Acute lymphoblastic leukemia & agressive lymphoma in children - PowerPoint PPT Presentation

Acute lymphoblastic leukemia & agressive lymphoma in children BHS training course, 14/12/2019 Barbara De Moerloose Dept. Pediatric Hematology-Oncology and Stem Cell Transplantation Ghent University Hospital barbara.demoerloose@uzgent.be

Age specific incidence of pediatric cancer * Cancer incidence in children (<16y): ~ 150 per million per year * 1/600 children is diagnosed with cancer before 16 years of age * Belgium: ~ 300-350 new cases (<14y) per year Male Female per 1.000.000 Age (years)

(2004-2013)

Acute lymphoblastic leukemia Neuroblastoma Acute myeloid leukemia Retinoblastoma Nephroblastoma Hepatoblastoma Leeftijd Age specific incidence rate (/1.000.000) Hodgkin lymphoma Non Hodgkin lymphoma Burkitt lymphoma Other lymphoma

Incidence: 5.2 (M) and 3.9 (F)/100.000 N = 181 in 2012 N = 502 in 2012 52% M – 48% F 56% M – 44% F 54% younger than 20y Med age: 64 y Med age: 27/31 y (M/V)

Pediatric leukemia and lymphoma types (Belgian Cancer Registry, 2004-2013) Leukemia 25% Lymphoma 13% Hodgkin lymphoma 4% Non Hodgkin lymphoma 9% Burkitt lymphoma (50-60%) 3% Diffuse large B-cell lymphoma (DLBCL) Lymphoblastic lymphoma (25-30%) T-cell (~4/5) Precursor B-cell (~1/5) Anaplastic large cell lymphoma (ALCL) (10-15%)

Agressive lymphoma in children Non Hodgkin lymphoma: Burkitt lymphoma Lymphoblastic lymphoma DLBCL ALCL Sandlund and Martin, Hematology 2016

Burkitt lymphoma

Burkitt lymphoma • 50-60% of pediatric NHL • > abdominal localisation • Murphy stage I to IV – Burkitt leukemia • Typical morphologic features: FAB L3 cells • Immunophenotyping: mature B: sIg, CD19-20-22-10 • Cytogenetic – molecular: c-myc (chrom 8) translocation t(8;14), t(8;22), t(2;8) Heavy-chain Ig gene Light-chain Ig gene

Burkitt lymphoma • Histology: “small round blue cell” tumor • = diagnostic dilemma • “starry sky” pattern

Burkitt lymphoma • Treatment: intensive polychemotherapy • Survival : ’70: 10 % → ’90: 90 % • Inter-B NHL 2010 Low/Intermediate risk No immunodeficiency, Stage I-III, LDH <2xULN • • Inter-B NHL Ritux 2010 High risk Stage III + LDH ≥ 2xULN, Stage IV, B-leukemia • High proliferation rate High tumor burden  Risk of tumor lysis syndrome !

Inter-B NHL 2010 Low/Intermediate risk

Inter-B NHL Ritux 2010

Lymphoblastic lymphoma

Lymphoblastic lymphoma • 25-30% of pediatric NHL • 80% T-cell and 20% precursor B-cell T → mediastinal involvement • pB → skin, subcutaneous tissue, bone • Ducassou et al, Br J Haematol 2011 53 pts, LMT96 & EORTC 88-95 • Overall survival 85% (ALL treatment protocol)

Mediastinal Non Hodgkin lymphoma Urgency ! Morphologic (Immunoflow) evaluation of blood and BM Imaging: diameter of the trachea TD<50% TD>50% High anesthesia risk Low anesthesia risk Minimal touch ! Pleural fluid removal (local anesthesia/upright position) Biopsy of a lesion outside the thorax (lymph node) under local anesthesia If unpossible or too risky: start empirical treatment

WBC 21 580/µL 40% blasts (T-cells) LDH 1657 U/L

Leukemia in children CML <5% AML 10-15% ALL ANLL CML ALL 80-85% ALL = acute lymphoblastic leukemia → 70 children/year in Belgium AML = acute myeloïd leukemia → 10 children/year in Belgium CML = chronic myeloïd leukemia → 1-2 children/year in Belgium

ALL: symptoms and clinical presentation Pallor, fatigue Petechiae, purpura, bleeding tendency Fever, infections Bone pain, limping Enlarged lymph nodes Hepatosplenomegaly …

Diagnostic examinations Blood: WBC with microscopy, hemoglobin, platelets LDH, tumorlysis parameters (K, P, Ca, uric acid), renal function Bone marrow aspirate (<< biopsy) Lumbar puncture (with injection of chemo!) Imaging: RX thorax - abdominal ultrasound

Bone marrow analysis in pediatric ALL: Cytomorphology: % blasts, FAB L1-L2 Immunophenotyping (flow cytometry): T or pB Conventional cytogenetics (karyotyping, FISH) Array CGH Molecular analysis Prognostic markers used in risk stratification

Outcome of pediatric ALL Survival (%) Years from diagnosis Tasian & Hunger, Br J Haematol 2016

BFM treatment for pediatric ALL General design Induction Maintenance Interval Reinduction Consolidation Prephase Protocol I a + b HD MTX Protocol II total 8 wks 2 w 10 wks 2 w 2 w 6 wks 2 years BFM = Berlin-Frankfurt-Münster

BFM treatment for pediatric ALL Prephase Prednisone; IT 1 week Induction (IA) Prednisone; VCR; 4 weeks asparaginase; Daunorubicine; IT Consolidation (IB) 6-MP; AraC; 4 weeks Cyclofosfamide; IT Interval 6-MP; HD-MTX; IT 8 weeks Reinduction (IIA) Dexa; VCR; 4 weeks asparaginase; Doxo Reconsolidation (IIB) 6-TG; AraC; 2 weeks Cyclofosfamide; IT Maintenance 6-MP; MTX 74 weeks Hallmarks : 4-drug induction, high cumulative asparaginase dose, delayed intensifications, prophylactic CNS treatment

Risk factors in pediatric ALL Unfavorable: Age < 1 year or ≥ 10 years WBC count at diagnosis ≥ (50 or) 100x10 9 /L Extramedullary disease CNS or gonadal involvement Immunophenotype T-cell Cytogenetic/molecular Low hypodiploidy, near- characteristics haploidy, t(9;22), t(4;11), 11q23, t(17;19), iamp21 ≥ 1x10 9 /L blasts in PB Response to pred prephase ≥ 5% blasts in BM at D35 Response to induction ≥ 10 -2 D35 or ≥ 10 -3 D90 Minimal residual disease New characteristics IKZF1 deletion

ALL frontline treatment according to EORTC 58081 + cyclo Allo-HSCT if indicated

Additional risk factors in childhood ALL

Ped ALL treatment protocols in Belgium Frontline Relapse VLR = low risk (20%) IntReALL SR 2010 protocol AR1 = average low (48%) IntReALL HR 2010 protocol AR2 = average high (12-15%) CD19 CAR-T AR2-B & AR2-T VHR = high risk (10-15%) Future protocols Mature B-ALL (3%) AYA (adolescents and young adults)? Inter-B Ritux 2010 Resistant ALL? Infant ALL (4%) Interfant-06 (modified) Future frontline protocol (Q2 2020) Phi+ ALL (4%) “ALLTogether” : 1-> 45y EsphALL protocol (imatinib) Dose modifications for Down syndrome patients!

ALLTogether: Overall adaptive trial design R2 – IR-low R1 - SR De-escalation De-escalation Diagnostics Stratifying Backbone risk-stratified therapy Dx Therapy: Clinical LR, IR, HR Genetics MRD ! R3 – IR-high R4 – IR-high New Drug (InO) TDM+6TG R5 – HR CAR-T Pilot-study Inotuzumab – proof of principle+toxicity Phase 2

Risk stratification MRD: • – Methods: 1. PCR 2. Flow 3. NGS/NGF development followed closely – SR: neg TP1 excluding HR genetics – HR: pos >5% TP1 or >5x10 -4 (>0,05%) TP2 or t(17;19) – IR: all others, including technical failures Genetics: • – HR genetics: MLL, near haploidy (24-29 chr), low hypodiploidy (30-39 chr), iamp21, and rearrangements affecting ABL1, ABL2, PDGFRB and CSF1R ( =ABL class fusions) -> Exclude from SR, IR low. IR-high or HR based on MRD. -> ABL class fusions: start TKI D15

Overview of the risk stratification algorithm for the ALLtogether 1 trial Standard risk group IR-low End of induction MRD evaluation ( TP1 ) MRD 0%* unless high risk ETV6-RUNX1 & TP1 MRD<0.1% genetics present** HeH & TP1 MRD <0.03% BCP NCI Standard risk GR-CNA*** & TP1 MRD<0.05% (3 drug) TP2 MRD evaluation T-ALL & TP2 MRD 0%* Intermediate risk group IR-high MRD >0% and <5% Diagnosis All patients ≥16 years plus high risk genetics with High risk genetics MRD 0% Remaining BCP-ALL patients BCP NCI High risk T-ALL & TP2 MRD > 0% T-cell patients (4 drug) High risk group TP2 MRD >0.05% MRD >5% or TCF3-HLF • 0% = undetectable MRD by IG/TCR PCR; • ** High risk genetics : KMT2A/MLL gene fusions, near haploidy, low hypodiploidy, iAMP21 and rearrangements affecting ABL1, ABL2, PDGFRB and CSF1R (except BCR-ABL1 which are excluded from the study); • *** CNA profile as per Moorman et al (2014) Blood;124(9):1434-44. GR profile : no deletion of IKZF1, CDKN2A/B, PAR1, BTG1, EBF1, PAX5, ETV6, RB1 ; isolated deletions of ETV6, PAX5, BTG1 ; or ETV6 deletions with a single additional deletion of BTG1, PAX5, CDKN2A/B.