Leukemia

What are common extra-medullary sites for ALL?

-lymphadenopathy -hepato/splenomegaly -CNS disease -testicular involvement -cutaneous infiltration

What are some long term effects of ALL?

-neurodevelopmental impairment 2/2 toxic agents during developmental age -growth retardation -Cardiotoxicity -risk for second malignancies (common with radiation) -impaired glucose and insulin metabolism -infertility

What are some causes of leukemia?

-transform from MDS, myeloproliferative disorders, aplastic anemia, breast ca -2/2 chemo or radiation -2/2 toxic exposure (atomic bomb survivors have increase risk for ML) -2/2 inherited syndromes or disease (Downs, gene arrangements) -DeNovo (unknown)

What is the MC childhood cancer?

ALL!

How is leukemia classified?

According to cell type and whether it is acute or chronic Myelogenous: leukemia that starts in the myeloid cells -AML (acute myeloid leukemia) -CML (chronic myeloid leukemia) Lymphocytic: leukemia that starts in the lymphoid progenitor cells -ALL (acute lymphoblastic leukemia) -CLL/SLL (chronic lymphocytic leukemia)

What is acute leukemia?

Acute Leukemia is a clonal malignant disorder resulting from genetic alterations in normal hematopoietic stem cells. -Alterations induce differentiation arrest and/or excessive proliferation of abnormal immature cells, which results in decreased normal blood cell production.

What is ALL? Who commonly gets it? What does it affect?

Acute lymphoblastic leukemia, characterized by the expansion and proliferation of the lymphoid cells in bone marrow, blood and other organs. -bimodal age distribution: 2-5yo and then 50yo. -MC childhood cancer -most cases are NOT associated with genetics or enviro risk factors -usually 2/2 chromosome translocation in utero or associated with Downs. HIV

What is the MC type of acute leukemia in adults?

Acute myeloid leukemia

What is AML? Who gets it? What does it produce? Is it treatable

Acute myeloid leukemia. In AML there is a clonal proliferation of Myeloid precursors. Therefore a large numbers of immature/abnormal myeloid cells (blasts) are produced and released into the bloodstream. -immature cells cannot produce their usual functions -MC acute leukemia in adults. Avg age or presentation is 65yo -more common in males *AML develops and advances very quickly; requires immediate treatment!*

What is needed to diagnose AML?

Bone marrow biopsy -molecular, cytogenetic, and morphologic characteristics are used to better classify the AML.

How do you diagnose ALL?

Bone marrow biopsy (shows infiltration lymphoblasts) -Morphology, flow cytometry, and immunphenotyping confirm the diagnosis -chromosomal abnmls are common in childhood ALL. studies can help with risk group stratification and help guide therapy

How do you diagnose MDS?

Bone marrow biopsy and peripheral smear. Requires both: -Changes in one or more of the blood and bone marrow elements. -Morphologic evidence of significant dysplasia in peripheral blood smear and bone marrow biopsy. (blasts must account for less than 20% of the total cells of the bone marrow/peripheral smear) Detection of certain chromosomal abnormalities distinguishes between MDS and AML

What are the 3 phases of CML?

Chronic Phase (early stage, does not behave like malignancy) -~ 85-90% are diagnosed in this phase. Phase can last years. Accelerated or Intermediate Phase -Increase in blasts in bone marrow or blood Blast Phase/Crisis ->/=20% blast in BM and/or blood -Difficult to control -if left untreated, behaves like an acute leukemia *Natural course usually does not include all 3 phases

What is CML? What does it affect? How does this happen?

Chronic myeloid leukemia, A myeloproliferative disorder characterized by increased proliferation of Myeloid Cells which proliferate & circulate in the peripheral blood -median age: 55-65yo, slight male preference -not inherited, it is acquired. Chromosome translocation (Philadelphia chromosome) -Two genes BCR and ABL fuse into 1 gene BCR-ABL.

What phase of CML are most pts diagnosed during?

Chronic phase

How is MDS classified?

Classified using the World Health Organization (WHO) classification system based upon a combination of morphology, immunophenotype, genetics, and clinical features. or International Prognostic Scoring System?

What distinguished MDS and AML?

Detection of certain chromosomal abnormalities distinguishes between MDS and AML

AML translocation

FYI

What is FAB classification?

French-American-British (FAB) method of classifying AML -Based on Morphology (microscope findings).

What are the goals of treatment for CML?

Goals: to reduce/eliminate the cells with Philadelphia chromosome -Hematologic Remission (expected to occur within 3 months): normal CBC, normal physical exam -Cytogenic remission (expected to occur within 3-6 months): when less than 35% of metaphases contain the Philadelphia chromosome -Molecular Remission (desired within 12 months, 3-log reduction of the bcr/abl transcript as measured by quantitative PCR): negative BCR/ABL mutation analysis by PCR/FISH *want to see remission in all 3 categories

What is the Philadelphia chromosome?

Hallmark of CML -Translocation between the long arms of chromosomes 9 and 22. -Two genes BCR and ABL fuse into 1 gene BCR-ABL. KNOW THIS, BOARDS QUESTION

What are the common s/s of ALL? PE findings?

Hard to get complaints from peds patients...rely on hx and PE -s/s: fever, infection, bleeding, bone pain, HA, pancytopenia, night sweats, joint pain PE: hepatomegaly, splenomegaly, lymphadenopathy, testicular enlargement . +/- masses *50% of children with leukemia have at least one of the following: palpable liver, palpable spleen, pallor, fever, or bruising. *parents will notice things! bruising

How is ALL classified (the cells)?

Leukemia cells in ALL are classified according to immunophenotype. Antibodies on cell surfaces "cluster of differentiation" markers are used. Diagnosis and classification are based upon specialized tests (morphology, immunophenotype, and cytogenetics) that are performed on leukemic lymphoblasts.

What PE finding distinguished AML from ALL?

Lymphadenopathy! -only seen in ALL, about 50% of the patients

What diagnosis should be considered in ANY pt with unexplained cytopenias?

MDS -pancytopenia without blasts

What would you see under a peripheral slide in a patient with acute myeloid leukemia (AML)?

Myeloblasts with Auer rods! KNOW THIS BOARDS QUESTION

What is MDS?

Myelodysplastic syndromes (not a true leukemia). Heterogeneous group of malignant hematopoietic stem cell disorders characterized by dysplastic and ineffective blood cell production -> fibrosis -> rough bone marrow -usually 2/2 chemo/radiation/chemical exposure or arises de novo -Age of dx: 65yo -can evolve into AML

Is AML staged?

No, because AML is generally all over the body, does not form tumors -instead we use subtyping to classify AML types: FAB and WHO

What is the clinical presentation of a pt with MDS?

Nonspecific s/s CBC: -anemia (generally associated with low reticulocyte response) -neutropenia and thrombocytopenia are variable -50% have leukopenia Peripheral blood smear usually shows dysplasia in the red and white blood cell series

How do you go about diagnosing and working up CML?

Order CBC with diff: -leukocytosis with no etiology/infection (MC finding) -Thrombocytosis -anemia Dx: bone marrow aspiration and biopsy -Hypercellular with increased myeloid cell line -cytogenetic analysis, PCR, FISH (can use any of these, usually use all 3 to make sure): Philadelphia chromosome (BCR/ABL)

What are some side effects of chemotherapy for AML?

Pancytopenia: -Neutropenia -Thrombocytopenia -Anemia GI toxicity Hair loss Organ dysfunction *patients are very sick in the hospital during induction chemo! normal cells in the BM, the hair follicles, and the lining of the GI tract are all growing. Effects of CTx on these and other normal tissues cause SEs during treatment, including hair loss, nausea, low counts -Chemo kill AML cells over the first 7 to 14 days; it then takes the normal bone marrow about 14 to 28 more days to recover and produce normal blood cells again.

CML prognosis

Patients who achieve hematological, cytogenetic and molecular remission have an excellent prognosis -worse prognosis if targets are not achieved or if new mutations/abnml develop -major cause of failure is non-compliance -disease can become resistant to tx

How do you treat MDS?

Prompt treatment is indicated for patients with symptomatic cytopenias. Asymptomatic lower risk MDS patient may be followed -must have supportive care Low intensity therapies: can improve quality of life but not curative. -good for older pts who cannot tolerate harsh therapy High intensity therapies: intensive chemotherapy and allogeneic hematopoietic cell transplantation.

How do you treat AML?

Rapidly fatal if left untreated! -sx: extreme SOB, fatigue, fevers, bruising/bleeding Tx: intensive chemotherapy! exact treatment depends on specific subtype -Induction chemo (inpatient): huge blast of chemo, basically wipes out the bone marrow. Last about 28 days (Ara-C, Idarubicin, Daunorubincin) -Consolidation chemo: maintenance chemo Goal: produce complete remission and maintain it *for high risk disease: refer for stem cell transplant

Is there risk for relapse of AML?

Relapse is most likely to occur within the first two years after completion of induction chemotherapy, and it becomes less common later. -relapse is usually harder to treat. should refer for SCT

How do you treat ALL?

Successful treatment of children with ALL involves administration of a COMPLEX multidrug regimen that is divided into several phases and includes CNS ppx treatment -most treatment can take 2-3 years to complete! -overall cure rate for children is 90% -w/o CNS ppx (intrathecal ppx), relapse is probable 2-3 years of tx that includes: -induction chemo -intensified consolidation -maintenance chemo -CNS ppx

How do you treat CML?

Tyrosine kinase inhibitors (TKIs): inhibits BCR-ABL tyrosine kinase (the abnormal enzyme created by gene translocation). Direct targeting -1st Generation: imatinib mesylate (Gleevec) -2nd Generation: dasatinib (Sprycel): nolotinib (Tasigna) *PO meds that you have to take everyday -need to monitor with PCR assay q3mo If no good response, refer pt for stem cell transplant (curative)

What are the s/s of CML? PE findings?

Usually, pts are asx. But can present with Fatigue (over production of WBC), Weight loss, Early satiety and Poor appetite (2/2 enlarged spleen), Low-grade fevers, Excessive sweating PE: Hepatomegaly, Splenomegaly, Petechiae, Ecchymoses, Pallor

What is WHO classification?

World Health Organization (WHO) way of -Newer classification. Takes into account the many factors (chromosome etc) that affect prognosis.

What are blasts?

immature white blood cells (myeloblasts) -if you see these on a CBC, ALWAYS WORK UP. That is NOT NORMAL -usually leukemia

Immunophenotype abnormalities for AML (FYI)

immunophenotype: the immuno-chemical and immuno-histological characteristics of a cell or group of cells.

What are the s/s of AML?

mostly related to normal bone marrow cells being replaced by leukemia cells -Fatigue -Anemia -Thrombocytopenia (petechiae) -Neutropenia (vulnerable to infections) -Leukostasis (increase in WBC production to try and attack leukemia cells, they get clogged up) -Hepatosplenomegaly -Bone pain (too many WBC, clogging it up) -Fever -blasts with auer rods on peripheral smear *can have high or low WBC count

Risk assessment for ALL (table)

slide 27

What are good prognostic factors for AML?

•< 40 years of age •De Novo (not related to treatment or underlying heme disorder) •WBC < 10,000 •No DIC •Normal LDH •Normal albumin •Complete remission with first induction therapy

What are poor prognostic factors for AML?

•> 60 years of age •Secondary leukemia •WBC > 100,000 •Platelet count < 30,000 •Presence of DIC •Elevated LDH •Decreased albumin •M0, M5, M6, M7 •Multi-drug resistance phenotype - MDR1 gene •Residual disease after initial induction therapy