Aggressive Lymphome/Akute lymphatische Leukämie II
V583 Ein autochthones Mausmodell liefert eine Rationale für kombinierte BTK- und BCL2- Inhibition in MYD88-mutiertem Diffus großzelligen B-Zell-Lymphom
Ruth Flümann, Köln, D
Biologically and clinically Diffuse large B cell lymphoma (DLBCL) represents a highly heterogeneous disease. Historically, DLBCL has been subdivided into germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL on the basis of gene expression profiling, which separates DLBCL according to the presumed cell of origin (COO). In addition to this classic transcriptome-based stratifier, two recent comprehensive genomic analyses of human DLBCL samples led to the discovery of partially overlapping genetically-defined DLBCL subsets based on clustering of recurrent genetic alterations. Cluster 5 (C5) in the study by Chapuy et al. as well as Cluster MCD by Schmitz et al. are defined by concurrent MYD88- and CD79B- mutations, as well as mutations driving a plasma cell differentiation block. Recently, we developed a mouse model in which B cell specific expression of Myd88 L252P and overexpression of BCL2 lead to development of ABC-DLBCL- like disease. However, these lymphomas display a plasmablastic phenotype due to cell surface expression of CD138. Here, we generated a series of refined mouse models of ABC-DLBCL, which we engineered to harbor genomic aberrations enriched in cluster 5 DLBCL, including aberrations of Myd88, BCL2, Prdm1 or Spib. These models develop lymphoma which mimics human C5/MCD DLBCL with regard to surface marker expression and transcriptome profile. We could show that combined BTK and BCL2 inhibition displays substantial activity in these models. Moreover, we treated a series of 6 relapsed non-GCB DLBCL patients with a combination of the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax and observed a similar clinical activity of this regimen. Altogether, we provide novel autochthonous mouse models of cluster 5 DLBCL, which we employed to devise and clinically validate combined BTK and BCL2 inhibition in this clinical scenario.
V230 ECHELON-2, (NCT01777152), 5-jahres-ergebnisse einer randomisierten, doppelblinden phase-3-studie von brentuximab-vedotin + CHP an der front gegen CHOP bei patienten mit CD30-positivem peripherem T-zell-lymphom
Lorenz Trümper, Göttingen, D
Introduction: The phase 3 ECHELON-2 (NCT01777152) study, established superiority of frontline brentuximab vedotin + cyclophosphamide, doxorubicin, and prednisone (A+CHP) vs cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for treatment of patients (pts) with systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCLs). We report exploratory 5-year data from ECHELON-2, including progression-free survival (PFS) per investigator (INV) and the following secondary endpoints: overall survival (OS), PFS in sALCL pts, complete remission (CR) rate and objective response rate (ORR) in re-treated pts.
Methods: Adults with untreated CD30-positive PTCL (targeting 70-80% with sALCL) were randomized 1:1 to receive 6-8 cycles of A+CHP or CHOP. Pts were stratified by histological subtype and international prognostic index (IPI) score. Brentuximab vedotin-based subsequent therapies were allowed.
Results: Of 452 pts enrolled, 70% had sALCL and 81% had advanced disease (27% Stage III, 53% Stage IV; 78% IPI ≥2). At data cutoff, median follow-up was 47.6 months for PFS and 66.8 months for OS. A+CHP was favoured over CHOP with a hazard ratio (HR) for PFS per INV of 0.70 (95% confidence interval [CI]: 0.53, 0.91; p=0.0077) and OS HR of 0.72 (95% CI: 0.53, 0.99; p=0.0424). Median PFS was 62.3 months (95% CI: 42.0, unevaluable) for A+CHP, and 23.8 months (95% CI: 13.6, 60.8) for CHOP. Estimated 5-year PFS was 51.4% (95% CI: 42.8, 59.4) and 43.0% (95% CI: 35.8, 50.0) with A+CHP and CHOP, respectively. Neither arm reached median OS. Estimated 5-year OS was 70.1% (95% CI: 63.3, 75.9) for A+CHP vs 61.0% (95% CI: 54.0, 67.3) for CHOP. HR for PFS (0.55 [95% CI: 0.39, 0.79], p=0.0009) also favoured A+CHP over CHOP in pts with sALCL, with an estimated 5-year PFS of 60.6% (95% CI: 49.5, 69.9) vs 48.4% (95% CI: 39.6, 56.7), respectively. Median time to retreatment for pts in the A+CHP arm was 15.0 mos (range, 3-64); 17 pts (ORR: 59%) had CR (n=11) or partial remission (n=6) after retreatment with brentuximab vedotin monotherapy (n=25) or a brentuximab vedotin-containing regimen (n=4). Of the treatment-emergent peripheral neuropathy (PN), 72% in the A+CHP arm and 78% in the CHOP arm had resolved or improved.
Conclusion: After 5 years' follow-up, frontline A+CHP continued to provide clinically meaningful improvements in PFS and OS vs CHOP and a manageable safety profile, including continued resolution or improvement of PN.
V456 Nivolumab in Kombination mit Gemcitabine und Oxaliplatin (GemOx) bei rezidivierten/refraktären T-Zell Lymphomen: vorläufige Ergebnisse des experimentellen Arms der Niveau Studie
Gerhard Held, Kaiserslautern, D
lntroduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of diseases. Blocking the PD1/PDL1 synapse in this lymphoma may Iead to tumor regression or progression.
The NIVEAU trial is an ongoing international, phase 3 study testing Nivolumab (Nivo) in combination with (Rituximab), Gemcitabine, Oxaliplatin (GemOx) for patients with aggressive (B and T-cell) lymphoma in first relapse or progression (NCT03366272). We performed a preliminary analysis of the experimental arm (Nivo-GemOx) of the PTCL cohort to assess safety and efficacy.
Methods: Key eligibility criteria include: first relapse or progression, ineligibility for high dose therapy, only one prior chemotherapy regimen including an anthracycline. Pts receive 8 cycles Nivo (3mg/kg) plus GemOx biweekly followed by additional 18 Nivo biweekly as consolidation or until progression.
Results: The analysis (data cut-off 19-April-2021) included 12 PTCL pts: 4 (33%) PTCL NOS, 3 (25%) AITL, 1 (8%) PTCL TFH-type, 2 (17%) ALCL ALK-, 1 (8%) EATL, and 1 (8%) MEITL. Median age was 69.5 years (range, 53-80), and 5 (42%) were refractory to first line therapy. Treatment was prematurely discontinued in 10 pts (7 during induction and 3 during consolidation), due to progression (n=7), toxicity (n=2) and an intercurrent disease (n=1). Nine (75%) pts achieved an objective response (4 CR and 5 PR). There were 9 progressions. Two pts experienced primary progression. Median PFS2 (time from randomisation to 2nd rel/prog/death) was 6.9 months (95% Cl: 0.3-13.5) vs 7.7 months (95% Cl: 7.2-8.2) for PFS1 (time from diagnosis to 1st rel/prog). PFS2 was superior to PFS1 in 4 out of 11 pts (36%), and not informative in 1 pt who died prematurely due to infection (pt 8) (Figure 1). After a median follow-up of 32.9 months, 7 pts have died (5 from Iymphoma and 2 from infection) and 5 are alive.
Conclusions: Nivo-GemOx induced high response rates in PTCL. Prolonged PFS2 compared to PFS1 is encouraging. The translational research program might identify predictive markers for efficacy of PD-1 blockade in combination with chemotherapy. The trial is actively enrolling and updated results will be presented at the meeting.
Supported by BMS
V24 Polatuzumab Vedotin plus Bendamustin und Rituximab bei rezidiviertem/refraktärem diffus großzelligen B-Zell Lymphom: aktualisierte Ergebnisse einer randomisierten Phase Ib/II Studie sowie vorläufige Ergebnisse einer Single-Arm Extension
Georg Heß, Mainz, D
Introduction: In the randomized (rand) cohort of the GO29365 Ph Ib/II study (NCT02257567; data cut Apr 30, 2018), Pola+BR improved progression-free survival (PFS) and overall survival (OS) vs BR alone in patients (pts) with R/R DLBCL (Sehn et al. 2020). A Ph II extension (Ext) cohort of pts receiving Pola+BR was later included. We report updated data from the rand Ph II arms and Ext cohort.
Methods: Pts with R/R DLBCL were aged ≥18 years and stem cell transplant-ineligible. Pts with Gr >1 peripheral neuropathy [PN] were excluded. Pola+BR efficacy/safety was assessed with a Pola dose of 1.8mg/kg IV, given with 6 cycles of BR. The primary endpoint was complete response (CR) by PET-CT (modified Lugano) at end of treatment (EOT). Secondary endpoints were objective response rate (ORR), best objective response (BOR), duration of response (DOR), PFS, OS, and safety (endpoints assessed by independent review committee; IRC).
Results: Median follow-up on Jan 2, 2020, for Pola+BR pts was 42.9 months (mo; rand N=40), and 9.7 mo (Ext N=106). Baseline characteristics (Table 1) were similar in the study groups. In the rand Pola+BR arm, 6 pts (15%) had a DOR of >24 mo (range, 26.6-38.6). In the rand cohorts (Pola+BR vs BR), median PFS (95% CI) was 9.2 (6.0-13.0) vs 3.7 (2.1-4.5) mo (HR 0.2-0.7); median OS (95% CI) was 12.4 mo (9.0-32.0) vs 4.7 (3.7-8.3) (HR 0.4; 0.2-0.7) (Figure). In the Ext cohort (N=106), PET-CR at EOT was 39.6% (N=42; 30.3-49.6; Table 2), consistent with the rand Pola+BR arm (16/40; 40.0%); BOR rate was 56.6% and best CR was 52.8%. Median (95% CI) PFS and OS were 6.1 mo (5.1-8.0) and 11.0 (8.3-14.2), respectively; however, OS was not mature. There were no new safety signals with Pola+BR. In all pts receiving Pola+BR, 121/151 (80.1%) had Gr 3-4 AEs (mainly cytopenias), 84 (55.6%) had serious AEs and 18 (11.9%) had Gr 5 AEs (mainly infections). 46 (30.5%) pts had PN events of any grade. 4 (2.6%) pts had secondary malignancies.
Conclusions: The improvement in PFS and OS seen with Pola+BR vs BR persisted with additional follow- up. Efficacy was consistent in the Ext cohort and rand Pola+BR arm. These data confirm that Pola+BR is effective for pts with R/R DLBCL.