Peripheral T-cell Lymphomas Seok Jin Kim MD, PhD

Department of Medicine

Sungkyunkwan University Samsung Medical Center

T-cell and NK cell subsets

αβ T-cells CD4+ (mainly helper) or CD8+ (mainly cytotoxic)

γδ T-cells CD4-CD8- or CD4-CD8+

NK cells Usually CD4-CD8-, but may be CD8+ NK-associated antigen: CD11b, 16, 56, 57

Immune system

Innate immune system Primitive defense system in mucosa and skin NK-cells and γδ T-cells γδ T-cells: < 5% of normal T cells Splenic red pulp, intestinal mucosa, other epithelial

sites

Adaptive immune system αβ T-cells: majority of normal T cells Recognition of MHC-restricted antigen

T-cell differentiation

Jaffe ES. Blood 2008

Extranodal presentation

Children/adults

Nodal presentation

More often

adults

Question 1

Adaptive immune system is 1) αβ T-cells 2) NK-cells 3) γδ T-cells 4) I don’t know 5) I don’t care

Peripheral T-cell lymphoma

Nodal

Extranodal Cutaneous

Disseminated and leukemic

Peripheral T-cell lymphomas Nodal Peripheral T-cell lymphoma, not otherwise

specified (PTCL-NOS) Angioimmunoblastic T-cell lymphoma (AITL) Anaplastic large cell lymphoma (ALCL)

Extranodal Extranodal NK/T-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Hepatosplenic T-cell lymphoma

• Cell origin • αβ T-cells; γδ T-cells; NK cells

Nodal PTCL

ALCL, ALK+

Common in 10-30s Mostly stage III/IV

Lymphadenopathy Bone, skin, soft tissue, lung, liver Common B Sx

Recurrent genetic alteration: ALK+ ALK gene (2p23) with others e.g. NPM1 (5q35) NPM-ALK translocation: constitutive activation of ALK

tyrosine kinase Therapeutic target

Good prognosis with 5-yr OS: 70-80%

ALCL, ALK+

Pathology ‘Hallmark cells’ with

horseshoe-shaped nuclei and ALK/CD30+ Cytoplasmic and nuclear ALK+

Membraneous CD30+

Nodal PTCL

ALCL, ALK-

Same morphology without ALK Age: 40 – 65 years Nodal invasion is more common than

extranodal invasion Pathology CD30: homogeneous strong positive

Differential diagnosis with HL PAX5: positive for HL

Overall Survival of ALCL

ALK +

ALK -

Nodal PTCL

T follicular helper cells (TFH)

Located in germinal center (GC) Interact with GC B-cells Contribute to high-affinity plasma cell/memory B

cells

Involved chemokine/receptor IL-21, CXCL13 for B-cell recruitment/activation CXCR5: receptor to CXCL13 Positive for PD1

AITL

De-novo T-cell lymphoma derived from αβ T-cells of follicular helper type (TFH)

Median age: 65, M:F = 1:1 No case in children

Advanced disease presentation Lymphadenopathy, hepatosplenomegaly Skin rash with pruritus Polyclonal hypergammaglobulinemia with

autoimmune phenomenon

AITL

Neoplastic cells positive for PD1

CD21 positive perivascular follicular dendritic cell (FDC)

meshwork

Endothelial venules

Nodal PTCL

PTCL, NOS 25% of all T-cell lymphomas Diagnosis of exclusion Similar to DLBCL, NOS

Mature T-cell phenotype Mostly, CD4 +

Clinical features Median age: 60, M:F = 2:1 Nodal presentation: ~90% Extranodal presentation: ~10%

Skin, GI tract

Question 2

What is correct about AITL? 1) More common in 40-50 year-old male 2) Combined with monoclonal gammopathy 3) Follicular helper γδ T-cells origin 4) PD1-positive neoplastic T cells 5) Loss of CD21+ follicular dendritic cell

(FDC) meshwork

Treatment of nodal PTCL Clinical trial (Preferred)

ALCL, ALK+

- CHOP-21, CHOEP-21

Other histology (ALCL, ALK-; PTCL, NOS; AITL; EATL)

- Preferred regimens (in alphabetical order)

CHOEP, CHOP-14, CHOP-21

Dose-adjusted EPOCH

- Alternative regimens (in alphabetical order)

CHOP followed by IVE (ifosfamide, VP16, epirubicin) alternating

with intermediate-dose MTX

HyperCVAD alternating with high-dose MTX and cytarabine NCCN Guideline v.2. 2015

Question 3

A 57-year old male (newly diagnosed ALK-negative ALCL, stage II) achieved CR after 6 cycles of CHOP. What would you do next?

1) Observation 2) Involved field radiotherapy 3) Autologous stem cell transplantation 4) Allogeneic stem cell transplantation 5) Clinical trial with maintenance therapy

Question 4

A 57-year old male (newly diagnosed ALK-negative ALCL, stage IV) achieved CR after 6 cycles of CHOP. What would you do next?

1) Observation 2) Involved field radiotherapy 3) Autologous stem cell transplantation 4) Allogeneic stem cell transplantation 5) Clinical trial with maintenance therapy

Treatment of nodal PTCL

NCCN Guideline v.2. 2015 Localized areas can be irradiated before or

after ASCT

First-line consolidation: SCT

Consolidation with high-dose chemotherapy and stem cell rescue should be considered

Patients with low IPI ALK+ ALCL in remission do not need consolidative transplant

NCCN Guideline v.2. 2015

Auto-SCT (n = 128)

Non-auto-SCT (n = 124)

5-yr OS (%) 48 26 5-yr PFS (%) 41 20

Clin Cancer Res; 20(20); 5240–54.

Extranodal PTCL

Extranodal NK/T-cell lymphoma, nasal type

Mainly upper aerodigestive tract EBV in situ +, CD56+, surface CD3-,

cytoplasmic CD3Ɛ+ Extranasal involvement: poorer prognosis Mainly NK cell origin, some cytotoxic T cell Synonyms Angiocentric T-cell lymphoma Malignant midline reticulosis Polymorphic reticulosis, Lethal midline granuloma

ENKTL

Treatment of extranodal NK/T-cell lymphoma

L-asparaginase-based combination chemotherapy AspaMetDex; SMILE

Concurrent chemoradiotherapy CCRT plus DeVIC or VIPD

Sequential chemoradiation SMILE or VIPD followed by RT

RT alone

NCCN Guideline v.2. 2015

Treatment of extranodal NK/T-cell lymphoma

NCCN Guideline v.2. 2015 Allogeneic SCT preferred, if matched donor available

Enteropathy-associated T-cell lymphoma Aggressive lymphoma with poor prognosis Intraepithelial T-cells of the intestine

Type 1 Type 2

Frequency 80-90% 10-20%

Morphology Variable Monomorphic

CD8 Mostly Negative Mostly Positive

CD56 Negative (> 90%) Positive (> 90%)

Geographic Northern Europe World wide

Underlying disease Celiac disease No celiac disease

Location > 90% jejunum/ileum > 90% jejunum/ileum

8q24 (MYC) 27% 73%

Intraepithelial lymphocytosis

Am J Gastroenterol 2010; 105:2103–2110

Question 5

What is correct about type II EATL? 1) More common in northern Europe 2) Combined with Celiac disease 3) Mostly intraepithelial γδ T-cells origin 4) CD8-negative/CD56-negative neoplastic

T cells 5) More frequent MYC amplification

Hepatosplenic T-cell lymphoma Aggressive lymphoma

originating from γδ cytotoxic T-cells (rarely, αβ T-cells)

Adolescents and young adults Strong male predominance Risk group Chronic antigenic stimulation Immunosuppression Crohn’s disease treated with IST

HSTL

Clinical features Systemic symptoms, thrombocytopenia, marked

hepatosplenomegaly Absence of lymphadenopathy

Prognosis Survival < 3 years Rapid relapse and fatal outcome even if very

good response to initial therapy

Peripheral T-cell lymphomas

Cutaneous Mycosis fungoides/Sezary syndrome Primary cutaneous CD30+ T-cell lymphoma Primary cutaneous anaplastic large cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Primary cutaneous γδ T-cells lymphoma Primary cutaneous CD8+ aggressive epidermotrophic

cytotoxic T-cell lymphoma

• Cell origin • αβ T-cells; γδ T-cells; NK cells

세조

세조는 꾸준한 온천 행궁에도 고질적인 피부병에 차도가 없었으며 결국 피부병과 정신질환이 악화돼 죽음을 맞았다.

천태종 구인사 벽화

Mycosis fungoides

Mycosis fungoides Definition Epidermotropic primary cutaneous T-cell lymphoma Infiltration of T-cells with cerebriform nuclei Skin lesion: patch, plaque and tumor

Indolent Clinical features Widespread skin lesion with slow progression Sometimes visceral involvement

Poor prognosis Advanced stage, Tumor stage Extracutaneous invasion

Sezary syndrome Triad Erythroderma Generalized lymphadenopathy Neoplastic T-cells with cerebriform nuclei (Sezary

cells) in skin, lymph nodes and blood Additional hematologic features: at least one Absolute Sezary cell count ≥ 1000/mm3

CD4/CD8 ratio > 10 Aggressive 5yr OS 10-20%, Opportunistic infection

MF vs. SS

Mycosis fungoides 50% of CTCL Adults/elderly Male CD4 T-cell origin Similar morphology Indolent

Sezary syndrome 5% of CTCL Over 60 years Male CD4 T-cell origin Similar morphology Aggressive

Treatment for MF/SS Skin Directed

Topical steroids

Topical nitrogen mustard: mechlorethamine

Topical bexarotene gel

Phototherapy

– NBUVB

– PUVA

Radiation therapy

– Total skin electron beam

– Localized electron beam

Systemic

Bexarotene capsules

Vorinostat capsules

Methotrexate

Interferon

Extracorporeal photochemotherapy

Denileukin diftitox

Single-agent chemotherapy

Combination chemotherapy

Subcutaneous Panniculitis like T-cell lymphoma

Wide age distribution Median age: 35 years

Subcutaneous nodules on extremities and trunk

Pathology Subcutaneous lesion sparing dermis CD8+, CD56- Originating from cytotoxic αβ T-cells Positive cytotoxic markers: TIA1, perforin, granzyme B

SPTCL

Combined with autoimmune disease ~20%: e.g. SLE

Combined with hemophagocytosis ~15-20%, severe cytopenia and liver dysfunction Poor prognosis

Lymph node invasion and other sites involvement are rare

Relatively good prognosis 5-yr OS > 80%

Primary cutaneous ALCL Same morphology with ALCL, ALK- Cutaneous tumors of anaplastic large cells with

CD30 positivity Excellent prognosis: > 90% of 5-yr OS Regional LN involvement: not necessarily indicate

aggressive course Treatment strategy Local therapy: Main treatment modality Systemic therapy Watch and wait: Spontaneous regression is possible

Primary cutaneous ALCL

Peripheral T-cell lymphomas

Disseminated/leukemic T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorders of NK cells Aggressive NK cell leukemia EBV-positive T-cell lymphoproliferative disease Adult T-cell leukemia/lymphoma

• Cell origin • αβ T-cells; γδ T-cells; NK cells

T-cell prolymphocytic leukemia

Alemtuzumab

Aggressive NK-cell leukemia

Systemic neoplastic proliferation of NK cells Almost always associated with EBV

Young to middle-aged adults NK cell origin Involved sites PB, BM, liver, spleen

Manifestation Fever, constitutional symptoms

Aggressive NK-cell leukemia

Lab Leukemic blood picture: low or high leukemic cells Pancytopenia with hemophagocytosis Markedly elevated serum LDH Coagulopathy

Pathology Identical to ENKTL

Prognosis Extremely poor: < 2 years

Question 6 : ANKL vs. ENKTL stage IV

What is more close to ANKL than ENKTL? 1) Older age 2) More frequent skin invasion 3) Lack of CD16 expression 4) Better outcome 5) Markedly elevated serum LDH

Outcome of relapsed/refractory PTCL

Poor progression-free survival (median, 3.7 months) and overall survival (median, 6.5 months) of PTCL patients after first relapse or progression

J Clin Oncol 2013; 31: 1970-1976

New agents for relapsed PTCL Drug Subtypes n ORR/CR

PFS/DOR

(months)

Prior

therapies

Pralatrexate PTCL, 53%; ALCL, 15%

AITL, 12%; tMF, 18% 111 29%/19% 3.5/10.1 3 (1–13)

Romidepsin PTCL, 53%; AITL, 21% 130 26%/15% 4/16 1 (1-8)

Brentuximab PTCL, 57%; AITL, 37% 35 41%/23% 6.7/2.6 2 (1-9)

Bendamustine AITL, 53%; PTCL, 38% 60 50%/28% 3/6.6 1 (1-3)

Belinostat PTCL, 64%; AITL, 18%

ALCL, 10% 129 25.8%/10.8% 1.6/13.6 2 (1-8)

Alisertib PTCL, 30%; AITL, 21%

tMF, 16%; ATLL, 10% 42 24%/5%

3/not

reached 3 (1-18)

Pralatrexate

Dihydrofolate reductase inhibitor Higher affinity for

reduced folate carrier type-I than MTX

Higher intracellular concentration and potency

Romidepsin Cyclic peptide Intravenous agent HDAC class I target FDA approval: Relapsed CTCL/PTCL after at

least one prior systemic chemotherapy

Overall therapeutic effect Induction of apoptosis, cell cycle arrest,

autophagy, immune modulation etc

Romidepsin in ENKTL

Kim SJ, et al, In submission, Unpublished data

Brentuximab vedotin

Drug conjugated CD30 monoclonal antibody FDA approval:

Relapsed ALCL after systemic chemotherapy

Treatment of relapsed/refractory PTCL

- Clinical trial (Preferred)

- Bendamustine, Belinostat, Bretuximab vedotin

- DHAP, ESHAP, Dose-adjusted EPOCH

- GDP (gemcitabine, dexamethasone, cisplatin)

- GemOx (gemcitabine, oxaliplatin)

- ICE (ifosfamide, carboplatin, etoposide)

- Pralatrexate, Romidepsin

- Alemtuzumab, Bortezomib, Gemcitabine (Only for non-

candidate for hiogh-dose chemotherapy) NCCN Guideline v.2. 2015

CR1 PR/primary induction

failure

Chemosensitive relapse Chemorefractory

relapse

More than CHOP? Study Alemtuzumab

-CHOP Bortezomib

-CHOP Bevacizumab

-CHOP Denileukin

-CHOP Everolimus

-CHOP

Treatment

CHOP-14 alemtuzumab 30 mg/day on d 1, 5, 10

CHOP-21 bortezomib 1.6 mg/m2 on d 1, 8

CHOP-21 bevacizumab 15 mg/kg on d 1 Maintenance : bevacizumab 15 mg/kg on day 1 q 3 weeks

CHOP-21 on d 3-7 denileukin diftitox 18 μg/kg/day on day 1, 2

CHOP-21 everolimus 5 mg/day on d 1-14

Number 20 46 39 49 30 Study period 2005-2007 2007-2009 2006-2009 2004-2009 2011-2013 Median follow-up 29 months 41 months 36 months 22 months 35 months

Planned number of cycles 8 6 8 6 6

Objective response rate 90% (18/20) 76% (35/46) 90% (35/39) 65% (32/49) 90% (27/30)

CR rate 65% (13/20) 65% (30/46) 49% (19/39) 55% (27/49) 57% (17/30) Median PFS 10 months 9 months 8 months 12 months 11 months 2-year PFS 27% 37% (2-year) 25% (2-year) 43% 33% Median OS 27 months 27 months 22 months Not reached Not reached 2-year OS 55% 52% (2-year) 42% (2-year) 65% 70%

Ongoing study for newly diagnosed PTCL

Romidepsin-CHOP (Ro-CHOP) vs CHOP Estimate number: 420 over 43 months

Pralatrexate vs. Observation following CHOP Pralatrexate IV 30 mg/m2 weekly for 3 weeks of a 4-

week cycle (n = 549) Brentuximab/CHOP for CD30-positive mature

T-cell lymphomas Comparison of Brentuximab/CHP with CHOP

Take Home Message

Problems of PTCL Heterogeneous subtypes Efficacy of induction therapy: unsatisfactory Efficacy of SCT: auto vs. allo

Development of novel drugs Expansion of new indication Combination with other drugs

Identification of newer therapeutic targets is warranted