Ana Mae Quintal-Quetua, M.D. Mary Antoniette Tan, M.D .

1. Mortality & morbidity conference Ana Mae Quintal-Quetua, M.D. Mary Antoniette Tan, M.D.

2. Case Objectives • To present a case of a patient with Myelodysplastic Syndrome who had multiple medical problems, and developed acute ST-elevation myocardial infarction • To discuss the management and treatment options for a patient with MDS who had STEMI • Hematologic- overview of AA and MDS • Cardiac

3. Patient Data • M.L. • 61 years old • Female • Known HPN, on Diltiazem • Known asthmatic • Non-diabetic • Obese class II

4. Patient Data March 2009, 2nd week - consult at MMC for pancytopenia; BMA done Bone Marrow cytology report (Mar-17-09) 60-70% marrow hypercellularity with erythroid hyperplasia and mild dyserythropoiesis Diagnostic comment: correlation with cytogenetic studies for chromosomal haploinsufficiency is recommended Started on Prednisone; platelet counts improve with increased doses

5. Patient Data March 2009, 4th week- sought 2nd opinion at SLMC; 2nd BMA done Bone Marrow cytology report (Apr-03-09) 5-10% marrow hypocellularity with pancytopenia with relative lymphocytosis; marrow space occupied mainly by fibroadipose tissue Cellular smears with dyserythropoiesis and dysgranulopoiesis Conclusion: Thrombocytopenia secondary to Severe Aplastic Anemia , cannot rule out low-grade Hypoplastic Myelodysplastic Syndrome

6. Patient Data April 5- 9, 2009 - admitted at MMC for ATG administration (with Solumedrol) and was started on Cyclosporine 300mg OD; discharged stable April 2009, 4th week - Prednisone dose was increased up to 100mg OD Steroid-induced hyperglycemia, on Humulin R 8-0-2 and Humulin N 28-0-10

7. History of Present Illness 3 days PTA, (+) productive cough, throat irritation and hoarseness but (-) fever, DOB, chest pain, bleeding 12 hours PTA, (+) blood-tinged sputum May 6, 2009 - admitted for blood transfusion due to decreased platelet count (PC 10,000)

8. Physical Examination on Admission

9. Admitting Impression • Severe Aplastic Anemia vs Hypoplastic Myelodysplastic Syndrome • Upper Respiratory Tract Infection vs Community Acquired Pneumonia • Laryngitis, Oral Candidiasis

10. COURSE IN THE WARDS PROBLEM-BASED

11. 1. Pancytopenia BM biopsy (May-29-09, MMC) • 10-20% hypocellularity with panhypoplasia, dyserythropoiesis, left- shift granulocytic maturation focal collagen fibrosis, Inc Iron stores • CONCLUSION: presence of significant dysplasia favors a diagnosis of Hypocellular Myelodysplatic Syndrome

12. MYELODYSPLASTIC SYNDROME • Ineffective hematopoiesis due to abnormal differentiation and maturation, leading to bone marrow failure • Peripheral cytopenia, dysfunctional blood elements • Possibility of leukemic conversion APLASTIC ANEMIA • Marrow failure secondary to inability to produce blood cell components • Maybe immune- mediated (T- cells) or due to direct bone marrow injury (drugs, chemicals) • Pancytopenia, Bone marrow hypocellularity

13. MYELODYSPLASTIC SYNDROME • Bone marrow maybe hypercellular, hypocellular or normal • Cytogenetic abnormality involving chromosome 5, 7, 11, 12 and 20 deletions, and/or trisomy 8 • Recurrent chromosome deletions- • Loss of tumor suppressor genes are involved in the pathogenic process APLASTIC ANEMIA • Bone marrow consists primarily of fatty space and stromal cells • Evolution of AA to MDS/ AML is marked with increased proliferative activity +/- development of cytogenetic abnormalities • 9% risk of developing to AML

14. Differentiating AA from Hypoplastic MDS: Diagnosis dictates management and prognosis • A hypocellular bone marrow is seen in 20% of MDS , which maybe confused with AA • Hypoplastic MDS- cytopenia, marrow dysplasia and marrow hypocellularity • Incidence of 7.7% among a large series of MDS patients evaluated • Increase in mast cells and lymphoid cells

15. Cytogenetic studies: changes in chromosome 7, especially monosomy 7 • 3/5 cases transforming from AA to H- MDS showed monosomy 7 • Monosomy 7 found in Hypoplastic MDS indicates a poor prognosis, with patients progressing to refractory cytopenia, with 80% risk of evolving into Acute Myeloid Leukemia • Trisomy 8- immune pathophysiology; often responds clinically to immunosuppressive Tx

17. International Prognostic Scoring System

18. Treatment Algorithm

19. Treatment MYELODYSPLASTIC • Poor response to cytotoxic chemotherapy • Stem Cell Transplantation offers cure, 50% survival rate at 3 yrs • Demthylating agents-Pyrimidine analogues (Azacitidine, Decitabine) • Lenalidomide, Cyclosporine, ATG, GCSF APLASTIC ANEMIA • Immunosuppression: Combination of Cyclosporine & Anti- Thymocyte Globulin • Stem Cell Transplantation • Supportive - transfusion

20. 1. Pancytopenia ISSUES • Hemoglobin: 6.3 – 12.4 g/dl • WBC: 410 – 5,100 • Platelet count: 2,000 – 160,000 • Persistent pancytopenia despite multiple blood transfusion and repeated GCSF admin. • Risk for severe infection, hemodynamic instability and bleeding

21. 1. Pancytopenia MANAGEMENT • Multiple transfusion of blood products • ATG • Cyclosporine • Repeated GCSF administration • Steroid administration • Erythropoietin, thrombopoietin • Vitamin K and tranexamic acid administration

22. Effect of Multiple Blood Transfusion • Supportive therapy: PLT transfusion • However, repeated PLT transfusion may fail to show the desired increment in PLT counts • PLT refractoriness develop in 30-70%; maybe due to the underlying condition (fever, sepsis, drugs) or it may be due to alloimmunization • Patients with transfusion failure due to HLA- antibodies may be given HLA- matched PLT components

23. 1. Pancytopenia ETIOLOGY • Thrombocytopenia secondary to Severe Hypoplastic Myelodysplastic Syndrome • Platelet refractoriness secondary to multiple blood transfusion • Unresolving Sepsis secondary to Pneumonia in the Immunocompromised

24. 2. Pneumonia and Fungal Laryngitis in the Immunocompromised ISSUES Severe infection; sepsis Unresolving lung infiltrates and persistent pleural effusion Persistent wheezing/bronchospasm sec. to hyperreactive airways

25. 2. Pneumonia and Fungal Laryngitis in the Immunocompromised MANAGEMENT Sputum cultures, blood cultures Chest radiographs, chest UTZ, chest CT scan Attempted thoracentesis/chest pigtail insertion Use of broad-spectrum antibiotics, antifungals, antivirals Inhaled and systemic bronchodilators and mucolytics; steroid administration

26. CT scan of the chest, plain(May 31, 2009) • Pneumonia, left lower lobe • Soft tissue density in the LUL and pulmonary nodular opacities in the right lung may still be related to the infectious process • Subcentimeter granuloma, RLL • Minimal pleural effusion, left • Calcified lymph nodes, right paratracheal and right hilar regions. These were already noted in the study of April 4, 2009.

27. 3. Respiratory Failure CAUSES Severe infection (laryngeal candidiasis and unesolving pneumonia) and sepsis in the immunocompromised Pulmonary congestion sec.to hypervolemia, hypoalbuminemia Persistent wheezing/bronchospasm sec. to hyperreactive airways Anemia Airway and intrathoracic bleeding Empyema/pyothorax considered

28. 3. Respiratory Failure MANAGEMENT Alternating BIPAP and in-line neb. Endotracheal intubation and subsequent tracheostomy Inhaled and systemic bronchodilators in increased doses Inhaled and systemic mucolytics

29. 4. Hypoalbuminemia CAUSES Nutritional Hepatic failure ISSUES Third spacing: congestion, effusion and edema MANAGEMENT Repeated IV infusions of 25% human albumin

30. 5. Hyperglycemia CAUSES Steroid-induced Stress-induced ISSUES Risk for uncontrolled infection, cardiovascular/coronary events MANAGEMENT CBG monitoring and insulin administration

31. 6. Renal Failure CAUSES Sepsis Decreased renal perfusion sec. to anemia (shunting of blood away from the kidney for protection of O2 delivery to vital organs) Drugs (Cyclosporine, Amphotericin, antibiotics)

32. 6. Renal Failure ISSUES Hypervolemia (increased BP and CVP 14-19 cmH2O, edema) due to multiple transfusions, steroid admin. On the 22nd HD, (+) oliguria with rising serum crea 2.0 from 0.9 mg/dl (est. crea clearance 21 ml/min from 47 ml/min)

33. 6. Renal Failure MANAGEMENT Dose adjustments of antibiotics and other medications 12-hour urine collection Diuresis (Furosemide, Spironolactone, Bumetanide) Subsequent hemodialysis

34. 7. Abdominal Distension CAUSES Septic ileus Ileus sec.to metabolic derangement Pseudomembranous colitis considered ISSUES Increasing abdominal girth with intermittent episodes of voluminous watery stools

35. 7. Abdominal Distension MANAGEMENT NPO Plain film of the abdomen CT scan of the abdomen Prokinetics, laxatives, enemas Vancomycin per orem Rectal tube insertion Total parenteral nutrition

36. CT scan of the abdomen, plain(May 31, 2009) Ileus Few descending colon diverticula Distended gall bladder Atrophic pancreas Possible right renal cortical cyst Subcentimeter appendicolith vs. inspissated barium with no associated inflammatory changes The rest is normal

37. 8. Metabolic Encephalopathy CAUSES Sepsis Electrolyte derangements Hypovolemia episodes during hemodialysis Hepatic failure

38. 8. Metabolic Encephalopathy MANAGEMENT Referral to Neurology service on the 27th HD Cranial MRI and MRA of intracranial vessels requested EEG showed encephalopathy probably sec. to hypovolemia (hypotension episodes during dialysis) Correction of electrolyte abnormalities; manage sepsis

39. 9. Elevated Blood Pressure (130-200/70-100 mmHg) CAUSES Volume overload sec. to multiple blood transfusion, steroid use Increased cardiac output sec. to tachycardia Catecholamine release (stress-induced)

40. 9. Elevated Blood Pressure (130-200/70-100 mmHg) MANAGEMENT Ca-channel blockers (Amlodipine, Nicardipine, Verapamil) Clonidine Diuresis

41. 10. Tachycardia with PACs and PVCs (100 – 180 bpm) CAUSES Sepsis/stress-induced Anemia Metabolic derangements (i.e. electrolyte imbalance) Bronchodilators in increased doses

44. 10. Tachycardia with PACs and PVCs (100 – 180 bpm) MANAGEMENT 2D-echocardiogram with CFDS Electrolyte correction Beta-blockers (Metoprolol, Nebivolol) Digoxin stat doses Verapamil Amiodarone Ivabradine Trimetazidine

46. 2D-echocardiogram with CFDS (baseline) May 15, 2009 - Normal LV dimension with NWMC, EF 75%; calcified non- coronary cusp of aortic valve without restriction of motion. Calcified aortic walls; normal MV, TV, PV; minimal pericardial effusion; color flow Doppler= MR, mild; TR, mild; mild pulmonary hypertension as evidenced by pulmonary acceleration time of 100 msec; Doppler evidence of impaired LV relaxation.

47. On the 35th hospital day… Tracheostomy done O2 desaturation noted ~ 90% HR much controlled: 78 bpm BP 104/55 mmHg 12-lead ECG post-trache showed: new T-wave inversions at V1 – V3, ST-elevations at II and AVF

49. Cardiac Enzymes May 13: TCPK 60, CKMB 1.5, Trop I 0.08 June 10: TCPK 47, CKMB 7, Trop T 0.51 June 11: TCPK 29, CKMB 2.9, Trop I 0.37 May 13: serum BNP 4,071

50. 2D-echocardiogram with CFDS (repeat) June 11, 2009 - concentric LVH with NWMC, EF 55%; color flow Doppler = MR, mild; Doppler evidence of LV diastolic dysfunction (E/A velocity ratio and isovolumic relaxation time); mild pulmonary hypertension by pulmonary acceleration time 108 msec; compared with previous study done may 15, increase in LV wall thickness; no note of pericardial effusion.