Researchers say they have come one step closer to determining the cause of R-CHOP failure in diffuse large B-cell lymphoma (DLBCL) by ruling out a potential cause.
Randy D. Gascoyne, MD, of the British Columbia Cancer Agency, and colleagues found that CD20 mutations involving the rituximab epitope are not the source of R-CHOP resistance. In fact, the mutations are rare in both de novo and relapsed DLBCL.
The rituximab epitope is located in exon 5 of the MS4A1 gene, so Dr Gascoyne and colleagues sequenced this region in DLBCL samples taken at diagnosis and relapse (1 month after completion of 6 cycles of R-CHOP). The team successfully sequenced 264 diagnostic samples and 15 relapsed samples.
The samples could be considered representative of the DLBCL population in British Columbia because clinical characteristics were similar to those observed in previous studies, according to the researchers. In addition, most of the patients had nodal disease with a minimum of 80% tumor, which was sufficient for detecting mutations.
Only 1 of 264 diagnostic samples showed a CD20 mutation involving the rituximab epitope—a 13 base pair heterozygous deletion at position IVS5(+8) in intron 5. Dr Gascoyne and colleagues were unable to determine if this was a polymorphism or a somatic mutation.
This patient achieved a complete response to R-CHOP and is still in remission more than 2 years after diagnosis. This outcome rules out the possibility of mutation-induced rituximab resistance.
As with the diagnostic samples, only 1 of the relapsed samples showed a CD20 mutation involving the rituximab epitope. This was a heterozygous 4 base pair deletion (TAAT) at nucleotide position 353-356, which predicted for a premature termination at amino acid position 121, well before the critical ANPS binding site.
The researchers were unable to establish whether this mutation was present at diagnosis, but they did determine there were no single nucleotide polymorphisms in exon 5 of the CD20 gene.
The rarity of mutations in the rituximab epitope observed in this study suggests these mutations cannot be responsible for the majority of R-CHOP treatment failures. However, Dr Gascoyne and colleagues said they cannot exclude the possibility that R-CHOP resistance might result from mutations at other sites in MS4A1, as these sites were not evaluated.
These findings appear in the March issue of haematologica.
