Acute Lymphoblastic Lymphoma

11/02/09 Pediatrics Wards Presentation TTUHSC SOM ALL Acute Lymphoblastic Leukemia Acute Lymphoblastic Lymphoma Path: Precursor B cells (sometimes T cells; lymphoblasts); hyperploidy (>50 chromosomes), t(12;21) w CBF α and ETV6, t(9;22), t(4;11) Etiology: 2500 new cases dgx/yr. <15yo, peak at 4yo (teens if T cell). Whites>>Nonwhites. M>F. 2.1% of Downs pts have ALL. Protective Factors: Stat!Ref Daycare attendance, early common infx, longer breast feeding, HiB vaccine, residence in remote rural counties. SSx: Abrupt onset (eg <weeks), fatigue, fever due to low mature leukocytes, bleeding, petechiae, ecchymoses, epistaxis, gum bleeding, bone pain, lymphadenopathy, hepato/splenomegaly, HA, vomiting, nerve palsies due to meningeal spread; Pancytopenia ssx eg bleeding, easy bruising Dgx: Anemia, neutropenia, thrombocytopenia; Microscopy=condensed chromatin, inconspicuous nuclei, scant agranular cytoplasm; normal tissue infiltrated w lypmhoblasts. Immunophenotyping: B-lineage ALL: CD 19, 20, 22, 79a and/or surface or cytoplasmic immunoglobulin T-lineage ALL: CD2, surface or cytoplasmic CD3, CD4, CD5, CD7, and/or CD8 Staining: TdT staining to differentiate bw L1-L2 and L3 (Burkitt Lymphoma; TdT neg). CXR to eval x presence of mediastinal lymphadenopathy/exclude infx Tx: Cyclophosphamide 1200mg/m2 iv on day 1 Daunorubicin 45mg/ m2 iv x 3-4days Prednisone 60mg/ m2 PO x 7-21 days Vincristine 1.4mg/ m2 IV w a Max 2mg, weekly x 2-4 doses

L-Asparaginase 6000IU/ m2 sc 2x weekly x 4-7 doses (3-4 weeks) Prognosis: With aggressive tx 90% reach remission, 2/3rds can be considered "cured". Favorable if low WBC count, 2-10yo, B phenotype, hyperploidy, t(12;21); No tx; Poor prognosis if <2yo cuz of choromosome 11 involvement, teen/adult presentation, t(9;22) DDx: AML Biphenotypic Leukemia Mantle Cell Lymph\oma (blastic variant) Gamma Delta T cell hepatosplenic lymphoma Plasma Cell Leukemia Other CA Considerations: Pts may be at risk for Minimal Residual Dss Multidrug resistance is possible and must be evaluated for. MDR related proteine 1, pglycoprotein, lung resistance protein and breast cancer resistance protein are some examples. 10% exhibit MDR. Allogenic transplantation shows benefit in some studies, but not in others.

History and Physical Examination Elements for ALL Category Element Notes There is a 4-fold higher risk of leukemia in patients with siblings who have leukemia than in the Siblings with History general population. In identical twins, the other leukemia twin has an increased chance of being diagnosed with ALL within 1 year (17) History Genetic disorders Down syndrome (2% of ALL cases in children) (18) History Maternal age Risk is higher in children of mothers aged >35 (18) History Paternal age Risk is higher in children of fathers age >35 (19; 20) Risk is higher in children of mothers with history of History History of fetal loss fetal loss (19; 20) Increased weight at Risk is higher in patients with higher birth weight History birth (19; 20) History Exposures Ask about exposure to radiation, chemotherapy History Habits Ask about smoking Risk is higher in children of higher socioeconomic History Socioeconomic status status (20) History Malaise and fatigue May be due to anemia History Dyspnea May be due to profound anemia or pneumonia May be due to thrombocytopenia and/or rarely History Easy bruising disseminated intravascular coagulopathy May be due to leukemic cell infiltration or growth in History Bone pain the bone marrow History Headache May be due to CNS leukemia or anemia Look for neurologic deficits, including blurred Other neurologic vision or cranial nerve dysfunction manifested by History symptoms numbness or hyperesthesia, e.g., numb-chin syndrome (21; 22) History Infections Look for pneumonia and other infections Physical exam Fever Usually due to infection Skin exam for pallor, ecchymoses, Pallor may be due to anemia and ecchymoses, Physical exam petechiae, petechiae; hemorrhage due to thrombocytopenia hemorrhage Eye exam for Physical exam Rare (23) leukemic hypopyon Lymph node exam for Physical exam Frequency ~30% (17; 18; 19; 20) lymphadenopathy Abdominal exam for Physical exam Frequency ~30% (17; 18; 19; 20) hepatosplenomegaly Physical exam Genital exam for Rare (17; 18; 19; 20)

testicular enlargement <10%, usually asymptomatic (17; 18; 19; 20). Examples include blurred vision or cranial nerve dysfunction manifested by numbness or hyperesthesia ALL = acute lymphoblastic leukemia; CNS = central nervous system.

Neurologic exam for Physical exam CNS involvement

Laboratory and Other Studies for ALL Test Notes CBC Leukocyte count ≥30 × 109/L occurs in approximately 25%-63% of patients with ALL (13; 14; 15) and indicates a trend toward a worse outcome (13). Platelet count ≥50 × 109/L occurs in approximately 50% of patients with ALL. There is a trend toward shorter survival with lower platelet count (13). Hemoglobin <10 g/dL occurs in approximately 69% of patients with ALL (13) Serum bilirubin Hyperbilirubinemia is associated with worse outcome (13) Lactic dehydrogenase Elevated in 40%-59% of patients with ALL (13; 15) Chemical survey Electrolytes including uric acid, phosphorus, and renal function LFTs Evaluate the ability to administer chemotherapy Coagulation studies PT, APTT, fibrinogen, FDP, and D-dimer to exclude DIC Blood type For transfusion HLA A, B, and DR For transplantation candidates Urinalysis To confirm dehydration, uric acid nephropathy, DIC, infection Blood cultures Needed in febrile patients to evaluate for infection Chest x-ray

Needed to evaluate for infection Head MRI/CT If neurologic symptoms are present. Required in patients with neurologic findings Lumbar puncture Required in patents with neurologic findings pending results of head MRI/CT Peripheral blood smear To examine cellular elements and to look for lymphoblasts of specific morphologic subtype Bone marrow examination To examine morphology of leukocyte precursors, looking for lymphoblasts of specific morphologic subtype Cytochemistry Peroxidase negative (25) and nonspecific staining for Sudan black B (27; 28; 29) and terminal deoxynucleotidyl transferase (30; 31; 32) Immunophenotyping B-lineage ALL: CD19, CD20, CD22, CD79a and/or surface/cytoplasmic immunoglobulin and T-lineage ALL: CD2, surface/cytoplasmic CD3, CD4, CD5, CD7, and/or CD8 (33) Cytogenetic analysis Specimens are processed directly or following a short-term (24-72 hours) culture. The chromosomes are labeled with G-banding and a minimum of 20 metaphases is analyzed (43) Molecular testing PCR with patient-specific junctional regions of rearranged immunoglobulin for B-lineage disease or T-cell receptor genes for T-lineage disease (43) ALL = acute lymphoblastic leukemia; APTT = activated partial thromboplastin time; CBC = complete blood count; CT = computed tomography; DIC = disseminated intravascular coagulation; FDP = fibrinogen degradation product; HLA = human leukocyte antigen; LFTs = liver function tests; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; PT = prothrombin time.

Comparison of the FAB and WHO Classifications for ALL FAB Classifications WHO Classifications* ≥30% blasts ≥20% blastsa L1/L2 (morphology subgroups) Precursor B- or T-cell ALL (cytogenetic subgroups) t(9;22)(q34;q11) BCR/ABL t(v;11q23) MLL rearranged t(1;19)(q23;p13) E2A/PBX1 t(12;21)(p12;q22) ETV/CBF-α (TEL/AML1)

L3

Burkitt-cell leukemia

* In the WHO classification, ALL and lymphoblastic lymphoma are regarded as a single entity with different clinical presentation. a A disease with <20% blasts is defined as lymphoblastic lymphoma. ALL = acute lymphoblastic leukemia; BCR = breakpoint cluster region; FAB = French-American-British classification; WHO = World Health Organization.

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