1. Associate professor of Internal Medicine
LEUKEMIA
Dr. Hayam Hebah
Associate professor of Internal Medicine
AL Maarefa College

2. objectives
Introduction to leukemias
c/p of uremia
Management
AML
ALL

3. Introduction:

4. Background and epidemiology:
Leukemias are a group of heterogeneous neoplastic disorders of stem cell compartment , characterised by increased white blood cells count in bone marrow &/or peripheral blood.
Leukemias are acute or chronic, based on their untreated course ( course may vary from days or weeks to years).
Males are affected more than females
Geographical variation occur in incidence
Most childhood leukemias are acute :ALL
Whites are more affected than blacks in ALL & CLL

9. C/P and DD:
Acute leukemias usually present as hemorrhage, anemia, infection, or infiltration of organs.
Chronic leukemias are asymptomatic. Other patients present with splenomegaly, fever, weight loss, malaise, frequent infections, bleeding, thrombosis, or lymphadenopathy. 
Some chronic leukemias enter a blast phase where the clinical manifestations are similar to the acute leukemias.

12. Diagnosis of leukemia CBC and differentiaL:
Abnormal blood count( often ↑ WBCs)
Bone marrow examination:
Abnormal cells : the morphology of blasts usually can differentiate between ALL & AML.
Cell surface markers( immunophenotyping) using multiparameter flow cytometry  identifies the B or T cell origin of the lymphoblasts
Clone specific chromosome abnormality: philadelphia chromosome in CML .Chromosomal analysis of the leukemic cell currently provides the most important pretreatment prognostic information in AML
4-Molecular changes

13. ACUTE LEUKEMIAS AML is 4 times more common in adults > ALL.
In children ALL>AML
Anemia with N or ↑MCV
WBCs /mm³( majority /mm³)
Thrombocytopenia
Blood film :± blasts
BM: hypercellular with replaced normal elements by leukemic blast cells.(>20%)
Auer rods in blast cell cytoplasm=myeloblastic type

14. Fever >38°c>1 h in a neutropenic patient denotes possibility of septicemia.
Organisms associated with severe neutropenic sepsis: G+ve bact . as Staph aureus, Staph epidermidis from skin via cannulas.
G-ve infections from GIT
ALL patients are susceptible to Pneumocystis jirovecii and pneumonia
Oral and pharyngeal candidiasis
Systemic fungal infections
Herpes simplex infection

15. Management of acute leukemia
Specific therapy
Supportive therapy
Remission induction
Remission consolidation
Remission maintenance
In ALL:
cranial irradiation
intrathecal chemotherapy
high dose methotrexate
*****Haematopoietic stem cell transplantation
Red cell concentrate transfusion
Platelet transfusion
Blood products must be irradiated to prevent transfusion-associated graft versus host disease (GVHD)
Broad spectrum antibiotics
Antibiotic prophylaxis during chemotherapy in ALL
Monitor fluid balance, renal, hepatic and hemostatic function
Anorexia &diarrhea ttt
TTT of tumor lysis syndrome
Psychological support

16. Management of metabolic problems.
Iv fluids and electrolytes for the anorexia and drinking difficulties.
Antibiotics induced renal toxicity as with aminoglycosides and amphotericin.
Tumor lysis syndrome during induction therapy with hyperkalemia, hyperuricemia, hyperphosphatemia and hypocalcemia

17. ACUTE MYELOID LEUKEMIA

18. Epidemiology: AML is more in developed countries.
more in whites ,Men> women.
the prevalence of AML increases with age. The median age of onset is approximately 70 years. However, AML affects all age groups. hematopoietic precursors are arrested in an early stage of development. 
cc by presence of more than 20% blasts in the bone marrow
AML is divided into categories depending on the morphology

19. FAB subtypes M0: AML minimally differentiated
M1: AML without maturation.
M2:AML with maturation
M3: Acute promyelocytic anemia.
M4: Acute myelomonocytic leukemia
M5: Acute monocytic leukemia
M6: Acute erythroleukemia
M7: Acute megakaryoblastic leukemia

20. WHO CLASSIFICATION recently
AML with recurrent genetic abnormalities( M3 Acute promyelocytic anemia d.t presence of t(15;17).
AML with MLD(multilineage dysplasia) prior MDS.
AML therapy related
AML not otherwise categorised (FAB subtypes M0,M1,M2,M4,M5,M6,M7)

21. Etiology:
Antecedent hematologic disorders : commonest is myelodysplastic syndrome(patients with high-risk MDS develop AML but those with low risk MDS do not.Also, aplastic anemia. And MPD.
Congenital disordersDown syndrome ,congenital neutropenia, Fanconi anemia
Familial syndrome with genetic abnormalities: Turner and kleinfelter syndrome.
Environmental exposures: radiation exposure, exposure to benzene , smoking.

22. 5-Previous exposure to chemotherapeutic agent: The typical latency period between drug exposure and acute leukemia is approximately 3-5 years for alkylating agents( cyclophosphamide) /radiation exposure, but it is only 9-12 months for topoisomerase inhibitors. **However, most patients who present with de novo AML have no identifiable risk factor.

23. c/p: General fatigue , fever,
Symptoms of bone marrow failure :related to anemia, neutropenia, and thrombocytopenia.
(Patients with AML often have decreased neutrophil levels despite an increased total white blood cell (WBC) count) (Patients with the lowest absolute neutrophil counts (ANCs) (ie, < 500 cells/µL, especially < 100 cells/µL) have the highest risk of infection.)
Bleeding may be caused by thrombocytopenia, coagulopathy that results from disseminated intravascular coagulation (DIC), or both.

24. Symptoms of organ infiltration with leukemic cells: The most common sites of infiltration include the spleen, liver, gums, and skin( leukemia cutis).
Patients with markedly elevated WBC counts (>100,000 cells/µL) can present with a medical emergency with symptoms of leukostasis (ie, dyspnea ,chest pain , headache and altered mental status , cranial nerve palsies.

25. Examination:
Physical signs of anemia, including pallor and a cardiac flow murmur
 Fever and other signs of infection as pneumonia.
petechiae, particularly on the lower extremities in thrombocytopenic patients.
Purpura and ecchymosis(with DIC).
hepatosplenomegaly and, to a lesser degree, lymphadenopathy
Signs relating to leukostasis include respiratory distress and altered mental status.

26. Differential Diagnoses
Acute Lymphoblastic Leukemia
Anemia
Aplastic Anemia
B-Cell Lymphoma
Bone Marrow Failure
Chronic Myelogenous Leukemia
Lymphoblastic Lymphoma
Myelodysplastic Syndrome

27. Bone marrow examination: for cytochemistry, flow cytometry and cytogenetics
Markers for AML include positive myeloperoxidase staining, CD33, CD13, CD41 and glycophorin A.

28. investigations CBC: with differential .
Pancytopenia or wbcs >100000/μl
WBCs may be N, ↑ or ↓
Anemia
Thrombocytopenia.
Coagulation studies.
DIC with ↑PT, ↓fibrinogen and ↑FDPs.
Peripheral blood smear Circulating blasts are usually seen> 20%
Blood chemistry profile

29. Chemotherapy for Acute Myelogenous Leukemia
Induction therapy: Cytarabine for 7 days and an anthracycline for 3 days
Consolidation therapy in younger patient may be effective but in old age >75 years there is usually poor response
Stem cell transplantation
Supportive Care:
Replacement of blood products
Antibiotic therapy
Treatment of hyperuricemia
Growth factors( G-CSF)

30. Acute Lymphoblastic Leukemia

31. ACUTE LYMPHOBLASTIC LEUKEMIA

32. Acute lymphocytic leukemia (ALL) is a malignant clonal disorder of the bone marrow lymphopoietic precursor cells. In ALL, progressive medullary and extramedullary accumulations of lymphoblasts are present that lack the potential for differentiation and maturation. An inhibition of the normal development of hematopoietic cell elements occurs.
Bimodal age distribution , one peak at 4-5 years and second increase after 50 years.
3 subtypes: precursor B cell , mature B cell( Burkitt lymphoma ) and T cell
Philadelphia chromosome may be present

33. The clinical presentation
progressive weakness and fatigue, fever and bleeding ( When 50% of BM is replaced, then peripheral blood cytopenias are observed)
Extremity joint pain may be the only manifestation in children.
lymphadenopathy and splenomegaly
Leukostasis is uncommon
CNS may be involved
ALL associated with anterior mediastinal mass( in T cell subtypes ) or large abd. LN ( in B cell type).

34. diagnosis Basic workup BM hypercellular, blasts>30%
30% of adult patients exhibit ph. Chromosome
Treatment:
Induction, consolidation,and maintenance for 2 years.
Because of CNS , prophylactic intrathecal therapy during induction and consolidation phases.
Allogenic stem cell Tx.

35. Thank you