‘Our Responsibility Should Be to Give You the Closest Thing to a Normal Life’

Around the time AstraZeneca’s Carlos Doti, MD, joined the pharmaceutical leader a decade ago, the company was presenting its first abstract for the second-generation Bruton tyrosine kinase (BTK) inhibitor acalabrutinib at the American Society of Hematology (ASH).

Fast-forward to the 2025 ASH Annual Meeting & Exposition in Orlando, Florida, and AstraZeneca had 65 abstracts, including 15 oral presentations, involving 8 different medicines and 11 diseases.1 For Doti, a hematologist who is now vice president of US medical affairs for oncology, the timing offered an opportunity to reflect on the growth of AstraZeneca’s footprint in hematology during an on-site interview with The American Journal of Managed Care®.

Carlos Doti, MD | Image: AstraZeneca

“We always say the same thing,” Doti said. “We want to become a leader in oncology—and you cannot be a leader in oncology unless you’re a leader in hematology as well.”

The data presented covered everything from its mainstay acalabrutinib, sold as Calquence, to the eye-catching AZD0120, an investigational chimeric antigen receptor (CAR) T-cell therapy that targets both BCMA and CD19 in patients with multiple myeloma; the treatment essentially behaves like a bispecific but with a one-and-done administration.1

In the wide-ranging interview, Doti discussed several key trials presented at ASH while looking ahead to 2026. Today’s therapeutic strategies, he said, are focused not just on increasing progression-free survival (PFS) but also on reducing adverse events, limiting the duration of treatment, and improving patient quality of life (See Related Article).

TrAVeRse in Mantle Cell Lymphoma

Acalabrutinib, Doti said, “is our flagship molecule that got us into hematology—and I think it’s making a huge difference.” In 2024, acalabrutinib had $3.13 billion in global sales, up 24.5% from the prior year, and it had another 8.4% sales jump in the first half of 2025.2 The therapy is approved in both frontline and relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL),3 and in mantle cell lymphoma (MCL).4

Doti noted that previously, the phase 3 ECHO trial (NCT02972840) had already shown the combination of acalabrutinib with bendamustine and rituximab (Rituxan) led to significantly improved PFS in patients age 65 years and older previously untreated for MCL compared with chemoimmunotherapy, at 66.4 months vs 49.6 months. This translated into a 27% reduction in the risk of disease progression or death. That was encouraging, but safety data remained similar between the 2 groups.5

In TrAVeRse (NCT05951959), an open-label, phase 2 study, treatment-naive patients with MCL receive a combination of acalabrutinib, venetoclax (Venclexta; AbbVie), and rituximab (AVR); the primary objective is to assess the rate of minimal residual disease (MRD)–negative complete response (CR) at end of induction after completing 13 cycles. Patients who achieved MRD-negative CR at the end of AVR induction were randomly assigned to continued acalabrutinib or observation. Those who progress during observation may receive retreatment with acalabrutinib.6

Early data for 12 patients who had completed AVR induction showed all had achieved MRD-negative CR. With most of the 106 patients still on induction therapy, 95.4% had achieved MRD negativity, including 88% by the end of cycle 6. Estimated 6-month PFS was 97.1%, estimated overall survival was 98.1%, and estimated duration of response was 98.0%. Of the 17 patients with TP53 mutations, 15 (88.2%) achieved objective response, 11 (64.7%) achieved CR, and 16 (94.1%) achieved MRD negativity during AVR induction.7

“It’s very early days,” Doti said. “Ever since I was practicing medicine, we tried to eradicate chemotherapy as part of our usual therapy.” This combination could become the first chemotherapy-free regimen approved for first-line MCL, he said.

While several chemotherapy-free regimens are being studied, none have received FDA approval.

Previously, the investigator-initiated BOVen study (NCT03824483) led to the inclusion of the combination of zanubrutinib (Brukinsa; BeOne Medicines), venetoclax, and obinutuzumab (Gazyva; Genentech) in the National Comprehensive Cancer Network guidelines for TP53-mutated MCL.8

AMPLIFY and Fixed-Duration Therapy

TrAVeRse was among dozens of studies at ASH 2025 that involved a time-limited or MRD-directed treatment regimen, with the goal of achieving the best possible outcomes without the long-term effects patients experience in a treat-to-progression approach.Follow-up results for one of the showstoppers of ASH 2024, AMPLIFY (NCT03836261), enhanced acalabrutinib’s position as part of a proven fixed-duration combination.

Initially approved as a continuous therapy in the ELEVATE-TN (NCT02475681) and ASCEND (NCT02970318) trials (for patients with first-line and relapsed/refractory disease, respectively),3 acalabrutinib was the focus of AMPLIFY, which showed that fixed-duration acalabrutinib combinations with or without obinutuzumab significantly prolonged PFS compared with chemoimmunotherapy in patients with untreated CLL.6

These results gained relevance at ASH 2025, which produced the first head-to-head trial comparing the 2 therapeutic approaches in CLL—continuous ibrutinib, a first-generation BTK inhibitor, or fixed-duration combinations featuring venetoclax, a BCL2 inhibitor. Results from CLL17 (NCT04608318) showed that fixed-duration regimens are noninferior but offer significant quality of life benefits and cost savings.

“Since I started my career in hematology, we always try to do finite therapy,” Doti said. “Because if you’re not receiving therapy, then you’re not exposed to adverse events of the therapy itself. So, you have the best results by stopping.… So that is our goal.”

Doti speaks with patients frequently, and he said there’s no question what they prefer. “It’s loud and clear that everyone wants to go back to a more normal life…and that is potentially without continuous therapy,” he said.

Doti recalled that ibrutinib, approved by the FDA for MCL in 2013 and for CLL in 2014,9 was the established BTK inhibitor when studies for acalabrutinib began.

“The AMPLIFY study started almost at the same time as ELEVATE-TN, because even at that time, we knew that treat to progression is a very good option for patients,” he explained. “But if we can establish a finite therapy for some or even all patients, then we will, because CLL is a chronic disease—and if you’re not curing the patient, our responsibility should be to give you the closest thing to a normal life, and that is potentially without receiving therapy.”

At ASH 2025, an exploratory analysis from AMPLIFY explored the associations between the presence of certain mutations and unmutated IGHV status.10 More readouts from AMPLIFY will be forthcoming, Doti said, pointing to work by Dana-Farber Cancer Institute investigator Matthew Davids, MD, MMSc, associate director of their CLL Center, who is evaluating doublets and triplets of targeted therapies, as well as an AstraZeneca medical affairs study, MAJIC (NCT05057494), comparing venetoclax-obinutuzumab vs acalabrutinib-venetoclax.11

Have the results from AMPLIFY propelled more use of the fixed-duration option? Doti noted the regimen is not yet approved in the United States, but in Europe there’s definitely been uptake. The German study group that produced CLL17 have always advocated finite therapy, Doti said, and “were pioneers in the combinations with venetoclax and the BTK [inhibitors].”

AstraZeneca is now engaged with this study group on 2 initiatives—one involving frail patients and another involving high-risk patients—both involving combinations of acalabrutinib and venetoclax, Doti said.

Easing Treatment in the Community—With CAR T-Cell Therapy

So much knowledge has been gained in the past decade about combining acalabrutinib with other therapies, Doti said. The monitoring required during ramp-up with venetoclax to avoid tumor lysis syndrome made many smaller practices balk at offering this therapy; today, hematologists can use a BTK monotherapy for debulking ahead of the venetoclax combination, which “makes the ramp-up more easygoing.”

With studies that have an AV arm that is all oral, he continued, “you don’t require the same facilities.”

The need to make therapies friendly to oncologists outside academic centers carries over as AstraZeneca studies its CAR T-cell therapy entrant, AZD0120, acquired in 2024 from the China-based biotech Gracell Biotechnologies for $1 billion.12 The dual-targeting autologous therapy is being developed using AstraZeneca’s FasTCAR platform, Doti said, which reduces manufacturing time to 3 days, with a mean time to ship following leukapheresis of 14 days.

Just as important, he said, by bringing the process “in house,” T-cell fitness and reliability have vastly improved. “This translates not only into really good efficacy, comparable to BCMA-directed therapies that are available today, but in my opinion, the best safety profile of all BCMA that we have data [on] today,” Doti said.

Serious or late-occurring cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity (ICANS) were significant challenges in the early days of CAR T-cell therapy but are less common today as mitigation strategies, such as the use of tocilizumab, have evolved. Still, the fear of patients developing these conditions and requiring care at a community hospital—especially on a weekend—is seen as a barrier to uptake in outpatient settings.

At ASH 2025, the efficacy and safety data for AZD0120 were encouraging. In DURGA-1 (NCT05850234), a phase 1b/2 study, investigators evaluated 2 dose levels in 25 patients with relapsed/refractory multiple myeloma. Patients in dose 1 received 1×105 cells per kg (n =12); those in dose 2 received 3×105 cells per kg (n=13). Median time to infusion was 28 days; 5 patients received bridging therapy. Median follow-up was 1.4 months. No dose-limiting toxicities were reported; 64% of patients reported CRS, none of grade 3 or above. No cases of ICANS were reported. For efficacy-evaluable patients (n=15), overall response rate is 100%; CR rates were 30% in dose 1 (n=10) and 40% in dose 2 (n=5). All MRD-evaluable patients were MRD negative by next-generation sequencing at 10–5.13

“We have zero grade 3 CRS,” Doti said. Only 1 case of CRS occurred prior to day 6. “So, it’s very predictable. We don’t have any late toxicities,” he said. “We believe this can be a game changer, to what we call democratizing CAR T into the community space.”

The particular combination of targets is notable because at present, blinatumomab (Blincyto; Amgen) is the only bispecific T-cell engager that targets CD19, Doti said.

Beyond the positive data, he said, 7% of the patients in the study so far have been “fully managed outpatient,” which means “we are building trials to make sure we capture that component, to bring confidence that this is a CAR that can be used in the outpatient setting, which will benefit community practices.”

He was asked: Where are the areas of unmet need? What areas of hematology would be the focus in upcoming years? Would it be CLL, MCL, or multiple myeloma?

Doti replied, “All of them.”

References

1. AstraZeneca advances hematology and cell therapy ambition with largest-ever presence at ASH. News release. AstraZeneca. December 4, 2025. Accessed December 26, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/AstraZeneca-advances-hematology-and-cell-therapy-ambition-with-largest-ever-presence-at-ASH.html
2. Slatko J. AstraZeneca 2025: getting bigger. PharmaLive. October 7, 2025. Accessed December 29, 2025. https://www.pharmalive.com/astrazeneca-2025-getting-bigger/
3. Project Orbis: FDA approves acalabrutinib for CLL and SLL. FDA. November 21, 2019. Accessed December 29, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-approves-acalabrutinib-cll-and-sll
4. FDA grants accelerated approval mantle cell lymphoma. FDA. October 31, 2017. Accessed December 29, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-acalabrutinib-mantle-cell-lymphoma
5. Wang M, Salek D, Belada D, et al; ECHO Investigators. Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma. J Clin Oncol. 2025;43(20):2276-2284. doi:10.1200/JCO-25-00690
6. A study of acalabrutinib plus venetoclax and rituximab in participants with treatment naïve mantle cell lymphoma (TrAVeRse). ClinicalTrials.gov. Updated October 21, 2025. Accessed December 29, 2025. https://www.clinicaltrials.gov/study/NCT05951959
7. Wojtowicz MM, Hawkes E, Romejko-Jarosinska J, et al. Acalabrutinib plus venetoclax and rituximab in patients with treatment-naïve mantle cell lymphoma (MCL): results from the phase 2 TrAVeRse study. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Paper 0884.
8. Lawrence L.BOVen regimen NCCN-approved option for TP53-mutated MCL. ASH Clinical News. December 2024. Accessed December 20, 2025. https://ashpublications.org/ashclinicalnews/news/8393/BOVen-Regimen-NCCN-Approved-Option-for-TP53
9. de Claro RA, McGinn KM, Verdun N, et al. FDA approval: ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3586-3590. doi:10.1158/1078-0432.CCR-14-2225
10. Ghia P, Eichhorst B, Wrobel T, et al. Impact of prognostic mutations on outcomes with fixed-duration acalabrutinib-venetoclax combinations versus chemoimmunotherapy: an exploratory analysis from AMPLIFY. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Abstract 3898.
11. Ryan CE, Davids MS, Hermann R, et al. MAJIC: a phase III trial of acalabrutinib + venetoclax versus venetoclax + obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Future Oncol. 2022;18(33):3689-3699. doi:10.2217/fon-2022-0456
12. Waldron J. AstraZeneca pays $1B to take wheel of Gracell’s CAR T “fast car.” December 27, 2023. Accessed December 29, 2025. https://www.fiercebiotech.com/biotech/astrazeneca-pays-1b-take-wheel-gracells-car-t-fast-car
13. Richard S, Gaballa MR, Gregory TK, et al. Safety and efficacy of AZD0120, a BCMA/CD19 dual-targeting CAR T-cell therapy, in relapsed/refractory multiple myeloma: preliminary results from DURGA-1 phase 1b/2 study. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Paper 269.