Childhood Acute Lymphoblastic Leukemia (Childhood ALL) 台北醫學大學附設醫院 小兒血液科 張家堯醫師 Case 1: 3 y/o boy • Abdominal pain and fever, when UTI diagnosed (10/13) WBC/Hb/MCV/PLT=3700/8.5/81/202K • One week later OPD F/U (10/22) WBC/Hb/MCV/PLT=6300/6.7/80/303K two weeks later OPD F/U (11/8) WBC/Hb/MCV/PLT=5800/6.1/80/209K • No hepatosplenomegaly Case 1: • Reticulocyte count: 0.58% • PB smear: RBC: anisocytosis, tear drop, stippled RBC WBC: 1% atypical lymphocyte Platelet: giant platelet • Ferritin: 473 ng/ml • Coombs test (direct/indirect): negative BUN/Cr: 9/0.7, LDH: 360, AST/ALT: 25/8 ALK-P: 198, iP: 3.4 Na/K/Cl:137/4.1/100 Case 1: • R/O leukemia, histocytosis, osteomyelitis, lymphoma, neuroblastoma • Beta-HCG/AFP: normal • VMA 24 hrs urine: normal • Bone scan and Gallium scan: normal • Bone marrow aspiration : numerous lymphoblast, ALL impressed. Introduction • The most common malignancy in childhood (< 15 y/o): leukemia, brain tumor, lymphoma, neuroblastoma 比例: • Childhood leukemia: ALL:AML:CML about 75:20:<5 • The most common malignancy in teenager: lymphoma Background (1) • Acute lymphoblastic leukemia (ALL) is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. • The peak incidence in patients aged 2~5 years. Background (2) • The only known cause of ALL is ionized radiation • A small percentage of cases are associated with inherited genetic syndromes • The cause of ALL remains largely unknown. • Race: ALL occurs more frequently in whites than in blacks (42/Mil : 24/Mil). Pathophysiology • The malignant cells of ALL are lymphoid precursor cells (ie, lymphoblasts) that are arrested in an early stage of development. • This arrest is caused by an abnormal expression of genes, often as a result of chromosomal translocations. • Anemia, thrombocytopenia, and neutropenia occur to varying degrees. Clinical manifestation - protean nature • Bone marrow failure: BM is replaced with leukemic cells • Organ infiltration: leukemic cells spread through blood to other organ • Tumor lysis syndrome: metabolic agents released from tumor cells due to tumor lysis Bone marrow failure (1) WBC • WBC: 500 ~ 1000000/ul • Patients with ALL can have a high, normal, or low WBC count, but usually exhibit neutropenia (lymphocyte predominte) • Symptoms: low-grade fever, URI ~ sepsis (septic shock) • Hyperleukocytosis: WBC > 100000/ul Leukostasis: risk of CVA, respiratory failure Bone marrow failure (1) RBC • Hb: normal ~ 2.5 g/dl • Symptoms: No symptoms ~ pale ~ dizziness, fatigue ~ tachycardia ~ tachypnea ~ congestive heart failure • Hb < 7: C.O.↑ • Hb < 4: CHF Bone marrow failure (3) PLT • PLT: normal ~ < 10K/ul • Symptoms: No symptom ~ prolonged bleeding of wound ~ petechiae ~ internal organ bleeding • PLT < 100K/ul: BT prolonged • PLT < 20K/ul: petechiae, spontaneous B • PLT < 10K/ul: ICH Organ Infiltration • RE systems: liver, spleen, lymph node, thymus • Bone, joint • CNS, cranial nerve • Skin: leukemia cutis • Genital organ: ovary, testis • Urologic organ: kidney, bladder, ureter • GI, heart Tumor lysis syndrome • TLS often occurs in ALL, AML, CML, NHL, huge tumor (except HD) • Risk: LDH > 1500 mg/dl • Time: spontaneous or during the first 5 days of Chemo • Signs: Hyperkalemia, Hyperuricemia Hyperphosphotemia, Hypocalcemia LDH, Alk-p Indication of Bone Marrow Aspiration (BMA) • > or = Two of three series in CBC are abnormal and could not be explained reasonably. • Anytime you suspect the possibility of leukemia or bone marrow failure syndrome in patients A case diagnosed after 2.5 months of symptom onset (1) • A 11 y/o boy, migratory pain over bil. lower limb (knee and ankle) and fever • Normal CBC-DC (no blast) • No hepatosplenomegaly • ANA (-) • Bone marrow aspiration: mild hypocellularity, otherwise np A case diagnosed after 2.5 months of symptom onset (2) • Tentative impression: Juvenile rheumatic arthritis (JRA) • Tx with steroid, but in vain (still bone pain) • Repeat BMA at 2.5 mon of symptom onset: numerous lymphoblast about 77% in BM, T-cell ALL diagnosed How to approach bone pain and joint pain in children (1): DDx 1.Trauma: fracture, sprain, overuse 2.Infection: osteomyalitis, septic arthritis, viral synovitis, 3.Bleeding tendency: hemophilia 4.Vasculitis: HSP 5.Connective tissue disease: RA, JRA, SLE 6.Malignancy: leukemia, lymphoma, metastatic cancer (neuroblastoma); osteosarcoma; (benign bone tumor),… 7.Growth pain: exclusion of other causes How to approach bone pain and joint pain in children (2): approach • Hx: trauma, URI, bleeding tendency, BW loss? • PE: erythematous change, swelling, local heat, pain? lymphadenopathy? hepatomegaly? splenomegaly? Abdominal mass? • Lab: CBC-DC, PB smear, CRP, B/C, Alk-p, LDH • Imaging: local X-ray • Others: Bone scan, Gallium scan, BMA if needed • The above exam showed normal dose not mean healthy. The most important thing is to follow up. If necessary, repeat the above exam. Diagnosis (1) • Lymphoblast > 25% of nucleate cell in BM • Normal BM: blast < 5% • Lymphoblast = 5~25%: Dx: NHL with BM involvement • Dx of AML: myeloblast > 30% of nucleated cell in BM Diagnosis (2) • Question 1: If hepatomegaly(+) with abnormal CBC, but no blast in peripheral blood smear • Question 2: If blast found in peripheral blood smear, whether leukemia is confirmed? DDx: • Infectious mononucleosis • Aplastic anemia • Idiopathic thrombocytopenia purpura • Juvenile rheumatic arthritis • Leukemoid reaction DDx: Leukemia v.s. Leukemoid reaction Leukemia Leukemoid reaction WBC ↓ or N or ↑↑ ↑ or ↑↑ Hb N or ↓ N PLT N or ↓ N Hepatosplenomegaly (+) or (-) (-) LAP score, N/L ratio ↓ or N ↑ Infection signs (+) or mild (+), marked Response to antibiotic No response improved BM smear Hypercellularity, Normocellularity, blast > 25% blast < 5% Morphologic classification French-American-British Classification (FAB): ALL: L1, L2, L3 AML: Mo ~ M7 High N/C ratio Nucleoli generally not visible FAB-L1 ALL Fab-L2 ALL 10-15% of ALL Low N/C ratio Conspicuious nucleoli, irregular nucleoli outlines, bigger blast older children 1% of ALL; almost B cell Large, dense basophilic, heavy, vacuolated FAB-L3 ALL FAB Classification Incidence FAB Adults Children ALL ALL L1 35% 85 % L2 60 % 14 % L3 5% 1% FAB morphologic classification • Only used in fresh patient • L1, L2: not associated with prognosis • L2 is like AML, M0, M6, M7 are like ALL • Unable to DDx mixed lineage leukemia Immunophenotyping 方法:用單株抗體染芽細胞表面標記 Cell surface markers showing lineage Cytogenetic study • Chromosome abnormality in 70 ~ 75% ALL • Some relate to prognosis: better prognosis: t(12,21) poor prognosis: t(4,11), t(9,22) Molecular classification • AEL-AML1 • E2A-PBX1 • MLL rearrangement • HOX11 • MYC • BCR-ABL Prognosis • The most only important prognosis of childhood ALL is the risk-adapted chemotherapy • The most important prognosis are age at diagnosis and initial WBC Treatment of childhood ALL Nature history • Relapse: 1.Most common: BM relapse (80~90%) 1~2 months after C.R. if no maintain Tx 2.2nd common: CNS relapse (70~80%) 3~4 months after C.R. if no IT, R/T 3.3rd common : testis relapse (40%) 診斷：做兩側的wedge biopsy Risk Grouping of childhood ALL • SR: standard risk • HR: high risk • VHR: very high risk • B-ALL: 3~ 6 months intensive C/T Very high risk (VHR) ALL • T-cell ALL • WBC > 100000/ul • T(9,22), t(4,11) • Lymphoblastic leukemia with blast > 25% • Age < 1 y/o • MLL gene rearrangement • Age > 10 y/o Strategy of treatment • Induction therapy • Consolidation therapy • CNS prophylaxis • Maintain therapy Induction therapy • Three or four drugs combination: (prednisolone + Vincristin + Epirubicin + L-asparaginase) • Induction to complete remission • Increase long-term relapse-free survival • Complete remission rate: 95% • 99% ~ 99.9% blasts are killed Complete remission • CBC-DC: normalized BM: normalized cellularity, blast < 5% Organomegaly: disappear • C.R. dose not mean cure Consolidation therapy • About half of intensity of induction therapy • To consolidate the effect of induction therapy • Improve the outcome CNS Prophylaxis • 在確定診斷後，要抽CSF來測是否有CNS disease • 不論是否有CNS disease，都要做CNS prophylaxis • MTX + intrathecal C/T (MTX, Ara-C, steroid) • High risk (HR) and very high risk (VHR): 加上cranial radiation Maintain therapy • Long term low-dose oral Chemo: 2 years • To prevent BM relapse Survival rate • Cure: no relapse 7 years after diagnosis or 4 years after full course of Chemo • Long term survival rate: 75% SR: 80~85% HR: 60% VHR: 25~50% Indication of Bone Marrow Transpalntation (BMT) for childhood ALL • Congenital ALL or infantile ALL • t(4,11), t(9,22) • Induction failure (5%) or C.R.after 1 month • Relapsed ALL • Secondary ALL due to prior C/T Management of acute leukemia • Oncologic emergency: priority 1.Tumor lysis syndrome: hyperkalemia 2.Bleeding tendency, DIC: 3.Septic shock: 4.Hyperleukocytosis: leukostasis 5.SVC syndrome: • Supportive care: B/T (PRBC, PLT, FFP), keep U/O, antibiotics • Risk grouping: C/T (not emergent) The End Thank you for your attention!