dlbcl rr

Managing relapsed and refractory DLBCL Andy Davies a.davies@southampton.ac.uk Oxford Lymphoma Course June 2018 DLBCL is a curable disease Overall survival: All randomised 83.0% 82.0% HR=0.907 p=0.549 Real World Data Haematological Malignancies research Network 2017 Events occur early… Overall survival from diagnosis Overall survival from years event free Maurer M J et al JCO 2014;32:1066-1073 Outcomes of R-CHOP population 100% 90% 15-25% refractory 80% 5% PR patients 70% 20-30% relapses 60% 50% 40% 30% 20% 10% 0% Coiffier and Sarkozy et al 2016 50-60% cured How can we identify those patients that may not respond well…? IPI Age greater than 60 years Stage III or IV disease Elevated serum LDH ECOG > More than extranodal site Age adjusted IPI Stage LDH Performance status Ziepert at al J Clin Oncol 28:2373-2380 Primary Refractory Eligible for HDT consolidation Reinduction regimen (I hate ‘salvage’) Followed by HDT+PBSCT Early relapse Late relapse Not eligible for HDT • Age • Co-morbidity • No response to reinduction • No stem cells at harvest Reinduction regimen Primary Refractory Eligible for HDT consolidation Reinduction regimen (I hate ‘salvage’) Followed by HDT+PBSCT Early relapse Late relapse Not eligible for HDT • Age • Co-morbidity • No response to reinduction • No stem cells at harvest Reinduction regimen PARMA Trail (Phillip NEJM 1995) • PARMA study (n=215 aggressive relapsed disease) • 109 demonstrated chemosenstivity after DHAP x2: randomised DHAP x4 more or BEAC + ABMT • OS 53 vs 32% at years (P=0.038) • Time to relapse (< or > 12 months most important prognostic factor, along with second line aaIPI and response to salvage PR vs CR Guglielmi et al, JCO 1998 PARMA TRIAL: ABMT vs DHAP (A) Actuarial PFS curves in responding early relapses (less than 12 months from initial diagnosis) according to treatment arm (ABMT versus DHAP) (B) Actuarial PFS curves in responding late relapses (more than 12 months from initial diagnosis) according to treatment arm (ABMT versus DHAP) JULIET: Response rates Best overall response rate (N=81) Response at months (n=81) Response at months (n=46) ORR (CR + PR) 53* 38 37 CR 40 32 30 PR 14 Response rate, % *P28 days 27% 26 patients (26%) were infused as outpatients 20/26 patients (77%) remained outpatient for ≥3 days after infusion Pts TRANSCEND (Juno/Celgene) Study design • JCAR017 (Liso-cell) CD19 4-1BB • EGFR truncated domain, allow quantification and tracking • CD4 and CD8, expanded separately Allow to deliver in defined dose 1:1 ratio Different cell infusions 5x107; double dose low dose chemo bridging -optional TRANSCEND: Consort diagram PIVOTAL core DLBCL cohort (n=67) Dose find and dose expansion N=91 (Full) TRANSCEND: Patient demographics * * * PIVOTAL core DLBCL cohort (n=67) Dose find and dose expansion N=91 (Full) TRANSCEND: Duration of response TRANSCEND: CRS and neurotoxicity Immune effector cell team • • • • Disease specific team (lymphoma/allograft) Stem cell lab (receiving cells back) Apheresis team/capacity/processing Neurology, infectious diseases, ICU, immunology, radiology • Nursing team • Pharmacy • Case manager from commercial entity Potential long term issues Long term problems • B cell aplasia – IVIG replacement – Infection monitoring – B cell counts • Cytopenias beyond 28 days • Complications of prior therapies Potential • Second malignancies: – Insertional mutagenesis – B cell aplasia: Immune dysregulation COBALT clinical trial design: Evaluation of CAR19 T-cells as an optimal bridge to allogeneic transplantation ENTRY CRITERIA Relapsed or refractory DLBCL/tfFL CD19+ Allogeneic transplant eligible Age 16-65y ALEXANDER: PHASE I/II STUDY OF AUTO3, CAR TCELL TARGETING CD19 AND CD22 FOLLOWED BY CONSOLIDATION WITH ANTI PD1 Ab IN R/R DLBCL • Phase I (Dose Escalation): – Up to dose levels (50 × 106 to 300 × 106) – Maximum 24 patients with DLBCL/transformed FL – Consolidation therapy with pembrolizumab (200 mg i.v D14, 35, 56 post CART • Phase II (Dose Expansion): – 81 patients • PS 0-1 – – – – neutrophil count ≥1.0 × 109/L Absolute lymphocyte count ≥0.5 × 109/L (at enrolment/prior leukapheresis Haemoglobin 80 g/L Platelets 75 ì 109/L ã Exclusion: Prior PD1/PDL-1/prior allo-SCT Prospective randomised Phase 2nd line therapy for R/R DLBCL: KITE/GILEAD ZUMA-7 • 2nd line therapy for R/R DLBCL (