non Hodgkins lymphoma ultra short review .pptx

short review of dlbcl

1. Riya Bakar

WHO classification 2016/ICC 2022 and WHO Haem 5 revisions

Diffuse large B-cell (NOS) BE ot NHL DrKannan S
Germinal Centre B-cell type

Activated B-cell type

EBV+ DLBCL, NOS
EBV+ mucocutaneous ulcer

Primary mediastinal lymphoma

Intravascular large B-cell lymphoma

Primary effusion lymphoma

Plasmablastic lymphoma

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6
rearrangement

Ibal

Gopinathan M

Kalpesh Pam.

2. Riya Balikar

Rapidly growing mass of anterior mediastinum Drkamans
Frequent el ncy presentation

+ Bulk common
amitkhurana

+ Young patient po
TYA
+ Female predominance (2:1)

pulation (median age 35)..many

+ Diagnos

a result of symptoms compressing

mediastinal structures. SVCO present in 40%

+ Recurrent laryngeal nerve palsy with hoarse

voice inathan M

+ Breast swelling

Cough/chest pain/dyspnoea/dyspha

Kalpesh Pam.

3. Riya Balikar

Origins in thymic B-cells

Thymic B-cells

amitkhurana

| Grey zone

lymphoma
Asi eal

Classical NS Primary

Hodgkin mediastinal

| Om: lympl homa

4. Pathology

Cytologically resembles many
‘other large B cell lymphomas

Large transformed cells
resembling centroblasts.

‘Abundant pale cytoplasm
Diffuse involvement

Areas of fine
‘compartmentalising sclerosis

Expression of B-cell antigens: CD20 and
CD79a positive, but lack sig

Evidence of somatic hypermutation
CD30 often present (>80%), typically weak
CD23: Frequent (73%)

BCL2: variable (50-80%, no t(14;18))

BCL6: variable (45-100%)

CD10: less common (8-30%)

CD15: almost always negative

MAL (70%) - normal expression in thymic
medullary cells, CD54, CD95, nuclear REL,
TRAF

Riya Balikar

DrKannan S

amitkhurana

LA

As lgbal|

Kalpesh Pam.

5. Riya Balikar

Comparing the diseases

EEES

Drkannans

Gender F>M F>M M>F arittizara
svco Rare Common Sometimes =
Morphology R-Scells Large cellsin Pleomorphic | E ml

uniform sheets large cells +/-RS

cells staal

Inflammatory Copious Absent Sparse
cells
Sclerosis Large bands Fine bands Focal bands

Kalpesh Pam,

6. Riya Balikar

Comparing the diseases

DrKannan S

Gender F>M F>M M>F mita
svco Rare Common Sometimes
Morphology R-S cells Large cellsin Pleomorphic.

uniform sheets large cells +/- RS

cells

Inflammatory Copious Absent Sparse
elle vaarun
Sclerosis Large bands Fine bands Focal bands

Kalpesh Pam.

7. Immunophenotype

LA A Tu

ri

cDas + variable
cD30 + +weak +

cp1s + E + variable
cD20 2 + +

sig a E

PAX-5 +weak + +
BOB-1/OCT-2 - + +

MAL 20% 70% 40%

Er
I N nl

Kalpesh Pam.

8. Genomic
aberrations

Frequent gains of 2p and 9p
including JAK2 (9p24)(75%) and
REL (2p16)(70%)

Few regions of genomic loss
(median size of loss 6 Mb
compared to 30 Mb gains)

Rare BCL2 or BCL6
rearrangements, unlike DLBCL

Bea, S. Blood 2005;106:3183-3190

Riya Balikar
DrKannan S
amitkhurana

|

Asif bal

Kalpesh Pam.

9. Recurrent gene alterations in PMBL il

[ene thway/fencion Frequency %
Copy number gain DrkannanS
pouıypoı2 induction of T-eshustion/apoptonk @
sana ILHAKSTAT pathway/hstone modifiers 5 Li
smuoze Histone modification a

Chromosomal translocation/rearrangement

Coding sequence mutation

socsi IWAK STAT pathway ss pew
stare WIAKSTAT pathway 35
Ais NE pathway ES
me Transenptonalregulston/chromatn emodeling >
m 953 pathway 5 e

Promoter hypermethylation

16m Celleyle progression, 53 pathway 9 en

Stei

© Blood 2011;118:2659.2669

11. Consequences of 9p24 amplification E

9p24 Dr Kannan S
amplification

aa zu A

PD-1 ligand / T

PD-1 receptor JAK2 2

neutralizing ——]| inhibitor —U

antibody

Gopinathan M

Immune Increased

evasion proliferation
Kalpesh Pam.

Green M Ret al. Blood 2010;116:3268-3277

12. Riya Balikar

The 9p24 amplicon

Dr Kannan S

* PDL1 and PDL2 ligands are also in the common 9p24

amplicon

+ Surface molecules over expressed in PMBL amitdurana

+ Inhibitory effect on T-cells

+ Further mechanism of escape from immune surveillance | e]
5

Asif bal

— aix Wc isn Green MR et al. Blood 2010;116:3260-3277 LEST

13. JAK-STAT Pathway

Major regulator of cellular proliferation.
This pathway is activated in PMBL

Gene expression profiling: high levels
of IL13, JAK2, STAT1 and 6

Genomic amplification of (9p24) in
60% cases. Includes JAK2 (increased
gene dose)

SOCS1 (suppressor of cytokine
signalling) mutated in 45%
STAT6 somatic mutations (36%)

zw 29M
Ctvenosomal Region 924

fy Bakar
un
| E pal

Asif bal

Kalpesh Pam.

15. Algorithm for Second-line Therapy of LBCL

Time from 1L therapy

5%

ST yea

ible for ASCT?

Yes
-50%|

2L Salvage +/- ASCT

Eligible for CAR T-cell?

Yes
|-70%

No
~30%

No
~50%|

2 or 3L+ therapy options
+ Investigational agent/regimen
+ * Immunochemotherapy
«+ CAR Teall if not given in 2L)

2L CAR T-cell (axi-cel or liso-cel)

+ Polatuzumab vedotin + BR

-30-40% + Selnexor -40-50%]
+ Tafasitamab + lenalidomide
+ Loncastuximab tesi
© Best supportive care or XRT

Projected Cure Cure

(-20% of all 2L LBCL) (5% of all 2L LBCL)

Westin and Sehn 2022

es
LE GNT

Riya Balikar

Gopinathan M

Krishnarathn

16. Do we have comparative data? (..retrospective again n=144)

(0S and PFS were similar, the hazard ratio for DA-R-EPOCH chemotherapy was in favour of
this more intensive regimen at both endpoints, although not statistically significance.

Al a” :

i
1

3

amitkhurana

Riya Balikar

Gopinathan M

Demographics well balanced
Dose escalation as per DA-PROCH-R protocol in only 63%
Consolidative RT 59% R-CHOP; 13% DA-EPOCH-R

neutropenic fever (33% vs. 13%,P < 0.01) and need hospitalization for acute

toxicities (35% vs. 16%, P = 0.02)

Shah et al, BJH 2017

17. Fertility

Impact uncertain

No doubt escalated
cyclophosphamide dosing
associated with impaired
gonadal function

From NCI cohort. Of 23
patients, 75% returned to
mestruration with 6/20
pts having healthy
deliveries. In 6 pts >40
yrs all premature

Menopause (Dunleavy Blood 2013;

122: 1779)

Cardiac function

What is long-term impact of
escalated doxorubicin dosing on
cardiac function? High cumulative
exposure >400mg/m?

Dunleavy et al NEJM 2013

Ee

Dr Kannan S
amitkhurana
Riya Balikar
Gopinathan M

Parathan Kar

Krishnarathn,

18. Algorithm for Second-line Therapy of LBCL

Time from 1L therapy

5%

ST yea

ible for ASCT?

Yes
-50%|

2L Salvage +/- ASCT

Eligible for CAR T-cell?

Yes
|-70%

No
~30%

No
~50%|

2 or 3L+ therapy options
+ Investigational agent/regimen
+ * Immunochemotherapy
«+ CAR Teall if not given in 2L)

2L CAR T-cell (axi-cel or liso-cel)

+ Polatuzumab vedotin + BR

-30-40% + Selnexor -40-50%]
+ Tafasitamab + lenalidomide
+ Loncastuximab tesi
© Best supportive care or XRT

Projected Cure Cure

(-20% of all 2L LBCL) (5% of all 2L LBCL)

Westin and Sehn 2022

es
LE GNT

Riya Balikar

Gopinathan M

Krishnarathn

19. Algorithm for Second-line Therapy of LBCL

Time from 1L therapy

5%

ST yea

ible for ASCT?

Yes
-50%|

2L Salvage +/- ASCT

Eligible for CAR T-cell?

Yes
|-70%

No
~30%

No
~50%|

2 or 3L+ therapy options
+ Investigational agent/regimen
+ * Immunochemotherapy
«+ CAR Teall if not given in 2L)

2L CAR T-cell (axi-cel or liso-cel)

+ Polatuzumab vedotin + BR

-30-40% + Selnexor -40-50%]
+ Tafasitamab + lenalidomide
+ Loncastuximab tesi
© Best supportive care or XRT

Projected Cure Cure

(-20% of all 2L LBCL) (5% of all 2L LBCL)

Westin and Sehn 2022

es
LE GNT

Riya Balikar

Gopinathan M

Krishnarathn

20. Riya Balikar

Dr Kannan S

CD58 [a receptor of the CD2
molecule expressed by T and

NK cells] mutations as a 5
ner JR

amitkhurana

marker for all outcome
parameters

Ast abal
DUSP2 mutations, our study
also identified a very good Gopinathan M
risk marker

May guide therapy selection ita

21. Algorithm for Second-line Therapy of LBCL

Time from 1L therapy

5%

ST yea

ible for ASCT?

Yes
-50%|

2L Salvage +/- ASCT

Eligible for CAR T-cell?

Yes
|-70%

No
~30%

No
~50%|

2 or 3L+ therapy options
+ Investigational agent/regimen
+ * Immunochemotherapy
«+ CAR Teall if not given in 2L)

2L CAR T-cell (axi-cel or liso-cel)

+ Polatuzumab vedotin + BR

-30-40% + Selnexor -40-50%]
+ Tafasitamab + lenalidomide
+ Loncastuximab tesi
© Best supportive care or XRT

Projected Cure Cure

(-20% of all 2L LBCL) (5% of all 2L LBCL)

Westin and Sehn 2022

es
LE GNT

Riya Balikar

Gopinathan M

Krishnarathn

22. Pathology

Cytologically resembles many
‘other large B cell lymphomas

Large transformed cells
resembling centroblasts

‘Abundant pale cytoplasm
Diffuse involvement

Areas of fine
‘compartmentalising sclerosis

Expression of B-cell antigens: CD20 and
CD79a positive, but lack sig

Evidence of somatic hypermutation

CD30 often present (>80%), typically weak
CD23: Frequent (73%)

BCL2: variable (50-80%, no t(14;18))

BCL6: variable (45-100%)

CD10: less common (8-30%)

CD15: almost always negative

MAL (70%) - normal expression in thymic
medullary cells, CD54, CD95, nuclear REL,
TRAF

E

Asif lgbal|

Kalpesh Pam.