CML and Resistance to Gleevec

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CML and Resistance to Gleevec

• Geoffrey L. Uy

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Case Presentation

• Pt is 60 y/o WF was incidentally found to have an
  elevated WBC 70K composed of predominantly
  mature neutrophils during routine screening
  examination.

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Case Presentation

• Bone marrow aspirate confirmed the diagnosis of
  CML with 20/20 cells demonstrating the presence
  of t(922)(q34q21). She was treated with
  Gleevec at 400 mg per day with normalization of
  her blood counts.

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Philadelphia chromosome
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(No Transcript)
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Mechanism of Action of Gleevec
BCR-ABL
BCR-ABL
ATP
Gleevec
Substrate
Substrate
P
P
P
P
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International Randomized Interferon Versus STI571
(IRIS)OBrien, S.G. et al. N Engl J Med
2003348994-1004.

• Phase III trial comparing Gleevec with IFN-a
  combined with Ara-C
• 1106 patients in 16 countries with newly
  diagnosed, previously untreated, Ph CML in
  chronic phase
• Crossover design with time to progression as
  primary endpoint

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Response Rates to Gleevec
Complete Cytogenetic Response
Hematologic Response
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Time to Progression
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Frequency of Major Molecular Responses
Hughes, T.P et al. N Engl J Med 20033491423-32.
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Progression-Free Survival by Molecular Response
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Case Presentation

• At 6 months after the patient started Gleevec, a
  bone marrow biopsy was performed which showed
  persistence of the Ph chromosome in 8/40 cells.

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Definitions of Resistance

• PRIMARY RESISTANCE
• Absence of hematologic response within 3 months
• Failure to achieve at least minor cytogenetic
  response at 3 months
• Failure to achieve major cytogenetic response
  after 6 months
• Failure to achieve a complete cytogenetic
  response after 12 months

• ACQUIRED RESISTANCE
• Loss of hematologic response
• Loss of complete cytogenetic response
• Increase of 30 or more in number of Ph marrow
  metaphases
• Acquired cytogenetic abnormalities in the Ph
  clone
• Increase in the BCR-ABL/control gene ratio of one
  log or more on serial testing

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• Increase dose of Gleevec
• Allogeneic Transplant
• Add a second agent
• Change to INF Ara-C

Current Treatment Options For Incomplete Response
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High-dose imatinib mesylate therapy in newly
diagnosed Ph chronic phase CMLKatarijan et al.
Blood 2004 1032873-2878

• 114 patients with newly diagnosed CML treated
  with Gleevec 400 mg BID compared to historical
  controls (n50)
• Response Study Historical
• (n114) (n50)
• Compete Hematologic 112 (98) 49 (98)
• Cytogenetic
• Complete 103 (90) 37 (74)
• Partial 6 (5) 9 (18)
• Molecular (n112 46)
• Major (lt 0.05) 71 (63) 26 (56)
• Complete 31 (28) 10 (22)

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Responses to High Dose Gleevec
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Progression Free Survival
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Case Presentation

• At 12 months after the initial diagnosis, the
  patient remains in chronic phase with a normal
  WBC. She undergoes another bone marrow biopsy.
  At this time, 18/20 cells are Ph.

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Mechanisms of Resistance in CML

• BCR-ABL enzymatic activity restored in vast
  majority of patients with relapsed disease
• BCR-ABL remains essential for leukemic potential
• Emphasizes the importance of identifying and
  targeting Gleevec

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Gene Amplification
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Decreased Intracellular Concentration of Imatinib

• Drug inactivation by binding to plasma proteins
  (alpha-1-acid glycoprotein)
• Drug efflux by p-glycoprotein

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BCR-ABL Mutations

• Detected in up 90 of patients who develop
  secondary resistance to Gleevec
• Rare in patients with primary resistance
• Caveat PCR techniques used may only identify
  most dominant clonses

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BCR-ABL Kinase Domain Mutations
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Kinase Domain Mutations

• Evidence for clonal selection of preexisting
  BCR-ABL selection
• Sequences upstream of kinase domain do not show
  additional mutations
• Multiple independent BCR-ABL mutations found in
  several patients who relaps within 3 months of
  therapy
• Oligonucleotide-PCR to detect specific mutations

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Strategies to Overcome Gleevec Resistance

• Novel BCR-ABL kinase inhibitors
• Target other aspects of BCR-ABL protein
• Inhibit downstream signaling

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New Compounds

• Hsp-90 Inhibitors
• Geldamycin (17-AAG)
• Farnesyl Transferase Inhibitors
• Downregulate Ras-MAPK pathway
• SRC/ABL kinase inhibitors
• PD166326 Can bind both inactive and active abl
  conformations
• BMS-354825 Active against 14/15 imatinib
  resistant BCL-ABL isoforms including all
  mutations located in phosphate binding P-loop

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Conclusions

• Based on diversity of mutations and mechanisms
  causing imatinib resistance unlikely that a
  single agent will be effective
• Identification of resistance mechanisms may be
  able to guide therapy in future