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).

Figure 1.

Disposition of the patients. Eighty-two patients were included. In 14 patients, MYC fluorescence in situ hybridization (FISH) was performed immediately at diagnosis, these patients started with R2CHOP (lenalidomide in combination with rituximab cyclophosphamide, doxorubicin, vincristine, and prednisolone) in cycle 1. In 68 patients, MYC results became available during the first cycle of R-CHOP; these patients were registered after the first cycle of R-CHOP and started with R2CHOP in the second cycle and continued lenalidomide for 14 days after the sixth cycle of R-CHOP. During treatment 13 patients went off protocol (progressive disease [n=7], toxicity [n=2; pulmonary embolism and diarrhea], other reasons [n=3; new diagnosis of colon cancer, patient refusal, and vertebral fracture]). R: rituximab, R2: rituximab + lenalidomide

Figure 2.

Survival analyses. (A) Overall survival (OS; time from registration to death, n=82); (B) disease-free survival (DFS; time from achievement of first complete metabolic response [CMR] on protocol until relapse or death whichever comes first, n=69); (C) event-free survival (EFS; defined as the time from registration to lack of CMR on end of treatment [EOT] positron emission tomography [PET]-computer tomography [CT] scan, relapse or death, n=82) of MYC+ LBCL patients.

Figure 3.

Survival according to end-oftreatment PET-CT scan result. Patients who have achieved complete metabolic response (CMR) at the end of treatment (EOT) positron emission tomography (PET)-computer tomography (CT) scan experienced a reduced risk of death compared to patients who have not yet achieved CMR (Hazard ratio [HR] 0.1, 95% Confidence interval [CI]: 0.03– 0.33, P<0.001). Response was simplified to “CMR” versus “no-CMR”.