Obinutuzumab vs rituximab for advanced DLBCL: a PET-guided and randomized phase 3 study by LYSA

Abstract

Rituximab plus polychemotherapy is standard of care in diffuse large B-cell lymphoma (DLBCL). GAINED trial compares obinutuzumab to rituximab. GAINED (NCT01659099) is an open-label, randomized phase 3 trial. Transplant-eligible patients (18-60yrs) with untreated aged-adjusted international prognostic index (aaIPI) ≥1 DLBCL were randomized (1:1) between obinutuzumab or rituximab. Patients were stratified by aaIPI (1; 2-3) and chemotherapy regimen (ACVBP; CHOP). Consolidation treatment was determined according to response assessed by centrally reviewed interim semi-quantitative PET. Responders after cycle 2 and 4 (PET2-/PET4-) received planned immuno-chemotherapy consolidation. Responders only after cycle 4 (PET2+/4-) received high-dose methotrexate plus transplantation. The primary objective was an 8% improvement (HR=0.73; 80% power; alpha risk 2.5%; one-sided) in 2-year event-free survival (EFS) in the obinutuzumab arm. Events included death, progression, PET 2 or 4 positivity, modification of planned treatment. From September 20, 2012, 670 patients were enrolled (obinutuzumab n=336; rituximab n=334). 383 (57.2%) were aaIPI 2-3, 339 (50.6%) received CHOP and 324 (48.4%) received ACVBP. Median follow-up was 38.7 months. The 2-year EFS were similar in obinutuzumab and rituximab groups (59.8% vs 56.6%; p=0.123; HR=0.88). The 2-year PFS in the whole cohort was 83.1% (95%CI 80-85.8). PET2-/4- and PET2+/4- had similar 2-year PFS and OS (89.9% vs 83.9%) and 94.8% vs 92.8%). The 2-year PFS and OS for PET4+ patients were 62% and 83.1%. Grade 3-5 infections were more frequent in the obinutuzumab arm (21% vs 12%). Obinutuzumab is not superior to rituximab in untreated aaIPI≥1 DLBCL transplant-eligible patients.

Nonclassical monocytes are prone to migrate into tumor in diffuse large B-cell lymphoma

“…To validate the prognosis value of ncMO obtained on this training cohort, we analyzed by flow cytometry the proportion of monocyte subsets in an independent cohort of 155 DLBCL samples from the recently published GAINED trial (NCT01659099). 24 With the previously calculated thresholds, high proportion of ncMO and high absolute count of ncMO was associated with a lower overall survival (P = .017 and P = .011, respectively) (Figure 5A and Figure S8B). A univariate analysis on the validation cohort showed that Ann Arbor Stage III-IV, ECOG status >1, elevated LDH, PET4 positivity, and increase in circulating ncMO were associated with lower OS (Table S4).…”

“…22 Prognosis scores were validated in a second cohort of 155 DLBCL patients from the recently published GAINED trial (ClinicalTrials.gov Identifier: NCT01659099). 24 Clinical characteristics of DLBCL patients enrolled in this validation cohort are listed in Table 1. Finally, we reanalyzed CyTOF data (Flow Repository FR-FCM-Z2CA, already published by our group) 23 from myeloid cells from DLBCL tumors (n = 7).…”

CAR T-Cell therapies in lymphoma: current landscape, ongoing investigations, and future directions

“…Large B-cell (R/R) DLBCL Axi-cel (ZUMA-1) [10] Tisa-cel (JULIET) [11] Liso-cel (TRANSCEND) [9] 1st line (high-risk): Axi-cel (ZUMA-12) [37] 2nd line: Axi-cel (ZUMA-7) [35] , Tisa-cel (BELINDA) [36] , Liso-cel (TRANSFORM) CAR T plus (R/R): Axi-cel (ZUMA-6; atezolizumab) [54] , Tisa-cel (PORTIA; pembrolizumab) [55] , Tisa-cel (NCT03876028; ibrutinib), Liso-cel (PLATFORM; durvalumab, CC-122/220) Allogeneic CAR (R/R): ALLO-501A (ALPHA-2), CAR-NK (NCT03056339) [62] HGBCL…”

“…However, there may be a population of patients at high risk of relapse who benefit from even earlier administration of CAR T-cells, although identifying these patients in the upfront setting can be challenging. ZUMA-12 is an ongoing phase 2, multicenter, open-label single arm study of axi-cel in patients with high risk large B-cell lymphoma who have a positive interim PET after 2 cycles of standard frontline chemoimmunotherapy [37] . For the 12 response-evaluable patients in a planned interim analysis, the ORR was 92% with a CR rate of 75%, and 75% of patients had ongoing responses at data cut off.…”

Towards ecosystem integration for a better understanding of aggressiveness of B‐cell lymphomas

“…Therapy efficacy is continuously improving in MCL, through the optimization of chemotherapy-based standards of care 1 or the recent development of chemo-free targeted therapy combinations. 2,3 Nevertheless, MCL is still considered incurable due to iterative relapses. In addition, MCL patients present heterogeneous clinical courses from indolent to very high risk, the early identification of the latest being a central question in the field nowadays.…”