A1) CML Alliance is a global program to help healthcare providers and their patients fully optimize therapy and achieve the best possible outcomes in the treatment of Ph+ CML.

CML Alliance provides support and educational materials for both healthcare professionals and patients.

• Glivec blood level testing
• Standardized molecular testing
• Educational information on the molecular biology and management of Ph+ CML
• Information about CML clinical trials on investigational agents and existing therapies in CML

• Unique programs designed to help patients better understand CML, its treatment, and the importance of adherence to their CML therapy
• Valuable educational information about living with CML

The affiliates of Novartis AG believe that the best way to optimize therapy in all CML patients worldwide is to provide these services as part of a single, integrated program. Services provided through CML Alliance are customized in each country in which it is offered, depending on local legal and regulatory specifications. For specific information and services available in each country, please contact your local Novartis organization.

A2) Depending on local rules and regulations in each country, CML Alliance is available to patients with Ph+ CML, those transitioning to Tasigna, and those on Glivec.

A3) CML Alliance is a comprehensive program available in many countries around the world.

CML Alliance is customized in each country to best meet the local needs and regulatory and legal requirements of each country.

Please click here to request more information about CML Alliance services in your country.

A4) Please click here to request information about CML Alliance services in your country.

Interactive Blood Level Testing

Enrollment in CML Alliance is voluntary. Healthcare providers and patients are under no obligation to enroll or maintain their participation in the program.

A5) CML Alliance fully complies with all privacy and confidentiality regulations of the countries in which it is implemented. For example, in the United States, CML Alliance complies with all HIPAA regulations.

A6) There is no cost to enroll this Program.

A7) Blood level testing may play an important role in optimizing therapy with Glivec. Studies have shown that Glive blood levels correlate with clinical response ¹.^{[Larson/p4026/col.2/Fig.4/A,B, ln 2-4, 7-8]}

Establishing a baseline measurement at the beginning of therapy and subsequently monitoring Glivec blood levels can help identify issues with therapy, such as drug-drug interactions or adherence.

Click here for more information on Glivec blood level testing

Blood Level testing

A8) Glivec led to a fundamental shift in care, as Ph+ CML evolved into a chronic disease that now requires long-term treatment. Decline in patient adherence can be an issue with long-term oral therapy. ^{2 [Osterberg NEJM/page 488/column 1/para 1/lines 1-3]} .

• On average, patients (N = 3502) took only 75% of their prescribed Glivec over the 14-month
  study period ^{3 [TSANG/Results/lines1-3/Methods/lines 2-4]}
• Patients were on therapy an average of only 62% of the study period (256 days out of 14 months)^{3 [TSANG/Conclusions/lines 3-4]}
• Adherence began to decline after 4 months of treatment

In another study, it was shown that patients may overestimate their adherence to oral cancer therapies by a factor of 2 in discussions with their physicians. ^{4[Partridge/page 656/col 2/para 2/lines 3-4]}

Nonadherence to treatment is a major issue in patients with chronic conditions who do not exhibit illness-related symptoms of their disease and may, over time, forget how important it is to take their therapy exactly as prescribed. Suboptimal adherence to oral therapy can lead to disease progression or death.^{2 [Osterberg NEJM/page 488/column 1/para 1/lines 1-3]}

A9) Where permissible under local laws and regulations, Glivec blood level testing will be performed free of charge for all patients enrolled in CML Alliance. Shipping of samples is also free through CML Alliance. The cost of the actual doctor's visit and blood draw are not covered.

Glivec blood level testing is available in over 60 countries. To request information and services that are available in your country, please click here.

Map

A10) Blood level testing is only available for Glivec through CML Alliance.

A11) Evaluation of molecular response, the disappearance or reduction in bcr-abl transcript levels, has significant prognostic
value in Ph+ CML therapy.^{5 [NCCN/p33/MS-10/col.1/par.2/lines 1-3 and MS-9/col.2/par.3/line 1-2]}

Molecular responses help further evaluate the depth of a patient's hematologic and cytogenetic response to ensure that a patient's treatment is optimized over time.^{6[Baccarani/page 1812/col 1/fig 1; 1812/1/3]}

Molecular response has been found to correlate with both cytogenetic response and long-term progression-free
survival.^{5[NCCN/p33/MS-9/col.1/par.2/lines 1-3 and MS-10/col 2/para 3/lines 4-5]}

In the International Randomized Study of Interferon and STI571 (IRIS) trial, 53% of patients who had complete cytogenetic response achieved major molecular response after one year on Glivec and at 4 years, 80% of these patients had reached this milestone.⁷ Long-term follow-up of patients who continue to respond to Glivec demonstrate an MMR rate of 85-90% at 5-6 years.^{7[Druker/page 2412/col 2/ para 3/lines 1-8]}

Regular molecular testing is recommended by the NCCN guidelines and ELN Recommendations

NCNN guidelines

ELN guidelines

A12) Quantitative "real-time" reverse transcriptase-polymerase chain reaction (Q-RT-PCR) is the most sensitive method to determine the levels of bcr-abl transcripts.^{5[NCCN/p33/MS-9/col.2/par.4/lines 1-2 and para 5/lines 2-3]}

Q-RT-PCR can detect a single bcr-abl–positive cell per 105 normal cells and changes in transcript levels can be detected even when cytogenetic changes are not evident.^{5[NCCN/p33/MS-9/col.2/par.4/lines 2-5/ NCCN/p33/MS-9/col.2/par.4 /lines 5-8]}

Q-RT-PCR results can differ considerably between labs, and also drift over time for an individualized lab, making interpretation difficult. An international scale for reporting of bcr-abl transcript measurements was established to minimize variation and allow for easy interpretation between laboratories. ^{8[Hughes/p29/col 1/para 2/ lines 5-18].} Standardized Q-RT-PCR allows physicians to evaluate results in relation to clinical trial data and consensus guideline recommendations to help optimize therapy for patients with Ph+ CML.

A13) Where permissible under local laws and regulations, CML Alliance will offer standardized Q-RT-PCR testing through certified laboratories that utilize the international scale. This will provide physicians with access to consistent and easily interpretable PCR results for better management of Ph+ CML patients. Services through CML Alliance will be customized to best meet the needs and regulatory and legal requirements of each country. For specific information and services available in your country, please contact your local Novartis organization.

References

1. Larson RA, Druker BJ, Guilhot F, et al; for the IRIS (International Randomized Interferon vs ST1571) Study Group. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study.Blood.2008;111(8):4022-4028.

2. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487-497.
3. Tsang JP et al. J Clin Oncol. 2006;24. Abstract 6119.
4. Partridge AH, Avorn J, Wang PS, et al. Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst. 2002;94:652-661.
5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Chronic myelogenous leukemia. V.2.2009 CML-F. http://www.nccn.org. Accessed June 1, 2009.
6. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809-1820.
7. Druker BJ, Guilhot F, O'Brien SG, et al. for the IRIS investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006. 355(23):2408-2417.
8. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108(1):28-37.