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Targeted Therapies for Acute Myelogenous Leukemia _AML

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Targeted Therapies for Acute Myelogenous Leukemia _AML Powered By Docstoc
					Targeted Therapies for Acute
Myelogenous Leukemia (AML)

   David Kuperman, M.D.
   Fellow in Hematology/Oncology
   Washington University in St. Louis
   6/17/05
Acute Myelogenous Leukemia
 Acute Myelogenous Leukemia (AML) is a lack
  of differentiation and proliferation of myeloid
  precursor cells.
 AML is the most common acute leukemia in
  adults.
 It can be primary malignancy or it can evolve
  out of a myelodysplastic syndrome.
 The incidence is about 2.7 cases per
  100,000.
 Morphologically there are 8 different subtypes
  by the FAB classification system
Lowenberg, B. et al. N Engl J Med 1999;341:1051-1062
Acute Myelogenous Leukemia
 More   important than the morphology of
  the cells are the genetic abnormalities
  seen in the leukemic cells.
 These abnormalities play an essential
  role in the prognosis and treatment of
  these malignancies.
Standard Therapy for AML
 Standard therapy for AML is based on
  cytotoxic chemotherapy.
 Typically the patient will require induction
  therapy followed by consolidation with high
  dose chemotherapy or bone marrow
  transplant.
 The standard induction regimen is continuous
  infusion cytarabine and an athracycline (7 +
  3).
Standard Therapy for AML
 Approximately   60 to 80% of patients will
  receive a complete response with this
  regimen.
 Unfortunately, this is a very aggressive
  form of therapy requiring hospitalization
  for at least 3 weeks due to neutropenia
  and thrombocytopenia and a high rate
  of neutropenic fever/sepsis.
Standard Therapy for AML
 There  is a lot of room for improvement
  when it comes to long term survival.
 In health patients below the age of 55
  with good, intermediate, and poor
  cytogenetics; the 5 year survivals are
  70%, 48%, and 15% respectively
  receiving aggressive treatment.
Standard Therapy for AML
 These results are much poorer in those who
  most commonly get AML, i.e. patients over 60
  years of age.
 They have a poor outcome with conventional
  therapy.
 With standard 7 + 3 induction therapy,
  approximately 47% of patients over the age
  of 60 with good performance status achieved
  a complete response.
Standard Therapy for AML
 The  median survival of those over the
  age of 60 is 7 to 15 months.
 The differences in outcomes in older
  patients is often attributed to the higher
  frequency of poor cytogenetics in these
  patients and the inability to tolerate
  aggressive cytotoxic chemotherapy.
Promise of Targeted Therapy
 The goal of targeted therapy is to
  maximize the treatment of leukemia with
  fewer side effects.
 As we have learned more about the
  development of leukemia, we have
  developed new targets for therapy.
Promise of Targeted Therapy
 These   targets can be divided into
  several groups:
 Surface markers identifying the
  leukemia.
 Processes that lead to abnormal Cell
  differentiation.
 Processes that lead to abnormal Cell
  proliferation.
Surface markers
 One    cell surface protein that is more
  commonly found on leukemic cells is
  CD33.
 CD33 is expressed on >90% of
  leukemic cells.
 It is also expressed, to a much lesser
  degree, on normal granulocyte,
  monocyte, and erythroid precursors.
Gemtuzumab ozogamicin
 Gemtuzumab     ozogamicin (Mylotarg) is
  a humanized mouse monoclonal
  antibody which is linked to calichamicin.
 It binds to CD33 and is rapidly
  integrated into the leukemic cell.
 It has been used successfully to treat
  AML.
Gemtuzumab ozogamicin
 In three phase II trials examined by Severs et
  alia, 142 patients with AML in first relapse
  were treated with 2 infusions of gemtuzumab
  9 mg/m2 given 2 weeks apart.
 30% of patients had a CR.
 Subgroup analysis showed 34% under the
  age of 60 had a CR while 26% of those over
  60 had a CR.
Gemtuzumab ozogamicin
 The median survival was 5.9 months
  and the one year survival was 13%.
 Significant toxicity, however, was
  reported.
 Severe myelosuppression was the rule.
 Grade III or IV hyperbilirubinemia
  occurred in 23%.
 Elevated LFT’s occurred in 17%.
Gemtuzumab ozogamicin
 Reports of Venocclusive disease have
  also been reported.
 Gemtuzumab is now FDA approved for
  AML patients over the age of 60 in first
  relapse who are not considered
  candidates for cytotoxic chemotherapy.
Processes that lead to
abnormal Cell differentiation
 The model for this therapy is based on Acute
  Promyelocytic Leukemia (APL).
 In APL, a gene for a retinoic acid receptor is
  fused with another gene.
 This leads to the formation of a complex that
  prevents the transcription of genes necessary
  to lead to differentiation past the
  promeylocyte stage.
Processes that lead to
abnormal Cell differentiation
 When   these patients are given all trans
  retinoic acid (ATRA), the gene product
  preferentially binds to the ATRA
  allowing the genes necessary for
  differentiation to be transcribed.
 Because of this targeted therapy, APL
  has the highest 5 year survival rate of
  any acute leukemia.
Processes that lead to
abnormal Cell differentiation
 We  are trying to duplicate the success
  of APL in the other acute myelogenous
  leukemias.
 Unfortunately, the other AML’s are
  much more diverse cancers.
 We do, however, have some targets.
Histones
 DNA    is found wrapped around proteins
  called histones.
 Off of the many body of the histones, a
  tail is found.
 This tail consists of evolutionary
  conserved lysine, arginine and serine
  residues.
Histones
 The  tail can be modified by enzymes
  that alter the ability for the DNA to be
  transcribed.
 One of the most important modifications
  is acetylation.
 By adding acetyl groups to the lysines,
  the histone is relaxed and can be
  transcribed.
Histones
 By removing the acetyl groups, the
 histone complex is compressed leading
 to the inability to transcribe it.
Histone Deacetylase Inhibitors
 Since many of the genetic abnormalities
 in AML lead to inability to transcribe
 important genes that lead to
 differentiation by a transcriptional
 repressor complex which includes a
 HDAC, these are tempting targets.
Histone Deacetylase Inhibitors
 Several  inhibitors have been tried in
  phase I trials.
 Thus far they have had very limited
  results.
DNA Methylation
 Methylation  is the addition of methyl
  groups to CpG islands.
 In analysis of leukemic cells,
  hypermethylation of promoter genes
  have been shown to be associated with
  disease progression and worse
  outcomes.
DNA Methylation
 Itis most likely from silencing tumor
  suppressor genes and preventing
  differentiation.
Demethylation Therapy
 Decitabine   is a pyramidine analog when
  integrated into DNA irreversibly binds to
  methyltransferases.
 This leads to hypomethylation which
  promotes tumor suppressor genes and
  differentiation.
 In one phase I trial in patients with AML,
  8 of 35 patients had a response.
Demethylation Therapy
 The drug was well tolerate with the most
  common difficulty being prolonged
  neutropenia.
 This is currently in Phase II clinical trial.
Processes that lead to
Abnormal Cell Proliferation
 Processes   that lead to abnormal cell
  proliferation are good targets for
  therapy.
 Several tyrosine kinases involved in
  proliferation are overexpressed in AML.
 Two of the most prominent are FLT-3
  and RAS.
FLT-3
 FLT-3  is a receptor tyrosine kinase.
 It is mutated in about 30% of AML.
 This mutation causes overactivity of the
  FLT-3 which leads to proliferation.
FLT-3 inhibitors
 There are currently 4 FLT-3 tyrosine
  kinase inhibitors in clinical trial:
 PKC-412 (Novartis)
 CEP-701 (Cephalon)
 MLN-518 (Millenium)
 SU11248 (SuGen)
Agent     Number of   Number of              Percentage of
          Patients    Responses              response


PKC412    8           6 (decreased
                      blasts in peripheral
                      blood)
SU11248   16          13 (decreased
                      blasts in peripheral
                      blood)
SU11248   29                                 >50% with
                                             reduction in FLT-3
                                             activity
CEP-701   5           1 (CRp)
MLN518    6                                  66% (decreased
                                             blasts in peripheral
                                             blood)
FLT-3 Inhibitors
         in trial combined with cytotoxic
 Currently
 chemotherapy.
RAS
 Mutations   in RAS leading to overactivity
  occur in about 50% of AML.
 In order for RAS to be active, it must
  first must have a farnesyl group
  transferred to it.
Farnesyl Transfer Inhibitors
(FTI)
A  number of trials have been under
  taken with FTI.
 One of the most studied in AML is
  R115777 (Zarnestra).
 Zarnestra is an oral FTI taken twice a
  day.
 The initial results have been very
  promising.
Farnesyl Transfer Inhibitors
A  phase I study showed a response in
  10 of 34 patients with poor risk AML.
 The primary toxicities were leukopenia
  and reversible neurotoxicity at high
  doses.
 A phase II study of zarnestra is currently
  undergoing.
Farnesyl Transfer Inhibitors
 In this trial, patients with refractory or
  relapsed AML are receiving zarnestra 600 mg
  po BID for 21 days of a 4 week cycle.
 We have some initial results back from this
  trial.
 Of the 50 patients analyzed, 17 had less than
  5% blasts in the marrow and 31 had a >50%
  reduction in bone marrow blasts.
Farnesyl Transferase
Inhibitors
 Inanother phase II trial currently
  underway, untreated patients >60 are
  being treated with zarnestra.
In Summary…
 There   are many new drugs currently in
  trial for AML.
 While most of the results are
  preliminary, some appear quite
  promising.
References
 P. Bernasconi,et alia, Molecularly Targeted
  Therapy in Acute Myelogenous Leukemia.
  Annals of the New York Academy of Sciences
  1028 (2004), pp. 409–422.
 J. Lancer and J. Karp, Farnesyl transferase
  inhibitors in myeloid malignancies. Blood
  Reviews 17 (2003), pp. 123-129.
 B. Lowenberg, et alia, Medical Progress:
  Acute Myeloid Leukemia. NEJM 341 (1999),
  pp. 1051-1062.
References
   F. Ravandi, et alia, New agents in acute
    myeloid leukemia and other myeloid
    disorders. Cancer 100 (2003), pp. 441-454.
   M. Tallman, et alia, Drug Therapy for Acute
    Myeloid Leukemaia. Blood (2005),
    Published Online May 3, 2005.
   ASH Education Book
   UpToDate

				
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