3% Chronic leukemia Chronic myelocytic leukemia Juvenile myelomonocytic leukemia Risk Factors for Childhood Acute Leukemia

(1)

CHILDHOOD LEUKEMIA



97% Acute leukemia

75% Acute lymphoblastic leukemia 20% Acute myeloblastic leukemia Acute mixed lineage leukemia Acute undifferentiated leukemia



3% Chronic leukemia

Chronic myelocytic leukemia

Juvenile myelomonocytic leukemia

Risk Factors for Childhood Acute Leukemia

Genetic Down ALL, AML

NF1 ALL, AML, JMML

Bloom ALL, AML

Schwachman ALL, AML Ataxia Telangiectasia ALL

Fanconi Anemia AML

Kostmann Granulocytopenia AML Environmental Ionizing Radiation ALL, AML

In Utero X-ray ALL

Benzene AML

Pesticide AML

Alkylating /Topo-II Inhib. AML

In Utero Topo II Inhib. Infant Und L. DNA damaging

Higher incidence among identical twins

ALL- Epidemiology



The most common malignancy in childhood



Incidence 3-4 cases per 100000 children



Peak incidence between 2-5 y

(2)



White >Black



Genetic predisposition <5%

Clinical Features at Diagnosis in Children with Acute Lymphoblastic Leukemia

Clinical features/ Symptoms % of patients

Fever 61

Bleeding (petechiae or purpura) 48

Bone pain 23

Lymphadenopathy 50

Splenomegaly 63

Hepatosplenomegaly 68

Laboratory Features at Diagnosis in Children with Acute Lymphoblastic Leukemia

Laboratory features % of patients Leukocyte count (mm3) <10,000 53 10,000-49,000 30 >50,000 17 Hemoglobin (g/dl) <7.0 43 7.0-11.0 45 >11.0 12 Platelet count (mm3) <20,000 28 20,000-99,000 47 >100,000 25

DIAGNOSIS



Blood count and smear



Bone marrow: Morphology

Cytochemical stains Immunophenotype

(3)

ALL TESTICULAR

INVOLVEMENT

CNS LEUKEMIA

DIFFERENTIAL DIAGNOSIS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

Nonmalignant conditions

Juvenile rheumatoid arthritis Infectious mononucleosis

Idiopathic thrombocytopenic purpura Pertussis; parapertussis

Aplastic anemia

Acute infectious lymphocytosis Malignancies Neuroblastoma Retinoblastoma Rhabdomyosarcoma Unusual presentations Hypereosinophilic syndrome phenotype ALL  Incidence 15%

 Median age : 12y

 Male > Female

 High blood count

 Mediastinal mass

 Organomegaly

 CR < 90 %

 High relapse rate, CNS, Extra medullary

RINCIPLES OF TREATMENT  Risk group  Combination chemotherapy: Remission induction • CNS prevention Consolidation Maintenance

(4)

 Irradiation

 BMT

 Late effect consideration

AML

ML subtypes

CUTE MYELOCYTIC LEUKEMIA: AML

Prognostic factors

• WBC > 100,000 • Secondary • Monosomy 7 (7q-) • ? Very young • ? Splenomegaly • ? M4 and M5

• ? M1 w/o Auer rods

AML: INDUCTION THERAPY

• Two cycles of cytosine arabinoside + daunorubicin +/-thioguanine and other agents gives remissions in 70-90%

• Timed sequential therapy (giving the second cycle at a specified time) does not the increase remission rate but does increase long-term cures when compared to waiting for

(5)

marrow recovery (or failure) before giving the second cycle (Blood 87:4979, 1996)

AML: Post-induction Therapy

• Chemotherapy alone has given 30-50 % cure rates.

• Cure is higher after timed-sequential induction therapy (42% vs. 27%).

• Short (4-12 months) of post-induction therapy is adequate

• CNS leukemia is less common than in ALL; ‘prophylaxis’ may be accomplished with high dose

• Ara-C +/- intrathecal Ara-C

AML: Bone Marrow Transplantation

• Bone marrow transplantation from a matched sibling donor during first remission gives better cure rates than

chemotherapy (50-60 % vs. 30-50 %)

• Autologous BMT during first remission gives results similar to chemotherapy

• BMT from a matched sibling in second remission gives 30-40 % cure rate but is limited by the difficulty in achieving

second remission.

AML Treatment Issues

• 50% incidence of serious bacterial infection: therefore use of G-CSF accepted

• New protocol is European-based and returns to the old high-dose Ara-C, with the addition of myelotarg (anti-CD33, aka gemtuzumab).

(6)

Special circumstances

• Granulocytic sarcoma • Down syndrome

– Increased incidence of all leukemias; ALL still > AML total, but

RELATIVE increase of AML

– Do not use intensive timing (increased toxicity with therapy), but OK to

use anthracyclines even with CHD

– M7 AML most often

– Transient Myeloproliferative Disease occurs in newborn period

• M3 (the 15;17 translocation) .

•

PROMYELOCYTIC LEUKEMIA: M3

• Characterized by a translocation [t(15;17)] that fuses the retinoic acid receptor and PML genes

• The t(15;17) transcript blocks differentiation that depends upon the normal receptor

• High dose all-trans retinoic acid overcomes this blockade

• Arsenic trioxide may cause apoptosis or may induce differentiation in PML cells.

Promyelocytic Leukemia: M

3

• Induction: all-trans retinoic acid +/- an anthracycline

• Intensification: anthracycline +/- Ara-C

• Continuation: intermittent all-trans retinoic acid +/- chemotherapy.

(7)

CML overview

• BCR-ABL fusion protein is generally P210, whereas Ph+ALL is usually P190.

• 3 phases

– Chronic

• Some systemic sxs;

peripheral and marrow blasts < 10% (NCI says 5%), thrombo- and leukocytosis

– Accelerated

• Progressive sxs including splenomegaly; blasts 10 (5?) -30%, baso’s+eo’s > 20%

– Blast

• Extramedullary disease symptoms;

blasts > 30%, blasts that look like ALL or AML

CML treatment

• Gleevac: aka STI571, aka imatinib mesylate

tyrosine kinase inhibitor that blocks the function of the BCR-ABL fusion protein

– Morphologic vs cytogenetic vs molecular remission

• Additional chemo required if disease has progressed

– IFN, Ara-C, hydroxyurea

• Transplant still the Rx of choice for Peds.

(8)

Concerns in enlarged LN

• Size >1-2 cm

• Increasing size over 2-4 weeks • Matted or fixed

• Supraclavicular LN

When to biopsy

• Supraclavicular node

• Increasing size over 2-4 weeks

• Constitutional symptoms

• Asymptomatic enlarged node-not decreasing in size

over 6 weeks or not normal after 8-12 weeks.

STAGING EVALUATION

• Laboratory -CBC with smear -Chem profile LHD, uric acid • Disease specific -ESR, IL2R for HD -LP if head/neck NHL -BMA/Bx for all NHL,

only IIB or higher HD

Lymphoma Staging

• Murphy  Ann Arbor

• I: tumor at one site (nodal or extranodal -- “E”) • II: two or more sites; same side of body

(9)

• III: both sides of body but not IV (& unresec. GI & mediastinal for NHL) • IV: CNS or marrow involvement (Murphy);

lung, liver, marrow, or bone for Ann Arbor (< 25% marrow) • “B” sxs are defined for HD, as is “bulky disease”

• Head and neck (possibility of CNS involvement) is a further consideration for NHL

• PET or gallium

NON-HODGKIN’S LYMPHOMA

Malignant solid tumor of immune system Undifferentiated lymphoid cells

Spread: aggressive, diffuse, unpredictable Lymphoid tissue; BM and CNS infiltration High growth fraction and doubling time Dx and Rx ASAP

Rapid CTX response; tumor lysis concern.

Incidence/Etiology – NHL

6% childhood cancer

60% of childhood lymphomas

Peak age of 5-15; M:F ratio of 2.5:1 Increased with

SCIDS, HIV, EBV

post t-cell depleted BMT post solid organ transplant

Geographic, viral, genetic & immunologic factors.

TYPES OF NHL

(10)

– 90 % immature T cells (very similar to T-ALL)

• remainder pre-B phenotype (as in ALL)

– 50-70% anterior mediastinum

– neck, supraclavicular, axillary adenopathy – Classic: older child with intussusception

Small non-cleaved cell (40-50%)

--Mature B-cell phenotype

--Burkitt's and non-Burkitt's

--90% abdomen

--Ascites and intusussception

--Endemic in Africa (Burkitt's), with EBV 97% .

BURKITT FACTS

• 100 new cases/year in US, 2-3:1 male:female; mean age 11 years (in non-endemic form)

• small, noncleaved cell; mature B phenotype; intraabdominal (sporadic) or jaw (endemic) most common primary site • 90% have t(8;14)

– (8 ~ c-myc; 14 ~ heavy chains)

• others are 8;2 or 8;22

– (2, 22 ~ light chains)

• Extremely rapidly-growing; tumor lysis issues.

BURKITT PROGNOSIS

Adult Data

:

Stage: EFS OS

I-II

91% 78%

(11)

but in patients < 40 yo 70% 60%

Large-cell lymphoma (15-20%)

- Anaplastic (Ki-1) lymphoma – ALK fusion protein - Diffuse Large B-cell lymphoma (DLBCL)

-frequent Mediastinal involvement

-More like Hodgkin lymphoma than other NHLs

- “Peripheral T-cell” lymphoma

- Often involves skin, CNS, lymph nodes, lung, testes, muscles, and GI tract

• “low grade” lymphomas – rare in children

– Follicular

– marginal zone/MALT

– primary CNS (often seen with HIV infection) – peripheral cutaneous (mycosis fungoides)

CLINICAL PRESENTATIONS

Abdomen: (35%): pain, distention, jaundice, GI problems, mass Head/neck (13%): lymphadenopathy, jaw swelling, single

enlarged tonsil, nasal obstruction, rhinorrhea, cranial nerve palsies

Mediastinum (26%): SVC syndrome

CNS (rare): HA, V, irritability, papilledema

+Fever, malaise, night sweats, wt. loss,

Staging of NHL

I Single tumor /node NOT in mediastinum or abdomen II 1-2 nodes same side of diaphragm or resectable GI

(12)

primary

III 2+ nodes both sides of diaphragm; intrathoracic or extensive intra-abd

IV Any of above with CNS and/or BM

PROGNOSIS AFFECTED BY…

Incomplete remission in first 2 mos. Rx Large tumor burden (LDH >1000)

Stages III and IV: CNS or BM involvement Delay in treatment

Relapse

**More favorable: Stage I or II, head/neck, peripheral nodes, GI tract

NHL Treatment

Surgery for diagnostic bx or second look

Radiation Therapy: emergency airway obstruction or CNS

complication – may be used for local control of residual mass

Chemotherapy: Combination chemo is usual, with overall cure

rates 60-80+%; high risk of tumor lysis and hyperuricemia

Relapse: Re-induction, followed by BMT

NHL chemotherapy overview

• Low-stage NHL’s are treated with CHOP (+/- rituximab – anti-CD20) • Higher-stage lymphoblastic lymphomas are treated on leukemia

protocols

• Higher-stage non-lymphoblastic NHLs require extremely aggressive chemotherapy with significant infectious risks, but still have

(13)

• High-dose chemotherapy with stem cell rescue is considered an option for relapse, though without the success rates of HD; T cell disease probably requires an allogeneic response.

HODGKIN’S DISEASE



Immune system malignancy, involving B or T

lymphocytes



Reed-Sternberg cells



Spread: slow, predictable, with extension to contiguous

lymph nodes



Infiltration to non-lymphoid organs is rare

INCIDENCE AND ETIOLOGY



Hodgkin’s 5% of childhood cancers



Bimodal peaks, at 15-35 and >50;

rare < 5



M:F ratio of 3:1; variation r/t geography and SES, and

type



Increased in immunologic disorders, HIV, EBV.

TYPES OF HODGKIN’S LYMPHOMA

Nodular sclerosing (NS), 40-60%, lower cervical,

supraclavicular, mediastinal nodes

Mixed cellularity (MC), 15-30%; advanced disease with

extranodal involvement

Lymphocyte predominance (LP), 5-15%, presents as localized

(14)

Lymphocyte depletion (LD) (<5%); widespread disease.

CLINICAL PRESENTATION

Painless lymph node swelling (90%) that persists despite

antibiotic therapy

Palpable non-tender, firm, mobile, rubbery nodes; Mediastinal

adenopathy (60%); SVC

Bulky: when mass is > 1/3 thorax diameter

B symptoms: Fever of >38C for 3 days, drenching night sweats,

10% weight loss.

MEDIASTINAL MASSES

• Risk for anesthesia (esp. if tracheal compression > 50% by

CT)

• Least invasive diagnostic procedure therefore indicated

(incl. thoracentesis)

• Emergent steroids or RT generally acceptable prior to

biopsy

• HD and DLBCL tend to have areas of necrosis and

therefore look more “bumpy” than T-ALL.

HODGKIN’S ANN ARBOR STAGING

I Single lymph node region

II Two+ node regions on same side of diaphragm

III Nodes on both sides of diaphragm, or localized extralymphatic spread

IV Diffuse or disseminated involvement of one+ extralymphatic organs or tissues.

(15)

PROGNOSIS

FAVORABLE:

<10, F, favorable subtypes (LP and NS) and Stage I non-bulky disease

UNFAVORABLE:

Persistently elevated ESR; LD histopathology;

bulky disease--largest dimension >10cm; B symptoms;

TREATMENT AND PROGNOSIS

Dependent on age, stage, and tumor burden RT alone, CTX alone

RT: varies from involved field for localized disease to extended

field to total nodal irradiation, inverted Y plus mantle

most often multimodal therapy, with low-dose involved field RT

and multi-agent CTX

Combined modality 70-90% LT cure.

Hodgkin Px and Rx

• Splenectomy generally no longer used

• Exact type and ratio of combined modality therapy

changes… due to differences in success rates for

salvage therapy and concerns for late effects of

therapy

– Second malignancy risks