Chronic Myeloid Leukemia (CML)
Treatment Options & Assessment of Response

Reviewed / Updated: February 2012

Treatment Options

Treatment decisions for patients with CML are complex due to the variety of therapies now available. They include:

1. Oral tyrosine kinase inhibitors (imatinib mesylate, dasatinib, nilotinib)
2. Parenteral therapeutic agents (interferon alpha +/- cytarabine)
3. Oral chemotherapeutic agents (busulfan and hydroxyurea)
4. Hematopoietic stem cell transplantation (myeloablative allogeneic and non-myeloablative allogeneic)

In general, first-line therapy for all patients newly diagnosed with CML-CP is the tyrosine kinase inhibitor imatinib. Alternatives to imatinib include second generation tyrosine kinase inhibitors (nilotinib and dasatinib), interferon alpha, oral chemotherapeutic agents and stem cell transplantation. For patients with advanced phase disease, initial therapy with imatinib is recommended and consideration of allogeneic stem cell transplantation is appropriate for those who are transplant eligible.

Tyrosine Kinase Inhibitors (Imatinib Mesylate/Gleevec)

Imatinib (IM) is a recently developed compound that can selectively inhibit the aberrant tyrosine kinase resulting from the BCR/ABL gene fusion characteristic of CML. Results comparing IM with IFN for patients with CML-CP have shown superior rates of complete hematologic response (97 vs 69%), major cytogenetic response (87 vs 35%), and complete cytogenetic response (76 vs 14%) at 18 months of therapy. These results should be considered preliminary however, as the durability of responses to IM is unknown. IM is generally well tolerated with few side effects. The recommended starting dose is 400 mg orally once daily. IM can also provide short-term disease control in CML-AP and CML-BP where it is now considered the drug of choice (recommended starting dose is 600 mg/day). Responses can be transient however, and allogeneic hematopoietic stem cell transplantation is recommended for responding AP or BP patients (if feasible).

Second Generation Tyrosine Kinase Inhibitors (Dasatinib and Nilotinib)

Dasatinib and nilotinib are both more potent tyrosine kinase inhibitors compared to imatinib. They are effective against a number of bcr-abl mutations and are currently licensed for use for CML patients with either resistance or intolerance to imatinib.

Interferon alpha (IFN)

IFN results in hematologic remissions in the majority of patients with CML-CP. However, only approximately 10-30% of patients achieve a major cytogenetic response (<35% Ph negative cells in the bone marrow) resulting in an improved overall survival (median, 7-10 years). The recommended dose is 5 x 10(6) U/m2 SQ per day, however responses may be seen with lower doses (2 x 10(6) U/m2 daily). The addition of low-dose cytarabine (20 mg/m2 SQ per day for 10 days each month) has been shown to increase the number of major cytogenetic responses at 12 months. IFN alone or in combination with cytarabine can result in considerable toxicity particularly in the elderly and its use has now largely been replaced by imatinib mesylate. Results with IFN in CML-AP or CML-BP are poor and its use is not recommended.

Oral Chemotherapeutic Agents

The most commonly utilized agents are hydroxyurea and busulfan. The majority (~90%) of patients will have a hematologic remission with these agents, however therapy will not be curative, has not been shown to prolong overall survival and rarely results in a cytogenetic response. Therefore, therapy with these agents is considered palliative, although hydroxyurea can provide excellent blood count control with minimal toxicity while more definitive therapies are explored such as tyrosine kinase inhibitors, IFN or stem cell transplantation.

Hematopoietic Stem Cell Transplantation (HSCT)

Results of HSCT for CML are directly related to the phase of disease at the time of transplant; CML-CP transplanted within 1 year from diagnosis results in the best outcome with 65-70% chance at long-term disease-free survival as compared to 35-40% chance of being “cured” if transplanted in AP. Patients with CML-BP will be considered potential transplant candidates if they first respond to more conservative therapy (ie. IM or second generation tyrosine kinase inhibitors or multiagent chemotherapy). Decisions regarding the timing and type of transplant (allogeneic myeloablative vs non-myeloablative, sibling donor vs unrelated donor) should be made in consultation with a member of the Leukemia/BMT group.

Assessment of Response

Criteria

• Complete Hematologic Response (CHR): complete normalization of peripheral blood white count (< 10 x 10⁹), and platelet count (< 450 x 10⁹) sustained for at least 4 weeks.
• Major Cytogenetic Response (MCR): < 35% Philadelphia positive bone marrow metaphases by conventional cytogenetic analysis. This is equivalent to a 1 log reduction in BCR/ABL transcripts from baseline as measured by QPCR
• Complete Cytogenetic Response (CCR): No Philadelphia postive bone marrow metaphases by conventional cytogenetic analysis. This is equivalent to a 2 log reduction in BCR/ABL transcripts from baseline as measured by QPCR
• Major Molecular Response (MMR): Greater than or equal to a 3 log reduction in BCR/ABL fusion transcripts compared to baseline by PCR analysis
• Complete Molecular Response (CMR): No detectable BCR/ABL transcript

The goal of therapy is to reach a complete cytogenetic response (> 2 log reduction in BCR/ABL transcripts) and preferably a major molecular response (> 3 log reduction in BCR/ABL transcripts) with minimal toxicity within 18 months of starting therapy. See treatment algorithms for detailed milestone objectives.

Follow-up Evaluation

Tests & Intervals

• CBC and differential - weekly until CHR then monthly
• Serum creatinine, uric acid, liver function tests - weekly until stable then monthly
• Peripheral blood QPCR - every 3 months until MMR achieved and maintained for at least 6 months, then QPCR is measured every 6 months
• Bone marrow aspirate and biopsy - at diagnosis, then as clinically indicated

The information contained in these guidelines is a statement of consensus of Leukemia/BMT Program of BC professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. Use of these guidelines and documents is at your own risk and is subject to the Leukemia/BMT Program of BC’s terms of use available at Terms of Use.