Acalabrutinib Yields High ORR in Steroid-Refractory Chronic GVHD

Acalabrutinib (Calquence) demonstrated efficacy and tolerability across multiple organs affected by steroid-refractory chronic graft-vs-host disease (cGVHD), according to primary findings from a multicenter phase 2 trial (NCT04198922) presented at the 2026 Transplantation & Cellular Therapy Meetings.¹

The estimated best overall response rate (ORR) was 62% (95% CI, 47%-75%). The estimated best ORR among patients who had received acalabrutinib for at least 1 cycle (n = 45) was 69% (95% CI, 53%-82%). At 6 months and 12 months, the estimated failure-free survival (FFS) rates were 59% (95% CI, 44%-72%) and 36% (95% CI, 24%-52%), respectively. Additionally, the median duration of response (DOR) among patients who achieved a complete response (CR) or partial response (PR) was 28 weeks.

“The study shows some evidence of improved safety with this drug [vs ibrutinib (Imbruvica)] in the cGVHD setting,” Joseph A. Pidala, MD, PhD, said in a presentation of the data.¹ “[Fewer] patients discontinued therapy for toxicity, and [no] adverse effects [AEs] of special interest have been noted.”

Pidala is a medical oncologist in the Blood and Marrow Transplant Department at Moffitt Cancer Center and an associate professor of oncology in the Department of Oncologic Sciences at the University of South Florida in Tampa.

Study Rationale

Ibrutinib was approved by the FDA in 2017 for the treatment of adult patients with cGVHD who have progressed on at least 1 prior line of systemic therapy.² This approval was based on findings from the phase 2 PCYC-1129 trial (NCT02195869). In the pivotal trial, 24% of patients discontinued treatment because of AEs, and 26% of patients required dose reductions due to AEs.

The second-generation Bruton tyrosine kinase inhibitor acalabrutinib was approved by the FDA in 2017 for the treatment of adult patients with relapsed/refractory mantle cell lymphoma who have received at least 1 prior line of therapy, and in 2019 for the treatment of adult patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.^3,4 Pidala noted that this agent is considered to have a more favorable toxicity profile than ibrutinib. Therefore, the current phase 2 trial investigators aimed to determine the efficacy of acalabrutinib in patients with cGVHD and to assess whether this agent has a reduced toxicity profile compared with ibrutinib in this population.

Study Design

This trial enrolled 50 patients aged 18 years and older with moderate to severe cGVHD per National Institutes of Health (NIH) criteria who had previously received steroid therapy.¹ Patients also needed to have a Karnofsky performance score of at least 70%. The enrollment criteria had no minimum or maximum number of prior lines of immunosuppressive therapy.

“This has opened up the possibility of treating patients with much higher treatment experience,” Pidala noted.¹

Patients received 100 mg of acalabrutinib orally twice daily in 28-day cycles for a total of 6 cycles. Patients who responded to therapy had the option to continue treatment for a total of 24 cycles. Concomitant medications were not permitted.

In patients who experienced grade 3/4 AEs, acalabrutinib treatment was held until recovery to grade 1 AEs or baseline status. AEs for which acalabrutinib was held included grade 4 neutropenia lasting more than 7 days; thrombocytopenia that was grade 3 with bleeding or grade 4; grade 3/4 nausea, vomiting, or diarrhea; and other grade 3/4 treatment-related AEs. After recovery from the first and second occurrences of these AEs, patients resumed acalabrutinib treatment at the original dose. After the third occurrence, patients received acalabrutinib at 100 mg daily. After the fourth occurrence, treatment was discontinued. Acalabrutinib treatment was also held for 7 days before and after surgery.

Full acalabrutinib discontinuation occurred after acalabrutinib treatment had been held for more than 28 days for any reason, after patients received a new line of systemic immunosuppressive therapy, after patients had recurrent unresolved toxicities despite dose reductions, if patients were not adherent, or at investigator or patient discretion.

Best ORR per NIH criteria served as the primary end point. Secondary end points included safety, DOR, organ-specific response rates, patient-reported outcomes (PROs), and FFS.

Additional Efficacy Findings

Patients had a median age of 49 years (range, 21-74). Most were White (84%), had acute myeloid leukemia/myelodysplastic syndromes/acute lymphoblastic leukemia (76%), and had received reduced-intensity or nonmyeloablative conditioning therapy. Patients had received 1 (18%), 2 (24%), 3 (20%), 4 (20%), 5 (10%), 6 (4%), or 7 (4%) prior lines of therapy. Prior systemic immunosuppressive therapies included prednisone (92%), ruxolitinib (Jakafi; 56%), tacrolimus (48%), belumosudil (Rezurock; 48%), sirolimus (38%), mycophenolate mofetil (16%), extracorporeal photopheresis (14%), methotrexate (8%), rituximab (Rituxan; 6%), other steroids (6%), axatilimab (Niktimvo; 4%), and bortezomib (Velcade; 2%).¹

Organ-specific response rates (CR and PR, respectively) included, as follows:

• Skin (n = 33; 12%; 18%)
• Eye (n = 34; 6%; 35%)
• Mouth (n = 28; 14%; 46%)
• Esophagus (n = 9; 56%; 0%)
• Lower gastrointestinal (n = 6; 83%; 0%)
• Lung (n = 14; 21%; 21%)
• Joint (n = 25; 4%; 44%)
• Liver (n = 18; 50%; 22%)

Treatment with acalabrutinib also yielded a clinically meaningful change in PROs per Patient-Reported Outcomes Measurement Information System measures and the Lee Symptom Score.

Safety Profile

Acalabrutinib dose holds due to toxicity or infection occurred in 30% of patients. Toxicities leading to dose holds included headache (n = 3), neutropenia (n = 2), myalgia/fatigue (n = 1), anxiety/palpitations (n = 1), edema (n = 1), diarrhea (n = 1), and cystitis (n = 1). Infections leading to dose holds (n = 1 each) included COVID-19, sepsis, fungal pneumonia, and conjunctivitis.¹

Acalabrutinib dose reductions due to drug interactions only (not toxicities) occurred in 12% of patients, all of whom underwent a protocol-required decrease for moderate CYP3A4 inhibitors.

Acalabrutinib discontinuation within 6 cycles of treatment occurred in 18% of patients due to headache with or without nausea (n = 2), anxiety/palpitations (n = 1), worsened oral pain (n = 1), dizziness (n = 1), grade 4 neutropenia (n = 1), conjunctivitis (n = 1), fatigue (n = 1), and patient decision (n = 1).

“We need more extensive follow-up to understand the burden of late secondary malignancy,” Pidala concluded.¹

DISCLOSURES: Pidala reported receiving consulting fees from Deciphera, Incyte, and Sanofi; and receiving clinical trial support from AstraZeneca, Bristol Myers Squibb, CTI BioPharma, Incyte, Johnson & Johnson, Novartis, and Sanofi.

REFERENCES

1. Pidala J, Choe H, Alousi A, et al. Acalabrutinib for treatment of steroid-refractory chronic graft vs host disease: primary trial results. Presented at: 2026 Transplantation & Cellular Therapy Meetings; February 4-7, 2026; Salt Lake City, UT. Abstract 11.

2. FDA expands ibrutinib indications to chronic GVHD. FDA. August 2, 2017. Accessed February 4, 2026. https://tinyurl.com/46vszfmx

3. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. FDA. October 31, 2017. Accessed February 4, 2026. https://tinyurl.com/e8m599dj

4. Project Orbis: FDA approves acalabrutinib for CLL and SLL. FDA. November 21, 2019. Accessed February 4, 2026. https://tinyurl.com/598bjsy4