OSCO/OU ASH-SABC Review Lymphoma Update Mohamad Cherry, MD
Outline Diffuse Large B Cell Lymphoma Double Hit Lymphoma Follicular and Indolent B Cell Lymphomas Mantle Cell Lymphoma T Cell Lymphoma Hodgkin s Lymphoma
Outlines Diffuse Large B Cell Lymphoma Double Hit Lymphoma Follicular and Indolent B Cell Lymphomas Mantle Cell Lymphoma T Cell Lymphoma Hodgkin s Lymphoma
Microarray Analysis and Diffuse Large B-Cell Lymphoma Heterogeneity 1.0 All Patients GCB-DLBCL 0.5 GC B like 19 patients, 6 deaths ABC-DLBCL Alizadeh AA, et al. Nature. 2000;403:503-511. Probability 0 Activated B like 21 patients, 16 deaths P =.01 0 2 4 6 8 10 12 OS (Yrs)
Algorithm for Subtype classification of DLBCL GCB GCB + - CD10 - Bcl-6 + MUM1 + Non-GCB - Non-GCB The concordance rate of the Han s Algorithm to gene profiling studies is 80% Hans et al, Blood 2004, 103: 275-282
Lenalidomide vs Investigator Choice in DLBCL IC: Gemcitabine, rituximab, etoposide, or oxaliplatin Len : 25 mg/day, 21 days of 28-day cycle
Chimeric Antigen Receptor (CAR) T cells for treatment of Cancer CD19 CAR Ab to CD 19 Native TCR 1. Construct a chimeric antigen receptor (CAR) CD8 CD3 ζ TAA CAR 3. Transduce and expand patient T cells ex vivo 4. Infuse transduced T cells to eradicate CD 19 + tumor cells 2. Subclone CAR gene into a retroviral vector (SFG) 5 LTR SD ψ SA Ab CD19 scfv V H V L SFG-CAR CD8 ζ chain 3 LTR CD19
CAR T Cell Therapy in R/R DLBCL
Outlines Diffuse Large B Cell Lymphoma Double Hit Lymphoma Follicular and Indolent B Cell Lymphomas Mantle Cell Lymphoma T Cell Lymphoma Hodgkin s Lymphoma
Highly Proliferative Variants of DLBCL Lymphomas with characteristics intermediate between DLBCL and Burkitt s Recurrent breakpoints (translocations) activating multiple oncogenes, one being MYC BCL2+/MYC+ most common BCL6, CCND1 and BCL3 may also occur Campo E, et al. Blood. 2011;117:5019-5032. Jaffe ES, et al. Hematology Am Soc Hematol Educ Program. 2011;2011:506-514.
True Double Hit vs Double Expressors Double Hit: Double translocations in MYC and BCL2 (FISH) Majority (91%) of GCB type 5% of all DLBCL cases Poor OS of just 27% at 5 years Double Expressor: Protein Expression (MYC and BCL2) by IHC 29% of all DLBCL cases Majority (73%) of non-gcb type Poor OS of 27-43% at 5 years Johnson NA et al. J Clin Oncol. 2012 Green TM et al. J Clin Oncol. 2012
Chromosomal breakpoints in DLBCL Study N MYC+ total % MYC+ SH % BCL2/ MYC+ DH % BCL6/ MYC+ DH % BCL2/ BCL6/ MYC+ TH % All DH and TH % Barrans 2010 245 14% 2% 8% 1% 3% 12% Obermann 2009 220 4% 3% 0 0 0 1% Yoon 2008 137 7% 7% 1% 1% 1% 3% Tibiletti 2009 74 16% 4% 7% 7% 1% 12% Copie-Bergman 2009 Van Imhoff 2006 68 3% 3% 0 0 0 0 58 15% 8% 5% 2% 0 7% Savage 2009 135 9% 7% 2% NA NA NA Klapper 2008 117 8% NA NA NA NA NA Aukema et al, Blood 2011 Aukema et al, Blood 2011
Clinical features of Study DH (n) Med age St III/IV % LDH > Nl % BM + % CNS + % > 1 ENS % IPI Hi % Bertrand 2007 Johnson 2009 Kanungo 2006 Le Gouill 2007 Macpherson 1999 10 58 70% NA NA NA NA 56% 54 62 76% 50% 71% NA 35% 70% 14 55 NA 93% 79% 21% 57% NA 16 61 100% 100% 94% 50% 88% 81% 15 65 92% 80% 69% NA 62% 90% Niitsu 2009 19 61 100% 100% 84% 21% 63% 89% Snuderl 2010 20 64 95% 100% 59% 45% 30% 85% Tomita 2009 27 51 96% 93% 65% 9% 65% 87% Aukema et al, Blood 2011
Study Treatment and outcome No. of DH/tot (%) Treatment Regimen Overall RR % Median survival, y Bertrand 2007 10/17 (59%) NA 50% < 1 Johnson 2009 54/54 (100%) R-CHOP; HDC +/- SCT; CHOP; P NA R-CHOP, 1.4; HD, 0.26; CHOP, 0.42 Kanungo 2006 14/14 (100%) Le Gouill 2007 16/16 (100%) Macpherson 1999 CT-NOS; CT and BMT NA < 1 R-CHOP; CHOP; HDC+/- SCT (incl.allo) 75% 0.42 15/39 (38%) CHOP-like; HDC +/- SCT; P NA 0.21 Niitsu 2009 19/19 (100%) Snuderl 2010 20/20 (100%) Tomita 2009 27/27 (100%) CycloBEAP; CHOP + hi dose MTX; CHOP; R-CHOP R-ICE/SCT; CHOP; R-CHOP; CODOX-M/IVAC; EPOCH-R CHOP; CODOX-M/IVAC; HyperCVAD 89% 1.5 50% 0.38 26% 0.5 Aukema et al, Blood 2011
Frontline DA-EPOCH+Rituximab
Outlines Diffuse Large B Cell Lymphoma Double Hit Lymphoma Follicular and Indolent B Cell Lymphomas Mantle Cell Lymphoma T Cell Lymphoma Hodgkin s Lymphoma
Lenalidomide + Rituximab (R 2 ) Len 15 mg daily continuously
Idelalisib
Ibrutinib Monotherapy Relapsed or Refractory FL Study Population: Relapsed/refractory follicular lymphoma Grade 1, 2, 3a Progressed regimen Bartlett, ASH, 2014, Abstract 800 Study Design (N=40) Ibrutinib 560 mg/day aft Endpoints: Primary: ORR Secondary: Safety and tolerability OS Time to response Time to treatment failure Time to subsequent treatment Duration of response PFS Baseline Characteristics Median age, years (range) PD or unacceptable toxicity 64 (46-82) FLIPI 3, 52.5 GELF criteria, % 63 B-symptoms, % 10 Prior regimens, median n (range) Prior treatment, % HSCT R-refractory Refractory to most recent treatment 3 (1-11) 20 45 35
Ibrutinib Monotherapy Relapsed or Refractory FL Median time to response: 2.8 months (range, 1.8-7.4) 1-year PFS 50.1% (95% CI 35.3, 71.1%) Best Clinical Response by CT Patients (N = 40) ORR, % (95% CI) 28 (15-44) CR,* % 5 PR,* % 23 SD, % 55 PD, % 12 Not evaluable, % 5 Response by previous rituximab therapy Rituximab refractory, % (n/n) 6% (1/18) Rituximab sensitive, % (n/n) 42% (8/19) Rituximab naive, % (n/n) 67% (2/3) Bartlett, ASH, 2014, Abstract 800
Phase 1 Trial of Duvelisib Monotherapy in Relapsed/Refractory inhl Continuous administration 28-d Cycles Duvelisib 25 mg BID (N=32) Dose escalation to 75 mg BID MTD Baseline Patient Characteristics Disease subtype 25 mg BID* n=19 FL=14, SLL=4, WM=1 All Doses N=36 FL=24, SLL=5, WM=1, MZ=2, NOS=1 Median age, years (range) 63 (37-76) 64 (37-78) Male, % 14 (74) 21 (58) ECOG Score 0 / 1 / 2 / missing, n 9 / 9 / 0 / 1 14 / 20 / 1 / 1 Prior systemic therapies, median (range) 3 (1 7) 3 (1 8) Receipt of 3 prior systemic therapies, 11 (58) n (%) 22 (61) <6 months from most recent therapy, n (%) 7 (37) 12 (33) 3 FLIPI factors at screening, 6/14 n (43) (%) 10/24 (42) Stage IV, n (%) 7/19 (37) 15/35 (43) * Includes 1 patient dosed at 15 mg BID Flinn, ASH, 2014, Abstract 802
Best Response and Lymph Node Reduction Patients Best Response, n (%) Median time to response, Population n CR PR MR SD PD ORR months (range) 25 mg BID 18 6 (33) 6 (33) 1 (6) 4 (22) 1 (6) 13 (72) 1.8 (1.7 5.5) All Doses 34 7 (21) 13 (38) 1 (3) 11 (32) 2 (6) 21 (62) 1.8 (1.5 5.5) Includes efficacy evaluable patient = at least 1 on-study response assessment or PD without a response assessment ORR = CR + PR + MR 76% (13/17) of patients at 25 mg BID had 5 reduction in adenopathy Flinn, ASH, 2014, Abstract 802
Outlines Diffuse Large B Cell Lymphoma Double Hit Lymphoma Follicular and Indolent B Cell Lymphomas Mantle Cell Lymphoma T Cell Lymphoma Hodgkin s Lymphoma
R 2 In The Front line Setting Len 20 mg daily on days 1-21 of a 28-day; Rituximab weeklyx4 then Q2 cycles. Response irrespective to MIPI score or Ki 67%.
Lenalidomide vs Investigat Choice Phase 2 Sprint Study N = 254 patients 25 mg/day on days 1-21 of each 28-day IC: cytarabine, rituximab, gemcitabine, fludarabine, or chlorambucil.
Outlines Diffuse Large B Cell Lymphoma Double Hit Lymphoma Follicular and Indolent B Cell Lymphomas Mantle Cell Lymphoma T Cell Lymphoma Hodgkin s Lymphoma
Frontline Romidepsin + CHOP in PTCL A total of 18 patients were included in the phase 1b trial, with 19 in phase 2. ORR of 68% (24/35 evaluable patients), including a 51% CR rate. 12-month PFS was about 57%, and the estimated 12-month OS rate was 82%. Dupuis J, et al. ASH 2014. Abstract 504.
Outlines Diffuse Large B Cell Lymphoma Double Hit Lymphoma Follicular and Indolent B Cell Lymphomas Mantle Cell Lymphoma T Cell Lymphoma Hodgkin s Lymphoma
BV Maintenance after Autologous SCT Phase 3 RC study. N= 327 patients. BV 1.8 mg/kg Q 3 W for up to 16 cycles (~1y). Moskowitz CH et al. ASH 2014. Abstract 673.
Potential Effects of Anti-PD-1 Antibody in Therapy of Cancer McDermott and Atkins. Cancer Medicine 2: 662-673, 2013.
Nivolumab in R/R Lyphoma Hodgk Nivolumab 3 mg/kg every 2 weeks until confirmed tumor progression or excessive toxicity
Response Duration
Pembrolizumab i Lymphoma Pembrolizumab 10 mg/kg IV every 2 weeks until tumor progression, excessive toxicity.
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