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.

Circulating Tumor DNA–Based Genotyping and Monitoring for Predicting Disease Relapses of Patients with Peripheral T-Cell Lymphomas

“…In addition to the RHOA mutation, IDH2 mutations were frequent in these nodal lymphomas of TFH origin, which is consistent with a recent study that reported frequent mutations of IDH2 affecting residue R172 in patients with AITL (Fig. 2A) [25]. We also found that TP53 mutations occurred commonly in PTCL-NOS, similar to the results of previous studies reporting the role of genetic alterations including TP53 in these tumors [26].…”

Advances and Personalized Approaches in the Frontline Treatment of T-Cell Lymphomas

“…A phase II study of 40 patients with newly diagnosed PTCL receiving lenalidomide + CHOEP resulted in an ORR of 69% with a CR of 48%; however, AEs (mainly hematological) led to a high discontinuation rate [64]. A similar study combining lenalidomide with CHOP specifically in elderly patients with AITL yielded similar results and did not reach the primary endpoint [65]. In response, induction chemotherapy has been replaced by other novel agents, notably in a recently reported phase II study investigating the combination of induction lenalidomide with romidepsin for elderly patients who are not candidates for intensive chemotherapy.…”

Role of lenalidomide in the treatment of peripheral T-cell non-Hodgkin lymphomas

“…An integrative analysis of this trial has been recently published, lenalidomide was given in association with CHOP every 21 d for eight total cycles[ 65 ]. CHOP was administered on day 1, and lenalidomide was added at a daily dose of 25 mg for 14 d every 21 d. Out of 78 patients included in the efficacy analysis, ORR was 56%, with a CR rate of 41%.…”

“…CHOP was administered on day 1, and lenalidomide was added at a daily dose of 25 mg for 14 d every 21 d. Out of 78 patients included in the efficacy analysis, ORR was 56%, with a CR rate of 41%. The median dose intensity for lenalidomide was 81%, and 55% of total cases completed the study; the most common reasons for early treatment discontinuation were PD and toxicity[ 65 ]. After a median follow-up of 45 mo, 2-year PFS and OS were 42.1% and 59.2%, respectively; the presence of DNMT3A mutation appeared related with shorter PFS.…”

“…After a median follow-up of 45 mo, 2-year PFS and OS were 42.1% and 59.2%, respectively; the presence of DNMT3A mutation appeared related with shorter PFS. Unfortunately, the primary end-point to improve a positron emission tomography-based CR rate from 45% to 60% was not reached, and the authors suggest the lack of benefit from adding lenalidomide to CHOP as AITL first-line therapy[ 65 ]. In 2 refractory AITL cases, lenalidomide was investigated in association with bortezomib and dexamethasone, achieving a CR and a PR with a manageable safety profile[ 66 ].…”