1. Jonathan W. Friedberg M.D., M.M.Sc.
Should DLBCL patients be treated with frontline therapy based on the molecular characteristics of their disease?
YES!
Jonathan W. Friedberg M.D., M.M.Sc.
University of Rochester Medical Center

2. Years from Registration
Progression-Free Survival: S0433
R-CHOP + I-tositumomab for DLBCL
100%
Relapsed/refractory DLBCL remains a problem in the rituximab era
80%
60%
40%
20% 0% 1 2 3 4
Years from Registration
Friedberg et al, B J Heme 2014 in press

3. Years from Registration
Progression-Free Survival: S0433
R-CHOP + I-tositumomab for DLBCL
100%
“Primary refractory”
80%
60%
40%
20% 0% 1 2 3 4
Years from Registration
Friedberg et al, B J Heme 2014 in press

4. Why do patients with DLBCL relapse?
Insights from cell of origin and gene expression studies
GC genes
Macrophages
Angiogenesis
Lenz G, Staudt LM. N Engl J Med 362:1417

5. Why do patients with DLBCL relapse?
Insights from cell of origin and gene expression studies
“Survival predictor score” can be determined based upon gene expression at diagnosis of DLBCL.
Lenz G, Staudt LM. N Engl J Med 362:1417

6. Optimizing salvage therapy for DLBCL based upon cell of origin: CORAL analysis
R-ICE salvage
R-DHAP salvage
GCB
ABC
GCB
ABC
Patients with GCB genotype had superior outcome with R-DHAP chemotherapy compared with R-ICE chemotherapy.
Thieblemont et al JCO 29:4079
Vose JCO 29:4065

7. Differential Efficacy of Bortezomib Plus Chemotherapy Within Molecular Subtypes of DLBCL
Gene expression profiling (GEP)
Immuno-histochemistry (IHC)
Relapsed/Refractory DLBCL (N=49)
CD10
Bcl-6
MUM1
Biopsy
Proceed to Part B if clinically indicated
Part A Bortezomib (N=23)
ABC DLBCL (N=5)
GCB DLBCL (N=10)
ABC DLBCL (N=12)
GCB DLBCL (N=12)
Treat until disease progression or maximum allowable cycles
DLBCL subtype classification
Part B Bortezomib + DA-EPOCH (N=44)
ABC DLBCL (N=12)
GCB DLBCL (N=15)
Treat until disease progression or maximum allowable cycles
Dunleavy et al. Blood. 2009; 113:

8. Differential Efficacy of Bortezomib Plus Chemotherapy Within Molecular Subtypes of DLBCL
Dunleavy et al. Blood. 2009; 113:

9. Randomized evaluation of molecular guided therapy for DLBCL with bortezomib
UK study NHS Foundation Trust
New diagnosed DLBCL:
R-CHOP x 1
Cell of origin determination
Stratification and separate analysis
Randomization
RCHOP x 5 vs. RCHOP + bortezomib x 5

10. Targeting angiogeneis/microenvironment: Lenalidomide single agent trial
DLBCL N=108
ORR DLBCL= 28%
Median response duration 10 months
Key toxicities:
Neutropenia
Thrombocytopenia
DLBCL
Witzig et al Ann Oncol 22:1622, 2011 10 10

11. Hernandez et al, Cancer 117:5058
Differential response to lenalidomide monotherapy: DLBCL
GCB
ABC
CD10
Non GCB
GCB
BCL-6
MUM1
Hernandez et al, Cancer 117:5058

12. Targeting BCR signaling in ABC DLBCL: CR after Ibrutinib therapy (BTK) Response after 8 weeks of therapy
BEFORE RX
Pretreatment
Large liver lesion
Post therapy
PET negative

13. Rapid Normalization of LDH Following Treatment with
Ibrutinib (PCI-32765)
Ibrutinib
started

14. Partial Remission of ABC DLBCL in Patient #3
on Pilot Trial of Ibrutinib (PCI-32765)
Before Rx
On Rx: week 3

15. Moving ibrutinib upfront: R-CHOP + ibrutinib
Part 2 dose expansion at RP2D (approx. 15 pts)
Newly diagnosed treatment naïve DLBCL
Part 1 dose escalation (3+3 pts / dose level)
Ibrutinib 280 mg
+ R-CHOP
Ibrutinib 420 mg
Ibrutinib 560 mg
Younes et al, ASCO 2013

16. Dose-Limiting Toxicity (DLT) and recommended phase 2 dose (RP2D)
In the 280 mg cohort, 2 patients had a DLT:
1 with transient syncope - grade 3
1 with peri-orbital cellulitis - grade 3
In the 560 mg group, 1 patient had a DLT:
1 with gastritis - grade 2
The RP2D was established at 560 mg ibrutinib + RCHOP

17. Conclusions: R-CHOP + ibrutinib
The combination of ibrutinib and R-CHOP has an acceptable safety profile
No new toxicities were noted with the addition of ibrutinib to R-CHOP therapy
In the preliminary efficacy evaluation, the addition of ibrutinib to R-CHOP therapy was associated with an ORR of 100%
A randomized phase III trial is now underway in patients with nonGCB (Hans criteria) DLBCL:
R-CHOP vs. R-CHOP + ibrutinib

18. Why do patients with DLBCL relapse
Why do patients with DLBCL relapse? MYC+ DLBCL: Outcome with conventional therapy
Myc-
non-IG/MYC, n=17 (2.9 y)
Myc+
IG/MYC, n=24 (0.3y)
8-14% of DLBCL are myc+; some without aggressive features.
Outcome of myc+ is extremely poor; high rate of CNS progression.
Savage et al, Blood 114:3533; Barrans et al, JCO 28:3360

19. Defines a group of patients for novel therapeutics
Myc positive status represents poor prognosis group in relapsed DLBCL: CORAL analysis
Defines a group of patients for novel therapeutics
Myc – (N=133)
Myc + (N=28)
Cuccuini et al, ASH 2011, abstract 594

20. “Double hit” lymphoma: Possible therapeutic approaches
Clinical trial preferred
Dose adjusted R-EPOCH
Early consolidation with HDT/ASCT
Dose intensive regimens
These patients should be studied and treated in a unique way, different from “routine” DLBCL.

21. Conclusion: Molecular characteristics of DLBCL should impact treatment choice
Cell of origin signatures indicate DLBCL consists of several diseases, with differential response rates to conventional and novel therapeutic agents.
NCCN and future WHO guidelines recommend molecular evaluation of all patients with DLBCL.
Several ongoing trials are selecting patients based upon molecular signatures.
Double hit DLBCL represents greatest unmet need, and should be treated differently from conventional DLBCL.
Friedberg, Clin Cancer Res 17:6112

22. Thank you!
Questions?