalabrutinib plus venetoclax and obinutuzumab (n = 286) was NR vs 47.6 months for those treated with chemoimmunotherapy (n = 290). The HR for acalabrutinib plus venetoclax vs chemoimmunotherapy was 0.65 (95% CI, 0.49-0.87; P = .0038) and 0.42 (95% CI, 0.30-0.59; P < .0001) for acalabrutinib plus venetoclax and obinutuzumab vs the control arm. The uMRD4 rates were 26.8%, 66.4%, and 51.0% in the doublet, triplet, and control arms, respectively, at the time of the key secondary end point analysis in the intent-to-treat population.

“The comfort of doing a time-limited [treatment] with a BTK-based therapy [is that it] gives us more options with the triplet,” Alvaro J. Alencar, MD, noted. “I’m skeptical about routinely adding a bispecific monoclonal antibody to the combination. You may deepen the response, but you are paying a price for that—the infections are not trivial. On the AMPLIFY trial, [there were] issues with serious infectious complications [from] the bispecific [antibody]. What I tend to do is bide my time in the first few cycles for those patients [who] seem to be dragging and not really having a response; sometimes they have bad hemolytic anemia that might give you another edge in terms of adding the antibody. [However,] I do not routinely add a triplet in the first line.”

CAR T, Combinations, and Novel Agents Emerge in Relapsed/Refractory CLL

During the ASH meeting, investigators presented results of a real-world treatment sequencing analysis that examined 16 of the most frequently utilized treatment sequences in patients with relapsed/refractory CLL/SLL in community-based settings.6

The unadjusted median OS results were as follows: For patients who received BTK inhibitor monotherapy and then CD20 antibody monotherapy, 63 months (95% CI, 55-74); BTK inhibitor monotherapy then BCL2 inhibitor monotherapy, 81 months (95% CI, 74-not estimable [NE]); chemoimmunotherapy then chemoimmunotherapy, 72 months (95% CI, 58-NE); CD20 antibody monotherapy then BTK inhibitor monotherapy, 82 months (95% CI, 68-NE); and CD20 antibody monotherapy then chemoimmunotherapy 93 months (95% CI, 54-NE). The median OS was NE for all other sequences that were examined.

“In reality, what we’re deciding on in the first and second line are BTK inhibitor vs BCL2 inhibitor data,” Alencar commented. “In general, if [a patient] is on a covalent BTK inhibitor and has issues with tolerability, they may switch over to a different agent and still maintain the response with different toxicities. On the other hand, if patients progress on a BTK inhibitor, it’s unlikely that a similar class BTK inhibitor will rescue that patient. For a patient who started a BTK inhibitor in the first line, what is the switchover? In general, it’s going to be a BCL2 inhibitor–based approach.”

Also presented at ASH were results from a phase 2 study (NCT05168930) examining the combination of zanubrutinib and venetoclax for the treatment of patients with relapsed/refractory CLL.7 At a median follow-up of 8 months, the ORR in the overall population (n = 26) was 95%, with a complete response (CR) rate of 17%. Patients who were BTK and BCL2 inhibitor naive (n = 13) achieved an ORR of 91%; those who received a prior BTK and/or BCL2 inhibitor and stopped therapy for reasons other than disease progression (n = 12) and those who experienced disease progression on a BTK inhibitor without a BTK C481 mutation (n = 1) all achieved ORRs of 100%. Six patients reached the end-of-treatment time point, with 1 achieving uMRD4.

Following BTK and BCL2 inhibitor exposure, treatment with CAR T-cell agents represents a potential option for patients with relapsed/ refractory CLL. In the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198), liso-cel is being examined in patients with relapsed/refractory CLL/ SLL, including those who experienced disease progression on a BTK inhibitor and venetoclax.8 The primary end point is CR/CR with incomplete marrow recovery (CRi) rate; key secondary end points include ORR and uMRD rate.

At a median follow-up of 23.8 months (range, 0.4-59.6), patients who received liso-cel at a dose of 100 x 106 CAR T cells (n = 88) achieved a CR/CRi rate of 20% (95% CI, 13%-30%) and an ORR of 48% (95% CI, 37%-59%). The median duration of response (DOR) among patients with CR/CRi/partial response (PR)/non-PR was NR (95% CI, 24.0-NR), the median PFS was 18.0 months (95% CI, 9.4-30.1), and the median OS was 52.2 months (95% CI, 30.3-NR).

“It took a long time in CLL to get our first CAR T-cell [therapy] approved compared with lymphoma; this was liso-cel, which was approved…in March 2024,” Lamanna said. “It seems very apparent for the patients who achieve a CR—in this study, it was about 20%—those patients have a durable remission, which is excellent, but for those who don’t, the PFS is very short.”

Pirtobrutinib monotherapy represents another potential option for patients with relapsed/ refractory CLL. The phase 3 BRUIN CLL-321 trial (NCT04666038) is the first randomized study conducted exclusively in BTK inhibitor–pretreated patients, evaluating pirtobrutinib vs investigator’s choice of therapy with idelalisib (Zydelig) plus rituximab or bendamustine plus rituximab.9 The primary end point is PFS; secondary end points include OS, event-free survival (EFS), and safety.

Data from BRUIN CLL-321 revealed that the median PFS per independent review committee in the pirtobrutinib arm (n = 119) was 14.0 months (95% CI, 11.2-16.6) compared with 8.7 months (95% CI, 8.1-10.4) in the control arm (n = 119; HR, 0.54; 95% CI, 0.39-0.75; 2-sided P = .0002), meeting the study’s primary end point. The median EFS was 14.1 months (95% CI, 11.4-17.0) vs 7.6 months (95% CI, 4.8-8.8), respectively (HR, 0.39; 95% CI, 0.28-0.53; 2-sided P < .0001).

The panelists concluded their discussion by highlighting data on novel agents in relapsed/ refractory CLL. In the phase 1a/1b NX-5948-301 study (NCT05131022), the novel BTK degrader NX-5948 is being evaluated in patients with relapsed/refractory B-cell malignancies, including CLL.10 The coprimary end points are safety and tolerability and establishing the maxi- mum tolerated dose (MTD) and recommended phase 2 dose (RP2D).

Among response-evaluable patients with CLL (n = 49), the ORR was 75.5% (95% CI, 61.1%-86.7%). Thirteen patients experienced a DOR exceeding 6 months, and 5 remained on treatment for more than 1 year. In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) among patients with CLL/SLL (n = 60) included purpura/contusion (36.7%), fatigue (26.7%), and petechia (26.7%).

In another phase 1 study, CaDAnCe-101 (NCT05006716), the BTK degrader BGB-16673 is also being examined in patients with relapsed/ refractory CLL/SLL.11 The primary end point is safety and tolerability, as well as determining the MTD and RP2D.

Efficacy-evaluable patients in the overall population (n = 49) achieved an ORR of 77.6%, including a CR/CRi rate of 4.1%. The respective rates among those treated at the 200-mg dose level (n = 16) were 93.8% and 6.3%. Any-grade TEAEs included fatigue (30.0%), contusion (28.3%), and neutropenia (25.0%); 1 dose-limiting toxicity was reported, and the MTD was NR.

“I’m very excited by some of the new agents and combinations, [including] both BTK degrad- ers and the bispecific antibodies,” Lamanna said in conclusion. “These are exciting classes [of agents] that will help our [patients with] multiple-relapsed/refractory [disease]. I’m [also] hoping that we’ll get more data regarding how to utilize MRD in our patients. That’s something that we’ve seen [with] multiple combinations, and it’s a moving target [in terms of it being] time-limited. Hopefully, we can make that more granular and easier for the community to [utilize] MRD and solidify testing [practices].”

Matthew S. Davids, MD, MMSc, is the Director of Clinical Research in the Division of Lymphoma and an Associate Professor of Medicine at Harvard Medical School/Dana-Farber Cancer Institute in Boston, MA

Alvaro J. Alencar, MD, is an Associate Professor of Clinical Medicine and Associate Chief Medical Officer in the Division of Hematology at the University of Miami Health System in Miami, FL

Marc S. Hoffmann, MD, is an Associate Professor of Hematologic Malignancies and Cellular Therapeutics, the Medical Director of Lean and Quality Improvement, and the Medical Director of Lymphoma and Myeloma, Hematologic Malignancies, and Cellular Therapeutics at the University of Kansas Medical Center in Kansas City, KS

Brad S. Kahl, MD, is the Director of the Lymphoma Program and a Professor of Medicine in the Division of Oncology at Washington University in St Louis in St Louis, MO

Nicole Lamanna, MD, is an Associate Clinical Professor of Medicine in the Hematologic Malignancies Section in the Hematology/Oncology Division at the Columbia University Herbert Irving Comprehensive Cancer Center in New York, NY

References

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