Monitoring CML Treatment:
Addressing the Issues for the
Community Hematologist/Oncologist
Hagop M. Kantarjian, MD
Ronjay Rakkhit, MD
Chairman; Professor, Department of Leukemia
University of Texas, MD Anderson Cancer Center
Houston, Texas
Oncology Consultants
Houston, Texas
Jorge E. Cortes, MD
Chair, CML Section, Division of Cancer Medicine
University of Texas, Department of Leukemia,
MD Anderson Cancer Center
Houston, Texas
William S. Velasquez, MD
Allopathic & Osteopathic Physicians
Internal Medicine Hematology &
Oncology
Houston, Texas
CML: Epidemiology
• It accounts for 0.34% of all cancers, 3.6% of
hematologic malignancies, and 0.08% of all cancer
mortality.[a]
• 5050 new cases were estimated in the United States
in 2009, and 470 people with CML were estimated to
die in the same time period.[a]
• From 2003 to 2007, age-adjusted incidence rates of
the disease were 2.0 per 100,000 men and 1.1 per
100,000 women.[b]
a. Jemal A, et al. CA Cancer J Clin. 2009;59:225-249.
b. NCI/SEER. Available at: http://seer.cancer.gov/statfacts/html/cmyl.html
CML: Pathophysiology
• Myeloproliferative disorder of the primitive hematopoietic
stem cell[a]
• Arises from a translocation t(9;22)(q34;q11), known as the
Philadelphia chromosome[a]
• Resulting bcr-abl1 fusion gene codes for a constitutively active
tyrosine kinase[a,b]
a. Kantarjian H, et al. Blood. 1993;82:691-703.
b. Quintás-Cardama A, Cortés JE. Blood. 2009;113:1619-1630.
CML: Advent of Imatinib
• Most cases are diagnosed in the chronic phase (CP).[a]
• Before the advent of imatinib therapy, the median survival was
approximately 3-4 years.[b]
• The advent of imatinib changed the natural history of CML.[c]
a. Faderl S, et al. N Engl J Med. 1999;341:164-172.
b. Kantarjian H, et al. Cancer. 2008;113(suppl):1933-1952.
c. Weisberg E, et al. Nat Rev Cancer. 2007;7:345-356.
CML: FDA-Approved Second-line TKIs
Weisberg E, et al. Nat Rev Cancer. 2007;7:345-356.
CML: IRIS Trial 5- and 8-Year Follow-up[a]
• At 8 years, estimated overall survival was 85%, and 93% when only
CML-related deaths were considered.[b]
a. Druker BJ, et al. N Engl J Med. 2003;355:2408-2417.
b. Deininger M, et al. ASH 2009. Abstract 1126.
Bone Marrow Analysis in the Community
Setting
Appropriate in Patients With Suspected CML
at Diagnosis?
Bone Marrow Analysis in the Community
Setting
Appropriate and Important in Patients With
Suspected CML at Diagnosis
May Provide Information About Additional
Chromosomal Abnormalities and Number of Blasts
Patients With Newly Diagnosed CML-CP
Nilotinib vs Imatinib: Phase 3 ENESTnd Trial
Response (%)
MMR
• At 12 mo (ITT)
• At 18 mo (n = 525)
• At 24 mo (n = 145)
CCyR
• At 12 mo (ITT)
• At 18 mo (n = 442)
Nilotinib
300 mg BID
(n = 282)
Nilotinib
400 mg BID
(n = 281)
Imatinib
400 mg QD
(n = 283)
44*
69
86
43*
63
88
22
36
48
80*
99
78†
99
65
89
Rate of progression to AP/BC CML
• Nilotinib 300 mg BID: 0.7% (P = .006 vs imatinib)
• Nilotinib 400 mg BID: 0.4% (P = .003 vs imatinib)
• Imatinib 400 mg QD: 4.2%
Larson RA, et al. ASCO 2010. Abstract 6501.
*P < .0001 vs imatinib
†P < .001 vs imatinib
Patients With Newly Diagnosed CML-CP
Dasatinib vs Imatinib: Phase 3 DASISION Trial
Dasatinib
n (%)
IM
P
CCyR (≥ 20 metaphases)
3 mo
140 (54)
80 (31)
6 mo
189 (73)
154 (59)
12 mo
216 (83)
186 (72)
3 mo
21 (8)
1 (<1)
6 mo
70 (27)
21 (8)
12 mo
119 (46)
73 (28)
.0011
MMR
Kantarjian H, et al. ASCO 2010. LBA6500.
< .0001
Optimal Monitoring in the Community
Practice
Which Method, When, and How Often?
Frequent Monitoring
Importance and Rationale
• Identify patient with suboptimal response early
– Do not wait until the patient loses hematologic response
• Intervene early
– Optimize dose
– Change therapy
– Increase probability of good response and long-term
favorable outcome
Patients With Cytogenetic Relapse Typically Respond Better to SecondGeneration TKIs Than Patients With Hematologic Relapse.
Imatinib Failure
Operational Criteria
Evaluation Time (mo)
Failure
Baseline
NA
3
Less than CHR
6
No CyR (Ph + > 95%)
12
Less than PCyR (Ph + > 35%)
18
Less than CCyR
Any time during treatment
Loss of CHR; loss of CCyR;
mutations; CCA/PH+
CCA = clonal chromosome abnormalities
Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051.
Patient in CCyR With Rising Q-PCR
Intervene or Just Monitor and Continue With
The Same Treatment?
Patient in CCyR With Rising Q-PCR
Value of Any Intervention Is Unknown; Keep
Monitoring
Compliance
Major Effect on Response
Marin D, et al. J Clin Oncol. 2010;28:2381-2388.
Patient in CCyR With Rising Q-PCR
If Dose Is Reduced Earlier, Try Optimizing
Dose
Monitoring CML
Proposed Approach
Kantrajian H, et al. Blood. 2008;111:1774-1780.
Role of Allogeneic Transplant Today
Second-, Third-, or Occasionally First-line
Therapy?
Role of Allogeneic Transplant Today
Rarely a First-line Therapy Even in Patients in
Accelerated or Blastic Phase or Those Who
Failed to Respond to Imatinib (Except in
Patients With T315I Mutation)
Patients With T315I Mutation
Emerging Therapies
• Omacetaxine (homoharringtonine)
• AP24534
• DCC230326