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Childhood Acute Lymphoblastic Leukemia _Childhood ALL_

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Childhood Acute Lymphoblastic Leukemia _Childhood ALL_ Powered By Docstoc
					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!

				
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