t-cell lymphoma and hodgkin lymphoma · t-cell lymphoma and hodgkin lymphoma steven m. horwitz m.d....
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T-Cell Lymphoma and Hodgkin Lymphoma
Steven M. Horwitz M.D.Associate MemberLymphoma ServiceMemorial Sloan Kettering Cancer Center
• Consultancy: ADC Therapeutics, Aileron, Seattle Genetics, Takeda, Kyowa Hakka Kirin, Verastem, Portola, Corvus , Innate, BeiGene
• Research Funding: Aileron, Celgene, Seattle Genetics, Takeda, Kyowa Hakka Kirin, Verastem, ADCT Therapeutics, Spectrum, Forty-Seven
Disclosures for Steven M. Horwitz, MD
Conflict of Interest Disclosure
I hereby declare the following potential conflicts of interest concerning my presentation:
Rudiger et al. Ann Oncol. 2002;13(1):140-149.
T-cell Lymphomas“Heterogeneous and B.A.D”
T-cell lymphomas are highly heterogenousCTCL Extranodal Nodal Leukemia
Mycosis fungoides Extranodal NK/T cell Peripheral T-cell NOS Adult T-cell LL
Sezary Syndrome Enteropathy-associated Angioimmunoblastic T-cell PLL
SPTCL Hepatosplenic T-cell Follicular T-cell T-cell LGL
CD30+ T-cell LPDs (LyP,pcALCL)
Monomorphic epitheliotropicintestinal
Nodal T-cell lymphoma with TFH phenotype*
Aggressive NK-cell leukemia
PC γδ T-cell Indolent T-cell LPD of GI ALCL; ALK-pos Chronic LPD of NK
PC CD8+ epidermotropiccytotoxic
Breast implant-associated ALCL* ALCL; ALK-neg *
PC acral CD8+ TCL* Systemic EBV+ TCL of childhood*
PC CD4+ small/med Hydroa Vacciniforme-like
Swedish National Registry: PFS in 755 patients with PTCL.
Fredrik Ellin et al. Blood 2014;124:1570-1577
ALK+ ALCL
ALK- ALCL ALK U ALCL
PTCL NOSAITL
TCL-U
d'Amore et al. JCO 2012;30:3093-3099
Best outcomes in first-line among clinical trial participants
5 yr OS 51% 5 yr PFS 44%
Pralatrexate N=109
Romidepsin N=130
Mak V et al. JCO 2013;31:1970-1976, O’Connor OA, et al. J Clin Oncol. 2011;29:1182-1189, Coiffier B, et al. J Clin Oncol. 2012;30 :631-636, O’Connor OA et al ASCO 2013, Pro B, et al. J ClinOncol. 2012;30:2190-2196, Horwitz SM et al. Blood 2014;123:3095-3100
Belinostat N=129
PFS 3.7 months
BCCA
PFS 1.6 months
PFS 4 months
PFS 3.5 months
ALCL N=56
PFS 13.3 months
>5-10% CD30+
PTCL N=21; AITL N=13
1.6 months
6.7 months
Approval data in relapsed/refractory setting 100% CD30+, biomarker-driven
Time (months)
Brentuximab vedotin, anti-CD30 ADC
ECHELON-2 Study Design (NCT01777152)
Key Eligibility Criteria
• Age ≥18 years
• CD30-expression (≥10% cells)
• Previously-untreated PTCL:
o Systemic ALCL (sALCL)*
including ALK(+) sALCL with IPI
≥2, ALK(-) sALCL
o PTCL-NOS, AITL, ATLL, EATL,
HSTCL
Stratification Factors
• IPI score (0-1 vs. 2-3 vs. 4-5)
• Histologic subtype (ALK-positive
sALCL vs. all other histologies)
R
(1:1
)
N=226
N=226
EOT
PET
A+CHP
(A) brentuximab vedotin 1.8 mg/kg +
(C) cyclophosphamide 750 mg/m2 +
(H) doxorubicin 50 mg/m2 +
(P) prednisone 100 mg (Days 1-5)
+ placebo vincristine
Q3W for 6 to 8 cycles
CHOP
(C) cyclophosphamide 750 mg/m2 +
(H) doxorubicin 50 mg/m2 +
(O) vincristine 1.4 mg/m2 +
(P) prednisone 100 mg (Days 1-5)
+ placebo brentuximab vedotin
Q3W for 6 to 8 cycles
*targeting 75% (±5%) ALCL per EU
regulatory commitment
AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase ATLL, adult T-cell leukaemia/lymphoma; EATL, enteropathy-associated T-cell lymphoma; EOT, end of treatment; GCSF, granulocyte-colony stimulating factor; HSTCL, hepatosplenic T-cell lymphoma; IPI, international prognostic index
Per investigator discretion:
GCSF primary prophylaxis, consolidative RT and SCT
Series Definition of + Subtype CD30+ % (N)
Sabbatini 2013 > 25% PTCL-NOS 52% (45/87)
AITL 21% (9/42)
ENKTCL 70% (7/10)
MF 13% (4/32)
ALL Types 43% (83/192
Went 2006 > 30% PTCL-NOS 3% (4/145)
AITL 0% (0/42)
CD30 Expression in TCL other than ALCL
Sabbatini et al Haematologica. 2013 August; 98(8): e81–e82
Went et al. J Clin Oncol. 2006 Jun 1;24(16)
Baseline Characteristics
A+CHP
(N=226)
CHOP
(N=226)
Male, n (%) 133 (59) 151 (67)
Age in years,
median (range)58 (18-85) 58 (18-83)
IPI score, n (%)
0-1 53 (23) 48 (21)
2-3 140 (62) 144 (64)
4-5 33 (15) 34 (15)
Stage III/IV, n (%) 184 (81) 180 (80)
A+CHP
(N=226)
CHOP
(N=226)
Disease diagnosis, n (%)
sALCL 162 (72) 154 (68)
ALK+ 49 (22) 49 (22)
ALK- 113 (50) 105 (46)
PTCL-NOS 29 (13) 43 (19)
AITL 30 (13) 24 (11)
ATLL 4 (2) 3 (1)
EATL 1 (0) 2 (1)
Progression-free Survival
3-yr PFS
57%44%
Events HR (95% CI) P
A+CHP 95 (42%) 0.71(0.54, 0.93)
0.011CHOP 124 (55%)
Median PFS (95% CI)
48.2 mo (35.2, NE)20.8 mo (12.7, 47.6)
Median Follow-up 36.2 months
Agar et al. J Clin Oncol 2010;28:4730
Prognosis of early vs advanced stage MF and SS:
Appropriate risk-stratification for treatment selection
Kim et al, Arch Dermatol 1996;132:1309
Stage IA vs. control population:
Life-expectancy is not altered in patients with limited
patch/plaque disease
Early
(IA-IIA)
vs
Advanced
(IIB-IV)
F-MF or LCT with worse clinical outcome
F-MF not sig independent factor in
advanced MF/SS (CLIC Scarisbrick et al, 2015)
Arch Dermatol 146:607, 2010, J Clin Oncol 28:4730, 2010,
Blood 119:1643, 2012, J Clin Oncol 2015;33:3766
ALCANZA: a randomized, open-label, phase 3 trial of brentuximab vedotin vs physician’s choice (methotrexate or bexarotene) in patients with CD30+ CTCL
Inclusion:
• Diagnosis of CD30+ MF or pcALCL
• ≥10% CD30+
• MF patients with ≥1 prior systemic therapy
• pcALCL patients with prior radiotherapy or ≥1 prior systemic therapy
Screening*
Treatment
Ra
nd
om
iza
tio
n
Methotrexate: by mouth weeklyor
Bexarotene: by mouth daily
Brentuximab vedotin: IV, every 3 weeks
Up to 48 weeks (16x 21-day cycles)
Post-treatmentfollow-up
Every 12 weeks for 2 years and
then every 6 months
thereafter
* within 28 days of randomization
Endpoint
Brentuximab vedotin
N=64
Physician’s ChoiceN=64
Difference Between Arms
(95% CI)Statistical
Significance
Primary endpoint
ORR4, n (%) 36 (56.3%) 8 (12.5%) 43.8% (29.1, 58.4) p<0.0001
Key secondary endpoints
CR, n (%) 10 (15.6%) 1 (1.6%) 14.1% (-4.0, 31.5) p=0.0046 adj
Median PFS, months 16.7 3.5
p<0.0001 adj
HR=0.270 (95% CI: 0.169,
0.430)
Mean maximum reduction in Skindex-29 symptom domain, points
-27.96 -8.62 -18.9 (-26.6, -11.2) p<0.0001 adj
Primary and key secondary endpoint analyses (ITT population)
HM Prince et al. Lancet. 2017 Aug 5;390(10094):555-566
• Pi3k-duvelisiib
• Pralatrexate-Romidepsin
• Romidepsin-5-AZA
• Ruxolitinib
• Cerdulatinib syk/jak
• Tipifarnib
• MDM2 inhibitorsEZH1/2 inhibitors
• New ADCs
• Mogamulizumab-Anti CCR4 Ab-CTCL, ATLL-FDA approved CTCL
• Anti CD47 strategies
• Checkpoint inhibitors
• CART
Therapies in Development in TCL/other targets
Amengual et al Blood 2018 131:397-407; Falchi et al ASH 2017; Hamlin et al ASCO 2018Witzig et al ICML 2017; Kim et al Lancet Oncol 2018
PTCL
High unmet need
Upfront CHOP or CHOEP-ASCT
CD30+-BV-CHP
Relapsed-many therapies early in development
CTCL
More Chronic-sequential therapies
T-Cell Lymphoma
HL by the Numbers
Optimal Upfront Treatment8000 pts
Favorable ES
Unfavorable ES
Unfavorable ES with Bulk
Favorable AS Unfavorable AS
1000 2500 1000 2500 1000
100 Fail 300 Fail 200 Fail 500 Fail 300 Fail
700 Pts ≥ 70 yearsNo standard TX
TREATMENT FAILS IN 1400 PATIENTS
RAPID: ≥5cm mass defines group that may need something more…..
PET
IFRT, 30 Gy No further treatment
PET –PET +
ABVD x1 ➡ IFRT Randomization
ABVD x3
PET
Radford J et al, N Engl J Med (2015) 17:1598-607Illidge T et al, ISHL 2018
5-year EFS:
tumor <5cm (n=172) = 93.6%
tumor ≥5cm (n=39) = 79.3%
No further treatment
Johnson et al. ICML 2015
UK RATHL Trial: Interim FDG-PET-adapted therapy for advanced stage cHL
CS II (adverse); CS III and IVIPS 0-7; PS 0-3; Age > 18
BEACOPP-14 x4 ORBEACOPP escalated x4
ABVD x2
PET
Deauville 1-3Deauville 4-5
ABVD x4 AVD x4
R
RT or SLT
No Further RxPET
BEACOPP-14 x1 ORBEACOPP escalated x1
• Primary endpoint
– 3-year PFS of ABVD v AVD
• Non-inferiority design
– 90% power to exclude AVD being > 5%worse than ABVD
RATHL: Outcome in PET-negative radomization ABVD v AVD (@ median follow up 36.3 months)
∆ABVD-AVD = 1.4% (95% CI ‐3.6 - +5.2)
Per Protocol AnalysisIntent to Treat Analysis
HR: 1.11 (0.79-1.54), p = 0.53 3-year PFS:
ABVD 85.4% (95% CI: 81.6-88.5)AVD 84.4% (95% CI: 80.7-87.6)
HR: 1.09 (0.78-1.53), p = 0.59 3-year PFS:
ABVD 85.3% (95% CI: 81.6-88.4)AVD 84.6% (95% CI: 80.8-87.7)
Johnson et al. ICML 2015
3-year OSABVD: 97.1 (94.7-98.4)AVD: 97.4 (95.0-98.6)
Bleomycin can be eliminated if PET-2 is negative
ABVDC1-2
ABVDC3-6
AVDC3-6
P
Neutropenia 57.3 58.4 57.5 0.78
Thrombocytopenia 1.3 1.3 3.2 0.045
Neutropenic fever 2.1 4.7 2.2 0.032
Infection 6.3 14.5 10.1 0.040
Thromboembolism 1.4 4.9 2.6 0.061
Respiratory AE 0.7 3.6 0.6 0.002
Any non-heme AE 16 31 21 <0.001
% of patients experiencing grade 3-4 events
RATHL: Outcome in PET-positive patients (@ median follow up 36.3 months)
Johnson et al. ICML 2015
OSPFS
3-year PFS: BEACOPP-14 66.0% (95% CI 55.0-74.9%)
escBEACOPP 71.1% (59.0%-80.2%)
3-year OS: BEACOPP-14 89.6% (95% CI 80.0%-94.7%)
escBEACOPP 82.2% (70.5%-90.2%)
Outcome of PET-2 positive patients improved compared to historical controls
ECHELON-1: Phase 3 Study of BV+AVD Versus ABVD in Newly Diagnosed, Advanced cHL1
1. Connors JM et al. 60th American Society of Hematology Annual Meeting & Exposition (ASH 2017). Abstract 6.
Scr
ee
nin
g
CT
/PE
T s
can
ABVD x 6 cycles (n = 670)
BV+AVD x 6 cycles (n = 664)BV 1.2 mg/kg IV infusion
Days 1 and 15
EO
TC
T/P
ET
sca
n Follow-up every 3
months for 36 months, then
every 6 months until study closure
218 study sites in 21 countries worldwide
1:1R
N = 1,334
End-of-cycle-2 PET scan• Deauville 5; could receive alternate therapy per
physician’s choice (not an mPFS event)
Inclusion Criteria• cHL stage III or IV• ECOG PS 0, 1, or 2• Age ≥18 years• Measurable disease• Adequate liver and renal function
mPFS Per Independent Review
TimeBV+AVD(95% CI)
ABVD(95% CI)
2-year82.1
(78.7-85.0)77.2
(73.7-80.4)
TimeBV+AVD(n = 117)
ABVD(n = 146)
Progression 90 102
Death 18 22
Modified progression• Chemotherapy• Radiotherapy
972
22157
Number of Events
mPFS Estimates
Median follow-up (range): 24.9 mo (0.0-49.3)
1. Connors JM et al. ASH 2017. Abstract 6.
Post-transplant brentuximab vedotin maintenance
Moskowitz CH, et al. Lancet 2015;385:1853-62Moskowitz CH, et al. ISHL 2018
• AETHERA: Phase III study evaluating post-transplant maintenance BV for higher risk patients
• Risk factors: Relapse within 1 year of initial treatment, primary refractory disease, extranodal disease
• 329 patients received brentuximab vedotin (BV) (n=165) or placebo (n=164)
5-Year PFS Rates
BV=59% Placebo=41%
HR=0.521
Other active agents in Rel/Ref HL
Drug n ORR Reference
Bendamustine 36 53% Moskowitz AJ, et al. JCO 2013
Everolimus 57 42% Johnston, et al. ASH 2012
Panobinostat 129 27% Younes, et al. JCO 2012
Entinostat 38 12% Batlevi, et al. Haematologica 2016
Mocetinostat 51 33% Younes, et al. Lancet Oncol. 2011
Lenalidomide 36 19.5% Fehniger, et al. Blood. 2011
ADCT-301 (Cami-T) 60 69% Hamadani et al. ASH 2018
CD30 CARTs Ramos/Grover ASH 2018
Frontline
Early stage Short course ABVD
Advanced stage : ABVD vs BV-AVD
Relapsed-standard
BV if not given upfront
Nivo/Pembro
Relapsed-investigational
CART
ADCT-301
Hodgkin Lymphoma
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