Lymphoma in children. Prof. Dr. Geneviève Laureys. Pediatrische Hematologie, Oncologie en Stamceltransplantatie. UZ Gent
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1 Lymphoma in children Prof. Dr. Geneviève Laureys Pediatrische Hematologie, Oncologie en Stamceltransplantatie UZ Gent BHS educational course: Seminar 12 - Hodgkin s lymphoma & aggressive lymphoma
2 Lymphoma in children: General aspects, different from treating adult cancer Hodgkin Lymphoma Non Hodgkin Lymphoma Conclusions 2
3 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 y) PHO zorgplan/plan cancer (MB 02/04/2014) < 16 y Pediatrie zorgplan/ (MB 02/04/2014) < 15 y 3
4 Lymphoma in children: general aspects 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 4
5 Lymphoma in children: general aspects Childhood cancers in Belgium: 320 new pts/year 40 à 45 pts with Lymphoma ICCC-3 I II III IV IIa IIb IIc IId IIe V VI VII VIII IX X XI XII Label Leukaemias, myeloproliferative and myelodysplastic diseases Lymphomas and reticuloendothelial neoplasms Hodgkin lymphoma Non-Hodgkin lymphoma Burkitt lymphoma Miscellaneous lymphoreticular neoplasms Unspecified lymphoma CNS and miscellaneous intracranial and intraspinal neoplasms Neuroblastoma and other peripheral nervous cell tumours Retinoblastoma Renal Tumours Hepatic tumours Malignant bone tumours Soft tissue and other extraosseous sarcomas Germ cell tumours, trophoblastic tumours and neoplasms of gonads Other malignant epithelial neoplasms and malignant melanomas Other and unspecified malignant neoplasms
6 Lymphoma in children: general aspects 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 6
7 Lymphoma in children: general aspects 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) 7
8 Lymphoma in children: general aspects 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 8
9 Lymphoma in children: general aspects 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 9
10 Lymphoma in children: general aspects 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 10
11 Lymphoma in children: general aspects, different from adult cancer Should Adolescents With Acute Lymphoblastic Leukemia Be Treated as Old Children or Young Adults? 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 Boissel N et al., J. Clin Oncol 2003 Mar 1;21(5):
12 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 12
13 Hodgkin Lymphoma in children 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? Diagnostic evaluation Physical examination, Blood, Rx, lymph node biopsy, ultrasound, PET CT scan. Bone marrow biopsy > IIA disease., 13
14 Hodgkin Lymphoma in children Histology 1. Classical - nodular sclerosing - mixed cellularity - lymphocyte-rich classical - lymphocyte depletion 2. Lymphocyte-predominant Staging:Ann Arbor Staging System adapted I II III IV A/B Antigen Class HL LP HL CD-20 other B-cell antigens Occasionally pos Usually neg Usually pos Usually pos CD-30 pos negative CD-15 Usually pos negative Ig expression absent present single lymph node region or single extralymphatic site 2 or more lymph node regions same side of diafragma lymph node regions on both sides diafragma may include spleen or extralymphatic sites diffuse extralymphatic disease (liver, bone marrow, lung, skin) depending on symptoms 14
15 Hodgkin Lymphoma in children 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/mm 3 or higher) Anemia (hemoglobin lower than 11.0 g/dl). Male gender 15
16 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 % 16
17 Hodgkin Lymphoma in children: Clinical case
18 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 18
19 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 19
20 PHL-C1 study 20
21 Hodgkin Lymphoma in children 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 21
22 Hodgkin Lymphoma in children Results of PHL-C1 study: TG 1 Identification of high risk group in TG 1 22
23 Hodgkin Lymphoma in children COPP and COPDAC: similarly efficacious -> COPDAC (FSH ~normal after COPDAC, increased after COPP ) 23
24 Hodgkin Lymphoma in children 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) 24
25 Hodgkin Lymphoma in children 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) 25
26 Hodgkin Lymphoma in children Prognosis EFS: > 90 % OS : > 85 % Late effects - Growth impairment after radiation - Hypothyroidy - Second tumours 26
27 Non Hodgkin Lymphoma in children Almost all NHL in children are high grade Different NHL subtypes require different treatment strategies Epidemiology Incidence Diagnostic evaluation Histology Staging Prognostic factors Clinical cases Treatment/European trial Prognosis and Late effects 27
28 Non Hodgkin Lymphoma in children 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) 28
29 Non Hodgkin Lymphoma in children 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) 29
30 Diagnostic work-up, classification, and stratification of childhood non-hodgkin lymphoma (NHL) subtypes into treatment groups Reiter A Hematology 2007;2007: by American Society of Hematology
31 Enlarge Category (WHO Classification/ Updated REAL) Category (Working Formulation) Immuno-phenotype Clinical Presentation Chromosome Translocation Genes Affected Burkitt and Burkittlike lymphomas Diffuse large B-cell lymphoma Lymphoblastic lymphoma, precursor T-cell leukemia, or precursor B-cell lymphoma Anaplastic large cell lymphoma, systemic ML small noncleaved cell ML large cell Lymphoblastic convoluted and nonconvoluted ML immunoblastic or ML large Mature B cell Mature B cell; maybe CD30+ Pre-T cell Pre-B cell CD30+ (Ki-1+) T cell or null cell Intra-abdominal (sporadic), head and neck (non-jaw, sporadic), jaw (endemic), bone marrow, CNS Nodal, abdominal, bone, primary CNS (when associated with immunodeficiency), mediastinal Mediastinal, bone marrow Skin, bone, mediastinal Variable, but systemic symptoms often prominent t(8;14)(q24;q32), t(2;8)(p11;q24), t(8;22)(q24;q11) No consistent cytogenetic abnormality identified MTS1/p16ink4a; Deletion TAL1 t(1;14)(p34;q11), t(11;14)(p13;q11) t(2;5)(p23;q35); less common variant translocations involving ALK C-MYC, IGH, IGK, IGL TAL1, TCRAO, RHOMB1, HOX11 ALK, NPM Anaplastic large cell lymphoma, cutaneous CD30+ (Ki-usually) T cell Skin only; single or multiple lesions Lacks t(2;5) 31
32 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 32
33 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 33
34 Non Hodgkin Lymphoma in children: clinical cases Open biopsy: Diagnosis: Burkitt- NHL, kappa positive Staging PET CT: no other localisations Bone marrow: negative CNS: negative Stage III according to Murphy 34
35 1. Mature B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma) 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 betweentreatment- intervals short efficient CNS-directed therapy to address the strong tendency for invasion of the CNS 35
36 Non Hodgkin Lymphoma in children 1. Mature B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma) 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 36
37 Non Hodgkin Lymphoma in children 1. Mature B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma) 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 % 37
38 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 38
39 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! 39
40 Non Hodgkin Lymphoma in children: clinical cases 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 01/02/2013: most likely diagnosis: T-NHL 04/02/2013: after 3 days of corticosteroids 40
41 Non Hodgkin Lymphoma in children: clinical cases 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 % 41
42 Non Hodgkin Lymphoma in children 2. LBL: Lymphoblastic Lymphoma 80 % T 20 % precursor B Excellent survival with treatment ~Acute Lymphoblastic Leukemia protocols (Belgium/France: EORTC: ) Result: T-NHL: EFS and OS: EORTC trial Uyttebroeck et al., 42
43 Non Hodgkin Lymphoma in children: clinical cases 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 43
44 Non Hodgkin Lymphoma in children: clinical cases Girl, 8 y Biopsy skin and LN: ALCL, high risk EMA positive, CD15 pos, CD30 pos, ALK: pos T2;5 presence of NPM-ALK transcripts Stage 3 St Jude 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 44
45 Non Hodgkin Lymphoma in children 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. 45
46 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,
47 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 47
48 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. 48
49 49
50 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. 50
51 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. 51
52 Non Hodgkin Lymphoma in children 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 52
53 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 % 53
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