A Polymorphism in the C1qA Component of Complement Correlates with Prolonged Complete Remission Following Rituximab Therapy of Follicular Lymphoma.
Authors: Racila Emilian , Weng Wen-Kai , Wooldridge James E. , Link Brian K. , Levy Ronald , Weiner George J. 
Published: April 2020

There is indirect but intriguing evidence that complement plays a role in the clinical response to rituximab and other mAb-based therapies of cancer. We identified a non-coding polymorphism in the C1qA component of complement that appears to result in a post-translational splice variant of the C1qA protein. We examined this polymorphism in 90 patients with follicular lymphoma who were treated with single agent rituximab to assess whether a correlation exists with clinical efficacy. The presence of an A versus a G allele at the C1qA[276] locus was determined using restriction fragment length polymorphism analysis by investigators blinded to the clinical outcome of the patients. The molecular and clinical data was then analyzed according to C1qA polymorphism, including measurement of radiographic response and duration of response, using methods similar to those used to evaluate the correlation between polymorphisms in CD16/CD32 genes and clinical outcome. No statistically significant difference in response rate was found based on C1qA polymorphism. However, prolonged remission was noted among those subjects that achieved remission (either PR or CR) for individuals who were carriers of the A allele at the C1qA[276] locus (AA or AG) compared to homozygous GG subjects. The strongest correlation was found among those subjects that achieved a complete remission to single agent rituximab. In this group, GG subjects had a time to progression of 250 days, while AA /AG subjects had time to progression of 830 days (HR=4.1, 95% CI=2.1–96.9). Multivariate Cox regression analysis of the joint effects of the C1qA, CD32 and CD16 polymorphisms showed that C1q[276] A allele was an independent factor for good prognosis, while FcgRIIIa 158 phenylalanine carrier and FcgRIIa 131 arginine carrier indicated poor survival. Thus, the relative risk was 0.2 for C1qA[276] AA/AG versus GG after controlling for CD32 and CD16 polymorphisms. The relative risks were 4.8 for CD32 HR versus HH and 6.16 for CD32 RR versus HH after controlling for complement and CD16 polymorphisms. The relative risks were 4.57 for CD16 VF against VV and 3.69 for CD16 FF versus VV after controlling for complement and CD32 polymorphisms. These data suggest polymorphisms in C1qA may impact on duration of response to rituximab therapy of follicular lymphoma. Ongoing studies are expanding this cohort, assessing whether this polymorphism correlates clinically with outcome in other malignancies or with other therapeutic approaches in lymphoma patients, and exploring the functional significance of this C1qA polymorphism. If further studies confirm that C1qA genetic polymorphisms correlate with duration of response to rituximab, it will have major implications on our understanding of the role of complement in the immune response to lymphoma, and on development of the next generation of mAb-based cancer treatments.

Total AA+AG GG p (log-rank test) TTP=Median time to progression (days) All Subjects 90 70 20 Responders 59 46 13 CR 27 22 5 TTP Overall 177 173 191 0.64 TTP Responders 352 456 334 0.12 TTP CR 798 830 250 0.007

Complement C1qA polymorphism associates with freedom from progression in follicular lymphoma patients who achieve a CR after anti-CD20 therapy. Progression-free survival logrank curves were plotted by C1qA[276] AA and AG vs GG genotype. Cheson criteria were used to estimate complete clinical remission after one round of anti-CD20 therapy. Complement C1qA polymorphism associates with freedom from progression in follicular lymphoma patients who achieve a CR after anti-CD20 therapy. Progression-free survival logrank curves were plotted by C1qA[276] AA and AG vs GG genotype. Cheson criteria were used to estimate complete clinical remission after one round of anti-CD20 therapy.