Debate: How best to manage patients with relapsed mantle cell lymphoma? Cell based therapies with

AlloHCT or CAR-T

Mehdi Hamadani, MDMedical College of Wisconsin & CIBMTR

A symptomatic, stage IV MCL patient received R-CHOP/R-DHAP induction following by autoHCTconsolidation in 2016. He relapsed in 2018 & started ibrutinib/ixazomib (on trial). After 18 cycles, the patient relapsed again (Current age 69; ECOG=1)

Next steps: Targeted therapy à allogeneic HCT or Cell Therapy?

Churnetski & Cohen. Manuscript submitted.

Survival after ibrutinib failure?

• Median post relapse OS in ibrutinib responders = 5months

• Median post relapse OS in ibrutinib non responders = 1month

Simple Tools to Identify Poor-risk MCL at Relapse?

Post autoHCT relapse > 2yrsMedian OS = 132mons

Post autoHCT relapse ≤ 2yrsMedian OS = 22mons

Epperla & Hamadani. Hematol Oncol. 2017;35:528-35.

Fenske T & Hari P. J Clin Oncol. 2014;32(4):273-81.

AlloHCT Exerts Meaningful Immune Effects in MCLPr

obab

ility,

%

0 1 2 53

100

0

20

40

60

80

4

AlloHCT in CR1/PR1

Late AlloHCT

P>0.05

Overall Survival Relapse

Years

Cum

ulat

ive

Inci

denc

e, %

0 1 2 53

100

0

20

40

60

80

4

Early AlloHCT

Early AutoHCT

Late AlloHCT

Hamadani M & Lazarus H. Biol Blood Marrow Transplant. 2013;19:625-31.

GVL Effects Relevant Even in Refractory MCL

Adju

sted

Pro

babi

lity,

%

100

0

20

40

60

80

RIC

Myeloablative

1 3 752 4 6Years

0

PFS MAC RIC P value1yr 31 (20-42) 38 (29-48) 0.313yrs 20 (11-32) 25 (17-34) 0.53

Adju

sted

Pro

babi

lity,

%

100

0

20

40

60

80

RIC/NMA

Myeloablative

0 1 3 752 4 6Years

OS MAC RIC P value1yr 33 (22-44) 46 (37-54) 0.063yrs 25 (16-36) 30 (22-39) 0.45

CIBMTR: Unpublished data

Recent U.S. Trends in Allogeneic HCT Utilization (2010-18)

0

20

40

60

80

100

120

140

2010 2011 2012 2013 2014 2015 2016 2017 2018

Matched Related Haploidentical Matched Unrelated UCB

109

133

110

87 82 84 80 84

53

Shah N. & Hamadani M. Blood Adv. 2018;2:933-40.

Advanced Age Should Not be a Barrier for AlloHCTProgression-Free Survival Overall Survival

Adju

sted

Pro

babi

lity,

%

Years

100

0

20

40

60

80

0 2 5431

55-64 years

≥65 years

Adju

sted

Pro

babi

lity,

%

Years

100

0

20

40

60

80

0 2 5431

55-64 years

≥65 years

N=1183 55-64 Years ≥65 YearsPFS @ 4-year 37 (34-40)% 31 (26-35)%OS @ 4-year 51 (48-54)% 46 (41-51)%

p=0.14 p=0.10

Ghosh N. & Hamadani M. J Clin Oncol. 2016;34:3141-9.

Donor Availability is No Longer a LimitationOverall Survival100

0

20

40

60

80

Prob

abilit

y, %

Years0 1 32

HaploidenticalHLA Identical Siblings p=0.82

Chronic GVHD100

0

20

40

60

80

Cumu

lative

Incid

ence

, %

Years0 1 32

Haploidentical

HLA Identical Siblings

p<0.001

N=987 1-year 3-yearsHaplo Sibling Haplo Sibling

cGVHD 12% 45% 15% 52%Overall Survival 77% 78% 61% 62%

Why is Allogeneic HCT Use in the U.S. Declining?

CIBMTR: Unpublished data

Recent U.S. Trends in Allogeneic HCT Utilization (2010-18)

0

20

40

60

80

100

120

140

2010 2011 2012 2013 2014 2015 2016 2017 2018

Matched Related Haploidentical Matched Unrelated UCB

109

133

110

87 82 84 80 84

53

Ibrutinib & lenalidomideAcalabrutinib

Zanubrutinib 2019

In developmentBcl-2 inhibitors

Next generation BTKiAntibody-drug

conjugatesBi-specific antibodies

HCT Related Morbidity & Mortality

Fenske T & Hari P. J Clin Oncol. 2014;32(4):273-81.

Cum

ulat

ive

Inci

denc

e, %

Years0 1 2 53

100

0

20

40

60

80

4

Early Allo

Early Auto

Late Allo

Treatment-related Mortality

CAR-T cells: Knocking on the door

Already approved in:– R/R B-ALL (≤25yrs)– R/R DLBCL– DLBCL transforming

from FL– Primary Mediastinal

CAR-T cells in MCL: ZUMA-2

Courtesy: Dr. Michael Wang (MD Anderson Cancer Center)

Phase 2

Primary Endpoint• ORR (IRRC-

assessed per the Lugano classification1)

Optional BridgingTherapy

Dexamethasone 20 – 40 mg or equivalent PO or IV daily

for 1 – 4 days, or ibrutinib 560 mg PO daily, or acalabrutinib

100 mg PO twice daily

ConditioningChemotherapy

Fludarabine 30 mg/m2 IV and

cyclophosphamide500 mg/m2 IV

on Days −5, −4, −3

CAR T Cell Dose

2 × 106

KTE-X19 cells/kg single IV infusion on

Day 0

Enrollment/Leukapheresis

R/R MCL(1-5 prior line

of therapy)

Follow-UpPeriod

First tumor assessmenton Day 28b

Key Secondary Endpoints

• DOR• PFS• OS• AEs

• ORR (Investigator-assessed per revised IWGcriteria2)

• EQ-5D

• Levels of CAR T cells in blood and cytokines in serum

Patient Disposition: ZUMA-2

Wang M et al. ASH abstract 2019

• KTE-X19 was successfully manufactured for 71 patients (96%) and administered to 68 (92%)• Median time from leukapheresis to delivery of KTE-X19 to the study site was 16 days

• Data cutoff: July 24, 2019

• Primary efficacy analysis (n = 60) according to the protocol was conducted on the first 60 treated patients

• Safety analysis was conducted onall treated patients (n = 68)

Enrolled/Leukapheresed(N = 74)

Conditioning Chemotherapy (n = 69)

Received KTE-X19 (n = 68)

• Patients not treated (n = 5)− Manufacturing failure (n = 3)− Death due to PD (n = 2)

• Patients not treated after conditioning chemotherapy, found ineligible (n = 1)

Patient Characteristics

Wang M et al. ASH abstract 2019

Characteristic N = 68Median age (range), years 65 (38 – 79)

ECOG 0 or 1, n (%) 100 (100)

Intermediate/high-risk MIPI, n (%) 38 (56)

Ki-67 proliferation index ≥ 50%, n/n (%)a 34/49 (69)

TP53 mutation, n/n (%) 6/36 (17)Median no. of prior therapies (range)a 3 (1 – 5)

Relapsed after autologous HCT 29 (43)

BTKi, n (%) 68 (100)

BTKi refractory, n (%) 46 (68)

Response Rates & Toxicity

Wang M et al. ASH abstract 2019

100

90

80

70

60

50

40

30

20

10

0

PR

CR

Best

Obj

ectiv

e R

espo

nse,

%

93% ORR

67% CR(n = 40)

27% PR(n = 16)

3%(n = 2)

3%(n = 2)

ORR SD PD

Parameter N = 68CRS, n (%)

Any grade 62 (91)Grade ≥ 3 10 (15)

Neurologic events, n (%)Any grade 43 (63)Grade ≥ 3 21 (31)

AE management CRS, n (%)Tocilizumab 40 (59)Corticosteroids 15 (22)

Median time to CRS onset (range),days

2 (1 – 13)

Median time to CRES onset (range), days

7 (1 – 32)

Progression-free and Overall Survival

Wang M et al. ASH abstract 2019

Median PFS and median OS were not reached after a median follow-up of 12.3 months

Phase 1 Bispecific LV20.19 CAR-T cells

Courtesy: Dr. Nirav Shah (Medical College of Wisconsin)

• CD3z 41BB lentiviral construct

• Flu/CY Lymphodepletion

• Point-of-care production with CliniMACS Prodigy Device

• MCL, N=7 (CR = 57%)

Allogeneic HCT vs. Engineered Cell Therapy?AlloHCT CAR-T

Immune vs lymphoma effects? +++ +++Response to salvage Required Not neededLong term Relapse / OS 20-35% / 40-50% ?Toxicity Chronic GVHD

TRM ~20%CRS/CRESTRM ~5%

Cost $$ $$$$Available as SOC? Yes (mostly) No (not yet)Mutually exclusive No No

Allogeneic HCT vs. Engineered Cell Therapy?

R/R Mantle Cell Lymphoma

Targeted / conventional

Therapy

NO

High-risk Features?POD24 post autoHCT

High MIPIcTP53 mutated

BTKi REFRACTORYComplex karyotype

Blastoid?High Ki67?

Consider Immune Effector Cell Therapy

YES

CAR-T Allogeneic HCT

Commercial approvalAvailable trial

Poor KPSComorbid conditions

Marrow FailureDeveloping MDS

Clonal hematopoiesisTP53 mutation?

A symptomatic, stage IV MCL patient received R-CHOP/R-DHAP induction following by autoHCTconsolidation in 2016. He relapsed in 2018 & started ibrutinib/ixazomib (on trial). After 18 cycles, the patient relapsed again (Current age 69; ECOG=1)

Undergoing an “ACTR” Cell Therapy Trial