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Most patients who receive immunotherapies will experience few, if any, treatment-related adverse effects (AEs). But some patients receiving these treatments can experience serious AEs caused by an overactivation of the immune system and its effects on healthy cells.

Tackling the Adverse Events of Immunotherapy

Igor Puzanov discusses the rare cardiologic adverse events that can occur when a patient is on checkpoint inhibitors.

Igor Puzanov on Monitoring Cardiologic Toxicities from Checkpoint Inhibitors

Compared with 2 trials that led to its FDA approval, second-line treatment with lisocabtagene maraleucel (liso-cel; Breyanzi) demonstrated safety and efficacy outcomes that were comparable among patients with relapsed/refractory large B-cell lymphoma (LBCL), according to real-world findings.

Results from the observational, post marketing study using data collected from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry were compared again the pivotal, phase 3 TRANSFORM (NCT03575351) and phase 2 PILOT (NCT03483103) trials.

At a median follow-up of 6.4 months (95% CI, 6.1-6.5; range, 0.2-14.8) the median progression-free survival (PFS) and overall survival (OS) in the overall second-line cohort (n = 156) was not reached (NR; 95% CI, NR-NR). In the TRANSFORM-ineligible cohort the median PFS and OS was NR (95% CI, 5.8-NR) and NR (95% CI, NR-NR), respectively. For the cohort of patients whose eligibility for TRANSFORM was unknown or eligible, the median PFS was NR (95% CI, 6.0-NR) and the median OS was NR (95% CI, NR-NR).

The 6-month PFS rates in the overall, TRANSFORM-ineligible, and TRANSFORM-unknown/eligible cohorts were 61% (95% CI, 52%-69%), 58.5% (95% CI, 48%-68%), and 65% (95% CI, 49%-77%), respectively. The 6-month OS rates in these respective populations were 87% (95% CI, 80%-92%), 85% (95% CI, 76%-91%), and 90% (95% CI, 76%-96%).

Additional efficacy findings illustrated that the objective response rate (ORR) in the second-line cohort was 84% (95% CI, 77%-89%), with a complete response (CR) rate of 70% (95% CI, 62%-77%). The ORRs in the TRANSFORM-ineligible and TRANSFORM-unknown/eligible cohorts were 84% (95% CI, 75%-90%) and 84% (95% CI, 71%-93%), respectively. The respective CRs in these populations were 68% (95% CI, 58%-76%) and 75% (95% CI, 60%-86%). The median duration of response (DOR) was NR in all 3 cohorts, with 6-month DOR rates of 73% (95% CI, 62%-81%), 70% (95% CI, 57%-80%), and 78% (95% CI, 59%-89%) in the second-line, TRANSFORM-ineligible, and TRANSFORM-unknown/eligible cohorts, respectively.

“Liso-cel continued to demonstrate consistently deep responses in this broad, real-world patient cohort. Median DOR, PFS, and OS were NR for the overall population, or the subgroups analyzed. While longer follow-up in a larger cohort is needed, these results support the use of liso-cel as [a] second-line standard-of-care treatment for patients with relapsed/refractory LBCL regardless of age,” lead study author María Silvina Odstrcil Bobillo, MD, a hematology fellow at the University of Utah School of Medicine in Salt Lake City, said in a presentation of the results.

FDA approved liso-cel for adult patients with LBCL

 who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation due to comorbidities or age.

The approval was based on data from the randomized TRANSFORM and single-arm PILOT trials in patients with transplant-eligible and -ineligible disease, respectively. In the former, treatment with liso-cel led to a median PFS that was NR vs 6.2 months with standard-of-care therapy (HR, 0.422) and respective CR rates of 74% and 43%. In the latter, liso-cel led to a CR rate of 54% (95% CI, 41%-67%).

Study Eligibility and Baseline Characteristics

To be eligible for inclusion in the analysis presented at the 2024 ASH Annual Meeting, patients needed to have relapsed/refractory LBCL and received commercial liso-cel infusion in the second line.

 At least 1 evaluation for safety and response following infusion was also required.

Efficacy end points included ORR, CR rate, DOR, PFS, and OS. Safety end points included adverse effects (AEs) of special interest, non–relapse mortality (NRM), and deaths. ORR, CR rate, DOR, PFS, and OS by TRANSFORM eligibility criteria, refractory or relapsed disease status, and age were also evaluated in subgroup analyses.

Data for 1,067 patients who had received commercial liso-cel were pooled from the CIBMTR registry. A total of 911 patients were excluded from the analysis because they didn’t receive liso-cel in the second line (n = 867), had no post infusion assessment (n = 43), or had no response data available (n = 1), leaving 156 eligible patients. A total of 105 of the 157 patients who received liso-cel in the second line were evaluated separately because they would have been ineligible for inclusion in TRANSFORM.

Within the second-line cohort (n = 157) the median age was 72 years (range, 27-85) and most patients were male (57%). Diffuse large B-cell lymphoma represented the most common histology (84%), followed by high-grade B-cell lymphoma (11%) and other, including primary mediastinal large B-cell lymphoma (4%). Most patients had active disease at the time of infusion (88%); 50% had primary refractory disease and 48% had early relapse. Central nervous system involvement was documented in 3% of patients. Most patients had an ECOG performance status of 0 or 1 (95%) although 60% had at least 1 comorbidity. Additionally, 72% of patients received bridging therapy, and R-CHOP was the most common regimen patients had received (87%) prior to liso-cel.

Subgroup Analyses According to Disease Status and Age

Among the patients with refractory disease (n = 78) the median PFS and OS were NR (95% CI, 3.9-NR) and NR (95% CI, NR-NR). Patients with primary refractory disease had a median PFS and OS that were both NR (95% CI, NR-NR). The 6-month PFS rates were 53% (95% CI, 40%-64%) and 69% (95% CI, 57%-79%) in the refractory and early relapse cohorts, respectively. The respective 6-month OS rates were 85% (95% CI, 74%-91%) and 91% (95% CI, 81%-96%).

The ORR in the refractory cohort was 83% (95% CI, 73%-91%), with a CR rate of 63% (95% CI, 51%-74%). In the early relapse cohort, the ORR was 84% (95% CI, 74%-92%), with a CR rate of 78% (95% CI, 67%-86%). The median DOR was NR in either cohort; the 6-month DOR rates were 60% (95% CI, 44%-73%) and 86% (95% CI, 72%-93%) in the refractory and early relapse cohorts, respectively.

With respect to age, patients 70 years of age or younger achieved an ORR of 85% (95% CI, 74%-92%), with a CR rate of 77% (95% CI, 65%-87%). Patients over the age of 70 achieved an ORR of 84% (95% CI, 74%-91%), with a CR rate of 65% (95% CI, 54%-75%). The median DOR was NR in either age group; the 6-month DOR rates were 81% (95% CI, 66%-90%) and 65% (95% CI, 49%-77%) in the less than 70 and over the age of 70 cohorts, respectively.

The median PFS and OS in both age groups were NR. The 6-month PFS rates in the younger and older cohorts were 68% (95% CI, 55%-79%) and 55% (95% CI, 43%-65%), respectively. The respective 6-month OS rates were 91% (95% CI, 79%-96%) and 84% (95% CI, 74%-91%).

CRS, ICANS, and Other Adverse Effects of Special Interest

Cytokine release syndrome (CRS) occurred in 45% of patients (grade 1, 31%; grade 2, 12%; grade 3, <1%; grade 4, <1%; grade 5, <1%). Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 20% of patients (grade 1, 8%; grade 2, 4%; grade 3, 5%; grade 4, 1%); 2 cases had yet to be determined by the time of data cutoff. The median time to onset of CRS and ICANS was 4 (IQR, 3-7) and 8 (IQR, 5-9) days, respectively. The median duration of each event was 3 (IQR, 2-5) and 10 (IQR, 4-378) days, respectively. Most patients received treatment for either CRS (82%) or ICANS (91%), the most common being tocilizumab (Actemra; 59%) for CRS and corticosteroids (48%) for ICANS.

“The safety profile was consistent with previous reports; most patients did not experience, or had low-grade CRS, ICANS, prolonged cytopenia, or infections,” Bobillo said. Bobillo also noted that despite a higher incidence of CRS and ICANS for the TRANSFORM-ineligible, refractory, and older patient cohorts, the differences were not statistically significant, with the exception of ICANS for older patients.

Regarding other AEs of special interest, 11% of patients experienced prolonged cytopenia, 33% experienced clinically significant infections, 4% developed second primary malignancies––all of which were solid tumors apart from 1 case of myelodysplastic syndrome, 5% had grade 3/4 organ toxicity, and 0.6% developed tumor lysis syndrome.

Within the overall second-line cohort 78% of patients remained alive. The most common reason for death was progressive disease (n = 14%), followed by other and unknown causes (3% each), infections (1%), and CRS (≤1%).

The 6-month cumulative incidence of NRM was 1.3 (95% CI, 0.3-4.3), and the 6-month cumulative incidence of relapse/progression or death due to primary disease was 37.9 (95% CI, 29.6-46.0).

“These results continue to highlight that liso-cel is utilized in the second-line setting in a broad population of patients with relapsed/refractory LBCL with efficacy and safety outcomes consistent with pivotal clinical trials,” Bobillo concluded.

Bobillo MSO, Thiruvengadam SK, et al. Lee D, et al. Real-world (rw) outcomes of lisocabtagene maraleucel (liso-cel) as second-line (2L) therapy in patients (pts) with relapsed or refractory (r/r) large B-cell lymphoma (lbcl): first results from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry. 

. 2024;144(suppl 1):470. doi:10.1182/blood-2024.199723

FDA approves lisocabtagene maraleucel for second-line treatment of large B-cell lymphoma. FDA. Updated June 27, 2022. Accessed December 8, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lisocabtagene-maraleucel-second-line-treatment-large-b-cell-lymphoma

Real-world treatment with liso-cel showed a broad spectrum of outcomes that were comparable to those in the pivotal TRANSFORM and PILOT trials in patients with relapsed/refractory large B-cell lymphoma.

Liso-Cel Shows Comparable Real-World Outcomes in Relapsed/Refractory LBCL 

Treatment with asciminib (Scemblix) yielded superior efficacy and safety vs investigator-selected tyrosine kinase inhibitors (IS-TKIs) in chronic myeloid leukemia (CML), meeting key secondary end points of the phase 3 ASC4FIRST trial (NCT04971226).

Data presented at the 2024 ASH Annual Meeting showed that the major molecular response (MMR) rate at week 96 continued to be superior among patients who received asciminib (n = 201) vs all IS-TKIs (n = 204), meeting a key secondary end point of the trial; rates were 74.1% vs 52.0%, respectively with investigators noting the difference was 22.4% (95% CI, 13.6%-31.3%; 

 < .001). This represented an increase in MMR as the 48-week MMR rates were 67.7% and 49.0%, respectively, which originally met the primary end point of the trial.

“The 96-week data that I am showing you today for the first time [reveal that] all of these comparisons against all TKIs, imatinib [Gleevec], and second generation TKIs, favor asciminib.The ones that are powered [for it] are statistically significant [as well],” Jorge E. Cortes, MD, said in a presentation of the data. Cortes isdirector for the Georgia Cancer Center and the Cecil F. Whitaker Jr, GRA Eminent Scholar Chair in Cancer in Augusta.

The 96-week MMR rates were also consistently higher with asciminib across the trial strata. In the imatinib stratum, patients who received asciminib (n = 101) experienced a 96-week MMR rate of 76.2% vs 47.1% among those in the IS-TKI arm (n = 102), for a difference of 29.7% (95% CI, 17.6%-41.8%; 

 < .001). In the second-generation TKI stratum, the 96-week MMR rates were 72.0% in the asciminib arm (n = 100) and 56.9% in the IS-TKI arm (n = 102) for a difference of 15.1% (95% CI, 2.3%-28.0%).

The FDA Approval of Asciminib and ASC4FIRST Trial Enrollment

The October 29, 2024 FDA accelerated approval of asciminib for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase (CP) was based on the 48-week MMR data from ASC4FIRST.

 Findings supporting the approval showed that the 48-week MMR rate was 68% (95% CI, 61%-74%) in the asciminib arm vs 49% (95% CI, 42%-56%) in the IS-TKIs arm, for a difference of 19% (95% CI, 10%-28%, 

 < .001), meeting one of the trial’s primary end points.

 The other primary end point, 48-week MMR rate with asciminib vs IS-TKIs in the imatinib stratum, was also met in the primary analysis of ASC4FIRST with high statistical significance.

 The MMR rate was 69% (95% CI, 59%-78%) vs 40% (95% CI, 31%-50%), respectively, for a difference of 30% (95% CI, 17%-42%; 

ASC4FIRST enrolled adult patients newly diagnosed Philadelphia chromosome-positive CML-CP who had not been previously treated with a TKI. Patients received asciminib at 80 mg once daily or IS-TKIs at label doses.

 Physicians and patients consulted to select a TKI should the patient be randomly assigned to the IS-TKI arm of the trial and stratification occurred by prerandomization TKI selection and EUTOS long-term survival score (ELTS) risk category. Secondary end points of the trial included 96-week MMR with asciminib vs all IS-TKIs and 96-week MMR with asciminib vs IS-TKIs in the imatinib stratum.

“The patient characteristics were very well balanced,” Cortes said. “When you look at the individual strata, however, it becomes obvious that the patients in the imatinib strata were somewhat older and had a higher Framingham [risk] score, whereas the patients in the second-generation TKI strata tended to have more patients in the high-risk ELTS risk classification.”

At the October 22, 2024, data cutoff, more patients were ongoing treatment with asciminib (81.6%) than all IS-TKIs (60.3%). Patients in the asciminib arm vs all IS-TKIs arm discontinued treatment (17.9% vs 38.2%, respectively) due to unsatisfactory therapeutic effect (9.5% vs 20.6%), adverse effect (AE; 6.0% vs 12.7%), progressive disease (1.0% vs 2.0%), physician decision (0.5% vs 0.0%), protocol deviation (0.5% vs 1.0%), patient decision (0.5% vs 1.5%), or pregnancy (0.0% vs 0.5%).

“The discontinuation rate was twice as high with all IS-TKIs compared with asciminib,” Cortes noted.

Furthermore, the cumulative incidence of MMR was higher with asciminib (80.5%) vs all IS-TKIs (62.1%) at 96-weeks.

 Across strata, this was also true; in the imatinib stratum rates were 80.0% in the asciminib arm and 56.5% in the IS-TKI arm, and in the second-generation TKI stratum rates were 81.0% in the asciminib arm and 67.6% in the IS-TKI arm.

At week 96, data on deep molecular responses revealed that 48.8% of patients who received asciminib achieved an MR4 and 30.9% achieved an MR4.5; these respective rates were 27.5% and 17.7% in the all IS-TKIs arm. In the imatinib stratum 52.5% of patients treated with asciminib experienced an MR4 and 35.6% experienced an MR4.5; respective rates were 23.5% and 11.8% in the IS-TKI arm. Additionally, in the second-generation TKI stratum, 45.0% of patients treated with asciminib experienced an MR4 and 26.0% experienced an MR4.5; respective rates were 31.4% and 23.5% in the IS-TKI arm.

“There is a continued and increasing difference in favor of asciminib [vs IS-TKI] for both MR4 and MR4.5,” Cortes explained. “One important analysis is to look at the difference in subsets of patients. These are small subsets [and the study was] not powered for any one of them, but it is very good to see that in any individual subgroup—whether it’s by ELTS, sex, race and ethnicity, age category, [or] Framingham score—all of them favor the treatment of asciminib in terms of the rate of MMR at [week] 96. There’s really no subset of patients where we don’t see at least a trend in benefit for asciminib compared with the investigator selected control [arm].”

Investigators also examined postbaseline treatment-emergent 

 gene mutations by next-generation sequencing. “In summary, all the mutations that emerged in this study with the treatment [of] asciminib have been myristoyl pocket mutations,” Cortes noted.

Asciminib’s Safety Profile Continues to Best Imatinib and Second-Generation TKIs

By the 96-week data cutoff, safety and tolerability data continued to be more favorable with asciminib compared with imatinib and second-generation TKIs. The risk of treatment discontinuation due to AEs was 54% lower with asciminib vs second-generation TKIs (HR, 0.46; 95% CI, 0.215-0.997).

“Asciminib’s safety and tolerability profile continued to be better than that of imatinib and second-generation TKIs after longer follow-up and [data were] consistent with its known safety profile,” Cortes said.

In the safety populations of patients who received asciminib (n = 200), imatinib (n = 99), and second-generation TKIs (n = 102), grade 3 or higher AEs (44.5% vs 49.5% vs 59.8%, respectively), AEs leading to treatment discontinuation (5.0% vs 13.1% vs 12.7%), and AEs leading to dose adjustment/interruption (33.0% vs 41.4% vs 57.8%) occurred.

Additionally, arterial occlusive events (AOEs) did not occur frequently with any agents in the trial. Four patients experienced at least 1 AOE in the asciminib arm (n = 200), and 3 patients experienced at least 1 event in the second-generation TKI group (n = 102); 1 patient in each of the aforementioned arms experienced a grade 3 or greater event and no patients in the imatinib group (n = 99) experienced an AOE.

“Asciminib’s favorable risk-benefit profile compared with all IS-TKIs, imatinib, and second-generation TKIs in patients with newly diagnosed CML-CP reinforces the use of asciminib as a SOC for this patient population,” Cortes concluded.

Disclosures: Dr Cortes cited having a consultancy role with Biopath Holdings, Nerviano, Syndax, Rigel, Sun Pharma, Pfizer, Novartis, and Lilly. He has received research funding from Ascentage, AbbVie, Sun Pharma, and Novartis. Cortes cited having membership on an entity’s Board of Directors or advisory committee with Biopath Holdings and he is a current holder of stock options as well.

1.Cortes JE, Hochhaus A, Hughes TP, et al. Asciminib (ASC) demonstrates favorable safety and tolerability compared with each investigator-selected tyrosine kinase inhibitor (IS TKI) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) in the pivotal phase 3 ASC4FIRST study. 

. 2024;144(suppl 1):475. doi:10.1182/blood-2024-203757

2.FDA grants accelerated approval to asciminib for newly diagnosed chronic myeloid leukemia. FDA. October 29, 2024. Accessed December 8, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-asciminib-newly-diagnosed-chronic-myeloid-leukemia

Secondary end points of the ASC4FIRST trial continue to show superior results with the use of asciminib, over standard-of-care TKIs in CML.

ASC4FIRST Trial Supports Asciminib With Secondary End Points in CML

Treatment with the second generation BTK inhibitor acalabrutinib (Calquence) plus venetoclax (Venclexta), with or without obinutuzumab (Gazyva), significantly improved progression-free survival (PFS), compared with standard-of-care (SOC) chemoimmunotherapy in patients with treatment-naive chronic lymphocytic leukemia (CLL), according to data from an interim analysis of the phase 3 AMPLIFY trial (NCT03836261) presented at the 2024 ASH Annual Meeting.

At a median follow-up of 40.8 months, the median progression-free survival (PFS) was not reached by blinded independent central review (BICR) with acalabrutinib plus venetoclax (AV) and acalabrutinib plus venetoclax and obinutuzumab (AVO) arms and was 47.6 months with investigator’s choice of fludarabine plus cyclophosphamide and rituximab (Rituxan; FCR) or bendamustine plus rituximab (BR). Treatment with the doublet regimen reduced the risk of disease progression or death by 35% (HR, 0.65; 95% CI, 0.49-0.87; 

 = .0038), and the triplet reduced this risk by 58% (HR, 0.42; 95% CI, 0.30-0.59; 

 < .0001). The estimated 36-month PFS rates with acalabrutinib plus venetoclax, with or without obinutuzumab, respectively, were 83.1% and 76.5%, compared with 66.5% with SOC chemoimmunotherapy.

“AMPLIFY provides the first phase 3 evidence of fixed duration therapy with a combination of venetoclax and a second generation BTK inhibitor in patients with treatment-naive CLL,” Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School in Boston, said during a press briefing at the meeting.

The randomized, multicenter, open-label, phase 3 AMPLIFY study enrolled patients with treatment-naive CLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia 2018 criteria who are at least 18 years of age and whose tumors are without del(17p) or 

 mutations. Patients were required to have an ECOG performance status of 2 or lower. Patients were excluded from the trial if they had a Cumulative Illness Rating Scale-Geriatric of over 6 or if they had significant cardiovascular disease.

A total of 867 patients were randomized 1:1:1 to receive one of the following regimens:

Oral acalabrutinib at 100 mg twice daily for cycles 1 to 14 plus oral venetoclax daily with a 5-week dose ramp-up of 20 mg, 50 mg, 100 mg, 200 mg, and 400 mg for cycles 3 to 14

The same acalabrutinib and venetoclax dosing plus intravenous obinutuzumab at 1000 mg for days 1, 8, and 15 of cycle 2 and day 1 of cycles 3 to 7

Investigator’s choice of FCR or BR per standard dosing protocol for cycles 1 to 6

Crossover between arms was not allowed. Patients were stratified by age (older than 65 years vs 65 years or younger), IGHV mutational status, Rai stage (3 or higher vs less than 3), and geographic region.

BICR-assessed PFS of the acalabrutinib/venetoclax regimen vs SOC chemoimmunotherapy, served as the primary end point. Brown noted that if the primary end point was met, secondary end points would be tested in the following fixed, sequential hierarchy: BICR-assessed PFS of the triplet regimen vs FCR/BR; undetectable minimal residual disease (uMRD) with the doublet vs FCR/BR, uMRD with the triplet vs FCR/BR, and overall survival (OS) of the doublet followed by the triplet regimen, both compared with FCR/BR. There were no plans to compare outcomes between the doublet and triplet regimens, according to Brown.

Additional efficacy findings showed that PFS was improved with acalabrutinib plus venetoclax, with or without obinutuzumab, regardless of IGHVstatus. “Particularly noticeable is the fact that in the [triplet] arm, those patients with unmutated IGHV [36-month PFS rate, 82.8%] are doing as well as those with mutated 

 [36-month PFS rate, 83.6%], suggesting that the addition of obinutuzumab may overcome the adverse impact of unmutated IGHV,” Brown explained.

The hazard ratios (HRs) for PFS with AV vs FCR/BR in patients with mutated and unmutated IGHVstatus were 0.67 (95% CI, 0.39-1.14) and 0.69 (95% CI, 0.48-0.97), respectively. The HRs for PFS with AVO vs FCR/BR in patients with mutated and unmutated IGHV status were 0.58 (95% CI, 0.32-1.02) and 0.35 (95% CI, 0.23-0.53), respectively.

Further, investigators found the highest rate of undetectable minimal residual disease (uMRD) among those who received the regimen with obinutuzumab. Of the patients who were evaluable at end of therapy, uMRD rates at a sensitivity level 10

 in the peripheral blood were 45.0% in the doublet arm, 95.0% in the triplet arm, and 72.9% in the investigators’ choice arm.

The 36-month OS rates with the doublet, triplet, and FCR/BR regimens were 94.1%, 87.7%, and 85.9%, respectively. The HR for OS with AV vs FCR/BR was 0.33 (95% CI, 0.18-0.56); with AVO vs FCR/BR, the HR for OS was 0.76 (95% CI, 0.48-1.18). “Of note, the study was conducted at the height of the pandemic, and COVID-19 deaths were seen in 10 patients on the [doublet] arm, 25 on the [triplet] arm, and 21 on the chemoimmunotherapy arm,” Brown explained. Therefore, after pre-planned censoring, the adjusted rates were 97.5%, 96.2%, and 93.7%, respectively. The HRs for OS with AV or AVO vs FCR/BR were 0.27 (95% CI, 0.11-0.60) and 0.47 (95% CI, 0.22-0.95), respectively.

The most common grade 3 or higher adverse effect (AE) was neutropenia, occurring in 26.8% of those who received the AV regimen (n = 291), 35.2% of those given AVO (n = 284), and 32.4% of those given FCR/BR (n = 259). Serious AEs were seen in 24.7%, 38.4%, and 27.4% of patients, respectively.

Patients with treatment-naive CLL have a variety of options, such as a fixed-duration regimen of venetoclax and ibrutinib (Imbruvica); however, Brown noted that despite deep and durable responses, cardiac toxicity remains. When evaluating AEs of interest, 9.3% and 12.0% of patients in the doublet and triplet arms experienced a cardiac event, compared with 3.5% of those in the FCR/BR arm; grade 3 or higher cardiac events occurred in 1.7%, 2.5%, and 1.2% of patients, respectively. However, rates of grade 3 or higher atrial fibrillation (0.3% vs 0.7% vs 0.8%, respectively) and hypertension (2.7% vs 2.1% vs 0.7%) remained low.

Of note, Brown acknowledged that the study was limited by the control group treatment regimen no longer being considered the SOC, which occurred after the trial began in 2019. “I think when physicians are considering whether to use the 2 or the 3-drug regimen, they have to take account of the patient in front of them,” she concluded.

“Based on these impressive data from the AMPLIFY trial, Calquence is only the second-generation BTK inhibitor to demonstrate efficacy in the front-line treatment of patients with chronic lymphocytic leukemia as both a treat-to-progression and a fixed-duration approach,” Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, stated in a press release on the data.

 “This advance is an important development for patients and their physicians who seek new options and more flexibility in managing this disease in the long term.”

Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab Versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial. 

. 2024;144(suppl 1):1009. doi:10.1182/blood-2024-200701

Fixed-duration Calquence plus venetoclax demonstrated superior PFS vs. standard of care in previously untreated CLL, with 77% of patients progression free at three years in AMPLIFY Phase III trial. AstraZeneca. December 8, 2024. Accessed: December 8, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/fixed-duration-calquence-plus-venetoclax-demonstrated-superior-pfs-vs-standard-care-previously-untreated-cll-with-77-of-patients-progression-free-3-years-amplify-phase-iii-trial.html

Treatment with acalabrutinib plus venetoclax, with or without obinutuzumab, improved PFS over standard-of-care chemoimmunotherapy in patients with treatment-naive CLL.

Igor Puzanov, MD, MSCI, FACP

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