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Systemic T Cell Lymphomas
Massimo FedericoUniversity of Modena and Reggio Emilia
Città di Lecce Hospital - GVM Care & Research
My Disclosures
• Consultancy, Advisory Boards, Research funds
✓ Allos
✓ Spectrum
✓ Celgene
✓ Takeda
✓ Mundipharma
M. Federico, Kyiv, November 3-4, 2016
T-Cell LymphomasKey facts
• Orphan disease that needs more care
• Poor outcome
• (Too) Many different entities
• Uncertainity on standard treatment
Mature T- and NK- cell neoplasm (29
entities)
PTCLs: Epidemiology
• accounts for ~ 10% to 15% of all NHL
• rare in Western populations, prevalence slightly higher in Asia and Central–South America
• unique geographic distribution of different subtypes
• by some estimates, the incidence of PTCLs is growing significantly✓ may be driven by an aging population
✓ improvements in diagnosis techniques may also be driving the apparent growth in incidence
• Different clinical entities confirmed – fairly high rate of
different diagnosis on review
• Clinical outcomes different for subtypes; however many
have very poor outcomes with current therapies
• IPI or PIT may be helpful for prognosis and planning
• Outcomes not much different by anthracycline or
platinum agents used – alternative novel therapies needed
• Possible improvement by early intensive therapy – needs
confirmation with randomized clinical trials
Julie M. Vose
International Peripheral T-Cell Lymphoma ProjectCONCLUSIONS
www.tcellproject.orga project by the International T-Cell non-Hodgkin's Lymphoma Study Group
SouthAmerica
PTCL-NOS 41%AITL 8%ALCL,ALK- 26%ALCL,ALK+ 8%NKTCL 10%Extranodal PTCLs, other 4%Unclassifiable PTCLs 2%
North AmericaPTCL-NOS 35%AITL 21%ALCL,ALK- 13%ALCL,ALK+ 9%NKTCL 8%Extranodal PTCLs, other 11%Unclassifiable PTCLs 3%
Europe
Asia
PTCL-NOS 40%AITL 16%ALCL,ALK- 8%ALCL,ALK+ 13%NKTCL 11%Extranodal PTCLs, other 11%Unclassifiable PTCLs -
PTCL-NOS 37%AITL 21%ALCL,ALK- 14%ALCL,ALK+ 9%NKTCL 7%Extranodal PTCLs, other 9%Unclassifiable PTCLs 3%
Subtypes by geographic area(N=1391 validated Pts registered as of 30/04/2016)
PTCL-NOS 29%AITL 17%ALCL,ALK- 5%ALCL,ALK+ 5%NKTCL 29%Extranodal PTCLs, other 9%Unclassifiable PTCLs 6%
Middle East
CHOP, CHOP and once more CHO(E)P
Combination Chemotherapy in PTCL
Regimen Pts, n CR, % 5-yr OS, % Reference
CHOP 96144
-49
2632
RudigerLopez-Guillermo
ACVBP 228 49 35 Gisselbrecht
COPADEM-CYVE 77 52 40 Delmer
VACPE 27 77 48 Karakas
ESHAP 58 33 36 (2-yr) Bouabdallah
Meta-analysis of Frontline Anthracycline-Based Therapy for PTCL: overall survival
PTCL Subgroup Study, Yr 5-Yr OS Rate 95% CI 5-Yr OS Rate and 95% CI
AITL Pautier et al, 1999Savage et al, 2004Sonnen et al, 2005Vose et al, 2008AITL summary estimate Fixed
Random
0.3600.3600.2800.3200.3210.321
0.217-0.5340.134-0.6720.155-0.4510.264-0.3810.272-0.3750.272-0.375
ALCL Gisselbrecht et al, 1998Savage et al, 2004 Sonnen et al, 2005 ALCL summary estimate Fixed
Random
0.6400.4300.6100.5730.565
0.512-0.7510.275-0.6000.394-0.7900.479-0.6620.428-0.692
Alk-neg ALCL Vose et al, 2008 Alk-neg ALCL summary estimate Fixed
Random
0.4900.4900.490
0.377-0.6040.377-0.6040.377-0.604
ETTL Savages et al, 2004 Vose et al, 2008 ETTL summary estimate Fixed
Random
0.2200.2000.2030.203
0.055-0.5770.118-0.3180.125-0.3120.125-0.312
Non-ALCL PTCL Gisselbrecht et al, 1998 Rudiger et al, 2002
0.3500.260
0.291-0.4140.182-0.357
PTCL-NOS Savage et al, 2004 Sonnen et al, 2005 Vose et al, 2008
0.3500.4500.320
0.269-0.4400.338-0.5670.273-0.371
PTCL combined Karakas et al, 1996 Kim et al, 2002Reiser et al, 2002
0.4800.5260.550
0.303-0.6630.415-0.6330.429-0.665
0% 50% 100%
▪ 31 studies: 2815 Pts; 5-yr OS (all PTCL): 38.5%
CHOP remains the standard of care for both PTCL-NOS and AITL
• VIP-rABV: etoposide, ifosfamide, cisplatin alternating with adriamycin, bleomycin, vinblastine, and dacarbazine
• PEGS: cisplatin, etoposide, gemcitabine, and methylprednisolone
• CHOP-EG: CHOP + etoposide e gemcitabine
Schmitz N & de Leval L, 2016
Is there something better than CHOP?
CHOP vs CHOEP
EFS of Pts <60 years and with normal LDH(NHL-B1 and HiCHOEP phase II/III trials)
▪ The addition of etoposide to CHOP (CHOEP) improves the EFS of young Pts with normal LDH, but not OS (P=0.176)
▪ In Pts >60 years neither shortening the time interval (CHOP-21 vs CHOP-14), number of cycles (8 vs 6 CHOP-14), or the addition of etoposide (CHOEP) yielded any advantage, mainly due to added toxicities
2010
▪ In patients > 60 years 6 courses of CHOP administered
every 3 weeks remains the standard therapy
▪ Patients with ALK-neg ALCL, PTCLU, or AITL presenting
with IPI > 1 have a poor prognosis and should be considered
candidates for novel treatment strategies
2010
•Role of HDT ASCT
Treatment of PTCLsOpen questions
Authors N° Pts Regimen TX rate CR rate PFS OS
Rodriguez2007
26 Mega CHOP+/- IFEBEAM ASCT
73% 89% 53 % ( 3yrs) 73% (3yrs)
Corradini2006
62 HDS or MACOP-B + Mito- AracMito/ Alk or BEAM ASCT
74% 66% 30 % (12yrs) 34 % ( 3yrs)
Mercadel2008
41 Mega CHOP/ESHAPBEAM ASCT
70% 51% 30 % ( 3yrs) 39 % ( 3yrs)
Reimer2008
83 CHOP CTX-TBI ASCT
66% 58% 36 % ( 3yrs) 48 % ( 3yrs)
D’ Amore2011
160 CHOEP14-BEAM ASCT 71% 56% 44 % ( 5yrs) 51 % ( 5yrs)
Sieniawsky2010
26* IVE/MTXMito /Melph TBI or BEAM-ASCT
53% 65% 52 % ( 5yrs) 60 % ( 5yrs)
Corradini 2014
61 A-CHOP + HyperCHIDAMASCT (14) Allo ASCT (23)
60% 54% 44 % ( 4yrs) 49 % ( 4yrs)
*All patients with diagnosis of EATL
First line chemotherapy and ASCT in PTCL:prospective phase II studies
CHO(E)P-14d x 3
CHO(E)P-14d x 3
(stem cell collection)
HDT (BEAM)
Follow-up
Excluded:
• Precursor TCL
• alk+ ALCL
• CTCL
• Primary leukemic PTCL
CHO(E)P :
18-60 yrs: CHOEP-14 (n=118)
61-67 yrs: CHOP-14 (n=42)
CR, PR NC,PD
CR, PR NC,PD
60 mo median follow-up
160 patients
PLHSL T/NK
EATL
ALCL
AILTNOS
ORR pre-Tx 131 (82%)
CR/CRu 82 (51%)
PR 49 (31%)
% Tx 115 (72%)
CR/CRu 100d post-Tx 90 (56%)
5 yrs PFS 44%
5 yrs OS 51%
2012
21
Second PFS and OS of Patients with PTCL Treated at time of Relapse or Progression
31(16):1970-1976,2013
V. Mak et al.
22
Dismal outcome of t-cell lymphoma patients failing
first-line treatment: results of a population-based
study from the Modena Cancer Registry.
33: 147-151,2015
✓TCL failing first line systemic therapy
✓Diagnosis between 1997 and 2010
✓53 cases
Survival after relapse
median SAR 2.5 mo
3-yr SAR 19%
Survival after relapse according to
performance status and type of failure
In conclusion …..
▪ The outcome of PTCL continues to be dismal in the majority of cases
▪ No improvement in OS compared to older series
▪ Treatment remains challenging
▪ New therapies are welcome !
Therapeutic Options for T-Cell Lymphomas
Monotherapy with Biological Agents in R/R PTCL
Compound ORR
Monoclonal antibodies
Alemtuzumab (CD52) 36%1
Siplizumab (CD2) 31%2
Zanolimumab (CD4) 26%3
Mogamulizumab 34%4
HDAC inhibitors
Belinostat 26%5 (approved US)
Romidepsin 25%6 (approved US)
Antifolate
Pralatrexate 29%7 (approved US)
Biologic response modifiers
Denileukin Diftitox 40%8
Compound ORR
Antibody drug conjugates
Brentuximab vedotin (CD30)
86%9 (ALCL, approved US,EU)
Kinase inhibitors
Alisertib 24%10
Duvelisib 47%11
Crizotinib 90%12 (ALK+ ALCL)
Sorafenib 42%13
Farnesyltransferase inhibitor
Tipifarnib 50%14
Organic arsenic compound
Darinaparsin 28.6%15
References: 1. Enbald G. et al. Blood. 2004;103:2920-2924. 2. O’Mahony D. et al. CCR. 2009; 15:2514-2522. 3. d’Amore F. et al. BJH. 2010; 150:565-573. 4. Ogura M. et al. J Clin Oncol. 2014; 32:1157-1163. 5. O’Connor O.A. et al. J Clin Oncol. ASCO 2013; abstract 8507. 6. Coiffier B. et al. J Clin Oncol. 2012; 30:631-636. 7. O’Connor O.A. et al. J Clin Oncol. 2011; 29:1182-1189. 8. Foss F. et al. ASCO 2010; abstract 8045. 9. Pro B. et al. J Clin Oncol. 2012; 30:2190-2196. 10. O’Connor O.A. et al. ASH 2015; abstract 341. 11. Horwitz S. et al. ASH 2014; abstract 803. 12. Gambacorti Passerini C. et al. JNCI. 2014; 106:djt378. 13. Gibson J.F. et al. Br J Haematol. 2014;167(1):141–4. 14. Witzig T.E. et al. Blood. 2011;118(18):4882–9. 15. Hosein P.J. et al. Am J Hematol. 2012;87(1):111–4.
26
Response Rates Based on Overall IRC andInvestigators’ Assessments
Coiffier et al., JCO 2012 FDA APPROVAL
27
Romidepsin: Trials are examining in combination
✓First-line patients – In combination with chemotherapy
• Ro-CHOP
• Ro-CHOEP
• Ro-DHAP
– Maintenance
✓Relapsing patients– In combination with chemotherapy
• With bendamustine
• With gemcitabine
• Ro-ICE
RoCHOP Trial
• Open-label, randomized, phase 3 trial in 420 patients with untreated PTCL
Delarue R et al. J Clin Oncol. 2013;31 (suppl; abstr TPS8616).
Primary endpoint: PFS
Select secondary endpoints: OS, response rate, duration of response, safety, QoL
Randomizat ion
Romidepsin CHOP Q3 wk
CHOP Q3 wk
Romidepsin: 12 mg/m2 dosed days 1 and 8 of each CHOP cycle (6 cycles)Dose reductions allowed to 10 and 8 mg/m2
Treatment Phase
Phase I/II trial Pts ≥18 yrs ≤ 65 yrs
Phase I : Romidepsin 8,
10, 12, 14 mg/sqm; starting
with 12 mg/sqm
Phase II: Romidepsin at
MTD
Ro-CHOEP21 x 3
Response Evaluation
<PR CR or PR
Ro-CHOEP21 x 3
PR CR PD or SD
ALLO - SCT AUTO - SCT Other
treatments (investigators’ choice)
Other treatments
(investigators’
choice)
For PR
start donor search
Response Evaluation
DHAP – Stem Cell Harvest
Follow-up
ORR: 26% (n 31; CR: 13; PR: 18)
These results have led to FDA and EMAapproval of belinostat for this indication
31
Pralatrexate—PROPEL Data
70% of responders did so in cycle 1 Central Review
n = 109
Investigator
Assessment n = 109
Best response n % n %
CR+CRu*PR 32 29% 43 39%
CR 11 10% 17 16
CRu 1 1% 3 3%
PR 20 18% 23 21%
Med DOR 10.1 months
Med PFS 3.5 months
Med OS 14.5 months
• Most common AEs:
• Mucositis (71%), nausea (41%),
thrombocytopenia (41%), and
fatigue (36%)
• Most common grade 3-4 AEs:
• Thrombocytopenia (33%),
mucositis (22%), neutropenia
(22%), and anemia (18%)AEs, adverse events; CR, complete response; CRu, CR
unconfirmed; DOR, duration of response; OS, overall survival; PFS,
progression-free survival; PR, partial response
O‘Connor OA, et al. J Clin Oncol. 2011;29(9):1182-1189.
FDA APPROVAL
Pralatrexate + Romidepsin: a well tolerated and effective combination for PTCL
Patients with PTCL 13
Patients dosed at the MTD (P 25 mg/m2 & R 12mg/m2 QOW) did not experience any toxicities
ORR 77%
CR 31%
DoR 6.55 months (range 1.6 – 26.5+)
Mean PFS 6.13 months (range 1.5 – 30.2+)
Amengual et al.ASH 2016; abs 1824; poster
33
Phase II Study of Brentuximab Vedotin in Patients
with R/R sALCL: Response and Outcomes
Pro B et al, 2012
IRF (N=58)
ORR, % (95% CI) 86 (74.6, 93.9)
CR, % (95% CI) 57 (43.2, 69.8)
PR, % 29
SD, % 3
PD, % 5
Histologically ineligible, % 3
NE, % 2
Median duration of OR, months (95% CI) 12.6 (5.7, NE)
Median duration of response in patients with CR, months (95% CI)
13.2 (10.8, NE)
Median PFS, months (95% CI) 13.3 (6.9, NE)
Median OS, months (95% CI) NR (14.6, NE)
12-mo OS, % 70
34
Phase II Study of Brentuximab Vedotin in
Patients with R/R sALCL
Pro B et al, 2012
97% of patients achieved tumour reduction
Long-Term Survival Data from Pivotal
Phase 2 Clinical Trial of BV in R/R sALCL
• Estimated Five-Year Overall Survival Rate was 60
Percent and Five-Year Progression-Free Survival
Rate was 39 Percent
• In the 66 Percent of Patients who Achieved
Complete Remission, Both Median Overall Survival
and Progression-Free Survival Not Yet Reached
• “Publication of the five-year follow up results
represents a significant milestone for the sALCL
community by demonstrating that treatment with
single-agent BV resulted in high response rates and
durable, long-term remissions
35October 3, 2017 (Press release)
36
2014
37
SGN35-011: Phase 1 study of frontline brentuximab vedotin
plus multi-agent chemotherapy in ALCL and CD30-positive
mature T-cell and NK-cell lymphomas Response
Primary objectives:
▪ Safety profile
▪ Determine recommended dose of brentuximabvedotin in combination with CHP
Secondary objective:
▪ Antitumor activity
Eligibility:
▪ CD30+ MTCL including sALCL
Fanale M et al. ASH 2013, New Orleans, LA, USA (Abstract 4386)
38
ECHELON-2: Phase III trial of brentuximab vedotin and CHP
vs. CHOP in frontline CD30+ mature T-cell lymphomas
Endpoints:• Primary: PFS per IRF
• Secondary:
- PFS per IRF for patients with sALCL
- Others: CR rates per IRF following completion of treatment, Overall survival, ORR
per IRF, Safety and tolerability
Study Design: Patients with newly diagnosed CD30+ MTCL
Brentuximab Vedotin
1,8 mg/kg q3w
+
CHP
21-day cycles
CHOP
21-day cycles
R
A
N
D
O
M
I
Z
E
E
V
A
L
U
A
T
I
O
N
39
Brentuximab vedotin or physician's choice in CD30-positive
cutaneous T-cell lymphoma (ALCANZA): an international,
open-label, randomised, phase 3, multicentre trial
Inclusion:
• Diagnosis of CD30-positive
MF or pcALCL
– ≥10% CD30-positive on either
neoplastic cells or lymphoid
infiltrate by central review of
≥1 biopsy (≥2 required for MF)
• MF patients with ≥1 prior
systemic therapy
• pcALCL patients with prior
radiotherapy or ≥1 prior
systemic therapy
Exclusion:
• Progression on both prior
methotrexate and bexarotene
Screening*
Ran
do
miz
ati
on
Methotrexate: 5–50 mg PO, weekly
or
Bexarotene: 300 mg/m² (target dose)
PO, daily
Brentuximab vedotin:
1.8 mg/kg IV, every 3 weeks
Up to 48 weeks (16 x 21-day cycles)End of
treatment
visit
Post-
treatment
follow-up
Every 12
weeks for
2 years
and then
every 6
months
thereafter
30 days
after last
dose of
study drug
*within 28 days of randomization
• Methotrexate or bexarotene was managed as standard of care, targeting maximum tolerated effective dose
• International study of 52 centers, 13 countries
Prince HM, Kim YH, et al. Lancet June 2017.
40
Youn H Kim et al.
• 131 pts (97 MF, 31 pcALCL, 3 excluded)
BV = 64 (1.8 mg/Kg IV, once every 3 weeks),
PC = 64:- MTX (5-50mg PO weekly)- Bex (300mg/m2 PO daily) for up to 16x 3 week cycles
41
Youn H Kim et al.
Endpoint BV N = 64
PCN = 64
Differences BetweenArms (95% CI)
Statistical Significance
Primary endopoint
ORR4, n (%) 36 (56.3%) 8 (12.5%) 43.8% (29.1, 58.4) p<0.0001
Key secondary endopoints
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 maximumreduction in Skindex-29 symptom
domain, points
-27.96 -8.62 -18.9 (-26.6, -11.2) p<0.0001 (adj)
▪ Results at median follow-up 17.5 months
42
Brentuximab vedotin or physician's choice in CD30-positive
cutaneous T-cell lymphoma (ALCANZA): an international,
open-label, randomised, phase 3, multicentre trial
Prince HM, Kim YH, et al. Lancet June 2017 .
• Phase 3 Lumière trial of alisertib versus investigator’s choice (pralatrexate,
gemcitabine, romidepsin) in R/R PTCL (NCT01482962)1
Alisertib (Aurora A Kinase Inhibitor)
Comparator
Response Alisertib(n=96)
All pts (n=85) Pralatrexate (n=45) Gemcitabine (n=22)
Romidepsin (n=18)
ORR 36% 46% 44% 36% 61%
CR 19% 28% 29% 23% 33%
PR 17% 18% 16% 14% 28%
SD 30% 20% 24% 14% 17%
PD 34% 34% 31% 50% 22%
References: 1. O’Connor O.A. et al. ASH 2015; abstract 341. 2. Friedberg J.W. et al. J Clin Oncol. 2014; 32(1):44-50. 3. Barr P.M. et al. J Clin Oncol. 2015; 33(21):2399-2404.
Ongoing Clinical Trials
Agent Targeting site Phase ClinicalTrial.gov ID
Endostar Angiogenesis inhibitor II NCT02520219
Selinexor Selective inhibitor of nuclear export II NCT02314247
Tipifarnib Farnesyltransferase inhibitor II NCT02464228
Darinaparsin Organic arsenic compound INCT01435863
NCT01689220
Ixazomib Proteasome inhibitor II NCT02158975
Denileukin diftitox Interleukin fusion protein IINCT00050999
NCT00051012
Forodesine PNP inhibitor I/II NCT01776411
Ruxolitinib JAK inhibitor II NCT01431209
Temsirolimus mTOR inhibitor I NCT01614197
Carfilzomib Proteasome inhibitor I NCT01336920
Panobinostat Pan-deacetylase inhibitor II NCT01261247
Clofarabine DNA synthesis inhibitor I/II NCT00644189
MK2006 AKT inhibitor II NCT01258998
Sorafenib Multikinase inhibitor II NCT00131937
Alefacept Immunosuppressive dimeric fusion protein I NCT00438802
Pembrolizumab PD-1 antibody II NCT02535247
References: 1. Zhang Y. et al. J Hematol Oncol. 2016 Apr 12;9:37.
45
In conclusion …..
▪The outcome of PTCL continues to be dismal in the majority of cases;
▪Limited improvement in OS compared to older series;
▪Treatment remains challenging;
▪New therapies are welcome!
THE (TRUE) END