Upload
faith-conway
View
226
Download
1
Tags:
Embed Size (px)
Citation preview
Acute Lymphoblastic LeukemiaAn Overview
Aziza Shad, MD
Case 1• History:
3yo boy presents to Emergency Department with a 5 day history of back pain and pain/difficulty walking
• On exam: Febrile with pallor, bruising, petechiae, mild hepatosplenomegaly
• Labs:CBC: Hgb 6.0g, Hct 18.0, Plts 11k, WBC 13.6 (10p, 60l, 24 atypical lymphocytes, 6 blasts) ANC 136CHEM: K normal, Uric acid 7.0 ↑, LDH 2200 ↑• CXR: Reported as normal
Peripheral smear
Maslak, P. ASH Image Bank 2004;2004:101159
Blasts with scant cytoplasm and prominent nucleoli
Bone marrow aspirate and biopsy
• BMA: Blasts have a high nuclear to cytoplasmic ratio and lack granules in the cytoplasm
Maslak, P. ASH Image Bank 2002;2002:100400 and 100526
BMBx: Bone marrow architecture is replaced by monotonous population of blasts
Diagnosis?
Acute Leukemia(most likely ALL)
Maslak, P. ASH Image Bank 2004;2004:101200
Making the diagnosis:
Morphology and Immunophenotype
Morphologic classification –
French American British (FAB) subtypes
L1 – 85%Small, uniform cell sizeFine, homogeneous chromatinScant cytoplasmInconspicuous nucleoli
L2 – 14%Large, heterogeneous cell sizeIrregular, clefted nucleiVariable amount of cytoplasmNucleoli usually visible
L3 – 1%Large, homogeneous cell sizeProminent vacuolizationBasophilic cytoplasmNucleoli usually visible
Leukemia is a Bone Marrow Diagnosis!
Introduction
• Leukemia accounts for about a third of all childhood cancers
• About 80% of children with leukemia have ALL • 17% have AML • The remainder have rare forms of chronic
leukemia
Pediatric Acute Lymphoblastic Leukemia
• Most common cancer of childhood• Affects children from 0 -20 years• Peak incidence is between 3 -6 years• Untreated, life expectancy is days to weeks• Modern risk-based therapy has brought the
cure rate up to 75 -85%• for some sub-groups, the cure rate is close to
90%, for others, it is < 20%
Acute Lymphoid LeukemiaAcute Lymphoid Leukemia Incidence by Age Incidence by Age
AGE IN YEARS
NU
MB
ER
OF C
AS
ES
0
20
40
60
80
100
120
140
0 2 4 6 8 10 12 14
Epidemiology of Pediatric ALL• Most common form of childhood leukemia
• 2,500-3,000 children annually in U.S. (3 per 100,000)
• Sibling relative risk is 2-4x
• Monozygotic twin concordance 25% - highest in infancy, no increased risk after 7 years of age – mechanism in monozygotic twins is shared in utero
circulation, with transfer of preleukemic from one twin to the other
Pathophysiology
• Most cases – cause unknown• Inherited genetic syndromes:
• Downs syndrome, Bloom’s syndrome, Nijmegen breakage syndrome, ataxia telangiectasia
• Environmental exposures
Ionizing radiation, benzene, prior chemotherapy• Other possible environmental influences
• High birth weight, parental tobacco/alcohol, maternal diet, exposure to pesticides or solvents, prenatal vitamins (protective)
• Symptoms directly related to marrow infiltration– Decreased WBC : fevers, infections
– Decreased RBC :signs and symptoms of anemia
– Decreased platelets: bruising, bleeding
– Marrow infiltration: bone pain, limp
– Extramedullary infiltration : lymphadenopathy, hepatosplenomegaly, mediastinal mass
Clinical Presentation
Remember…
• A given case may have several symptoms or only a few
• A normal CBC does not rule out leukemia!• Back pain/limp in pediatrics is a red flag and
requires work-up• Before treating any child with steroids for any
reason, stop and think about whether leukemia is in the differential diagnosis
Differential Diagnosis
• Non Malignant conditions:• Juvenile rheumatoid arthritis
• Infectious Mononucleosis
• ITP
• Pertussis and Parapertusis
• Aplastic Anemia
• Other viral illnesses
Differential Diagnosis
• Malignancies:• Neuroblastoma
• Retinoblastoma
• Rhabomyosarcoma
• NHL
• Other small round blue cell tumors
• Hyper-eosinophilia, other aplastic presentations
Standard Work-up for ALL
• History and Physical Exam• CBC, electrolytes, LDH, Uric acid• Peripheral smear• Chest X-Ray• Bone marrow aspirate and biopsy with special stains• Immunophenotyping ( flow cytometry)• Cytogenetics• Molecular diagnostics
Immunophenotype
CD138
CD
10
CD22
CD
19
Sid
e-s
catt
er
CD45
Molecular genetics
• Favorable risk– TEL-AML1 (ETV6-RUNX1) fusion,
t(12;21)– Hyperdiploidy (esp triple trisomies –
chr 4, 10, 17; or double trisomies – chr 4, 10)
• High risk– Philadelphia chromosome, t(9;22)– MLL rearrangement (11q23)– Hypodiploidy (<44 chromosomes)
fusion signal
Back to our patient…
• Received hydration, PRBC and platelet transfusions, tumor lysis lab monitoring and prophylaxis (allopurinol)
• Consented to start induction chemotherapy• Bone pain and fevers resolve within a few
days, discharged home to follow up for ongoing outpatient chemotherapy
• What is his prognosis?
Cure Rates
• Over the last 50 years, survival rates for childhood cancer have risen from 10% to almost 80%
• Remarkable progress has been made in the past decade in the treatment and understanding of leukemia
• Collaborative clinical trials implementing risk-stratified therapy have dramatically improved cure rates in ALL
• Outcome in ALL has gone from a 6-month median survival to an 80% overall cure rate
1975-781972-75
0 2 4 86 10
80
60
40
20
100
Years after Study Entry
%
Survival
1989-93
1983-89
1978-83
1970-72
1968-70
3,402
3,711
2,9841,313
936
499
402
Years of Diagnosis
Number ofChildren
16,131Total Number ofPatients Treated:
1993-95 1,585
1995-97 1,299
Legend: Survival of CCG Patients with Newly-Diagnosed Acute Lymphoblastic Leukemia, 1968-1997. Bleyer A, Hather N, Personal Communication
Prognostic Factors in Childhood ALL
• Age• WBC count at presentation• Immunophenotype• Recurrent chromosomal abnormalities• Response to initial therapy• These prognostic factors have been used to stratify
therapy following induction remission• Gene expression analysis• Pharmacogenomics
Risk adapted therapy for Pediatric ALL
• Standard, high or very-high risk groups– Patients with ‘high risk’ features get intensified
chemotherapy– Patients with ‘very-high risk’ features are
candidates for BMT– ‘Low risk’ group being studied – reduced intensity
treatment
Prognostic Factors in Childhood ALL
• Clinical and Lab featuresClinical and Lab features
• Leukemia cells characteristics
• Response to initial therapy
Prognostic Variables
• Clinical and Lab Variables:• Age:
– 1-9 yrs Best outcome 5 yr EFS 88%– 10-15 yrs 73%– >15 yrs 69%– < 12 mths 44%– < 6 mths poor outcome
• Infants: Poor outcome– MLL gene, Increased WBC, CNS Leukemia– CD10 Negative– Poor initial response
Pui et al, Lancet 2008
Prognostic Variables
• Clinical and Lab Variables:• WBC Count at Presentation:
– Increasing WBC confer a poor outcome especially in patients with Precursor B-cell ALL
– T-cell ALL patients with WBC > 100k have a higher risk of CNS relapse
Prognostic Variables
• Leukemic Cell Characteristics:• Immunophenotype:Immunophenotype:• Precursor B ALL: CD19, CD10 (cALLa), HLA-DRPrecursor B ALL: CD19, CD10 (cALLa), HLA-DR
80%- 85% of ALL80%- 85% of ALL 80% CD10 positive80% CD10 positive
• Early pre-B (no sIg or cyIg) Early pre-B (no sIg or cyIg) • Pre-B (cy Ig)Pre-B (cy Ig)• B-cell (sIg) 3% (FAB L3, CMYC gene trans)B-cell (sIg) 3% (FAB L3, CMYC gene trans)Mature B-cell phenotype no longer confers a poor prognosisMature B-cell phenotype no longer confers a poor prognosis
Prognostic Variables
• Leukemic Cell Characteristics:• Immunophenotype:• T- Cell ALL : CD2, CD7, CD5, CD3
Males, Older Age, High WBC, Mediastinal mass
12 % of ALLT-cell phenotype no longer confers a poor prognosis T-cell phenotype no longer confers a poor prognosis
Prognostic Variables
• Cytogenetics:• Favorable Prognosis
– High Hyperdiploidy: 51 -65 chromosomes/cellor DNA index > 1.16
– Trisomies 4, 10, 17– TEL/AML1 t(12;21)
• Poor Prognosis– Hypoploidy: < 44 chromosomes– Philadelphia chromosome– T(4;11) with MLL-AF4 fusion
Prognostic Variables
• Response to Initial Therapy:
– Day 7 and Day 14 BM responsesRapid response is favorableCurrent COG protocols
– Peripheral blood response to steroidsDay 7 (blasts< 1000/ul) GR is favorableBFM protocols
EARLY RESPONSE TO THERAPY
• Rapidity of response to initial chemotherapy is a significant predictor of long-term outcome
Treatment
• Induction of Remission (4 -6 weeks)
• Consolidation ( 4 -8 weeks)
• Interim Maintenance (8 weeks)
• Delayed Intensification (8 weeks)
• Maintenance (2 -3 years)
Treatment• Induction of Remission
Standard or Low RiskDexamethasoneVincristineL Asparaginase
High Risk Dexamethasone/Prednisone VincristineL AsparaginaseAnthracyclines (Daunomycin)
Treatment• Induction of Remission
Dexamethasone Low RiskLess CNS and BM relapsesBetter EFS
Use in Adolescents Aseptic Necrosis
Use in High Risk Infections
Treatment
• Consolidation:– Intensified CNS therapy
• Delayed Intensification:– improves outcome– Anthracyclines, Cyclophosphamide
Treatment
• Maintenance Therapy:– Daily oral 6MP and weekly oral MTX
– Severe hematopoietic toxicity with Thiopurine S Methyl Tranferase deficiency
– CNS prophylactic therapy
Treatment
Maintenance Therapy:– VCR + Prednisone/ Dexamethasone Pulses
1. VCR/Prednisone pulses improved EFS2. Dexamethasone in 1-9 yr SR patients showed fewer CNS
relapses and improved EFS compared to Prednisone3. Use of Dexamethasone in Adolescents: Risk of Aseptic
Necrosis and bone fractures
Treatment
• T-cell ALL:Intensified chemotherapy protocolsIntensified chemotherapy protocolsPilot trials with ARA-GPilot trials with ARA-G
• Infant ALL:Intensive chemotherapy protocols
• Philadelphia +ve ALL: BMT from matched related or MUDImatinib
Relapsed ALL
• Timing of Relapse:Early Relapse: Survival < 10-20% [ Relapse on therapy or 6 months off ]
Late Relapse: Survival 30-40% (chemotherapy)[ Relapse 12 months off therapy]
T-cell ALL: Survival < 20%
Treatment of Relapsed ALL
• Bone Marrow Transplantation:Early RelapseHigh Tumor Load (>10,000 blasts/ul)
• Chemotherapy
Conclusions
• ALL is the commonest leukemia of childhood• Minimal evaluation should include a good
H&P, peripheral smear and bone marrow exam
• Simple treatment protocols utilizing common agents used for ALL treatment should be used initially
• Treatment modifications should be based on institutional experience and results