Acalabrutinib/Axi-Cel Generates Preliminary Responses in Relapsed/Refractory B-Cell Lymphoma

The addition of acalabrutinib (Calquence) to the anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) was found to be well tolerated and safe in patients with relapsed/refractory B-cell lymphoma, in whom it also produced high and potentially durable response rates, according to data from a phase 1/2 open-label trial (NCT04257578) presented at the 2024 Transplantation & Cellular Therapy Meetings.¹

Results showed that 94% of patients (n = 17/18) were successfully bridged from leukapheresis to lymphodepletion with single-agent acalabrutinib, with 1 patient requiring additional radiation therapy. Furthermore, 67% of patients achieved a complete response (CR). At 12 months, 61% of patients were still in CR. Notably, 40% (n = 2) of the patients with partial responses at 1 month post–CAR T-cell therapy converted to CR with additional time and acalabrutinib administration.

Further assessment of survival showed that at a median follow-up of 15.2 months (range, 1.9-35.6), 78% of patients were alive and 11 were progression free. Both the median progression-free survival (PFS) and median overall survival (OS) were not yet reached at the time of data cutoff. The 6- and 12-month OS rates were both 78%, and the 6- and 12-month PFS rates were both 61%.

“Similar to previous studies in chronic lymphocytic leukemia [CLL], acalabrutinib may attenuate the severity of cytokine release syndrome [CRS], as grade 3 and higher CRS was not observed in this study,” lead author Christina Poh, MD, a medical oncologist at Fred Hutchinson Cancer Center and an assistant professor in the Division of Hematology and Oncology at the University of Washington School of Medicine, both in Seattle, stated in an oral presentation of the data. “Acalabrutinib may [also] serve as an effective bridge to CAR T-cell therapy, [as] this regimen maintained high CR rates...”

The second-generation covalent BTK inhibitor acalabrutinib has been previously approved by the FDA for patients with hematologic malignancies.2 It was first granted accelerated approval in 2017 for the treatment of adult patients with mantle cell lymphoma who have received at least 1 prior therapy, followed by its 2019 approval for the treatment of adult patients with CLL or small lymphocytic lymphoma.

“CD-19–targeted CAR T-cell therapy has revolutionized the relapsed/refractory B-cell lymphoma treatment landscape, starting with multiply-relapsed disease, and more recently with proven efficacy and comparable safety signals in earlier lines of treatment,” Poh explains during the presentation. “Despite these major therapeutic advances, limitations of effective CAR T-cell therapies still exist, such as the inability to control disease prior to CAR T, lack of sustained remissions following CAR T, and the potential for life-threatening adverse effects [AEs], such as CRS and immune effector cell–associated neurotoxicity syndrome [ICANS].”

In several preclinical models, BTK inhibitors were found to be immunomodulatory and had the potential to augment CAR T expansion, engraftment, and tumor clearance, as well as decrease the incidence and severity of CRS in CLL.1 Accordingly, investigators hypothesized that acalabrutinib may enhance the efficacy and safety of CD19-targeted CAR T-cell therapy, thereby serving as a feasible bridging strategy for patients with B-cell lymphoma. A study of the safety and efficacy of acalabrutinib plus anti-CD19 CAR T-cell therapy in this population was therefore conducted along with an immune correlative analysis.

The trial enrolled patients 18 years of age or older with histologically confirmed large B-cell lymphoma (LBCL) and indolent follicular lymphoma (FL) who met the criteria for receiving commercial axi-cel per the FDA label. LBCL subtypes included primary mediastinal LBCL, high-grade B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), and DLBCL arising from FL. Patients were also required to have adequate organ and marrow function, radiologically measurable disease, and an ECOG performance status of 0 or 1.

“When the study was initially designed, the only published data supporting CAR T-cell therapy was from the phase [1/2] ZUMA-1 trial [NCT02348216], and therefore our intent was to match this study population,” Poh explained. “When axi-cel became approved [by the FDA] for indolent FL, and for second-line use in LBCL, the eligibility criteria for this study were modified to match those approvals. The one difference in eligibility was that this study allowed for additional bridging therapy upon progression on acalabrutinib.”

The study included 3 main phases: bridging, cell therapy, and maintenance. The bridging stage commenced from 3 weeks to 24 hours before leukapheresis and persisted until lymphodepletion. The cell therapy stage spanned from lymphodepletion until 30 days after axi-cel infusion, and the maintenance phase extended from 30 days to 1 year post–axi-cel infusion or until unacceptable toxicity or disease progression. Acalabrutinib was consistently given at a dosage of 100 mg twice daily throughout the 3 study phases, and axi-cel administration followed institutional guidelines.

The primary end point of the study was safety based on rates of grade 3 or higher CRS or ICANS within 30 days of axi-cel infusion. Rates of bridging success, defined as receiving acalabrutinib between leukapheresis and lymphodepletion without requiring additional treatment, were also assessed. Other key end points included overall response rate and CR following axi-cel infusion, PFS, OS, and immune response biomarkers.

As of January 2024, 18 patients were enrolled onto the study and received axi-cell infusion. The median age of patients was 58 years (range, 34-74), and 67% of patients were 60 years of age or younger. The majority of patients were White (89%) and had LBCL (83%), and 78% of patients had DLBCL not otherwise specified. A total of 17% of patients had FL. Of the patients with relapsed disease (67%), 50% experienced relapse within 1 year of initial therapy. The median number of prior treatments administered to patients was 3 (range, 1-5), and 28% of patients had received prior stem cell transplant. Thirty-three percent of patients had disease bulk over 5 cm when they started on acalabrutinib. The median time from initiation of acalabrutinib to lymphodepletion was 32 days.

Investigators also assessed CR rates according to biologic covariates, such as disease bulk, disease refractoriness, cell of origin, and mixed status.

“CR rates were higher in patients with more than 5 cm disease bulk, relapsed rather than primary refractory disease, non–germinal center B-cell [GCB] rather than GCB subtype, and without MYC overexpression or translocation,” Poh reported.

Additionally, myeloid-derived suppressor cell (MDSC) levels were found to decrease from baseline throughout the treatment course.

“Of 6 patients, all had a decrease in MDSC levels ranging from 59% to 97% between [the time before] acalabrutinib initiation to post–CAR T-cell therapy,” Poh says, adding that no association between MDSC levels and CR was observed at any time point, contrary to findings from prior publications.

A correlative exploratory analysis was conducted to assess the correlation between 110 cytokine levels at various time points during treatment and CRS severity. A decrease in the levels of BDNF, PDGF-BB, CXCL12, IL-6R alpha, and CD163 between baseline and pre-lymphodepletion was associated with lower-grade CRS. Moreover, lower-grade ICANS was correlated with a decrease in CCL11, VCAM-1, CXCL12 (beta), and PDGF-BB between baseline and pre-lymphodepletion. However, no cytokine changes during the bridging period correlated with clinical responses.

The safety analysis revealed that any-grade CRS and ICANS occurred in 94% and 56% of patients, respectively; however, no instances of grade 4 or 5 CRS or ICANS were observed. The median time from axi-cel infusion to the peak of CRS was 5 days (range, 4-8), with a median duration of CRS of 4 days (range, 1-7). The median time after axi-cel infusion until the peak of ICANS was 7 days (range, 4-12), with a median duration of ICANS of 4 days (range, 2-17). No patients received prophylactic dexamethasone, and all CRS and ICANS resolved with dexamethasone, tocilizumab or anakinra administration.

The most common any-grade nonhematologic toxicities included bradycardia and headache, which each occurred in 5% of patients. There were no grade 3 or greater nonhematologic AEs, and no treatment-related deaths were observed. Acalabrutinib was temporarily held in 3 patients for a median of 6 days, but no patients discontinued treatment at any time due to toxicity.

“[Acalabrutinib was held in] 1 patient for grade 1 bradycardia of unclear etiology, which spontaneously resolved after 5 days; 1 [patient] for nausea/vomiting due to radiation during bridging; and 1 [patient] for systemic inflammatory response syndrome criteria with an unknown source, which resolved with augmentin. In all cases, acalabrutinib was successfully restarted without recurring symptoms,” Poh clarified.

Dr Poh reports receiving research funding from Incyte, Dren Bio, and Astex; and serving as a consultant for Acrotech, Beigene, Seagen, and Ipsen.

References

1. Poh C, Chow VA, Lynch RC, et al. Acalabrutinib in combination with anti-CD19 chimeric antigen receptor T-cell therapy in relapsed/refractory B-cell lymphoma: a phase I/II study of safety, efficacy and immune correlative analysis. Presented at: 2024 Transplantation & Cellular Therapy Meetings; February 21-24, 2024; San Antonio, TX. Abstract 37.
2. Acalabrutinib. Prescribing information. FDA; 2019. Accessed February 22, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210259s006s007lbl.pdf