MYC/BCL2/BCL6 triple hit and TP53 deletion in a case of high-grade B cell lymphoma receiving CAR T cell immunotherapy

Abstract

High-grade B cell lymphoma with MYC, BCL2, and BCL6 rearrangements (HGBL-TH) is rare and often portends poor outcome after standard chemoimmunotherapy. Adoptive chimeric antigen receptor (CAR) T cell therapy is a new paradigm for the treatment of refractory/relapsed (r/r) lymphomas, but its therapeutic effects in treating HGBL-TH remain inconclusive. Here, we report a patient with HGBL-TH who failed to achieve complete remission (CR) and progressed rapidly after first-line and second-line therapies. Furthermore, he was resistant to the CAR19 and CAR22 T cell cocktail therapy following autologous hematopoietic stem cell transplantation (ASCT), and disease progressed again after the anti-B cell maturation antigen (BCMA) CAR T cell immunotherapy. Comprehensive analyses were performed to explore the inherent mechanism for resistance, which indicated that tumorderived antigen escape, clonal evolution, and T cell defects were involved in it. This is the first report of an HGBL-TH patient with TP53 deletion and additional germline (PIM1) and somatic mutations (TP53, KMT2D, and IGLL5) who was treated with ASCT, CD19/22 CAR T cell cocktail therapy and BCMA CAR T cell immunotherapy. The clinical evolution and genetic features of this case may help to explain the underlying mechanism of treatment resistance and provide novel insights into lymphoma treatment. Trial registration: ChiCTR-OPN-16009847

T Cell Defects: New Insights Into the Primary Resistance Factor to CD19/CD22 Cocktail CAR T-Cell Immunotherapy in Diffuse Large B-Cell Lymphoma

“…Pathogenic germline alterations provide evolving insights into primary resistance mechanisms. Previously, our therapeutic center reported two patients who harbored germline mutations and received murine monoclonal anti-CD19 and anti-CD22 CAR T-cell “cocktail” therapy ( 5 , 46 ). A pathogenic PIM1 mutation (c.403G>A, p.Glu135Lys, heterozygous) was detected in a MYC/BCL2/BCL6 triple-hit DLBCL patient, and a pathogenic TP53 germline mutation (c.818G>A, p.R273H, heterozygous) was found in another DLBCL patient ( 5 , 46 ).…”

“…Previously, our therapeutic center reported two patients who harbored germline mutations and received murine monoclonal anti-CD19 and anti-CD22 CAR T-cell “cocktail” therapy ( 5 , 46 ). A pathogenic PIM1 mutation (c.403G>A, p.Glu135Lys, heterozygous) was detected in a MYC/BCL2/BCL6 triple-hit DLBCL patient, and a pathogenic TP53 germline mutation (c.818G>A, p.R273H, heterozygous) was found in another DLBCL patient ( 5 , 46 ). These two patients had weak C max and T last values (C max < 10,000 copies/μg, T last < 3 months), and the disease progressed, which met the criteria of “T-defect” group.…”

Immunophenotypic transformation in relapsed/refractory mantle cell lymphoma treated with human anti-CD5 chimeric antigen receptor T cells: A Case Report

“…In the present case, the patient had double-hit MCL with TP53 mutation and rearrangement of IgH-CCND1 and MYC, and an immunophenotypic transformation occurred after treatment with CAR T-cell treatment; the specific mechanism for this is unclear. In CAR T cell therapy, tumor antigen escape is a common cause of disease control failure (22). CD5+ lymphoma antigens, which is the primary challenge in CAR T-cell therapy.…”

A unique hub‐and‐spoke model to optimize patient management in lymphoma using novel CAR‐T cell therapy in Southeast and South Asia

“…17 Genetic markers such as myc translocations may also have predictive value; however there is no consensus to date. 18 Nonetheless, it appears likely that there are multiple mechanisms involved in determining treatment outcomes, including tumor-specific alterations to the genome. 19 Future research will no doubt shed more light on the complex interplay of the various factors involved in the patient response to CAR-T cell therapy.…”

“…For instance, extranodal involvement and total metabolic tumor volume, and elevated levels of biomarkers such as lactate dehydrogenase and C‐reactive protein, are considered to be predictors of poor outcomes after CAR‐T therapy 17 . Genetic markers such as myc translocations may also have predictive value; however there is no consensus to date 18 . Nonetheless, it appears likely that there are multiple mechanisms involved in determining treatment outcomes, including tumor‐specific alterations to the genome 19 .…”