Acute Myeloid Leukemia

1
Acute Myeloid Leukemia

• Peter M. Voorhees, M.D.
• The University of North Carolina at Chapel Hill
• Division of Hematology-Oncology
• Lineberger Comprehensive Cancer Center

2
Outline

• Molecular Pathogenesis
• Classification
• Prognosis
• Treatment

3
Molecular Pathology of AML

• Abnormal cell proliferation
• FLT3 mutations
• Ras mutations
• Others c-KIT mutations
• Block in differentiation
• CBF AML (t(821) and inv(16))
• PML-RARa (t(1517))
• MLL translocations (11q23)
• Hox gene translocations
• C/EBPa mutations
• Suppression of apoptosis
• Bcl-2 over-expression
• Capacity for indefinite self-renewal

4
Proliferation FLT3

• A receptor tyrosine kinase expressed in 70 100
  of AML cases.
  
• Activating mutations in FLT3 are seen in 30 of
  AML cases.
  
• Tandem duplication of the juxtamembrane region.
• Point mutation within the activation loop of the
  kinase domain.
  
• Activation of FLT3 leads to deregulated
  proliferation of AML cells.

5
Proliferation Ras

• Small guanine nucleotide binding proteins that
  play a role in several cell signaling pathways.
  
• Activating point mutations seen in 25 of AML
  cases.
  
• N-Ras 10 25
• K-Ras 5 15
• H-Ras Rare
• Activation of Ras leads to deregulated cell
  proliferation.

6
Differentiation Core Binding Factor (CBF)-a in
M2 AML

• CBFs heterodimeric complexes (CBFa and CBFß)
  that regulate expression of genes involved in
  hematopoietic cell differentiation.
  
• CBFa AML1.
• t(821)(q22q22) AML1-ETO fusion gene.
• AML1-ETO is a transcriptional repressor.
• recruits the nuclear co-repressor complex and
  histone deacetylases to CBF sites

7
Differentiation Core Binding Factor-ß

• CBFß is located at 16q22.
• Inv(16)(p13q22) and t(1616)(p13q22)
  CBFß-MYH11 fusion gene that functions as a
  dominant negative inhibitor of CBF.
  
• The result is the suppression of transcription of
  genes crucial for hematopoiesis / differentiation.

8
Differentiation the Retinoic Acid Receptor-a
(RARa) in APL

• RARa involved in transcription of genes
  necessary for hematopoiesis / differentiation.
  
• t(1517)(q22q22) fusion gene PML-RARa.
• t(1117) PLZF-RARa
• t(517) NPM-RARa
• PML-RARa is a transcriptional repressor
• recruits the nuclear co-repressor complex and
  histone deacetylases.
  

9
Differentiation the Mixed Lineage Leukemia (MLL)
Gene

• MLL is a protein that regulates Hox gene
  expression.
  
• Hox family members play critical roles in
  transcription of genes involved in
  hematopoiesis.
  
• Normal MLL requires cleavage by taspase into its
  mature form ? dysregulated Hox gene expression ?
  block in differentiation.

10
Pathogenesis Summary

• Strategies that interfere with over-activation of
  signaling pathways and the block in cellular
  differentiation have the potential to improve
  patient outcomes in AML.

11
The FAB Classification
12
The WHO Classification
13
Prognosis Cytogenetics from the MRC AML 10 trial
in patients 14
Prognosis Cytogenetics from the MRC AML 11 trial
in elderly patients
15
Prognosis in normal cytogenetic group NPM1 and
FLT-3

• Mutations in nucleophosmin1 good
• FLT-3 ITD bad
• NPM1/FLT-3 ITD- with improved RFS and OS (HR
  0.34 and 0.43).
  
• RFS at 4 yrs 61 (MRD) and 57 (no MRD) for
  NPM1/FLT-3- pts.
  
• RFS at 4 yrs 47 (MRD) and 23 (no MRD) for
  NPM1-/FLT-3 ITD pts.

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Treatment

• Chemotherapy
• Induction
• Consolidation
• Transplantation
• Autologous
• Allogeneic
• Novel Therapies
• Relapsed / Refractory Disease
• AML in the elderly

17
Treatment Induction Chemotherapy

• 7 3
• 7-day continuous IV infusion of cytarabine at 100
  mg/m2/day.
  
• 3-day bolus IV infusion of anthracycline.
• First piloted in the late 1970s.
• CR rates in the 60 80 range.

18
Induction Chemotherapy Is more better?

• Priesler et al (Blood 69 1441, 1987)
• Phase III study of 7 3 vs. 10 3 vs. 7
  3 6-TG.
  
• No differences in response rate or survival.
• Bishop et al (Blood 75 27, 1990)
• Phase III study of 7 3 vs. 7 3
  etoposide (75 mg/m2/day x 7 days).
  
• Improved remission duration but no effect on
  response rate or OS.
  
• Subset analysis suggested improved OS in pts (9 months vs. 17 months, p0.03).
  
• Farag et al (JCO 23 482, 2005)
• Comparison of 7 3 vs. 7 3 etoposide
  across CALGB studies in AML pts
  cytogenetics.
  
• CR rate improved with 3 drugs (82 vs. 73,
  p0.04).
  
• OS unchanged.

19
Induction Chemotherapy Does the choice of
anthracycline matter?

• Rowe et al (Blood 103 479, 2004)
• 7 3 (daunorubicin vs. idarubicin vs.
  mitoxantrone) in older patients with
  newly-diagnosed AML.
  
• No differences in CR rates.
• AML Collaborative Group
• Meta-analysis of 5 studies comparing idarubicin
  vs. daunorubicin.
  
• Idarubicin had an improved CR rate (62 vs. 53)
  and OS at 5 years (13 vs. 9).
  
• This analysis has been criticized given
  controversy regarding whether equivalent doses of
  the 2 drugs were administered in all trials.

20
Induction Chemotherapy Is there a role for G-CSF
priming?

• Hypothesis driving more AML cells into cell
  cycle with the use of growth factors may
  sensitize them to cell cycle-specific, cytotoxic
  chemotherapy.
• Lowenberg et al. NEJM 349 743, 2003.
• Phase III trial of 7 3 with or without G-CSF
  priming.
  
• No difference in CR rate or OS but improved DFS
  at 4 years (42 vs. 32).
  
• Subset analysis revealed an OS benefit to
  patients without unfavorable cytogenetics.
  
• Hiddeman et al. Ann Hematol 83 suppl 1 S53,
  2004.
  
• Phase III trial of induction chemotherapy with or
  without G-CSF priming.
  
• No differences in CR rate, DFS or OS.

21
Supportive care after induction CSF prophylaxis?

• Special issues
• AML blasts express receptors for G-CSF and
  GM-CSF.
  
• The bone marrow is invariably compromised at
  initial diagnosis of AML.
  
• The intensity of the therapy is substantial, with
  grade 4 hematologic toxicity expected.
  
• Heil et al. Phase 3 study of G-CSF in AML
  induction and consolidation
  
• No difference in DFS or OS.
• G-CSF-treated patients
• Achieved neutrophil recovery 5 days earlier
• Shorter duration of fever (7 vs. 8.5 days)
• Shorter duration of parenteral abx use (15 vs.
  18.5 days)
  
• Shorter duration of hospitalization (20 vs. 25
  days)
  
• Less frequent use of anti-fungal tx (34 vs 43).

22
Supportive care after induction antibacterial
prophylaxis?

• Gafter-Gvili et al. Meta-analysis.
• Risk for death reduced with prophylaxis (RR 0.67,
  95 CIs 0.55 to 0.81).
  
• Risk for adverse events increased with
  prophylaxis (RR 1,69, 95 CIs 1.14 to 2.50).
  
• Quinolone prophylaxis
• Decreased mortality (RR 0.52, 0.35 to 0.77)
• Reduced infection-related mortality, fever,
  clinically-documented infection,
  microbiologically-documented infections.
  
• Increased risk of harboring quinolone-resistant
  bacilli (RR 1.69, 0.73 to 3.92) and adverse
  events (RR 1.30, 0.61 to 2.76).

23
Supportive care after induction antibacterial
prophylaxis?

• Bucaneve et al.
• Phase 3 study of levofloxacin vs. placebo in
  high-risk patients
  
• Acute leukemia, lymphoma, solid tumors
• At risk of neutropenia of 7
  days.
  
• Reduced incidence of fever
• 65 vs. 85 (p0.001)
• Decreased microbiologically-documented
  infections.
  
• Decreased gram-negative and polymicrobial
  bacteremia.
  
• No difference in overall mortality (3 vs. 5) or
  infection-related mortality (2 vs. 4).
  

24
Supportive care after induction antifungal
prophylaxis?

• Cornely et al.
• Phase 3 study of posaconazole vs. fluconazole.
• AML/MDS patients with expected ANC 7 days.
  
• Posaconazole decreased
• Proven and probable fungal infections (2 vs.
  8).
  
• Invasive aspergillosis (1 vs. 7).
• 100-day all-cause mortality (14 vs. 21). NNT
  14 patients.
  
• 2 vs. 5 fungal-specific death.
• Posaconazole increased SAEs probably or possibly
  drug-related (6 vs. 2).
  

25
Blood product support

• Leukoreduced products
• Reduced febrile infusion reactions
• Decreased platelet alloimmunization
• Decreased likelihood of transplkant rejection
• Decreased CMV exposure in seronegative patients
• Irradiated products
• Prevent GVHD.
• At UNC, all products are leukoreduced.
• Irradiation must be requested.
• Once requested, all subsequent products are
  irradiated.
  

26
Treatment Post-Remission Chemotherapy

• Mayer et al. NEJM 331 896, 1994.
• Phase III trial comparing 3 different
  consolidation strategies for patients with AML in
  CR (HIDAC, IDAC, low-dose cytarabine).
  
• In patients 29, and 24, respectively.
  
• For patient 60, the DFS was 16 or less for all
  groups.

27
Post-Remission Chemotherapy How many cycles of
consolidation should be given?

• 3-4 HIDACs are better than 1 in good risk
  patients
  
• Byrd et al. JCO 17 3767, 1999. Byrd et al.
  JCO 22 1087, 2004.
  
• 3-4 cycles of HIDAC vs. 1 cycle of HIDAC followed
  by 2 cycles of combination chemotherapy.
  
• Subset analysis of t(821) and inv(16) / t(1616)
  patients.
  
• RFS was better for both subtypes, although OS
  benefit was only seen in the t(821) group.
  
• Are 4 HIDACs better than 3?
• Farag et al. JCO 23 482, 2005. Comparison of
  patients treated on different CALGB studies.
  
• Patients
• 28 vs. 41 4-year DFS. No difference in OS.

28
Post-Remission Therapy Autologous Stem Cell
Transplantation
29
Post-Remission Therapy Allogeneic Stem Cell
Transplantation
30
AML and Transplantation Conclusions

• Autologous and allogeneic transplant improve RFS
  in most studies.
  
• An OS has never been proven in a phase III
  randomized trial of transplant.
  
• Phase III studies of transplant are hampered by
• Donor availability
• Patient drop-out
• Transplant is a moving target with improving
  supportive care, conditioning regimens, GVHD
  proph., etc.

31
Treatment Summary

• Good Risk Cytogenetics
• t(1517) APL-based therapy
• t(821), inv(16), t(1616) Standard induction
  followed by HIDAC based consolidation
  
• Intermediate Risk Cytogenetics
• Standard induction
• Consolidation controversial
• 4 cycles of HIDAC
• Auto- or allo-transplant
• Bad Risk Cytogenetics
• Allogeneic stem cell transplantation in first CR
• Outcomes of transplant in this group of patients
  are not terribly good but better than outcomes
  with chemotherapy alone.

32
Novel Therapies Gemtuzumab Ozogamicin

• A monoclonal anti-CD33 antibody conjugated to
  calicheamicin.
  
• In a phase II study of patients with relapsed
  AML, the CR CRp rate was 30.
  
• Interim analysis of MRC AML 15 (GO vs. no GO)
  DFS 51 vs 40 (p0.008), OS 53 vs. 46 (pNS)
  at 3 yrs.
  

33
Novel Therapies Tipifarnib

• A farnesyltransferase inhibitor.
• An oral drug that inhibits farnesylation and
  subsequent tethering of Ras to the inner leaflet
  of the plasma membrane.
  
• Preliminary results of a multi-center phase II
  study in older patients with AML showed a CR PR
  rate of 34 and a CR rate of 18.
  
• Responses did not correlate with Ras mutational
  status.
  
• The FDA denied approval of this agent given a
  lower than expected response rate.
  
• 2 phase III studies are ongoing
• Tipifarnib vs. best supportive care for elderly
  patients not eligible for chemotherapy.
  
• Tipifarnib vs. observation maintenance in
  patients in first or greater remission who are
  not transplant candidates.

34
Novel Therapies FLT3 Inhibitors

• PKC412
• Phase II single agent study in relapsed or
  refractory FLT3-positive AML
  
• Transient reductions in peripheral blood blasts
  of 50 in 70 of patients.
  
• 50 reductions in bone marrow blast burden in 6
  of 57 patients.
  
• Combination trials ongoing.
• Others
• MLN518
• SU11248
• CEP-701

35
Novel Therapies Others

• Histone Deacetylase Inhibitors
• Proteasome Inhibitors
• AKT / mTor inhibitors
• Clofarabine
• Apoptotic agents
• Genasense
• MDR modulators
• Zosuquidar

36
Treatment of Relapsed and Refractory AML The EPI

• European Prognostic Index
• Relapse-free interval from first CR
• 6 months 5 points
• 7 to 18 months 3 points
• 18 months 0 points
• Original cytogenetics
• Good 0 points
• Intermediate 3 points
• Bad 5 points

• Age at relapse
• 35 0 points
• 36 to 45 1 point
• 45 2 points
• Prior transplant
• No 0 points
• Yes 2 points
• 5-year overall survival
• 1 to 6 points 22 to 46
• 7 to 9 points 12 to 18
• 10 to 14 points 4 to 6

37
Treatment of Relapsed and Refractory AML

• Transplant when possible
• 5 year OS in first relapse or second CR
• First CR 6 months 35.
• First CR
• Primary treatment failure 15
• Beyond second CR or refractory first relapse 5
  
  
• Clinical trials!!!
• Salvage chemotherapy
• MEC
• ME
• HIDAC
• HIDAC L-asparaginase
• Gemtuzumab

38
AML Therapy in the Elderly

• Advanced age is a poor prognostic factor.
• Disease biology different.
• Frequent adverse cytogenetic profile.
• High levels of MDR1 (P-glycoprotein) expression.
• Frequent antecedent hematologic disorder.
• These patients should be referred for a clinical
  trial when possible.

39
AML Therapy in the Elderly

• Standard induction chemotherapy, esp. for
  patients with intermediate or good risk
  cytogenetics.
  
• A phase III trial comparing best supportive care
  and induction chemotherapy with cytarabine,
  daunorubicin, and vincristine demonstrated
  improved survival (21 vs. 11 weeks) and no
  difference in days hospitalized.
• Low-dose cytarabine.
• Similar overall response rate and less toxicity
  c/w cytarabine and rubidazone.