1. Acute Leukemia: Clinical Cases and Correlates Daniel A. Nikcevich, MD, PhD Duluth Clinic Cancer Center May 13, 2008

2. Patient R.A. 45 yo male presents with fevers, chills, diffuse adenopathy. What are you thinking?

3. Acute Myelogenous Leukemia Definition Clinical features Evaluation Classification Prognosis Treatment

4. AML Uncontrolled clonal proliferation and accumulation of neoplastic hematopoietic precursor cells of myeloid lineage –Inhibition of normal hematopoiesis –Defective maturation –Dissemination into blood and other tissues –20% myeloblasts in BM (WHO) or 30% myeloblasts in BM (FAB)

5. Clinical Features 10,600 new cases in US in 2002 7,400 deaths in US in 2002 Median age diagnosis: 63 (80% >15) Increased risk with Down Syndrome, Ataxia telangiectasia, Fanconi anemia, Li Fraumeni syndrome, Wiskott-Aldrich, familial leukemia, myelodysplasia, PNH, Secondary AML described with prior chemotherapy, radiation exposure, benzene

6. Clinical features Pancytopenia –Anemia (often asymptomatic in elderly) –Neutropenia –Thrombocytopenia B symptoms: fever, night sweats, chills, malaise, weight loss Extramedullary disease –Monocytic leukemias most common –Skin, CNS, orbits, bone, lung, kidney, bone, spleen, liver, ovary Hyperleukocytosis –>100,000 blast count/ml –APML, monocytic AML, inv(16), 11q23 –Treat promptly with hydroxyurea, leukopheresis, chemotherapy Coagulation abnormalities –DIC with APML (M3)

7. Evaluation History and physical examination CBC, blood film, CMP, PT/PTT, fibrinogen Bone marrow aspirate and biopsy –Flow cytometry –Cytogenetics Evaluate cardiac function Lumbar puncture if other clinical evidence of extramedullary disease exists HLA typing (patient and siblings) Place central venous access –PICC line only with APML

8. AML

9. Classification FAB WHO

10. FAB –>30% BM myeloblasts M0 (undifferentiated myeloid leukemia) M1 (acute myeloid leukemia without maturation) M2 (acute myeloid leukemia with maturation) M3 (acute promyelocytic leukemia) M4 (acute myelomonocytic leukemia) M5 (acute monocytic leukemia) M6 (acute erythroleukemia) M7 (acute megakaryocytic leukemia)

11. WHO –>20% BM myeloblasts AML with recurrent cytogenetic abnormalities –t(8;21), t(15;17), t(inv16), 11q23 AML with multilineage dysplasia AML and MDS, therapy-related AML not otherwise categorized –similar to FAB list Acute biphenotypic leukemia

12. Prognostic Features Cytogenetics Everything else

13. What about everything else? Favorable features –Age < 55 –Absence of infection or sepsis –Absence of antecedent MDS –Low WBC –Good risk cytogenetics: t(8;21), t(16;16), t(15;17) –Presence of Auer rods

14. Unfavorable features –Poor risk cytogenetics –Age > 60 –Presence of infection or sepsis –Poor performance status –Presence of prior MDS –Secondary AML –Extreme leukocytosis –Extramedullary disease

15. Cytogenetics The single most important prognostic factor –Favorable risk: t(8;21), t(16;16), t(15;17) –Intermediate risk (normal karyotype) –Unfavorable risk (del 5, del 7, trisomy 8, 11q23, other complex karyotypes)

16. Figure 1. Overall survival of patients with favorable cytogenetic abnormalities, irrespective of the presence of additional abnormalities. The group with normal karyotype is included for comparison. Blood (1998) 92:2322

17. Figure 2. Overall survival of patients with adverse cytogenetic abnormalities, irrespective of the presence of additional abnormalities. The group with normal karyotype is included for comparison. Blood (1998) 92:2322

18. Treatment Age < 60 Induction chemotherapy with anthracycline (daunorubicin, mitoxantrone, idarubicin) plus cytosine arabinoside. “7 + 3” regimen If remission obtained (60-70% remission rate), then consolidation chemotherapy or transplantion If no remission, then especially poor prognostic sign. –If remission induced with alternative regimen, then consider allogeneic transplantion

19. Consolidation or Transplant? Consolidation chemotherapy –High-dose cytosine arabinoside x 4 cycles –Good risk cytogenetics (8;21, inv16, 15;17) –Intermediate risk cytogenetics w/o matched sibling donor or unwilling/unable to have transplant in 1 st CR

20. Transplant Allogeneic stem cell transplantation –Poor risk cytogenetics –Intermediate-risk cytogenetics with matched sibling donor –Extramedullary disease (chloroma) –Ist or 2 nd relapse –Donor sources include siblings, children, parents, MUD, umbilical cord blood Autologous stem cell transplantation –No proven benefit over consolidation chemotherapy in 1 st CR –Consider for patients w/o an allogeneic donor

21. NEJM (1998) 339:1649

22. Treatment Age > 60 Induction chemotherapy with anthracycline (daunorubicin, mitoxantrone, idarubicin) plus cytosine arabinoside. “7 + 3” regimen If remission obtained (60% remission rate), then consolidation chemotherapy with reduced intensity cytosine arabinoside Probably no role for allogeneic transplant Mylotarg (anti-CD33 moAb coupled to calicheamicin) for relapsed disease Consider observation and supportive care in lieu of induction chemotherapy

23. Patient R.A. Diagnosed with AML-M0 with extra-medullary disease in lymph nodes and CSF Obtained remission (bone marrow and adenopathy) with induction chemotherapy Cleared CSF with 8 cycles IT methotrexate Rocky course with hectic fevers (culture negative), pancytopenia, probable typhlitis Allogeneic matched-sibling transplant –AML remains in remission –Chronic GVHD

24. Patient C.W. 37 yo male previously well. 2 weeks of fatigue, malaise, fevers Presents to primary care physician with epistaxis What’s next? HISTORY Exam Labs

25. Patient C.W. WBC 47K HgB 9.8 g/dL Platelets 18K INR 3.7 aPTT 58 sec Fibrinogen 76

26. Now what to do? Look at the blood film or bone marrow

27. Copyright ©2004 American Society of Hematology. Copyright restrictions may apply. Maslak, P. ASH Image Bank 2004;2004:101126 Figure 3. Promyelocytes are heavily granulated

28. Copyright ©2002 American Society of Hematology. Copyright restrictions may apply. Maslak, P. ASH Image Bank 2002;2002:100587 Figure 1. This cell found in the bone marrow of a patient with APL contains multiple Auer rods in the cytoplasm

29. Copyright ©2004 American Society of Hematology. Copyright restrictions may apply. Maslak, P. ASH Image Bank 2004;2004:101126 Figure 1. Mononuclear infiltrate is evident under low power

30. Acute promyelocytic leukemia (M3) Most with t(15;17). Creates fusion gene, PML/RAR-alpha. Poor risk disease with t(11;17) Induction therapy with ATRA plus anthracycline- based chemotherapy Consolidation with 2 courses anthracycline- based chemotherapy 2 years maintenance chemotherapy with ATRA, 6-MP, and methotrexate Relapse –arsenic trioxide

31. Acute promyelocytic leukemia (M3) Index of suspicion Look at the blood film Yourself! M3 very commonly with Auer rods DIC a common presentation –Coagulopathy –Depressed fibrinogen –Thrombocytopenia –Fatal hemorrhage If M3 and DIC, then desire to start ATRA (all- trans retinoic acid) in <6 hours

32. Patient C.W. Started promptly on ATRA Induced into remission –Complete cytogenetic and molecular remission –Absence of 15;17 chromosome translocation by cytogenetics –Absence of PML/RAR-alpha fusion gene by RT/PCR Completed maintenance therapy and doing extremely well

33. Don’t let the sun set on M3

34. Patient B.P. 50 yo female presents with fatigue, headache, blurred vision. What’s next? HISTORY Exam Labs

35. Patient B.P. WBC 235K HgB 6.0 g/dL Platelets 49K Coags nl What’s next?

36. Copyright ©2005 American Society of Hematology. Copyright restrictions may apply. Maslak, P. ASH Image Bank 2005;2005:101304 Figure 1. Hyperleukocytosis in the peripheral smear of a patient with AML

37. Patient B.P. AML-M4 Hyperleukocytosis –Hyperviscosity –Sludging in vasculature with ischemia and/or infarct Leukopheresis to reduce WBC to <100K

38. Patient B.P. Brief (3 months) remission with 7+3 Refractory disease despite additional chemotherapy, mylotarg Pursued best supportive care with hospice

39. Questions? dnikcevich@smdc.org