acute leukemia: clinical cases and correlates daniel a. nikcevich, md, phd duluth clinic cancer...
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Acute Leukemia:Clinical Cases and Correlates
Daniel A. Nikcevich, MD, PhD
Duluth Clinic Cancer Center
May 13, 2008
Patient R.A.
• 45 yo male presents with fevers, chills, diffuse adenopathy.
• What are you thinking?
Acute Myelogenous Leukemia
• Definition
• Clinical features
• Evaluation
• Classification
• Prognosis
• Treatment
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)
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
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)
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
AML
Classification
• FAB
• WHO
• 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)
• 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
Prognostic Features
•Cytogenetics• Everything else
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
• 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
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)
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
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
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
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 1st CR
Transplant
• Allogeneic stem cell transplantation– Poor risk cytogenetics– Intermediate-risk cytogenetics with matched sibling
donor– Extramedullary disease (chloroma)– Ist or 2nd relapse– Donor sources include siblings, children, parents,
MUD, umbilical cord blood• Autologous stem cell transplantation
– No proven benefit over consolidation chemotherapy in 1st CR
– Consider for patients w/o an allogeneic donor
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
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
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
Patient C.W.
• WBC 47K
• HgB 9.8 g/dL
• Platelets 18K
• INR 3.7
• aPTT 58 sec
• Fibrinogen 76
• Now what to do?
• Look at the blood film or bone marrow
Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2004;2004:101126
Figure 3. Promyelocytes are heavily granulated
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
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
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
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
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
• Don’t let the sun set on M3
Patient B.P.
• 50 yo female presents with fatigue, headache, blurred vision.
• What’s next?
• HISTORY
• Exam
• Labs
Patient B.P.
• WBC 235K
• HgB 6.0 g/dL
• Platelets 49K
• Coags nl
• What’s next?
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
Patient B.P.
• AML-M4
• Hyperleukocytosis– Hyperviscosity– Sludging in vasculature with ischemia and/or
infarct
• Leukopheresis to reduce WBC to <100K
Patient B.P.
• Brief (3 months) remission with 7+3
• Refractory disease despite additional chemotherapy, mylotarg
• Pursued best supportive care with hospice
