LEUKEMIA

Leukemia
Introduction
Stem cells (sc) Myeloid Stem cells. Proerythroblast -> -> reticulocytes -> erytherocytes Megakaryoblast -> megakaryocyte -> platelets Myeloblast: Monoblast -> promonocyte -> monocyte -> macrophages N. promyelocyte -> myelocyte ->metamyelocyte -> band ->neutrophil B. promyelocyte -> basophil E. promyelocyte -> eosinophil Lymphoid Stem cells. Lymphoblast B-cells T-cells Natural killer (NK) cells N.B in normal bone marrow, there is 2-4 % of blast cells.

Acute Leukemia
Denition: Clonal proliferation of hematopoietic progenitors with decreased ability to differentiate into mature elements. Decreased RBCs, platelets, and neutrophils production More blast cells in bone marrow and prepherally 20% of bone marrow cells are blast cells (myeloblasts or lymphoblasts) Epidemiology: AML: median age is 65 year old of age, > 80% of adult cases of acute leukemia ALL: median age is 10 year old of age (i.e more common in children), bimodal with second peak in elderly. Risk Factors: Radiation Chemotherapy (alkylating agents, topoisomerase II inhibitor) Benzene Smoking N.B: any cancer is a multistep hypothesis
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Associated diseases as a risk factors: Acquired hematopoietic diseases: Myelodysplastic syndrome, myeloproliferative disorder (specially CML), aplastic anemia, paroxysmal nocturnal haemoglobinuria. Inherited diseases: Down syndrome, Klinefelters syndrome, fanconi anemia, ataxia telangiectasia. Classications: Many classications depends on different things, for example, there are morphic and cytochemical classication, Immunophenotypic classication, cytogenetic classication and nally molecular classication. AML classications: Until the year 2000 the Dx of AML was based on FAB(French- American British) classication, which include presence of 30 of myeloblast in B.M, and further classication based on morphology and cytochemistry (major subtype M0M7 ), then the WHO modied the FAB schema by reducing the number of blasts required for Dx and incorporating cytogenetic, morphologic and clinical features in dening disease entities. The FAB classication (M0 M7): M0: minimal differentiated leukemia. M1:myeloplastic leukemia. M2: myeloplastic leukemia with maturation. M3:promyelocytic leukemia (APL = Acute promyelocytic leukemia ) M4:myelomonocytic leukemia. M5:monocytic leukemia. M6:erythroleukemia (Di Guglielmo disease) M7:megakaryoblastic leukemia. The WHO classication (, , ,IV) :AML with recurrent genetic abnormalities. : AML with myelodyslasia related changes. : therapy related eg: alkylating agents or topo inhibitors. IV: not otherwise specied . ALL classication: Depends on immunohistochemistry like the presence of TDT,CD, WHO immunophenotype classication of ALL: Precursor B-cell. Precursor T-cell. Burkitts lymphpma (-ve TDT) NB. Burkitts lymphoma can present as acute leukemia

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Clinical Manifestations: AML (more common in AML) ALL (more common in ALL)

Pancytopenia Anemia: symptoms e.g. fatigue. Thrombocytopenia: Bleeding. Neutropenia: Recurrent infections. N.B. Infections happen in areas where normal ora habits. Examples for infections: URTI and pneumonia. Gastroenteritis. Abscess. Also in Monocytic AML (M5). Hepatomegaly. Lymphadenopathy. Myeloblast are larger and less likely to cause Hence lymphoblast are small cells and have these things. adherent molecules: they can cross the BBB (blood brain barrier): Hence myeloblast are larger cells, leukostasis: CNS involvement: Hyperviscosity syndrome: Cranial nerve palsy. Headache, blurred vision, tinnitus Seizures. Hyperviscosity retinopathy (e.g. Nausea, vomiting, headache. Engorgement of retinal veins, hemorrhage, Also, can cause Testicular mass: U/S is exudate..). indicated. Thrombi in brain, lung, heart. Anterior mediastinal mass (especially in T-cell). Leukemic inltration in the skin: (This is in M4 "myelomonocytic" and M5 "monocytic"). Gum hypertrophy. Subcutaneous Nodules: Chloroma. DIC: in M3 "promyeloblast" (APL= Acute promyeloblastic leukemia). Promyelocyte are larger, granular cells and have creased nucleus : May release tissue factors which may cause DIC and massive bleeding. Investigations: N.B; we will mention 2 emergencies in the investigations 1.CBC WBC ! (leukocytosis) Rarely, Normal, aleukemic Leukemia (in ALL only) Low leukocyte (Febrile Neutropenia) *The 1st Emergency*
!

! Neutrophil ! Monocyte ! Basophil ! Eosinophil ! Lymphocyte: ! The lab won't differ between lymphocyte and lymphoblast but it will show this sign " [Flagging System] but on blood film: it will appear as blast cells.

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Febrile Neutropenia Denition: Fever: single oral temp. 38.3 Or 38 1h Neutropenia: neutrophils <500 cells /l or <0.5 They are more caused by gram negative Rods especially pseudomonas aeruginosa, they are more likely to cause septic shock. Septic screen will be 50% -ve Treatment: Aggressive hydration Abx (each hospital has its own protocol): 1st : "which cover Gr -ve" : Cefepime or Tazocin or Meropenem 2nd : (if still fever >24h): cover gram+ve 3rd : (if still fever): cover fungal -continue the investigations2.Blood lm : Blast cell Myeloblast Lymphoblast

Then you will do :

3.Bone marrow aspiration or bone marrow biopsy ( take 5 sample ) : I.Morphology ( under microscope ) : 20% or more blast cell " remember the denition " . Others : Aure rod ( eosinophilic needle shape inclusions ) Granules +ve = AML II.Cytochemistry -ve = ALL +ve myeloperoxidase and\or non specic estrase = AML
+ve TDT ( terminal deoxynucleo5dyl transferase) found in 95% of ALL " not in burki+'s lymphoma ".

Dx for AML

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III.Flowcytometry : Determine the immunophenotype :

Myeloid ( m0 m7 )

Lymphoid B or T cell precursor or burkiI's

Breast prostate

Inltra5ve

Thyroid GI

N.B if CD4 is ve = it is inltraDve not B.M in origin IV. Cytogenetic lab : It is for : 1-Dx 2-Prognosis 3-Rx 4-Follow up i.e. for risk stratication : low \ intermediate \ high . Examples : For Dx. : t ( 15: 17 ) = diagnostic for m3 AML = APL . t ( 8 : 21 ) or t ( 16 : 16 ) = Dx for AML . For prognosis : Philadelphia chromosome (ph) t( 9: 22 ) = very bad prognosis for ALL . N.B ph chromosome is also found in CML . V.Molecular analysis ( PCR ) : Look for oncogen. 4.Urea and Electrolyte : As a base line . Look for " Tumor lysis syndrome " = the 2nd emergency . Because of the rapid cell turnover : urate, LDH, k , phosphate . but LOW Ca . It can cause an obstructive nephropathy = acute renal failure . N.B tumor lysis syndrome can occur de novo .

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LEUKEMIA

Chronic Myelogenous Leukemia (CML)

Denition: It is one of the myeloproliferative disorder with clonal overproduction of myeloid stem cell N.B: Myeloproliferative disorder:

polycythemia vera CML Essential Thrombocytosis Mylobrosis

Philadelphia chromosome (ph)= t(9:22) BCR-ABC genes fusion tyrosine kinase activity Dx: presence of BCR-ABL fusion. Prognosis: worse if (ph chromosome) not present. Epidemiology and Risk factor: Median age is 50 years Increased risk with radiation Clinical manifestations: Triphasic clinical course: (history of the disease) Chronic phase ( <10% of blasts in B.M)

-Asymptomatic general symptoms ,fatigue ,fever. -Weight lose, Night sweets, abdominal discomfort (splenomegaly).

Accelerated phase (10-20% blasts in B.M) -Worsening symptoms and refractory luckocytosis -Bleeding (platelets) ,infection (neutropenia) -Progressive increase in spleen size -Features of gout (purine breakdown) -Pruritis (basophilia) Blastic phase (>20% of blasts in B.M). -This is acute leukemia. Signs:1-Splenomegaly (>75%) often massive very important sign N.B massivesplenomegaly means spleen below umbilicus Causes of massive splenomegaly:1- hematological (CML Myelobrosis). 2- infections (chronic malaria schistosomiasis kala azar). 3- others (tropical spleenomegaly gauchers disease rarely). 2-Hepatomegaly. 3-Anemia. 4-Bruising.

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Investigations :-CBC :- WBC, lift shifted with all stages of myeloid maturation , basophils , anemia , thrombocytosis. -Bone marrow :- hypercellular with myloid to erythroid ratio. -NAP score (neutropiil alkaline phosphatase): low N.B this will be high in polycythemia rubra vera. -uric acid level , B12 level. -Cytogenetics: Philadelphia chromosome Treatment: Tyrosine kinase inhibitors: imatinib, dasatanib, nilotinib Allogenic bone marrow transplantation.

CLL (chronic lymphocytic leukemia)

Denition: monoclonal accumulation of mature B-cells, which is functionally incompetent, as they escape programmed cell death. Epidemiology: most common adult leukemia, median age is 65. Clinical: Often asymptomatic (present with lymphocytic count) Lymphoma B symptoms: fatigue,night sweats, weight loss. Signs: lymphadenopathy (80%), hepatosplenomegaly(50%) Complications: Autoimmune hemolytic anemia (AIHA), and ITP (idiopathic thrombocytopenic purpura) Hypogammaglobulinemia : neutropenia: infections Bone marrow failure Aggressive transformation: Richters syndrome = transformation into a high grade lymphoma. Monoclonal gammopathy CLL Staging(just for reading) Rai system Stage 0 I II III IV Description Lymphocytosis alone + Lymphadenopathy + Hepatosplenomegaly + Anemia (not AIHA) + Thrombocytopenia (not ITP) > 10 y 7y Median survival Binet system Description < 3 node areas > 3 node areas Anemia or Thrombocytopenia Stage A B

1-2 y

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Investigation: -CBC: - Lymphocyte , Hb , Neutrophils , Platelets. -Bone marrow: inltration with B-lymphocytes. -Blood lm: smudge cells ( damage to abnormal lymphocyte while making the smear ). -Lymph node biopsy: inltrated with lymphocyte. - FlowCytometry & Cytogenetics: see acute leukemias. Treatment: - Indications for Rx: - Rai stageIII II , Binet stage C. - Symptomatic. - Recurrent infections. - AIHA or ITP. - progressive disease , Resistant to steroid. -Rx options: - Fludarabine ( purine analog ) + cyclophosphamide. - Chlorambucil for elderly. - Monoclonal Ab against CD20(Rituximab) or CD52 (Alemtuzumab) - Radiotherapy: for lymphadenopathy or splenomegaly. -Supportive: Steroid AIHA or ITP , Recurrent infections I.V immunoglobulin , transfusion. -Hypersplenism splenectomy.

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