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