Hematology Case Management

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

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.

– 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, Px is on regular ff-up c/o hematology OPD. Px had no signs and symptoms of bleeding but still with low platelet count.

– 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.

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

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

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 ( ) – (-) IUD/BTL use

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

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

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

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 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.

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 Px also complained of epigastric pain. She was given omeprazole 20 mg/tab OD and ribamipide 100mg TID.

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 For BT of 6 more ‘u’ PC.

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.

Assessement Acute myelogenous leukemia Acute tonsillopharyngeal congestion

Acute Myelogenous Leukemia

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

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

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

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

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

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

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

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

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

MANAGEMENT AML

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

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

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

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

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

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

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

Agents under Study for AML Treatment in Adults Class of DrugsExample Agents MDR1 modulators Cyclosporine, LY 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