1. ASCO 2019 Updates in Lymphoma and CLL
Marc S. Hoffmann, MD
Division of Hematologic Malignancies and Cellular Therapeutics
University of Kansas Cancer Center

2. Disclosures Speaker for Janssen and Pharmacyclics
Consultant for Celgene

3. CLL Updates

4. MDACC and CLL8: FCR Highly Effective
Philip A. Thompson et al. Blood 2016;127:
Kirsten Fischer et al. Blood 2016;127:
Suggestion that FCR may be curative in IgHV mutated patients
©2016 by American Society of Hematology

5. Woyach JA et al. N Engl J Med 2018;379:2517-2528
PFS – BR vs ibrutinib
Discuss down-regulation of CD20 after ibrutinib exposure
Woyach JA et al. N Engl J Med 2018;379:

6. PFS better regardless of cytogenetics
17p deletion
11q deletion
Neither 17p nor 11q deletion
Discuss that BR in del11 did much better than expected – 51mos vs 41mos
Woyach JA et al. N Engl J Med 2018;379:

7. Subgroup Analysis
Discuss ZAP70 as surrogate for IgHV – concordance with IgHV was ~75% in supplement

8. No Overall Survival Benefit
41% crossover at progression
Leaves open question of optimal frontline therapy with respect to overall survival
Patients in BR arm who progressed could cross over to ibrutinib monotherapy within 1 year of progression

9. ECOG-ACRIN Study Design
Arm A - Ibrutinib + Rituximab:
Ibrutinib 420mg PO daily continuous
Rituximab 50 mg/m² IV day 1, 325 mg/m² day 2 of cycle 2;
Rituximab 500 mg/m² IV day 1 cycles 3-7
Eligibility:
Treatment naïve CLL
Requires therapy by IW CLL 2008 criteria
Age < or = 70
ECOG 0-2
CrCL > 40
No deletion 17p by FISH
Fit for FCR at investigator discretion
N=354
Randomize 2:1
Arm B - FCR:
Fludarabine 25 mg/m² IV days 1-3
Cyclophosphamide 250 mg/m² IV days 1-3
Rituximab 50 mg/m² day 1, 325 mg/m²
day 2 of cycle 1;
then 500 mg/m² day 1 cycles 2-6
N=175
Take time to carefully go through eligibility criteria and 2:1 randomization

10. 6 deaths from CLL in FCR vs 1 death in IR arm from CLL in spite of 2:1 randomization; in effect, there were 12 deaths from CLL in FCR compared to 1 death from IR
HR for PFS = 0.35 (95% CI ; P<.0001)
HR for OS = 0.17 (95% CI ; p=0.0003)
Tait D. Shanafelt et al. Blood 2018;132:LBA-4
©2018 by American Society of Hematology

11. 7 year follow up for ibrutinib monotherapy in CLL
John C. Byrd et al. Blood 2018;132:3133
©2018 by American Society of Hematology

12. Original Article Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions
Kirsten Fischer, M.D., Othman Al-Sawaf, M.D., Jasmin Bahlo, Ph.D., Anna-Maria Fink, M.D., Maneesh Tandon, M.D., Mark Dixon, M.Sc., Sandra Robrecht, Ph.D., Simon Warburton, M.Sc., Kathryn Humphrey, B.Sc., Olga Samoylova, M.D., Anna M. Liberati, M.D., Javier Pinilla-Ibarz, M.D., Ph.D., Stephen Opat, M.D., Liliya Sivcheva, M.D., Katell Le Dû, M.D., Laura M. Fogliatto, M.D., Carsten U. Niemann, M.D., Ph.D., Robert Weinkove, M.D., Sue Robinson, M.D., Thomas J. Kipps, M.D., Ph.D., Sebastian Boettcher, M.D., Eugen Tausch, M.D., Rod Humerickhouse, M.D., Barbara Eichhorst, M.D., Clemens-Martin Wendtner, M.D., Anton W. Langerak, Ph.D., Karl-Anton Kreuzer, M.D., Matthias Ritgen, M.D., Valentin Goede, M.D., Stephan Stilgenbauer, M.D., Mehrdad Mobasher, M.D., M.P.H., and Michael Hallek, M.D.
N Engl J Med
Volume 380(23):
June 6, 2019

13. Baseline Patient Demographic and Disease Characteristics
Patients had to have indication for therapy per iwCLL and either:
CIRS > 6
CrCl < 70
Prognostic Factors:
13.8% of the patients had TP53 deletion, mutation, or both
59.8% had unmutated IGHV
Table 1 Selected Patient Demographic and Disease Characteristics at Baseline (Intention-to-Treat Population).
Fischer K et al. N Engl J Med 2019;380:

14. Progression-Free Survival
Minimal residual disease (MRD) measured by allele-specific oligonucleotide polymerase-chain-reaction (ASO-PCR) to 10-4
On peripheral blood (PB) at 7, 9 and 12 months, then every 3 months long-term
On bone marrow (BM) at 9 months and 3 months after completion of therapy
At 3 months after completion of therapy MRD negativity higher for venetoclax in both
Peripheral blood (75.5% vs. 35.2%, P<0.001)
Bone marrow (56.9% vs. 17.1%, P<0.001
Figure 2 Progression-free Survival and Treatment Response. Shown are the percentages of patients with investigator-assessed progression-free survival (Panel A), independent review committee–assessed progression-free survival (Panel B), and treatment response 3 months after completion of treatment (Panel C). Tick marks indicate censored data.
Fischer K et al. N Engl J Med 2019;380:

15. Grade 3 or 4 Adverse Events (Safety Population).
No high grade tumor lysis syndrome (TLS) observed
Significant TLS seen only during obinutuzumab induction
Table 2 Grade 3 or 4 Adverse Events (Safety Population).
Fischer K et al. N Engl J Med 2019;380:

16. Fatal (Grade 5) Adverse Events (Safety Population).
Table 3 Fatal (Grade 5) Adverse Events (Safety Population).
Fischer K et al. N Engl J Med 2019;380:

17. VG – Conclusions
Front-line fixed duration combination therapy without cytotoxic chemotherapy led to high rates of MRD negative remissions in medically ill patients with CLL
Durability of remissions and response to subsequent therapy remain critical questions
Toxicities and TLS rates were acceptable
Again, we have a registration superiority study against a meaningless comparator arm, and are left without clear direction as to optimal therapy
Cooperative group trials should answer this question
Table 3 Fatal (Grade 5) Adverse Events (Safety Population).

18. EA9161: Study Design Eligibility: Treatment naïve CLL
Requires therapy by iwCLL 2008 criteria
Age
No deletion 17p by FISH
Randomize 1:1
Arm A
Ibrutinib:
Cycles 1-19: 420mg PO daily
Obinutuzumab:
Cycles 1: mg IV d 1, 900mg IV d 2
1000mg d 8 and 15
Cycles 2-6: 1000mg IV d 1
Venetoclax:
Cycle 3: mg uptitration weekly
Cycles 4-14: 400mg PO daily
Arm B
Ibrutinib:
Cycle 1: 420mg PO daily until progression
Obinutuzumab:
Cycles 1: mg IV d 1, 900mg IV d 2
1000mg d 8 and 15
Cycles 2-6: 1000mg IV d 1

19. A041702: Study Design Eligibility: Treatment naïve CLL
Requires therapy by iwCLL 2008 criteria
Age > or = 70
Randomize 1:1
Arm A
Ibrutinib:
Cycles 1-19: 420mg PO daily
Obinutuzumab:
Cycles 1: mg IV d 1, 900mg IV d 2
1000mg d 8 and 15
Cycles 2-6: 1000mg IV d 1
Venetoclax:
Cycle 3: mg uptitration weekly
Cycles 4-14: 400mg PO daily
Arm B
Ibrutinib:
Cycle 1: 420mg PO daily until progression
Obinutuzumab:
Cycles 1: mg IV d 1, 900mg IV d 2
1000mg d 8 and 15
Cycles 2-6: 1000mg IV d 1

20. CLL – Conclusions
Targeted therapy is preferred in frontline therapy for CLL in nearly all risk strata with exception of:
Young, fit patients with IgHV mutated status, no high risk cytogenetic or molecular factors who could tolerate FCR x 6
Ibrutinib monotherapy or combination of venetoclax and obinutuzumab are both highly effective, tolerable regimens in younger and older patients
Detailed discussion regarding risks, benefits and goals of both therapies, accounting for specific patient preferences and co-morbidities, should guide therapy decisions
Approaches have not been compared head-to-head
Both treatments are absolutely remarkable
Rituximab adds no benefit to ibrutinib monotherapy
Please enroll on ECOG and Alliance protocols!

21. NHL and Hodgkin’s Updates

22. >10 large, phase 3 randomized clinical trials have failed to show survival benefit over R-CHOP in spite of promising phase 2 data
One consistent observation has been that the control arm in these studies consistently outperforms historical controls

23. High risk patients with diffuse large B cell lymphoma are not enrolled on clinical trials.
Retrospective analysis of DLBCL or high grade B-cell lymphoma patients (pts) with a pathological diagnosis of (HGBL) at University of Rochester (4/14-6/16) and New York-Presbyterian Hospital/Weill Cornell Medicine (NYP/WCM) (4/14-4/17)
Ten clinical trials were opened during this time. Participants were divided into 3 groups:
those treated in trial,
those not enrolled in trial because of need for urgent treatment,
those not enrolled in trial for any other reason.
Center-stratified Cox proportional hazards model to estimate association of trial enrollment with progression-free survival (PFS; time from start of treatment until progression/death or the last date the pt was known to be progression free) and overall survival (OS)
Alshaibani et al ASCO 2019

24. High risk patients with diffuse large B cell lymphoma are not enrolled on clinical trials.
263 pts were identified and 45 pts (17%) enrolled in a trial.
Reasons for non-enrollment included:
not meeting eligibility criteria (n = 98),
physician choice (n = 50),
pt choice (n = 38).
For 32 pts, reasons were unclear.
Of the 50 pts who were not enrolled because of physician choice, the primary reason for non-enrollment was the need for urgent treatment (n = 46).
Compared with those treated in trial and those not enrolled in trial for any other reason, those not enrolled in trial due to need for urgent treatment had an inferior PFS (HR 2.61, 95% CI 1.23–5.16) and OS (HR 2.27, 95% CI 1.21–4.06). 
52% of patients with DLBCL or HGBL required urgent chemotherapy and failed to enroll on trials.

25. Impact of surveillance imaging on follicular lymphoma patients
1121 FL pts were enrolled in Iowa/Mayo Lymphoma SPORE database (MER) from , of which 117 had relapsed and were eligible.
Median age at diagnosis was 60 years (range 35-83), and 61% were men. Median time to relapse of the 117 pts was 26 months (range 9-125). At a median follow-up from relapse of 69 months (range ), 26 pts died.
Pts completed a median of 3 imaging studies (range 0-15) during post-induction surveillance. 63 relapses (56%) were detected based on CS; 50 (44%) were detected by SI; and 4 were unknown.
No difference in OS from relapse for those with relapse detected via CS vs. SI (HR = 0.98 [0.45,2.12], p = 0.96). 

26. Polatuzumab vedotin: anti-CD79b antibody drug conjugate

27. Polatuzumab vedotin + BR in DLBCL
Regimen just FDA approved for relapsed or refractory DLBCL with 2 or more prior lines of therapy
Based on phase Ib/II study enrolling:
80 patients each with follicular lymphoma or DLBCL ineligible for autologous SCT
Patients randomized 1:1 between: BR
BR + polatuzumab vedotin
Principal toxicities of polatuzumab vedotin include neutropenia, peripheral neuropathy and hepatotoxicity
SAEs higher in pola+BR v BR were febrile neutropenia (FL, DLBCL) and infection (FL).
Grade 5 AE rates were similar between treatment arms: 5% (FL) and 18% (DLBCL).

28. Polatuzumab vedotin – Efficacy
Follicular Lymphoma
DLBCL
Pola+BR (n=39)
BR (n= 41)
Pola+BR (n=40)
BR (n= 40)
CR by PET (%) 69 63 40 15
Median PFS, months (95% CI)
17 (13.4-NR)
17.3 (12.5-NR)
6.7 ( )
2 (
Median OS, months (95% CI) NR
11.8 (9.5-NR)
4.7 ( )
OS significantly improved in Pola+BR arm (p = )

29. Polatuzumab vedotin – Selected ongoing Studies
In DLBCL:
Phase 3 randomized study R-CHOP vs R-CHP + pola
Phase 2 of CHP + anti-CD20/CD3 BiTE + pola
In FL:
Pola + lenalidomide + obinotuzumab

30. Chemotherapy for Waldenstroms (WM)
Retrospective analysis ( ) from Mayo Clinic of 172 pts with active WM treated with:
Bendamustine and Rituximab (BR, n=67)
Dexamethasone, rituximab, cyclophosphamide (DRC, n=75)
Bortezimib, dexamethasone, rituximab (BDR, n=30)
Median follow-up for the entire cohort was 3.7 years

31. Efficacy in WM BR DRC BDR p value (BR vs DRC) (BR vs BDR) (DRC vs BDR)
ORR % 98 85 76
0.01
0.004
0.3
MRR % 96 60 52
<0.0001
0.5
Median EFS (y)
4.5
4.3
1.4
0.04
0.003
0.1
Median TTNT (y) NR
1.8
0.0015
3yr OS % 95 89
0.4
0.7
0.8
ORR: Overall response rate, MRR: Major response rate, EFS: Event (progression, toxicity or death that led to permanent discontinuation of therapy) free survival, TTNT: Time to next therapy, OS: Overall survival, NR: Not reached

32. WM conclusions
If you are giving chemoimmunotherapy, BR is the preferred regimen
There is no quality data comparing BR to ibrutinib

33. ECHELON-1 Longer Term Follow Up
1200+ patients with advanced cHL (Stage III/IV or II (bulky)) randomized to ABVD vs A+AVD
A+AVD was AVD at standard doses with brentuximab vedotin 1.2mg/kg q2wks
Primary endpoint is modified PFS (mPFS) with goal of capturing induction failures:
Clear radiographic progression; or,
Clinical review feeling that “more therapy necessary”
OS was secondary endpoint

34. Forest-Plot Analysis of Modified Progression-free Survival.
On long-term follow up, ongoing benefit in modified PFS is maintained at 3 years
There continues to be no difference in overall survival
Largest benefit on original study was found in men with Stage IV disease and high IPI
Figure 2 Forest-Plot Analysis of Modified Progression-free Survival. This forest plot shows modified progression-free survival according to the independent review committee in key prespecified subgroups. The hazard ratio for treatment with A+AVD versus ABVD and the 95% confidence intervals (CIs) were based on an unstratified Cox proportional-hazards regression model, with treatment as the explanatory variable. The intention-to-treat population included all the patients who underwent randomization. The International Prognostic Score (IPS) ranges from 0 to 7, with higher scores indicating increased risk of treatment failure: low risk, 0 or 1; intermediate risk, 2 or 3; and high risk, 4 to 7. The Ann Arbor staging system ranges from I to IV, with higher stages indicating more widespread disease. B symptoms consist of night sweats, unexplained fever (temperature >38°C), or loss of more than 10% of body weight. Values for the Eastern Cooperative Oncology Group (ECOG) performance status range from 0 to 5, with higher scores indicating greater disability.
Connors JM et al. N Engl J Med 2018;378:

35. Lenalidomide and Rituximab in Relapsed Indolent Lymphoma
R2 is a non-cytotoxic regimen with complementary immune- based cytotoxicity in FL tumor cells1
Phase II/III studies of R2 showed clinically-meaningful activity and a tolerable safety profile in first‑line and R/R iNHL2-5
AUGMENT recently reported median PFS of 39.4 mo for R2 vs mo for R-placebo in R/R iNHL (P < )6
Enhanced NK cell
AUGMENT
Activated T cell
FL cells
Increased tumor apoptosis with complementary mechanisms of R2
1. Chiu et al. Br J Haematol. 2019;185: Leonard et al. J Clin Oncol. 2015;33: Tuscano et al. Br J Haematol. 2014;165: Chong et al. Clin Cancer Res. 2015;21: Morschhauser et al. N Engl J Med. 2018;379: Leonard et al. J Clin Oncol. 2019;37:

36. MAGNIFY: Multicenter, Open-label, Randomized Phase IIIb Study
Lenalidomide 20 mg/d*, d1-21/28 + Rituximab 375 mg/m2 weekly c1 (d1, 8, 15, 22), then d1 every other cycle (c3, 5, 7, 9, 11)
R/R NHL
FL grade 1-3b, tFL, MZL, or MCL
ECOG PS ≤ 2
Stage I-IV disease
≥ 1 Prior therapy
Optional Lenalidomide 10 mg/d, d1-21/28
Arm B Rituximab 375 mg/m2 d1 every other cycle (c13, 15, 17, 19, 21, 23, 25, 27, 29)
Arm A Lenalidomide 10 mg/d, d1-21/28 +
Rituximab 375 mg/m2 d1 every other cycle (c13, 15, 17, 19, 21, 23, 25, 27, 29)
Randomization
CR/CRu, PR, or SD
Stratified by
Histology (FL:MZL:MCL)
Lines of therapy (≤ 2:> 2)
Age (< 65:≥ 65 y)
RANDOMIZE 1:1
R2 Initial Treatment
12 × 28-day cycles
Extended Treatment
18 × 28-day cycles up to PD
Objectives of this analysis for initial treatment in FL/MZL patients
Evaluate the efficacy in the initial R2 treatment period in patients receiving ≥ 1 treatment with baseline and postbaseline assessments
Analyze subgroups: histology, rituximab-refractory, early-relapse, and double-refractory
NCT
*Lenalidomide is given at 10 mg if CrCl is ≥ 30 to < 60 mL/min. †Assessed per CT/MRI and 1999 IWG criteria with modifications to include extranodal disease.

37. MAGNIFY: Baseline Characteristics and Treatment History
Characteristic, n (%)
Total (N = 370)
Age, median (range), y
≥ 65 y
66 (35-91)
208 (56)
Male
199 (54)
ECOG PS at enrollment* 1 2
181 (49)
178 (48)
8 (2)
Positive BM involvement
114 (31)
Ann Arbor disease stage at enrollment†
I/II
III IV
61 (16)
92 (25)
216 (58)
Histology FL
MZL
295 (80)
75 (20)
Rituximab refractory
131 (35)
Early relapse
129 (35)
Double refractory
69 (19)
Characteristic, n (%)
Total (N = 370)
Prior systemic therapies, median (range)*
2 (1-8)
Number of prior therapies 1 2 3
≥ 4
150 (41)
89 (24)
51 (14)
78 (21)
Prior therapies
Rituximab containing
Rituximab + chemotherapy
Rituximab monotherapy
Stem cell transplantation†
352 (95)
260 (70)
161 (44)
28 (8)
Rituximab refractory: Best response of PD or SD to rituximab or rituximab- containing regimen or a response lasting < 6 months after last rituximab dose
Early relapse: Progression or relapse ≤ 2 years or initial diagnosis
Double refractory: Refractory to both rituximab (monotherapy or combination) and an alkylating agent
Data cutoff 10 Aug 2018.
*3 patients had missing ECOG PS. †1 patient had missing Ann Arbor disease stage. ‡Includes chemotherapy, immunotherapy, and radioimmunotherapy; does not include stem cell transplant. §Included 1 allogeneic SCT.

38. MAGNIFY: Grade 3/4 TEAEs* With ≥ 5% Occurrence (n = 359)
Median treatment duration was 9.7 months for all patients in the initial treatment safety population
73 patients (20%) are ongoing treatment
Most common grade 3/4 TEAEs were neutropenia (34%), thrombocytopenia (6%), fatigue (5%), and leukopenia (5%)
Similar rates of grade 3/4 TEAEs were observed in subgroups, although neutropenia rates appeared higher in double refractory patients (54%)
Data cutoff 10 Aug DR, double refractory; ER, early relapse *Assessed per NCI CTCAE v4.03. TEAEs include any AEs occurring on or after first dose date of initial treatment through 28 days after the last dosing date of study treatment.

39. MAGNIFY: PFS By Histology and R-Refractory (Initial Treatment Safety)*
Rituximab-Refractory Status
Non-R-ref
MZL FL
All
All
R-ref
Median PFS in FL/MZL subgroups were similar to the total population, while R-refractory patients had shorter PFS
Median PFS, mo (95% CI)
All patients
36.0 (26.5-NR) FL
30.2 (23.0-NR)
MZL
38.4 ( )
R-refractory
18.1 ( )
Non-R-refractory
NR (36.0-NR)
Data cutoff 10 Aug *If patients were already in maintenance at data cutoff, then response assessments also contributed to PFS.

40. MAGNIFY: PFS in in ER/DR (Initial Treatment Safety)*
Early Relapse Status
Double Refractory Status
Non-DR
Non-ER
All
All ER DR
Median PFS was shorter in ER and DR patients compared to non-ER and non-DR patients
Median PFS, mo (95% CI)
All patients
36.0 (26.5-NR) ER
23.0 (15.9-NR)
Non-ER
39.4 (30.2-NR) DR
15.5 ( )
Non-DR
39.4 (36.0-NR)
Data cutoff 10 Aug *If patients were already in maintenance at data cutoff, then response assessments also contributed to PFS.

41. Conclusions
R2 therapy showed favorable clinical activity in patients with R/R iNHL including by FL or MZL histology, rituximab-refractory, double-refractory, and early-relapse statuses
Currently the median PFS in all patients is 36.0 months
Most common grade 3/4 TEAEs were neutropenia (34%), thrombocytopenia (6%), leukopenia (5%), and fatigue (5%)
MAGNIFY trial is ongoing to compare R2 vs rituximab extended treatment in patients with R/R FL and MZL
150 patients have completed 12 cycles of initial treatment, and 142 have proceeded to extended treatment
R2 should be given with caution with patients who may be eligible for autologous stem cell transplant in the future

42. Revlimid and Rituximab vs R-chemotherapy in Frontline follicular lymphoma
~1100 patients with untreated low grade (1, 2 or 3a) follicular lymphoma randomized to:
Revlimid and rituximab
R-chemotherapy at investigator’s discretion:
72% received R-CHOP, 23% received BR, 5% R-CVP
All patients received rituximab maintenance q8wks for 2 years per PRIMA

43. Progression-free and Overall Survival
Figure 1 Progression-free Survival and Overall Survival in the Intention-to-Treat Population. Panel A shows estimates of progression-free survival as assessed by an independent review committee, and Panel B shows estimates of overall survival.
Morschhauser F et al. N Engl J Med 2018;379:

44. Adverse Events during the Treatment Period in the Safety Population
Recall that 72% of patients had R-CHOP, so this really a comparison between R-CHOP and R2
More rash and diarrhea in Revlimid arm, more febrile neutropenia in chemotherapy arm
Table 3 Adverse Events during the Treatment Period in the Safety Population.
Morschhauser F et al. N Engl J Med 2018;379:

45. Conclusions – RELEVANCE
Regimens have equivalent activity and differing safety profiles
More neutropenia with chemo, more rash with Revlimid
Recall that 72% of patients had R-CHOP, so this really a comparison between R-CHOP and R2
R-CHOP has more neutropenia and febrile neutropenia than BR
BR just shown in long-term follow up to be superior to R-CHOP in frontline FL in long term follow up of STiL and BRIGHT
Given role of stem cell transplant in early relapse poor risk FL, frontline Revlimid may not be optimal