WBC=11.7K/ul, Hgb=9.

4g/dl, Plat=83K/ul

DIFF: 56 blasts, 3 bands, 39 Lymphs, 2 mono

BM diff: 87% blasts, 12.4 % lymphs

Flow: TdT+ DR+, CD34 partial + CD19+, CD20 weak CD10+ Cytoplasmic mu -neg Kappa, Lambda -neg

Diagnosis: Acute lymphoblastic leukemia (ALL), Precursor B cell type (common precursor B)

Acute Lymphoblastic Leukemia

Morning Report August 2005

Acute Leukemia
~30

% of all childhood malignancies ALL 5X more common than AML ~2500-3500 new ALL cases/year in the U.S. 2.8 cases per 100,000 incidence in the U.S. Peak incidence age 2-5 years Boys > Girls

Signs and Symptoms

Nonspecific (common)
fever bleeding bone pain lymphadenopathy

Lymphadenopathy (~50% on presentation)

Size
Enlarged if >10 mm in diameter epitrochlear nodes >5 mm inguinal nodes >15 mm

Musculoskeletal pain

Limp/Refusal to bear weight Bone pain (21-33% on presentation)

Nontender Consistency
Firm Rubbery Matted

Leukemic involvement of the periosteum Aseptic osteonecrosis

Signs and Symptoms

CNS symptoms

Headache (<5% cases) Increased ICP

HA Vomiting Lethargy Papilledema Nuchal rigidity

Mediastinal mass
Tracheal compression Associated pleural effusions Superior vena cava syndrome
Pain Dysphagia Dyspnea Swelling of the neck, face, and upper limbs

Cranial nerve abnormalities

Testicular enlargement
painless unilateral

Peripheral Blood Abnormalities

Anemia Thrombocytopenia

75% have platelet count <100,000 at diagnosis 50% present with bleeding
Variable

WBC

50% have WBC counts <10,000 20% have WBC >50,000 initially

Differential Diagnosis
Juvenile rheumatoid arthritis Osteomyelitis Epstein-Barr virus Idiopathic thrombocytopenic purpura Pertussis Parapertussis Aplastic anemia Acute infectious lymphocytosis Non-Hodgkins Lymphoma Other malignancies with bone marrow involvement (neuroblastoma, retinoblastoma, rhabdomyosarcoma, and Ewing's sarcoma) Hypereosinophilic syndrome

Musculoskeletal pain
JRA/JIA Morning stiffness Rash LAD HSM Acute Leukemia Nocturnal pain Nonarticular bony pain LAD HSM

Initial Evaluation

CBC with manual differential PT, PTT Electrolytes Uric Acid BUN/Creatinine Liver function tests Baseline viral titers
CMV EBV HIV Hepatitis B Varicella Zoster Virus

Diagnosis
Bone

marrow examination

Indications
Atypical cells in the peripheral blood Unexplained depression of more than one cell line Unexplained LAD or HSM with cytopenia

If bone marrow cannot be obtained, cells from peripheral leukopheresis or pleural effusions can be used
CSF

examination to diagnose CNS leukemia

Risk Group Stratification

WBC count
Higher risk WBC > 50,000 Prognostic in precursor B-cell ALL Less predictive of outcome in T-cell ALL

Immunophenotype
High Risk
Precursor T-cell ALL Mature B-cell

Response to induction therapy

% lymphoblasts in the blood or bone marrow during and after completion of induction Rapid response favorable Slow response or failure of induction (>5% lymphoblasts) is a poor prognosticator

Age at the time of diagnosis

Higher risk: > 10 years or < 1 year Prognostic in precursor B-cell ALL Less predictive of outcome in T-cell ALL

Risk Group Stratification

Cytogenetics
Low risk
Hyperdiploidy (lymphoblasts exhibiting 50 to 67 chromosomes), particularly if combined with trisomies of chromosomes 4, 10, or 17, t(12;21) TEL/AML1 rearrangements in precursor B-cell ALL

Poor Prognosis/High Risk

Near-tetraploidy (82 to 94 chromosomes) t(1;19) E2A/PBX1

Very High Risk

Hypodiploidy (<45 chromosomes) t(9;22) t(4;11) MLL/AF4

Treatment

Induction

weekly vincristine for 3-4 weeks Daily corticosteroids 6-12 doses of L-asparaginase Doxorubicin or daunorubicin for high-risk patients Bone marrow examination to assess response

Consolidation

initiated soon after attainment of complete remission Goal is to prevent leukemic regrowth, reduce residual tumor burden, and prevent the emergence of drug-resistance usually lasts from four to six months. Agents include: cytarabine, etoposide, MTX, daunorubicin/doxorubicin, cyclophosphamide/ifosfamide

Treatment

Maintenance less intensive continuation regimen

Daily oral 6-mercaptopurine Weekly MTX Periodic intrathecal therapy pulses of additional chemotherapeutic agents (vincristine and steroids)

CNS directed therapy

begins during the induction phase and continues throughout the remainder of the treatment regimen intrathecal chemo agents Craniospinal radiotherapy associated with cognitive impairment and altered white matter development Now reduced or eliminated from many CNS preventive therapy protocols CNS radiation is warranted in CNS involvement and in some high-risk ALL cases

Adverse Effects

Toxicity from the chemotherapeutic agents Tumor lysis syndrome Thrombosis

Bleeding

intracranial dural sinus thrombosis with hemorrhage DVT PE Thrombocytopenia Vitamin K dependent coagulopathy for those on chronic Abx

Infection Mucositis Pancreatitis Hyperglycemia

Tumor Lysis Syndrome

Characteristics

Release of intracellular uric acid, potassium, and phosphate from rapid turnover of malignant cells Usually precipitated by chemotherapy, but can occur before Most often with high tumor burden or T-cell leukemia Components of tumor lysis: -Hyperuricemia -Renal precipitation can progress to acute renal failure -Hyperkalemia -Can progress to fatal arrhythmia -Hyperphosphatemia/Hypocalcemia -Increased phosphate can cause hypocalcemia and renal precipitation renal failure

Mangement Provide hydration and diuresis, avoid supplemental potassium

Treat hyperkalemia emergently, if necessary Decrease uric acid with allopurinol or urate oxidase Consider oral phosphate binders Initiate dialysis for acute renal failure Transfer urgently to a pediatric oncology tertiary care center

Late Adverse Effects

CNS impairment linear growth Cardiotoxicity Infertility incidence of secondary cancers

~2 to 3 %childhood ALL survivors Greatest risk s/p cranial radiotherapy Brain tumors (astrocytoma, glioblastoma multiforme) Hematologic malignancies (AML)