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, 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.

– 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): 1st 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

• 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 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.

• 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.

• 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.

• 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

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 abnormalitiesAML with t(8;21)(q22;q22);RUNX1/RUNX1T1b 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 dysplasiaFollowing a myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative disorder

Without antecedent myelodysplastic syndrome

III. AML and myelodysplastic syndromes, therapy-relatedAlkylating agent–related

Topoisomerase type II inhibitor–related

Other types

IV. AML not otherwise categorizedAML minimally differentiated Acute erythroid leukemia

AML without maturation Acute megakaryoblastic leukemia

AML with maturation Acute basophilic leukemia

Acute myelomonocytic leukemia Acute panmyelosis with myelofibrosis

Acute monoblastic and monocytic leukemia Myeloid sarcoma

French-American British (FAB) Classification

FAB Classification Incidence (%)

M0: Minimally differentiated leukemia 50

M1: Myeloblastic leukemia without maturation 30

M2: Myeloblastic leukemia with maturation 20

M3: Hypergranular promyelocytic leukemia 10

M4: Myelomonocytic leukemia 20

M4Eo: Variant: Increase in abnormal marrow eosinophils

M5: Monocytic leukemia 10

M6: Erythroleukemia (DiGuglielmo's disease) 4

M6: Erythroleukemia (DiGuglielmo's disease) 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 inclusionsWhen present, myeloid lineage is certain

MANAGEMENTAML

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 treatment1. Induction Phase2. 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/m2 every 12h on D1,3, and 5) effective than standard dose (100 mg/m2 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 Drugs Example AgentsMDR1 modulators Cyclosporine, LY335979

Demethylating agents Decitabine, 5-azacytidine, zebularine

Histone deacetylase inhibitors Suberoylanilide hydroxamic acid (SAHA), MS275, LBH589, valproic acid

Heavy metals Arsenic trioxide, antimony

Farnesyl transferase inhibitors R115777, SCH66336

FLT3 inhibitors SU11248, PKC412, MLN518, CHIR-258

HSP-90 antagonists 17-allylaminogeldanamycin (17-AAG) or derivatives

BCR-ABL PDGFR/KIT inhibitors Imatinib (ST1571, Gleevec), dasatinib, nilotinib

Telomerase inhibitor GRN163L

Cell cycle inhibitors Flavopiridol, CYC202 (R-Roscovitine), SNS-032

Nucleoside analogues Clofarabine, troxacitabine

Humanized antibodies Anti-CD33 (SGN33), anti-DR4, anti-DR5, anti-KiR

Toxin-conjugated antibodies Gemtuzumab ozogamicin (Mylotarg)

Radiolabeled antibodies Yttrium-90-labeled human M195