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The prognosis of AML in the elderly is very poor, with 5-year survival rates less than 10% in patients aged 65 years and older. However, Have we begun to witness an improvement in the survival of these patients?
Several clinical trials and observational registration studies have made it very clear that, without treatment, the survival in AML is very short – ranging from 11-16 weeks (for patients enrolled in therapeutic trials who received best supportive care only) to only 6-8 weeks in the “real-world” setting, based upon observational studies.1,2,3,4
These data are very meaningful because older AML patients often do not receive active therapy. As recently as 2009, SEER data indicate that 50% of patients aged 65 years or older receive no treatment for AML. This trend appears to be changing, based upon data from the AMLSG in 2012-2014, in which only a minority of patients in this age range received best supportive care only for their AML.
Knowing the very poor outcomes of patients who are not treated for AML, along with a high number of patients who are not treated, we must next ask whether any treatment at all is superior to no treatment. The data appear relatively clear on this question, with two representative publications highlighting the superiority of treatment vs. no treatment. First, in the SEER registry analysis by Medeiros et al., treated patients had a median survival of 5 months, compared with 2.5 months in untreated patients, and there was an unequivocal survival advantage attributed to treatment after adjustment for covariates and propensity score matching. Treatment included both traditional induction regimens and hypomethylating agent (HMA) therapy. Similarly, a phase 3 clinical trial testing low-dose cytarabine (LDAC) vs. best supportive care demonstrated survival improvement with LDAC (odds ratio, 0.60).
Recognizing that treatment improves survival in older adults with AML and that there is an upward trend in the percent of patients who receive active therapy, we can reasonably ask next whether survival has begun to trend upward over the past several years. This, of course, is a challenging question, but one that can be at least partially addressed through analyses of registration cohorts.
SEER data regarding AML patients aged 65 and older from the 1970s to 2013 suggest modestly improved 2-year survival, from less than 10% in the 1970s to 10%-15% since the early 2000s. The Moffitt Cancer Center database of patients aged 70 years and older also indicates a strong trend toward modestly improved survival after 2005, compared with prior to 2005 (unpublished data). Although the precise reason for trending improvements in overall survival of these patients over time is not clear, it is reasonable to suggest that a greater proportion of patients who receive actual therapy for AML could explain the modest improvements being observed. Improvements in supportive care through the years could also contribute to survival improvement trends over time, though this hypothesis has not been formally tested.
Next, we should ask about the most effective currently available therapy for older adults with AML. Standard treatment options for these patients, as mentioned previously, include high-intensity (traditional induction chemotherapy) and lower-intensity (LDAC, HMAs) regimens. Unfortunately, a prospective, randomized comparison between such regimens has not been undertaken, so it is impossible to declare with any certainty as to the superiority of one approach versus another. Larger database analyses, utilizing multivariate cox regression analyses, have been performed, suggesting that HMAs and intensive therapies perform similarly, such that offering an older adult with AML frontline therapy with a lower-intensity regimen is very reasonable.5
It is quite important to address the possibility that newer therapies in AML are changing the natural history of the disease. First of all, strategies utilizing HMA therapy with 5-azacitidine or decitabine have been widely studied. Unfortunately, a clear and convincing signal of survival benefit of frontline HMA therapy, compared with conventional care regimens (most commonly LDAC) has not been demonstrated, although trends toward a very modest survival advantage favoring HMAs were observed.6,7
Interestingly, in the AZA-AML-001 study, only the subgroup of patients who were preselected to receive best supportive care achieved survival benefit from 5-azacitidine, again suggesting that treatment vs. no treatment is among the most important factors leading to survival improvement in elderly AML.
Other novel agents are coming to the forefront, with the potential to change the natural history of AML in elderly patients. CPX-351 is a liposomal product that encapsulates cytarabine and daunorubicin in a fixed and synergistic molar ratio, thereby allowing delivery of both agents to the leukemic cell in the optimal fashion for cell kill. A recently completed phase 3 trial in older adults with secondary AML demonstrated statistically significant survival improvement with CPX-351 as compared with traditional daunorubicin plus cytarabine induction. A substantial minority of patients on this trial went to allogeneic hematopoietic cell transplant during first remission, and a landmark analysis performed at the time of transplant indicated better survival among patients who had received initial therapy with CPX-351.8
These data suggest that, in selected older adults with secondary AML who are fit enough to receive induction chemotherapy, CPX-351 offers a survival advantage, even among traditionally higher-risk subgroups, including patients with adverse karyotype of above age 70 years. As such, CPX-351 (Vyxeos) received FDA approval as frontline therapy for secondary AML in 2017.
Newer targeted therapies for older adults with AML also appear to hold promise. Glasdegib, an inhibitor of SMO (part of the hedgehog signaling pathway) was recently studied in combination with LDAC versus LDAC alone in a randomized phase 2 trial in older patients considered unfit for intensive induction chemotherapy. In this trial, patients assigned to glasdegib plus LDAC had longer median and overall survival than patients treated with LDAC alone, suggesting a promising novel agent on the horizon.9
Another example of a promising and novel targeted agent for AML is venetoclax, an inhibitor of BCL-2. Encouragingly high response rates and overall survival in phase 2 trials that combined venetoclax with LDAC or HMAs have driven randomized trials to definitively ascertain a survival advantage in older patients considered unfit for intensive therapy.10,11
The question also arises as to whether therapeutic outcomes can be optimized by better selection of currently available therapies for any given. This concept requires development of a decision analysis model that can be used to accurately predict outcomes among older patients with newly diagnosed AML. At Moffitt Cancer Center, such a model is being developed using a systematic review of the literature, followed by validation in a large institutional database. To date, there is the strong initial suggestion that initial therapy selection can be optimized for best outcome, taking into account variables including ECOG performance status, Charlson Comorbidity Index, and cytogenetic risk.12
The goal of improving survival in older adults with AML remains elusive. The decision to treat (regardless of high vs. low intensity) appears critical toward achieving this goal. New therapies such as CPX-351, glasdegib, and venetoclax also hold promise in further improving survival in subgroups of older patients. Finally, development of accurate predictive models to optimize initial therapy will be of critical importance for improving survival in this very heterogeneous disease that afflicts a very heterogeneous group of patients.
Dr. Lancet is chair of the department of malignant hematology at H. Lee Moffitt Cancer Center in Tampa. He has received consulting fees from Astellas, BioSight, Celgene, Janssen R&D, and Jazz Pharmaceuticals.
References
1. Burnett AK et al. Cancer. 2007 Mar 15;109(6):1114-24.
2. Harousseau JL et al. Blood. 2009 Aug 6;114(6):1166-73.
3. Medeiros BC et al. Ann Hematol. 2015 Mar 20; 94(7):1127-38.
4. Oran B et al. Haematologica. 2012 Dec;97(12):1916-24.
5. Lancet JE et al. J Clin Oncol. 2017. doi: 10.1200/JCO.2017.35.15_suppl.7031.
6. Dombret H et al. Blood. 2015 Jul 16;126(3):291-9.
7. Kantarjian HM et al. J Clin Oncol. 2012 Jul 20;30(21):2670-7.
8. Lancet JE et al. Blood 2016 128:906.
9. Cortes JE et al. Blood 2016 128:99.
10. DiNardo CD et al. Blood 2017 130:2628.
11. Wei A et al. Blood 2017 130:890.
12. Extermann M et al. SIOG 2017.
The prognosis of AML in the elderly is very poor, with 5-year survival rates less than 10% in patients aged 65 years and older. However, Have we begun to witness an improvement in the survival of these patients?
Several clinical trials and observational registration studies have made it very clear that, without treatment, the survival in AML is very short – ranging from 11-16 weeks (for patients enrolled in therapeutic trials who received best supportive care only) to only 6-8 weeks in the “real-world” setting, based upon observational studies.1,2,3,4
These data are very meaningful because older AML patients often do not receive active therapy. As recently as 2009, SEER data indicate that 50% of patients aged 65 years or older receive no treatment for AML. This trend appears to be changing, based upon data from the AMLSG in 2012-2014, in which only a minority of patients in this age range received best supportive care only for their AML.
Knowing the very poor outcomes of patients who are not treated for AML, along with a high number of patients who are not treated, we must next ask whether any treatment at all is superior to no treatment. The data appear relatively clear on this question, with two representative publications highlighting the superiority of treatment vs. no treatment. First, in the SEER registry analysis by Medeiros et al., treated patients had a median survival of 5 months, compared with 2.5 months in untreated patients, and there was an unequivocal survival advantage attributed to treatment after adjustment for covariates and propensity score matching. Treatment included both traditional induction regimens and hypomethylating agent (HMA) therapy. Similarly, a phase 3 clinical trial testing low-dose cytarabine (LDAC) vs. best supportive care demonstrated survival improvement with LDAC (odds ratio, 0.60).
Recognizing that treatment improves survival in older adults with AML and that there is an upward trend in the percent of patients who receive active therapy, we can reasonably ask next whether survival has begun to trend upward over the past several years. This, of course, is a challenging question, but one that can be at least partially addressed through analyses of registration cohorts.
SEER data regarding AML patients aged 65 and older from the 1970s to 2013 suggest modestly improved 2-year survival, from less than 10% in the 1970s to 10%-15% since the early 2000s. The Moffitt Cancer Center database of patients aged 70 years and older also indicates a strong trend toward modestly improved survival after 2005, compared with prior to 2005 (unpublished data). Although the precise reason for trending improvements in overall survival of these patients over time is not clear, it is reasonable to suggest that a greater proportion of patients who receive actual therapy for AML could explain the modest improvements being observed. Improvements in supportive care through the years could also contribute to survival improvement trends over time, though this hypothesis has not been formally tested.
Next, we should ask about the most effective currently available therapy for older adults with AML. Standard treatment options for these patients, as mentioned previously, include high-intensity (traditional induction chemotherapy) and lower-intensity (LDAC, HMAs) regimens. Unfortunately, a prospective, randomized comparison between such regimens has not been undertaken, so it is impossible to declare with any certainty as to the superiority of one approach versus another. Larger database analyses, utilizing multivariate cox regression analyses, have been performed, suggesting that HMAs and intensive therapies perform similarly, such that offering an older adult with AML frontline therapy with a lower-intensity regimen is very reasonable.5
It is quite important to address the possibility that newer therapies in AML are changing the natural history of the disease. First of all, strategies utilizing HMA therapy with 5-azacitidine or decitabine have been widely studied. Unfortunately, a clear and convincing signal of survival benefit of frontline HMA therapy, compared with conventional care regimens (most commonly LDAC) has not been demonstrated, although trends toward a very modest survival advantage favoring HMAs were observed.6,7
Interestingly, in the AZA-AML-001 study, only the subgroup of patients who were preselected to receive best supportive care achieved survival benefit from 5-azacitidine, again suggesting that treatment vs. no treatment is among the most important factors leading to survival improvement in elderly AML.
Other novel agents are coming to the forefront, with the potential to change the natural history of AML in elderly patients. CPX-351 is a liposomal product that encapsulates cytarabine and daunorubicin in a fixed and synergistic molar ratio, thereby allowing delivery of both agents to the leukemic cell in the optimal fashion for cell kill. A recently completed phase 3 trial in older adults with secondary AML demonstrated statistically significant survival improvement with CPX-351 as compared with traditional daunorubicin plus cytarabine induction. A substantial minority of patients on this trial went to allogeneic hematopoietic cell transplant during first remission, and a landmark analysis performed at the time of transplant indicated better survival among patients who had received initial therapy with CPX-351.8
These data suggest that, in selected older adults with secondary AML who are fit enough to receive induction chemotherapy, CPX-351 offers a survival advantage, even among traditionally higher-risk subgroups, including patients with adverse karyotype of above age 70 years. As such, CPX-351 (Vyxeos) received FDA approval as frontline therapy for secondary AML in 2017.
Newer targeted therapies for older adults with AML also appear to hold promise. Glasdegib, an inhibitor of SMO (part of the hedgehog signaling pathway) was recently studied in combination with LDAC versus LDAC alone in a randomized phase 2 trial in older patients considered unfit for intensive induction chemotherapy. In this trial, patients assigned to glasdegib plus LDAC had longer median and overall survival than patients treated with LDAC alone, suggesting a promising novel agent on the horizon.9
Another example of a promising and novel targeted agent for AML is venetoclax, an inhibitor of BCL-2. Encouragingly high response rates and overall survival in phase 2 trials that combined venetoclax with LDAC or HMAs have driven randomized trials to definitively ascertain a survival advantage in older patients considered unfit for intensive therapy.10,11
The question also arises as to whether therapeutic outcomes can be optimized by better selection of currently available therapies for any given. This concept requires development of a decision analysis model that can be used to accurately predict outcomes among older patients with newly diagnosed AML. At Moffitt Cancer Center, such a model is being developed using a systematic review of the literature, followed by validation in a large institutional database. To date, there is the strong initial suggestion that initial therapy selection can be optimized for best outcome, taking into account variables including ECOG performance status, Charlson Comorbidity Index, and cytogenetic risk.12
The goal of improving survival in older adults with AML remains elusive. The decision to treat (regardless of high vs. low intensity) appears critical toward achieving this goal. New therapies such as CPX-351, glasdegib, and venetoclax also hold promise in further improving survival in subgroups of older patients. Finally, development of accurate predictive models to optimize initial therapy will be of critical importance for improving survival in this very heterogeneous disease that afflicts a very heterogeneous group of patients.
Dr. Lancet is chair of the department of malignant hematology at H. Lee Moffitt Cancer Center in Tampa. He has received consulting fees from Astellas, BioSight, Celgene, Janssen R&D, and Jazz Pharmaceuticals.
References
1. Burnett AK et al. Cancer. 2007 Mar 15;109(6):1114-24.
2. Harousseau JL et al. Blood. 2009 Aug 6;114(6):1166-73.
3. Medeiros BC et al. Ann Hematol. 2015 Mar 20; 94(7):1127-38.
4. Oran B et al. Haematologica. 2012 Dec;97(12):1916-24.
5. Lancet JE et al. J Clin Oncol. 2017. doi: 10.1200/JCO.2017.35.15_suppl.7031.
6. Dombret H et al. Blood. 2015 Jul 16;126(3):291-9.
7. Kantarjian HM et al. J Clin Oncol. 2012 Jul 20;30(21):2670-7.
8. Lancet JE et al. Blood 2016 128:906.
9. Cortes JE et al. Blood 2016 128:99.
10. DiNardo CD et al. Blood 2017 130:2628.
11. Wei A et al. Blood 2017 130:890.
12. Extermann M et al. SIOG 2017.
The prognosis of AML in the elderly is very poor, with 5-year survival rates less than 10% in patients aged 65 years and older. However, Have we begun to witness an improvement in the survival of these patients?
Several clinical trials and observational registration studies have made it very clear that, without treatment, the survival in AML is very short – ranging from 11-16 weeks (for patients enrolled in therapeutic trials who received best supportive care only) to only 6-8 weeks in the “real-world” setting, based upon observational studies.1,2,3,4
These data are very meaningful because older AML patients often do not receive active therapy. As recently as 2009, SEER data indicate that 50% of patients aged 65 years or older receive no treatment for AML. This trend appears to be changing, based upon data from the AMLSG in 2012-2014, in which only a minority of patients in this age range received best supportive care only for their AML.
Knowing the very poor outcomes of patients who are not treated for AML, along with a high number of patients who are not treated, we must next ask whether any treatment at all is superior to no treatment. The data appear relatively clear on this question, with two representative publications highlighting the superiority of treatment vs. no treatment. First, in the SEER registry analysis by Medeiros et al., treated patients had a median survival of 5 months, compared with 2.5 months in untreated patients, and there was an unequivocal survival advantage attributed to treatment after adjustment for covariates and propensity score matching. Treatment included both traditional induction regimens and hypomethylating agent (HMA) therapy. Similarly, a phase 3 clinical trial testing low-dose cytarabine (LDAC) vs. best supportive care demonstrated survival improvement with LDAC (odds ratio, 0.60).
Recognizing that treatment improves survival in older adults with AML and that there is an upward trend in the percent of patients who receive active therapy, we can reasonably ask next whether survival has begun to trend upward over the past several years. This, of course, is a challenging question, but one that can be at least partially addressed through analyses of registration cohorts.
SEER data regarding AML patients aged 65 and older from the 1970s to 2013 suggest modestly improved 2-year survival, from less than 10% in the 1970s to 10%-15% since the early 2000s. The Moffitt Cancer Center database of patients aged 70 years and older also indicates a strong trend toward modestly improved survival after 2005, compared with prior to 2005 (unpublished data). Although the precise reason for trending improvements in overall survival of these patients over time is not clear, it is reasonable to suggest that a greater proportion of patients who receive actual therapy for AML could explain the modest improvements being observed. Improvements in supportive care through the years could also contribute to survival improvement trends over time, though this hypothesis has not been formally tested.
Next, we should ask about the most effective currently available therapy for older adults with AML. Standard treatment options for these patients, as mentioned previously, include high-intensity (traditional induction chemotherapy) and lower-intensity (LDAC, HMAs) regimens. Unfortunately, a prospective, randomized comparison between such regimens has not been undertaken, so it is impossible to declare with any certainty as to the superiority of one approach versus another. Larger database analyses, utilizing multivariate cox regression analyses, have been performed, suggesting that HMAs and intensive therapies perform similarly, such that offering an older adult with AML frontline therapy with a lower-intensity regimen is very reasonable.5
It is quite important to address the possibility that newer therapies in AML are changing the natural history of the disease. First of all, strategies utilizing HMA therapy with 5-azacitidine or decitabine have been widely studied. Unfortunately, a clear and convincing signal of survival benefit of frontline HMA therapy, compared with conventional care regimens (most commonly LDAC) has not been demonstrated, although trends toward a very modest survival advantage favoring HMAs were observed.6,7
Interestingly, in the AZA-AML-001 study, only the subgroup of patients who were preselected to receive best supportive care achieved survival benefit from 5-azacitidine, again suggesting that treatment vs. no treatment is among the most important factors leading to survival improvement in elderly AML.
Other novel agents are coming to the forefront, with the potential to change the natural history of AML in elderly patients. CPX-351 is a liposomal product that encapsulates cytarabine and daunorubicin in a fixed and synergistic molar ratio, thereby allowing delivery of both agents to the leukemic cell in the optimal fashion for cell kill. A recently completed phase 3 trial in older adults with secondary AML demonstrated statistically significant survival improvement with CPX-351 as compared with traditional daunorubicin plus cytarabine induction. A substantial minority of patients on this trial went to allogeneic hematopoietic cell transplant during first remission, and a landmark analysis performed at the time of transplant indicated better survival among patients who had received initial therapy with CPX-351.8
These data suggest that, in selected older adults with secondary AML who are fit enough to receive induction chemotherapy, CPX-351 offers a survival advantage, even among traditionally higher-risk subgroups, including patients with adverse karyotype of above age 70 years. As such, CPX-351 (Vyxeos) received FDA approval as frontline therapy for secondary AML in 2017.
Newer targeted therapies for older adults with AML also appear to hold promise. Glasdegib, an inhibitor of SMO (part of the hedgehog signaling pathway) was recently studied in combination with LDAC versus LDAC alone in a randomized phase 2 trial in older patients considered unfit for intensive induction chemotherapy. In this trial, patients assigned to glasdegib plus LDAC had longer median and overall survival than patients treated with LDAC alone, suggesting a promising novel agent on the horizon.9
Another example of a promising and novel targeted agent for AML is venetoclax, an inhibitor of BCL-2. Encouragingly high response rates and overall survival in phase 2 trials that combined venetoclax with LDAC or HMAs have driven randomized trials to definitively ascertain a survival advantage in older patients considered unfit for intensive therapy.10,11
The question also arises as to whether therapeutic outcomes can be optimized by better selection of currently available therapies for any given. This concept requires development of a decision analysis model that can be used to accurately predict outcomes among older patients with newly diagnosed AML. At Moffitt Cancer Center, such a model is being developed using a systematic review of the literature, followed by validation in a large institutional database. To date, there is the strong initial suggestion that initial therapy selection can be optimized for best outcome, taking into account variables including ECOG performance status, Charlson Comorbidity Index, and cytogenetic risk.12
The goal of improving survival in older adults with AML remains elusive. The decision to treat (regardless of high vs. low intensity) appears critical toward achieving this goal. New therapies such as CPX-351, glasdegib, and venetoclax also hold promise in further improving survival in subgroups of older patients. Finally, development of accurate predictive models to optimize initial therapy will be of critical importance for improving survival in this very heterogeneous disease that afflicts a very heterogeneous group of patients.
Dr. Lancet is chair of the department of malignant hematology at H. Lee Moffitt Cancer Center in Tampa. He has received consulting fees from Astellas, BioSight, Celgene, Janssen R&D, and Jazz Pharmaceuticals.
References
1. Burnett AK et al. Cancer. 2007 Mar 15;109(6):1114-24.
2. Harousseau JL et al. Blood. 2009 Aug 6;114(6):1166-73.
3. Medeiros BC et al. Ann Hematol. 2015 Mar 20; 94(7):1127-38.
4. Oran B et al. Haematologica. 2012 Dec;97(12):1916-24.
5. Lancet JE et al. J Clin Oncol. 2017. doi: 10.1200/JCO.2017.35.15_suppl.7031.
6. Dombret H et al. Blood. 2015 Jul 16;126(3):291-9.
7. Kantarjian HM et al. J Clin Oncol. 2012 Jul 20;30(21):2670-7.
8. Lancet JE et al. Blood 2016 128:906.
9. Cortes JE et al. Blood 2016 128:99.
10. DiNardo CD et al. Blood 2017 130:2628.
11. Wei A et al. Blood 2017 130:890.
12. Extermann M et al. SIOG 2017.