Linfoma linfoblastico

Vincenzo Cassibba

Divisione di Ematologia e TMO

Ospedale S. Maurizio, Bolzano

BACKGROUND

Lymphoblastic lymphoma (LBL) is a neoplasm of lymphoblasts committedto the B-cell (B-LBL) or T-cell lineage (T-LBL).

They are postulated to arise from precursor B in bone marrow (BM) orthymic T cells at varying stages of differentiation.

Within each lineage group, there is a significant biological and clinicaloverlap between neoplasms diagnosed as LBL and acute lymphoblasticleukemia (ALL). Accordingly, LBL and ALL should be considered the samedisease with different clinical presentations.

By convention, the word “lymphoma” is used if there is a bulky lesion inthe mediastinum or elsewhere, with no or minimal evidence of peripheralblood (PB) and bone marrow (BM) involvement. In general, a threshold of<25% BM blasts is used for defining lymphoma.

Epidemiology and ClinicalCharacteristics of LBL

• Frequency: T-LBL 1.7%, B-LBL <1%within all NHL

• Incidence: in U.S.A. 0.2/100,000 in males,0.1/100,000 in females

• Median age: 22-37 years

• Sex: male (61-75%) >female

• Blasts in BM: <25%

• Mediastinum involvement: 61-85%

• Stage III-IV: 58-95%

• B symptoms: 16-48%

• Elevated LDH: 48-84%

• CNS involvement: 0-10%D Hoelzer and N Gökbuget, Best Practice &Research in Clinical Haematology, 2003

Clinical Characteristics Accordingto Immunophenotype

B-LBL Frequency: 10% of LBL Median age: <18 years Sex: male predominance Sites of involvement: skin, soft

tissue, bone, lymph nodes Outcome: approximately 80%

of children appear to be cured,while this figure is less than50% for adults

T-LBL Frequency: 85-90% of LBL Median age: 20-30 years Sex: male predominance Sites of involvement: mediastinal mass,

pleural/cardiac effusion, lymph nodes, BM,less commonly skin, tonsil, liver, spleen,Weldeyer’s ring, CNS, gonades.

Others: stage III-IV, B symptoms, ⇧LDH Outcome: inferior to B-LBL if treated with

less intensive protocols

WHO 2008

Immunophenotype Analysis ofLBL

B-LBL:TdT+/cCD22+/CD19+/cCD79a+

Pro-B): CD19+, cCD79a+, cCD22+ Common: CD10+ Late pre-B: CD20+, c-µ heavy chain+

CD99+, CD34+ (40%), CD13 (14%),and/or CD33 (16%)

T-LBL: TdT+/cCD3+ Pro-T: cCD3+, CD7+, CD2-, CD1a-, CD34+/-, CD4- and CD8- Pre-T: cCD3+, CD7+, CD2+, CD1a-, CD34+/-, CD4- and CD8- Cortical T: cCD3+, CD7+, CD2+, CD1a+,

CD34-, CD4+ and CD8+ Medullary T: cCD3+, CD7+, CD2+, CD1a-,

sCD3+, CD4+ or CD8+, CD34-,

CD99+, CD34+, CD13+ and CD34+ (19-32%)

immunophenotype does not affect DFS

Genes that Distinguish T-ALL fromT-LBL

E A Raetz et al, Pediatr Blood Cancer, 2006

Prognostic Factors

Higher age (>30-40 years) Stage III-IV BM/CNS involvement Mediastinal involvement Elevated LDH B symptoms Time to CR IPI (age, extranodal sites, LDH, stage, PS)

Risk factors according to Coleman et al, JCO, 1986: stage IV, BM or CNSinvolvement or initial LDH>300 IUL (normal<200).5 years RFR in low risk patients; RFR 94% vs 19% in high-risk patients.

A CONVINCING PROGNOSTIC MODEL HAS NOT YET BEEN DEFINED FOR ADULTLL

Remissioninduction/consolidation + mediastinal irradiation

TREATMENT RESULTS IN ADULT LBL

34-44%57-83%Highgrade NHL*(LSA2-L2)

23-56%79-100%Modified NHL(Stanford/NCOG)

45-67%55-100%ALL protocols

23-53%53-71%Conventional NHL(CHOP)

DFSCRRegimens

*Only one study wich included SCT reached a DFS of 75% (Santini et al, BM Trasp 1989)

Treatment Overview of GMALLStudies 04/89 and 05/93

AC indicates cytarabine; ASP, asparaginase; CYCLO, cyclophosphamide;HD, high dose; MITOX, mitoxantrone; MTX, methotrexate; VM 26, teniposide

D Hoelzer et al, Blood, 2002

Consolidation I

Overall Results in 45 adult T-LBL (1989-1998)

D Hoelzer et al, Blood, 2002

Residual mediastinal tumor was most frequently the reason for late achievement of CR.

Median follow-up: 41 mo. (range 5-89 mo.)

**

**

***

***

Estimate for OS and DFS at 7 Yearsin Adult T-LBL

D Hoelzer et al, Blood, 2002

Median treatment duration: 8 months (range, 38 days-18 months)

Initial Involvement, Relapse Localization,Time to Relapse, and Survival in 15/42

(36%) Relapse Patients

D Hoelzer et al, Blood, 2002

Median time to relapse:147 d. (range, 23-426 d.)

CNS relapse= 2%

GMALL T-LBL Study 1/2004

V I IIInduction

CNS RT24 GY

Med RT36 Gy

Cons 1°

SC-Apher.

CRuCR

CLAEGSCT (Auto, allo)PR

Fail

HD-MTXASP

6MP

IIIRenduction

HD-MTXASP

6MP

VM26ARAC

CYCLOARAC

HD-MTXASP

6MPEnd of Therapy

4 11 16 22 3630 41 46 531

MRD MRD MRD MRD (MRD) MRD MRDMRD

I. T.Weeks

CT CTCT/PET

+RT 46 Gy PET+

D A Thomas et al, Blood, 2004No PCRT; IFRT (30-39 Gy) for all pts with med. dis (70%).

Outcome with the Hyper-CVAD Regimen in33 patients with LBL (1992-2001)

D A Thomas et al, Blood, 2004

CR= 91%3-yr OS=70%3-yr PFS=66%Median follow-up:

48 mo. (range 8-110mo.)

Pattern of Relapse in 10/33 (30%)Patients with LBL

Treated with the Hyper-CVAD Regimen

D A Thomas et al, Blood,2004

Clinical Outcome of 27 Children and Adolescentswith B-LBL Treated with ALL Protocols (BFM 86

and 90)

O Neth et al, Med Pediatr Oncol, 2000

ALL-type Therapy for 105 Childrenwith T-LBL (BFM 90)

A Reiter et al, Blood,2000

MTX 5g/sqm

18 12 Gy

LRT omitted

(LRT 30 Gy+AlloSCT)

Clinical Outcome

A Reiter et al, Blood, 20001/105 sAML (0.95%)

Treatment of childhood T-LBL according to thestrategy for ALL, without radiotherapy: Long term

results of the EORTC CLG 58881 trial

Patients: 121 Treatment: BFM without PCRT and LRT EFS at 6 years: 77.5% OS at 6 years: 86%

A Uytterbroeck et al, Eur J Cancer, 2008

HDT with Auto/Allo-SCT ?

Study Design of a RandomizedTrial of EBMT and UKLG

J W Sweetenham et al, JCO, 2001

Results

J W Sweetenham et al, JCO, 2001

3yr=24%

3 yr=55%N=119

Response to inductiontherapy:

- ORR= 82%

- CR= 56%

- TRM= 0.8%

Randomized pts= 69%

3-yr= 45 vs 56%

Conclusion: the use of HDT and ASCT in adult patients with LBL in 1st remissionafter intensive remission induction therapy did not improve OS compared withconventional-dose therapy in this randomized trial.

P=.065

Probability of DFS and OS by Type ofTransplant (IBMTR/ABMTR) (1989-1998)

J E Levine et al Blood,2003

N=76

N=128

DFS OS

Cumulative incidence of treatment relatedmortality or relapse by type of transplant

E Levine et al Blood, 2003

TRM RELAPSE

M Aljurf and ZA Zaidi, Biol Blood Marrow Transplant, 2005

M Aljurf and Z A Zaidi, Biol Blood Marrow Transplant 2005

• Assessing CT-PET and MRDto boost risk-oriented therapy

Maximum Standardized Uptake Value(SUV) in Four Types of Lymphoma

N Tsukamoto et al, Cancer2007

N Tsukamoto et al, Cancer 2007

Diagnostic PET in T-Lymphoblastic Lymphoma

Sites of involvement:Sites of involvement:MEDIASTINUMMEDIASTINUMR HILUMR HILUMR AXILLAR AXILLALIVER (sIV-sV) LIVER (sIV-sV) D8-D10D8-D10

Postinduction PET in T-Lymphoblastic Lymphoma

MRD: defines sensitivity to early treatmentMRD: defines sensitivity to early treatment 1. surrogate marker of long-term response 1. surrogate marker of long-term response 2. decisional aid for risk-adapted therapy2. decisional aid for risk-adapted therapy

Overt ALLOvert ALL

MRDMRD(RQ-PCR)(RQ-PCR)

1010-3-3

1010-5-5

1010-1-1

CRCR

risk of relapse

risk of relapse

11

22

TIMETIME

INDIND CONSOLIDATION CONSOLIDATION MAINTENANCEMAINTENANCE

33 cure possiblecure possible

11 MRD persistenceMRD persistence22 MRD relapseMRD relapse33 MRD clearingMRD clearing

BM BM (in T-LBL reveals occult disease)(in T-LBL reveals occult disease)

Molecular markerMolecular marker(Ig/TCR(Ig/TCRrearrangement)rearrangement)

ImmunophenotypeImmunophenotype(TdT/cyCD3, (TdT/cyCD3, ……))

Prospective NILG Study (2000)Prospective NILG Study (2000)MRD based treatment decisionsMRD based treatment decisions

MaintenanceMaintenance(1-Y)(1-Y)

11 2828 70701010

1151151616

1541542222

prepreC1C1 C2C2 C3C3 C5C5 C6C6 C8C8HD4HD4 HD7HD7

DayDayWeekWeek

Diagnosis Diagnosis CRCR TP1TP1 TP2TP2 TP3TP3

HH

MRDMRDnegneg

MRDMRDu/ku/k SR SR

MRDMRDpospos

MRDMRDu/k u/k HRHRH/CH/C

11H/CH/C

22H/CH/C

33H/CH/C

44

RR RR RR RR

MaintenanceMaintenance(2-Y)(2-Y)

allogeneicallogeneicSCTSCT

oror (no donor) (no donor)

MRDMRD

MRDMRD

PDN-CYPDN-CY

IDR, VCR, ASP, PDN (ind); IDR, VCR, CY, DXM (cons)IDR, VCR, ASP, PDN (ind); IDR, VCR, CY, DXM (cons)

HD MTX-AraC HD MTX-AraC

Cranial RTRCranial RTR

Treatment elementsTreatment elements

maintenancemaintenance 6MP-MTX for 2 yy6MP-MTX for 2 yyV-P alternating monthly with CY-AraC V-P alternating monthly with CY-AraC (1st y)(1st y)

HD 6MP-VP-melHD 6MP-VP-mel

HD MTX-Ara-CHD MTX-Ara-CHH Blood stem cell harvest / reinfusionBlood stem cell harvest / reinfusionRR

VHRVHR Ph/t(4;11)+Ph/t(4;11)+allogeneic SCTallogeneic SCT

Clinical Characteristics of 30 LBL PatientsTreated with NILG ALL 09/00 Protocol

17 (57) Ann Arbor stage III-IV

17/13 (57/43) Sex: M/F

22/30 (73%) Mediastinal involvement

Characteristics value No of pts (%) number 30 (100)

median age yrs (range) 27 (16-57)

Elevated LDH 18 (60)

Immunophenotype: T-lineage B-lineage

24 (80) 6 (20)

% of blasts in BM: <5 5-20

18 (60) 12 (40)

Clinical Outcome of 30 LBL PatientsTreated with NILG ALL 09/00 Protocol

2 (7)Death in CR (sAML, sDLBCL)

Outcome Value No of pts (%) CR 28 (93)

PR/NR 2 (7)

Relapse:(4 BM; 1 abd.;1mediast.*)

5/30 (17)

1st CCR** 21 (75)

*Mediastinal irradiation (Gy 24-32): 7/22 (32%)

**Median follow-up, years (range): 3.9 (0.8-9.2)

Overall Survival of 30 LBL Patients(NILG Protocol 09/00)

0.0

00.2

50.5

00.7

51.0

0

Cum

ula

tive s

urv

ival

0 2 4 6 8 10

years

.

72% at 5 yrs (n=30)

Disease-Free Survival of 30 LBLPatients (NILG Protocol 09/00)

0.00

0.25

0.50

0.75

1.00

Cum

ulat

ive s

urviv

al

0 2 4 6 8 10years

.

77% at 5 yrs (n=28)

Cumulative Incidence of Relapse(NILG Protocol 09/00)

0.0

00.2

50.5

00.7

51.0

0

Cum

ula

tive s

urv

ival

0 2 4 6 8 10

years

.

18% at 5 yrs (n=28)

Study DesignELIGIBILITY/REGISTRATION

(Clinical Trial: age 18-65 years)AND INDUCTION/CONSOLIDATION

C1

C2

CT-PET (MEDIASTINAL IRRADIATION 36 Gy if residual mass >2 cm) MRD-1 (eligible to ALLO-SCT if >10-4)

C4

C6

C8

chest X-Ray/CTMRD-2

CT-PET MRD-3

C3:C3: MTX 5 g/mMTX 5 g/m 2 2 + Ara+ Ara --CC

CT-PET NEGand MRD NEG

CT-PET POSand/or MRD POS

MAINTENANCEMAINTENANCE ALLOGENEIC SCTALLOGENEIC SCT

orAUTOLOGOUS SCTAUTOLOGOUS SCT +

= IT MTX/AraC/PDN

C5:C5: MTX 5 g/mMTX 5 g/m 2 2 + + AspAsp

C7:C7: MTX 5 g/mMTX 5 g/m 2 2 + Ara+ Ara--CC

w10TP-1

w22TP-3

w16TP-2

ONLY IRRADIATED PATIENTS:ALL PATIENTS:

ALL PATIENTS:

ALL PATIENTS:

MAINTENANCEMAINTENANCE

prew1/d1

w5/d29

w8/d50

w11/d71

w14/d92

w17/d113

w20/d134

w23/d155

RISK-ORIENTED THERAPY

*

*Stem cell harvest

Conclusions

• Intensive ALL-type programs are associated withimproved outcome.

• IT chemotherapy is required to reduce CNS relapse rate.The role of PCRT as an addition to IT prophylaxis isunclear.

• Local recurrence most frequently involves themediastinum. Consolidative mediastinal RT and/or moreintensive ALL-type intensification may decreasemediastinal relapse.• A convincing prognostic model has not yet beendefined. Better assessment of individual risk may bebased on evaluation of early MRD and CT-PET response.

• Patients with adverse prognostic features should beconsidered for SCT.

Rare Oral Cavity Presentation of aB-LBL

A: CD20 diffusely and strongly positive in all neoplastic cellsB: TdT strong nuclear reactivity in neoplastic cellsC: BCL2D: CD99 diffuse cytoplasmic reactivity

DP Cox et al,OOOOE, 2007

Risk Stratification According to IPIin Adult T-LBL

J W Sweetenham et al, JCO, 2001

ALLOGENEIC SCTALLOGENEIC SCT

orAUTOLOGOUS SCTAUTOLOGOUS SCT + MAINTENANCEMAINTENANCE

MAINTENANCEMAINTENANCE

CT-PET NEG MRD NEG

CT-PET POS MRD POS

CY

CY

V/P

V/P

CY

CY

V/P

V/P

CY

CY

V/P

V/P

mo.1

mo.4

mo.8

mo.12

mo.16

mo.20

mo.24

CT-PETMRD

CT-PETMRD

CT-PETMRD

MRD

MRD

MRD

RISK-ORIENTED THERAPY

FOLLOW-UPPROTOCOL

= IT MTX/AraC/PDN

Key:CY

=CY dd 1-4, 6MP/MTX dd 8-28

V/P =VCR d1, PDN dd 1-5, 6MP/MTX dd 8-28

1 YEAR1 YEAR

Evaluation of MRD and PostremissionTherapy

1 rel, alive in 2° CR4 alive in CR

3 alive in CR; 3 deathsin relapse; 1 death inCR (1 DLBCL)

1 alive in CR

1 alive in CR

5 maintenance

7 hypercycle

1 allog. Transpl.

1 RT

14/25 (56)Unknown

3 alive in CR2 deaths in relapse

1 maintenance3 allog. transpl.1 hypercycle

5/25 (20)Positive

5 alive in CR1 death in CR (AML)

6 maintenance6/25 (24)Negative

Outcome Phase B therapyNo of patients (%) MRD

A retrospective analysis of 92 patientswith adult LBL (LNH 87/93)

S Le Gouill et al, Leukemia 2003

5 yr= 32%

5-yr=22%

TRM=4%

Comparative Studies

R Bouabdallah et al, Ann Oncol, 1998

M Hunault et al, Haematologica, 2007

CR= 71%

7-yr OS= 64%

7-yr RFS= 65%

None of theNone of thepatientspatientsreceivedreceived

Mediastinal/Mediastinal/Local RTLocal RT

Genetics of B-LBL

B lymphoblastic leukaemia/lymphoma, not otherwise specified:Nearly all cases have clonal DJ rearrangements of the IGH@gene. Inaddition T-cell receptor gene rearrangement may be seen in up to70% of cases. The majority of patients have cytogeneticabnormalities: del (6q), del (9p), del (12p), t (17;19).

B lymphoblastic leukaemia/lymphoma with recurrent geneticabnormalities:

t(9;22)(q34;q11.2); BCR-ABL1 t(v;11q23); MLL rearranged t(12;21)p13;q22); TEL-AML 1 (ETV6/RUNX1) Hyperdiploidy Hypodiploidy t(5;14)(q31;q32); IL3-IGH t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1)

WHO 2008

M Aljurf and Z A Zaidi, Biol Blood Marrow Transplant, 2005

No chromosomal or molecular abnormalities have been consistently shown to carryprognostic significance except the t(9;17)(q34;q23) karyotype, which has beenassociated with an aggressive clinical course in children.

Genetics of T-LBL