CHRONIC MYELOGENOUS LEUKEMIA The Story Never Ends

1. CHRONIC MYELOGENOUS LEUKEMIAThe Story Never Ends… ?????? ????? ?????? ?? ?????? ????? ????????? ?????? ???? ???? CML ?? ????? ???? ?????? ?"? IMATINIB?????? ????? ?????? ?? ?????? ????? ????????? ?????? ???? ???? CML ?? ????? ???? ?????? ?"? IMATINIB

2. 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

3. CML: Peripheral Blood Smear

4. Clinical Course: Phases of CML 

5. Ph Chromosome

6. the Ph Chromosome

8. Bcr-Abl Signal Transduction Pathways

9. Evaluation of Response to Rx. in CML Patients ?????? ???? ????? ?????? ?????? ?????? ????? CML ????? ????????? ????? ???? ????? ??? "??????? ????? ????????? ????? ???? ??? ???? ????????? ???????? ????? ????????? ????? ???? ??? ???? ?????????? BCR-ABL ??????? ??????????? ?????? ?????? ???? ????? ?????? ?????? ?????? ????? CML ????? ????????? ????? ???? ????? ??? "??????? ????? ????????? ????? ???? ??? ???? ????????? ???????? ????? ????????? ????? ???? ??? ???? ?????????? BCR-ABL ??????? ??????????? ??????

13. DETECTION OF MINIMAL RESIDUAL DISEASE IN LEUKEMIA 

14. METHODOLOGIES FOR DETECTING MRD Conventional cytogenetics FISH Nucleic acid amplification techniques Qualitative RT-PCR Quantitative RT-PCR

16. METHODS TO DETECT MRD IN LEUKEMIA ?????? ???????? ?????? ???? ?????? ???????? ?-CML ??????: ?????????? ????? -??? ???? ????? ??????? ????????. ?????? ????? ???? ?? ??? ?? ?? ??? ???? ??????? ???????, ??????? ???? ????? - ??? 1-10% ?????? ?????? ??? ???????. ?? ???, ????? ?? ????? ????? ?-gold standard, ???? ??? ?????? ????? ?????? ???????????? ?????? ??????? ?? ????????. ???? ?-FISH ?????? ?"? ????? ?????? ??? ?????? BCR-ABL ???? ?-DNA, ??? ?????? ?? ?? ????? ??? ???, ??????? ??? ??? 0.2 - 5% ?????? ?????? ??? ??????? ?????? ?-RT-PCR ?????? ?? ????? ?-multiplex/ nested/ quantitative PCR. ????? ?-MULTIPLEX ??? ????? ????? ??????, ???? ?????? ?-nested ???????? ???????? ?? ????? ?????? ?? ????? ?? ???? ??? ??? 100,000 - 1,000,000 ???? ??????. ????? ?????? ?? ????? ?-multiplex ??-nested ???? ????? ????? ?-band ????? ??? ???? ????? ??????????.?????? ???????? ?????? ???? ?????? ???????? ?-CML ??????: ?????????? ????? -??? ???? ????? ??????? ????????. ?????? ????? ???? ?? ??? ?? ?? ??? ???? ??????? ???????, ??????? ???? ????? - ??? 1-10% ?????? ?????? ??? ???????. ?? ???, ????? ?? ????? ????? ?-gold standard, ???? ??? ?????? ????? ?????? ???????????? ?????? ??????? ?? ????????. ???? ?-FISH ?????? ?"? ????? ?????? ??? ?????? BCR-ABL ???? ?-DNA, ??? ?????? ?? ?? ????? ??? ???, ??????? ??? ??? 0.2 - 5% ?????? ?????? ??? ??????? ?????? ?-RT-PCR ?????? ?? ????? ?-multiplex/ nested/ quantitative PCR. ????? ?-MULTIPLEX ??? ????? ????? ??????, ???? ?????? ?-nested ???????? ???????? ?? ????? ?????? ?? ????? ?? ???? ??? ??? 100,000 - 1,000,000 ???? ??????. ????? ?????? ?? ????? ?-multiplex ??-nested ???? ????? ????? ?-band ????? ??? ???? ????? ??????????.

18. Changes in Cytogenetic and Molecular Findings in a Patient Responding to Rx.

19. 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

21. NOVEL THERAPEUTIC OPTIONS IN HEMATOLOGIC MALIGNANCIES

22. DRUGS DON’T JUST POP OFF THE SHELVES !!!Specificity in drug development

23. Bcr-Abl Signal Transduction Pathways

24. IMATINIB

27. 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”

28. Toxicity minimal Nausea Arthralgias Myalgias Hematological toxicities Fluid retention - edema Abnormal liver function tests Diarrhea Vomiting Fatigue Rash

29. IRIS Study Design:  Imatinib Versus IFN-? + Ara-C [slide 52] IRIS Study Design: Imatinib Versus IFN-? + Ara-C1 From June 2000 to January 2001, 1106 patients were enrolled in the IRIS study. This was the largest and most rapidly accrued phase III CML study. The IRIS Study (106) protocol allows for a cross-over in the case of lack of response, loss of response, or intolerance of treatment. After interim analysis of the trial data, the IRIS study initial protocol was amended by the Independent Data Monitoring Board (IDMB) to enable patients in the IFN-? + Ara-C arm of the study to switch to imatinib if no MCR had occurred after 1 year of treatment (instead of 2 years as initially proposed in the protocol). Reference 1. Data on file. Novartis Pharma AG, Basel, Switzerland.[slide 52] IRIS Study Design: Imatinib Versus IFN-? + Ara-C1 From June 2000 to January 2001, 1106 patients were enrolled in the IRIS study. This was the largest and most rapidly accrued phase III CML study. The IRIS Study (106) protocol allows for a cross-over in the case of lack of response, loss of response, or intolerance of treatment. After interim analysis of the trial data, the IRIS study initial protocol was amended by the Independent Data Monitoring Board (IDMB) to enable patients in the IFN-? + Ara-C arm of the study to switch to imatinib if no MCR had occurred after 1 year of treatment (instead of 2 years as initially proposed in the protocol). Reference 1. Data on file. Novartis Pharma AG, Basel, Switzerland.

30. Imatinib is Superior to IFN-? + Ara-c in Every Parameter [slide 68] Imatinib Is Superior to IFN-? + Ara-C in Every Parameter1 By all parameters measured, imatinib is significantly superior to IFN-a and low-dose Ara-C. This includes the rates of CHR, MCR, prevention of progression to accelerated phase or blast crisis, and intolerance of therapy. Reference 1. Data on file. Novartis Pharma AG, Basel, Switzerland.[slide 68] Imatinib Is Superior to IFN-? + Ara-C in Every Parameter1 By all parameters measured, imatinib is significantly superior to IFN-a and low-dose Ara-C. This includes the rates of CHR, MCR, prevention of progression to accelerated phase or blast crisis, and intolerance of therapy. Reference 1. Data on file. Novartis Pharma AG, Basel, Switzerland.

31. 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 It is well known that the degree of tumor load reduction as measured by cytogenetic response is an important prognostic factor for CML patients treated with IFN or BMT. Since the majority of CML patients treated with imatinib achieve major cytogenetic response, the appropriate method to measure response and compare between patients is RT-PCR. It is well known that the degree of tumor load reduction as measured by cytogenetic response is an important prognostic factor for CML patients treated with IFN or BMT. Since the majority of CML patients treated with imatinib achieve major cytogenetic response, the appropriate method to measure response and compare between patients is RT-PCR.

32. 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) > 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?)

33. Monitoring patients on imatinib

34. 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

35. 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

36. IRIS Study – 7 year follow-up: Imatinib arm Estimated overall survival @ 7 years: 86% (94% considering only CML related deaths) Estimated EFS @ 7 years: 81%: Estimated rate without AP/BC @ 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 Aug-12 36

41. 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 Aug-12 41

42. May 2007 42 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

43. May 2007 43

44. May 2007 44

45. 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

47. May 2007 47

48. Resistance workup A thorough history to ascertain the patient’s 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 Aug-12 48

49. 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

50. Novel Agents in CML Therapy:Tyrosine 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 Aug-12 50

51. Novel Agents in CML Therapy:Tyrosine 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-ATP–competitive Bcr-Abl tyrosine kinase inhibitors inhibitors acting on targets found in signaling pathways downstream of Bcr-Abl targets without established links with Bcr-Abl Aug-12 51

52. Bcr-Abl Signal Transduction Pathways

53. IMATINIB

54. Second Generation ATP-Competitive Bcr-Abl Inhibitors Nilotinib Dasatinib Bosutinib INNO-406 Aug-12 54

57. Adverse Effects Hematologic Gastrointestinal Pleural / Pericardial Effusion Edema Rash Flushing Headaches

61. Adverse Effects Hematologic Gastrointestinal Increase in LFT Increase in lipase Dry skin Rash Alopecia

62. Aug-12 62

63. 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 Aug-12 63

64. Non-ATP TKI Kinase inhibitors ONO12380 Aurora kinase inhibitor: MK-0457 (VX-680) Pha-739358 SGX393 XL228 AP24534 AP23846 Aug-12 64

65. 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 Aug-12 65

66. Aug-12 66

67. 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 Aug-12 67

68. 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 

69. 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

70. 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 August 12 70

71. Present Goal of Therapy in CML An aim for 100% survival An aim for normal quality of life August 12 71

72. 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 August 12 72

73. Aim Optimize management of CML Standardize management of CML August 12 73

74. 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 August 12 74

75. August 12 75

76. 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% August 12 76

77. 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 August 12 77

78. Imatinib Dose Issues The French SPIRIT Study: Borderline superiority of imatinib 600 mg compared with 400 mg @ 12 months: CCgR rate- 65%vs. 57% MMolR rate - 52% vs. 40% Novartis-sponsored study: Significant superiority for 800 mg over 400 mg regarding MMolR rate: @ 3 months - 12% vs. 3% @ 6 months - 34% vs. 17% @ 9 months - 45% vs. 33% BUT not @ 12 months - 46% vs. 40% August 12 78

79. 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 @ 12 months - 64% vs. 58% MMolR @12 months - 40% vs. 33%, August 12 79

80. 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 August 12 80

81. Resistance and BCR-ABL1 Kinase Domain Mutations Advanced stage -resistance frequently associated with point mutations Chronic phase - resistance associated with point mutations in <50% 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 August 12 81

82. August 12 82

83. Treatment Discontinuation and Interruption 6/12 patients who were in CMolR for more than 2 years did not experience relapse @ 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 August 12 83

84. August 12 84

85. 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 August 12 85

86. 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 August 12 86

87. Imatinib First Line, Response-Related Prognostic Factors @ 3 mos. - failure to achieve a CHR: The probability of achieving a CCgR is small The 5-year OS & PFS significantly shorter @ 3 mos.- completely Ph+: low probability of achieving a CCgR later on @ 6 mos. - 95% Ph+: low chance of subsequent CCgR & MMolR August 12 87

88. Imatinib First Line, Response-Related Prognostic Factors @ 12 mos. - CCgR better than PCgR & PCgR better than less than PCgR @ 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 August 12 88

89. 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 <10%, mainly those with -7 August 12 89

90. 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 August 12 90

91. 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 August 12 91

92. Response Definitions Optimal response No indication to change therapy Survival close to 100% @ 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 August 12 92

93. A new definition of optimal response An earlier definition of: suboptimal response - cytogenetic resistance @ 3 mos. failure - hematologic resistance @ 3 mos. failure - Cytogenetic resistance @ 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 August 12 93

94. 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 August 12 94

95. August 12 95

96. Provisional but warranted… August 12 96

97. August 12 97

98. SUMMARY

99. 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 CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; IFN, interferon; SCT, stem cell transplantation. Chronic myeloid leukemia used to be a fatal disorder that, with rare exception, carried a poor prognosis. In the 1980s, median survival was 3-4 years. The only curative treatment was allogeneic stem cell transplantation, which was available to 40% to 70% of patients. However, transplantation was also toxic and associated with significant mortality and morbidity. Long-term survival did not exceed 50%, even with a matched donor. For patients who underwent unrelated-donor transplantation, survival rates were even lower. Interferon alpha was introduced in 1980. In combination with cytarabine, it produces complete cytogenetic response rates from 20% to 30% and a median survival of 5-7 years. In a clinical trial conducted at the University of Texas M.D. Anderson Cancer Center in Houston, median survival was slightly longer than 7 years, but the interferon/cytarabine combination produced severe adverse effects and was difficult to administer. Other treatment options include hydroxyurea and busulfan, but these drugs only maintain the disease rather than treat it.CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; IFN, interferon; SCT, stem cell transplantation. Chronic myeloid leukemia used to be a fatal disorder that, with rare exception, carried a poor prognosis. In the 1980s, median survival was 3-4 years. The only curative treatment was allogeneic stem cell transplantation, which was available to 40% to 70% of patients. However, transplantation was also toxic and associated with significant mortality and morbidity. Long-term survival did not exceed 50%, even with a matched donor. For patients who underwent unrelated-donor transplantation, survival rates were even lower. Interferon alpha was introduced in 1980. In combination with cytarabine, it produces complete cytogenetic response rates from 20% to 30% and a median survival of 5-7 years. In a clinical trial conducted at the University of Texas M.D. Anderson Cancer Center in Houston, median survival was slightly longer than 7 years, but the interferon/cytarabine combination produced severe adverse effects and was difficult to administer. Other treatment options include hydroxyurea and busulfan, but these drugs only maintain the disease rather than treat it.

100. 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 CML, chronic myeloid leukemia; SCT, stem cell transplantation; TKI, tyrosine kinase inhibitor. The prognostic outlook for patients with CML has changed dramatically since the introduction of tyrosine kinase inhibitor therapy. Whereas median survival was 3-4 years before tyrosine kinase inhibitor therapy, 90% of patients are now alive at 5 years. Interestingly, one half of the patients who die within 5 years of being diagnosed do so from reasons other than the disease itself. This is not an age-adjusted statistic. Therefore, the current mortality rate from CML is actually 5% at 5 years, and this number continues to decline. The relative mortality risk per year was higher in Years 1 and 2 than in Years 3, 4, and 5. Median survival may be closer to 25 years, although this could easily extend to 40 years, provided that the current decline in risk continues, thus giving patients with CML normal life expectancies. The standard of care for frontline treatment of CML is imatinib mesylate. Second-line treatment still includes stem cell transplantation as well as use of other novel tyrosine kinase inhibitors. Dasatinib was approved by the US Food and Drug Administration (FDA) in 2006, and a new drug application has been submitted for nilotinib. Third-generation drugs are currently being tested, some of which target known resistance mutations to tyrosine kinase inhibitor therapy. CML, chronic myeloid leukemia; SCT, stem cell transplantation; TKI, tyrosine kinase inhibitor. The prognostic outlook for patients with CML has changed dramatically since the introduction of tyrosine kinase inhibitor therapy. Whereas median survival was 3-4 years before tyrosine kinase inhibitor therapy, 90% of patients are now alive at 5 years. Interestingly, one half of the patients who die within 5 years of being diagnosed do so from reasons other than the disease itself. This is not an age-adjusted statistic. Therefore, the current mortality rate from CML is actually 5% at 5 years, and this number continues to decline. The relative mortality risk per year was higher in Years 1 and 2 than in Years 3, 4, and 5. Median survival may be closer to 25 years, although this could easily extend to 40 years, provided that the current decline in risk continues, thus giving patients with CML normal life expectancies. The standard of care for frontline treatment of CML is imatinib mesylate. Second-line treatment still includes stem cell transplantation as well as use of other novel tyrosine kinase inhibitors. Dasatinib was approved by the US Food and Drug Administration (FDA) in 2006, and a new drug application has been submitted for nilotinib. Third-generation drugs are currently being tested, some of which target known resistance mutations to tyrosine kinase inhibitor therapy.

101. Overview of Historical vs Modern Perspective CML, chronic myeloid leukemia; IFN, interferon; SCT, stem cell transplantation; TKI, tyrosine kinase inhibitor. Before 2000, CML was a fatal disease with a poor prognosis. Currently, it is being regarded as an indolent disease with an excellent prognosis. Interferon improved median survival from 3-6 years to nearly 7 years. Now, patients with CML have the potential to survive for decades. Imatinib has replaced interferon and allogeneic stem cell transplantation as frontline treatment. In the past, there were few second-line treatment options available. Now, even more powerful tyrosine kinase inhibitors can overcome resistance to imatinib. Additionally, allogeneic transplantation remains a therapeutic option.CML, chronic myeloid leukemia; IFN, interferon; SCT, stem cell transplantation; TKI, tyrosine kinase inhibitor. Before 2000, CML was a fatal disease with a poor prognosis. Currently, it is being regarded as an indolent disease with an excellent prognosis. Interferon improved median survival from 3-6 years to nearly 7 years. Now, patients with CML have the potential to survive for decades. Imatinib has replaced interferon and allogeneic stem cell transplantation as frontline treatment. In the past, there were few second-line treatment options available. Now, even more powerful tyrosine kinase inhibitors can overcome resistance to imatinib. Additionally, allogeneic transplantation remains a therapeutic option.

102. Survival in Early Chronic-Phase CML CML, chronic myeloid leukemia. These data are taken from the M.D. Anderson Cancer Center. In the 1960s, the 2.5-year median survival rate was worse than the average survival. In the 1970s, patients with CML were treated with combination chemotherapy, an approach similar to that used in the treatment of patients with acute myeloid leukemia. Either daunomycin or idarubicin were used in conjunction with cytarabine. Interferon was subsequently introduced in the 1980s and extended median survival to approximately 7 years, while the 10-year survival rate increased to approximately 40%. Combination treatment with interferon further increased the 10-year survival rate to 50%, with more than 40% of patients alive at 15 years. However, that percentage is misleading, given that many of these patients were eventually switched to tyrosine kinase inhibitor therapy. The introduction of imatinib extended the projected 6-year survival rate to 90%. Data regarding imatinib-associated survival rates from the M.D. Anderson Cancer Center match that of other international clinical trials. Figure reproduced with permission of faculty.CML, chronic myeloid leukemia. These data are taken from the M.D. Anderson Cancer Center. In the 1960s, the 2.5-year median survival rate was worse than the average survival. In the 1970s, patients with CML were treated with combination chemotherapy, an approach similar to that used in the treatment of patients with acute myeloid leukemia. Either daunomycin or idarubicin were used in conjunction with cytarabine. Interferon was subsequently introduced in the 1980s and extended median survival to approximately 7 years, while the 10-year survival rate increased to approximately 40%. Combination treatment with interferon further increased the 10-year survival rate to 50%, with more than 40% of patients alive at 15 years. However, that percentage is misleading, given that many of these patients were eventually switched to tyrosine kinase inhibitor therapy. The introduction of imatinib extended the projected 6-year survival rate to 90%. Data regarding imatinib-associated survival rates from the M.D. Anderson Cancer Center match that of other international clinical trials. Figure reproduced with permission of faculty.

103. Historic Development of CML Therapy

104. 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 - leukämie–Berlin, 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(9;22), 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

105.  IMATINIB STILL THE BEST TREATMENT FOR CML Don’t Change Winning Horses !

107. 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