Management of high-risk diffuse large B cell lymphoma: case presentation

Transcription

1 Management of high-risk diffuse large B cell lymphoma: case presentation Daniel J. Landsburg, MD Assistant Professor of Clinical Medicine Perelman School of Medicine University of Pennsylvania January 26, 2018

2 Disclosure information I have the following financial relationships to disclose: Consultant for: Curis, Inc Research funding: Curis, Inc; Takeda I will discuss the following off label use and/or investigational use in my presentation: TAK659, ibrutinib, venetoclax, lenalidomide

3 Objectives To understand the first-line treatment options for diffuse large B cell lymphoma (DLBCL) To understand the management of relapsed/refractory DLBCL To understand the role of novel therapeutics in the management of DLBCL

4 Case: R.S. 57 y/o male without significant past medical history Noted weight gain/abdominal bloating/fatigue in April 2017 Evaluated in local ED with progressive symptoms

5 Case: R.S. May 2017 CT abdomen/pelvis:

6 Case: R.S. Core needle biopsy of omental tissue: Diffuse large B cell lymphoma Immunostains show that the infiltrating cells are positive for CD20, CD10, BCL2, BCL6, while negative for CD3, CD5, CyclinD1, CD30, c-myc, and EBER (ISH). CD21 is positive on subset of neoplastic cells. CD23 shows no follicular dendritic cell meshworks. Ki-67 shows a proliferation index of 50-60%. FISH studies are positive for BCL2-IGH [translocation t(14;18)] gene rearrangement (40%), and negative for MYC rearrangement and BCL2(3q27) break point translocation.

7 Case: R.S. Receives R-CHOP x1 (urgently) in mid-may 2017 PET-CT performed the next day:

8 Case: R.S. Seen in consultation at Penn Therapy changed to dose-adjusted EPOCH- R for cycle #2 PET-CT after 3 total cycles (July 2017): Complete metabolic response

9 Case: R.S. Receives 3 additional cycles of doseadjusted EPOCH-R (6 total) Post-chemotherapy PET-CT (October 2017): Progressive disease

10 Case: R.S. Core needle biopsy of omental nodule: Diffuse large B cell lymphoma IHC: C-MYC is positive on approximately 30-40% of cells in the intact areas of the infiltrate. Next generation sequencing: DNA Quality not sufficient

11 Case: R.S. Receives 2 cycles of R-DHAP Subsequent PET-CT (November 2017): Progressive disease

12 Case: R.S. Discussion of treatment options: saf Salvage Ibrutinib Venetoclax TAK659 (SYK inhibitor) Bendamustine Consolidation Axicabtagene Ciloleucel (Yescarta) Allogeneic stem cell transplantation

13 Case: R.S. Enrolled onto: Phase 2 Study of TAK-659 in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma After at Least 2 Prior Lines of Chemotherapy C1D1 mid-december 2017 Removed from study after 2 weeks for disease progression

14 Case: R.S. Subsequent course High-dose dexamethasone x 4 days Admission for intractable pain Bendamustine 90 mg/m2 IV x 1 day PCA/IV narcoitcs oral regimen POD at last office visit Awaiting insurer decision on appeal for ibrutinib Undergoing insurance authorization and evaluation for Axicabtagene Ciloleucel (Yescarta)

15 Management of DLBCL in 2018

16 DLBCL first line therapy R-CHOP 2006: R-CHOP > CHOP, age : CHOP ~intensive regimens N Engl J Med Apr 8;328(14): Lancet Oncol May;7(5): J Clin Oncol Jul 1;24(19): : R-CHOP > CHOP, age 60

17 DLBCL high risk for R-CHOP failure CD5 MYC/BCL2 IHC MYC-R (including DHL) PD-L1 Blood Nov 5;126(19): Oncotarget Mar 20;6(8): J Clin Oncol Jul 10;28(20): J Clin Oncol Oct 1;30(28): Blood May 18;129(20): BCL2 TL

18 MYC IHC+ (30%) DEL (25%) DLBCL and MYC MYC FISH+ (12%) DHL/THL (8%) Newly-diagnosed DLBCL (MYC FISH % of HGBL) ~35% of newly- diagnosed DLBCL with MYC alteration Curr Hematol Malig Rep Jun;11(3):

19 DLBCL intensive therapy R-hyperCVAD DA-EPOCH-R Excellent PFS for DLBCL treated with intensive front-line therapies Leuk Lymphoma Dec;54(12): Haematologica May;97(5):

20 DLBCL benefit to intensive therapy? CALGB DHL SHL No survival benefit to DA-EPOCH-R for DLBCL Blood :469 Blood Oct 9;124(15): Br J Haematol Nov;175(4): PFS benefit for DA-EPOCH-R in DHL and SHL

21 DLBCL front-line therapy in practice R-CHOP remains standard-of-care Excuse to give DA-EPOCH-R: Double hit (MYC and BCL2 and/or BCL6 rearrangement by FISH) Single hit (MYC rearrangement only by FISH) Sometimes others: Double expressor (MYC/BCL2 overexpressed by IHC) High grade B cell lymphoma (HGBL) histology Hospitalization required at diagnosis Unfavorable clinicopathologic picture

22 DLBCL standard therapy relapse autologous stem cell transplantation Pre-rituximab era (PARMA) Rituximab era (CORAL) Relapse > 12 mo Relapse <12 mo Survival benefit for ASCT compared to salvage chemo without ASCT N Engl J Med Dec 7;333(23): J Clin Oncol Sep 20;28(27): Low probability of survival if early relapse in rituximab era

23 DLBCL subsequent treatment Small molecule inhibitors Commercial: Ibrutinib Venetoclax (Lenalidomide) Experimental: PI3K inhibitors SYK inhibitors BET inhibitors EZH2 inhibitors Many others J Clin Oncol Mar 20;35(9):

24 DLBCL subsequent treatment TAK-659 (SYK/FLT-3) inhibitor Phase I dose-escalation/expansion for R/R NHL and CLL DLBCL (n=79) Median age (years): 65 Stage III-IV (%): 61 Median lines of prior therapy: 3 Transformed IL: 35% Double/triple hit: 13% Median time to response: 55 days* Blood :1554

25 DLBCL subsequent treatment Axicaptagene ciloleucel (Yescarta) R/R DLBCL (incl PMBL/tFL), n=101 69% 3 lines of prior therapy 26% primary refractory 21% relapsed after ASCT Conditioning: Flu 30mg/m2 days -5 to -3 Cy 500 mg/m2 days -5 to -3 Response (minimum of 6 mo f/u): ORR 83% CR 55% SD 9% PD 4% Toxicity: Grade 3 CRS: 13% Grade 3 neurotoxicity: 28% N Engl J Med Dec 28;377(26):

26 DLBCL in 2018 unresolved issues Front-line: Subgroups who benefit from intensive therapy Benefit of addition of targeted therapies Best immunochemotherapy backbone Relapsed/refractory: Second-line fit for ASCT: Preferred salvage for those failing intensive front-line therapy Consolidation with ASCT vs CAR T therapy Subsequent/unfit for ASCT: Targeted therapies palliative or bridge to CAR T therapy/allogeneic stem cell transplantation

27 Discussion/Questions