Alexis Claudel

Patients with follicular lymphoma who experience disease progression within 24 months of diagnosis (POD24) have a lower survival. Positron emission tomography (PET) response and circulating tumor DNA (ctDNA) minimal residual disease (MRD) assessment at end of induction (EOI) may allow their early identification. A representative cohort of 141 patients from the RELEVANCE phase 3 trial with both available serum samples for ctDNA testing and PET images at randomization and at EOI (week 24) was investigated. Twelve percent were POD24. ctDNA was analyzed using a customized 130-kilobase capture panel, with phased variant (PV) enriched regions representing 39% of the panel. ctDNA was detected in 140 patients (99.3%) at baseline. To optimize specificity, only PVs, found in 124 patients (88%), were considered for ctDNA MRD assessment at EOI. Median progression-free survival (PFS) from EOI was not reached (NR) for the 112 patients with undetected ctDNA at EOI vs 17.7 months (95% confidence interval [CI], 1.4 to NR) for patients with positive ctDNA (MRD+) (P = .0038). Similarly, median PFS was NR for the 104 patients with undetected disease on PET at EOI vs 28.3 months (95% CI, 2.9 to NR; P = .0002) for patients with PET positivity. Both tests had a negative predictive value (NPV) of >90% for POD24. The positive predictive value was 58.3% for ctDNA MRD and 45% for PET but increased to 85.7% when both parameters were combined, without alteration of NPV. These data show that the combination of PET response and ctDNA MRD at EOI allows an early prediction of POD24, which may lead to a preemptive treatment decision. This trial was registered at www.clinicaltrials.gov as #NCT01650701.

Follicular helper T-cell lymphoma (TFHL) is the most common non-cutaneous T-cell lymphoma in the Western world and is associated with a poor prognosis. Neoplastic cells rely heavily on the tumor microenvironment, demonstrated by the absence of TFHL-derived cell lines, which hinders therapeutic progress. To overcome this limitation, we developed and characterized patient-derived xenograft TFHL (TFHL-PDXs). Fifteen TFHLs were implanted into immunodeficient mice, generating nine PDXs. The tumor microenvironment was detected in the first passage but progressively disappeared in subsequent passages. TET2 mutations persisted in all cases and TFHL-specific mutations were observed in most. The models were treated with azacitidine and patient sensitivity was fully recapitulated. To elucidate the mechanism of action of azacitidine, we analyzed the differences in DNA methylation and gene expression in six TFHL-PDX models. Global DNA hypomethylation occurred in azacitidine-treated cells in drug-sensitive models but not in the resistant ones. DNA hypomethylation was associated with global upregulation of gene expression, including that of various cancer-related pathways, suggestive of p53-pathway-mediated cytotoxicity. Overall, the PDXs recapitulated TFHL features and exhibited sensitivity to azacitidine. They also made it possible to decipher the mechanism responsible for the effect of azacitidine, revealing the activation of p53-mediated apoptosis associated with DNA hypomethylation.