polymorphic allele ABCB1 again VEGF Pharmacogenetic analysis of germline biomarkers in the phase 3 MCL0208 trial (NCT02354313) showed that lenalidomide (Revlimid ) could predict the effectiveness of1
polymorphism of ABCB1 again VEGF Expressed in 69% and 79%, respectively, of 278 patients included in the pharmacogenetic study and predicted better progression-free survival (PFS) outcome compared with homozygous wild-type patients ABCB1 again VEGF Lenalidomide in the arm. The 3-year PFS rate for patients receiving lenalidomide was ABCB1 The variant was 85% vs 70%. ABCB1wild-type (P. = .05), and 3-year PFS rates for patients with VEGF The variant was 85% vs 60%. VEGF wild-type (P. = .0021).
The prospective, multicenter MCL0208 trial observed and compared the efficacy and safety of upfront therapy with rituximab (Rituxan) followed by high-dose chemotherapy and lenalidomide maintenance therapy after ASCT in treatment-naive MCL patients younger than 66 years and investigated. The 3-year PFS rate in the enrolled population (n = 300) was 67%, and the 3-year overall survival (OS) rate was 84%.2
Of the 248 patients who underwent ASCT, 205 were randomly assigned to receive maintenance lenalidomide (n = 104) or observation (n = 101). The 3-year PFS rate was 80% (95% CI, 70%–87%) in the lenalidomide group compared to 64% (95% CI, 53%–73%) in the observation group (stratified HR, 0.51; 95%CI, 0.30-0.87; P. = .013).
“We studied specific germline polymorphisms of transmembrane transporters, metabolic enzymes and cell surface receptors. [ABCB1, ABCG2, VEGF-A, FCGR2A, NCF4, GSTP1, CRBN] It may predict the efficacy and safety of chemoimmunotherapy and lenalidomide maintenance therapy,” study lead author Simone Ferrero, MD, of the University of Turin, Turin, Italy, and colleagues said in 2006. in a paper summarizing published data. Brad Advances.1
This analysis used bone marrow and peripheral blood samples collected at diagnosis and during follow-up from patients enrolled in MCL0208. MCL0208 had no clinically significant comorbidities and received 3 cycles of R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) followed by rituximab with high-dose cyclophosphamide, rituximab and 300 patients who received two cycles of high-dose cytarabine were enrolled. , ASCT. Patients randomly assigned after ASCT either received lenalidomide 15 mg from day 1 to 21 every 28 days or were observed for 24 months.
Of all patients enrolled, 93% (n = 278) had sufficient data available for inclusion in pharmacogenetic studies. In total, 96% (n = 197/205) of the randomized population were genotyped, including 97% (n = 101/104) of patients in the lenalidomide group and 95% (n = 101/104) of patients in the observation group. = 96/104) were included. 101).
The frequency of 3 is ABCB1 Single nucleotide polymorphisms (wild-type homozygous, heterozygous polymorphism, and homozygous polymorphism) were 18.8%, 51.5%, and 29.7%, respectively, in the lenalidomide group and 16.7%, 50.0%, and 33.3%, respectively, in the observation group. was. . The researchers reported no significant difference in haplotype distribution between the two groups or between the enrollment and randomization populations (χ2 = 0.264; P. = .876).
Among the polymorphisms investigated were: ABCB1 rs2032582 and VEGF rs699947 was associated with PFS and OS benefits from lenalidomide. In the randomized population, 31% (n = 60), 54% (n = 107), and 15% (n = 30) of patients were wild-type homozygous, heterozygous, or polymorphic homozygous was a mold. ABCB1 Twenty-one percent (n = 42), 49% (n = 96), and 30% (n = 59) of patients were wild-type homozygous, heterozygous, or polymorphic homozygous. VEGF variations of each.
In total, 70% (n = 137) of the randomized population had at least one ABCB1 rs2032582 polymorphic allele. Patients with heterozygous or polymorphic homozygous variants had better outcomes compared with patients with wild-type homozygous variants in the lenalidomide group, but not in the observation group. The 3-year OS rate was 98% for patients with a heterozygous or polymorphic homozygous variant compared to 90% for patients with a wild-type homozygous variant (P. = .026).
In a randomized patient population, VEGF-A For variants, the 3-year OS rate was 90% for patients with heterozygous or polymorphic homozygous variants compared to 86.5% for patients with a wild-type homozygous variant (P. = .094).
patient ABCB1 again VEGF-A Mutants tended to have deeper minimal residual disease clearance in bone marrow after 6 months of lenalidomide treatment compared with wild-type homozygous mutants ABCB1 again VEGF-A.
Greater PFS benefits were observed in patients with at least one mutation when the randomized population was stratified by pharmacogenomic background. ABCB1 (HR vs. ABCB1 wild-type, 0.41. 95% CI, 0.22-0.75) or VEGF-A (HR vs. VEGF-A wild type, 0.51; 95% CI, 0.30–0.87; P. = .012).
Patients with both wild types ABCB1 and VEGF-A Mutants (n = 17) benefited less from lenalidomide than observed (P. = .632).
Dose reduction of lenalidomide CRBN rs1705814 genotype. Across the population, 41% (n = 113), 33% (n = 91), and 26% (n = 73) of patients were wild-type homozygotes, heterozygotes, or homozygotes for the polymorphism. CRBN variations of each. In addition, his 28% (n = 28) of patients in the lenalidomide group had polymorphic homozygous variants. These patients were at increased risk of requiring a ≥66% reduction in the maintenance dose of lenalidomide or discontinuation of lenalidomide compared with wild-type homozygous or heterozygous patients. CRBN variant (odds ratio, 3.24; CI, 1.69-6.21; P. = .013). However, in the lenalidomide group, researchers observed no statistically significant effect. CRBN rs1705814 Single nucleotide polymorphism for infectious disease or hematological toxicity.
Across the population, the three polymorphisms associated with hematotoxicity are: ABCB1 rs2032582, NCF4 rs1883112, and GSTP1 rs1695. 17 percent of patients (n = 46) ABCB1 TT/AT/AA genotypes were found to have a lower risk of hematologic toxicity after the first R-CHOP cycle compared to patients with heterozygous or wild-type homozygous genotypes (grade 3 odds ratio for ≥ toxicity, 0.39; CI, 0.15–0.88; P. = .033).Additionally, 58% of patients (n = 162) had NCF4 The AG/GG genotype had a lower risk of developing hematologic toxicity during induction compared with the wild-type homozygous genotype (odds ratio, 0.56; CI, 0.34–0.92; CI, 0.34–0.92; P. = .024). Additionally, 10% of patients (n = 28) had GSTP1 Those with the GG polymorphism homozygous genotype had a lower risk of toxicity than those with heterozygous or wild-type homozygous genotypes, odds ratio 0.35 (CI, 0.15–0.79; CI, 0.15–0.79; P. = .014).
The researchers also identified a subgroup of 48 patients who were homozygous for wild-type. NCF4 and GSTP1Genotype with increased risk of hematologic toxicity during induction therapy (odds ratio, 2.26; CI, 1.09–4.83; P. = .031). However, these single nucleotide polymorphisms did not affect hematotoxicity during later therapeutic phases or post-ASCT hematologic recovery.
Furthermore, the population as a whole ABCB1 rs1045642 and CRBN rs1705814 was associated with infections during chemoimmunotherapy.for ABCB1 c.3435.C>T, 25% (n = 70), 51% (n = 143), and 23% (n = 65) of patients were wild-type homozygous (CC), heterozygous (CT) , and had polymorphisms. each homozygous (TT) genotype.for CRBN rs1705814 T>C, 41% (n = 113), 33% (n = 91), and 26% (n = 73) of patients were wild-type homozygous (TT), heterozygous (TC), and polyzygous had type homozygous (CC)) genotypes, respectively.A total of 65 patients ABCB1 Wild-type homozygous genotypes had a lower risk of infection than genotypes with CT or CC genotypes (odds ratio 0.53; CI 0.30–0.95; CI 0.30–0.95; P. = .030).In addition, 73 patients with polymorphic homozygosity CRBN The rs1705814 genotype had a lower risk of infection than the wild-type homozygous or heterozygous genotypes (odds ratio for grade ≥3 AEs, 0.39; CI, 0.22–0.68; P. = .001). There were no single nucleotide polymorphisms that predicted the development of infection while on lenalidomide.
“Our main findings were ABCB1 and VEGF-A polymorphisms in enhancing the clinical activity of post-ASCT lenalidomide maintenance in MCL,” the study authors concluded.
References
- Ferrero S, Grimaldi D, Arigoni E et al. Candidate germline biomarkers for efficacy of lenalidomide in mantle cell lymphoma: the FIL MCL0208 study. Blood Advance. Published online on April 14, 2023. doi:10.1182/blood advances.2022009504
- Radetto M, Ferrero S, Evangelista A, et al. Lenalidomide maintenance after autologous transplantation prolongs PFS in young MCL patients: results from the Fondazione Italiana Linfomi (FIL) randomized phase III MCL 0208 trial. blood. 2018;132(Supplement 1):401. Doi: 10.1182/blood-2018-99-110289