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