lymphomas in the immunocompromised patient...daan dierickx 10 february 2017 32nd general annual...

Daan Dierickx

10 February 2017

32nd General Annual Meeting of the Belgian Hematology Society

Dolce La Hulpe, Brussels

Lymphomas in the immunocompromised

patient

Immunodeficiency

PID

HIV

PTLD

Otheriatrogenic

Immunodeficiency-associatedLymphoproliferative Disorders

Swerdlow H, et al. IARC Press: Lyon 2008

• Who is at risk?

• Does EBV matter?

• How we treat…

• The future

Lymphomas in the immunocompromised patient

• Who is at risk?

• Does EBV matter?

• How we treat…

• The future

Lymphomas in the immunocompromised patient

Low LK & Song JY. Surg Pathol 2016;9:55-77

Tangye SG, et al. J Exp Med 2017 Jan 20.[Epub ahead of print]

PID

Gruhlich AE et al. Lancet 2007;370:59-67

HIV

Gruhlich AE et al. Lancet 2007;370:59-67

HIV

Carbone A, et al. Nat Rev Clin Oncol 2014;11:223-38

HIV

Franceschi S, et al. Br J Cancer 2010;103:416-22

HIV

Gruhlich AE et al. Lancet 2007;370:59-67

PTLD

Type of transplanted organ

EBV status at time of transplantation (recipient negative/donor positive)

Intensity/duration of immunosuppressive therapy

Underlying disorder

Infectious agents other than EBV (CMV?, HCV?)

Age of donor and recipient

Number and severity of rejection episodes

Cytokine gene polymorphisms

HLA alleles/haplotypes/mismatches/antibodies

PTLD

PTLD

Organ Incidence (%)

Haplo-identical HSCT Up to

Multivisceral >10

Heart-lung >10

Heart 5

Lung 3

Liver 2.5

HSCT 1,5

Kidney 1,5

Total 2-2,5

High risk

(+pediatric)

Standard

risk

Based on registry observations

and single center studies

Incidence: 3.2%

Maksten EF, et al. Transpl Int 2016;29:483-93

Registry

data +

extensive

pathology

review

PTLD

Baecklund E, et al. Arthritis Rheum 2006;54:692-701

Smedby KE, et al. J Int Med 2008;264;514-27

Otheriatrogenic

autoimmunedisorder

treatment

lymphoma

Consistently associated

with lymphoma risk

Possibly associated

with lymphoma risk

Not convincingly

associated with

lymphoma risk

RA, Sjögren’s syndrome,

SLE, coeliak disease,

dermatitis herpetiformis,

Hashimoto thyroiditis

Psoriasis, Crohn’s

disease, systemic

sclerosis, sarcoidosis

Ukcerative colitis, multiple

sclerosis, ankylosing

spondylitis, systemic

vasculitides, type 1

diabetes mellitus

Askling J, et al. Ann Rheum Dis 2009;68:648-53

Otheriatrogenic

Baecklund E, et al. Sem Cancer Biol 2014;24:61-70

Swerdlow H, et al. IARC Press: Lyon 2008

Hansen A, et al. Nat Clin Pract Rheumatol 2007;3:561-9

Otheriatrogenic

9680/3 DLBCL associated with chronic inflammation

• Who is at risk?

• Does EBV matter?

• How we treat…

• The future

Lymphomas in the immunocompromised patient

Bollard CM, et al. Nat Rev Clin Oncol 2012;

9:510-9

Taylor GS, et al. Annu Rev Immunol 2015;

33:787-821

EBV

Saha A , Robertson E S Clin Cancer Res 2011;17:3056-63

EBV

POST-TRANSPLANT LYMPHOPROLIFERATIVE

DISORDERS

• Early lesions

– Reactive plasmacytic hyperplasia

– Infectious mononucleosis-like

• Polymorphic PTLD

• Monomorphic PTLD

– B-cell neoplasms (DLBCL; BL; PCM; plasmacytoma-like lesions,

other)

– T-cell neoplasms (PTCL,NOS; HSTCL; other)

• Hodgkin lymphoma/Hodgkin-like lymphoma

Classification: WHO 2008

80-90% CD20+

DLBCL

Swerdlow H, et al. IARC Press: Lyon 2008

Classification: WHO 2008

Early lesions Polymorphic PTLD Monomorphic PTLD

Underlying

architecture

(Partially) preserved Destructed Destructed

Cells Plasma cells, small

lymphocytes,

immunoblasts

Complete spectrum

of B cell maturation

Fulfill criteria for

lymphoma

IHC No diagnostic value Mixture of B and T

cells

Mostly CD20+, mostly

ABC type

EBV 100% > 90% 60-85%

Clonality In most cases no Variable Yes

Oncogenic mutations No Variable (BCL6) Oncogenes (N-Ras, c-

MYC,…); tumor

suppressor genes

(p53,…)

Swerdlow H, et al. IARC Press: Lyon 2008

Nelson BP, et al. Am J Surg Pathol 2000;24:375-85

Luskin MR, et al. Am J Transplant 2015;15:2665-73

• Increasing incidenceRole of newer immunosuppressive medication?Other infections?Loss of EBV (‘hit and run’ hypothesis)?Later after transplantation

• Significant higher number of late and monomorphic PTLDs

Real PTLD or de novo EBV negative lymphoma?

EBV

Nelson BP, et al. Am J Surg Pathol 2000;24:375-85

Luskin MR, et al. Am J Transplant 2015;15:2665-73

Trappe RU, et al, J Clin Oncol 2016 Dec 19 [Epub ahead

of print]

Real PTLD

EBV- EBV+

Kidney transplantation Thoracic transplantation

Tacrolimus Cyclosporine

Monomorphic (90%) Polymorphic (35%)

5/18 response to RIS

p=0.793ORR EBV + vs EBV - PTLD

86% vs 92% (p=0.255)

EBV

Craig et al. Diagn Mol Pathol 2007;16:158–68

Vakiani et al. Hematol Oncol 2008; 26: 199–211

de novo EBV negative lymphoma

EBV

Morscio J, et al. Am J Transplant 2013;13:1305-16

de novo EBV negative lymphoma

Upregulated in EBV+ PT DLBCL

PDL1 FC 2,7 FDR <0,05

IDO1 FC 3 FDR <0,05

CD163 FC 2,6 FDR <0,05

EBV

Finalet Ferreiro J, et al. Am J Transplant 2016;16:414-25

de novo EBV negative lymphoma

EBV+ 48%

EBV- 83%

Recurrent CNA in EBV+ PT-DLBCL

CNA/cytoband Frequency

gain 1q25.2q41 2 (9.5%)

loss 6p22.2p24.3 2 (9.5%)

loss 6q26q27 2 (9.5%)

loss 7q31.31q35.3 2 (9.5%)

gain 9p24.1p24.3 5 (23.8%)

gain 9p12p24.1 3 (14.3%)

gain 9q34.13q34.3 2 (9.5%)

gain 11q24.1q25 2 (9.5%)

gain 12p13.33q21.2 2 (9.5%)

loss 18q22.3q23.3 2 (9.5%)

CNAs

PDL2 expression

EBV

FOXP1

B-cell

EBV

IgM+

Early following

SCT

Treatment:

bortezomib +

antivirals

IgM-

Late(r) following

SOT

Treatment: blocker

of PDL-PD1 axis in

subgroup

EBV-negative

DLBCL

27

EBV-positive

DLBCL

Courtesy to Professor Thomas Tousseyn

Morscio J, et al. Modern Pathol 2017 Jan 6.[Epub ahead of print]

EBV

• Who is at risk?

• Does EBV matter?

• How we treat…

• The future

Lymphomas in the immunocompromised patient

Gottschalk, et al. Annu Rev Med 2005;56:29-44

Treatment

Treatment

Dierickx D, et al. Blood 2015; 126:2774-83

Trappe RU, et al. J Clin Oncol 2016 Dec 19. [Epub ahead of print]

Risk Stratified Sequential

Treatment

Treatment: CD20+

Trappe RU, et al. J Clin Oncol 2016 Dec 19. [Epub ahead of print]

n = 152 (SOT)

mOS=6,6 years

25%: CR at interim staging

Treatment: CD20+

Results PTLD-1 trial

Risk factors predictive for OS:

IPI score

Response to rituximab at interim staging

Type of transplant

• SC administration of rituximab

• Risk stratification:• IPI

• Response to rituximab

• Thoracic organ

Trappe RU, et al, Am J Transplant

2014;15:1091-100

clinicaltrials.gov

Treatment: CD20+

clinicaltrials.gov

Treatment: CD20+

Treatment

Zimmermann H, Trappe R. Hematology Am Soc Hematol Educ Program 2013;2013:95-102

Evens A, et al. Am J Transplant 2013;13:1512-22

Crane GM, et al. Oncotarget 2015;6:33849-66

Treatment: PCNSL

HD MTx-eligible?

yes no

RIS +

4 x RR-MTx 3 gr/m² every 14-21

days

RIS +

(R) +

WBRT

Intolerance/no CR

Treatment: PCNSL

RIS + R + CHOP RIS + short intensive

chemotherapy

Gong JZ, et al. Am J Surg Pathol 2003;27:818-27

Xicoy B, et al. Leuk Lymphoma 2003;44:1541-3

Zimmermann H, et al. Cancer 2012;118:4715-24

Treatment: BL

Short intensive

chemotherapy-eligible?

yes no

RIS +

2 x RR-SIC (+ 2 following CR)RIS +

2 x RR-Low intensity therapy* (+ 2

following CR) with IT therapy

* SC-EPOCH-RR

Dunleavy K, et al. N Engl J Med 2013;369:1915-25

Treatment: BL

Castillo JJ, et al. Blood 2015;125:2323-30Leuven: 7% of all PTLDs

Treatment: PBL

Localized?

yes no

RIS +

RT or surgery +

2x V(C )D

RIS +

??

DA-EPOCH

VCD

Treatment: PBL

New drugs

• Checkpoint inhibitors?

• Brentuximab?

Holderness BM, et al. J Clin Oncol 2013;31:e197-9

Laurent C, et al. Haematologica 2016;101:976-84

Treatment: PBL

Herreman A, et al. Leuk Lymphoma 2013;54:2190-9

Treatment: T-NHL

Trappe R, et al. Haematologica 2011;96:1067-71

Rosenberg AS, et al. Clin Lymphoma Myeloma Leuk 2016;16:684-92

Treatment: plasmacytoma-like/MM

Epstein-Barr virus status of tumor:

not reported in 79%!

Rosenberg AS, et al. Am J Hematol 2017;91:560-5

Ann Arbor stage: missing in 70%

Epstein-Barr virus status of tumor:

not reported in 51

Treatment: HL

• Who is at risk?

• Does EBV matter?

• How we treat…

• The future

Lymphomas in the immunocompromised patient

Future

Dierickx D, et al. Blood

2015; 126:2774-83

Biomarkers

Future

Imaging

Future

Transplant

PTLD

Patient

National registry

BHS + BTS

(1) development of a registry to define‘best practices’ for diagnosis and treatment of PTLD

(2) development of a platform forconducting observational and interventional clinical trials

(3) establishing a national collectionpoint of samples from patients withPTLD to facilitate future studies

Future

Future

• Adoptive immunotherapy (Merlo A, et al. Haematologica 2010;

Dharnidharka VR & Mohanakumar T. N Engl J Med 2015)

• Ibrutinib (Schutt SD, et al. OLoS One 2015)

• PI3K inhibition/mTOR inhibition (Furukawa S, et al. Am J

Transplant 2013)

• Proteasome inhibition (Morscio J, et al. Mod Pathol 2017)

• Radioimmunotherapy (Rossignol J, et al. Am J Transplant 2015)

• Checkpoint inhibition? (Barnett R, et al. N Engl J Med 2017)

– CTLA-4 pathway? No

– PD1/PDL1 pathway? Possible

Relapsed/refractory PTLD: the future

AcknowledgementsDepartment of hematology/

medical oncology

Gregor Verhoef

Peter Vandenberghe

Vibeke Vergote

Johan Maertens

Ann Janssens

Mariëlle Beckers

Hélène Schoemans

Michel Delforge

Timothy Devos

Department of pathologyThomas Tousseyn

Julie MorscioLukas Marcelis

Department of nuclear medicine

Olivier Gheysens

Department of human genetics

Iwona WlodarskaJulio Finalet Ferreiro

Jan CoolsSofie DemeyerEllen Geerdens

Nena Testelmans

Department of organ

transplantation

Geert Verleden

Lieven Dupont

Robin Vos

Dirk Kuypers

Ben Sprangers

Maarten Naesens

Johan Van Cleemput

Frederik Nevens

Marleen Renard

Anne Uyttebroeck

Veerle Labarque

Isabelle Meyts

Jacques Pirenne

Diethard Monbaliu

Albert Herelixka

Department of biostatistics

Steffen Fieuws

Department of immunologyXavier Bossuyt

Department of HLA typing

Marie-Paule Emonds

Rega InstitutePatrick MatthysRobert Snoeck

Graciela AndreiErika Trompet

Department of radiologyVincent Vandecaveye

Katja De PaepeIlse Roeben

Department of lab medicine

Nancy Boeckx

Belgian PTLD working group?