Hematologic Malignancies WFUBMC Pediatric Residency Noon Conference Pamela Bensimhon, MD 4/28/08.

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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

APL (10%)

Myelogenous (20%)800-900 cases/yr

Acute (~99%)

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?

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

QuickTime™ and a decompressor

are needed to see this picture.

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

• 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

• 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

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

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

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,

• 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.

Hematologic Malignancies WFUBMC Pediatric Residency Noon Conference Pamela Bensimhon, MD 4/28/08.

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