Post on 11-Jan-2016
Hematologic Malignancies
WFUBMC Pediatric Residency Noon Conference
Pamela Bensimhon, MD4/28/08
Pediatric Cancer Distribution
Leukemia (31%)Lymphoma (14%)CNSNBLRetinoblastomaWilms/ RenalHepaticBoneRMS/ NRSTSGerm cellother
The preceeding stats reflect all of childhood, but the incidence actually varies with age
Pre-B (80%)
T cell (20%)
Mature B
Lymphoblastic (80%)2500 cases/yr
AML
APL (10%)
Myelogenous (20%)800-900 cases/yr
Acute (~99%)
CML
Chronic (~1%)
Leukemia (~70%)
Nodular Sclerosing
Classical Nodular Lcyte Pred
Hodgkins
Anaplastic
T Cell
Burkitts
Diffuse Large B cell
B Cell
Mature
Lymphoblastic
Precurser
NHL (45%)
Lymphoma (~30%)
Hematologic Cancer
Leukemogenesis• First hit can occur in utero
– Translocations can be found on guthrie cards
– Time to development variable• Requires second hit
• Predisposing factors– Down syndrome– Chromosome fragility syndromes
• Bloom Syndrome/ Fanconi Anemia/ AT
– Twins/ siblings• Monozygotic twin of <5yo with Leuk has
20% risk• Sibings have 4-fold increased risk from
general pop
– Ionizing radiation/ Drugs– Syndromes:
• Li-Fraumeni, Klinefelter, Schwachman-Diamond, Kostman, Diamond-Blackfan, Ataxia-Telangiectasia, NF, etc
Differentiation or Maturation BlockSecond Hit
Time to second hit variable
Proliferation and SurvivalChanges
Clinical Evolution of Disease
DNA DamageFirst Hit
Congenital or accumulated over years
Acute Leukemia: Classic Presentations
•3 yo lethargic, pale, refusing to walk, with fevers and some bruising. WBC 4.5, Hb 9.5, plts 50K
•16yo boy with cough, decreasing stamina on the soccer field, has large medistinal mass and high WBC
•13yo with fatigue, fever and menorrhagia, has gingival hyperplasia, an orbital mass and a WBC of 110K, plt ct 40K
Acute Leukemia: Classic Presentations
• 3 yo lethargic, pale, refusing to walk, with fevers and some bruising. WBC 4.5, Hb 9.5, plts 50K– Pre B-cell ALL
• 16yo boy with cough, decreasing stamina on the soccer field, has large medistinal mass and high WBC– T-cell ALL
• 13yo with fatigue, fever and menorrhagia, has gingival hyperplasia, a WBC of 110K, plt ct 40K, and an orbital mass.– AML
Acute Leukemia: Clinical Presentation
• Most common– Lethargy– Fever
• “Classic”– Limp or refusal to
walk• From periosteal or
joint infiltration
– Medistinal mass• Thymus in T-cell
disease
• Other common signs and sx– Bruising/ bleeding– Pallor– HSM, LAD
• Less common considerations:– CNS – Chloromas– Testicular disease– SVA syndrome from
LAD– Skin, renal, GI, etc
Leukemic Lines
Lucent metaphyseal band. When seen in children over two years of age, if bilateral,
are usually indicative of leukemia.
Leukemia: Work-Up• CBC can look like almost anything
– WBC can be normal, low, or high (>50K in ~ 20%)• May be neutropenic regardless of WBC
– Hb usually <11 (80%)
• Platelets are the most reliable– 92% have low platelet counts – 75% <100K
• +/- Blasts– Sometimes misread as atypical lymphocytes
Leukemia: Work-Up• LDH/ Uric acid
– Usually increased with higher WBC or more extrameduallry dz
• Coag profile– Factors V, IX, X and fibrinogen can be
decreased in AML
What were this patient’s presenting symptoms?
What were this patient’s presenting symptoms?
Nonproductive cough x 2 weeks not responsive to OTC cough medicine. No
limitation of normal activity or noted shortness
of breath.
Leukemia: Workup• CXR
– Mediastinal mass must be r/o before patient is sedated for bone marrow• Can be surprisingly asymptomatic• Compression of airway by >50% or
orthopnea portend poor tolerance of anesthesia
• Bone Marrow/ Flow cytometry– >5% blasts suggests malignant process– >25% blasts defines leukemia
• This is the differentiating factor between ALL and lymphoblastic lymphoma
• CSF
BM/ Flow Results: A Fork in the Road
Burkitt's
Mature B T cell Pre-B
Risk Stratification
Lymphoblastic
AML APL
Myelogenous
Leukemia
>25% blasts
Lymphoblastic Lymphoma
<25% blasts and RE dz
Bone Marrow
ALL Risk Stratification
• Initial risk grouping:– Standard vs High– High risk features
• WBC 50K• Age <1 or 10 yrs• T cell disease
– Determines 3 vs 4 drug induction therapy
– Infants go on separate protocol
• Subsequent risk assessment:– Based on
• Response to induction
• Cytogenetics• CNS disease
– Determines further therapy
Subsequent Risk Assessment:
Prognostic FactorsPositive
Triple trisomy 4, 10, 17
TEL-AML translocation
Hyperdiploid (>50 chrom)
Rapid Early Responder
No Minimal Residual Disease
No CNS disease
PoorMLL
rearrangement
Slow Early ResponderMinimal Residual Disease
CNS disease
BadPhiladelphia chrom
(9;22)Hypodiploidy (<44
chrom)Induction failure
Portends VERY high risk stratification
What happened in the 1960s?
What happened to Improve Outcome?
• 1950s– Multidrug therapy to avoid drug resistance
• First remission achieved, but not durable
• 1960s– CNS therapy regardless of CNS disease status
• Increased long term survival by ~ 50%
• 1970-1990s– Improvements in supportive care– Chemotherapy adjustments
ALL Therapy• Induction to achieve remission
– 3 vs 4 drugs
• CNS prophylaxis or therapy– IT chemotherapy– +/- XRT
• Consolidation• Intermittent intensification of therapy• Long maintenance phase • Total therapy
– 2.5 yrs for girls– 3.5 yrs for boys
ALL Outcomes
• Low risk: 90-95%• Standard risk 80%• High risk 70%• Very high risk 35%
• Relapsed disease:– Outcome dependent on time to and site of
relapse• Extramedullary relapse >2.5 yrs from initial dx:
77% EFS @ 5 yrs• Bone marrow relapse <2 years from initial dx: 7%
EFS @5 yrs
ALL Late Effects• Neuropsychologic issues
– Intrathecal therapy, cranial XRT
• AVN (esp in adolescent males)– Steroids
• Cardiomyopathy– Anthracylcines (esp preteen girls)
• Infertility– Cyclophosphamide, testicular XRT
• Secondary AML, brain tumors– Etoposide, cranial XRT
• Endocrine abnormalities (obesity, precocious puberty, short stature)– Cranial XRT
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Back to the Fork in the Road
Burkitt's
Mature B T cell Pre-B
Risk Stratification
Lymphoblastic
AML APL
Myelogenous
Leukemia
>20% blasts
Lymphoblastic Lymphoma
<20% blasts and RE dz
Bone Marrow
AML
• Subtypes less important than they used to be– Treated the same
• except M3 (APL)
– Can give limited prognostic information• M0, M6, M7 worse• M3 better
– Some have associated translocations
AML: Prognostic Factors
• Good– Down Syndrome
<4 yo– Rapid remission– t(8;21)– t(15;17) (APL)– Inv 16 (M4e)– FLT 3 ITD
• Poor– WBC >100K– Infant AML – AA race– Induction failure/ MRD
present after induction– Relapsed or Secondary
AML– Monosomy 5 or 7 – Del 5q– Abn 3q– Complex karyotype– MLL rearrangement
AML: Therapy
• Highly intensive therapy required for cure– CNS prophylaxis included
• Matched sibling BMT after induction if available
• Treatment related mortality rate: 20-30%– Reaching the ceiling of intensification
• BMT considered without matched sibling if:– Infant AML– Monosomy 5 or 7– Induction failure– Relapse
AML: Outcomes
• Overall survival ~60-70%• As low as 30% survival with the poorest
prognostic factors
• Relapse: – Overall survival of relapsed/ refractory disease
• 5-10% if relapse <1 year after therapy• ~35% if relapse > 1 year after therapy• quality of remission at transplant is an important
factor
AML Late Effects• Neuropsychologic issues
– Intrathecal therapy, cranial XRT, BMT
• Cardiomyopathy– Anthracylcines (esp preteen girls)
• Infertility– Cyclophosphamide, testicular XRT, BMT
• Secondary cancers– Etoposide, cranial XRT
• Endocrine abnormalities (obesity, precocious puberty, short stature)– Cranial XRT, BMT
• Restrictive lung disease– BMT
• CGVHD– BMT
APL
• Acute Promyelocytic Leukemia (M3)– Increased frequency of associated
coagulopathy/ hemorrhage– t(15;17) PML-RAR
• ATRA sensitive– Induces maturation and apoptosis
– Often better prognosis
Down Syndrome and Leukemia
• First 3 yrs AML>ALL• AML is frequently preceeded by myelodysplastic
syndrome• For AML, better outcome with less intensive
therapy (incl. no BMT)• Can be difficult to distinguish from Transient
Meyloproliferative Disease• Rare types more common
– Erythroblastic (M6)– Megakaryocytic (M7)– Prognosis for M6/7 not as poor as usual in DS
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Leukemia Supportive Care• Tumor Lysis Syndrome
– In rapidly growing or extensive disease– Aggressive alkalinized hydration– Allopurinol/ Rasburicase– Close monitoring of labs for
• Uric acid , phos , K , BUN/ Cr • Ca
– Can lead to renal failure, pulmonary edema, arrythmias
• Fever and neutropenia– Highest risk with very intensive chemo or
prolonged neutropenia– Treat all fevers with broad spectrums
antibiotics
Leukemia Therapy Supportive Care
• Bactrim– PCP prophylaxis x 6 months after therapy
• Immunizations– No live vaccines– No OPV to close contacts (per CDC Varicella is
recommended)– Response to killed or inactivated vaccines may be
suboptimal– Exposure to varicella w/o previous immunity
• Continuous household contact, >1 hr indoor play, or hospital contact
• VZIG in 72-96 hours of exposure• IV Acyclovir if sx develop
– Live vaccination can restart when off therapy for at least 3 months per the CDC.
Hematopathology
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Leukemia (~70%)
Nodular Sclerosing~70-80% in teens
Classical Nodular Lcyte Pred
Hodgkins~600 cases/year in kids
4% of cancer in kids <14yo, 16% in >15yoM>F
Anaplastic
T Cell
Burkitts Diffuse Large B cell
B Cell
Mature
LymphoblasticT or B cell
Precurser
NHL (45%)
6% of cancer in kids <14yo, 9% in >15 yo
Lymphoma (~30%)
10% of cancer in kids <14yo25% of cancer in kids >15yo
Hematologic Cancer
Hodgkin’s Disease: Clinical Presentation
• Lymphadenopathy– Enlarged, usually nontender, often discreet,
rubbery, elastic– Always be leary of the supraclavicular node
• Common locations– Neck (75%)– Mediastinum (>60%)– Spleen, Axilla, Inguinal, Lung, bone marrow,
pericardium, liver, etc.
• Involved nodal groups usually contiguous• Clinical presentation reflects location of LAD• +/- Systemic symptoms
Hodgkin’s Disease: Clinical Presentation
• Systemic symptoms:– Portends poorer prognosis
•B symptoms (30%)– Fever >101 – Drenching night sweats– Weight loss 10%
– Not prognostic•Puritis (15-25%)•Alcohol-induced pain in areas of nodal
involvement (5%)
HD: Work-Up•Labs:
–CBC•May have mild anemia•Eosinophilia in 15%, neutrophilia in 50%
–ESR/ CRP•May have prognostic value, certainly useful for surveillance
–CMP
HD: Work-Up
•Radiology–CXR–CT/MRI–PET scan–+/- Bone scan
•Procedures:–LN biopsy
•Preferably not FNA
–Bilateral BMBx
–CSF not required
HD: Staging and Risk Assessement
• Stage I-IV based on:– Number of nodal groups involved– Whether one vs both sides of diaphragm are
involved– Number of extranodal regions involved
• Risk group based on:– Stage– Presence of B symptoms (A/B)– Presence of bulky mediastinal disease (X)– Splenic or other extralymphatic involvement (S or
E)
HD: Therapy
• 2-8 short, pulsed cycles of chemotherapy– Number of cycles depends on risk group and
response
• Involved field radiation – Except in some low risk cases with very good
response– Mimized when possible in females
• Relapsed or refractory disease– Chemotherapy– Radiation if not already given– Auto-transplant
HD: Prognostic Factors
• Good– Female gender– Low stage
• Poor– Bulky or extranodal
disease– B symptoms– Higher stage– Anemia at diagnosis– Hypoalbuminemia at
diagnosis– Leukocytosis or
lymphopenia at diagnosis
– Persistently high ESR
HD: Outcomes
• Low/ intermediate risk: 90-95% overall survival– Given high survival rate, studies are currently aimed
at minimizing treatment toxicity/ long term effects
• High risk patients: 85% overall survival• Relapsed disease:
– Systemic, extranodal recurrence <1 year from therapy end:
• 40-50% OS
– Asymptomatic nodal recurrence >1 year from therapy end:
• 60-70% OS
HD: Late Effects
• Cardiomyopathy, arrythmias– Anthracylcines (esp
preteen girls), XRT
• Infertility– Cyclophosphamide
• Secondary cancers, especially breast cancer in girls– XRT, etoposide
• Pneumonitis, abn PFTs– Bleomycin, XRT
• Peripheral neuropathy– vincristine
• Avascular Necrosis– prednisone
• Hypothyroidism– XRT
Anaplastic
T Cell
Burkitts Diffuse Large B cell
B Cell
Mature
LymphoblasticT or B cell
Precurser
NHL (45%)
6% of cancer in kids <14yo, 9% in >15 yo
NHL: Mature
• T-Cell– Anaplastic NHL
• 10% of childhood NHL• Presents similarly to advanced HD, with
extranodal dz and B symptoms• May have waxing and waning (or
persistent) cutaneous disease
NHL: Mature• B-Cell
– Burkitt’s Lymphoma (= small noncleaved)• 40-50% of childhood NHL• Most common sites/ presentations (in USA):
– Abdominal » classic presentation: intussusception» Abdominal obstruction, “appendicitis”
– Head and neck, CNS, BM often involved
• Very rapidly growing– High risk of tumor lysis syndrome, even before
diagnosis
• If >25% marrow involvement, mature B cell leukemia
• “Starry Sky” histology due to histiocytes
– Diffuse Large B -cell Lymphoma
NHL: Mature• B-Cell
– Burkitt’s Lymphoma– Diffuse Large B cell Lymphoma
• 10% of childhood NHL• Can be difficult to distinguish from HD,
but more aggressive– Often with HSM– Can have Reed-Sternberg cells
NHL: Precurser
• Lymphoblastic Lymphoma– T >> B cell
• T cell commonly presents with mediastinal mass
– Most stage III/IV
• B cell often skin only– Most stage I/II
– Treated like ALL– Tdt + (because precurser disease) unlike
mature lymphomas
NHL: Work-Up
• Labs:– CBC– LDH/ Uric acid– CMP
• Radiology– CXR– CT head CAP–PET scan
• Procedures:– Biopsy of most
accessible disease•Flow, pathology,
cytogenetics– Bilateral BMBx– LP for CSF
exam• Unlike for HD
Lymphoma and Immunodeficiency
• T-cell deficiency patients– HIV, inherited immunodeficiency, post-
transplant, etc– 10-100x increased risk of lymphoma– Not increased with B cell def, neutropenia,
etc.
• Primary CNS lymphoma almost unheard of without underlying immunodeficiency
• Most often DLBCL
NHL: Staging• Disease is not contiguous like in HD, so staging
is different• “B”-like symptoms non-prognostic• Ann Arbor staging system used for adults is
not appropriate for kids with NHL due to differences in Lymphoma types and behavior– Ann Arbor is used in Hodgkins disease
• Use Murphy Staging system• Stages I-IV based on:
– Number and proximity of nodal and extranodal regions involved
– Location of involvement• Other > GI > primary thoracic or paraspinal > CNS or BM
– Extent of resection
NHL: Therapy
• Lymphoblastic– Treated like ALL
• All others– 3-52 weeks of short, pulsed therapy– CNS prophylaxis included– Radiation not generally employed
NHL: Prognosis• Localized Disease (Stg I/II)
– >95% EFS
• Stage III/IV disease– Mature B cell
• 90% EFS without poor prognostic factors• Mediastinal primary, CNS/ BM involvement: 65-
70% EFS
– Lymphoblastic Lymphoma• 85-90% EFS
– Anaplastic Large Cell• 75% EFS• Late recurrences more common
• Refractory/ Recurrent Dz– Very poor, even with BMT
Emergent Presentations of Leukemia/ Lymphoma
• Superior vena cava/Superior mediastinal syndrome– Facial/neck/UE swelling and cyanosis – Collateral vein engorgement– Cough, hoarseness, orthopnea,
wheezing• Spinal cord compression
• Hyperleukocytosis• Tumor Lysis Syndrome
Sources
• ASPHO: Pediatric Hematology/Oncology Review Course, 2006.
• Lanzkowsky P: Manuel of Pediatric Hematology and Oncology. Elseiver Academic Press, New York; 2005.