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PTCL update: Evidence for subtype-specifictreatment approaches
Francesco d’Amore, MD, DMScDept. of Hematology
Aarhus University HospitalAarhus, Denmark
May 3-4, 2019
7th TSH International SymposiumBangkok,
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Disclosures
• Advisory boards: Nordic Nanovector, ServierPharmaceuticals, Takeda
• Speaker’s honoraria: Takeda, Servier Pharmaceuticals
• Research support: Sanofi/Genzyme, Takeda, Roche, CTI Life Sciences, Servier Pharmaceuticals
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Structure of the talk
• Introduction
• Selected entities from the revised WHO classification
– TFH – selected updates on biology and and novel treatments
– GI TCL – WHO updates and some therapeutic considerations
– ALCL – selected updates on biology and therapy
– NK/T and HSTCL
• What about ‘the rest’? Role of SCT and experience from the large academic PTCL-specific trials run so far
• The ACT-1 trial
• Concluding remarks
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PTCL IncidenceUS SEER registry (8802 pts)
Petrich et al. Br J Haematol 2014
PTCL subtypes
Laurent et al. J Clin Oncol 2017
PTCL: a rare and heterogeneous diseaseNordic Lymphoma Group
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Updated Kiel Classification: the first major attempt to establisha specific classification for T-cell malignancies (J Clin Pathol 1987; 40, 995-1015)
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T-cell lymphomas over the last 30 years
Suchi-Lennert Classification1987
Morphology, IH
REAL Classification
1994
Morphology, IH,
FISH,cytogenetics
WHO Classification2001
Morphology, IH,
FISH, cytogenetics,
mol. biol.
WHO Classification
2008
Morphology, IH,
FISH,cytogenetics,
mol. biol., GEP
WHO Classification2016/2017
Morphology, IH,
FISH,cytogenetics,
mol. biol., GEP, NGS,
Nanostring, RNA seq, high-throughput of FFPEs
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WHO 2016: What is new in systemic PTCL?
AITL/ other TFH lymphomas Intestinal PTCL ALCL, ALK-negative
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WHO 2016: AITL is a disease of GC-derived TFH cells
CD3+, CD10+, BCL-6+/-, PD1+, CXCL13+, CD21+ FDC meshwork;Both EBVpos and neg B cells;Often clonal B-cells
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WHO 2016: Nodal PTCL of TFH cell origin
AITL
Follicularvariant
NodalPTCL-NOS
TFH cell
GEP and mutation analysis have helped to characterize the relationship between nodal PTCL entities og TFH origin
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Nodal PTCL 2008-2016: subtype migration2008
AITL
T-zone variant
Follicular variant
Lymphoepithelioid variant(Lennert’s lymphoma)
PTCL-NOS
International T-cell Lymphoma Project, J Clin Oncol 2008
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Nodal PTCL 2008-2016: subtype migration2016
T-zone variant
Follicular variant
Lymphoepithelioid variant(Lennert’s lymphoma)
PTCL-NOS
Nodal PTCL with TFH phenotype
AITL
Laurent et al. J Clin Oncol 2017
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TFH-derived PTCL: Actionable mutations in epigenetic modifier and other genes
IDH2 and TET2 mutations are mutually exclusivein AML but co-occur in TFH-derived TCL
Sakata-Yanagimoto M, et al. Nat Gen 2014;46:171-5
PTCL, peripheral T-cell lymphoma; IDH, isocitrate dehydrogenase; BCL, B-cell lymphoma gene; CXCR, chemokine receptor; PD-1, programmed cell death; AITL, angioimmunoblastic T-cell lymphoma, NOS, not otherwise specified; TET2, ten-eleven translocation DNMT3A, DNA (cytosine-5) methyltransferase 3 alpha; AML, acute myeloid leukemia; TFH, T follicular helper; TCL, T-cell lymphoma; mIDH2, mutant IDH
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PV ET MF CML Mastocytosis MPN-NOS Total
Chronic lymphocytic leukemia 8 6 2 1 - 14 31
Diffuse large B-cell lymphoma 8 2 2 2 1 5 20
Low grade lymphoma - NOS 4 - 3 - - 4 11
Peripheral T-cell lymphoma- ALCL ALK-neg- AITL
-2
-2
11
--
--
-3
18
Waldenström macroglobulinemia - 1 4 2 - 3 10
Lymphoblastic lymphoma - - - 5 - - 5
Marginal zone lymphoma - - 1 - - 4 5
Hodgkin’s lymphoma - 1 - 1 - - 2
Follicular lymphoma - 1 - 1 - - 2
Mantle cell lymphoma - - - - - 1 1
Primary CNS lymphoma - - - 1 - - 1
Total 22 13 14 13 1 34 97
Lymphoproliferative and myeloproliferative malignancies occurring in the same host: A nationwide discovery cohort
J.M.Holst, T.L.Plesner, M.B.Pedersen, H.Frederiksen, M.B.Møller, M.R.Clausen, M.Ludvigsen, P.Nørgaard, P.Johansen, T.Ramm-Eberlein, B.K.Mortensen, G.Mathiasen, A.Øvlisen, R.Wang, W.Tam, WC Chan, G.Inghirami, F.d’Amore
Holst J et al. Blood 2017 130:1525
Exp%: 3% >> Obs%: 12,5%4-5 fold
AITL: expected occurrence among NHL (i.e. without CLL and HL) => 3% of 64 = ca 2 => observed: 8 = 12,5%
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Clinical case 2 points: (i) ET/AITL; (ii) Mutational status
• 45 y/o man with known JAK2+ ET develops fever, fatigue, drenching sweats, PS 3
• Multiple supra- and infradiaphragmaticLN involvement and BM infiltration
• Cervical LN biopsy showed AITL • Elevated LDH (770 U/l)• Mutations: TET2+, IDH2+, JAK2+
CD3 CD4 CD10 EBER CXCL-13 PD1
at Dx
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PTCL subtype Pralatrexate Romidepsin BelinostatBrentuximabvedotin
All subtypes 29 25 26 ---
PTCL-NOS 31 29 23 33
AITL 8 30 46 54
ALCL 29 24 15 86
Subtype-specific responses (%) in FDA approved PTCL
PTCL subtype IDH2R140 IDH2R172 TET2
PTCL-NOS 0/43 0/43 22/58 (40%)
(FH 58% non-FH 24%)
AITL 25/101 (25%) 1/101 40/86 (47%)
ALCL 0/50 0/50 0/18
Mutations in epigenetic regulators are more frequent in TFH- derived PTCL
HdAc inhibitors: Best effect in PTCL with highest frequency of mutations in epigenetic modifier genes
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Romidepsin-CHOP vs CHOP
➢ Romidepsin MTD (phase 1b): 12mg/m2 x6 d1+8 at each cycle of CHOP
➢ Target population: 420 pts
➢ Enrolled pr Feb 2015: 108 pts
➢ 1st interim analysis at 84 events (30% of the total expected)
ICML, Lugano 2013: Median Follow-up: 10 months➢ n=27 evaluable➢ CR 15/27 (55.6%)➢ ORR 20/27 (74%)
Dupuis J, et al. Lancet Haematol 2015;2:e160-5
Delarue R, et al. ICML 2013;abstract OT02;
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Randomized Phase 3 Study Evaluating the Efficacy and the Safety of Oral Azacitidine (CC-486) Compared to Investigator's Choice Therapy in Patient With Relapsed or Refractory
Angioimmunoblastic T Cell Lymphoma
The ORACLE trial
Sponsor: LYSARC – PI: R.DelarueExternal partnership: CelgeneEudraCT number: 2017-003909-17 European centersAsian centersNLG participates with 4 centers: Aarhus, Copenhagen, Lund, Helsinki
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Summary -1
• Better definition of TFH derived lymphomas (prototype AITL), whichmay gradually become a more frequent diagnosis than PTCL-NOS
• Frequent mutations in epigenetic modifier genes, already described inmyeloid diseases, where they are mutually exclusive, while they can co-exist in AITL (TFH-TCL). These mutations can be targeted therapeutically(e.g. 5-Azacytidine, HdACi).
• AITL is the lymphoma subtype with the highest occurrence of associatedMPNs (in the same host). Common early pathogenetic events can behypothesized.
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Enteropathy-associated TCL 2008-20162008
EATL type I
Usually TCR αβ rearranged, CD8+, CD56-
Coeliac disease associatedNorthern European
EATL type II
Usually TCR γδ rearranged, CD8+,CD56+
EpitheliotropicNot associated with enteropathy
Asian, Hispanic
γδ
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Enteropathy-associated TCL 2016
EATL type I
Usually TCR αβ rearranged, CD8+, CD56-
Coeliac disease associatedNorthern European
Monomorphic epitheliotropic TCL
Usually TCR γδ rearranged, CD8+,CD56+, SETD2 mut. in 90% of pts
EpitheliotropicNot associated with enteropathy
Asian, Hispanic
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Indolent T-cell lymphoproliferative disease of the GI tract (provisional entity)
(Perry et al, Blood 2013)
• Adults, rare <20 yrs; M=F• Oral cavity, stomach, small intestine, colon• Diarrhea, pain, rectal bleeding• Chronic, indolent course• Usually no dissemination outside the GI-tract• Chemotherapy not useful
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Summary -2
• ‘Type-2 enteropathy-associated TCL’ is renamed ‘momonorphicepitheliotropic intestinal TCL’ (MEITL) due to the absence of enteropathyin these pts
• As opposed to type-1 EATL, MEITL is often CD56+ and has a mutatedSETD2 gene in 90% of the pts.
• Clinicians should be aware of the presence of these indolent GIT CD8+TCL, which rarely metastasize outside the GI tract, are often localized andchemoresistent. These pts should not be treated with combinationchemotherapy and/or stem cell transplant.
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Anaplastic Large Cell Lymphomas
• ALCL, ALK-positive• ALCL, ALK-negative (no longer provisional entity, but a definit entity)
o Differential diagnostic criteria vs CD30+ PTCL-NOS have been clarifiedo Should have similar morphology and phenotype as ALK+ALCL
• Primary cutaneous ALCL, Lymphomatoid papulosis• Breast-implant associated ALCL (now entered as provisional entity)• A majority of these tumors show activation of the JAK-STAT pathway
ALK +
ALK - CD30+ EMA+
de Leval et al, Histopathology, 2011
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Actionable mutations in sALCL within the JAK/STAT pathway
Crescenzo R, et al. Cancer Cell 2015;27:516-32
• Co-occurring somatic mutations and TF/TK fusions in STAT3+JAK1 in syst alk-ALCL>>oncogenic• JAK/STAT pathway inhibitors showed therapeutic efficacy in pre-clinical models• Phase 2 Ruxolitinib trial is ongoing
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Breast implant associated ALCLClinicopathological features
Molecular features
Seroma and cellular infiltrate
Treatment approaches
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Prognostic impact of ALK, DUSP22 and TP63 rearrangements in adult systemic ALCL
Parilla Castellar ER, et al. Blood 2014;124:1473-80
ALK, anaplastic lymphoma kinase; DUSP, dual specificity phosphatase; TP63, transformation-related protein 63; ALCL, anaplastic large cell lymphoma
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Parrilla Castellar et al (Blood 2014)
ALCL, only
• N=105 – 32 ALK positive (30%)
– 73 ALK negative (70%)
• ALK negative• N= 22 DUP22+ (30%)
• N= 6 TP63+ (8%)
• N= 45 -/-/- (62%)
Pedersen et al (Blood 2017)
PTCL-NOS, AITL, ALCL
• N= 138 – ALCL N=40
– 13 ALK positive (32%)
– 27 ALK negative (68%)
• ALK negative• N= 5 DUP22+ (21 %)
• N= 2 TP63+ (7%)
• N= 20 -/-/- (74 %)
DUSP22/TP63/triple neg: Comparison of frequency, subtype distribution and outcome
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Upfront HDT/ASCT and genetic subtype
+ HDT/ASCT (n=13)
- HDT/ASCT (n=5)
P=0.74n=18
+ HDT/ASCT (n=7)
- HDT/ASCT (n=21)
P=0.25n=28
- HDT/ASCT (n=6)
DUSP22+ ALK+ ALCL
TP63+ PTCL-/-/-
n=7
- HDT/ASCT (n=1)
(Pedersen et al, ASH abstr. Blood 2017 130:822)
n=152 P=0.036
low IPI high IPI
P=0.13 P=0.007
- HDT/ASCT
+ HDT/ASCT- HDT/ASCT
+ HDT/ASCT
Greatest benefit seems to be in high IPI pts
Upfront HDT in triple negative ALCL
- HDT/ASCT (n=73)
+ HDT/ASCT (n=79)
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Report on DUSP22 rearranged ALK-neg ALCL with less favorable outcome
Hapgood G, et al. BJH (corr) 2019, doi:10.1111/bjh.15860
5y PFS and OS: 40%
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Targeting CD30: Brentuximab vedotin in R/R ALCL
Tum
ou
r si
ze(%
ch
ange
fro
m b
ase
line
)
ORR 86% in R/R ALCL
Pro B, et al. J Clin Oncol 2012;30:2190-6
BV, brentuximab vedotin; R//R, relapsed/refractory; ALCL, anaplastic large cell lymphoma; ORR, overall response rate
CD
30
sta
inin
g
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ECHELON-2 Study Design (NCT01777152)
Key Eligibility Criteria
• Age ≥18 years
• CD30-expression (≥10% cells)
• Previously-untreated PTCL:
oSystemic ALCL (sALCL)*
including ALK(+) sALCL with
IPI ≥2, ALK(-) sALCL
oPTCL-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)
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)
Q3W for 6 to 8 cycles
*targeting 75% (±5%) ALCL
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; HSTCL, hepatosplenic T-cell lymphoma; IPI, international prognostic index
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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)
A+CHP
(N=226)
CHOP
(N=226)
Stage III/IV
disease, n (%)184 (81) 180 (80)
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)
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PFS and OS
3-yr PFS
57%44%
Events HR (95% CI) P
A+CHP 95 (42%) 0.71(0.54, 0.93) 0.011
CHOP 124 (55%)
Median PFS (95% CI)
48.2 mo (35.2, NE)20.8 mo (12.7, 47.6)
Deaths HR (95% CI) P
A+CHP 51 (23%) 0.66(0.46, 0.95) 0.0244
CHOP 73 (32%)
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Prespecified Subset Analyses: PFS
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Would like to know from the ECHELON-2 data set
• Distribution of DUSP22+ cases
• Outcome for DUSP22 rearranged, ALK-neg ALCL
• Outcome for TP63 rearranged, ALK-neg ALCL
• Outcome for triple neg ALCL
• Outcome for ALK-neg ALCL adjusted for DUSP22 and TP63
• Outcome for TFH derived TCL (AITL + PTCL-NOS with TFH phenotype)
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Crizotinib – ALK inhibitor
Parameter N
N 11
type R/R ALCL ALK+
Med prior lines of therapy
3
ORR 10/11 (91%)
2 yr OS and PFS 73% and 64%
Ph 1-2 in combination with chemotherapy–> only ALK+ ALCL
Gambacorti-Passerini C, et al. JNCI 2014; 106:2:djt378. doi: 10.1093/jnci/djt378
R/R ALCL ALK+: t(2;5) (NPM/ALK)Crizotinib monotherapy
ALK, anaplastic lymphoma kinase; R/R, relapsed/refractory; ALCL, anaplastic large cell lymphoma; NPM, nucleophosmin; med, median; ORR, overall response rate; yr, year; OS, overall survival; PFS, progression free survival; ph, phase
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Summary -3
• ALK-neg ALCL is no longer a provisional entity, but a definite one
• BIA-ALCL has been introduced as a provisional entity
• Genetic abnormalities in the JSAK/STAT pathways are often present in all subgroups of ALCL, inkl. BIA-ALCL. Clinical trial with JAK inhibitors are ongoing.
• Approx. 20-30% of all ALK-neg ALCL are DUSP22 rearranged. If this is the sole abnormality, pts haveoften a good prognosis with conventional approaches. However, cases with more aggressive clinicalbehaviour may occur.
• Approx. 7-8% of all ALK-neg ALCL are TP63 rearranged. These pts have often a very poor prognosis.
• Triple neg ALCL seem to benefit of upfront HDT, particularly those with high risk IPI.
• The ECHELON-2 trial has shown a significant outcome benefit of adding BV to a CHOP backbone inCD30+ PTCL. The benefit is primarily evident in ALCL. No information on DUSP22, TP63 and triple negstatus is currently provided.
• ALK inhibitors (e.g. crizotinib) have shown good efficacy in r/r ALK-pos ALCL. A ph 1-2 clinical trialwhere crizotinib is given in combination with chemotherapy is ongoing.
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Epidemiological and clinical features
Frequency North America andEurope: 1-5%Asia/Central-South America: >20%
Most common site
Nasal cavity/rhinopharynx
Less common Waldeyer ring, tonsils, sinuses
Other sites Skin, GIT, testes, sal.glands
EBV Stronglyassociated/driven
Quantitative p-EBVDNA is prognostic (PINK-E index, Lancet Oncol2016)
NK/T, natural killer T-cell lymphoma; p-EBVDNA, Epstein Barr Virus deoxyribose nucleic acid; PINK-E, prognostic index of natural killer lymphoma plus EBV DNA data; GIT, gastrointestinal tract; sal, salivary Kim SJ, et al. Lancet Oncology 2016;17:389-400
Extranodal NK/T cell lymphoma, nasal type
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L-asparaginase in ENKTCL: The SMILE regimen
1-yr OS 3-yr OS 3-yr PFS
All pts 55% 50% 45%
79%
Yamaguchi M, et al. J Clin Oncol 2011;29:4410-6ENKTCL, extranodal natural killer T-cell lymphoma; d, day; G-CSF, granulocyte colony-stimulating factor; SMILE, dexamethasone, methotrexate, ifosamide, L-asprarginase, etoposide; CR, complete response; PR, partial response; NR, non responder; PD, progressive disease; ED, early death; OS, overall survival; PFS, progression free survival, pts, patients
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ENKTL – CD38
• Short DoR
• Loss of target
• Maybe useful to improve QoR in
combination regimens within a
‘bridging-to-allo’ strategy
CD38 bright
CD56 bright
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Lancet Oncology 2016
➢PINK• Age >60• St III-IV• Distant l.nodes• Non-nasal sites
➢PINK-E• PINK factors• p-EBV DNA detectable
PINK-E: OS pr N of factors PINK-E: OS pr risk group
Kim SJ, et al. Lancet Oncology 2016;17:389-400PINK, prognostic index of natural killer lymphoma; PINK-E, prognostic index of natural killer lymphoma plus EBV DNA data; OS, overall survival; pr N, prognostic number; HR, hazard ratio; CI, confidence interval; St, stage; l.nodes, lymph nodes; EBV, Epstein Barr Virus
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HSTCL• Younger males• Often prior IBD and immunosuppression• Very aggressive clinical course• Marked hepato-splenomegaly• Bone marrow infiltration • Strong elevation of LDH and LFT’s• Isochromosome 7Int TCL Project J Clin Oncol 2008
• N=25• Allo SCT N=18 >> 3-yrs PFS: 48%• Auto SCT 5 of 7 relapsed
• ICE/IVAC induction preferred (MSKCC)• Median follow-up 5.5 yrs• Median PFS 13.3 mos• Median OS 59 mos
silencing
activatingactivatingactivating
McKinney M, et al Cancer Discovery 2017; doi:10.1158/2159-8290Tanase A, et al. Leukemia 2015
Voss MH, et al. Clin Lymph Myeloma Leuk 2013
The Genetic Basis of HSTCL
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Summary -4
• NK/T extranodal: improtance of L-asparaginase and EBV-DNA
• Novel therapeutic strategies are emerging (e.g.checkpoint proteininhibition, CD38 targeting)
• HSTCL is still an often refractory disease, but, if the pt is Tx eligibleand chemosensitive, upfront allo is recommended
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Ph 2 CEOP+Pralatrexate 2y PFS: 39%No obvious improvement on
historical CHOP dataAdvani et al.
Br J Haem 2015
Ph 2 R CHOP vs GEM-P
EOT-CR:CHOP 53%
GEM-P 47%(p=0.24)
1) No efficacy difference2) GEM-P: higher rate of
study withdrawals
Gleeson et al. Lancet Haematol
2018
What about ‘the rest’? CHOP/CHOEP (+/-HDT)
Design Regimen Outcome Comments Reference
Ph 2 CHOEP-14x6+ASCT 5y PFS: 44%No alk+ ALCL included
Best 5y PFS in alk-ALCL (61%)d’Amore et al.
JCO 2012
Other backbones?
Nordic Lymphoma Group
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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
JCO 2012;30(25):3093-9
60 mo median follow-up
N evaluable pts: 160
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NLG-T-01: Subtype-specific outcome (N=160)
d’Amore et al, JCO 2012
p=0.21 (logrank test)
0.0
0.4
0.2
0.6
0.8
1.0
0 12 24 36 48 60 72months
PTCL-NOS AILTAlk-negative ALCL EATL
OS, 4 major subtypes
p=0.26 (logrank test)
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60 72months
PTCL-NOS AILTAlk-negative ALCL EATL
PFS, 4 major subtypes
Histology 5-yr OS 95% CI 5-yr PFS 95% CI
ALCL 70% 50%-83% 61% 42%-76%
AILT 52% 33%-69% 49 % 30%-65%
EATL 48% 26%-67% 38 % 18%-57%
PTCL-NOS 47% 34%-59% 38 % 25%-50%
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German auto vs allo trial (AATT)
Schmitz N, et al. ICML 2015;abstract 33
Trial cohort
All Auto Allo
Randomized (tot) 104 --- ---
Interim analysis 58 30 28
Efficacy
All Auto Allo
ORR 51% 53% 50%
1y EFS 41% 48% 48%
1y OS 69% 61% 55%
This analysis showed no significant differences in survival for pts randomized to autoSCT or alloSCT.After interim futility analysis,…the DSMB/PIs decided to prematurely stop patient accrual.
ALLOGENEIC OR AUTOLOGOUS TRANSPLANTATION AS FIRSTLINE THERAPY FOR YOUNGER PATIENTS WITH PERIPHERAL T-CELL LYMPHOMA—RESULTS OF THE INTERIM ANALYSIS OF THE AATT TRIAL
Authors’ statement
Main problems: 1) 38% not reaching consolidative SCT2) GvL-effect of allo counterbalanced by high TRM
AATT, autologous allogeneic, transplantation trial; auto, autologous; allo, allogeneic; tot, total; ORR, overall response rate; y, year; EFS, event free survival; OS, overall survival; SCT, stem cell transplantation; GvL, graft verses lymphoma; TRM, treatment related mortality; pts, patients; DSBM, Data and Safety Monitoring Board, PI, principal investigators
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Horwitz S, et al. ASH 2018, abstr. #997d’Amore F, et al. ASH 2018;abstr. #998
Trümper L, et al. ASCO 2016; abstr.#7500 d’Amore F, et al. J Clin Oncol 2012;30:3093-9
4Schmitz N, et al. ICML 2015;abstract 33
Largest prospective upfront trials in PTCL
Study Type Design N pts Reference
ECHELON-2 (CHOP +/- BV ) CIS Ph 3 452 Final analysis ASH 2018
Nordic ACT-1 (younger) (CHOP+/- ALZ) IIS Ph 3 131 Final analysis ASH 2018
German ACT-2 (elderly) (CHOP+/- ALZ) IIS Ph 3 116 Final analysis ASCO 2016
Nordic NLG-T-01 (CHOEP+auto) IIS Ph 2 160 J Clin Oncol 2012
German (allo vs auto) IIS Ph 3 104 Stop at 1st interim-ICML 2015
Nordic Lymphoma Group
CIS= company-initiated studyIIS= investigator-initiated study
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2 yr
12%
7-10 yrs
Refractory Chemosensititve, but eventually relapsing
Long-term remission
18%
~40%
~30%
End of induction,
consolidation7 yrDiagnosis
d’Amore F, et al. J Clin Oncol 2012;30:3093-9 d’Amore F, et al. Ann Oncol 2015; 26 Suppl 5:v108-15
Response patterns in PTCL after 1st line treatmentNordic Lymphoma Group
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Summary - 5
• Auto Tx: The role of upfront ASCT in PTCL is debated. However,while new treatments are being developed it is still recommendedin chemosensitive patients particularly those with high risk IPI.
• Allo Tx: Good GvL effect, but still burdened by toxicity problems.Recommended upfront in very aggressive subtypes such as HSTCL.Otherwise, useful tool in relapsed Tx eligible pts.
• What have we learned from the large PTCL IITs? 1/3 of pts relapsesearly, some due to refractory disease, others due to frailty andsubsequent dose erosion. 1/3 completes induction in remission,but relapses either early (<2y=20%) or late (>2y=10%). The lastthird will be in long term CR.
New drugs
Improve PS
MRD, consolidate/maintain
MRD, consolidate/maintain
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Ref Compound ORR Approved Upfront ph3 trials
Enblad, Blood 2004 Alemtuzumab (CD52) 36% - ALZ-CHOP
O’Mahony, CCR 2009 Siplizumab (CD2) 31% -
O’Connor, ASCO 2013 Belinostat 26% US
d’Amore, BJH 2010 Zanolimumab (CD4) 26% -
O’Connor, JCO 2011 Pralatrexate 29% US
Coiffier, JCO 2012 Romidepsin 25% US RO-CHOP
Foss, ASCO 2010 Denileukin Diftitox 40% -
Pro, JCO 2012 Brentuximab vedotin (CD30) 86% (ALCL) US, EU CH[O]P+/-BV
Ogura, JCO 2014 Mogamulizumab (CCR4) 34% -
O’Connor, JCO in press Alisertib 24% -
Horwitz, ASH 2014 Duvelisib 47% -
Passerini, JNCI 2014 Crizotinib 90% (alk+ALCL) US (BTD)
Novel agents tested as monotherapy in R/R PTCL Nordic Lymphoma Group
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ACT-1
RANDOMIZATION
6 x CHOP-14+ autoSCT
6 x CHOP-14with ALZ
+ autoSCT
RANDOMIZATION
6 x CHOP-146 x CHOP-14
with ALZ
ACT-2
Trümper et al. ASCO 2016
Trial designNordic Lymphoma Group
ALCL, regardless of alk status, NOT included!
Slow accrual (N=136 pts, 44% of planned sample)
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CR and PD ratesNordic Lymphoma Group
CR rate PD rate
CHOP 42 42
ALZ+CHOP 52 23
0
10
20
30
40
50
60
%
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Months
Pro
po
rtio
n
0 10 20 30 40 50 60 70 80 90 100 110
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
6 x CHOP-14
(n=66)
6 x CHOP-14 + A
(n=65) p=0.448
Primary endpoint: EFSNordic Lymphoma Group
RNA seq analysis revealed molecularfeatures predictive for ALZ response
(next talk)
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Summary of subtype specific treatment featuresEntity/subtype Subtype-specific treatment feature
AITL/TFH 5-aza, HdAC
BIA-ALCL Do not omit surgical implant removal
ALK+ALCL @CD30, crizotinib
ALK-ALCL @CD30, DUSP22, TP63, JAK/STAT
ALCL triple neg CHOEP+HDT, @CD30
NK/T L-asparaginase
HSTCL alloTx upfront in eligible pts
PAR+ PTCL Low-dose ALZ+CHOP schedule
PAR: Predictor for alemtuzumab response; 5-aza: 5-azacytidine; HDT: High-dose therapy; BIA: Breast implant associated