CML is a myeloproliferative disease associated with the Philadelphia (Ph) chromosome and/or the BCR/ABL fusion gene. The disease is characterized by three phases: chronic phase (CML-CP), accelerated phase (CML-AP) and blast phase (CML-BP).
CBC and differential
Serum creatinine, uric acid, liver function tests
Bone marrow aspirate and biopsy with cytogenetic analysis
Molecular analysis for BCR/ABL [quantitative PCR (QPCR)] from peripheral blood or bone marrow
The diagnosis of CML-CP requires:
The majority of patients present with leukocytosis and/or thrombocytosis
Blasts < 10% of WBCs in peripheral blood and/or nucleated bone marrow cells
Peripheral blood basophils < 20%
Hypercellular bone marrow mainly due to myeloid hyperplasia
Presence of Ph chromosome t(9;22) on bone marrow cytogenetic analysis and/or evidence of BCR/ABL by molecular analysis
The diagnosis of CML-AP requires one or more of the following in addition to the presence of the Ph chromosome and/or BCR/ABL positivity:
Blasts 10-19% of WBCs in peripheral blood and/or of nucleated bone marrow cells
Peripheral blood basophils ≥ 20%
Persistent thrombocytopenia (<100 x 109/L) unrelated to therapy or persistent thrombocytosis (>1000 x 109/L unresponsive to therapy
Increasing spleen size or WBC count unresponsive to therapy
Cytogenetic evidence of clonal evolution
The diagnosis of CML-BP requires one or more of the following in addition to the presence of the Ph chromosome and/or BCR/ABL positivity:
Blasts ≥ 20% of peripheral blood white cells or of nucleated bone marrow cells
Extramedullary blast cell proliferation
Large foci or clusters of blasts in the bone marrow biopsy
A number of prognostic scoring systems have been developed to stratify patients with CML into various risk groups. The mostly widely used is the Sokal score (Blood 1984;63:789-99) or Hasford score (J Nat Cancer Inst 1998;90:850-858). These scoring systems can provide valuable information concerning an individual patient’s prognosis and may help to guide therapy.
Oral chemotherapeutic agents (busulfan and hydroxyurea)
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, dasatinib, bosutinib), third generation TKI (ponatinib), 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)
Imatinib (IM) is a tyrosine kinase inhibitor 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 (IRIS trial) 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.. 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 600-800 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, Nilotinib, Bosutinib)
Dasatinib, nilotinib and bosutinib are 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. Nilotinib and dasatinib also have Health Canada approval for first line use in newly diagnosed patients, however overall survival appears to be unchanged in comparison to IM for CML patients in chronic phase. Therefore consideration should be given to the relative toxicities and efficacy of these drugs for individual patients.
Third Generation Tyrosine Kinase Inhibitors (Ponatinib)
Ponatinib is the latest TKI to be developed and it has recently obtained Health Canada approval for the treatment of CML where other TKI inhibitor therapy is not indicated. The major advantage of ponatinib over the other TKIs is its efficacy against the T315I mutation in BCR-ABL. It has activity against a broad spectrum of mutations and is currently utilized for patients with resistance or intolerance to second generation TKIs or those patients with the T315I mutation.
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 TKI therapy. 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 or CP2. 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 & Follow-Up
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 MCR (> 1 log reduction in BCR/ABL transcripts) within 6 months of starting therapy, a complete cytogenetic response (> 2 log reduction in BCR/ABL transcripts) within 12 months of therapy and preferably a major molecular response (> 3 log reduction in BCR/ABL transcripts) within 18 months of starting therapy. See treatment algorithms for detailed milestone objectives.
Tests & Intervals
CBC and differential weekly until CHR then monthly until stable then every 3-6 months thereafter
Serum creatinine, uric acid, liver function tests - weekly until stable then every 3 months
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