Neil Shah, MD, PhD: How I Treat Chronic Myeloid Leukemia
Neil Shah, MD, PhD: How I Treat Chronic Myeloid Leukemia
The advent of tyrosine kinase inhibitors (TKIs) has radically altered the outcome of patients with chronic myeloid leukemia (CML). Patients with chronic-phase disease can now expect a 10-year survival of more than 80%, and may potentially be cured with continued TKI therapy. In addition, trials are under way to determine whether some patients with exceptional responses can have TKI therapy discontinued without subsequent relapse.
The major current issues include:
• Which TKI should be the initial preferred agent: the first-generation TKI imatinib, or the approved second-generation TKIs dasatinib and nilotinib, which appear to be more active in the short term, but so far have not had a long-term survival advantage over imatinib?
• Should physicians change TKIs early (3 months) on the basis of short-term disease response?
• What types of patients should be referred for discontinuation trials?
• How will treatment strategies change when imatinib becomes generic?
Both the European Leukemia Net (ELN) and the National Comprehensive Cancer Network (NCCN) have published guidelines outlining treatment milestones and choices based on the accomplishment—or not—of these goals. Shaping physician and patient behavior to be compliant with the monitoring regimen, so that optimal treatment management can be accomplished, remains an ongoing challenge.
To make sense of these options, as well as other issues in the management of CML, we are fortunate to have Neil P. Shah, MD, PhD, who leads the Hematopoietic Malignancies Program at UCSF Helen Diller Family Comprehensive Cancer Center, to describe his approach to treating CML.
—Jerald Radich, MD
Member, Clinical Research Division
Fred Hutchinson Cancer Research Center
Seattle, Washington
How do you pick an up-front TKI for a patient with newly diagnosed chronic-phase CML?
At the present time, my preference is to use the second-generation TKIs dasatinib and nilotinib in the first-line setting. I have been impressed by the ability of these agents to achieve significantly higher rates of milestone achievement compared with imatinib in large, randomized, head-to-head comparator studies, as well as their association with lower rates of disease transformation to accelerated- and blast-phase CML. Although the rate of transformation with imatinib is thankfully relatively low, it is important to bear in mind that the vast majority of these cases prove fatal, despite attempts to proceed with allogeneic stem cell transplantation when possible. When treating younger patients, in whom the goal is to potentially preserve decades of life, this issue is particularly relevant.
Furthermore, the ability of dasatinib and nilotinib to achieve a very deep molecular remission (≥ 4.5 logs) is encouraging, in light of evolving data that a proportion of patients who achieve and maintain such remissions for at least 1-2 years can discontinue TKI therapy and remain in molecular remission for at least several years. This may have considerable implications with respect to maintaining costs and minimizing the potential long-term toxicities of TKI therapy. Finally, the tolerability of these agents may be generally better than that of imatinib with respect to common bothersome side effects that many patients suffer.
Because there have been no head-to-head studies comparing nilotinib and dasatinib, and given that their superiority to imatinib appears generally comparable, I typically counsel patients that my preference is that they initiate therapy with one of these agents. I prefer to involve them in the decision-making process, and I inform them of the salient differences between the two drugs.
Nilotinib is administered twice daily while fasting; can be associated with pancreatitis, hyperglycemia, and cardiovascular and peripheral arterial occlusive events (which may be irreversible); and carries a US Food and Drug Administration-mandated black-box warning regarding sudden death and QT prolongation, which requires careful ECG monitoring. Dasatinib is administered once daily with or without food and can be associated with pleural effusion, an increased incidence of bleeding, and pulmonary arterial hypertension (which appears to be largely reversible).
I then leave the choice of which agent to initiate to the patient. Because adherence to therapy appears to be a critical determinant in response, I believe involving patients in the decision-making process can represent an important first step toward taking control of their medical care.
When do you switch TKIs—on the basis of early 3- or 6-month molecular response, or later?
Given the superior efficacy of second-generation TKIs, I switch TKI therapy in patients who initiate imatinib but fail to meet the 3-month or 12-month NCCN milestones despite reasonable adherence to therapy. Most progression events appear to occur early—within the first 3 years after initiating TKI therapy. I think it is especially important to identify patients who are not likely to fare well on imatinib early and to switch them to more active second-generation agents promptly.
In patients who initiate dasatinib or nilotinib in the front-line setting and fail to meet treatment milestones, the likelihood of responding to alternative agents is not as clear, so although a trial of an alternative second-generation agent or ponatinib is reasonable, it is also acceptable to give these agents a bit longer to achieve responses. However, these agents tend to achieve responses early, so I would start to think strongly about allogeneic stem cell transplantation or clinical trials in patients who may be suitable candidates.
When should ABL mutation testing be done, and how do you use this information?
Certainly, any patient with loss of response to therapy should have an ABL kinase mutation test performed to try to understand the mechanism of resistance and potentially steer the clinician toward the most appropriate next therapy. Of course, patients with loss of response should be questioned regarding adherence, because a patient who stops taking a TKI will appear to have acquired resistance to TKI therapy.
Any patient with failure to have a complete cytogenetic response (or a quantitative polymerase chain reaction level ≤ 1% on the International Scale) by 12 months should be evaluated for the presence of an ABL kinase mutation. Previous studies have shown that a proportion of such patients indeed have actionable mutations.
Although there are patients who fail to achieve 3-month milestone responses, I believe that mutation testing at this time is highly unlikely to identify a dominant mutation, simply because there has not been adequate time for TKI therapy to apply the degree of selective pressure required to observe mutations. However, there is certainly no harm in testing for mutations in patients who fail to achieve a 3-month milestone response. Methods of mutation detection are evolving, and there may be more sensitive clinical tests capable of identifying meaningful low-level actionable mutations in the near future.
It is especially important that a proper ABL kinase mutation test is performed. There are tests offered by some commercial vendors that assess whether a 35-nucleotide insertion of unclear significance is present in BCR-ABL, but will not assess for known resistance-conferring actionable kinase domain mutations. I see no utility in the 35-nucleotide insertion test at this time, and I strongly encourage clinicians to try to ensure that the proper assessment is performed, because it can have a profound impact on treatment response to alternative agents.
What patients should be enrolled in discontinuation trials?
I am aware of anecdotal cases of treatment discontinuation in which complete molecular remission had been maintained for more than 10 years. Formal treatment discontinuation studies represent a promising new frontier in the management of CML patients, and I would encourage all potentially eligible patients to participate in these trials.
At the moment, discontinuation studies are restricted to patients who were diagnosed with, and have remained in, chronic-phase CML. In some instances, enrollment is further restricted to patients who had low or intermediate (but not high) Sokal risk at diagnosis. Although the data evolving from the original discontinuation study are quite provocative and suggest minimal risk with discontinuation as long as careful monitoring is performed and therapy is promptly reinstituted when indicated, experience with discontinuation remains relatively limited to date. Therefore, discontinuation should not be formally recommended outside the context of a clinical trial. I cannot foresee clinical trials that would investigate treatment discontinuation in patients with a history of accelerated- or blast-phase CML.
How should generic imatinib be used?
Imatinib is scheduled to go off-patent in the United States in July 2015, and generic imatinib will reportedly be available in the United States in February 2016. At the present time, the cost of 1 year of imatinib approaches $100,000. The cost of generic imatinib remains to be determined.
Although it is reasonable to presume that generic imatinib will be equivalent to brand-name imatinib, there are likely to be concerns among CML patients and physicians with respect to this issue. Randomized clinical trials may be necessary to alleviate such fears. Presuming that generic imatinib is equipotent, there will probably be substantial pressure on practitioners to use imatinib whenever possible.
For unclear reasons, the cost of imatinib has more than tripled in the 13 years since it was approved. Newer TKIs have used the price of imatinib as a reference point and are priced 20%-50% higher. Given the current recommendations of indefinite administration in patients who are tolerating and responding to TKI therapy, coupled with the increasing prevalence of CML as a result of disease course modification by TKI therapy, the current situation appears unsustainable.
Previous studies have shown that 50%-60% of patients with chronic-phase CML who initiate imatinib remain on treatment and in complete cytogenetic response after 8 years. With this in mind, a reasonable approach may be to start generic imatinib in all patients, and assess response at 3 months. It is expected that 35% of patients will fail to achieve this milestone, and perhaps another 5%-10% may have tolerability issues, and these patients would be switched to second-generation agents. Such a strategy is predicted to result in long-term imatinib use in 50%-60% of patients and may result in considerable cost savings.
An alternative approach might involve rapid achievement of milestone response with dasatinib or nilotinib, followed by maintenance with generic imatinib. Of course, clinical data are currently lacking for such an approach, but these studies are very important from a pharmacoeconomic perspective. This may be a particularly attractive approach in younger patients, in whom minimizing disease transformation risk is especially critical.
It should be recognized that transformation rates with imatinib are relatively low, and one can argue that the likelihood of patients who receive a diagnosis at older ages (≥ 70 years) benefiting from initiation of second-generation TKI therapy is low. It may therefore be reasonable to initiate generic imatinib in all older individuals, who may be at greater risk of dying due to non–CML-related causes.
It may also be interesting to investigate the efficacy of lower doses of newer TKIs, which may be similar to the ultimate cost of generic imatinib. As an example from my clinical experience, I have several CML patients who have reduced their dasatinib dose from 100 mg to 50 or even 20 mg for tolerability reasons and have maintained their remission.
It is clear that there is much to be learned about generic imatinib and maximizing treatment outcomes in a fiscally responsible manner. To that end, the continued participation of patients in clinical trials is essential.
The advent of tyrosine kinase inhibitors (TKIs) has radically altered the outcome of patients with chronic myeloid leukemia (CML). Patients with chronic-phase disease can now expect a 10-year survival of more than 80%, and may potentially be cured with continued TKI therapy. In addition, trials are under way to determine whether some patients with exceptional responses can have TKI therapy discontinued without subsequent relapse.
|
|
|
Jerald Radich, MD |
The major current issues include:
• Which TKI should be the initial preferred agent: the first-generation TKI imatinib, or the approved second-generation TKIs dasatinib and nilotinib, which appear to be more active in the short term, but so far have not had a long-term survival advantage over imatinib?
• Should physicians change TKIs early (3 months) on the basis of short-term disease response?
• What types of patients should be referred for discontinuation trials?
• How will treatment strategies change when imatinib becomes generic?
Both the European Leukemia Net (ELN) and the National Comprehensive Cancer Network (NCCN) have published guidelines outlining treatment milestones and choices based on the accomplishment—or not—of these goals. Shaping physician and patient behavior to be compliant with the monitoring regimen, so that optimal treatment management can be accomplished, remains an ongoing challenge.
To make sense of these options, as well as other issues in the management of CML, we are fortunate to have Neil P. Shah, MD, PhD, who leads the Hematopoietic Malignancies Program at UCSF Helen Diller Family Comprehensive Cancer Center, to describe his approach to treating CML.
—Jerald Radich, MD
Member, Clinical Research Division
Fred Hutchinson Cancer Research Center
Seattle, Washington
How do you pick an up-front TKI for a patient with newly diagnosed chronic-phase CML?
|
|
|
Neil P. Shah, MD, PhD |
At the present time, my preference is to use the second-generation TKIs dasatinib and nilotinib in the first-line setting. I have been impressed by the ability of these agents to achieve significantly higher rates of milestone achievement compared with imatinib in large, randomized, head-to-head comparator studies, as well as their association with lower rates of disease transformation to accelerated- and blast-phase CML. Although the rate of transformation with imatinib is thankfully relatively low, it is important to bear in mind that the vast majority of these cases prove fatal, despite attempts to proceed with allogeneic stem cell transplantation when possible. When treating younger patients, in whom the goal is to potentially preserve decades of life, this issue is particularly relevant.
Furthermore, the ability of dasatinib and nilotinib to achieve a very deep molecular remission (≥ 4.5 logs) is encouraging, in light of evolving data that a proportion of patients who achieve and maintain such remissions for at least 1-2 years can discontinue TKI therapy and remain in molecular remission for at least several years. This may have considerable implications with respect to maintaining costs and minimizing the potential long-term toxicities of TKI therapy. Finally, the tolerability of these agents may be generally better than that of imatinib with respect to common bothersome side effects that many patients suffer.
Because there have been no head-to-head studies comparing nilotinib and dasatinib, and given that their superiority to imatinib appears generally comparable, I typically counsel patients that my preference is that they initiate therapy with one of these agents. I prefer to involve them in the decision-making process, and I inform them of the salient differences between the two drugs.
Nilotinib is administered twice daily while fasting; can be associated with pancreatitis, hyperglycemia, and cardiovascular and peripheral arterial occlusive events (which may be irreversible); and carries a US Food and Drug Administration-mandated black-box warning regarding sudden death and QT prolongation, which requires careful ECG monitoring. Dasatinib is administered once daily with or without food and can be associated with pleural effusion, an increased incidence of bleeding, and pulmonary arterial hypertension (which appears to be largely reversible).
I then leave the choice of which agent to initiate to the patient. Because adherence to therapy appears to be a critical determinant in response, I believe involving patients in the decision-making process can represent an important first step toward taking control of their medical care.
When do you switch TKIs—on the basis of early 3- or 6-month molecular response, or later?
Given the superior efficacy of second-generation TKIs, I switch TKI therapy in patients who initiate imatinib but fail to meet the 3-month or 12-month NCCN milestones despite reasonable adherence to therapy. Most progression events appear to occur early—within the first 3 years after initiating TKI therapy. I think it is especially important to identify patients who are not likely to fare well on imatinib early and to switch them to more active second-generation agents promptly.
In patients who initiate dasatinib or nilotinib in the front-line setting and fail to meet treatment milestones, the likelihood of responding to alternative agents is not as clear, so although a trial of an alternative second-generation agent or ponatinib is reasonable, it is also acceptable to give these agents a bit longer to achieve responses. However, these agents tend to achieve responses early, so I would start to think strongly about allogeneic stem cell transplantation or clinical trials in patients who may be suitable candidates.
When should ABL mutation testing be done, and how do you use this information?
Certainly, any patient with loss of response to therapy should have an ABL kinase mutation test performed to try to understand the mechanism of resistance and potentially steer the clinician toward the most appropriate next therapy. Of course, patients with loss of response should be questioned regarding adherence, because a patient who stops taking a TKI will appear to have acquired resistance to TKI therapy.
Any patient with failure to have a complete cytogenetic response (or a quantitative polymerase chain reaction level ≤ 1% on the International Scale) by 12 months should be evaluated for the presence of an ABL kinase mutation. Previous studies have shown that a proportion of such patients indeed have actionable mutations.
Although there are patients who fail to achieve 3-month milestone responses, I believe that mutation testing at this time is highly unlikely to identify a dominant mutation, simply because there has not been adequate time for TKI therapy to apply the degree of selective pressure required to observe mutations. However, there is certainly no harm in testing for mutations in patients who fail to achieve a 3-month milestone response. Methods of mutation detection are evolving, and there may be more sensitive clinical tests capable of identifying meaningful low-level actionable mutations in the near future.
It is especially important that a proper ABL kinase mutation test is performed. There are tests offered by some commercial vendors that assess whether a 35-nucleotide insertion of unclear significance is present in BCR-ABL, but will not assess for known resistance-conferring actionable kinase domain mutations. I see no utility in the 35-nucleotide insertion test at this time, and I strongly encourage clinicians to try to ensure that the proper assessment is performed, because it can have a profound impact on treatment response to alternative agents.
What patients should be enrolled in discontinuation trials?
I am aware of anecdotal cases of treatment discontinuation in which complete molecular remission had been maintained for more than 10 years. Formal treatment discontinuation studies represent a promising new frontier in the management of CML patients, and I would encourage all potentially eligible patients to participate in these trials.
At the moment, discontinuation studies are restricted to patients who were diagnosed with, and have remained in, chronic-phase CML. In some instances, enrollment is further restricted to patients who had low or intermediate (but not high) Sokal risk at diagnosis. Although the data evolving from the original discontinuation study are quite provocative and suggest minimal risk with discontinuation as long as careful monitoring is performed and therapy is promptly reinstituted when indicated, experience with discontinuation remains relatively limited to date. Therefore, discontinuation should not be formally recommended outside the context of a clinical trial. I cannot foresee clinical trials that would investigate treatment discontinuation in patients with a history of accelerated- or blast-phase CML.
How should generic imatinib be used?
Imatinib is scheduled to go off-patent in the United States in July 2015, and generic imatinib will reportedly be available in the United States in February 2016. At the present time, the cost of 1 year of imatinib approaches $100,000. The cost of generic imatinib remains to be determined.
Although it is reasonable to presume that generic imatinib will be equivalent to brand-name imatinib, there are likely to be concerns among CML patients and physicians with respect to this issue. Randomized clinical trials may be necessary to alleviate such fears. Presuming that generic imatinib is equipotent, there will probably be substantial pressure on practitioners to use imatinib whenever possible.
For unclear reasons, the cost of imatinib has more than tripled in the 13 years since it was approved. Newer TKIs have used the price of imatinib as a reference point and are priced 20%-50% higher. Given the current recommendations of indefinite administration in patients who are tolerating and responding to TKI therapy, coupled with the increasing prevalence of CML as a result of disease course modification by TKI therapy, the current situation appears unsustainable.
Previous studies have shown that 50%-60% of patients with chronic-phase CML who initiate imatinib remain on treatment and in complete cytogenetic response after 8 years. With this in mind, a reasonable approach may be to start generic imatinib in all patients, and assess response at 3 months. It is expected that 35% of patients will fail to achieve this milestone, and perhaps another 5%-10% may have tolerability issues, and these patients would be switched to second-generation agents. Such a strategy is predicted to result in long-term imatinib use in 50%-60% of patients and may result in considerable cost savings.
An alternative approach might involve rapid achievement of milestone response with dasatinib or nilotinib, followed by maintenance with generic imatinib. Of course, clinical data are currently lacking for such an approach, but these studies are very important from a pharmacoeconomic perspective. This may be a particularly attractive approach in younger patients, in whom minimizing disease transformation risk is especially critical.
It should be recognized that transformation rates with imatinib are relatively low, and one can argue that the likelihood of patients who receive a diagnosis at older ages (≥ 70 years) benefiting from initiation of second-generation TKI therapy is low. It may therefore be reasonable to initiate generic imatinib in all older individuals, who may be at greater risk of dying due to non–CML-related causes.
It may also be interesting to investigate the efficacy of lower doses of newer TKIs, which may be similar to the ultimate cost of generic imatinib. As an example from my clinical experience, I have several CML patients who have reduced their dasatinib dose from 100 mg to 50 or even 20 mg for tolerability reasons and have maintained their remission.
It is clear that there is much to be learned about generic imatinib and maximizing treatment outcomes in a fiscally responsible manner. To that end, the continued participation of patients in clinical trials is essential.
Source...