1. Hematology Case Management

2. History General Data – Patient is RB, 30/F from Pandacan, Manila, Jehovah’s Witness, nonsmoker, non-alcoholic beverage drinker, nonasthmatic, nondiabetic, nonhypertensive Chief complaint – Gum bleeding

3. History of present illness – 5 months prior to admission: Px noted recurrent hematoma and ecchymoses on her upper extremities. These would disappear spontaneously after 2 to 3 weeks. No consults/meds taken. – 4 months PTA: Px consulted at PGH OPD and her CBC showed a decreased platelet count. She was on regular follow-up at the OPD and was eventually referred to hematology.

4. – 3 months PTA: She was seen at the hematology OPD where she was given prednisone 20mg PO to be taken 3 times in the morning and 2 times during the evening. Bone marrow aspiration was also done. – 2 months PTA: BMA results showed AML. Prednisone was gradually tapered then discontinued last January 6, 2010. Px is on regular ff-up c/o hematology OPD. Px had no signs and symptoms of bleeding but still with low platelet count.

5. – 2 months PTA (Feb. 14, 2010): Px had epistaxis and gum bleeding and was rushed to the ER. She was eventually admitted at the ward and discharged 10 days later until – 9 days PTA: She was on her scheduled consult at the Cancer Institute when her CBC showed a platelet count of 20. She was then referred to the ER for low platelet and presence of gum bleeding and was admitted at the ward 2 days later.

6. Review of systems (-) difficulty breathing (-) fever (+) easy fatigability (-) epistaxis (-) melena (-) hemarthrosis (-) hematuria (-) hematochezia

7. Past Medical History – No history of goiter, heart problem, liver problem, kidney problem, allergy Family Medical History – Non-contributory

8. OB/Gyne History – G5P5 (5005): 1 st 4 children via SVD, youngest via cesarean section for breech presentation – No fetomaternal complications – Regular monthly menses, lasting 3-4days, consuming 3 pads/day, (-) dysmenorrhea – (+) OCP use (2006-2008) – (-) IUD/BTL use

9. Personal/Social History – Px works as a housewife. Her husband works as a mechanic. They live with her brother-in-law and his family. All children stopped going to school starting this year. – No vices, denies exposure to toxins/secondhand smoke

10. Physical Examination General Survey: awake, conversant, not in cardiorespiratory distress Vital signs: BP 90/60, HR 92 bpm, RR 18/min, temp 36.8 HEENT: pale conjunctivae, anicteric sclerae, (-) CLAD, (+) TPC, (-) gum bleeding, (-) epistaxis Chest/lungs: equal chest expansion, clear breath sounds, (-) rales, (-) rhonchi, (-) wheezes, adynamic precordium, distinct heart sounds

11. Normal rate, regular rhythm, no murmurs Abdomen: flat, normoactive bowel sounds, soft, (+) slight epigastic tenderness on deep palpation, (-) guarding, (-) masses, (-) organomegaly Skin/extremities: pale nailbeds, full and equal pulses, (-) cyanosis, (-) edema, (-) jaundice, (+) multiple erythematous macules on bilateral lower extremities

12. Course in the ER and Wards February 26, 2010: Px was at Cancer Institute and OPD for her regular check-up. Her CBC showed Hb 94, hct 0.28, plt 20, and WBC 36.7. She was immediately referred to the ER for admission due to her low plt and (+) gum bleeding. February 27, 2010: Px was seen by Hematology Service. BT of platelet concentrate was ordered.

13. February 28, 2010: Px was seen by the Day MHAPOD. BT of 6 ‘u’ PC and tranexamic acid 500mg cap q8 was ordered. Px was admitted at Ward 1. March 2, 2010: s/p BT of 4 ‘u’ PC. Px still had gum bleeding. Additional 6 ‘u’ PC was ordered. CBC showed Hb 90, hct 0.267, plt 10, WBC 37.6, RBC 2.64, blast 0.73. Px also complained of epigastric pain. She was given omeprazole 20 mg/tab OD and ribamipide 100mg TID.

14. March 3, 2010: s/p BT 4 ‘u’ PC. Px still has gum bleeding. For transfusion again of 6 ‘u’ PC. Px noted decrease in epigastric pain. March 5, 2010: s/p BT 5 ‘u’ PC. Px had fever and chills but no cough, abdominal pain, dysuria, or pallor. Post BT CBC showed Hb 80, hct 0.232, plt 21, WBC 40.1, RBC 2.32, blast 0.77, band/stab 0.01, promyelocyte 0.08. For BT of 6 more ‘u’ PC.

15. March 6, 2010: Px had no more fever, active bleeding, cough, and colds. On PE, (+) tonsillar walls congested with exudates. A> ATP. Px was given cefuroxime 750mg IV q8 and paracetamol 500mg/tab q4. UA and CXR were ordered. March 7, 2010: s/p BT 6 ‘u’ PC. Px had no new subjective complaints. Still with tonsillopharyngeal wall congestion. Present management continued.

16. Assessement Acute myelogenous leukemia Acute tonsillopharyngeal congestion

17. Acute Myelogenous Leukemia

18. Malignant bone marrow disease Hematopoietic precursors arrested in an early stage of development through activation of abnormal genes through chromosomal translocations and genetic abnormalities More common in men and in whites, affecting all age groups

19. Risk Factors: Antecedent hematologic disorder Congenital syndrome Heredity Environmental exposure – Radiation, smoking, benzene Exposure to chemotherapeutic agents – Alkylating agents  aberrancy in chromosomes 5 & 7 – topoisomerase-II-inhibitors  aberrancy in 11q23

20. I. AML with recurrent genetic abnormalities AML with t(8;21)(q22;q22);RUNX1/RUNX1T1 b x AML with abnormal bone marrow eosinophils [inv(16)(p13q22) or t(16;16)(p13;q22);CBFB/MYH11] b Acute promyelocytic leukemia [AML with t(15;17)(q22;q12) (PML/RAR) and variants] b AML with 11q23 (MLL) abnormalities II. AML with multilienage dysplasia Following a myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative disorder Without antecedent myelodysplastic syndrome III. AML and myelodysplastic syndromes, therapy-related Alkylating agent–related Topoisomerase type II inhibitor–related Other types IV. AML not otherwise categorized AML minimally differentiatedAcute erythroid leukemia AML without maturationAcute megakaryoblastic leukemia AML with maturationAcute basophilic leukemia Acute myelomonocytic leukemiaAcute panmyelosis with myelofibrosis Acute monoblastic and monocytic leukemiaMyeloid sarcoma

21. French-American British (FAB) Classification FAB ClassificationIncidence (%) M0: Minimally differentiated leukemia50 M1: Myeloblastic leukemia without maturation30 M2: Myeloblastic leukemia with maturation20 M3: Hypergranular promyelocytic leukemia10 M4: Myelomonocytic leukemia20 M4Eo: Variant: Increase in abnormal marrow eosinophils M5: Monocytic leukemia10 M6: Erythroleukemia (DiGuglielmo's disease)4 1

22. Symptomatology Nonspecific, beginning gradually or abruptly and often related to anemia, thrombocytopenia, leukocytosis or leukopenia: – Fatigue – Exertional dyspnea – Dizziness – Anginal pain – Fever with or without infection – Bleeding/easy bruising

23. Symptomatology Symptoms from organ infiltration by leukemic cells: – Early satiety – Gingivitis – Respiratory distress – Altered mental status – Bone pains

24. Physical Findings Fever Splenomegaly Hepatomegaly Lymphadenopathy Sternal tenderness Bleeding Signs of infiltration of gums, skin, soft tissues, meninges

25. Hematologic Findings Anemia Leukocytosis, leukopenia, or normal WBC count Presence of Auer rods Thrombocytopenia

26. Auer Rods - clumps of rod-shaped azurophilic granular material seen in the cytoplasm of leukemic blasts -composed of fused lysosomes and contain peroxidase, lysosomal enzymes, and large crystalliine inclusions When present, myeloid lineage is certain

27. MANAGEMENT AML

28. Diagnostics CBC – Leukocytosis – May also present as thrombocytopenia, anemia or leukopenia Peripheral blood smear – Confirms CBC findings – Presence of circulating blasts

29. Diagnostics Blood chemistry profile – Usually with elevated LDH and uric acid levels Bone marrow aspirate and biopsy – > 20% blasts; Auer rods – Evalueates degree of dysplasia Immunophenotyping (Flow cytometry) – Distinguish AML from ALL – Further classify into subtypes

30. Therapeutics Chemotherapy as the primary treatment 1.Induction Phase 2.Postremission Phase Supportive care

31. Induction Chemotherapy Often combination therapy with cytarabine and anthracycline (7 and 3 regimen) – Cytarabine: continuous IV infusion for 7 days – Daunorubicin IV on days 1, 2, and 3 Check BM after induction – if > 5% blasts exist with > 20% cellularity  re- treat or change the therapy Allogeneic SCT recommended after two failed induction courses

32. Supportive Care Recombinant hematopoietic factors Platelet transfusions pRBC transfusion Early initiation of empiric antibacterial and antifungal antibiotics

33. Postremission Therapy To eradicate residual leukemic cellsto prevent relapse and prolong survival High-dose cytarabine (3 g/m 2 every 12h on D1,3, and 5) effective than standard dose (100 mg/m 2 per day for 5 days by continuous infusion) Allogeneic SCT used in patients <70 years and with HLA-compatible donor

34. Relapse Patients eligible for allogeneic SCT should receive transplant at the first sign of relapse Poor outcome of early relapse patients (<12 months) Patients with longer first CR (>12 months) have higher chance of attaining CR but cure is uncommon For elderly patients (>70years) –antibody-targeted chemotherapy (gemtuzumab ozogamicin) has a CR rate of ~30% Consider exploring novel approaches

35. Agents under Study for AML Treatment in Adults Class of DrugsExample Agents MDR1 modulators Cyclosporine, LY335979 Demethylating agentsDecitabine, 5-azacytidine, zebularine Histone deacetylase inhibitorsSuberoylanilide hydroxamic acid (SAHA), MS275, LBH589, valproic acid Heavy metalsArsenic trioxide, antimony Farnesyl transferase inhibitorsR115777, SCH66336 FLT3 inhibitors SU11248, PKC412, MLN518, CHIR-258 HSP-90 antagonists17-allylaminogeldanamycin (17-AAG) or derivatives BCR-ABL PDGFR/KIT inhibitors Imatinib (ST1571, Gleevec), dasatinib, nilotinib Telomerase inhibitorGRN163L Cell cycle inhibitorsFlavopiridol, CYC202 (R-Roscovitine), SNS-032 Nucleoside analoguesClofarabine, troxacitabine Humanized antibodiesAnti-CD33 (SGN33), anti-DR4, anti-DR5, anti-KiR Toxin-conjugated antibodiesGemtuzumab ozogamicin (Mylotarg) Radiolabeled antibodiesYttrium-90-labeled human M195