CHRONIC MYELOGENOUS LEUKEMIA The Story Never Ends…

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CHRONIC MYELOGENOUS LEUKEMIAThe Story Never
Ends
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Clinical Presentation of CML

• Asymptomatic in 50 of cases
• Common Symptoms Common Signs
• Fatigue Palpable splenomegaly
• Weight loss/anorexia
• Abdominal fullness
• Common Laboratory Findings
• Abnormal differential
• Anemia
• Leukocytosis
• Basophilia
• Thrombocytosis

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CML Peripheral Blood Smear
Normal
Chronic phase CML
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Clinical Course Phases of CML
Advanced phases
Chronic phase Median duration 56 years
Accelerated phase Median duration69 months
Blast crisis Median survival36 months
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Ph Chromosome
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the Ph Chromosome
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Bcr-Abl Signal Transduction Pathways
Adapted from Kantarjian H et al. Hematology.
200090-109.
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Evaluation of Response to Rx. in CML Patients
MOLECULAR
CYTOGENETIC
HEMATOLOGICAL
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DETECTION OF MINIMAL RESIDUAL DISEASE IN LEUKEMIA

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METHODOLOGIES FOR DETECTING MRD

• Conventional cytogenetics
• FISH
• Nucleic acid amplification techniques
• Qualitative RT-PCR
• Quantitative RT-PCR

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DO YOU PREFER QUALITY TO QUANTITY???
Mathematics is the science of pure quantity but
what about medicine?
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METHODS TO DETECT MRD IN LEUKEMIA
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In the present mangament of leukemias I prefer
quantity to quality
It is the real time for real-time PCR
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Changes in Cytogenetic and Molecular Findings in
a Patient Responding to Rx.
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Historical Rx. for CML

• Palliative
• Arsenic trioxide 1865
• Spleen irradiation - 1903
• Busulfan -1953
• Hydroxyurea -1966
• Interferon alfa ARA -C -mid - 1980s
• Curative
• BMT - alloBMT - 1970s

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NOVEL THERAPEUTIC OPTIONS IN HEMATOLOGIC
MALIGNANCIES
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DRUGS DONT JUST POP OFF THE SHELVES
!!!Specificity in drug development
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Bcr-Abl Signal Transduction Pathways
Adapted from Kantarjian H et al. Hematology.
200090-109.
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IMATINIB
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Drug Gives Hope to Sufferers of Rare Leukemia
Time 28.5.01

• A new drug for treating a form of leukemia is
  
• achieving extraordinary results, restoring
  normal life to patients who believed they had no
  hope
• The patients are feeling well and have almost
  normal blood counts
• STI 571 is an extremely important drug.
• Its effectiveness would inspire more research
  into drugs that will work as well, using the same
  approach in other cancers

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Toxicity minimal

• Nausea
• Arthralgias
• Myalgias
• Hematological toxicities
• Fluid retention - edema

• Abnormal liver function tests
• Diarrhea
• Vomiting
• Fatigue
• Rash

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IRIS Study Design Imatinib Versus IFN-? Ara-C
1106 patients enrolled from June 2000 to January
2001
Imatinib


S
R




IFN
Ara-C


S screeningR randomisation



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Imatinib is Superior to IFN-? Ara-c in Every
Parameter
IRIS Study Summary of the 12-Month Data
Response
CHR complete hematological response MCR
major cytogenetic response PD progressive
disease AP accelerated phase BC blast
crisis.
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Early BCR-ABL Transcript Decline Predicts For
Cytogenetic Response in CML Patients Treated with
Imatinib

• The degree of tumor load reduction as measured by
  cytogenetic response is an important prognostic
  factor for CML patients on therapy
• Because of the high rate of CCyR observed with
  imatinib, the appropriate measure for response is
  molecular remission using RT-PCR

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Correlation Between Cytogenetic Response
(Chromosomal) and Molecular Response )RQ-PCR(

• Major cytogenetic response (MCyR) 1 log
  reduction
• Complete cytogenetic response (CCyR) 2 log
  reduction
• Major molecular response (MMR) gt 3 log reduction
• Good correlation between measurements of BCR-ABL
  transcripts in the marrow and PB
• Nevertheless, cytogenetic analysis should be
  repeated at regular intervals because Ph-negative
  clonal evolution has been observed (MDS?)

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Monitoring patients on imatinib
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Operational Definition of Failure Suboptimal
Response for Patients Treated with IM 400 mg
Daily

• Failure - patient should be moved to other
  treatments whenever available
• Suboptimal response - patient may still have a
  substantial benefit from continuing IM treatment,
  but the long term outcome is not likely to be
  optimal, so that the patient becomes eligible for
  other treatments
• Warnings - patient should be monitored very
  carefully and may become eligible for other
  treatments

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THE IRIS STUDY The Australian Group

• Proposed that a 3-log reduction be defined as a
  major molecular response
• It defined a group with remarkable stability of
  response
• It represented a further 1 log reduction below
  the level of CCyR

lt 0.1
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IRIS Study 7 year follow-up Imatinib arm

• Estimated overall survival _at_ 7 years 86 (94
  considering only CML related deaths)
• Estimated EFS _at_ 7 years 81
• Estimated rate without AP/BC _at_ 7 years 93
• MMR and the depth of molecular response increase
  over time
• No unique, previously unreported adverse event
  attributed to imatinib observed over the past 2
  years
• Imatinib 400 mg daily confirmed as the standard
  of care for the initial therapy of chronic phase
  CML

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Imatinib plasma levels

• In the IRIS trial, patients with low day-29
  imatinib trough concentrations were less likely
  to achieve a CCyR and MMR
• Plasma level monitoring is not currently part of
  routine management
• Measuring plasma concentrations may be useful in
  the case of resistance or unusually severe side
  effects

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Mechanisms of IM Resistance

• Oral biovailability
• Plasma-protein binding
• Changes in intracellular availability of imatinib
• Increased expression of BCR-ABL
• Clonal evolution
• Mutations in the ABL-kinase domain
• Quiescent stem cells

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ABL KINASE DOMAIN MUTATIONS

• The kinase domain of the BCR-ABL oncoprotein is
  identical to the kinase domain of the normal abl
  protein
• It can be divided into 4 parts
• ATP (phosphate) binding pocket P loop
• interveneing secquence
• Catalytic domain
• Activating loop
• Imatinib occupies mainly the P loop

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Resistance workup

• A thorough history to ascertain the patients
  adherence to the prescribed drug regimen
• Measurement of imatinib plasma concentrations
• Once a rise of BCR-ABL transcripts has been
  confirmed and compliance ascertained
• physical exam
• CBC
• bone marrow morphology
• karyotyping
• screening for BCR-ABL kinase domain mutations

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Approaches to Prevent or Overcome Imatinib
Resistance

• Increase imatinib dose to 600 -800 mg
• Combine imatinib with other drugs of known anti
  CML activity
• To use new BCR-ABL inhibitors or others
• BMT

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Novel Agents in CML TherapyTyrosine Kinase
Inhibitors and Beyond

• The emergence of resistance to imatinib has
  become a significant problem
• The most common cause of imatinib resistance is
  the selection of leukemic clones with point
  mutations in the Abl kinase domain that prevent
  the appropriate binding of imatinib

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Novel Agents in CML TherapyTyrosine Kinase
Inhibitors and Beyond

• Single agent therapy with imatinib may not be the
  best long-term option in CML for a proportion of
  patients
• A multitude of novel agents have been developed
• ATP competitive Bcr-Abl tyrosine kinase
  inhibitors
• non-ATPcompetitive Bcr-Abl tyrosine kinase
  inhibitors
• inhibitors acting on targets found in signaling
  pathways downstream of Bcr-Abl
• targets without established links with Bcr-Abl

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Bcr-Abl Signal Transduction Pathways
Adapted from Kantarjian H et al. Hematology.
200090-109.
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IMATINIB
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Second Generation ATP-Competitive Bcr-Abl
Inhibitors

• Nilotinib
• Dasatinib
• Bosutinib
• INNO-406

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Adverse Effects

• Hematologic
• Gastrointestinal
• Pleural / Pericardial Effusion
• Edema
• Rash
• Flushing
• Headaches

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Adverse Effects

• Hematologic
• Gastrointestinal
• Increase in LFT
• Increase in lipase
• Dry skin
• Rash
• Alopecia

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• Dasatinib and nilotinib represent the first of
  the newer generation TKIs which are effective and
  safe
• Subclones with novel Bcr-Abl mutants might
  develop in response to these new small-molecule
  inhibitors
• Therefore, alternative therapeutic approaches are
  required
• These may involve the combination of Bcr-Abl TKIs
  with inhibitors of non-Bcr-Abl targets or targets
  downstream of Bcr-Abl to achieve a synergistic
  effect

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Non-ATP TKI Kinase inhibitors

• ONO12380
• Aurora kinase inhibitor
• MK-0457 (VX-680)
• Pha-739358
• SGX393
• XL228
• AP24534
• AP23846

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T315I Kinase Inhibitors

• ON012380
• MK-0457, formerly known as VX-680, an Aurora
  kinase inhibitor
• Another Aurora kinase inhibitor, PHA-739358
• SGX393 is an azaindole

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• Allosteric Inhibitors
• Heat Shock Protein 90 Inhibitors
• Arsenic Trioxide
• Homoharringtonine
• Histone Deacetylase Inhibitors
• Proteasome Inhibitors
• Cyclin-Dependent Kinase Inhibitors
• DNA-Methyltransferase Inhibitors
• Targeting Pathways Downstream of Bcr-Abl
• Farnesyl Transferase Inhibitors
• Tipifarnib
• Lonafarnib

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Homoharringtonine (HHT)

• HHT is a natural alkaloid derived from certain
  trees and has been in use in China for many years
  for the treatment of AML and CML
• In the pre-imatinib era it was the most
  efficient treatment for interferon-a failures
• HHT inhibits protein synthesis and induces
  apoptosis by bcr/abl independent pathways and
  thus is active in imatinib resistant CML
  including patients with the T315I mutation
• Currently HHT and interferon-a are the only
  available drugs active against cells with the
  T315I mutation

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Omacetaxine (OMA)

• OMA is the semisynthetic derivative of HHT and is
  more available and less expensive
• It is also active against the T315I mutant and
  is currently being tested in Phase II trials in
  TKI-resistant patients with or without the T315I
  mutant
• OMA is given subcutaneously
• Toxicity is mild and manageable and is mainly
  myelosuppression

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The European LeukemiaNet Recommendations for
the Management of CML Revisited The Updated 2009
Version

• M. Baccarani, J. Cortes, F. Pane, D.
  Niederwieser,
• G. Saglio, J. Apperley, F. Cervantes, M.
  Deininger, A. Gratwohl, F. Guilhot, A. Hochhaus,
  M. Horowitz,T. Hughes, H. Kantarjian, R. Larson,
  J. Radich, B. Simonsson, R.T. Silver,
• J. Goldman, and R. Hehlmann

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Present Goal of Therapy in CML

• An aim for 100 survival
• An aim for normal quality of life

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The European LeukemiaNet (ELN) decided

• To review recent results of therapy
• To review standard monitoring procedures
• To review definitions of responses
• To update published recommendations

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Aim

• Optimize management of CML
• Standardize management of CML

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Methods

• Relevant papers that appeared after the
  publication of the original ELN recommendations
• Four panel meetings were held between December
  2007 and December 2008
• Treatment recommendations were limited to the 3
  registered TKIs alloHSCT

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Summary and Update of Imatinib Clinical Results

• The advantage of imatinib 400 mg daily compared
  with IFN- and LD-ARA-C was confirmed
• With a follow-up of 7 years imatinib was
  discontinued for
• Adverse events 5
• Lack of efficacy 15
• Other reasons 20

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Summary and Update of Imatinib Clinical Results

• 75 of patients with CCgRs have maintained the
  response so far
• The 6-year EFS -83
• The 6-year PFS -93
• The 6-year OS 88
• From 4th year - all the curves showed a tendency
  to plateau

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Imatinib Dose Issues

• The French SPIRIT Study
• Borderline superiority of imatinib 600 mg
  compared with 400 mg _at_ 12 months
• CCgR rate- 65vs. 57
• MMolR rate - 52 vs. 40
• Novartis-sponsored study
• Significant superiority for 800 mg over 400 mg
  regarding MMolR rate
• _at_ 3 months - 12 vs. 3
• _at_ 6 months - 34 vs. 17
• _at_ 9 months - 45 vs. 33
• BUT not _at_ 12 months - 46 vs. 40

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Imatinib Dose Issues

• An ELN study of high risk patients according to
  Sokal
• Did not show a significant superiority of
  imatinib 800 mg compared with 400 mg
• CCgR _at_ 12 months - 64 vs. 58
• MMolR _at_12 months - 40 vs. 33,

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Combination With Other Agents

• Imatinib is being tested in combination with IFN-
  and AraC
• The French SPIRIT Study
• 636 pts. with early chronic phase
• imatinib 400 mg
• imatinib 600 mg
• Imatinib 400 mg with pegylated IFN-2a
• Imatinib 400 mg with LD-AraC
• Best response in the arm with imatinib plus IFN
• However, 46 of patients discontinued IFN- during
  the 1st year

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Resistance and BCR-ABL1 Kinase Domain Mutations

• Advanced stage -resistance frequently associated
  with point mutations
• Chronic phase - resistance associated with point
  mutations in lt50 of pts.
• The poorer outcome of patients with P-loop
  mutations remains controversial
• T315I mutation is a marker of failure for all the
  available TKIs
• Methods to identify mutations
• DHPLC
• direct sequencing

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Treatment Discontinuation and Interruption

• 6/12 patients who were in CMolR for more than 2
  years did not experience relapse _at_ 9 - 24 months
• They had been pretreated with IFN
• The 6/12 patients who experienced relapse had
  been treated with imatinib only
• Two subsequent report did not show association
  with IFN pre-treatment

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Prognostic FACTORS
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Imatinib First Line - Baseline Prognostic Factors

• The prognostic classifications of Sokal / Hasford
  is valid for imatinib treatment
• In the IRIS study differences were significant
  according to Sokal regarding
• 12 months CCgR rates MmolR rates
• 6-year OS, PFS EFS rates
• Once a CCgR was achieved, outcome was not
  affected by pretreatment risk score

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Imatinib First Line - Baseline Prognostic Factors

• Del 9q- not confirmed as prognostic factor
• Variant translocations were not significant
• Other CCA/Ph predict shorter PFS OS

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Imatinib First Line, Response-Related Prognostic
Factors

• _at_ 3 mos. - failure to achieve a CHR
• The probability of achieving a CCgR is small
• The 5-year OS PFS significantly shorter
• _at_ 3 mos.- completely Ph
• low probability of achieving a CCgR later on
• _at_ 6 mos. - 95 Ph
• low chance of subsequent CCgR MMolR

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Imatinib First Line, Response-Related Prognostic
Factors

• _at_ 12 mos. - CCgR better than PCgR PCgR better
  than less than PCgR
• _at_ 18 mos. MMolR predicts for better 6-yr. EFS
• Loss of CHR/CCgR predicts shorter PFS OS
• Loss of MMolR - prognostic value controversial
• Increase in transcript level - closer monitoring

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Imatinib First Line, Response-Related Prognostic
Factors

• The detection of a kinase domain mutation
• The prognostic value of CCA/Ph- is not clear
• An evolution towards AML or MDS lt10, mainly
  those with -7

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Dasatinib Nilotinib, Baseline Response
Related Prognostic Factors

• In imatinib-intolerant patients
• No data predicting the response to dasatinib
  nilotinib at baseline
• In imatinib-resistant patients
• Reduced probability of response to dasatinib
  nilotinib
• Responses to dasatinib nilotinib should be
  rapid
• Detection of a new mutation during treatment with
  dasatinib nilotinib is important

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• Cytogenetics
• should be performed by chromosome banding
  analysis of marrow cell metaphases until CCgR has
  been achieved
• Interphase FISH
• Cannot be used to assess CR
• Can substitute for chromosome banding analysis to
  monitor the completeness of a CCgR

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Response Definitions

• Optimal response
• No indication to change therapy
• Survival close to 100 _at_ 6-7 years
• Suboptimal response
• The patient may still have a substantial
  long-term benefit from continuing a specific
  treatment
• The chances of an optimal outcome are reduced
• Failure
• A favorable outcome is unlikely
• The patient should receive a different treatment
• Warning
• Characteristics of the disease may adversely
  affect the response to that therapy
• Requires close monitoring

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• A new definition of optimal response
• An earlier definition of
• suboptimal response - cytogenetic resistance _at_ 3
  mos.
• failure - hematologic resistance _at_ 3 mos.
• failure - Cytogenetic resistance _at_ 6 mos.
• del9q - no longer a warning
• CCA/Ph
• at diagnosis - warning factor
• during treatment -a marker of treatment failure
• The significance of increase in transcript level
  2 -10

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• Hydroxyurea may be used only for a short period
• IFN- is still an option in case of pregnancy
• The standard dose of imatinib in CML-CP is 400 mg
  daily

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Provisional but warranted
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SUMMARY
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CML Historical Context Until 2000

• Fatal disorder with poor prognosis
• Median survival 3-5 years
• Allogeneic SCT curative in 40 to 70 of patients
• Associated with mortality and toxicity
• IFN alfa cytarabine CCyR of 20 to 30
• Median survival 6-7 years
• Also associated with adverse events
• Other options hydroxyurea, busulfan

Faderl S, et al. N Engl J Med. 1999131207-219.
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CML Clinical Perspective Since 2000

• Indolent disorder with excellent prognosis
• Estimated 5-year survival 90
• Median survival excellent, potentially
  multi-decade
• Functional cure
• Frontline treatment imatinib mesylate
• Second-line, postimatinib failure allogeneic SCT
• Evolving role of novel TKIs dasatinib, nilotinib

Druker BJ, et al. N Engl J Med.
20013441031-1037.
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Overview of Historical vs Modern Perspective
Faderl S, et al. N Engl J Med. 1999131207-219.D
ruker BJ, et al. N Engl J Med. 20013441031-1037.
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Survival in Early Chronic-Phase CML
1.0
0.8
90
0.6
Proportion Surviving
0.4
0.2
0.0
0
3
6
9
12
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Years From Referral
University of Texas M.D. Anderson Cancer Center
Database 1965-2005
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Historic Development of CML Therapy
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Historical Aspects of CML From Bennet to
Druker 160 Years of Attempts to Treat Cure
CML

• 1st description Hughes Bennet - lucocythaemia
  Edinburgh, 1845
• 2nd description Robert Virchow -
  leukämieBerlin, 1858
• Origin in BM Neumann, 1869
• Minot 166 cases of CML , 1924
• Whitby Britton comprehensive description of
  the clinical picture, 1935
• Bernard The term for blastic crisis,
  metamorphosis, 1959
• Nowell Hungerford description of the
  Philadelphia chromosome, 1960
• Janet Rowley describes the translocation
  t(922), 1973
• Bartram-Characterization of the BCR-ABL fusion
  gene, 1983
• BCR-ABL transfected BM cells induced leukemia in
  mice, 1990
• Druker - Gene targeted Rx , 1998

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IMATINIB STILL THE BEST TREATMENT FOR CML

• Dont Change Winning Horses !

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Final Decision, even more in the Imatinib
era Patient-physician shared decision
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CML"This is not the end, it is not even the
beginning of the end. But it is, perhaps, the end
of the beginning." London, November 10,
1942