R-CHOP resistance in diffuse large B-cell lymphoma: biological and molecular mechanisms

Abstract

Although the first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone regimen (R-CHOP) substantially improved outcomes for patients with diffuse large B-cell lymphoma (DLBCL), 40% of the patients suffered from relapsed/refractory disease and had poor survival outcomes. The detailed mechanism underlying R-CHOP resistance has not been well defined. For this review, we conducted a thorough search for literature and clinical trials involving DLBCL resistance. We discussed DLBCL biology, epigenetics, and aberrant signaling of the B-cell receptor ( BCR ), phosphatidylinositol 3-kinase ( PI3K ) /Akt , nuclear factor kappa light chain enhancer of activated B-cells ( NF-κB ), and the Janus kinase ( JAK )/signal transducer and activator of transcription 3 ( STAT3 ) pathways as defining mechanisms of DLBCL heterogeneity and R-CHOP resistance. The cell of origin, double- or triple-hit lymphoma and double-protein-expression, clonal evolution, tumor microenvironment, and multi-drug resistance help to contextualize DLBCL resistance in an (epi)genetically and biologically comparative manner. With better understanding of the biological and molecular landscape of DLBCL, a more detailed classification system and tailored treatments will ideally become available to further improve the prognosis of DLBCL patients.

Mutation profiling of circulating tumor DNA identifies distinct mutation patterns in non‐Hodgkin lymphoma

“…47 The mechanisms of resistance to first-line R-CHOP in DLBCL patients are complex, and the limited knowledge on the mutation profile of DLBCL patients who progress under treatment pressure has hampered the development of effective treatment strategies. 48 A high ctDNA VAF is considered to be an unfavorable prognostic marker. It has been reported…”

Calcium-dependent signalling in B-cell lymphomas

“…The R-CHOP therapy (a combination of RTX with cyclophosphamide, doxorubicin, vincristine and prednisolone) is a standard treatment for DLBCL patients. However, ~40% of the patients treated with R-CHOP are either resistant to the initial treatment or will subsequently relapse [ 105 ]. Elevated expression of a number of calcium-binding proteins has been associated with resistance to R-CHOP treatment in DLBCL patients.…”

CircPCBP2 promotes the stemness and chemoresistance of DLBCL via targeting miR‐33a/b to disinhibit PD‐L1

“… 2 The first‐line treatment for the disease is a combination of chemotherapy consisting of rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisolone (R‐CHOP). 3 Nevertheless, nearly 40% DLBCL patients develop drug resistance to the treatment afterward and suffer from the relapsed disease. 2 , 3 There is a necessity to uncover the molecular mechanisms of DLBCL development, particularly the mechanisms underlying CHOP resistance, to find new avenues to treat the disease.…”

“… 3 Nevertheless, nearly 40% DLBCL patients develop drug resistance to the treatment afterward and suffer from the relapsed disease. 2 , 3 There is a necessity to uncover the molecular mechanisms of DLBCL development, particularly the mechanisms underlying CHOP resistance, to find new avenues to treat the disease.…”