CML: Select TKI based on comorbidities, monitor toxicity and adherence

CHICAGO – Chronic myeloid leukemia is highly treatable, and a “functional cure” appears to be within reach, according to Dr. Michael J. Mauro.

In fact, an “embarrassment of riches” exists when it comes to initial therapy for CML: In the United States there are five approved tyrosine kinase inhibitors (TKIs), and three are approved for front-line therapy, Dr. Mauro of Memorial Sloan Kettering Cancer Center, New York, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Success, however, is contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and remaining vigilant for late effects of therapy, he said.

Given the multitude of treatment options and the breadth of available data, Dr. Mauro said he counsels newly diagnosed patients that various treatment options are valid, and that “there may not be a right or wrong answer” for initial therapy. He also counsels patients that tolerability is manageable – and finding the right fit is an important process, and that response milestones are crucial and should be optimized.

It is important, he said, to discuss late toxicity concerns, to review comorbid conditions to help predict potential problems and identify risk, to consider the ramifications of potential toxicity, and to consider adherence.

“We need to portray therapy as really being medium- to long-term,” he said, noting that the urgency to think about treatment-free remission should be tempered by the reality that years of treatment are required first.

Risks and benefits of treatment should be discussed, and the acceptable balance determined in conjunction with the patient, he said, explaining that toxicities vary for the different TKIs.

Imatinib, for example, can be associated with edema/fluid retention, myalgias, hypophosphatemia, and gastrointestinal effects. Dasatinib can be associated with pleural/pericardial effusion, pulmonary arterial hypertension, and bleeding risk. Other toxicities associated with certain TKIs include pancreatic enzyme elevation, rash, and vascular adverse events.

Whether newly diagnosed patients should be directed away from certain agents remains unclear, as available data are open to interpretation, and the mechanism of action for some crucial late effects is unknown. Vascular disease should, however, be considered when making the decision, he said.

Given the available data on late toxicity with various therapies, a cardiovascular evaluation is advisable when initiating TKI therapy, he added.

Consider partnering with primary care, cardiology, or cardio-oncology specialists, and manage risk factors and findings of the evaluation as appropriate, irrespective of the CML, he said. Monitor for progression of cardiovascular risks or adverse events carefully, he added.

His approach for following recently diagnosed CML patients involves:

• A cardiovascular evaluation, at least including age- and comorbidity-appropriate studies, and an up-to-date cardiovascular risk profile. If nilotinib is used, he screens for peripheral, cerebral, and cardiovascular disease – an approach increasingly supported by data. If dasatinib is used, echocardiography is warranted to look for changes that suggest pulmonary hypertension. “And of course we should monitor blood pressure, lipid, and glycemic control,” he added.

• Initial studies, including bone marrow and quantitative polymerase chain reaction – international scale (qPCR IS).

• Lab studies every 1-2 weeks for at least 6 weeks, with titration thereafter as indicated, including for change in therapy.

• A 3-month assessment using qPCR IS. This is very important for following patient response, he said, noting that if the response surpasses compete cytogenetic remission and blood count is acceptable and stable, a repeat bone marrow study may be unnecessary.

• Sequential molecular analyses at least every 3 months.

• Repeat cardiovascular evaluation if/when indicated.

The 3-month response is an opportunity to critically appraise therapy choice and response trajectory; a therapy change is possible based on this assessment, he said. Responses at 6 and 12 months are also important, and changes in therapy for missed milestones at these time points are warranted as deeper remissions are sought.

At 18 months, the focus is on major molecular response, he added, noting that as patients get into deeper molecular remissions, plateaus and fluctuations are common; the nuances of determining who is well enough to consider for treatment-free remission remain to be sorted out in clinical trials.

In general, it appears that 3 years of therapy with about 2 years of optimal minimal residual disease is required prior to consideration for treatment-free remission, he said.

Dr. Mauro has consulted for and/or received research funding from Ariad, Bristol-Myers Squibb, Novartis, and Oregon Health & Science University.

[email protected]

CHICAGO – Chronic myeloid leukemia is highly treatable, and a “functional cure” appears to be within reach, according to Dr. Michael J. Mauro.

In fact, an “embarrassment of riches” exists when it comes to initial therapy for CML: In the United States there are five approved tyrosine kinase inhibitors (TKIs), and three are approved for front-line therapy, Dr. Mauro of Memorial Sloan Kettering Cancer Center, New York, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Success, however, is contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and remaining vigilant for late effects of therapy, he said.

Given the multitude of treatment options and the breadth of available data, Dr. Mauro said he counsels newly diagnosed patients that various treatment options are valid, and that “there may not be a right or wrong answer” for initial therapy. He also counsels patients that tolerability is manageable – and finding the right fit is an important process, and that response milestones are crucial and should be optimized.

It is important, he said, to discuss late toxicity concerns, to review comorbid conditions to help predict potential problems and identify risk, to consider the ramifications of potential toxicity, and to consider adherence.

“We need to portray therapy as really being medium- to long-term,” he said, noting that the urgency to think about treatment-free remission should be tempered by the reality that years of treatment are required first.

Risks and benefits of treatment should be discussed, and the acceptable balance determined in conjunction with the patient, he said, explaining that toxicities vary for the different TKIs.

Imatinib, for example, can be associated with edema/fluid retention, myalgias, hypophosphatemia, and gastrointestinal effects. Dasatinib can be associated with pleural/pericardial effusion, pulmonary arterial hypertension, and bleeding risk. Other toxicities associated with certain TKIs include pancreatic enzyme elevation, rash, and vascular adverse events.

Whether newly diagnosed patients should be directed away from certain agents remains unclear, as available data are open to interpretation, and the mechanism of action for some crucial late effects is unknown. Vascular disease should, however, be considered when making the decision, he said.

Given the available data on late toxicity with various therapies, a cardiovascular evaluation is advisable when initiating TKI therapy, he added.

Consider partnering with primary care, cardiology, or cardio-oncology specialists, and manage risk factors and findings of the evaluation as appropriate, irrespective of the CML, he said. Monitor for progression of cardiovascular risks or adverse events carefully, he added.

His approach for following recently diagnosed CML patients involves:

• A cardiovascular evaluation, at least including age- and comorbidity-appropriate studies, and an up-to-date cardiovascular risk profile. If nilotinib is used, he screens for peripheral, cerebral, and cardiovascular disease – an approach increasingly supported by data. If dasatinib is used, echocardiography is warranted to look for changes that suggest pulmonary hypertension. “And of course we should monitor blood pressure, lipid, and glycemic control,” he added.

• Initial studies, including bone marrow and quantitative polymerase chain reaction – international scale (qPCR IS).

• Lab studies every 1-2 weeks for at least 6 weeks, with titration thereafter as indicated, including for change in therapy.

• A 3-month assessment using qPCR IS. This is very important for following patient response, he said, noting that if the response surpasses compete cytogenetic remission and blood count is acceptable and stable, a repeat bone marrow study may be unnecessary.

• Sequential molecular analyses at least every 3 months.

• Repeat cardiovascular evaluation if/when indicated.

The 3-month response is an opportunity to critically appraise therapy choice and response trajectory; a therapy change is possible based on this assessment, he said. Responses at 6 and 12 months are also important, and changes in therapy for missed milestones at these time points are warranted as deeper remissions are sought.

At 18 months, the focus is on major molecular response, he added, noting that as patients get into deeper molecular remissions, plateaus and fluctuations are common; the nuances of determining who is well enough to consider for treatment-free remission remain to be sorted out in clinical trials.

In general, it appears that 3 years of therapy with about 2 years of optimal minimal residual disease is required prior to consideration for treatment-free remission, he said.

Dr. Mauro has consulted for and/or received research funding from Ariad, Bristol-Myers Squibb, Novartis, and Oregon Health & Science University.

[email protected]

CHICAGO – Chronic myeloid leukemia is highly treatable, and a “functional cure” appears to be within reach, according to Dr. Michael J. Mauro.

In fact, an “embarrassment of riches” exists when it comes to initial therapy for CML: In the United States there are five approved tyrosine kinase inhibitors (TKIs), and three are approved for front-line therapy, Dr. Mauro of Memorial Sloan Kettering Cancer Center, New York, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Success, however, is contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and remaining vigilant for late effects of therapy, he said.

Given the multitude of treatment options and the breadth of available data, Dr. Mauro said he counsels newly diagnosed patients that various treatment options are valid, and that “there may not be a right or wrong answer” for initial therapy. He also counsels patients that tolerability is manageable – and finding the right fit is an important process, and that response milestones are crucial and should be optimized.

It is important, he said, to discuss late toxicity concerns, to review comorbid conditions to help predict potential problems and identify risk, to consider the ramifications of potential toxicity, and to consider adherence.

“We need to portray therapy as really being medium- to long-term,” he said, noting that the urgency to think about treatment-free remission should be tempered by the reality that years of treatment are required first.

Risks and benefits of treatment should be discussed, and the acceptable balance determined in conjunction with the patient, he said, explaining that toxicities vary for the different TKIs.

Imatinib, for example, can be associated with edema/fluid retention, myalgias, hypophosphatemia, and gastrointestinal effects. Dasatinib can be associated with pleural/pericardial effusion, pulmonary arterial hypertension, and bleeding risk. Other toxicities associated with certain TKIs include pancreatic enzyme elevation, rash, and vascular adverse events.

Whether newly diagnosed patients should be directed away from certain agents remains unclear, as available data are open to interpretation, and the mechanism of action for some crucial late effects is unknown. Vascular disease should, however, be considered when making the decision, he said.

Given the available data on late toxicity with various therapies, a cardiovascular evaluation is advisable when initiating TKI therapy, he added.

Consider partnering with primary care, cardiology, or cardio-oncology specialists, and manage risk factors and findings of the evaluation as appropriate, irrespective of the CML, he said. Monitor for progression of cardiovascular risks or adverse events carefully, he added.

His approach for following recently diagnosed CML patients involves:

• A cardiovascular evaluation, at least including age- and comorbidity-appropriate studies, and an up-to-date cardiovascular risk profile. If nilotinib is used, he screens for peripheral, cerebral, and cardiovascular disease – an approach increasingly supported by data. If dasatinib is used, echocardiography is warranted to look for changes that suggest pulmonary hypertension. “And of course we should monitor blood pressure, lipid, and glycemic control,” he added.

• Initial studies, including bone marrow and quantitative polymerase chain reaction – international scale (qPCR IS).

• Lab studies every 1-2 weeks for at least 6 weeks, with titration thereafter as indicated, including for change in therapy.

• A 3-month assessment using qPCR IS. This is very important for following patient response, he said, noting that if the response surpasses compete cytogenetic remission and blood count is acceptable and stable, a repeat bone marrow study may be unnecessary.

• Sequential molecular analyses at least every 3 months.

• Repeat cardiovascular evaluation if/when indicated.

The 3-month response is an opportunity to critically appraise therapy choice and response trajectory; a therapy change is possible based on this assessment, he said. Responses at 6 and 12 months are also important, and changes in therapy for missed milestones at these time points are warranted as deeper remissions are sought.

At 18 months, the focus is on major molecular response, he added, noting that as patients get into deeper molecular remissions, plateaus and fluctuations are common; the nuances of determining who is well enough to consider for treatment-free remission remain to be sorted out in clinical trials.

In general, it appears that 3 years of therapy with about 2 years of optimal minimal residual disease is required prior to consideration for treatment-free remission, he said.

Dr. Mauro has consulted for and/or received research funding from Ariad, Bristol-Myers Squibb, Novartis, and Oregon Health & Science University.

[email protected]