Team P (“,) – sec B2 HEMA2012

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CHRONIC MYELOPROLIFERATIVE DISORDERS

Erly Samson-Cruz,MD,FPCP Internist-Hematologist

Polycythemia vera chronic idiopathic myelofibrosis essential thrombocytosis chronic myeloid leukemia

• pathophysiology involves the clonal expansion of a multipotent hematopoietic progenitor cell with the overproduction of one or more of the formed elements of the blood

• may transform into acute leukemia naturally or as a consequence of mutagenic treatment

POLYCYTHEMIA /ERYTHROCYTOSIS

increase in circulating red blood cells above normal

elevated Hgb o Men 170g/L o women 150g/L

elevated Hct o Men >50% o women >45%

REAL/ABSOLUTE • primary (P. vera) • secondary ( appropriate or inappropriate)

associated with increases in EPO levels o physiologically adapted appropriate elevation based on

tissue hypoxia (lung disease, high altitude, CO poisoning, high-affinity hemoglobinopathy)

o abnormal overproduction (renal cysts, renal artery stenosis, tumors with ectopic EPO production)

APPARENT/SPURIOUS/RELATIVE

decrease in plasma volume

Gaisbock’s syndrome

Pointers in the history o Smoking history o Living at high altitude o History of congenital heart disease o PUD o Sleep apnea o Chronic lung disease o Renal disease

Manifestations

majority are asymptomatic

some with symptoms related to increase red cell mass or underlying disease process

symptoms related to hyperviscosity and thrombosis

neuro symptoms o vertigo o tinnitus o headache o visual disturbances

Physical examination

ruddy complexion

splenomegaly

cyanosis or evidence of a right-to-left shunt

cor pulmonale

A. POLYCYTHEMIA VERA

clonal disorder involving a multipotent hematopoietic progenitor cell in which there is accumulation of phenotypically normal red cells, granulocytes, and platelets in the absence of a recognizable physiologic stimulus

2 per 100,000 persons ETIOLOGY

unknown

nonrandom chromosome abnormalities such as 20q-, trisomy 8 or 9 have been documented in a small percentage of untreated polycythemia vera patients

no consistent cytogenetic abnormality has been associated with the disorder and no specific genetic defect has yet been identified

CLINICAL FEATURES

massive splenomegaly

high hemoglobin or hematocrit

aquagenic pruritus

uncontrolled erythrocytosis o neurologic symptoms o systolic hypertension o venous or arterial thrombosis o easy bruising, epistaxis, or gastrointestinal hemorrhage o hyperuricemia

DIAGNOSIS

red cell mass determination o 51Cr-tagged red cells o polycythemia vera, in contrast to erythropoietin-driven

erythrocytosis plasma volume is frequently elevated

plasma erythropoietin level o useful diagnostic test in patients with isolated

erythrocytosis

elevated plasma erythropoietin level o hypoxic cause for erythrocytosis o autonomous erythropoietin production

pulmonary function evaluate renal and hepatic anatomy

plasma erythropoietin level • normal erythropoietin level o hypoxic cause for erythrocytosis o polycythemia vera

arterial oxygen saturation is normal • low or unmeasurable

o most likely polycythemia vera

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Other Laboratory tests:

RBC count

MCV

RDW

Elevated leukocyte alkaline phosphatase

Elevated blood uric acid level

Elevated serum vitamin B12 or B12-binding capacity

bone marrow aspirate and biopsy will provide no specific diagnostic information

CRITERIA FOR CLINICAL DIAGNOSIS OF PV 1. Elevated red cell mass 2. Normal arterial oxygen saturation 3. Splenomegaly 4. In the absence of splenomegaly:

o leukocytosis and thrombocytosis COMPLICATIONS

related directly to the increase in blood viscosity associated with elevation of the red cell mass

indirectly to the increased turnover of red cells, leukocytes, and platelets and the attendant increase in uric acid and cytokine production

Erythromelalgia o syndrome of unknown etiology primarily involving the lower

extremities o manifested usually by erythema, warmth, and pain of the

affected appendage and occasionally digital infarction o occurs with a variable frequency in patients with a

myeloproliferative disorder o responsive to salicylates

TREATMENT • Maintenance of the hemoglobin level is mandatory to avoid the

thrombotic complications =140 g/L in men =120 g/L in women

o Phlebotomy • chemotherapy to reduce splenomegaly, leukocytosis, or pruritus

o hydroxyurea o IFN-a o allopurinol

• salicylates for erythromelalgia • Allogeneic bone marrow transplantation may be curative in

young patients

Prognosis

expected to live long and useful lives when their red cell mass is effectively managed with phlebotomy

chemotherapy is never indicated to control the red cell mass unless venous access is impossible

B. CHRONIC IDIOPATHIC MYELOFIBROSIS

agnogenic myeloid metaplasia (AMM)

myelofibrosis with myeloid metaplasia (MMM)

clonal disorder of a multipotent hematopoietic progenitor cell of unknown etiology characterized by marrow fibrosis, myeloid metaplasia with extramedullary hematopoiesis, and splenomegaly

uncommon disease

primarily afflicts individuals in their sixth decade

ETIOLOGY

etiology is unknown

nonrandom chromosome abnormalities such as 20q-, 13q-, and trisomy 1q are not uncommon

o no specific cytogenetic abnormality

fibrosis is associated with overproduction of transforming growth factor ß and thrombopoietin

fibroblasts in chronic idiopathic myelofibrosis are not part of the neoplastic clone

CLINICAL FEATURES

no specific signs or symptoms associated

most patients are asymptomatic at presentation

splenic enlargement

mild hepatomegaly

anemia, mild

abnormal blood counts during a routine examination

hyperuricemia and secondary gout

PBS features of extramedullary hematopoiesis

leukocyte and platelet counts are either normal, increased or low

LDH and serum alkaline phosphatase levels can be elevated

leukocyte alkaline phosphatase can be low, normal, or elevated

marrow may be unaspirable due to the myelofibrosis

bone x-rays may reveal osteosclerosis

DIAGNOSIS

diagnosis by exclusion

extramedullary hematopoiesis o teardrop-shaped red cells o nucleated red cells o myelocytes and promyelocytes

marrow is usually not aspirable due to increased marrow reticulin

marrow biopsy hypercellular marrow with trilineage hyperplasia and increased megakaryocytes

occurrence of autoimmune abnormalities such as immune complexes, antinuclear antibodies, rheumatoid factor, or a positive Coombs' test

Cytogenetic analysis of blood or marrow is useful o to exclude CML o for prognostic purposes

circulating CD34+ cells is markedly increased COMPLICATIONS

median survival of only 5 years (range 1 to 15 years)

marrow failure with transfusion-dependent anemia and increasing organomegaly

prone to deep-seated tissue infections, particularly of the lungs

can evolve from a chronic phase to an accelerated phase with constitutional symptoms and increasing marrow failure

~10% of patients develop an aggressive form of acute leukemia for which therapy is usually ineffective

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important prognostic factors for disease acceleration include o Anemia o Thrombocytopenia o Age o presence of complex cytogenetic abnormalities o constitutional symptoms

(unexplained fever, night sweats, wt loss)

nonrandom cytogenetic abnormality is associated with a shortened life span, and the presence or development of multiple cytogenetic abnormalities is highly indicative of disease acceleration

TREATMENT

no specific therapy exists for chronic idiopathic myelofibrosis

anemia may be exacerbated by deficiency of folic acid or iron, and in rare instances, pyridoxine therapy has been effective

Splenectomy may also be necessary if splenomegaly impairs alimentation and should be performed before cachexia sets in

Allopurinol can control significant hyperuricemia

Hydroxyurea useful for controlling organomegaly

IFN2-a may cause reversal of myelofibrosis

Glucocorticoids are used to control autoimmune complications and may ameliorate anemia alone or in combination with thalidomide

Allogeneic bone marrow transplantation should be considered in younger patients

C. ESSENTIAL THROMBOCYTOSIS • Essential thrombocythemia • idiopathic thrombocytosis • primary thrombocytosis • hemorrhagic thrombocythemia

a clonal disorder of unknown etiology involving a multipotent hematopoietic progenitor cell and is manifested clinically by the overproduction of platelets without a definable cause

an uncommon disorder

no clonal marker distinguishes it from the more common nonclonal, reactive forms of thrombocytosis

occur at any age in adults

occurs without symptoms or disturbances of hemostasis

female predominance

clinical criteria have been proposed to distinguish it from the other chronic myeloproliferative disorders, which may also present with thrombocytosis but have differing prognoses and treatment

o do not establish clonality o useful only in identifying

CML polycythemia vera myelodysplasia

ETIOLOGY – thrombopoietin enhances the proliferation of its target cells but

also enhances the reactivity of their end-stage product, the platelet

– thrombopoietin enhances the survival of multipotent hematopoietic stem cells

– clonality of essential thrombocytosis established by the use of of X-linked DNA polymorphisms, and by the identification of nonrandom, although variable, cytogenetic abnormalities

CLINICAL FEATURES – most often identified incidentally when a platelet count is

obtained during the course of a routine evaluation – no symptoms or signs are specific for essential thrombocytosis – Physical examination is generally unremarkable except

occasionally for mild splenomegaly – massive splenomegaly is more characteristic of the other

myeloproliferative disorders, particularly polycythemia vera or idiopathic myelofibrosis

– blood smear remarkable for the number of platelets present, some of which may be very large

– leukocyte alkaline phosphatase score is either normal or elevated

– prolonged bleeding time and impaired platelet aggregation can be present

– marrow biopsy usually reveals both megakaryocyte hyperplasia and hypertrophy

– slight increase in marrow reticulin may be present, but if extensive, another diagnosis should be considered

– presence of stainable iron – no consistently identifiable abnormality is notable, even

involving chromosomes 3 and 1 where the genes for thrombopoietin and its receptor Mpl, respectively, are located

DIAGNOSIS – determine if it is a consequence of another disorder – Cytogenetic evaluation is mandatory to determine if the

thrombocytosis is due to CML or a myelodysplastic disorder such as the 5q- syndrome

– anemia and ringed sideroblasts are not features of essential thrombocytosis, but they are features of idiopathic refractory sideroblastic anemia, in which thrombocytosis can also occur

– presence of massive splenomegaly should suggest the possibility of another myeloproliferative disorder

COMPLICATIONS – >1 × 106/uL

o very high platelet counts are associated primarily with hemorrhage due to acquired von Willebrand disease

– <1 × 106/uL o associated with thrombosis

TREATMENT – asymptomatic patient

o requires no therapy – symptoms must be clearly identified to be a consequence of

the elevated platelet count – if platelet reduction is deemed necessary on the basis of

neurologic symptoms refractory to salicylates o IFN-a o anagrelide, a quinazolin derivative, can reduce the

platelet count, but neither is uniformly effective nor without significant side effects

o Hydroxyurea considered only if these agents are not effective or tolerable

– bleeding associated with thrombocytosis o e-aminocaproic acid

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D. CHRONIC MYELOGENOUS LEUKEMIA INCIDENCE

• 1.5 per 100,000 people per year • age-adjusted incidence is higher in men than in women (2.0

versus 1.2) • incidence of CML increases age • CML incidence decreased slightly between 1973 and 1999

(1.9 versus 1.5)

DEFINITION • diagnosis is established by identifying a clonal expansion of a

hematopoietic stem cell possessing a reciprocal translocation between chromosomes 9 and 22

• Untreated, the disease is characterized by the inevitable transition from a chronic phase to an accelerated phase and on to blast crisis

ETIOLOGY • No clear correlation with exposure to cytotoxic drugs • no direct evidence of a viral etiology • Cigarette smoking has been shown to accelerate the

progression to blast crisis and therefore has an adverse effect on survival in CML

• large doses of radiation can induce CML

CLINICAL PRESENTATION Physical Findings

minimal to moderate splenomegaly

mild hepatomegaly, ocassionally

Lymphadenopathy and myeloid sarcomas prognosis is poor

. Phases o Chronic phase o Accelerated phase o Blastic phase

Hematologic Findings

Elevated white blood cell counts, with various degrees of immaturity of the granulocytic series

Usually <5% circulating blasts and <10% blasts and promyelocytes

Platelet counts are almost always elevated at diagnosis

normochromic normocytic anem

Leukocyte alkaline phosphatase is characteristically low in CML cells

Serum levels of vitamin B12 and vitamin B12-binding proteins are generally elevated

Phagocytic functions normal at diagnosis and remain normal during the chronic phase

Histamine production secondary to basophilia is increased in later stages, causing pruritus, diarrhea, and flushing

marrow cellularity, primarily of the myeloid and megakaryocytic lineages

marrow blast percentage is generally normal or slightly elevated

marrow or blood basophilia, eosinophilia, and monocytosis may be present

Disease acceleration

defined by the development of increasing degrees of anemia

cytogenetic clonal evolution

blood or marrow blasts between 10 and 20%

blood or marrow basophils =20%

platelet count <100,000/ul

Negative neutrophil alkaline phosphatase reaction

Negative neutrophil alkaline phosphatase (NAP) reaction. A low NAP score is seen in 95% of cases of chronic granulocytic leukaemia. This test is redundant if there is ready availability of karyotypic or molecular genetic analysis to detect t(9;22) and BCR-ABL fusion respectively. To compare with a normal neutrophil alkaline phosphatase reaction click on compare.

Blast crisis

defined as acute leukemia

blood or marrow blasts = 20%

hyposegmented neutrophils may appear

blast cells can be classified based on morphologic, cytochemical, and immunologic features

half the cases are myeloid one-third lymphoid 10% erythroid the rest are undifferentiated

DIAGNOSIS

Chromosomal Findings / cytogenetic hallmark

found in 90 to 95% of patients

t(9;22)(q34;q11.2)

Philadelphia chromosome presence of a shortened chromosome 22 (22q-)arises from

the reciprocal 9;22 translocation

TREATMENT Allogeneic SCT

only curative therapy for CML

when feasible, the treatment of choice

complicated by a high early-mortality rate owing to the transplant procedure

outcome of SCT depends on multiple factors including (1) the patient (e.g., age and phase of disease) (2) the type of donor [e.g., syngeneic (monozygotic twins) or

HLA-compatible allogeneic, related or unrelated] (3) the preparative regimen (4) GVHD (5) posttransplantation treatment.

Imatinib mesylate (Gleevec, STI571) 400 mg/d

functions through competitive inhibition at the adenosine triphosphate (ATP) binding site of the Abl kinase, which leads to inhibition of tyrosine phosphorylation of proteins involved in Bcr/Abl signal transduction

most patients with Imatinib induces apoptosis in cells expressing Bcr/Abl. therapy 95% of patients achieved complete hematologic remission 60% achieved major cytogenetic remission complete cytogenetic remission rate of 41%

Those who did not achieve at least a major cytogenetic remission following 3 months of therapy had a higher risk of disease progression to the accelerated/blastic phases of the disease

Patients in the accelerated/blastic phases of the disease are less sensitive to imatinib, and the treatment outcome is less favorable

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Interferons

treatment of choice before imatinib

potent, pleiotropic biologic effects, spanning a spectrum of antiviral, microbicidal, immunomodulatory, and antiproliferative properties

downregulate the expression of several oncogenes and cytokines

upregulate the expression of IFN regulatory factor-1 (a transcriptional activator with antioncogenic activity), adhesion molecules, and the histocompatibility genes

inhibit angiogenesis and induce a cellular immune response

Chemotherapy – rapid lowering of white blood cell counts – reduction of symptoms, reversal of symptomatic splenomegaly

Hydroxyurea

o ribonucleotide reductase inhibitor o initial dose is 1 to 4 g/d, halved with each 50% reduction of

the leukocyte count o cytogenetic remissions are uncommon

• Homoharringtonine (HHT) o plant alkaloid derived from a tree, Cephalotaxus fortuneii sp.

Harringtonii o blocks peptide bond formation after binding of the

aminoacyl-transfer RNA to the ribosome o patients whose disease progressed during treatment with

IFN-a or who were in later chronic phase (>1 year from diagnosis) 72% complete hematologic responses 15% major cytogenetic responses

o use of HHT before IFN-a in early chronic phase 92% complete hematologic response rate 27% major cytogenetic response rate

o Toxicity is mainly related to myelosuppression

• Busulphan o alkylating agent that acts on early progenitor cells o not recommend because of its serious side effects

myelosuppression pulmonary, endocardial, and marrow fibrosis Addison-like wasting syndrome

• Arsenic trioxide o mechanism(s) of action of in non-APL leukemias is

unknown o initial studies of arsenic trioxide in Bcr/Abl-expressing cell

lines demonstrated downregulation of Bcr/Abl expression as well as activation of apoptosis

• Intensive combination chemotherapy o used in chronic-phase CML o with 30 to 50% of patients achieving complete cytogenetic

responses but short-lived o being used today only to mobilize normal progenitors in the

blood in order to collect circulating stem cells for autologous transplantation

Autologous SCT

could potentially cure CML

normal hematopoietic stem cells appear with increased frequency in the blood of patients with CML during the recovery phase after chemotherapy and G-CSF

A role for imatinib before stem cell collection to achieve minimal residual disease and following transplantation to maintain this status is currently being investigated

only a few cases have been reported to successfully engraft following imatinib therapy. Therefore such approaches should be performed only in clinical trials.

Leukapheresis and Splenectomy

• Intensive leukapheresis o may control the blood counts in chronic-phase CML o expensive and cumbersome o useful in emergencies where leukostasis-related

complications such as pulmonary failure or cerebrovascular accidents

o treatment of pregnant women in whom it is important to avoid potentially teratogenic drugs

• Splenectomy o used in the past because of the suggestion that evolution

to the acute phase might occur in the spleen o symptomatic relief of painful splenomegaly unresponsive

to chemotherapy o For significant anemia or thrombocytopenia associated

with hypersplenism o Splenic radiation is used rarely to reduce the size of the

spleen Blast Crisis

treatment for all forms of blast crisis is generally ineffective

with imatinib 52% achieved hematologic remission (21% complete

hematologic remission) median overall survival was 6.6 months patients who achieve complete hematologic remission

or whose disease returns to a second chronic phase should be considered for allogeneic SCT

other approaches include induction chemotherapy tailored to the phenotype of the blast cell followed by imatinib, with or without additional chemotherapy and SCT

Blast crisis following initial therapy with imatinib carries a dismal prognosis

END

Team P (“,) – sec B2 HEMA2012

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ACUTE MYELOID LEUKEMIA

INTRODUCTION

heterogeneous group of diseases characterized by infiltration of the blood, bone marrow, and other tissues by neoplastic cells of the hematopoietic system

based on untreated course, the myeloid leukemias have traditionally been designated acute or chronic

INCIDENCE

• ~3.6 per 100,000 people per year • age-adjusted incidence is higher in men than in women (4.4

versus 3.0) • incidence increases with age

– 1.7 in individuals <65 years – 16.2 in those >65

ETIOLOGY

• Implicated in the development of AML – Heredity – Radiation – chemical and other occupational exposures – drugs

• No direct evidence suggests a viral etiology

CLASSIFICATION • Morphology • Cytochemistry • Immunophenotype • Cytogenetic and molecular techniques

I. Morphologic Classification – Dx established by the presence of > 20% myeloblasts in

blood and/or bone marrow – Myeloblasts have nuclear chromatin that is uniformly fine or

lacelike in appearance and large nucleoli (2 to 5 per cell) – Presence of cytoplasmic granules, Auer rods, or the nuclear

folding and clefting characteristic of monocytoid cells

French, American, and British (FAB) – dx established by the presence of > 30% myeloblasts in the

marrow – eight major subtypes, M0 to M7 based on morphology and

cytochemistry

WHO classification – dx established by the presence of > 20% myeloblasts in

blood and/or bone marrow – incorporating molecular (including cytogenetic), morphologic

(multilineage dysplasia), and clinical features (such as prior hematologic disorder) in defining disease entities

*WHO modified the FAB schema by reducing the number of blasts required for a diagnosis.

II. Cytochemical Classification – positive myeloperoxidase reaction in >3% of the blasts may

be the only feature – distinguishing AML from Acute Lymphoblastic Leukemia

(ALL)

Bone marrow aspirate from a patient with M0 AML showing

agranular blasts which were negative with myeloperoxidase, Sudan black B and esterase stains

Peripheral blood film in M1 AML showing type I and type II blasts

and a promyelocyte. In this case the blasts were heavily vacuolated

Bone marrow aspirate in M2 acute myeloid leukaemia stained with

a myeloperoxidase stain showing fine granular positivity in the cytoplasm of the blast cells. This positive reaction shows that the leukaemia is myeloid not lymphoid.

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Peripheral blood film in M4 AML showing two monoblasts and a

myeloblast. Note that monoblasts are large cells with voluminous cytoplasm. Their nuclei are sometimes lobulated and the cytoplasm may be vacuolated. The myeloblast is a smaller cell with a higher nucleocytoplasmic ratio. This myeloblast is a type I myeloblast. M4 AML is also referred to as acute myelomonocytic leukaemia

BMABone marrow aspirate (M4 AML) in M4 AML showing a monoblast, a monocyte and a number of myeloblasts.

Bone marrow aspirate in M5 acute myeloid leukaemia showing a

positive reaction for a-naphthyl acetate esterase, indicative of 'non-specific esterase' activity. Esterases are classified as specific or chloroacetate esterase, which is specific for the granulocytic lineage, and non-specific esterases, which are positive in monocytes and megakaryocytes and to a variable extent in other cells

Blood film from an infant with Down's syndrome with M7 AML or

acute megakaryoblastic leukaemia showing megakaryoblasts and one NRBC. The lineage of the blasts was identified by immunocytochemistry with a CD61 monoclonal antibody. Down's syndrome is associated with a greatly increased incidence of M7 AML

Bone marrow aspirate from a case of M7 AML presenting with the clinical features of acute myelofibrosis. The cytoplasmic blebs are typical of a megakaryoblast but are not specific for this lineage.

III. Immunophenotypic Classification – studied by multiparameter flow cytometry – example

M0 demonstration of the myeloid-specific antigens CD 13 or 33

M7 expression of the platelet-specific antigens CD41 and/or CD61

IV. Chromosomal Classification

most important pretreatment prognostic information in AML

two cytogenetic abnormalities invariably assoc with a specific FAB group t(l5;17)(q22;q12) with M3 inv(16)(p13q22) with M4Eo

recurring chromosomal abnormalities in AML have been associated with specific clinical characteristics associated with younger age are t(8;21) and t(l5;17) with older age, del(5q) and del(7q) myeloid sarcomas associated with t(8;21) Disseminated intravascular coagulation (DIC) with t(15;17)

molecular study of many recurring cytogenetic abnormalities has revealed genes that may be involved in leukemogenesis t(15;17) encodes a chimeric protein, Pml/Rara, which is

formed by the fusion of the retinoic acid receptor-a (RARa) gene from chromosome 17 and the promyelocytic leukemia (PML) gene from chromosome 15

– molecular aberrations are used for diagnosis and detection of residual disease after treatment

– molecular aberrations are also useful for classifying risk of relapse in patients without cytogenetic abnormalities

CLINICAL PRESENTATION

Symptoms

nonspecific symptoms

consequence of anemia, leukocytosis, leukopenia or leukocyte dysfunction, or thrombocytopenia

fatigue or weakness anorexia and weight loss fever bleeding/ easy bruising

occasionally bone pain, lymphadenopathy, nonspecific cough headache, or diaphoresis

rarely mass lesion located in the soft tissues, breast, uterus,

ovary, cranial or spinal dura, gastrointestinal tract, lung, mediastinum, prostate, bone, or other organs (granulocytic sarcoma, or chloroma)

more common in patients with 8;21 translocations

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Physical Findings

fever, splenomegaly, hepatomegaly, lymphadenopathy, sternal tenderness, and evidence of infection and hemorrhage

significant GI bleeding, intrapulmonary hemorrhage, or intracranial hemorrhage occur most often in APL

bleeding associated with coagulopathy in monocytic AML

retinal hemorrhages are detected in 15% of patients

Infiltration of the gingivae, skin, soft tissues, or the meninges with leukemic blasts at diagnosis is characteristic of the monocytic subtypes (FAB5 M4 and M5)

Hematologic Findings • Anemia is usually present at diagnosis

– usually normochromic normocytic – reduced reticulocyte count – erythrocyte survival is decreased by accelerated destruction – active blood loss also contributes to the anemia

• Platelet counts – <100,000/ul are found at diagnosis in ~75% of patients – about 25% have counts <25,000/ul – morphologic and functional platelet abnormalities can be

observed, including large and bizarre shapes with abnormal granulation and inability of platelets to aggregate or adhere normally to one another

• Median presenting leukocyte count is about 15,000/ul – 25 to 40% of patients have counts <5000/ul – 20% have counts >100,000/ul – <5% have no detectable leukemic cells in the blood – Poor neutrophil function may be noted functionally by

impaired phagocytosis and migration and morphologically by abnormal lobulation and deficient granulation

Pretreatment Evaluation

evaluate the overall functional integrity of the major organ systems

Assess factors that have prognostic significance, either for achieving complete remission (CR) or for predicting the duration of CR

Leukemic cells should be obtained and cryopreserved for future use as new tests and therapeutics become available

All patients should be evaluated for infection

Prompt replacement of the appropriate blood components, if necessary

Initiation of chemotherapy may aggravate hyperuricemia, and patients are usually started immediately on allopurinol or rasburicase and hydration at diagnosis

PROGNOSTIC FACTORS

Many factors influence the likelihood of entering CR, the length of CR, and the curability of AML

CR is defined after examination of both blood and bone marrow ANC must be =1500/ul platelet count =100,000/ul Circulating blasts should be absent Bone marrow cellularity should be >20% with trilineage

maturation bone marrow should contain <5% blasts, and Auer rods

should be absent Extramedullary leukemia should not be present

patients in CR to detect residual disease RT-PCR to detect AML-associated molecular

abnormalities FISH to detect AML-associated cytogenetic aberrations

Age at diagnosis is the most important pretreatment risk factors advancing age associated with a poorer prognosis leukemic cells in elderlypatients differs biologically

Performance status, independent of age, also influences ability to survive induction therapy and thus respond to treatment

Chromosome findings at diagnosis are an independent prognostic factor Patients with t(8;21), inv(16), or t(15;17) have good

prognoses no cytogenetic abnormality have a moderately favorable

outcome when treated with high-dose cytarabine complex karyotype, inv(3), or -7 have a very poor

prognosis

history of an antecedent hematologic disorder are other pretreatment clinical features that are associated with a lower CR rate and shorter survival time

Secondary AML developing after treatment with cytotoxic agents for other malignancies is extremely difficult to treat successfully

high presenting leukocyte count is an independent prognostic factor

FAB classification diagnosis has been found to be an independent prognostic factor in some series.

Expression of the MDR1 gene adversely influences outcome

several treatment factors correlate with prognosis in AML, including achievement of CR,rapidity with which the blast cells

disappear from the blood after the institution of therapy patients who achieve CR after one induction cycle have

longer CR durations than those requiring multiple cycles TREATMENT I. Induction Chemotherapy

initial goal is to quickly induce CR

most commonly used CR induction regimens consist of combination chemotherapy with cytarabine and an anthracycline

Cytarabine is a cell cycle S-phase-specific antimetabolite that becomes phosphorylated intracellularly to an active triphosphate form that interferes with DNA synthesis – Adm as continuous IV infusion at 100-200 mg/m2/day for 7 days Anthracyclines are DNA intercalaters – mode of action is inhibition of topoisomerase II, leading to DNA

breaks – Daunorubicin, 45 to 60 mg/m2, intravenously on days 1, 2, and 3

or – Idarubicin at 12 or 13 mg/m2 per day for 3 days in conjunction

with cytarabine by 7-day continuous infusion is at least as effective and may be superior to daunorubicin in younger patients

Etoposide added to regimen does not increase the CR rate but may improve the CR duration

After induction chemotherapy, the bone marrow is examined to determine if the leukemia has been eliminated

If >5% blasts exist with =20% cellularity, retreat with cytarabine and an anthracycline in doses similar to those given initially, but for 5 and 2 days

Patients who fail to attain CR after two induction courses should immediately proceed to an allogeneic SCT if an

appropriate donor exists ,applied to patients <65 to 70 y/o with acceptable end-organ function

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7 and 3 cytarabine/daunorubicin regimen 65 to 75% of adults with de novo AML achieve CR Two-thirds achieve CR after a single course of therapy one-third require two courses about 50% of patients who do not achieve CR have a drug-

resistant leukemia 50% do not achieve CR because of fatal complications of

bone marrow aplasia or impaired recovery of normal stem cells

High-dose cytarabine-based regimens have very high CR rates after a single cycle of therapy produced CR rates similar to those achieved with standard

7 and 3 regimens CR duration was longer after high-dose cytarabine than

after standard-dose cytarabine The hematologic toxicity is greater than 7,3 regimens

o Myelosuppression o pulmonary toxicity o significant and occasionally irreversible cerebellar

toxicity

II. Postremission Therapy

designed to eradicate any residual leukemic cells

to prevent relapse and prolong survival High-dose cytarabine

– more effective than standard-dose cytarabine – significantly prolonged CR and increased the fraction cured

in patients with favorable [t(8;21) and inv(16)] and normal cytogenetics

– no significant effect on patients with other abnormal karyotypes

SCT as postremission option

– improved duration of remission with allogeneic SCT compared to autologous SCT or chemotherapy alone

– overall survival is generally not different, the improved disease control with allogeneic SCT is erased by the increase in fatal toxicity

Supportive Care • Measures geared to supporting patients through several weeks

of granulocytopenia and thrombocytopenia • should be treated in centers expert in providing supportive

measures for their management • Both G-CSF and GM-CSF have reduced the median time to

neutrophil recovery by an average of 5 to 7 days • Multilumen right atrial catheters should be inserted • Adequate and prompt blood bank support is critical to therapy

of AML – Platelet transfusions to maintain a platelet count >10,000 to

20,000/ul – RBC transfusions to keep the hemoglobin level >80 g/L (8 g/dL) – Blood products leukodepleted by filtration should be used to

avert or delay alloimmunization as well as febrile reaction – Blood products should also be irradiated to prevent graft-

versus-host disease (GVHD • Prophylactic administration of antibiotics in the absence of fever

is controversial • Early initiation of empirical broad-spectrum antibacterial and

antifungal antibiotics has significantly reduced the number of patients dying of infectious complications

• An antibiotic regimen adequate to treat gram-negative and gram-positive organisms should be instituted at the onset of fever in a granulocytopenic patient after clinical evaluation

• Specific antibiotic regimens should be based on antibiotic sensitivity data obtained from the institution at which the patient is being treated

Promyelocytic Leukemia • Tretinoin

– 45 mg/m2 per day orally until remission is documented – plus concurrent anthracycline chemotherapy appears to be

the safest and most effective treatment for APL – drug that induces the differentiation of leukemic cells

bearing the t(15;17) – not effective in other forms of AML – does not produce DIC – produces another complication called the retinoic acid

syndrome – Treatment complication

Retinoic acid syndrome Occurring within the first 3 weeks of treatment characterized by fever, dyspnea, chest pain,

pulmonary infiltrates, pleural and pericardial effusions, hypoxia

related to adhesion of differentiated neoplastic cells to the pulmonary vasculature endothelium

Glucocorticoids, chemotherapy, and/or supportive measures can be effective treatment

mortality rate is about 10% • Arsenic trioxide

– produces meaningful responses in up to 85% of patients refractory to tretinoin

– The use of arsenic trioxide is being explored as part of initial treatment in clinical trials of APL

• The detection of minimal residual disease by RT-PCR amplification of the t(l5;17) chimeric gene product appears to predict relapse

Relapse • once relapse occurs after the standard induction and

postremission chemotherapy patients are rarely cured with further standard-dose chemotherapy

• Long-term disease-free survival is 30 to 50% with allogeneic SCT in first relapse or in second remission

• Chemotherapy is administered prior to allogeneic transplant if the AML is rapidly progressing

• The most important factors predicting response at relapse are the length of the previous CR, whether initial CR was achieved with one or two courses of chemotherapy, and the type of postremission therapy

• treatment with novel approaches should be considered if SCT is not possible

• For elderly patients (age >60) – gemtuzumab ozogamicin (Mylotarg) is another alternative – an antibody-targeted chemotherapy consisting of the

humanized anti-CD33 antibody linked to calicheamicin, a potent antitumor antibiotic

– CR rate in response to this therapy is ~30% – effectiveness of this agent in early relapsing (<6 months)

or refractory AML patients is limited, possibly due to calicheamicin being a potent Mdr1 substrate

– toxicity: myelosuppression, infusion toxicity, and venoocclusive disease

• Currently, studies are examining the efficacy of this treatment in combination with chemotherapy for both young and older patients with previously untreated AML

END

Team P (“,) – sec B2 HEMA2012

Page 10 of 12

ACUTE LYMPHOBLASTIC LEUKEMIA

• a neoplastic disease that results from somatic mutation in a single lymphoid progenitor cell at one of several discrete stages of development

• immunophenotype at diagnosis reflects level of differentiation achieved by the dominant clone

• most common malignancy under age of 15 years 25% of all cancers 76% of all leukemias

• M>F in all age groups

RISK FACTORS Genetic syndrome

Down Syndrome 10-30 fold increased risk of leukemia < 3 y/o AML M7 Older age ALL

Autosomal recessive dses with increased chromosomal fragility

Ataxia Telagiectasia Bloom syndrome Nijmegen breakage syndrome

Constitutional/Acquired Immunodeficiency states Congenital X linked agammaglobulinemia Ig A deficiency Variable immunodeficiency

Environmental Factors – exposure to diagnostic x-rays ( in utero) – parental cigarette before or during pregnancy – pesticide exposure – maternal alcohol consumption – increased consumption of dietary nitrites

most cases unknown

CLINICAL FEATURES OF ALL – Insidious or acute – features reflect the degree of marrow failure and extent of

extramedullary spread – fever

o induced by pyrogenic cytokines o results from infection o resolves within 72 hours after start of induction

– anemia manifestations o fatigue and lethargy o dyspnea o dizziness

– bone pain, arthralgia, limp o common in pediatric population o less severe in adults o leukemic infiltration of periosteum

– less common o headache o vomiting o alteration of mental function o oliguria o anuria

– occassionally o IC bleeding o Life threatening infection

– very rarely o no s/sx o detected during routine examination

PHYSICAL FINDINGS – Pallor – Petechiae – Ecchymosis – Bone tenderness – Organomegaly (liver, spleen, LN) – Anterior mediastinal mass

o SVC syndrome o SMS

– Enlargement of scrotum – Uncommon

o Ocular involvement o Subcutaneous nodules o Enlarged salivary gland o Cranial nerve palsy o Priapism o Cord compression

– Infiltration of other lymphoid organs

LABORATORY FEATURES – Anemia – Neutropenia – Thrombocytopenia

WBC 0.1-1500 x 109/L Median 10-12 x 109/L >100 x 109/L 10-16% of patients <0.5 x 109/L 20-40% rendering

High risk for infection

BMA >20% lymphoblast other cell lineage depressed

Hypereosinophilia

Increased LDH

Increased BUA

Coagulopathy, mild

DIAGNOSIS AND CELL CLASSIFICATION 1. MORPHOLOGY

Lymphoblast – Small with scanty, often light blue cytoplasm – a round, clefted or slightly indented nucleus – fine to slightly coarse and clumped chromatin – inconspicuous nucleoli – some are large with prominent nucleoli and moderate amount

of cytoplasm, with a admixture of smaller blasts ALL-L1 ALL-L2 ALL-L3

2. CYTOCHEMICAL ANALYSIS – special stains to discriminate between ALL and AML – stains that do not react with lymphoblasts

o myeloperoxidase o Sudan black o Non specific esterases

– Stain that is positive in 70% of ALL cases o Periodic Acid Schiff

Team P (“,) – sec B2 HEMA2012

Page 11 of 12

3. IMMUNOLOGIC CLASSIFICATION – lymphoblast lack specific morphologic and cytochemical

features – immunophenotyping is essential part of the diagnostic

evaluation – Highly sensitive markers

o CD 19 for B lineage cells o CD 7 for T lineage cells o CD 13 and 33 for myeloid cells

– Highly specific marker o CD 79a for B lineage cells o cytoplasmic CD3 for T lineage cells

cytoplasmic myeloperoxidase for myeloid cells

4. GENETIC CLASSIFICATION

arises from a lymphopoietic progenitor cell that has sustained specific genetic damage leading to malignant transformation and proliferation

DIFFERENTIAL DIAGNOSIS

ITP o Assoc recent viral infection o Large platelet o Normal Hgb o No leukocyte abnormalities

Aplastic Anemia o Hepatosplenomegaly and LAD are rare o Absent skeletal changes o Hypocellular BMA

IM other viral infections o Serologic evidence of EBV infection

Round cell tumors

Neuroblastoma

Rhabdomyosarcoma

Retinoblastoma o Primary lesions may be found with solid tumors o Disseminated tumor cells often present in characteristic aggregates absent immunophenotypic char of

lymphocytes

THERAPY • SUPPORTIVE CARE

Metabolic Complications

Hyperuricemia

Hyperphosphatemia

Secondary Hypocalcemia o IV hydration o Sodium Bicarbonate to alkalinize the urine o Allopurinol inhibit the de novo purine syn in leukemic blast

cells, and can reduce the peripheral blast cell count before chemotherapy

o Phosphate binder (eg. Al Hydroxide, CaCO3 or acetate) Hyperleukocytosis

WBC > 200x 109 /L

Leukopheresis

Exchange transfusion in small children

Pre induction with low dose glucocorticoids, adding vincristine and cyclophosphamide

Infection Control

Broad spectrum antibiotic until infection is excluded

Special precaution during Remission Induction chemotherapy o Reverse protective isolation o Air filtration o Elimination of contact with people with infectious o Avoid potentially contaminated food products

Raw cheese Uncooked vegetables Unpeeled fruits

o Antiseptic mouthwash o Sitz baths o G-CSF

Hasten the recovery from neutropenia Reduce the complication of intensive chemotherapy Does not improve the EFS rate

o Prophylaxis for Pneumocystis carinii pneumonia Co-Trimoxazole 3 days per week

Hematologic support

• Platelet transfusion o For overt bleeding o Prophylactic transfusion for Platelet ct < 10x 109 /L o Higher threshold for fever or infection

• PRBC transfusion o Anemia o Marrow suppression

• Granulocyte transfusion o Rarely needed

ANTILEUKEMIC THERAPY Remission Induction

to induce CR with restoration of normal hematopoiesis • Glucocorticoid • Vincristine

o Binding to tubulin a protein found n the cytoplasm of cells

o Leads to inhibition of the process of assembly at the mitotic spindle arresting cells in metaphase and inducing apoptosis

o Neurotoxicity >6mg/m2 • L asparaginase for children

o capable of rapidly depleting the serum level of L-asparagines, Induces an asparagines deficiency in lymphoid malignant cells

• Anthracycline for adults o Forming complex with DNA and topoisomerase II,

leading to double stranded DNA strand breaks CR rate 97-99% in children 70-90% in adults Intensification/Consolidation

Administered after remission induction

Administration of high doses of multiple agents not used during induction phase

Readministration of the induction regimen

Appears to improve outcome of treatment Continuation Therapy

Prolonged continuation therapy needed to kill residuals, slowly dividing leukemic cells or to suppress their growth allowing apoptosis to occur

Reduced the likelihood of relapse

2- 3 years

MTX weekly

6Mercapto purine daily

Team P (“,) – sec B2 HEMA2012

Page 12 of 12

Therapy for CNS

CNS frequent sanctuary for leukemic cells

Intrathecal CNS

Cranial irradiation 1200cGy provide protection against CNS relapse

Allogeneic Stem Cell transplant

Beneficial in some high-risk cases/unfavorable prognosis o Ph Chromosome + ALL o t(4;11)

Poor initial response to induction therapy or those who require extended induction therapy to attain remission

COURSE and PROGNOSIS • RELAPSE

Reappearance of leukemic cells at any site in the body

Occur during treatment or within the first 2 years after completion

Marrow most common site of relapse TREATMENT SEQUELAE

Death rate among older patients 30%

Neurotoxicity

Cardiotoxicity

Neuropsychiatric and

Endocrine abnormalities

Development of second cancer o Brain tumor o AML

PARAMETERS PROGNOSTIC FACTORS

GOOD POOR

WBC Low(<50,000) High

Age 1-10 years >10, infants

CALLA( CD10) Present Absent

Lymphoid cell type Early B cell T cell

Cytogenetics Normal Abnormal

FAB L1 L2

END

God bless in our midterm exam guys

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