ASH update Lymphoma #2

Anca Prica MD, MSc, FRCPCAssistant professor

University of TorontoPrincess Margaret Cancer Centre

Disclosures

• Honoraria from Amgen and Astra-Zeneca

Objectives

• First-line treatment of limited stage Diffuse Large B-cell Lymphoma updates

• Indolent lymphomas updates – Follicular lymphoma, Waldenstrom’s Macroglobulinemia and Mantle Cell lymphoma

FIRST-LINE LIMITED STAGE DLBCL

Clinical Trials in Limited Stage DLBCL in the Rituximab Era

Trial Design Patients PFS OSSWOG S0014Persky, JCO 2008

Ph II: R-CHOPx3 + IFRTStage-modified IPI≥1

(n=60)4-y: 88% 4-y: 92%

SWOG S0313Persky, Blood 2015

Ph II: CHOPx3 + IFRT + RITStage-modified IPI≥1

(n=46)5-y: 82% 5-y: 87%

MINT Trial,Pfreundschuh, Lancet 2011

Ph III: CHOPx6 v R-CHOPx6 (+IFRT for stage I bulky)

≤60y; aaIPI=0, <7.5cm (n=101) 6-y: 90% 6-y: 95%

FLYER TrialPoeschel, ASH 2018

Ph III: R-CHOPx6 v R-CHOPx4+2R ≤60y; aaIPI=0, <7.5cm (N=588)

3-y: 94 v 96%

3-y: 98 v 99%

LYSA/GOELMSLamy, Blood 2018

Ph III: PET-guided (PET-pos if >mediast)R-CHOPx4-6 v R-CHOPx4-6 + RT

Stage I/II, <7cm (n=319)

5-y EFS: 89 v 92%

5-y: 92 v 96%

NCTN S1001Persky, ASH 2019 #349

PH II: PET-guided (PET-pos D4,5)R-CHOPx4 v R-CHOPx3+IFRT+RIT

Stage I/II, <10cm(n=132)

5-y: 87% 5-y: 90%

PET-Directed Therapy for Patients with Limited-Stage Diffuse Large B-Cell Lymphoma

- Results of Intergroup NCTN Study S1001

Daniel O. Persky, MDUniversity of Arizona Cancer Center

Daniel O. Persky, MD, Hongli Li, MS, Deborah M. Stephens, DO, Steven I Park, MD, Nancy L. Bartlett, MD, Lode J. Swinnen, MBChB, Paul M. Barr, MD, Jerome D. Winegarden III, MD, Louis S. Constine, MD, Thomas J. Fitzgerald, MD, John P.

Leonard, MD, Brad S. Kahl, MD, Michael L. Leblanc, PhD, Joo Y. Song, MD, Richard I. Fisher, MD, Lisa M. Rimsza, MD, Sonali M. Smith, MD and Jonathan W. Friedberg,

MD

Schema:

R-CHOP x 3

iPET+

iPET-

Ibritumomabtiuxetan36-45 Gy IFRT

R-CHOP x 1

Stage I/II DLBCL by CT and PET

R-CHOP x 6Stage I/II DLBCL by CT but III/IV

by PET

Day 21-42 after IFRTCycle 3

Day 21-35

Eligibility criteria • Newly diagnosed DLBCL• Non-bulky (< 10 cm) stage I/II• Measurable or evaluable

disease• Excluded – CNS, testicular,

primary mediastinal, and concurrent/preceding indolent lymphoma

Deauville 4-5

Deauville 1-3

Cycle 3Day 15-18

CONSORT DiagramInitial Registration (n=159)

R-CHOP x 3 (n=132)

Not eligible (26):• Incorrect histology (21)• No specimen submitted (3)• Bulky bone disease (2)

Off treatment prior to iPET (4):• Removed after 1 cycle (2)• Died of sepsis (1)• Moved (1)

iPET-negative (n=110) iPET-positive (n=18)

Continued R-CHOP (n=113)• 2 did not receive tx

IFRT + Ibritumomab tiuxetan (n=12)

Deauville X (n=4)Patient death (1) Patient refusal (2)

iPET (Central Review)

Upstaged by PET (1)

N = 128

Patient Characteristic S1001 (n=132)

Median Age (years, range) 62 (18-86)

Age > 60 years 71 (54%)

Male 70 (53%)

Performance status: 012

89 (67%)39 (30%)

4 (3%)

Stage I (rest stage II) 82 (62%)

Median largest diameter (cm, range) 3.5 (1.0 - 9.7 cm)

Extranodal involvement 57 (43%)

Head and Neck-only involvement 87 (66%)

Stage modified (Miller) IPI (smIPI)0123

35 (27%)55 (42%)37 (28%)

5 (4%)

1. Persky et al, ASH 2017, a1553

Disease Characteristic Number Percent

Histologic subtype:DLBCL, NOSHGBL “double hit” HGBL, NOST-cell/histiocyte rich LBCLCentral pathology review not performed

98/1324/132

19/1322/1329/132

74%3%

14%2%7%

Cell of Origin by Lymph2Cx:Germinal CenterActivated B-cellUnclassifiable

59/8720/87

8/87

68%23%

9%

Double Protein Expressors1 (DPE):DPENon-DPEIndeterminant

21/12397/123

5/123

17%79%

4%

FISHBCL2 posBCL6 posMYC posMYC/BCL2 double hitMYC/BCL6 double hit

4/438/387/772/422/38

9%21%

9%5%5%

1. Stephens et al, ASH 2017, a4122

Progression-free Survival Overall Survival

5-year estimate 87% 5-year estimate 90%

Competing risks:5-yr 10.8%

5-yr 4.3%

Cum

ulat

ive

Inci

denc

e

0 %

4 6Years after Registration

5 %

10%

15 %Progression or death due to lymphomaDeath due to other causes

2

Outcomes by subgroups • iPET-pos and iPET-neg pts had similar outcomes – PFS 86% vs. 88%, OS

93% vs. 91%

• All 4 DHL pts maintain remission

• Stage-modified IPI is important:• PFS 97% for smIPI of 0, 86% for 1-2, and 30% for 3

• DPE (MYC/BCL2) pts had 5-yr PFS of 70, vs. 89% for non-DPE pts

1. Mareschal et al, Haematologica 2011. 2. Johnson et al, JCO 2012.

Long-term Follow-up of a PET-Guided Approach to Treatment of Limited Stage DLBCL in BC

LH Sehn, DW Scott, D Villa, AS Gerrie, CL Freeman, C Parsons, T Pickles, A Lo, P Farinha, GW Slack, D Wilson, RP Tonseth, JM Connors, KJ Savage

BC Cancer Centre for Lymphoid Cancer The University of British Columbia

Vancouver, Canada

PET-Guided Treatment Algorithm for Limited Stage DLBCL in BC

R-CHOP x 3R-CHOP x 1

XRTPET Pos

PET Neg

Study Designl Retrospective analysis of all patients identified in the BC Cancer

Lymphoid Cancer Database and the Department of Functional Imaging Database treated with curative intent according to PET-based algorithm:

– Age ≥ 16 years– Newly diagnosed confirmed DLBCL – Between Mar 2005 and Feb 2019– Limited stage (Stage I/II, non-bulky <10cm, no B-symptoms,

radiation encompassable) – PET after 3 cycles R-CHOP

FDG-PET/CT Scans

l FDG-PET/CT scans performed between days 14-21 after cycle 3 of 3-weekly R-CHOP

l All scans performed at a single centre

l PET-positive if uptake >mediastinum– 2005-2013: IHP guidelines– 2014-2019: Deauville criteria (D3-5 positive)

l Staging PET scans recommended since 2011

Involved-Site Radiation Therapy

l Administered approximately 4-6 weeks after cycle 3

l Area: original disease with a narrow margin (1-4 cm)

l 3500 cGy in 20 fractions (most common)

Patient Characteristics (n=319)Characteristic n %*

Median Age, yrs (range) 68 (19-92) -Male Gender 152 48Ann Arbor Stage

III

189130

5941

PS >1 25 8

Elevated LDH 38 13

Extranodal involvement 166 52Median mass size (range) 4 (1-9) -Stage-modified IPI

0123-4

55 13182 27

1945279

Missing values: PS, n=1; LDH, n=23; mass size, n=8; stage-modified IPI, n=24*Percentages calculated for patients with available data

PET Status Post 3 cycles R-CHOP

l 254 patients (80%) were PET-negative

l 59 patients (18%) were PET-positive

l 6 patients (2%) had an indeterminate PET

Management According to PET Status

l 254 PET-negative patientsØ 234 (92%) received 1 additional cycle R-CHOPØ 13 received XRTØ 7 received no further treatment

l 59 PET-positive patientsØ 55 (93%) received XRTØ 2 received 1 additional cycle R-CHOPØ 2 received no further therapy

Follow-up time: 6.25 y (range 0.42-14.25y)

0.00

0.25

0.50

0.75

1.00

Ove

rall

surv

ival

(%)

319 261 203 157 109 62 28 Number at risk

0 2 4 6 8 10 12

Time (years)

Ka pla n- M eie r su rv iva l e st im at e

Time-to-progression and Overall Survival of Entire Cohort (n=319)

5-y OS: 86% (95% CI 82-90%)

5-y TTP: 89% (95% CI 85-93%)

Tim

e-to

-pro

gres

sion

(%)

0.00

0.25

0.50

0.75

1.00

Prog

ress

ion-

free-

surv

ival (

%)

59 43 29 25 21 11 6PET-POS254 207 165 124 82 46 21PET-NEG

Number at risk

0 2 4 6 8 10 12

Time (years)

Ka pla n- M eie r su rv iva l e st im at es

p=0.04

PET-NEG5-y PFS: 87% (95% CI 83-92%)

PET-POS 5-y PFS: 74% (95% CI 63-87%)

Progression-Free Survival According to PET Status (n=313)

0.00

0.25

0.50

0.75

1.00

Over

all su

rviva

l (%

)

59 45 31 27 24 13 7PET-POS254 211 168 127 83 48 21PET-NEG

Number at risk

0 2 4 6 8 10 12

Time (years)

Ka pla n- M eie r su rv iva l e st im at es

p=0.11

PET-NEG5-y OS: 89% (95% CI 84-93%)

PET-POS5-y OS: 77% (95% CI 66-89%)

Overall Survival According to PET Status (n=313)

0.00

0.25

0.50

0.75

1.00

Tim

e-to

-pro

gres

sion

(%)

80 62 44 31 19 11 8Bulky disease>5cm166 142 120 93 63 35 13Non-Bulky

Number at risk

0 2 4 6 8 10 12

Time (years)

Ka pla n- M eie r su rv iva l e st im at es

0.00

0.25

0.50

0.75

1.00

Tim

e-to

-pro

gres

sion

(%)

14 11 9 6 4 3 3Bulky disease>7.5cm232 193 155 118 78 43 18Non-Bulky

Number at risk

0 2 4 6 8 10 12

Time (years)

Ka pla n- M eie r su rv iva l e st im at es

PET-POS 5-y TTP: 90%

p=0.6

PET-NEG 5-y TTP: 92%

PET-POS 5-yTTP:92%

Time-to-Progression in PET-Negative Patients According to Bulk of Disease

Bulk defined as ≥5cm Bulk defined as ≥7.5 cm

p=0.7

PET-NEG 5-y TTP: 93%

Limited stage DLBCL conclusions• Together with FLYER trial data, these studies confirm that 4 cycles of

RCHOP chemotherapy are sufficient for majority of low IPI, limited stage non-bulky DLBCL pts

• Majority of patients will be PET neg after 3 cycles of RCHOP chemotherapy, but delayed relapses do occur even in these pts

• For SmIPI 0 pts, outcomes excellent, thus reasonable to just plan for 4 cycles of RCHOP, complementing the Lamy and Flyer trials

• For SmIPI 1-2, a PET scan post-3 cycles of RCHOP can direct therapy, if negative, can complete 4 cycles of RCHOP, if positive, the clinician can decide to proceed to 6 cycles of chemotherapy and/or consolidate with radiation

INDOLENT LYMPHOMAS

Two years Rituximab maintenance versus observation after first line treatment with Bendamustine plus Rituximab inpatients with Waldenströms Macroglobulinemia (WM):

results from the StiL NHL7-2008 MAINTAIN trial

Results of a prospective, randomized, multicentre phase 3 study (Study of the StiL NHL7-2008 MAINTAIN trial)

Mathias Rummel, Christian Lerchenmueller, Manfred Hensel, Martin Goerner, Christian Buske, Holger Schulz, Burkhard Schmidt, Georgi Kojuharoff, Elisabeth Lange, Wolfgang Willenbacher, Jan Dürig, Erik Engel, Frank Kauff, Juergen Barth, Alexander Burchardt, Axel Hinke, Jasmin Müller and Richard Greil on behalf of the StiL Study group indolent Lymphomas

ASH 2019, Rummel et al.. oral presentation

0

0.25

0.5

0.75

1

0 12 24 36 48 60 72 84 96

Follicular Lymphoma: B-R + 2 yrs R vs. B-R + 4 yrs R Follicular Lymphoma: B-R (NHL1) vs B-R + R (NHL7)

Mantle Cell Lymyphoma: B-R vs. B-R + 2 years R Marginal Zone Lymyphoma: B-R vs. B-R + 2 years R

0

0.25

0.5

0.75

1

0 12 24 36 48 60 72 84

months(median)

PFSevents Hazard ratio p value

2 years R n. y. r. 33 0.73 (CI 0.44 – 1.21) 0.11254 years R n. y. r. 26

0

0.25

0.5

0.75

1

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

months(median)

PFSevents Hazard ratio p value

NHL7, 4yR n. y. r. 173 0.68 (CI 0.47 – 0.87) 0.0074NHL1, B-R 77.8 66

months(median)

PFSevents Hazard ratio p value

Obs. 54.7 29 0.71 (CI 0.41 – 1.23) 0.2267R maint. 72.3 21

0

0.25

0.5

0.75

1

0 12 24 36 48 60 72 84 96 108

months(median)

PFSevents Hazard ratio p value

Obs. 91.6 20 0.33 (CI 0.16 – 0.71) 0.0047R maint. n.y.r. 8

StiL NHL 7-2008 MAINTAIN trial: previous PFS results

StiL NHL 7-2008 in WM: Objective and endpoints

Ø Objective:

¥ Demonstrate PFS improvement of 2 years R-maintenance over observation after induction with B-R

Ø Primary endpoint:

¥ Progression free survival (PFS)

Ø Secondary endpoints include:

¥ Overall survival (OS), Time to next treatment (TTNT)

¥ Response rates

¥ Adverse events, short- and long-term toxicity, second primary malignancies

¥ Prospective, randomized, multicenter phase 3 study

¥ Cooperative Study group indolent Lymphoma (StiL)

¥ 91 centers in Germany and Austria

¥ NCT00877214 (clinicaltrials.gov)

¥ Investigator initiated trial

¥ Funding by Roche Pharma AG

¥ 296 patients with WM registered between Apr 2009 and Oct 2017

¥ Median follow-up 77 months (all pts.) and 80 months (rand. pts.)

StiL NHL 7-2008: Waldenström Macroglobulinemia (WM)

B-R + Watch & Wait vs. B-R + 2 years Rituximab

Bendamustine-Rituximab+ Watch & Wait

(n = 109)

Bendamustine-Rituximab+ 2 years Rituximab

q 2 months(n = 109)

WM B-R R

StiL NHL 7-2008 - MAINTAIN

n = 218

≥ PR

n = 296SD, PD

off study

Baseline characteristics

all rand. pts R + R-

Total (n) 218 109109

Age (median) 66 67 65

Pts aged >75 years 31 (14%) 16 (15%) 15 (14%)

Stage IV 216 (99%) 108 (99%) 108 (99%)

Hemoglobin <11 g/dl 149 (68%) 70 (64%) 79 (72%)

IgM g/l (median) 32.7 32.7 31.3

β2-Microgl. mg/l (median) 3.5 3.3 3.7

B-symptoms 75 (34%) 43 (39%) 32 (29%)

Bulky disease 13 (6%) 3 (3%) 10 (9%)

LDH > 240 U/l 33 (15%) 13 (12%) 20 (18%)

MJR

Response rates following B-R induction

ORR 247 (93%)MRR 235 (88%)

CR 3 (1%)VGPR 65 (24%)PR 167 (63%)MR 12 (5%)SD 3 (1%)PD 11 (4%)Early death * 5 (2%)

* Age of pts dying early: 65, 73, 74, 79, 79

266 patients evaluable for response evaluation

0

0.25

0.5

0.75

1

0 12 24 36 48 60 72 84 96 108 120 132

Prob

abilit

y

Time (months)

PFS all pts with B-R without R maintenance

Pts at risk B-R only 187 141 123 103 81 67 47 33 21 11

pat months events(n) (median) (n)

all pts 187 68.8 83

0

0.25

0.5

0.75

1

0 12 24 36 48 60 72 84 96 108 120 132

Prob

abilit

y

Time (months)

Progression free survival (80 months median follow-up)

Hazard ratio, 1.21 (95% CI 0.78 – 1.89)

p = 0.3982

months events(median) (n)

Observation 106.3 42R maint. 118.4 36

Pts at risk Observ. 109 102 92 79 62 54 39 27 18 9 3R maint. 109 109 96 83 65 52 41 30 25 11 1

0

0.25

0.5

0.75

1

0 12 24 36 48 60 72 84 96 108 120 132

Prob

abilit

y

Time (months)

Overall survival (80 months median follow-up)

months events(median) (n)

Observation nyr 19R maint. nyr 23

Pts at risk Observ. 109 103 96 86 75 69 55 40 26 12 3R maint. 109 109 101 91 75 61 51 40 32 12 1

Hazard ratio, 0.85 (95% CI 0.46 – 1.55)

p = 0.5962

0

0.25

0.5

0.75

1

0 12 24 36 48 60 72 84 96 108 120 132

Prob

abilit

y

Time (months)

Patients younger than 65 years Patients older than 65 years

PFS: Patient age

months(median)

PFSevents Hazard ratio p value

Obs. n. y. r. 17 0.75 (CI 0.38 – 1.51) 0.4177R maint. n. y. r. 16

months(median)

PFSevents Hazard ratio p value

Obs. 64.3 25 1.86 (CI 1.03 – 3.38) 0.0355R maint. 118.4 20

Hazard ratio 0.75 (95% CI 0.38 – 1.51)

p = 0.4177

Hazard ratio 1.86 (95% CI 1.03 – 3.38)

p = 0.0355

0

0.25

0.5

0.75

1

0 12 24 36 48 60 72 84 96 108 120 132 144

Prob

abilit

y

Time (months)

0

0.25

0.5

0.75

1

0 12 24 36 48 60 72 84 96 108 120 132 144

Prob

abilit

y

Time (months)

PFS OS

TTP < 24 m.TTP > 24 m.

TTP < 24 m. TTP > 24 m.

POD 24 months

Salvage:F-R 6 R-ICE, R-DHAP, APBSCT 3R-CHOP 5 Splenectomy 1BDR 2 Radiation 2Ibrutinib 2 No therapy 6

months(median)

OSevents Hazard ratio p value

TTP <24 m. 23.1 21 5.88 (CI 2.30–15.00) <0.0001TTP >24 m. n.y.r. 53

n = 29 n = 29

Ø High activity of B-R in Waldenström patients confirmed

Ø R-maintenance did not improve PFS or OS after B-R

Ø B-R without R-maintenance achieves a median PFS of 69 months

Ø Patients responding to B-R do have an excellent disease controlwith a median PFS of 10 or 9 years with or without R-maintenance

Ø Explratory subgroup analyses suggest that age (>65 yrs) appears to be a critical factor for a potential benefit of R-maintenance

Ø Patients with POD 24 showed poor survival outcome

Summary and conclusion

Conclusions and Practical Considerations in Canada• For limited stage, favourable risk DLBCL, a shorter course of RCHOP chemotherapy is acceptable

• For SmIPI 0 pts, outcomes excellent, thus reasonable to just plan for 4 cycles of RCHOP, complementing the Lamy and Flyer trial results

• For SmIPI 1-2, a PET scan post-3 cycles of RCHOP can direct therapy, if negative, can complete 4 cycles of RCHOP, if positive, the clinician can decide to proceed to 6 cycles of chemotherapy and/or consolidate with radiation

• In WM, BR should remain the recommended 1st line treatment, without Rituximab maintenance• If available/confirmed – EZH2 mutation could be a useful prognostic and predictive biomarker, if

mutated, CHOP/CVP may be the preferred chemo regimen (until more targeted approaches available)• Ibrutinib/venetoclax is a promising combination treatment in rel/refr mantle cell lymphoma patients,

with durable responses• Treatment cessation was feasible for MRD negative complete remission patients, which is very

attractive for the Canadian landscape

EXTRA SLIDES

Time-to-Progression According to PET StatusIn “FLYER” versus “Other” Patients

FLYER criteria: age ≤60y, aaIPI=0, bulk <7.5 cm

FLYER (n=85) Other (n=228)

0.00

0.25

0.50

0.75

1.00

Time-t

o-prog

ressio

n (%)

12 11 9 7 6 6 4PET-POS73 65 58 45 29 16 7PET-NEG

Number at risk

0 2 4 6 8 10 12

Time (years)

K ap lan -M e ier s ur viv al es tim a te s

*~15% were PET-POS0.00

0.25

0.50

0.75

1.00

Time-t

o-prog

ressio

n (%)

47 32 20 18 15 5 2PET-POS181 142 107 79 53 30 14PET-NEG

Number at risk

0 2 4 6 8 10 12

Time (years)

K ap lan -M e ier s ur viv al es tim a te s

PET-POS 5-y TTP: 75%

*~80% were PET-NEG with excellent outcome

PET-NEG 5-yTTP: 100%

PET-POS 5-y TTP: 100%PET-NEG 5-y TTP: 88%

0

0.25

0.5

0.75

1

0 12 24 36 48 60 72 84 96 108 120 132

Prob

abilit

y

Time (months)

Patients younger than 65 years Patients older than 65 years

OS: Patient age

months(median)

PFSevents Hazard ratio p value

Obs. n. y. r. 5 0.37 (CI 0.13 – 1.02) 0.0554R maint. n. y. r. 10

months(median)

PFSevents Hazard ratio p value

Obs. n.y.r. 14 1.37 (CI 0.64 – 2.92) 0.4166R maint. 118.4 13

Hazard ratio 0.37 (95% CI 0.13 – 1.02)

p = 0.0554

Hazard ratio 1.37 (95% CI 0.64 – 2.92)

p = 0.4166

Causes of death in R-maintenance (n=10): Alcohol abuse / liver, Cardiac, Liver, 2 x lymphoma, 3 x infection; Unknown, SPM

Ø High activity of B-R in Waldenström patients confirmed

Ø R-maintenance did not improve PFS or OS after B-R

Ø B-R without R-maintenance achieves a median PFS of 69 months

Ø Patients responding to B-R do have an excellent disease controlwith a median PFS of 10 or 9 years with or without R-maintenance

Ø Explratory subgroup analyses suggest that age (>65 yrs) appears to be a critical factor for a potential benefit of R-maintenance

WM conclusions