Daan Dierickx BHS Educational Course – Seminar 12 Hof Ter Musschen, 7th March 2015 BHS Educational Course on Hodgkin lymphoma and aggressive lymphoma Special situations
Daan Dierickx
BHS Educational Course – Seminar 12
Hof Ter Musschen, 7th March 2015
BHS Educational Course on Hodgkin
lymphoma and aggressive lymphoma
Special situations
Special situations
Primary central nervous system lymphoma (PCNSL)
Posttransplant lymphoproliferative disorder (PTLD)
AIDS related lymphoma (ARL)
Special situations
Primary central nervous system lymphoma (PCNSL)
Posttransplant lymphoproliferative disorder (PTLD)
AIDS related lymphoma (ARL)
PCNSL – definition and incidence
• Extranodal NHL limited to CNS (brain, cranial
nerves, leptomeninges, CSF, intraocular structures,
spinal cord)
no systemic involvement (= secondary
CNS lymphoma)
• Rare:
– <1% of all NHL
– 2-3% of all brain tumors
Question 1
What’s the most important risk factor for
development of PCNSL?
PCNSL – risk factors
• Immunodeficiency states
– Congenital
– Acquired
• PTLD
• HIV
• Immune competent patients
EBV
Villano JL, et al. Br J Cancer 2011;105:1414-18
PCNSL – presentation
• >95% DLBCL
• 20% intraocular involvement (rare: PIOL)
• Golden standard for diagnosis: stereotactic
biopsy (ideal: without steroids)
• Staging:
– MRI brain with gadolinium
– (PET?+) CT whole body
– Bone marrow examination
– Slit lamp examination
PCNSL – presentation
Wang CC, et al. Br J Haematol 2014;166:311-25
PCNSL – prognostic scores The International Extranodal Lymphoma Study Group (IELSG) prognostic
index (0-5 scale) : Age > 60 yr, performance state (ECOG ≥ 2), LDH, elevated protein concentration in CSF and involvement of deep brain structures
The Nottingham/Barcelona prognostic score (0-3 scale): Age >60 yr, performance state (ECOG ≥ 2), multifocal disease
The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score (0-2 scale): :
Age > 50 yr, performance state (ECOG ≥ 2)
Ferreri AJ, et al. J Clin Oncol 2003;21:266-72
Bessell EM, et al, Int J Radiat Oncol Biol Phys 2004;59:501-8
Abrey LE, et al, J Clin Oncol 2006;24:5711-5
Question 2
Which therapeutic regimen is the
backbone in the treatment of PCNSL?
PCNSL – treatment
Nelson DF, et al. Int J Radiat Oncol Biol Phys 1992;23:9-17
Median OS: 12 months
Majority (88%) of recurrences: within boost field
Major problem: delayed neurotoxicity (especially > 60 years)
PCNSL – adding chemotherapy to WBRT
Abrey L, et al. J Clin Oncol 2000;18:3144-50
DeAngelis LM, et al. J Clin Oncol 2002;20:4643-8
• CHOD no survival benefit
• HD-MTX based chemotherapy
BBB
Marked survival benefit: median OS 37-60 months
Late neurotoxicity (up to 25%)
PCNSL – eliminating WBRT
• Multiple retrospective and prospective phase
2 trials: inferior outcomes
• Only 1 prospective phase 3 study:
G-PCNSL-SG-1 trial
Thiel E, et al. Lancet Oncol 2010;11:1036-47
Thiel E, et al. Lancet Oncol 2010;11:1036-47
Korfel A, et al. Neurology 2015 Feb 25, [Epub ahead of print]
PCNSL – G-PCNSL-SG-1 trial: long term
follow up
PCNSL – G-PCNSL-SG-1 trial: long term
follow up
Thiel E, et al. Lancet Oncol 2010;11:1036-47
Korfel A, et al. Neurology 2015 Feb 25.[Epub ahead of print]
PCNSL – alternatives to WBRT
• Reduced dose radiotherapy (23.4 Gy)
• High dose therapy with autologous stem cell
transplantation
• Non-myeloablative chemotherapy (etoposide-
cytarabine)
Morris PG, et al. J Clin Oncol 2013;31:3971-9
Omuro A, et al. Blood 2015 Jan 7. [Epub ahead of print]
Rubenstein JL, et al. J Clin Oncol 2013;31:3061-8
PCNSL – other questions
• Rituximab?
• Intrathecal chemotherapy?
• MTX 3,5 gr/m² day 1
Cytarabine 2 x 2 gr/m² day 2 and 3
• Every 3 weeks
• Four cycles
• Followed by WBRT if no CR after 1 cycle HDT + ASTx
Ferreri AJM, et al. Lancet 2009;374:1512-20
PCNSL – treatment
Young, fit patients
Elderly PCNSL EORTC protocol
1. First cycle (induction chemotherapy)
• IV MTX 1 g/m2 days 1, 10, 20
• PO lomustine 40 mg/m2 day 1
• PO procarbazine 60 mg/m2 days 1–7
• IV or PO methylprednisolone 120 mg/m2 every other day from days 1–20 and 60 mg/m2 days 20–45
• (IT methotrexate 15 mg and cytarabine 40 mg days 1, 5, 10, and 15)
2. If SD or PD: stop
3. If CR or PR: five more cycles every 6 weeks (maintenance chemotherapy)
• IV methotrexate 1 g/m2 day 1
• PO lomustine 40 mg/m2 day 1
• PO procarbazine 60 mg/m2 days 1–7
• (IT methotrexate 15 mg and cytarabine 40 mg day 1)
Hoang-Xuan K, et al. J Clin Oncol 2003;21:2726-31
PCNSL – treatment
Special situations
Primary central nervous system lymphoma (PCNSL)
Posttransplant lymphoproliferative disorder (PTLD)
AIDS related lymphoma (ARL)
Gruhlich AE et al. Lancet 2007;370:59-67
Risk factors
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
Question 3
Which organ transplantation is associated
with the lowest risk for development of
PTLD?
Risk factors: 1. organ type
Organ Number of
transplantations
(% men)
Number of
PTLDs
% of PTLDs Organ specific
incidence (%)
Kidney 3566 (59%) 54 38.6 1.51
Liver 853 (53%) 24 17.1 2.81
Lung 568 (53%) 18 12.8 3.17
Heart 519 (80%) 26 18.6 5.01
HSCTx 1092 (59%) 18 12.9 1.65
Total 6598 (60%) 140 100 2.12
Dierickx D, et al. Leuk Lymphoma 2013;54:2433-40
• Mismatch (donor seropositive / receptor seronegative): significant increased risk (10-75x)
= most important risk factor
• EBV naive patients: higher risk explains higher incidence in childhood
• EBV naive patients:
– Often initially presentation with EBV-associated PTLD type early lesions or polymorfic type
– Often early onset PTLD
– Remains risk factor
Risk factors: 2. EBV status
Shahinian VB, et al. Transplantation 2003;75:851-6
Halloran PF. New Engl J Med 2004;351:2715-29
Risk factors: 3. immunosuppressive
therapy
Association Controversial No association
Tacrolimus
Azathioprin
ATG
OKT3
Belatacept
Efalizumab
Tofacitinib
Cyclosporin A
mTOR inhibitors
MMF
Alemtuzumab
Basiliximab/daclizumab
EBV+
Risk factors: 3. immunosuppressive
therapy
• 67%: EBV-associated PTLD
– Deficient EBV specific cellular immune response
• SOT: immune suppressive medication
• HSCTx: conditioning, T cell depletion and immune
suppressive medication
• 33%: EBV-negative PTLD
– Pathogenesis less clear
– Therapy similar (except for EBV-targeted therapy)
Pathogenesis
Thorley Lawson DA. Nat Rev Immunol
2001; 1:75-82
Thorley-Lawson DA. J Allergy Clin
Immunol 2005;116:251-61
Rezk SA, et al. Hum Pathol 2007;38:1293-304
Pathogenesis
Pathogenese
Hawkins JB, et al. PLoS Pathog 2013;9(10):e1003685
Saha A , Robertson E S Clin Cancer Res 2011;17:3056-63
Pathogenesis
Pathogenesis: role of EBV
IMMORTALIZATION
Thorley Lawson DA. Nat Rev Immunol 2001;1:75-82
Swerdlow H, et al. IARC Press: Lyon 2008
Immunodeficiency AssociatedLymphoproliferative Disorders
Lymphoproliferative diseases associated with primary immune disorders
Lymphomas associated with HIV infection
Post-transplant lymphoproliferative disorders
Other iatrogenic immunodeficiency-associated lymphoproliferative disorders
Classification: WHO 2008
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
Jaffe ES, et al. IARC Press: Lyon 2008
Classification: WHO 2008
Question 4
What is the critical step in the initial
treatment of PTLD?
Gottschalk, et al. Annu.Rev.Med 2005;56:29-44
Treatment
Gottschalk, et al. Annu.Rev.Med 2005;56:29-44
Treatment
Gottschalk, et al. Annu.Rev.Med 2005;56:29-44
Treatment
• PTLD = excess immune suppression
• No consensus/uniform guidelines:– STOP antimetabolites
– Reduce CNI dose
– Continue or increase steroids
• 1-4 weeks response rates: 0 - >50%
• Highest response rates:– Early lesions
– EBV positive
1. Reduction of immune suppression (RIS)
Treatment: restoring T cell function
Treatment Overall response
rate (CR)
Pennsylvania RIS only 45% (37%)
Baltimore Sequential therapy
(RIS – IFNα –
chemo)
6% (0%)
Reshef R, et al. Am J Transplant 2011;11:336-47
Swinnen LJ, et al. Transplantation 2008;86:215-22
Treatment: restoring T cell function
1. Reduction of immune suppression (RIS)
1. Reduction of immune suppression (RIS)
Treatment: restoring T cell function
Organ dependent
• Kidney: dialysis rescue
• Hematopoietic stem cell: less efficious
• Heart: risk sudden death
Switch to mTOR inhibition?
• Currently very controversial
Aull MJ, et al. Transplantation 2004;78:1676-82
2. Adoptive immunotherapy
Treatment: restoring T cell function
Kennedy-Nasser AA, et al. Mediterr J Hematol 2009;17;1(2):e2009010.
EBV specific CTLs
• Retrospective analysis IPITTR: PTLD following SOT
– n = 193
Regimen 5yrOS (%) PTLD-specific
mortality (%)
CHOP 24 34
ProMACE 25 34
Other multidrug 32 40
Monotherapy 5 48
Buell JF, et al. Transplant Proc 2005;37:956-7
Treatment: reduction of B cell mass
1. Chemotherapy
• Immuno-chemotherapy (Rituximab + CHOP):
standard of care in immune competent patients
• PTLD: higher TRM (infections)
Solutions?
Better supportive care G-CSF, anti-infectious agents
Low dose chemotherapy Only 1 prospective study in
children
Sequential therapy
Treatment: reduction of B cell mass
1. Chemotherapy
Stamataki Z, et al. PLoS One 2011;6:e25789
Treatment: reduction of B cell mass
2. Monoclonal anti-B cell antibodies
Prospective studies:
In most studies: rituximab 375 mg/m²/week during 4 consecutive weeks
* risk adapted extended treatment (PR): upgrading CR 34% 60.5%
Author Year Phase n ORR(%)
Oertel 2005 II 17 59
Blaes 2005 II 11 64
Choquet 2006 II 43 44.2
Gonzalez-Barca* 2007 II 38 60.5 (CRR)
Treatment: reduction of B cell mass
2. Monoclonal anti-B cell antibodies
Rituximab or chemotherapy?
• No prospective randomized trials
• Retrospective analysis (Pennsylvania University)– n = 35 (34 SOT, 1 HSCTx)
– 22 R, 23 chemo
– Rituximab: RR 68%, OS 31 months
Chemotherapy: RR 72%, OS 42 months
– Rituximab: excellent tolerance; chemotherapie TRM 26%
– Treatment failure after rituximab: salvage with chemotherapy later
• Important: better performance status following rituximab
Elstrom RL, et al. Am J Transpl 2006;6:569-79
Treatment: reduction of B cell mass
2. Monoclonal anti-B cell antibodies
PTLD1 trial
Sequential Treatment
Treatment: reduction of B cell mass
Trappe R, et al. Lancet Oncol 2013;13:196-206
0 10 20 30 40 50
100
75
50
25
0
CR or PR after 4 cycles of
rituximab (n=35)
SD or PD after 4 cycles
of rituximab (n=23)
p=0.0107
Months
Perc
en
t O
S
PTLD1 trial
Treatment: reduction of B cell mass
PTLD1 trial
Risk Stratified
Sequential Treatment
Treatment: reduction of B cell mass
Treatment
Zimmermann H, Trappe R. Hematology Am Soc Hematol Educ Program 2013;2013:95-102
Prophylaxis/prevention/preemptive
Problems
Who? High risk patients Definition?
Which test? EBV PCR, FLC(?),
sCXCL13
Source? Cut off?
Increase?
How? •RIS
•Rituximab
•Adoptive
immunotherapy
Mostly retrospective
single center data
Prophylaxis/prevention/preemptive
Rasche L, et al. Bone Marrow Transplant 2014;49:163-7
Prophylaxis/prevention/preemptive
Choquet S, et al. Am J Transplant 2014;14:857-66
Special situations
Primary central nervous system lymphoma (PCNSL)
Posttransplant lymphoproliferative disorder (PTLD)
AIDS related lymphoma (ARL)
Swerdlow H, et al. IARC Press: Lyon 2008
Immunodeficiency AssociatedLymphoproliferative Disorders
Lymphoproliferative diseases associated with primary immune disorders
Lymphomas associated with HIV infection
Post-transplant lymphoproliferative disorders
Other iatrogenic immunodeficiency-associated lymphoproliferative disorders
Classification: WHO 2008
Question 5
Is the incidence of ARL increasing or
decreasing?
Gruhlich AE et al. Lancet 2007;370:59-67
ARL – incidence
Carbone A, et al. Nat Rev Clin Oncol 2014;11:223-38
ARL – subtypes
Franceschi S, et al. Br J Cancer 2010;103:416-22
• Treatment:– Early initiation of cART (during chemotherapy)
– Lymphoma-specific treatment
– Supportive care
– New treatment strategies needed (PEL, PBL)
• Prognostic factors:– Low CD4 count, poor PS
– aaIPI, histological subtype
ARL – treatment and prognosis
Barta SK, et al. Ann Oncol 2015 [Epub ahead of print]
ARL – treatment and prognosis
Barta SK, et al. Ann Oncol 2015 [Epub ahead of print]
ARL – treatment DLBCL
DLBCL: R-CHOP or R-EPOCH
• Mostly advanced stage
• Higher CD4 counts
• EBV associated
• Subtype: NS, LD and MC
Montoto S, et al. J Clin Oncol 2012;30:4111-6
Hentrich M, et al, J Clin Oncol 2012;30:4117-23
Uldrick TS, Little RF. Blood 2015;125:1226-35
HL: ABVD
ARL – treatment HL
Galicier L, et al. Blood 2007;110:2846-54
Xicoy B, et al, Leuk Lymphoma 2014;55:2341-8
BL: short intensive chemotherapy + rituximab
ARL – treatment BL
Dunleavy K, et al, N Engl J Med 2013;369:1912-25
BL: short intensive chemotherapy + rituximab
or SC-EPOCH-RR?
ARL – treatment BL
• PCNSL: HD MTx/Ara-C +/- RT
• PBL and PEL: very poor prognosis
Castillo JJ, et al, Cancer 2012;118:5270-7
Schommers P, et al. Br J Haematol 2014 Nov 17.[Epub ahead of print]
PBL and PEL: new treatments needed
ARL – treatment