1. Acute Myeloid Leukemia

2. Case Presentation 33 yo Filipino male presents with back pain, fevers, weight loss, and general malaise 33 yo Filipino male presents with back pain, fevers, weight loss, and general malaise Not felt “normal” in two months Not felt “normal” in two months Previously healthy Previously healthy Sent to NMCSD by PCM for abnormal labs Sent to NMCSD by PCM for abnormal labs

3. PE Mostly unremarkable exam Mostly unremarkable exam BP: 187/110; HR: 123; T – 98.7; R - 16 BP: 187/110; HR: 123; T – 98.7; R - 16 Normal CV/Pulm exam Normal CV/Pulm exam No lymphadenapathy No lymphadenapathy Mild hepatomegaly, no spleenomegaly Mild hepatomegaly, no spleenomegaly No ecchymoses or rash No ecchymoses or rash Mild resting tremor Mild resting tremor

4. Labs CBC: CBC: H/H: 14.1/43 H/H: 14.1/43 WBC: 11.4 WBC: 11.4 Diff: N – 69/Bands - 7/L - 18/M - 10/E - 2 Diff: N – 69/Bands - 7/L - 18/M - 10/E - 2 Platelets: 54 Platelets: 54 Calcium – 11.0; Phos – 6.9 Calcium – 11.0; Phos – 6.9 LDH - 3752 LDH - 3752

5. AML – The Basics AML accounts for 40% of leukemia cases. AML accounts for 40% of leukemia cases. Approximately 10,000 cases are diagnosed in adults in the US annually. Approximately 10,000 cases are diagnosed in adults in the US annually. The incidence of AML increases steadily with increasing age. The median age is 55 to 60. The incidence of AML increases steadily with increasing age. The median age is 55 to 60. Males > females; whites > blacks. Males > females; whites > blacks. Abeloff: Clinical Oncology, 3rd ed

6. AML – The Basics Increased incidence with Down's syndrome, Bloom's syndrome, Fanconi's anemia Increased incidence with Down's syndrome, Bloom's syndrome, Fanconi's anemia Increased risk with MDS and MPS. Increased risk with MDS and MPS. Multiple environmental risk factors: Multiple environmental risk factors: exposure to radiation exposure to radiation chemical exposure to benzene, hydrocarbons, and solvents chemical exposure to benzene, hydrocarbons, and solvents treatment with alkylating agents treatment with alkylating agents Viruses??? Viruses???

7. Presentation Lethargy, granulocytopenia, and thrombocytopenia are most common. Lethargy, granulocytopenia, and thrombocytopenia are most common. 30% present with a significant skin, soft tissue, or respiratory infection. 30% present with a significant skin, soft tissue, or respiratory infection. Petechiae with or without bleeding may be present. Petechiae with or without bleeding may be present. Hyperuricemia is frequent; splenomegaly is present in about 1/3 of patients. Hyperuricemia is frequent; splenomegaly is present in about 1/3 of patients. Lymphadenopathy and hepatomegaly are uncommon. Lymphadenopathy and hepatomegaly are uncommon.

8. Work-up History History family, work, and medical history family, work, and medical history radiation and chemical exposure history radiation and chemical exposure history Physical Physical Temperature Temperature Cranial nerve exam and vision exam Cranial nerve exam and vision exam Lymph nodes and hepatosplenic exam Lymph nodes and hepatosplenic exam Special attention to potential sites of infection Special attention to potential sites of infection

9. Peripheral Smear Nonspecific findings: Nonspecific findings: Normochromic, normocytic anemia Normochromic, normocytic anemia Thrombocytopenia Thrombocytopenia Leukopenia (with granulocytopenia) Leukopenia (with granulocytopenia) May have leukemic blasts May have leukemic blasts

10. Diagnosis Bone Marrow Biopsy Bone Marrow Biopsy Cellularity Cellularity Stains: Stains: Wright's, Sudan black, esterase stains Wright's, Sudan black, esterase stains Periodic acid-Schiff reagent, iron stain, and immunofluorescent stain Periodic acid-Schiff reagent, iron stain, and immunofluorescent stain Aspirate for karyotyping and immunophenotyping Aspirate for karyotyping and immunophenotyping

11. Bone Marrow Biopsy Must have >30% blasts (WHO >20% blasts) Must have >30% blasts (WHO >20% blasts) Must be myeloid origin Must be myeloid origin Auer rods found in most AML Auer rods found in most AML http://www.microscopy-uk.org.uk/mag/artaug01/vrcoolpixb.html

12. Bone Marrow Biopsy Diagnosis confirmed by immunophenotype Diagnosis confirmed by immunophenotype

13. http://www.lmp.ualberta.ca/resources/pathoimages/Images-A/000p0360.jpg

14. AML -Pathology Abnormal clonal proliferation of a primitive myloid hematopoietic progenitor cell Abnormal clonal proliferation of a primitive myloid hematopoietic progenitor cell Accumulation in bone marrow results in pancytopenia Accumulation in bone marrow results in pancytopenia Leukemic cells released into circulation Leukemic cells released into circulation

15. Leukemic Cellular Origin

16. AML - Types Classified in the FAB system Classified in the FAB system Classified using: Classified using: Morphologic appearance of the blasts Myeloperoxidase stain Sudan black stain Nonspecific esterases Cytogenetic testing Immunologic testing

19. Treatment Induction Induction Daunorubicin (3 days) and cytarabine (7 days) have been used for past 30 years Idarubicin or mitoxantrone may be beneficial in young patients +/- myeloid growth factor +/- myeloid growth factor Post Induction Therapy Post Induction Therapy Allogenic bone marrow transplant Allogenic bone marrow transplant Autologous bone marrow transplant Autologous bone marrow transplant Chemotherapy Chemotherapy

20. Treatment Remission: Remission: Achieved after 7/3 in 70-80% of patients under the age of 60 Achieved after 7/3 in 70-80% of patients under the age of 60 Achieved in 50% of patients older than 60 Achieved in 50% of patients older than 60 Relapse Relapse Occurs on average 4 months after induction if no further treatment Occurs on average 4 months after induction if no further treatment

21. Prognosis

22. Prognosis after CR

23. Prognosis Overall for AML: Overall for AML: 70-80% CR 70-80% CR 20-30% DFS at 5 years 20-30% DFS at 5 years

24. Special Cases AML M3 (Acute promyelocytic leukemia) AML M3 (Acute promyelocytic leukemia) Induction with all-trans retinoic acid, followed by d Induction with all-trans retinoic acid, followed by daunorubicin and cytarabine High risk of DIC

25. Patient Presentation Bone Marrow biospy Bone Marrow biospy 1 st sample was fibrotic 1 st sample was fibrotic 2 nd sample – AML M7 2 nd sample – AML M7 Leukemic cells CD61 + Leukemic cells CD61 + Negative for other stains Negative for other stains Trilineage hypoplasia Trilineage hypoplasia Extensive bone marrow necrosis Extensive bone marrow necrosis Stain for CD61 (Glycoprotein IIIa) http://www.ihcworld.com

27. AML M7 Acute Megakaryoblastic Leukemia (FAB M7) Acute Megakaryoblastic Leukemia (FAB M7) Accounts for 3-5% of AML (not associated with prior treatment) Accounts for 3-5% of AML (not associated with prior treatment) Overall poor prognosis Overall poor prognosis Down Syndrome increases risk Down Syndrome increases risk Commonly presents with a dry bone marrow aspirate Commonly presents with a dry bone marrow aspirate Few large studies Few large studies

28. Diagnosis Anti glycoprotein IIb/IIIa (CD41a) Platelet peroxidase by electron microscope Immuno-cytochemistry stain for factor VIII From http://www.ehatol.org

29. AML M7 Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience From Blood, 2000 Followed 20 study patients with AML M7 1.2% of all new AML cases during study period Median age: 42.5 70% male predominance (14/20 cases)

30. Study Treatments Patients enrolled in 5 different studies Patients enrolled in 5 different studies Different doses Different doses daunorubicin and cytarabine Other agents added: 6-thiogranine, idarubicin, GM- CSF Consolidation with chemo or transplant

31. AML: the ECOG experience Outcomes: Outcomes: 50% CR rates 50% CR rates Medial remission: 10.6 months Medial remission: 10.6 months Median survival: 10.3 months Median survival: 10.3 months One patient survived 160+ months One patient survived 160+ months

32. AML: the ECOG experience

34. Study limitations Study limitations No children, so Downs cases not included No children, so Downs cases not included Fibrotic marrow makes diagnosis difficult Fibrotic marrow makes diagnosis difficult Poor prognosis may lead to less referral for studies Poor prognosis may lead to less referral for studies

35. Second Series Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center From Blood in 2006. 37 patient with AML M7 at MD Anderson from 1987-2003 2% of all patients with new diagnosis of AML Treated with one of five regimens

36. Cytogenetics

37. M.D. Anderson Cancer Center

38. Outcomes

39. Summary

40. Patient Presentation Achieved CR after induction chemo Achieved CR after induction chemo Outcome??? Outcome???

41. Conclusions AML M7 is a rare form of AML with a very poor prognosis AML M7 is a rare form of AML with a very poor prognosis +/- prognostic indicators are not well understood +/- prognostic indicators are not well understood Optimal treatment is not known at this time Optimal treatment is not known at this time

42. Questions?

43. Resources Abeloff: Clinical Oncology, 3rd ed., 2004 Churchill Livingstone Abeloff: Clinical Oncology, 3rd ed., 2004 Churchill Livingstone http://www.meds.com/leukemia/points/le ct1.html http://www.meds.com/leukemia/points/le ct1.html Lowenberg, B. et al. Acute Myloid Leukemia, N Engl J Med 1999;341:1051-62 Lowenberg, B. et al. Acute Myloid Leukemia, N Engl J Med 1999;341:1051-62 Martin, et al. Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience. Blood 2000; 96:2405-11 Martin, et al. Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience. Blood 2000; 96:2405-11 UpToDate UpToDate Yasuhiro, et al. Blood 2006; 107:880-84 Yasuhiro, et al. Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center. Blood 2006; 107:880-84

44. AML: the ECOG experience One surviving patient on trial: EST 3483: 1 – 2 courses of induction with daunorubicin 60 mg/m2 IV per day for 3 days, cytosine arabinoside 200 mg/m2 IV for 5 days plus 6-thioguanine 100 mg/m2 orally q12 hrs for 5 days. Then randomized to either one course of intensive consolidation therapy with high-dose cytosine arabinoside 3 gm/m2 IV q12 hours days 1 to 6, plus amsacrine 100 mg/m2 per day IV on days 7 to 9 or maintenance therapy for 2 years with 6-thiogranine 40 mg/m2 twice daily each week plus cytosine arabinoside 60 mg/m2 subcutaneously on day 5 each week or observation. Patients younger than 41 years with a histocompatible sibling were to undergo allogeneic transplantation.

45. M.D. Anderson Cancer Center Group 1 contained regimens with cytarabine (ara-C) and anthracyclines. Group 2 contained regimens with ara-C and fludarabine but not containing anthracyclines. Group 3 contained regimens with topotecan Group 4 contained regimens with ara-C and not anthracyclines, fludarabine, or topotecan. Group 5 was regimens without ara-C.