T Cell Lymphoma

Question 1

What is the immunophenotype of AITL?

Answer 1

CD3, CD4
+/- BCL6, CD10

May lose a subset of pan T-cell Antigens
=CD2, CD3, CD5, CD7

Question 2

What are the 2 types of Enteropathy-associated T ell lymphoma

Answer 2

Type I:

• Typically express CD3, but do not express CD4
• Mostly CD8-
• Large cells within tumor infiltrate CD30+
• TCR Beta gene is clonally rearranged.
• Many with a HLA haplotype-associated with celiac disease
• 50-60% have complex segmental amplification of the 9q34 region

Type II:

• CD8+, CD56+, TCR Gamma-delta+
• often with application of c-myc 8q24

Question 3

Most common T Cell Lymphoma?

Answer 3

PTCL, NOS

ALCL

AITL

EN NKT Cell

Question 4

What are the common cytogenetic changes typical/diagnostic of AITL?

Answer 4

Trisomy 3, 5

Additional X chromosome

Question 5

What is the Follicular Denditrtic Cell Network?

Answer 5

CD21, CD23, CD35

Usually present in AITL

Question 6

What are the differentials for AITL?

Answer 6

Other PTCLs
Hodgkin’s Lymphoma
EBV+ DLBCL, NOS

Question 7

How is AITL distinguished from other PTCLs?

Answer 7

CD10+
CXCl13+
PD-1+
FDC mesh work present (CD21, CD23, CD35)

Question 8

Tell me about Breast implant associated ALCL

Answer 8

Emerging entity
Described as development of ALCL around the implant (involving the fibrous capsule and/or Serena only)

Natural Hx appears generally more favorable with surgical removal to he implant alone as adequate therapy for most

Rare cases with parenchymal breast or nodal involvement may have an aggressive course more in line with systemic ALK-positive ALCL

Optimal treatment not well-defined, management should be individualized

Question 9

What is the Newcastle regimen?

Answer 9

CHOP –> IVE (Ifosfamide, Etoposide, epirubicin), alternating with intermediate dose MTX

• used only in patients with EATL
• includes HSCT

Question 10

What are the options for first line treatment of PTCL?

Answer 10

No standard treatment

Clinical trial is an option

If ALCL, ALK+,

• CHOP-21
• CHOEP

Other histologically:

• CHOEP
• CHOP-14
• CHOP-21
• DA-EPOCH
• CHOP-IVE
• HyperCVAD

1s line-consolidation

• to consider with high-dose therapy and stem cell rescue
• patients with low IPI ALCL, ALK+ disease in remission do not need Consolidative transplant

Question 11

What are the possible 2nd-line treatment options for TCL that are single agents?

Answer 11

Belinostat
Brentuximab for CD30+ PTCL
Pralatrexate
Romidepsin

Question 12

What are the available combination regimens for PTCL?

Answer 12

DHAP (Dexa, CDDP, Cytarabine)
ESHAP(Etoposide, Methylprednisolone, Cytarabine, CDDP)
GDP (Gem, Dexa, CDDP)
GemOx (Gem, Ox)
ICE (Ifosfamide, Carboplatin, Etoposide)

Question 13

Give me examples of primary nodal PTCLs

Answer 13

PTCL-NOS
ALCL - ALK+/ALK-
AITL

Question 14

Give me examples of primary Extranodal PTCL

Answer 14

Enteropathy-associated TCell lymphoma (EATL)
Extranodal-natural killer/T-Cell lymphoma (ENKTCL)
Hepatosplenic T cell lymphoma (HSTCL)

Question 15

What is the general epidemiology of PTCLs?

Answer 15

Uncommon and heterogenous
Originate from post-thymic (peripheral) T cells or mature NK Cells

10-15% of all NHL
Male: Female 2:1
Median age 6th to 7th decade
Both sex & age patterns vary according to different subtypes.

Some association with certain conditions:
EBV - ENKTCL
Celiac disease - EATL
Crohn’s - HSTCL

Question 16

What suggests that a given T-cell population is neoplastic?

Answer 16

1) Morphology
2) Aberrant T-Cell phenotype
3) Clonally rearranged T-Cell receptor (TCR) genes (alpha-beta vs gamma-delta)

Question 17

What is the presumed cell of origin for:

1) PTCL-NOS
2) AITL
3) ALCL

Answer 17

1) PTCL-NOS : variable, mostly T-helper cell
2) AITL : Follicular T-helper
3) ALCL : Cytotoxic T cell

Question 18

What suggests a cytotoxic profile?

Answer 18

TIA1, granzyme B, perforin

Question 19

What is the difference in immunophenotype between EATL Type I and II?

Answer 19

EATL Type I = CD8+/CD56-
EATL Type II = CD8-/CD56+

Type II is also not a/w pre-existing enteropathy

Question 20

What is the immunophenotype of ALCL?

Answer 20

CD30+, PAX5-, EMA+
1/3: CD45-

If t(2:5) present, ALK+

Question 21

What are the staging blood tests required?

Answer 21

FBC
Routine blood chemistry
LDH, Uric acid
HIV, HTLV-1, Hep B/C

Question 22

What is the management of HSTCL?

Answer 22

One of the worst prognoses. 5y OS and FFS

Question 23

What is the treatment for ENKTCL?

Answer 23

1st line - L-asparaginase containing regimens eg. SMILE and AspaMetDex
CHOP or CHOP-like tx not effective

Localized disease = Addition of RT to chemo

Stage I/II = concurrent = sequential
- RT ~>50Gy, but if radiosensitizers used, 40Gy
CNS prophylaxis not recommended
HDCT –> transplant controversial

Stage III/IV: L-asparaginase-containing regimens preferred. IF CR, then HDC with HSCT

Relapse:
Repeat biopsy
After anthracycilne-based –> L-asparagine see regimens –> gemcitabine-based –> auto/also transplant

Question 24

What are the treatment options for EATL?

Answer 24

1st line:
Outcome after standard CHOP poor
If can tolerate more aggressive chemo, IVE/MTX = Ifosfamide/vincristine/Etoposide/MTX
- this is followed by autoSCT.

CHOEP-14–>autoSCT

Relapse: no evidence. Consider allo.

Question 25

What is the treatment for nodal PTCL?

Answer 25

1) CHOEP - those 60yo or younger. With older patients, toxicity is a limiting factor. - consolidated by AutoSCT 2) localized Stage I disease: shortened chemo, followed by local RT 3) Brentuzimab in relapse - ORR 86% with CR rate 60% and median response duration 12.6m - can serve as a bridge to transplant as well

Question 26

What is the most common T Cell Lymphoma?

Answer 26

1) PTCL 2) AITL 3) NKTCL In Asia, PTCL-NOS and NKTL are almost as equally common

Question 27

What is the average 5y OS for the TCell Lymphomas 1) Cutaneous ALCL 2) ALK+ALCL 3) Nasal NK 4) PTCL-NOS 5) ALK-ALCL 6) Extranasal NKT

Answer 27

1) Cutaneous ALCL 90% 2) ALK+ ALCL 60% 3) Nasal NKT 40% 4) PTCL-NOS 35% 5) ALK-ALCL 35% 6) Extranasal NKT 10%

Question 28

Tell me about AITL

Answer 28

1) Age: middle-aged to elderly 2) P/w: generalized LAN, HSM, prominent systemic symptoms 3) Bloods: Polyclonal Ig increase, hemolytic anemia, cold agglutinin, cryoglobulinemia 4) Morphology: polymorphic infiltrate of small-medium lymphocyte with clear cytoplasm. Arborizing high endothelial venules. Proliferation of Follicular dendritic cells 5) IHC: CD4+, loss of pan TCell Ag uncommon. CD20+, CD10+, BCL6+

Question 29

Tell me about PTCL-NOS

Answer 29

1) Age: 60yo 2) P/w: nodal involvement. Can be a combination of nodal and Extranodal involvement. Majority p/w advanced disease 3) Morphology: inter follicular, diffuse infiltrates. Medium-large cells, multilobulated forms with prominent nucleoli and focal necrosis. 4) IHC : CD2, D3, CD5, CD7, - most single CD4+ or less often CD8+ - sometimes CD4- CD8-, rarely both positive - >85% express TCR alpha-beta.

Question 30

What are the different patterns of AITL?

Answer 30

Pattern 1: Hyperplastic GC Pattern 2: Regressed GC Pattern 3: Effaced GC Patterns 2 &3 a/w with worse survival outcome.

Question 31

What are the common molecular aberrations in AITL?

Answer 31

TET2 mutation 80% DNMT3A mutation 30% IDH2 mutation 20% RHOA mutation 70%

Question 32

Tell me about ALCL

Answer 32

1) Age: ALK+ most frequent in 1st 3 decades with male predominance - ALK+ with better prognosis 2) p/w: mostly with advanced stage and B symptoms 3) Morhpology: Large cells, horse-shoe or kidney-shaped nuclei. Donut cells tat appear to have cytoplasmic inclusions 4) IHC: - ALK+ ALCL: EMA+ CD3-

Question 33

Describe NKTCL

Answer 33

``` Asians/South Americans 53yo Male>Female Nasal cavity + other regions of upper aero digestive tract, skin, GI, Testis, soft tissue Aggressive tumor with poor prognosis ``` Morphology : small--> Moderate --> Large cells Angiocentric growth IHC: - CD2+ ,surface CD3-, cytoplasmic CD3+, CD56+ - CD4, CD8, TCR alpha-beta, TCR gamma-delta negative - TIA-1, granzyme B, Perforin usually positive - EBER +

Question 34

What are the first-line therapeutic options available for ALCL, ALK+?

Answer 34

CHOP-21 CHOEP-21 Low IPI ALCL, ALK+ disease in remission, do not need Consolidative therapy.

Question 35

What are the therapeutic options available for other T Cell lymphoma (excluding ALCL ALK+)

Answer 35

CHOEP CHOP-14 CHOP-21 CHOP--> IVE (Ifosfamide, Etoposide, epirubcin) alternating with intermediate dose methotrexate >> known as the Newcastle regimen, but studied only in EATL patients HyperCVAD alternating with HD MTX/Cytarabine Consider consolidation with HD Therapy and stem cell rescue

Question 36

What is Denileukin diffitox?

Answer 36

Denileukin Diffitox is a fusion protein that combines fragments of diphtheria toxin with IL2. IL2 domain targets tumor cells bearing IL2 receptor.

Question 37

What are the risks a/w Denileukin Diffitox?

Answer 37

Infusion reaction Neutropenia Rhabdomyolysis

Question 38

What is Denileukin Diffitox best used for?

Answer 38

AITL. ORR 80%

Question 39

What is the BENTLY trial?

Answer 39

Damaj JCO 2013 Ph II R/R TCL,

Question 40

What are the FDA approved agents for R/R PTCL?

Answer 40

Pralatrexate Romidepsin Belinostat Bendamustine

Question 41

Tell me about Romidepsin

Answer 41

Coiffier JCO 2012 ``` 2 prior lines of treatment N=130 ORR 25% with CR 15% Median duration of response 17m Med PFS 4m ```

Question 42

Tell me about pralatrexate

Answer 42

It is an anti-folate agent Binds DHFR and presents dihydrofolate coversion to tetrahydrofolate. Tetrahydrofolate is required for purine/pyrimidine and aa synthesis.

Question 43

Why does conventional chemotherapy not work well in PTCL?

Answer 43

1) Higher rate of primary refractory disease 2) Higher rate of relapse disease 3) Lack of efficacy of anthracyclines

Question 44

What is the NKT cell Lymphoma prognostic index?

Answer 44

S.L.A.B Serum LDH > Normal LN - N1 to N3, not M1 Ann Arbor Stage IV B symptoms ``` No of risk factors Low - 0 Low intermediate - 1 High intermediate - 2 High - 3 or 4 ```

Question 45

What are the treatment options available for Extranodal NKT cell Lymphomas?

Answer 45

1) Combination chemotherapy 2) Concurrent CRT 3) Sequential ChemoRT 4) Sandwich ChemoRT 5) RT alone 1) Combination chemo: - SMILE - AspaMetDex - GELOX 2) Concurrent ChemoRT - DeVic protocol (RT 50Gy, Chemo3#) - VPD 3) Sequential ChemoRT - For stage I, II SMILE --> RT 4) Sandwich CHemoRT - GELOX 2# --> RT --> GELOX 2-4# 5) RT alone