Acalabrutinib/lenalidomide in combination with rituximab or obinutuzumab generated uMRD6 CRs in previously untreated mantle cell lymphoma.
Acalabrutinib (Calquence) plus lenalidomide (Revlimid) and rituximab (Rituxan; ALR) or the combination of acalabrutinib, lenalidomide, and obinutuzumab (Gazyva; ALO) produced high rates of complete response (CR) with undetectable minimal residual disease at a 1 x 106 sensitivity (uMRD6) in patients with previously untreated mantle cell lymphoma (MCL), according to data from a phase 2 trial (NCT03863184).1
The trial evaluated either ALR (n = 24) or ALO (n = 10) in patients with previously untreated MCL who had measurable disease after a previous phase 2 trial (NCT01472562) evaluated lenalidomide plus rituximab alone in the same patient population.1,2
Findings published in Blood Advances showed that patients treated with ALR achieved an overall response rate (ORR) of 100% (90% CI, 88%-100%) and a CR rate of 83% (90% CI, 66%-94%) per Lugano criteria after 12 treatment cycles.1 The uMRD6 rate in this group was 67% after 12 cycles of therapy. Patients who received ALO achieved ORR and CR rates of 90% (90% CI, 61%-100%), and the uMRD6 rate was 90% after 12 cycles. Moreover, among patients with TP53 mutations who received ALR (n = 6), 86% achieved a uMRD6 CR following induction.
“The frontline phase 2 study of ALR…builds upon the LR doublet with the addition of the next-generation BTK inhibitor acalabrutinib and has similar demographic and disease risk stratification [compared with the prior phase 2 study],” lead study author Jia Ruan, MD, PhD, and coauthors wrote in the publication. “The ALR and ALO triplet regimens are highly effective with durable clinical and molecular remissions for both patients with wild-type TP53 and those with mutated TP53.”
Ruan is a professor of clinical medicine at Weill Cornell Medical College, as well as an attending physician at NewYork-Presbyterian Hospital in New York, New York.
The multicenter, open-label trial enrolled patients aged 18 or older with histologically confirmed MCL and measurable disease who required systemic therapy.1,3 Patients also needed to have an ECOG performance status of 2 or less, adequate organ function, and an absolute neutrophil count of at least 1 × 103/μL, a platelet count of 75 × 103/μL or more, and a total bilirubin of no more than 1.5 times the upper limit of normal were also required for enrollment.
If patients had blastoid histology, suspected or known central nervous system involvement, viral HIV infection, hepatitis B or C, clinically significant cardiovascular disease, or a prior history of malignancies other than MCL within 5 years of enrollment, they were not included in the trial.3
Acalabrutinib was administered at 100-mg, twice-daily doses in both study groups.1 From treatment cycles 1 to 12, patients received 15 mg of lenalidomide per day with permitted escalation to 20 mg if they tolerated the initial dose, followed by 15 mg during the maintenance phase; patients with a reduced creatinine clearance of 30 to 60 mL/minute received lenalidomide at 10 mg per day during induction and 5 mg during maintenance. Patients who received ALR were administered 4 doses of rituximab per week throughout cycle 1, followed by 1 dose every other cycle during induction and maintenance. In the ALO group, obinutuzumab was given to patients in 3 weekly doses in the first cycle of treatment, followed by monthly doses for cycles 2 to 6, and then once every other cycle for the rest of treatment.
Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal. Notably, patients who achieved a molecular CR with uMRD6 could discontinue acalabrutinib and lenalidomide after 24 cycles. All patients in the trial who achieved clinical remission were allowed to discontinue treatment after 36 cycles.
The proportion of patients achieving CR per Lugano criteria in addition to uMRD6 per clonoSEQ following 12 cycles of treatment served as the primary end point of the trial. Safety, overall survival (OS), progression-free survival (PFS), and ORR were secondary endpoints for the trial.
Baseline characteristics revealed that patients who received ALR had a median age of 64 years (range, 35-77); those who received ALO had a median age of 64 years (range, 37-82). All patients in the trial had an ECOG performance status of 1 or less and Ann Arbor stage III or IV disease. Most patients had bone marrow involvement for both the ALR (96%) and ALO (80%) groups. Regarding the MCL International Prognostic Index (MIPI), patients who received ALR had high- (21%), intermediate- (42%), and low-risk (37%) disease; these respective rates were 50%, 10%, and 40% for those who received ALO. TP53 wild-type disease was common in both treatment groups (ALR, 63%; ALO, 70%), whereas TP53 mutations (25%; 30%) and unknown TP53 status (13%; 0%) were less common.
At a median follow-up of 53 months (range, 46-60), the 4-year PFS rate was 76% (95% CI, 56%-95%) for ALR, and the 4-year OS rate was 91% (95% CI, 78%-100%).
At a median follow-up of 25 months (range, 15-28) in the ALO group, the 2-year OS and PFS rates were both 100% (95% CI, 100%-100%).
Regarding safety, all but 1 patient who received ALO entered maintenance; this patient withdrew from the study after the third induction cycle due to an asymptomatic abnormality on a liver function test. In the ALR arm, all 24 patients entered the maintenance phase.
Common any-grade hematologic adverse effects (AEs) for ALR during induction included neutropenia (67%), anemia (33%), and thrombocytopenia (29%). Common hematologic AEs of grade 3 or higher in this group included neutropenia (34%), thrombocytopenia (4%), and anemia (4%). Patients who received ALO experienced similar common any-grade or grade 3 or higher hematologic AEs during induction, including neutropenia (any-grade, 70%; grade ≥3, 40%), anemia (30%; 0%), and thrombocytopenia (50%; 30%). Other common any-grade AEs for each group during induction were rash (88%; 50%), fatigue (50%; 50%), headache (58%; 70%), and diarrhea (50%; 90%).
“The ALR/ALO study delineates longitudinal clonoSEQ-based MRD trajectories along with standard clinical response assessments for all study participants up to 5 years, establishing a benchmark of MRD dynamics during induction and maintenance treatment, as well as time off treatment,” Ruan and coauthors said.
