Treatment of patients with MYC rearrangement positive large B-cell lymphoma with R-CHOP plus lenalidomide: results of a multicenter HOVON phase II trial

Abstract

Patients with MYC-rearrangement positive large B-cell lymphoma (MYC+ LBCL) have an inferior prognosis following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) as compared to patients without MYC rearrangement. Although intensive chemotherapy regimens yield higher remission rates, toxicity remains a concern. Lenalidomide is an oral immunomodulatory drug which downregulates MYC and its target genes thereby providing support using lenalidomide as additional therapeutic option for MYC+ LBCL. A phase II trial was conducted evaluating the efficacy of lenalidomide (15 mg day 1-14) in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients identified through a nationwide MYC-FISH screening program. The primary endpoint was complete metabolic response (CMR) on centrally reviewed 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computer tomography (CT)-scan at end-of-treatment. Secondary endpoints were overall survival (OS), disease-free survival (DFS) and event-free survival (EFS). Eighty-two patients with stage II-IV MYC+ LBCL were treated with 6 cycles of R2CHOP. At EOT, 67% (confidence interval (CI) 58-75%) of the patients reached CMR. With a median follow-up of 25.4 months, 2-year estimates (95% CI) for OS, DFS, EFS were 73% (62-82%), 75% (63-84%) and 63% (52-73%) respectively. In this prospective trial for newly diagnosed MYC+ LBCL patients, we found that administering R2CHOP was safe, and yields comparable CMR and survival rates as in studies applying more intensive chemotherapy regimens. Hence, these findings offer new prospects for MYC+ LBCL patients and warrant comparison in prospective randomized clinical trials. This trial was registered at www.clinicaltrialsregister.eu (#2014-002654-39).

MYC-Positive Diffuse Large B-Cell Lymphoma in Leukemic Phase at Presentation: A Diagnostic and Therapeutic Challenge

“…They received R-CHOP combined with lenalidomide (15 mg for days 1 - 14) for six cycles, followed by two single doses with rituximab. The 2-year overall survival rate of these patients was 73% [ 11 ]. Our patient received this regimen 4 years ago.…”

Aberrant patterns of PET response during treatment for DLBCL patients with MYC gene rearrangements

“…For this analysis, we included 81 MYC + DLBCL patients from the multicenter phase 2 HOVON-130 trial (Eudra-CT: 2014-002,654-39) [11]. All patients included in this trial had confirmation of MYC rearrangement (8q24) by fluorescent in situ hybridization (FISH).…”

“…For EoT-PET scans, the NPV is very high in non-selected patients [10]. In MYC + DLBCL patients, the diagnostic performance of I-PET with regard to predicting EoT-PET response patients yielded a NPV of 79%, and a PPV of 60% [11].…”

Impact of MYC on Anti-Tumor Immune Responses in Aggressive B Cell Non-Hodgkin Lymphomas: Consequences for Cancer Immunotherapy

“…IRF-4 is downregulated after binding of IMiDs to Cereblon and consequent ubiquination and degradation of its substrate proteins [ 156 , 157 ]. Addition of lenalidomide to standard chemotherapy in patients with MYC overexpressing DLBCL is safe and results in comparable responses to outcomes of intensified chemotherapy regimens [ 158 ]. Similar studies investigating lenalidomide in combination with standard chemotherapy in patients with DLBCL are ongoing (DA-EPOCH; NCT02213913, or R-CHOP; NCT04164368).…”