Integrative analysis of a phase 2 trial combining lenalidomide with CHOP in angioimmunoblastic T-cell lymphoma

Abstract

Angioimmunoblastic T-cell lymphoma (AITL) is a frequent T-cell lymphoma in the elderly population that has a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Lenalidomide, which has been safely combined with CHOP to treat B-cell lymphoma, has shown efficacy as a single agent in AITL treatment. We performed a multicentric phase 2 trial combining 25 mg lenalidomide daily for 14 days per cycle with 8 cycles of CHOP21 in previously untreated AITL patients aged 60 to 80 years. The primary objective was the complete metabolic response (CMR) rate at the end of treatment. Seventy-eight of the 80 patients enrolled were included in the efficacy and safety analysis. CMR was achieved in 32 (41%; 95% confidence interval [CI], 30%-52.7%) patients, which was below the prespecified CMR rate of 55% defined as success in the study. The 2-year progression-free survival (PFS) was 42.1% (95% CI, 30.9%-52.8%), and the 2-year overall survival was 59.2% (95% CI, 47.3%-69.3%). The most common toxicities were hematologic and led to treatment discontinuation in 15% of patients. This large prospective and uniform series of AITL treatment data was used to perform an integrative analysis of clinical, pathologic, biologic, and molecular data. TET2, RHOA, DNMT3A, and IDH2 mutations were present in 78%, 54%, 32%, and 22% of patients, respectively. IDH2 mutations were associated with distinct pathologic and clinical features and DNMT3A was associated with shorter PFS. In conclusion, the combination of lenalidomide and CHOP did not improve the CMR in AITL patients. This trial clarified the clinical impact of recurrent mutations in AITL. This trial was registered at www.clincialtrials.gov as #NCT01553786.

Graphical abstract

Figure 1.

Flowchart of the study.

Figure 2.

Kaplan-Meier curves for PFS and OS. (A) PFS. (B) OS.

Figure 3.

Description of molecular, pathologic, biologic, and imaging features of 71 AITL/TFH patients in the REVAIL trial. The section “mutations in tumor” describes distribution of mutations in TET2, RHOA, DNMT3A IDH2, CD28, PLCG1, STAT3, and STAT5B. Patients represented in dark blue bore at least 2 TET2 mutations, whereas only 1 TET2 mutation was detected in light blue samples. DNMT3A^R882X variants are represented in dark green, whereas samples in light green harbored DNMT3A mutations altering another residue than R882. Sequencing failure, in gray, was because of the absence of enough material for DNA extraction or the presence of degraded DNA. In the section “BM/Blood,” BMI represents the presence of bone marrow involvement, as determined locally by the examination of BM trephine. Flow cytometry positivity means that cells with an aberrant phenotype were detected in blood by flow cytometry before treatment. PCR positive means that a significant (ie, representing at least 10% of the T-cell population) TCR clonal population was detected by denaturing gradient-gel electrophoresis PCR. EBV blood shows patients with a high level of EBV > 3 log, a low level of EBV (<3 log), or the absence of detectable EBV replication in blood. “pathological features and IHC” section describes the pathologic features of AITL biopsy. Blue is used to describe neoplastic cells, whereas the tumor microenvironment is scored in yellow. The percentage of neoplastic T cells was estimated by pathologists after IHC interpretation: >50% in darker blue cases, 30% to 50% in blue cases, and <30% in lighter blue cases. Clear cells with a large cytoplasm were detected in cases in dark blue, absent in cases in white, or unknown in gray. Immunohistochemistry assays for TFH markers (CD10, PD1, CXCL13, BCL6, ICOS) are described in the legend, with score 3 indicating >50% positive tumor cells, score 2 indicating 30% to 50% positive tumor cells, score 1 indicating <30% positive cells, and score 0 indicating no staining on tumor cells. FDC distribution was evaluated by CD21 and/or CD23 immunostaining and was assigned a score of 0 when the signal was restricted to germinal centers; 1 in case of perifollicular expansion; 2 in case of perifollicular and perivascular expansion; or 3 for diffuse expansion. The EBV status in large lymphoid cells was based on counting EBER-positive large cells and scored as follows: negative, absence of large EBV-positive cells; positive, up to 5 large EBV-positive cells per high power field (hpf); strongly positive, more than 5 per hpf or sheets or aggregates of large EBV-positive cells. As indicated in the legend, the sections “others” represent IPI at diagnosis (IPI 4-5 vs 1-3), CMR (CMR vs other response or nonevaluable), and SUVmax and TMTV, both being dichotomized at the median of the cohort.

Figure 4.

Forest plot representing the impact of clinical, biologic, and molecular features on CMR, PFS, and OS. BMI, bone marrow involvement; TMTV, total metabolic tumor volume; FCM, flow cytometry; PB EBV, EBV viral load measured in peripheral blood > median.