Interesting case in lymphoma

Kitsada Wudhikarn, MD

Division of Hematology, Department of Medicine

Faculty of Medicine, Chulalongkorn University

Eosinophilia

Benign reactive etiologies

1. Allergy 2. Infection 3. Secondary to medical

condition 4. Medication

Hematologic Malignancies with reactive or clonal

eosinophilia

1. Hodgkin lymphoma 2. B-cell and T cell NHL 3. AML with inv(16) or

t(16;16) 4. AML with t(8;21) 5. MPNs esp CML

Myeloid neoplasms associated with

PDGFRA, PDFGRB and FGFR1

rearrangement

Miscellaneous etiologies

1. CEL NOS 2. Lymphocytic variant HES 3. Paraneoplastic syndromes 4. Idiopathic HES

Differential Diagnosis of waxing and waning LAD

Non Malignant Reactive Process Chronic/intermittent infection or

reactivation

Autoimmune Lymphadenopathy

Follicular hyperplasia

Lymphoma mimicker Kikuchi-Fujimoto syndromes

Malignant Lymphoma Low grade lymphoma esp follicular

lymphoma

Hodgkin lymphoma

T cell lymphoma

Eosinophilia and Lymphoproliferative disorders

Frequency of eosinophilia

Clinical “HES” Mechanism of HE Serum

Biomarkers Impact on prognosis

Malignant T cell LPD Mycoses Fungoides Sezary Syndromes AITL cALCL PTCL-NOS EATL

20-25% (>700/µL) 6.5% (>1500/µL)

32-50% Uncommon Uncommon

2%

Rare

Advanced disease Rare Rare Rare Rare

IL-5, IL-4, IL-13

CCR4 IL-5

CCL11, CCR3, IL-4 IL-5, GATA-3

IL-5

CCL17, CCL22 CCL11, CCL26

N/A CCL17

N/A N/A

Negative

N/A None

Negative N/A N/A

Indolent T cell LPD L-HES LyP

100% Rare

Majority of cases

Rare (FIP1L1+)

IL-5, GM-CSF

FIP1L1

CCL17

N/A

Negative

Malignant B cell LPD cHL

B-ALL/Eo

15% (>500/µL)

<1%

Rare

Frequent (heart)

IL-5, GATA-3

t(5;14) w IL-3

CCL17, CCL22

IL-3

Positive (blood)

Negative (tumor) Bad if HES

Roufosse F et al. Semin Hematol. 2012 Apr;49(2):138-48

Exaggerated mosquito bite reaction

Tatsuno et al. J Dermatol Sci. 2016 Jun;82(3):145-52

EBV associated hypersensitivity

Well’s Syndromes Hematologic malignancy

MSG-specific T cells NK cell help

MSG-specific T cells Eosinophil help

MSG-specific T cells MSG-reactive B cells

Exaggerated reaction to mosquito bites

Angioimmunoblastic T cell Lymphoma

Distribution of T-cell lymphoma

Vose J et al. J Clin Oncol. 2008 Sep 1;26(25):4124-30

AITL in Asia

Subtype Frequency (%)

Worldwide North America Europe Asia Thailand

PTCL-NOS 25.9 34.4 34.3 22.4 32.4

AITL 18.5 16.0 28.7 17.9 11.3

ALCL 12.1 23.8 15.8 5.8 13.7

NKTCL 10.4 5.1 4.3 22.4 21.9

ATLL 9.6 2.0 1.0 25.0 -

EITL 4.7 5.8 9.1 1.9 0.8

PCALCL 1.7 5.4 0.8 0.7 0.1

HSTCL 1.4 3.0 2.3 0.2 0.8

SPTCL 0.9 1.3 0.5 1.3 7.3

Unclassified 2.5 2.3 3.3 2.4

Intlekofer AM and Younes A. Int J Hematol. 2014 Mar;99(3):249-62 Intragumtornchai T et al. Hematol Oncol. 2018 Feb;36(1):28-36

Peripheral T cell Lymphoma

Cutaneous Extranodal Nodal Leukemic

Mycoses fungoides

Sezary Syndromes

Primary cutaneous CD30+ T cell disorders

Primary cutaneous ALCL

Primary cutaneous G/D TCL

Primary cutaneous CD8+ aggressive

epidermotropic Primary cutaneous CD4+

small/medium

NK/TCL nasal type

Enteropathy associated TCL

Hepatosplenic G/D TCL

Subcutaneous panniculitis like TCL

Systemic EBV+ T-cell childhood LPD

Hydroa vacciniforme-like

Peripheral T cell Lymphoma-NOS

Angioimmunoblastic TCL

Anaplastic Large Cell Lymphoma

Adult T cell Leukemia

T-cell prolymphocytic Leukemia

T-cell LGL Leukemia

Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press, 2008

Clinical Presentation

Median age 65 years (60-70)

Most pts presented with generalized lymphadenopathy, hepatosplenomegaly & constitutional symptoms Mostly advanced stage at diagnosis but bulk of lymph node usually small

Clinical course: Moderate to highly aggressive with some spontaneous regression

More than 1/3 with autoimmune presentation Immune cytopenia Rashes Neuropathy Polyarthritis Vasculitis Diagnosis often follows an immune event, such as exposure to a medication, an infection, or an allergic

reaction

Some patients developed edema, effusion or ascites

60% with bone marrow involvement at the time of diagnosis

Clinical and laboratory features of AITL

1975 to 1999 (n=77) 2007 to 2016 (n=556) Thailand (n=55)

Gender (Males,%) 42-48 56-74 60

Median age range 62-68 62-65 59

Clinical presentation (%) B-symptoms ECOG PS > 1 LDH elevation Advanced stage Low risk IPI (0-1)

29-85

57 25-74

94 NA

55-77 37-50 60-86 81-92 11-21

69.1 27.3 61.8 76.4

49.1 (Low & Low-Intermediate)

Areas of involvement (%) Multiple nodal stations Bone marrow Skin rash

97-100

61 38-48

76-99 28-70 31-45

NA NA NA

Laboratory tests (%) Hypereosinophilia Anemia Positive DAT (Coomb’s test) Thrombocytopenia Hypergammaglobulinemia

29-39 40-83 43-57

9 50-77

32-34 33-65 13-75 20-31 50-84

NA NA NA NA NA

Intragumtornchai T et al. Hematol Oncol. 2018 Feb;36(1):28-36; Lunning MA et al. Blood. 2017 Mar 2;129(9):1095-1102

From angioimmunoblastic lymphadenopathy to AITL

1974: Description of angioimmunoblastic lymphadenopathy with dysproteinemia

1979: Atypical T cells immunoblastic T cell lymphoma

1980-88: Angioimmunoblastic T cell lymphoma - Clonal cytogenetic abnormalities - Clonal T-cell receptor (TCR) gene rearrangement

2005-7: Cell of origin of AITL: TFH Cell

2012: Specific mutational landscape (TET2, IDH2, DNMT3, RHOA

KIEL Updated

REAL

WHO Classification(s)

TFH cells in Human health and diseases

Immune deficiencies (Primary, HIV)

Autoimmune diseases (SLE, Sjogren’s, RA)

Lymphoid neoplasms Hodgkin lymphoma

Lymphoma derived from TFH cells

Tangye SG et al. Nat Rev Immunol. 2013 Jun;13(6):412-26

Nodal T cell lymphoma with follicular helper (TFH) phenotype

THF phenotype At least 2 of:

PD1, CD10, BCL6, CXCL13, ICOS, SAP and CCR5

Nodal PTCL with TFH phenotype

Follicular T cell Lymphoma

Angioimmunoblastic T cell Lymphoma

Pathologic features of AITL

CD3 CD20

CD21 CXCL13 ICOS PD1

H&E Sensitivity

Specificity

ICOS

C-MAF

PD-1

BCL-6

CXCL13

CD10

CD10

EBER

CD23

CD4+ αβT cells (TFH)

Genetic Signature of Mature T cell Lymphoma

Morphological diagnosis AITL ALK+ ALCL ALK- ALCL ATLL ENKTL PTCL-NOS

0

20

40

60

80

100

120

140

Diagnosis of PTCL-NOS (Waste basket) will become less as insight in molecular/genetic signatures continues to improve

Iqbal J et al. Blood. 2014 May 8;123(19):2915-23

Integrative clinicopathological & molecular analyses of nodal PTCL with TFH phenotype

Dobay MP et al. Haematologica. 2017 Apr;102(4):e148-e151

Integrative clinicopathological & molecular analyses of nodal PTCL with TFH phenotype

Dobay MP et al. Haematologica. 2017 Apr;102(4):e148-e151

Mutation

Nodal lymphomas of TFH cell origin

PTCL-NOS P-value across 4

entities AITL Other TFH-PTCL

TFH-like PTCL F-PTCL

TET2 48% 64% 75% 17% <0.01

DNMT3A 30% 10% 25% 4% 0.02

IDH2 33% 10% 0% 0% <0.001

RHOA (G17V) 58% 57% 60% 0% <1x10-6

RHOA CD28/CTLA4-

CD28 ITK-SYK PLCG1

TNFRSF21

IDH2 TET2

DNMT3A

Enhanced self-renewal

Hematopoietic stem cells T-cell

Lineage commitment Malignant transformation

T lymphoma

Nodal T cell lymphoma with follicular helper (TFH) phenotype

THF phenotype At least 2 of:

PD1, CD10, BCL6, CXCL13, ICOS, SAP and CCR5

Nodal PTCL with TFH phenotype

Follicular T cell Lymphoma

Angioimmunoblastic T cell Lymphoma

Mutations TET2 IDH2

DNMT3A RHOA CD28

Gene fusion ITK-SYK

CTLA4-CD28

Spectrum of B-­cell proliferations is broad in AITL

From scattered to “increased” immunoblasts to DLBCL–like

HRS-­like cells may be seen, should not be misdiagnosed as cHL or composite

EBV positive (more often) or EBV negative

Plasma cell proliferation (monotypic or not)

Up to one third of AITL show clonal B-­cell population: clonality analysis may be misleading

Attygalle AD et al. Histopathology. 2014 Jan;64(2):171-99

CD20/EBER

LMP1

Spectrum of B-­cell proliferations is broad in AITL

From scattered to “increased” immunoblasts to DLBCL–like

HRS-­like cells may be seen, should not be misdiagnosed as cHL or composite

EBV positive (more often) or EBV negative

Plasma cell proliferation (monotypic or not)

Up to one third of AITL show clonal B-­cell population: clonality analysis may be misleading

Attygalle AD et al. Histopathology. 2014 Jan;64(2):171-99

Treatment of AITL

Front line therapy Should AILT be treated like PTCL-NOS?

Is there an optimal front line regimen?

Relapsed disease Is there an optimal agent ?

Treatment of AITL (or most nodal peripheral T-NHL)

Induction treatment

Consolidation treatment

Transplant candidate

Non-Transplant candidate

ASCT vs Allo-HSCT

Relapse

CR/PR

R/R treatment

Palliative treatment

Relapse

PD

Natural History of peripheral T cell NHL

Long term survival approximately 30%

Fare worse than aggressive B cell lymphoma except ALK+ ALCL

Anthracycline based regimens are still considered the standard of care – CHOP most common

CR in 17-70% of cases but high risk of relapse

5 yr OS of 38-58% meta-analysis

Consolidate remission with high dose therapy and ASCT (phase 2 data) 0 10 20 30 40 50 60 70 80 90 100 110

Months

0

10

20

30

40

50

60

70

80

90

100

Perc

ent

Surv

ival

Event Free Survival

ALK+ ALCL

AITL

ALK- ALCL

PTCL-NOS

Others

Schmitz N et al. Blood. 2010 Nov 4;116(18):3418-25

Survival Outcomes of AITL

Adverse prognostic factors: Older age, Advanced Stage and Male sex

Overall Survival N=1207

1.0

0.8

0.6

0.4

0.2

0 2 4 6 8 10 12 14 16 18 20

Time from Dx (years)

Pro

bab

ility

of

surv

ival

Disease Specific Survival N=1207

1.0

0.8

0.6

0.4

0.2

0 2 4 6 8 10 12 14 16 18 20

Time from Dx (years)

Pro

bab

ility

of

surv

ival

2 year OS (%) 5 year DSS (%)

1992-1998 28.7 (20.3-37.7) 41.7 (31.2-51.8)

1999-2001 35.4 (27.2-43.7) 46.7 (37.2-55.8)

2002-2004 27.8 (22.3-33.6) 41.6 (34.2-48.4)

2005-2007 37.7 (31.9-43.6) 48.5 (41.9-54.8)

Xu B and Liu P. PLoS One. 2014 Mar 20;9(3):e92585

CHOEP in peripheral T cell lymphoma

Pts ≤ 60 years with normal LDH, etoposide improved improved 3-year EFS

IPI > 1 have a poor prognosis and should be considered candidates for clinical trials

Schmitz N et al. Blood. 2010 Nov 4;116(18):3418-25

0 10 20 30 40 50 60 70 80 90 100 110 Months

0 10 20 30

40 50 60 70

80 90

100

0 10 20 30 40 50 60 70 80 90 100 110 Months

0 10 20 30

40 50 60 70

80 90

100

CHOEP

CHOP

P=0.003

All patients

CHOEP

CHOP

P=0.057

Exclude ALK+ ALCL

EFS%

EFS%

Dose adjusted EPOCH for PTCL

Maeda Y et al. Haematologica. 2017 Dec;102(12):2097-2103

100

80

60

40

20

0 0 0.5 1 1.5 2

Years on study

PFS

OS Su

rviv

al

100

80

60

40

20

0 0 0.5 1 1.5 2

Years on study

PFS

OS

Surv

ival

100

80

60

40

20

0 0 0.5 1 1.5 2

Years on study

PTCL-NOS

AITL

Pro

gres

sio

n F

ree

Surv

ival

100

80

60

40

20

0 0 0.5 1 1.5 2

Years on study

PTCL-NOS

AITL

Ove

rall

Surv

ival

P=0.729 P=0.069

(≤ 60 years old) All patients

R-CHOP in Peripheral T cell NHL: GELA

Hypothesis: Disruption of putative B-T interactions and/or depletion of the EBV reservoir could improve the clinical outcome produced by conventional chemotherapy

Delfau-Larue MH et al. Haematologica. 2012 Oct;97(10):1594-602

Newly diagnosed

PTCL

R-CHOP + IT MTX q 3 weeks x 4 cycles

R-CHOP q 3 weeks x 4

cycles

Follow up CT #1

Follow up CT #2

Interim CT

3 mo 4 wk

R-CHOP in Peripheral T cell NHL: GELA

Not enough evidence that rituximab improved outcome of PTCL

EBV viral load was associated with survival outcome Delfau-Larue MH et al. Haematologica. 2012 Oct;97(10):1594-602

6 12 18 24 30 36 0

0.2

0.4

0.6

0.8

1.0

PFS (months)

6 12 18 24 30 36 0

0.2

0.4

0.6

0.8

1.0

OS (months)

Pro

bab

ility

of

surv

ival

Pro

bab

ility

of

surv

ival

42

R-CHOP in Peripheral T cell NHL: GELA

Not enough evidence that rituximab improved outcome of PTCL

EBV viral load was associated with survival outcome Delfau-Larue MH et al. Haematologica. 2012 Oct;97(10):1594-602

6 12 18 24 30 36 0

0.2

0.4

0.6

0.8

1.0

PFS (months)

Pro

bab

ility

of

surv

ival

42 0

P=0.0608

EBV < 100/µg

EBV > 100/µg

PET in PTCL

PET-CT improves accuracy of staging of PTCL as per Lugano Classification

Change of stage/treatment infrequent

End of treatment PET variably prognostic because of poor outcome

Interim PET-CT scan results variable depending upon parameter Deauville score

Total metabolic tumor volume

No data to support altering treatment on basis of interim scan

Better techniques in development to improve PET prediction

Novel targets for AITL

Iqbal J et al. Blood Rev. 2016 Mar;30(2):89-100

Molecular defined AITL: Oncogenic pathways NFKB, TGFB and IL-6 signaling identified

Novel targets for AITL

Iqbal J et al. Blood Rev. 2016 Mar;30(2):89-100

Upfront treatment clinical trial in PTCL

Regimen Phase N CR/PR (%) Survival outcomes Grade 3-4 toxicities

CHOP-based combinations

Bevacizumab+CHOP II 39 49/41 1-yr PFS/OS 44/NR

Bortezomib+CHOP II 46 65/9 2-yr PFS/OS 37/52% ANC ↓ 41%,

Everolimus+CHOP II 30 57/33 2-yr PFS/OS 33/70% ANC ↓ 80%, Plt ↓ 60%

Romidepsin+CHOP Ib/II 37 51/17 30-mo PFS/OS 41/71% ANC ↓ 89%, Plt ↓ 78%

Belinostat+CHOP Ib 23 72/17 NR ANC ↓ 26%, Hb ↓ 22%

Non-anthracycline combinations

CEOP alternate with pralatrexade

II 33 52/18 2-yr PFS/OS 39/60%

GVPM II 26 23/15 2-yr PFS/OS 14/36% ANC ↓ 45%, Hb ↓ 24%

GPM II 44 43/NA 2-yr PFS/OS 39/65%

GPP+Thalidomide II 52 52/15 2-yr PFS/OS 57/71% Myelosuppression 44%

Yi JH et al. F1000Res. 2017 Dec 12;6:2123

ASCT in AITL: EBMT Experience

N=146 (101 Front-line); 33% CR, 36% PR at time of ASCT. Median age 53 years

Median FU 31 months

TBI containing regimens with less relapse after ASCT

1.0

0.8

0.6

0.4

0.2

0 12 24 36 48 60 72

Time after ASCT (mo)

2-yr OS 67% 5-yr OS 59% O

vera

ll Su

rviv

al

1.0

0.8

0.6

0.4

0.2

0 12 24 36 48 60 72

Time after ASCT (mo)

2-yr PFS 55% 5-yr PFS 38%

Pro

gres

sio

n F

ree

Surv

ival

Kyriakou et al. J Clin Onc 2008

ASCT in AITL: EBMT Experience

Most important predictive factor for good outcome: CR at transplantation

24 12 48 36 72 60 0

0.2

0.4

0.6

0.8

1.0

Pro

gres

sio

n F

ree

Surv

ival

Time after ASCT (months)

CR (n=70): 3-yr 58%

Chemosens (n=56)

Chemoref (n=20)

24 12 48 36 72 60 0

0.2

0.4

0.6

0.8

1.0

Ove

rall

Surv

ival

Time after ASCT (months)

CR: 3-yr 80%

Chemosens

Chemoref

Kyriakou et al. J Clin Onc 2008

Fossard G et al. Ann Oncol. 2018 Mar 1;29(3):715-723

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15

Progression Free Survival (Years)

P=0.90

ASCT

No ASCT

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15

Overall Survival (Years)

P=0.66

ASCT

No ASCT

Pro

bab

ility

(%)

Upfront ASCT consolidation in PTCL: LYSA group

AITL Summary of OS

% OS

Meta-analysis 5-years = 30

Internation T cell Project

5-years = 33

Older Studies (Before 2000)

% OS

SEER (mainly CHOP) 3 year 33

RCHOP (GELA) 3 year 33

CHOEP 3 year 67.5

CHOEP + ASCT 3 year 55

Bortezomib + CHOP 3 year 60

Bevacizumab + CHOP 2 year 55

ASCT in CR 4 year 60

AlloHSCT with chemosensitive disease 3 year 81

Recent Studies (After 2000)

Outcome of AITL after failing first line treatment

Bellei M et al. Haematologica. 2018 Jul;103(7):1191-1197

0.75

0.50

0.25

0.00

1.00

0 12 24 36 48 60 72 84

Follow up (months)

Cu

mu

lati

ve p

rob

abili

ty

ALCL+

AITL

ALCL- PTCL-NOS

NKTCL

Novel drugs in R/R peripheral T cell Lymphoma

Overall Response Rate by common subtypes

Pralatrexate Romidepsin Belinostat Brentuximab

vedotin Lenalidomide Alisertib Mogamulizumab

PTCL-NOS

31% 29% 23% 33% 43 31 19

AITL 8% 30% 46% 54% 33 33 50

ALCL 29% 24% 15% 86% 10 50 100

Horwitz S et al. Blood 2014 Lunning WA and Vose JM. Blood. 2017 Mar 2;129(9):1095-1102

Bachy E and Coiffier B. Blood. 2014 May 15;123(20):3059-60

Cyclosporine Experience in AITL

High or High Intermediate IPI, age 47-83 years old

ORR (8/12): 66%

Duration of response 2-120 months (9 mo) most response by 4-6 weeks

AITL (n=12)

CSA induction

Responder

Non-Responder

3-5 mg/kg PO bid x 6-8 wks gradually taper by 50-100 mg q 1-3 wks

CSA maintenance

Level not monitored

50-100 mg PO bid for 6-12 months

Advani R et al. Leuk Lymphoma. 2007 Mar;48(3):521-5

Treatment of AITL or most nodal T cell NHL

PTCL-NOS or AITL

CHO(E)P 4-6 cycles

Younger, fit patients Transplant ineligible

ASCT

Relapse or progressive diseases

Intensive chemotherapy Single agent therapy

Allogeneic HSCT

Clinical trials vs Palliative care

Clinical trials

Conclusion

Clinical trial should always be the first choice if available Outcomes of AITL with novel agents in combination with chemo in front line

awaited

Future challenges: Identifying subsets who may benefit from maintenance strategy

Are there subsets where chemotherapy not required?

Combinations of targeted agents BV/HDAI/Len

Need a trial of ASCT vs no ASCT

Thank you for your attention