ELIAS JABBOUR, MD (left) is Associate Professor in the Leukemia Department of the University of Texas MD Anderson Cancer Center. HAGOP M. KANTARJIAN, MD, is Professor and Chairman of the Department of Leukemia and the Samsung Distinguished University Chair in Cancer Medicine at the University of Texas MD Anderson Cancer Center.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of one to two cases per 100,000 adults. It accounts for approximately 15 percent of newly diagnosed cases of leukemia in adults. CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome.
The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL1 oncoprotein. Three tyrosine kinase inhibitors (TKIs)--imatinib, nilotinib, and dasatinib--are approved by the United States Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic-phase (CML-CP).
Clinical trials with second-generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined. For patients who fail frontline therapy, second-line options include second- and third-generation TKIs. Although second- and third-generation TKIs are potent and selective TKIs, they exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients’ comorbidities, disease stage, and BCR-ABL1 mutational status.
Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least two TKIs, and for all patients in advanced phase disease.
Bone marrow aspiration is mandatory for all patients in whom CML is suspected, as it will confirm the diagnosis (e.g., cytogenetic analysis), and provide information needed for staging in terms of the blast and basophil percentages. Baseline reverse transcriptase-polymerase chain reaction is imperative to identify the specific type of rearrangement that can be appropriately followed when assessing for response to TKI therapy.
About two to five percent of patients have b2a3 or b3a3 (not b2a2 or b3a2) variants of p210 BCR-ABL1 or p230 transcripts that may yield a false-negative PCR by routine probes and (if not tested at diagnosis) would give the false impression that a patient may be in complete molecular response on TKI.
Frontline Treatment Options
Current guidelines recommend any of the three TKIs--imatinib, dasatinib, and nilotinib--as good therapeutic options with a category 1 recommendation for initial treatment of CML-CP. Second-generation TKIs produced a higher rate of early optimal responses, but have so far have had no impact on long-term survival (probably because of available effective salvage therapies).
The main advantage of second-generation TKIs is obtained in patients with high-risk disease; a relevant decrease in the rate of transformation to accelerated phase (AP) and blast phase (BP) was achieved with nilotinib and dasatinib. As such, second-generation TKIs in the frontline setting could be reserved to patients with higher-risk disease. Furthermore, when choosing an agent, we consider issues such as comorbidities, patient’s age, adverse event profile, risk stratification score, transcript’s type, and cost. Kinase domain mutation profile plays no role in selecting an initial TKI, but becomes relevant in the relapse setting.
Higher dose imatinib and combination approaches in the frontline setting are investigational due to conflicting results of various studies to date. These strategies are also not benign interventions, as they add to the economic and toxicity burden of the overall treatment plan.
Allogeneic stem cell transplantation (allo-SCT) or other chemotherapy agents are not recommended as upfront treatments for CML-CP given the excellent outcomes and long-term survival achieved with the TKIs. An exception may be in emerging nations where allo-SCT is a one-time procedure costing $ 14,000 to $20,000, accessible to most patients. On the other hand, generic imatinib in such geographies (e.g., India) costs only less than $400 per year of therapy.
At MDACC, patients with low-risk disease are offered frontline therapy with imatinib. Patients with high-risk disease are candidates for second-generation TKIs for the time being; this practice may change once the generic formulation of imatinib is available in the United States.
Because of the higher rates of durable complete molecular responses with second-generation TKIs (which could lead to discontinuation of TKI therapy and potential molecular cures discussed later), considerations of second-generation TKIs in younger patients with CML (e.g., age <50 years) versus older patients, may be entertained.
Monitoring Treatment Response: Surrogate Endpoints and Milestones
In several studies, the achievement of a complete cytogenetic response (CCyR; Ph-positive metaphases 0%; BCR-ABL1 transcripts [IS] ≤ 1%) at 12 months or later on TKI therapy was associated with significant survival benefit compared with achievement of lesser degrees of response.
Achievement of CCyR is the primary endpoint of TKI therapy. Achievement of BCR-ABL1 transcripts [IS] ≤ 0.1% (major molecular response; MMR) was associated with modest improvements in event-free survival rates, possible longer durations of CCyR, but not with a survival benefit.
The achievement of complete molecular response (CMR; non-measurable BCR-ABL1 transcripts) offers the possibility of treatment discontinuation in clinical trials only. Lack of achievement of MMR or of CMR should not be interpreted as a need to change TKI therapy or to consider allo-SCT. Response assessments at earlier times on frontline TKI therapy (3-6 months) have shown better outcomes with achievement of a major cytogenetic response by three to six months on imatinib therapy (Ph-positive metaphases ≤ 35%; BCR-ABL1 transcripts [IS] ≤ 10%).
While this is interpreted to mean that a change to second TKI therapy may be considered if such outcome is not obtained, no studies have shown that changing therapy from imatinib to second TKIs has improved patients ’outcomes.
When nilotinib or dasatinib are used in front-line therapy, achievement of complete cytogenetic response by three to six months of TKIs therapy has been associated with improved outcomes. At MDACC, our major treatment milestones are at 6 and 12 months. Patients with lack of partial cytogenetic response (PCyR; BCR-ABL1 transcripts [IS] > 10%) at six months, or without CCyR (BCR-ABL1 transcripts [IS] ≤ 1%) at 12 months, or with loss of response at any time are candidates for a switch of therapy. The choice of TKIs is based on the mutation profiles and patients comorbidities.
We do not consider a change of TKI therapy in patients in CCyR but without MMR.
Management of TKI Resistance
Second- and third-generation TKIs have not been compared head-to-head. Selection of one or the other is based on the side-effect profiles, mutations profile, drug interactions, compliance issues, and the patient's preexisting medical conditions. Mutational analysis are required in patients who are failing imatinib or second-generation TKIs, or those who progress to AP/BP. Baseline mutational analysis on patients with newly diagnosed CML-CP are not done, as this has not proven to predict treatment outcome.
At MDACC, post imatinib failure, the choice of second- or third-generation TKI is based on the disease phase, mutation profile, and patient’s comorbidities. In advanced phases, we favor a combination of chemotherapy and TKI (mainly ponatinib or dasatinib). In patients with CML-CP with T315I mutation, ponatinib will be the first choice followed by allo-SCT if a donor is available and an optimal response is not achieved.
Outside the context of T315I mutations, the type of mutation will dictate the choice of therapy. Of note, patients with poor response to imatinib and compound mutations may not respond well to second-generation TKI. A close monitoring should be offered. If an optimal response is not achieved, a switch of therapy to a third-generation TKI and/or allo-SCT is warranted.
In patients with no mutation or a mutation sensitive to all second-generation TKIs, the choice will be based on comorbidities. Patients with vascular risk factors and metabolic dysfunctions are not candidates for nilotinib, while patients with lung injuries are not candidates for dasatinib. Bosutinib may be the best choice for patients with cardiac and rhythmic problems.
Treatment Duration and Discontinuation
TKIs discontinuation studies in patients with durable CMR demonstrate that stopping TKI therapy is feasible, and some patients may be cured. While the results thus far are encouraging, it is still recommended that TKI therapy be stopped only under the auspices of a clinical trial. Many laboratories are not able to produce precise and reliable PCR results as those used in the above mentioned trials.
Going forward, it is important to continue to investigate the possibility of safe treatment cessation. Measures of quality of life and adverse event avoidance should be studied in subsequent trials. The economic impact of long-term discontinuation of imatinib is substantial. At MDACC, therapy discontinuation is offered only for patients in durable CMR and in the context of clinical trials.
Allo-SCT should be considered early in patients in CML-AP based on response to TKI therapy. The only curative option for patients in CML-BP disease is allo-SCT. TKIs alone or in combination with chemotherapy may serve as a good option for those who are not candidates for transplant, or as a bridge to allo-SCT.
The role of TKIs before and after transplant is being evaluated. Accumulating data show that TKIs do not increase transplant-related complications and when used after low-intensity conditioning regimens, may delay relapse rates and need for donor lymphocyte infusions.
At MDACC, patients with CML-BP are treated with combination of chemotherapy (type depends on the immunophenotype) and third-generation TKI followed by allo-SCT once a complete response is achieved and placed on maintenance TKI therapy. Patients with de-novo CML-AP are treated with frontline second-generation TKI infinitely if an optimal response (CCyR; BCR-ABL1 transcripts [IS] <1%) is achieved within six months of therapy All other patients in CML-AP are treated with second/third generation-TKI followed by allo-SCT.