Monitoring CML Treatment: Addressing the Issues for the Community Hematologist/Oncologist Hagop M. Kantarjian, MD Chairman; Professor, Department of Leukemia.

Monitoring CML Treatment: Addressing the Issues for the Community Hematologist/Oncologist

Hagop M. Kantarjian, MDChairman; Professor, Department of LeukemiaUniversity of Texas, MD Anderson Cancer CenterHouston, Texas

Jorge E. Cortes, MDChair, CML Section, Division of Cancer MedicineUniversity of Texas, Department of Leukemia, MD Anderson Cancer CenterHouston, Texas

Ronjay Rakkhit, MDOncology ConsultantsHouston, Texas

William S. Velasquez, MDAllopathic & Osteopathic Physicians Internal Medicine Hematology & OncologyHouston, 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;59:225-249.b. NCI/SEER. Available at: http://seer.cancer.gov/statfacts/html/cmyl.html

• 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;82:691-703.b. Quintás-Cardama A, Cortés JE. Blood. 2009;113:1619-1630.

• 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;341:164-172.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]

a. Druker BJ, et al. N Engl J Med. 2003;355:2408-2417.b. Deininger M, et al. ASH 2009. Abstract 1126.

• 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-CPNilotinib vs Imatinib: Phase 3 ENESTnd Trial

Larson RA, et al. ASCO 2010. Abstract 6501.

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) 69 63 36• At 24 mo (n = 145) 86 88 48CCyR• At 12 mo (ITT) 80* 78† 65• At 18 mo (n = 442) 99 99 89

*P < .0001 vs imatinib†P < .001 vs imatinib

Patients With Newly Diagnosed CML-CPDasatinib vs Imatinib: Phase 3 DASISION Trial

Kantarjian H, et al. ASCO 2010. LBA6500.

Dasatinib IMn (%) P

CCyR (≥ 20 metaphases)

3 mo 140 (54) 80 (31)

6 mo 189 (73) 154 (59)

12 mo 216 (83) 186 (72) .0011

MMR

3 mo 21 (8) 1 (<1)

6 mo 70 (27) 21 (8)

12 mo 119 (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 MonitoringImportance and Rationale

Patients With Cytogenetic Relapse Typically Respond Better to Second-Generation TKIs Than Patients With Hematologic Relapse.

Imatinib FailureOperational Criteria

Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051.CCA = clonal chromosome abnormalities

Evaluation Time (mo) FailureBaseline 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+

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

ComplianceMajor Effect on Response

Marin D, et al. J Clin Oncol. 2010;28:2381-2388.

If Dose Is Reduced Earlier, Try Optimizing Dose

Patient in CCyR With Rising Q-PCR

Monitoring CMLProposed Approach

Kantrajian H, et al. Blood. 2008;111:1774-1780.

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• DCC230326

Patients With T315I MutationEmerging Therapies