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11© 2008 Universitair Ziekenhuis Gent

Lymphoma in children

Prof. Dr. Geneviève Laureys

Pediatrische Hematologie, Oncologie en

Stamceltransplantatie

UZ Gent

BHS educational course: Seminar 12 - Hodgkin’s lymphoma & aggressive lymphoma 07-03-2015


Lymphoma in children:

• General aspects, different from treating adult

cancer

• Hodgkin Lymphoma

• Non Hodgkin Lymphoma

• Conclusions


Lymphoma in children: general aspects

“treating children with cancer (lymphoma) is

different from treating adults with cancer”

- Rare disease

- Definition of ‘Child’- Age limit: < 21, 18, 16, 15 y?

- International: 18 y

- Belgium:

• Cancer registry (2 groups: < 15 y and 15 - 19 y)

• PHO zorgplan/Plan cancer (MB 02/04/2014) < 16 y

• Pediatrie zorgplan/ (MB 02/04/2014) < 15 y



Lymphoma: 3rd Cildhood cancer: 13 %:

Belgium: ~40 à 45 new cases/ year

Non Hodgkin lymphoma:

Belgium < 15 y: ~25 patients/year, ~16 boys, 9 girls

Hodgkin lymphoma:

Belgium < 15 y: ~15 patients/year, ~9 boys, ~6 girls

ICCC-3 Label

ILeukaemias, myeloproliferative and

myelodysplastic diseases

IILymphomas and reticuloendothelial

neoplasms

IIa Hodgkin lymphoma

IIb Non-Hodgkin lymphoma

IIc Burkitt lymphoma

IIdMiscellaneous lymphoreticular

neoplasms

IIe Unspecified lymphoma

IIICNS and miscellaneous intracranial

and intraspinal neoplasms

IVNeuroblastoma and other peripheral

nervous cell tumours

V Retinoblastoma

VI Renal Tumours

VII Hepatic tumours

VIII Malignant bone tumours

IXSoft tissue and other extraosseous

sarcomas

XGerm cell tumours, trophoblastic

tumours and neoplasms of gonads

XIOther malignant epithelial neoplasms

and malignant melanomas

XIIOther and unspecified malignant

neoplasms


Childhood cancers in Belgium:

320 new pts/year

40 à 45 pts with Lymphoma



Classification:

HL: diagnosis and classification comparable to adults

NHL: in children: high grade, urgency!

1. Mature B-cell NHL (Burkitt and Burkitt-like

lymphoma/leukemia and diffuse large B-cell lymphoma)

2. Lymphoblastic lymphoma (T or precursor B)

3. Anaplastic Large Cell Lymphoma

4. Rare: others



Clinical international trials: (almost) all patients registered or

in study protocols

BSPHO: Belgian Society for Pediatric Hematology and

Oncology: 7 Childhood Cancer Centers

2 Belgian representatives for each cancer type at

international meetings/working groups, HL and NHL: Anne

Uyttebroeck (Leuven), Geneviève Laureys (Gent)

Common protocols:

HL: EuroNet-PHL-Study-Group

NHL: EICNHL : European Intergroup for Childhood

Non Hodgkin Lymphoma (mature B-NHL and ALCL)

EORTC: pre-B and T-NHL (~leukemia protocol)



Prognosis:

non-Hodgkin lymphoma (NHL), 5-year overall survival:

• 88% in children < 15 years,

• 77% for adolescents (15 -19 years)

Hodgkin lymphoma:

• 94% for children and adolescents

Treatment: particular problems related to Childhood Cancer Treatment

• Off label use of drugs

• Dosages: according to age, weight, pharmacy preparations

• Chemotherapy and radiotherapy: growth, maturation in

developing body



Rehabilitation:

to achieve optimal survival and quality of life

Education/school:

to continue

Contact peers:

beneficial

Long term toxicity:

fertility

second cancers

organ toxicity

Ado weekend



Children and adolescents with cancer:

Treated by -> multidisciplinary team of cancer specialists

with experience treating the cancers that occur during childhood

and adolescence, to insure that children receive treatment,

supportive care and rehabilitation that will achieve optimal survival

and quality of life.

Teacher Ado weekend


Lymphoma in children: general aspects, different

from adult cancerShould Adolescents With Acute Lymphoblastic Leukemia Be

Treated as Old Children or Young Adults?

Boissel N et al., J. Clin Oncol 2003 Mar 1;21(5):774-80.

Adolescents treated in the pediatric

protocol (FRALLE) had significantly

better results for remission

achievement and EFS than treated with

adult protocol (LALA).

Reason:

-dose intensity higher in pediatric

protocols

-Strict timing

Other studies: same conclusions

http://jco.ascopubs.org/content/21/5/774/F1.expansion.html

http://jco.ascopubs.org/content/21/5/774/F1.expansion.html


Hodgkin Lymphoma in children

one of the few pediatric malignancies that shares

aspects of its biology and natural history with

an adult cancer

Epidemiology

Incidence

Diagnostic evaluation

Histology

Staging

Prognostic factors

Clinical case

Treatment/European trial

Prognosis



Epidemiology:

The male-to-female ratio varies markedly by age.

Children younger than 5 years show a strong male

predominance (M:F = 5.3) and children aged 15 to 19

years show a slight female predominance

Incidence:

6 % of childhood cancers?


Physical examination, Blood, Rx, lymph node biopsy,

ultrasound, PET CT scan.

Bone marrow biopsy > IIA disease.,



Histology

1. Classical

- nodular sclerosing

- mixed cellularity

- lymphocyte-rich classical

- lymphocyte depletion

2. Lymphocyte-predominant

Staging:Ann Arbor Staging System adaptedI single lymph node region or single extralymphatic site

II 2 or more lymph node regions same side of diafragma

III lymph node regions on both sides diafragma may include

spleen or extralymphatic sites

IV diffuse extralymphatic disease (liver, bone marrow, lung,

skin)

A/B depending on symptoms

Antigen Class HL LP HL

CD-20 Occasionally

pos

Usually

pos

other B-cell

antigens

Usually neg Usually

pos

CD-30 pos negative

CD-15 Usually pos negative

Ig

expression

absent present



Prognostic factors:

Advanced stage of disease

Presence of B symptoms.

Presence of bulky disease.

Extranodal extension.

Elevated erythrocyte sedimentation rate.

Leukocytosis (white blood cell count 11,500/mm3 or

higher)

Anemia (hemoglobin lower than 11.0 g/dL).

Male gender


Hodgkin Lymphoma in children: Clinical case

girl, 14 years

Complaints: since a few weeks: fatigue, fever, night sweats,

weight loss, cough

Physical examination: LN supraclavicular right: 2x4cm, no

hepatosplenomegaly.

Blood: 10.3 g/dL, ESR: 59 mm, LDH: nl

Imaging: PET CT localisations: cervical, mediastinal,

parenchymatous lung lesions, spleen

Trachea: compression but not more than 50 %

• Hodgkin Lymphoma in children: Clinical case


Biopsy: LN supraclavicular: Hodgkin, nodular sclerosis

Stage : IVB: Treatment Group 3

ENT: negative

bilateral bone marrow biopsy: negative,

Stage IV because of lung involvement, not contiguous

Discussion: ovarium preservation?

Done (laparascopy), during insertion PAC

Therapy: 2 x OEPA

Response evaluation: PET-CT: evaluation after 2 OEPA: adequate

response

Further treatment: Randomisation: 4 x COPDAC and no

radiotherapy

Hodgkin Lymphoma in children: Clinical case


Hodgkin Lymphoma in children:

EuroNet-PHL-Study-Group C1: classic HL

Treatment groups:

TG-1: patients of stages I A/B and II A

TG-2: patients of stages IEA/B, IIEA, II B or III A

TG-3: patients of stages IIEB, IIIEA/B, III B or IV A/B

No radiotherapy if adequate reponse after 2 OEPA

Randomisation

TG-2 and TG-3: COPDAC versus COPP to avoid gonadal

damage


PHL-C1 study



Results of PHL-C1 study: 2033 pts

TG-1: patients of stages I A/B and II A: 570pts

61 % : no RT, 39 % RT

TG-2: patients of stages IEA/B, IIEA, II B or III A

50 % : no RT, 50 % RT: 348 pts

TG-3: patients of stages IIEB, IIIEA/B, III B or IV A/B: 675 pts

32 % : no RT, 68 % RT



Results of PHL-C1 study: TG 1

Identification of high risk group in TG 1



COPP and COPDAC: similarly efficacious

-> COPDAC (FSH ~normal after COPDAC, increased after COPP )



Interim phase: Treatment guidelines

Pts with bulk disease and ESR>30 mm: TG 2

OEPA: Vincristin (d1,8,15: 1.5 mg/m2),

Etoposide (d1-5, 125mg/m2),

Prednisone (60 mg/m2 d1-15)

Doxorubicin (d1, d15: 40 mg/m2)



Interim phase: Treatment guidelines

COPDAC: Vincristine (d1,8: 1.5 mg/m2)

Prednisone (40 mg/m2: d1-15)

Dacarbazine (d1-3: 250mg/m2)

Cyclophosphamide: (d1,8: 500 mg/m2)



Prognosis

EFS: > 90 %

OS : > 85 %

Late effects

- Growth impairment after radiation

- Hypothyroidy

- Second tumours


Non Hodgkin Lymphoma in children

Almost all NHL in children are high grade

Different NHL subtypes require different treatment

strategies

Epidemiology

Incidence


Histology

Staging

Prognostic factors

Clinical cases

Treatment/European trial

Prognosis and Late effects



1. Mature B-cell NHL (Burkitt and Burkitt-like lymphoma) and

diffuse large B-cell lymphoma

40 à 50 %, 5-y EFS: 90 %

2. Lymphoblastic lymphoma (primarily precursor T-cell

lymphoma, precursor B-cell lymphoma)

30 à 40 %, 5-y EFS: 85 %

3. Anaplastic large cell lymphoma (T-cell or null-cell

lymphomas)

10 à 15 %, 5-y EFS: 75 %

(4. Very rare: peripheral T-cell lymphoma, NK lymphomas,

cutaneous lymphomas, and indolent B-cell lymphomas (e.g.,

follicular lymphoma)



Diagnostic evaluation- Sample: tumour/ LN/ fluid/ BM

- Cytomorphology

- Histomorphology

- Immunophenotyping

- Cytogenetics

-> correct classification and allocation of patients to

appropriate treatment subgroups, according to the WHO

classification

ultrasound, PET CT scan, bone marrow (biopsy), CNS

Staging: St.Jude Staging system (Murphy)

Diagnostic work-up, classification, and stratification of childhood non-Hodgkin lymphoma

(NHL) subtypes into treatment groups

Reiter A Hematology 2007;2007:285-296

©2007 by American Society of Hematology


Category (WHO

Classification/

Updated REAL)

Category (Working

Formulation)Immuno-phenotype

Clinical

Presentation

Chromosome

Translocation Genes Affected

Burkitt and Burkitt-

like lymphomas

ML small

noncleaved cell

Mature B cell Intra-abdominal

(sporadic), head and

neck (non-jaw,

sporadic), jaw

(endemic), bone

marrow, CNS

t(8;14)(q24;q32),

t(2;8)(p11;q24),

t(8;22)(q24;q11)

C-MYC, IGH, IGK,

IGL

Diffuse large B-cell

lymphoma

ML large cell Mature B cell;

maybe CD30+

Nodal, abdominal,

bone, primary CNS

(when associated

with

immunodeficiency),

mediastinal

No consistent

cytogenetic

abnormality

identified

Lymphoblastic

lymphoma,

precursor T-cell

leukemia, or

precursor B-cell

lymphoma

Lymphoblastic

convoluted and non-

convoluted

Pre-T cell Mediastinal, bone

marrow

MTS1/p16ink4a;

Deletion TAL1

t(1;14)(p34;q11),

t(11;14)(p13;q11)

TAL1, TCRAO,

RHOMB1, HOX11

Pre-B cell Skin, bone,

mediastinal

Anaplastic large cell

lymphoma, systemic

ML immunoblastic

or ML large

CD30+ (Ki-1+) Variable, but

systemic symptoms

often prominent

t(2;5)(p23;q35); less

common variant

translocations

involving ALK

ALK, NPM

T cell or null cell

Anaplastic large cell

lymphoma,

cutaneous

CD30+ (Ki-usually) Skin only; single or

multiple lesions

Lacks t(2;5)

T cell

Enlarge

http://www.cancer.gov/cancertopics/pdq/treatment/child-non-hodgkins/HealthProfessional/Table2


Non Hodgkin Lymphoma in children:

Prognostic factors: Age:

> 15 years: poorer outcome, but attributable primarily to

patients with diffuse large B-cell lymphoma

rare in infants , < 1 %, but inferior outcome

Site:

no effect of bone, testicular disease

mediastinal involvement: inferior outcome

primary mediastinal B-cell lymphoma, 3-year EFS: 50% -

70%

CNS/BM disease at presentation: 3-year EFS : 70% (B-NHL)

Tumor burden

Response to treatment

Chromosomal Abnormalities


Non Hodgkin Lymphoma in

children: clinical cases

Boy, 8 years old

GP: for constipation, phys. examination: fecaloma?

R/ enema -> no result

Pediatrician in hospital: R/enemas, stools but still mass

palpable, examination: ultrasound, CT scan-> abdominal

mass suprapubic

Referral to UH Ghent: 01/03/2015

Blood: Blood counts: normal, LDH: elevated < less than 2

times upper limit




Open biopsy: Diagnosis: Burkitt- NHL, kappa positive

Staging

PET CT: no other localisations

Bone marrow: negative

CNS: negative

Stage III according to Murphy




Extremely high proliferative (treatment urgent)

Principles of treatment:

-maintain cytotoxic active drug concentrations over a

period sufficient to affect as many lymphoma cells as

possible during the vulnerable active cell cycle

combining drugs with different mechanisms of action

and few overlapping toxicities

high-dose intensity over time, keeping between-

treatment- intervals short

efficient CNS-directed therapy to address the strong

tendency for invasion of the CNS





• current highly efficacious regimen ~ considerable acute

toxicity

• 3% risk to die from treatment-related complications, ‘acute

tumour cell lysis syndrome’

• oro-intestinal mucositis, and severe neutropenia->

admissions for febrile neutropenia episods -> prompt

antibiotic treatment





• Most relapses occur during therapy

• Short treatment (cfr stage and risk group):

COP-COPADEM1-COPADEM2-CYM 1-CYM2: 14 ww

COP-COPADEM1-COPADEM2-CYVE1-(HDMTX)- CYVE 2- M1-

M2 (20 ww)

• no radiotherapy

• Few relapses after 1 year post stop treatment

• 5-y EFS: 90 %


Non Hodgkin Lymphoma in children: 1. Mature B-cell NHL

Treatment: Intergroup trial for children or adolescents with B-

cell NHL or B-AL: evaluation of Rituximab efficacy and

safety

Rationale:

Rituximab has extended the survival of adult pts with Diffuse

Large B-Cell lymphoma (DLBL) and is standard treatment of

B-cell lymphoma in adults.

Questions: Efficacy and safety of rituximab added to

chemotherapy in childhood lymphoma?

Results from adult B-NHL cannot be assumed to apply to

children, because of differences in biology, > 75 % of

childhood B lymphoma are Burkitt type (efficacy of

rituximab?) and not DLBL


Non Hodgkin Lymphoma in children: 1. Mature B-cell NHL

Evaluation of Rituximab efficacy and safety

EFS: is high in children: 90 %,

EFS: stage III with LDH > Nx2 and stage IV or B-AL: 84 %

Rituximab: expensive, severe side effects (prolonged B-

cell depletion): clinical case: not included (LDH)

randomised trial: evaluation whether 6 injections of

Rituximab to standard chemo improves EFS

Planned: inclusion of 600 pts (Stage III-Stage IV or B-AL)

registration: Primary mediastinal large B-cell lymphoma

(PMBL): same disease as in adults? all patients receive

Rituximab!


04/02/2013: after 3 days of corticosteroids01/02/2013: most likely diagnosis: T-NHL

Girl, no symptoms, referral to pediatric cardiologist because of

heart murmur heard by pediatrician 3 months before, during

consult for varicella. Mediastinal mass seen during

echocardiography! Supraclavicular LN

Cave: patency trachea






CT thorax: Diameter trachea (CT) < 50 %: High risk

general/local anesthesia! Minimal touch!

Cave: Vena cava superior syndrome!

Start of corticosteroids treatment without diagnostic

biopsy

biopsy was performed from supraclavicular lymph node

4 days later

Diagnosis T-NHL

Treatment: (cfr T-ALL treatment) EORTC 58801: based

on the principle of continuous exposure to cytostatics

over long period of time (2 years) , 5-y S: 85 %


Non Hodgkin Lymphoma in children2. LBL: Lymphoblastic Lymphoma

80 % T

20 % precursor B

Excellent survival with treatment ~Acute Lymphoblastic Leukemia

protocols (Belgium/France: EORTC: 589501)

Result: T-NHL: EFS and OS: EORTC trial

Uyttebroeck et al.,


Girl, 8 y

Complaints:

vomiting, diarrhea, fever,

paleness.

R/antibiotics

1 week later: Lymph nodes

enlargement, cervical, anorexia,

skin eruption

Physical examination:

hepatosplenomegaly, skin rash,

LN

Blood: normal

Non Hodgkin Lymphoma

in children: clinical cases


Girl, 8 y

Biopsy skin and LN:

ALCL, high riskEMA positive, CD15 pos, CD30 pos,

ALK: pos

T2;5 presence of NPM-ALK

transcripts

Stage 3 St Jude

Non Hodgkin Lymphoma

in children: clinical cases

Treatment:

EICNHL: European Inter-group Co-operation on Childhood Non-

Hodgkin Lymphoma -ALCL99

Relapse: before 4th intensive course

R/ relapse protocol and allogeneic BMT

FU: 9 y later: remission



3. ALCL: Anaplastic Large Cell Lymphoma

ALCL-99 :

Randomisation: All patients:

6 courses of MTX 1 g/m2 24 hrs and IT (MTX1 )

6 courses of MTX 3 g/m2 over 3 hours without IT (MTX3)

-> EFS comparable

Randomisation: Children and adolescents with high-risk ALCL:

After a prephase and one chemotherapy course

5 chemotherapy courses / 5 chemotherapy courses and vinblastine

injections (6 mg/m(2) during each course followed by weekly

vinblastine, 1 year of treatment.


ALCL-99

The OS is excellent

5-year OS rate of 92%, EFS 75%.

Residual tumor cells do not acquire

resistance to chemotherapy.

The chemotherapy sensitivity of ALCL

after relapse is quite unique

Prolonged treatment with single-drug

vinblastine can induce long-term

survival after

Anti-ALK antibody easily detected in

pts with ALK(+) ALCL

Role of Crizotinib (ALK inh) in future

trials?

Le Delay et al. J Clin Oncol, 2010

http://jco.ascopubs.org/content/28/25/3987/F2.large.jpg

http://jco.ascopubs.org/content/28/25/3987/F2.large.jpg


• Lymphoma in children: Conclusions

- Excellent cure rates

- Challenge: to minimize long term effects without

affecting excellent survival rates

- Role of radiotherapy? used for Hodgkin lymphoma if

insufficient response after 2 chemotherapy courses

- Hodgkin disease: presentation, staging and outcome in

children is comparable with Hodgkin lymphoma in adults

- Non Hodgkin lymphoma in children: high grade cancer,

urgent treatment necessary

- Non Nodgkin lymphoma subtypes of childhood exhibit

significant differences in terms of molecular and cellular

biology and clinical features: crucial for determining

therapeutic strategies


Lymphoma in children: Conclusions

- Invasive diagnostic procedures may be dangerous, e.g. in

case mediastinal tumour/v.cava superior syndrome,

typical for T-NHL, postpone biopsy and start treatment

first

- Children/adolescents with cancer -> to be treated by

multidisciplinary team of specialists with experience in

childhood cancer to ensure that children receive

treatment, supportive care, and rehabilitation that will

achieve optimal survival and quality of life.


“


STAGES OF HODGKIN’S LYMPHOMA ACCORDING TO THE

COTSWOLDS REVISION OF THE ANN ARBOR STAGING

SYSTEM

I Involvement of a single independent lymph node region or

lymph node structure

II Involvement of 2 or more lymph node regions on the same side

of the diaphragm

III Involvement of lymph node regions or lymph node structures

on both sides of the diaphragm

IV Involvement of extra-nodal sites beyond “E”-sites

A. No B symptoms

B. B. At least one of the following systemic symptoms

a. Inexplicable weight loss of more than 10% within the last 6

months

b. Unexplained persisting or recurrent temperature above 38 °C

c. Drenching night sweats

E. Involvement of a single extra-nodal site contiguous or

proximal to known nodal site.


CLINICAL STAGING SYSTEM FOR HIGH GRADE

NON-HODGKIN'S LYMPHOMA (MURPHY)

Stage

I A single tumor (extranodal) or single anatomic area (nodal) with the

exclusion of mediastinum or abdomen.

II A single tumor (extranodal) with regional node involvement.

Two or more nodal areas on the same side of the diaphragm.

Two single (extranodal) tumors with or without regional node involvement on

the same side of the diaphragm. A primary GI tract tumor, usually in the

ileocecal area, with or without involvement of associated mesenteric nodes

only.

III Two single tumors (extranodal) on opposite sides of the diaphragm.

Two or more nodal areas above and below the diaphragm.

All the primary intrathoracic tumors (mediastinal, pleural, thymic).

All extensive primary intra-abdominal disease.

All paraspinal or epidural tumors regardless of other tumors site(s).

IV Any of the above with initial CNS or bone marrow involvement.



Epidemiology:

Burkitt lymphoma mature B-cell lymphoma:

15% of cases in Europe or the United States will have EBV

detectable in the tumor tissue

immunodeficiency, both congenital and acquired (human

immunodeficiency virus infection [HIV] or posttransplant

immunodeficiency),

Rare as secondary malignancy

PTLD


• Non Hodgkin Lymphoma in children

1. Mature B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia

and diffuse large B-cell lymphoma).

40 à 50 %

Rapidly repeated dose-intense chemotherapy courses

5-y EFS: 90 %

2. Lymphoblastic lymphoma (LBL)

30 à 40 % (numbers may vary according to study/population/age

limit)

Therapeutic protocols cfr ALL, (Belgium: EORTC) based on the

principle of continual exposure to cytostatics over long period of

time

5-y EFS: 85 %

3. Anaplastic large cell lymphoma (mature T-cell or null-cell

lymphomas):

10 à 15 %

different therapeutic strategies? EICNHL-ALCL, 6 courses

5-y EFS: 75 %

prof. dr. geneviève laureys stamceltransplantatie uz gent...antigen class hl lp hl cd-20...

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