Monitoring CML Treatment: Addressing the Issues for the Community Hematologist/Oncologist Hagop M. Kantarjian, MD Chairman; Professor, Department of Leukemia University of Texas, MD Anderson Cancer Center 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 Ronjay Rakkhit, MD Oncology Consultants Houston, Texas William S. Velasquez, MD Allopathic & Osteopathic Physicians Internal Medicine Hematology & Oncology Houston, Texas

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] CML: Epidemiology a. Jemal A, et al. CA Cancer J Clin. 2009;59: b. NCI/SEER. Available at:

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] CML: Pathophysiology a. Kantarjian H, et al. Blood. 1993;82: b. Quintás-Cardama A, Cortés JE. Blood. 2009;113:

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] CML: Advent of Imatinib a. Faderl S, et al. N Engl J Med. 1999;341: b. Kantarjian H, et al. Cancer. 2008;113(suppl): c. Weisberg E, et al. Nat Rev Cancer. 2007;7:

CML: FDA-Approved Second-line TKIs Weisberg E, et al. Nat Rev Cancer. 2007;7:

CML: IRIS Trial 5- and 8-Year Follow-up [a] a. Druker BJ, et al. N Engl J Med. 2003;355: b. Deininger M, et al. ASH Abstract At 8 years, estimated overall survival was 85%, and 93% when only CML-related deaths were considered. [b]

Appropriate in Patients With Suspected CML at Diagnosis? Bone Marrow Analysis in the Community Setting

May Provide Information About Additional Chromosomal Abnormalities and Number of Blasts Appropriate and Important in Patients With Suspected CML at Diagnosis Bone Marrow Analysis in the Community Setting

Patients With Newly Diagnosed CML-CP Nilotinib vs Imatinib: Phase 3 ENESTnd Trial Larson RA, et al. ASCO Abstract 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% Response (%) Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) MMR At 12 mo (ITT) 44* 43*22 At 18 mo (n = 525) At 24 mo (n = 145) CCyR At 12 mo (ITT) 80* 78 † 65 At 18 mo (n = 442)99 89 *P <.0001 vs imatinib † P <.001 vs imatinib

Patients With Newly Diagnosed CML-CP Dasatinib vs Imatinib: Phase 3 DASISION Trial Kantarjian H, et al. ASCO LBA6500. DasatinibIM n (%)P CCyR (≥ 20 metaphases) 3 mo140 (54)80 (31) 6 mo189 (73)154 (59) 12 mo216 (83)186 (72).0011 MMR 3 mo21 (8)1 (<1) 6 mo70 (27)21 (8) 12 mo119 (46)73 (28)<.0001

Which Method, When, and How Often? Optimal Monitoring in the Community Practice

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 Frequent Monitoring Importance and Rationale Patients With Cytogenetic Relapse Typically Respond Better to Second- Generation TKIs Than Patients With Hematologic Relapse.

Imatinib Failure Operational Criteria Baccarani M, et al. J Clin Oncol. 2009;27: CCA = clonal chromosome abnormalities Evaluation Time (mo)Failure BaselineNA 3Less than CHR 6No CyR (Ph + > 95%) 12Less than PCyR (Ph + > 35%) 18Less than CCyR Any time during treatment Loss of CHR; loss of CCyR; mutations; CCA/PH+

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 Patient in CCyR With Rising Q-PCR

Compliance Major Effect on Response Marin D, et al. J Clin Oncol. 2010;28:

If Dose Is Reduced Earlier, Try Optimizing Dose Patient in CCyR With Rising Q-PCR

Monitoring CML Proposed Approach Kantrajian H, et al. Blood. 2008;111:

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) Role of Allogeneic Transplant Today

Omacetaxine (homoharringtonine) AP24534 DCC Patients With T315I Mutation Emerging Therapies