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Improving survival in older AML patients
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.
Potential therapeutic target for type of AML
New research suggests SHARP1 may be a therapeutic target in MLL-AF6 acute myeloid leukemia (AML).
Researchers found that SHARP1, a circadian clock transcription factor, is overexpressed in MLL-AF6 AML.
In mouse models, suppression of SHARP1 induced apoptosis in leukemic cells, while deletion of SHARP1 delayed AML development and weakened leukemia-initiating potential.
“We found that MLL-AF6 binds with SHARP1, leading to an increase in the level of SHARP1,” explained study author Dan Tenen, MD, of the Cancer Science Institute of Singapore.
“The increase of SHARP1 levels has the 2-fold effect of initiating leukemia development, as well as maintaining the growth of leukemic cells. [O]ur study also revealed that SHARP1 could act upon other target genes of MLL-AF6 to aggravate the progression of AML, but, by removing or reducing the level of SHARP1, the growth of leukemic cells could be stopped.”
Dr Tenen and his colleagues reported these findings in Nature Communications.
The researchers found that SHARP1 was overexpressed in MLL-AF6 AML, but its expression was decreased in most other subtypes of AML analyzed as well as in normal bone marrow CD34+ cells.
Experiments in AML cell lines revealed that SHARP1 expression is regulated by MLL-AF6/DOT1L. The researchers said MLL-AF6 and MEN1/LEDGF directly bind to the SHARP1 gene locus to positively regulate SHARP1 expression through DOT1L activity.
Dr Tenen and his colleagues performed knockdown experiments in mice and found that SHARP1 plays a “critical” role in maintaining clonogenic growth and preventing apoptosis in MLL-AF6 AML cells.
The team also assessed the effects of SHARP1 deletion in mouse models of MLL-AF6 AML.
SHARP1 knockout mice had superior survival compared to wild-type mice. In addition, the knockout mice exhibited signs of less aggressive disease—fewer AML cells, lower white blood cell counts, and higher red blood cell counts.
The researchers also found that SHARP1 deletion reduced MLL-AF6 leukemia-initiating ability but did not affect normal hematopoiesis.
Finally, the team discovered that SHARP1 cooperates with MLL-AF6 to regulate target genes in MLL-AF6 AML cells.
New research suggests SHARP1 may be a therapeutic target in MLL-AF6 acute myeloid leukemia (AML).
Researchers found that SHARP1, a circadian clock transcription factor, is overexpressed in MLL-AF6 AML.
In mouse models, suppression of SHARP1 induced apoptosis in leukemic cells, while deletion of SHARP1 delayed AML development and weakened leukemia-initiating potential.
“We found that MLL-AF6 binds with SHARP1, leading to an increase in the level of SHARP1,” explained study author Dan Tenen, MD, of the Cancer Science Institute of Singapore.
“The increase of SHARP1 levels has the 2-fold effect of initiating leukemia development, as well as maintaining the growth of leukemic cells. [O]ur study also revealed that SHARP1 could act upon other target genes of MLL-AF6 to aggravate the progression of AML, but, by removing or reducing the level of SHARP1, the growth of leukemic cells could be stopped.”
Dr Tenen and his colleagues reported these findings in Nature Communications.
The researchers found that SHARP1 was overexpressed in MLL-AF6 AML, but its expression was decreased in most other subtypes of AML analyzed as well as in normal bone marrow CD34+ cells.
Experiments in AML cell lines revealed that SHARP1 expression is regulated by MLL-AF6/DOT1L. The researchers said MLL-AF6 and MEN1/LEDGF directly bind to the SHARP1 gene locus to positively regulate SHARP1 expression through DOT1L activity.
Dr Tenen and his colleagues performed knockdown experiments in mice and found that SHARP1 plays a “critical” role in maintaining clonogenic growth and preventing apoptosis in MLL-AF6 AML cells.
The team also assessed the effects of SHARP1 deletion in mouse models of MLL-AF6 AML.
SHARP1 knockout mice had superior survival compared to wild-type mice. In addition, the knockout mice exhibited signs of less aggressive disease—fewer AML cells, lower white blood cell counts, and higher red blood cell counts.
The researchers also found that SHARP1 deletion reduced MLL-AF6 leukemia-initiating ability but did not affect normal hematopoiesis.
Finally, the team discovered that SHARP1 cooperates with MLL-AF6 to regulate target genes in MLL-AF6 AML cells.
New research suggests SHARP1 may be a therapeutic target in MLL-AF6 acute myeloid leukemia (AML).
Researchers found that SHARP1, a circadian clock transcription factor, is overexpressed in MLL-AF6 AML.
In mouse models, suppression of SHARP1 induced apoptosis in leukemic cells, while deletion of SHARP1 delayed AML development and weakened leukemia-initiating potential.
“We found that MLL-AF6 binds with SHARP1, leading to an increase in the level of SHARP1,” explained study author Dan Tenen, MD, of the Cancer Science Institute of Singapore.
“The increase of SHARP1 levels has the 2-fold effect of initiating leukemia development, as well as maintaining the growth of leukemic cells. [O]ur study also revealed that SHARP1 could act upon other target genes of MLL-AF6 to aggravate the progression of AML, but, by removing or reducing the level of SHARP1, the growth of leukemic cells could be stopped.”
Dr Tenen and his colleagues reported these findings in Nature Communications.
The researchers found that SHARP1 was overexpressed in MLL-AF6 AML, but its expression was decreased in most other subtypes of AML analyzed as well as in normal bone marrow CD34+ cells.
Experiments in AML cell lines revealed that SHARP1 expression is regulated by MLL-AF6/DOT1L. The researchers said MLL-AF6 and MEN1/LEDGF directly bind to the SHARP1 gene locus to positively regulate SHARP1 expression through DOT1L activity.
Dr Tenen and his colleagues performed knockdown experiments in mice and found that SHARP1 plays a “critical” role in maintaining clonogenic growth and preventing apoptosis in MLL-AF6 AML cells.
The team also assessed the effects of SHARP1 deletion in mouse models of MLL-AF6 AML.
SHARP1 knockout mice had superior survival compared to wild-type mice. In addition, the knockout mice exhibited signs of less aggressive disease—fewer AML cells, lower white blood cell counts, and higher red blood cell counts.
The researchers also found that SHARP1 deletion reduced MLL-AF6 leukemia-initiating ability but did not affect normal hematopoiesis.
Finally, the team discovered that SHARP1 cooperates with MLL-AF6 to regulate target genes in MLL-AF6 AML cells.
GO approved to treat AML in Europe
The European Commission has authorized use of gemtuzumab ozogamicin (GO, Mylotarg™) as a treatment for patients with acute myeloid leukemia (AML).
GO is now approved for use in combination with daunorubicin and cytarabine to treat patients age 15 and older who have previously untreated, de novo, CD33-positive AML, not including acute promyelocytic leukemia.
GO is an antibody-drug conjugate composed of the cytotoxic agent calicheamicin attached to a monoclonal antibody targeting CD33, an antigen expressed on the surface of myeloblasts in up to 90% of AML patients.
When GO binds to the CD33 antigen on the cell surface, it is absorbed into the cell, and calicheamicin is released, causing cell death.
Previous rejection
The European Commission’s approval of GO follows a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). In February, the CHMP recommended that GO receive marketing authorization for the aforementioned indication.
However, the CHMP previously issued a negative opinion of GO (first in 2007, confirmed in 2008), saying the drug should not receive marketing authorization.
The proposed indication for GO at that time was as re-induction treatment in adults with CD33-positive AML in first relapse who were not candidates for other intensive re-induction chemotherapy regimens and were either older than 60 or had a duration of first remission lasting less than 12 months.
The CHMP said there was insufficient evidence to establish the effectiveness of GO in AML, and the drug’s benefits did not outweigh its risks.
Phase 3 trial
The current marketing authorization application for GO is supported by data from an investigator-led, phase 3, randomized trial known as ALFA-0701. Updated results from this trial are available in the US prescribing information for GO.
ALFA-0701 included 271 patients with newly diagnosed, de novo AML who were 50 to 70 years of age.
Patients were randomized (1:1) to receive induction consisting of daunorubicin (60 mg/m2 on days 1 to 3) and cytarabine (200 mg/m2 on days 1 to 7) with (n=135) or without (n=136) GO at 3 mg/m2 (up to a maximum of 1 vial) on days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone.
Patients with a response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m2 on day 1 of first consolidation course; 60 mg/m2 on days 1 and 2 of second consolidation course) and cytarabine (1 g/m2 every 12 hours on days 1 to 4) with or without GO at 3 mg/m2 (up to a maximum of 1 vial) on day 1 according to their initial randomization.
Patients who achieved remission were also eligible for allogeneic transplant. An interval of at least 2 months between the last dose of GO and transplant was recommended.
Baseline characteristics were largely well balanced between the treatment arms, but there was a higher percentage of males in the GO arm than the control arm—55% and 44%, respectively.
The study’s primary endpoint was event-free survival. The median event-free survival was 17.3 months in the GO arm and 9.5 months in the control arm (hazard ratio=0.56; 95% CI: 0.42-0.76; P<0.001).
There was no significant difference in overall survival between the treatment arms. (Updated overall survival data have not been released).
All patients in this trial developed severe neutropenia, thrombocytopenia, and anemia. However, the incidence of prolonged, grade 3–4 thrombocytopenia in the absence of active leukemia was higher in the GO arm.
Treatment-emergent adverse events (AEs) considered most important for understanding the safety profile of GO were hemorrhage, veno-occlusive liver disease (VOD), and severe infections.
Treatment discontinuation due to any AE occurred in 31% of patients in the GO arm and 7% of those in the control arm. The most frequent AEs leading to discontinuation for patients on GO were thrombocytopenia (15%), VOD (3%), and septic shock (2%).
Fatal AEs occurred in 8 patients (6%) in the GO arm and 3 (2%) in the control arm. In the GO arm, 3 patients died of VOD, 4 died of hemorrhage-related events, and 1 died of a suspected cardiac cause. All 3 fatal AEs in the control arm were sepsis.
The European Commission has authorized use of gemtuzumab ozogamicin (GO, Mylotarg™) as a treatment for patients with acute myeloid leukemia (AML).
GO is now approved for use in combination with daunorubicin and cytarabine to treat patients age 15 and older who have previously untreated, de novo, CD33-positive AML, not including acute promyelocytic leukemia.
GO is an antibody-drug conjugate composed of the cytotoxic agent calicheamicin attached to a monoclonal antibody targeting CD33, an antigen expressed on the surface of myeloblasts in up to 90% of AML patients.
When GO binds to the CD33 antigen on the cell surface, it is absorbed into the cell, and calicheamicin is released, causing cell death.
Previous rejection
The European Commission’s approval of GO follows a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). In February, the CHMP recommended that GO receive marketing authorization for the aforementioned indication.
However, the CHMP previously issued a negative opinion of GO (first in 2007, confirmed in 2008), saying the drug should not receive marketing authorization.
The proposed indication for GO at that time was as re-induction treatment in adults with CD33-positive AML in first relapse who were not candidates for other intensive re-induction chemotherapy regimens and were either older than 60 or had a duration of first remission lasting less than 12 months.
The CHMP said there was insufficient evidence to establish the effectiveness of GO in AML, and the drug’s benefits did not outweigh its risks.
Phase 3 trial
The current marketing authorization application for GO is supported by data from an investigator-led, phase 3, randomized trial known as ALFA-0701. Updated results from this trial are available in the US prescribing information for GO.
ALFA-0701 included 271 patients with newly diagnosed, de novo AML who were 50 to 70 years of age.
Patients were randomized (1:1) to receive induction consisting of daunorubicin (60 mg/m2 on days 1 to 3) and cytarabine (200 mg/m2 on days 1 to 7) with (n=135) or without (n=136) GO at 3 mg/m2 (up to a maximum of 1 vial) on days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone.
Patients with a response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m2 on day 1 of first consolidation course; 60 mg/m2 on days 1 and 2 of second consolidation course) and cytarabine (1 g/m2 every 12 hours on days 1 to 4) with or without GO at 3 mg/m2 (up to a maximum of 1 vial) on day 1 according to their initial randomization.
Patients who achieved remission were also eligible for allogeneic transplant. An interval of at least 2 months between the last dose of GO and transplant was recommended.
Baseline characteristics were largely well balanced between the treatment arms, but there was a higher percentage of males in the GO arm than the control arm—55% and 44%, respectively.
The study’s primary endpoint was event-free survival. The median event-free survival was 17.3 months in the GO arm and 9.5 months in the control arm (hazard ratio=0.56; 95% CI: 0.42-0.76; P<0.001).
There was no significant difference in overall survival between the treatment arms. (Updated overall survival data have not been released).
All patients in this trial developed severe neutropenia, thrombocytopenia, and anemia. However, the incidence of prolonged, grade 3–4 thrombocytopenia in the absence of active leukemia was higher in the GO arm.
Treatment-emergent adverse events (AEs) considered most important for understanding the safety profile of GO were hemorrhage, veno-occlusive liver disease (VOD), and severe infections.
Treatment discontinuation due to any AE occurred in 31% of patients in the GO arm and 7% of those in the control arm. The most frequent AEs leading to discontinuation for patients on GO were thrombocytopenia (15%), VOD (3%), and septic shock (2%).
Fatal AEs occurred in 8 patients (6%) in the GO arm and 3 (2%) in the control arm. In the GO arm, 3 patients died of VOD, 4 died of hemorrhage-related events, and 1 died of a suspected cardiac cause. All 3 fatal AEs in the control arm were sepsis.
The European Commission has authorized use of gemtuzumab ozogamicin (GO, Mylotarg™) as a treatment for patients with acute myeloid leukemia (AML).
GO is now approved for use in combination with daunorubicin and cytarabine to treat patients age 15 and older who have previously untreated, de novo, CD33-positive AML, not including acute promyelocytic leukemia.
GO is an antibody-drug conjugate composed of the cytotoxic agent calicheamicin attached to a monoclonal antibody targeting CD33, an antigen expressed on the surface of myeloblasts in up to 90% of AML patients.
When GO binds to the CD33 antigen on the cell surface, it is absorbed into the cell, and calicheamicin is released, causing cell death.
Previous rejection
The European Commission’s approval of GO follows a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). In February, the CHMP recommended that GO receive marketing authorization for the aforementioned indication.
However, the CHMP previously issued a negative opinion of GO (first in 2007, confirmed in 2008), saying the drug should not receive marketing authorization.
The proposed indication for GO at that time was as re-induction treatment in adults with CD33-positive AML in first relapse who were not candidates for other intensive re-induction chemotherapy regimens and were either older than 60 or had a duration of first remission lasting less than 12 months.
The CHMP said there was insufficient evidence to establish the effectiveness of GO in AML, and the drug’s benefits did not outweigh its risks.
Phase 3 trial
The current marketing authorization application for GO is supported by data from an investigator-led, phase 3, randomized trial known as ALFA-0701. Updated results from this trial are available in the US prescribing information for GO.
ALFA-0701 included 271 patients with newly diagnosed, de novo AML who were 50 to 70 years of age.
Patients were randomized (1:1) to receive induction consisting of daunorubicin (60 mg/m2 on days 1 to 3) and cytarabine (200 mg/m2 on days 1 to 7) with (n=135) or without (n=136) GO at 3 mg/m2 (up to a maximum of 1 vial) on days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone.
Patients with a response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m2 on day 1 of first consolidation course; 60 mg/m2 on days 1 and 2 of second consolidation course) and cytarabine (1 g/m2 every 12 hours on days 1 to 4) with or without GO at 3 mg/m2 (up to a maximum of 1 vial) on day 1 according to their initial randomization.
Patients who achieved remission were also eligible for allogeneic transplant. An interval of at least 2 months between the last dose of GO and transplant was recommended.
Baseline characteristics were largely well balanced between the treatment arms, but there was a higher percentage of males in the GO arm than the control arm—55% and 44%, respectively.
The study’s primary endpoint was event-free survival. The median event-free survival was 17.3 months in the GO arm and 9.5 months in the control arm (hazard ratio=0.56; 95% CI: 0.42-0.76; P<0.001).
There was no significant difference in overall survival between the treatment arms. (Updated overall survival data have not been released).
All patients in this trial developed severe neutropenia, thrombocytopenia, and anemia. However, the incidence of prolonged, grade 3–4 thrombocytopenia in the absence of active leukemia was higher in the GO arm.
Treatment-emergent adverse events (AEs) considered most important for understanding the safety profile of GO were hemorrhage, veno-occlusive liver disease (VOD), and severe infections.
Treatment discontinuation due to any AE occurred in 31% of patients in the GO arm and 7% of those in the control arm. The most frequent AEs leading to discontinuation for patients on GO were thrombocytopenia (15%), VOD (3%), and septic shock (2%).
Fatal AEs occurred in 8 patients (6%) in the GO arm and 3 (2%) in the control arm. In the GO arm, 3 patients died of VOD, 4 died of hemorrhage-related events, and 1 died of a suspected cardiac cause. All 3 fatal AEs in the control arm were sepsis.
Art education benefits blood cancer patients
New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.
The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.
After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.
Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.
The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.
The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).
Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.
Intervention
The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.
Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.
Results
The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.
After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).
Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).
In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.
Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.
All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.
The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.
New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.
The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.
After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.
Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.
The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.
The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).
Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.
Intervention
The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.
Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.
Results
The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.
After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).
Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).
In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.
Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.
All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.
The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.
New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.
The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.
After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.
Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.
The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.
The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).
Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.
Intervention
The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.
Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.
Results
The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.
After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).
Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).
In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.
Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.
All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.
The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.
BET inhibitor has lasting effects in AML, MM
CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.
The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.
TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.
Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.
This research was presented at the AACR Annual Meeting 2018 (abstract 5790).
The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.
In vitro activity
Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.
The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC50 values were below 100 nM.
In the leukemia cell lines, EC50 values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).
In the MM cell lines, EC50 values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).
In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.
In vivo activity
For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.
At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.
For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.
At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.
The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.
The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.
Pharmacodynamic activity
In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.
The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.
The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.
The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.
“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.
“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”
CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.
The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.
TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.
Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.
This research was presented at the AACR Annual Meeting 2018 (abstract 5790).
The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.
In vitro activity
Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.
The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC50 values were below 100 nM.
In the leukemia cell lines, EC50 values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).
In the MM cell lines, EC50 values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).
In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.
In vivo activity
For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.
At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.
For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.
At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.
The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.
The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.
Pharmacodynamic activity
In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.
The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.
The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.
The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.
“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.
“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”
CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.
The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.
TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.
Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.
This research was presented at the AACR Annual Meeting 2018 (abstract 5790).
The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.
In vitro activity
Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.
The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC50 values were below 100 nM.
In the leukemia cell lines, EC50 values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).
In the MM cell lines, EC50 values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).
In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.
In vivo activity
For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.
At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.
For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.
At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.
The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.
The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.
Pharmacodynamic activity
In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.
The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.
The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.
The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.
“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.
“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”
Inhibitor outperforms rivals in leukemia, lymphoma
CHICAGO—Preclinical research suggests the pan-FLT3/pan-BTK inhibitor CG’806 is more effective than other kinase inhibitors in fighting certain hematologic malignancies.
In one study, CG’806 proved more potent than comparator drugs in primary samples of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL).
In another study, CG’806 demonstrated greater cytotoxicity than comparators in a range of malignant B cell lines.
Data from both studies were presented at the AACR Annual Meeting 2018 (abstracts 791 and 794).
The research was supported by Aptose Biosciences, Inc., the company developing CG’806.
CG’806 is a small molecule that inhibits wild-type (WT) FLT3, as well as FLT3 housing the ITD mutation or with point mutations in the tyrosine kinase domain (TKD, including D835G, D835Y, D835H) or in the gatekeeper region (F691L). CG’806 also inhibits BTK-WT and BTK-C481S.
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented results with CG’806 in primary patient samples.
The team found that CG’806 demonstrated greater potency against AML samples relative to other FLT3 inhibitors.
Median IC50 values in 188 AML patient samples were 0.0765 µM for CG’806, 0.125 µM for gilteritinib, 0.199 µM for quizartinib, 0.551 µM for dovitinib, 2.25 µM for midostaurin, 2.93 µM for sorafenib, and 5.01 µM for crenolanib.
The researchers said CG’806 sensitivity was enhanced in FLT3-ITD and FLT3-TKD positive cases.
In CLL patient samples, CG’806 exhibited greater potency and a greater range of activity than the BTK inhibitor ibrutinib. Across 95 CLL samples, the median IC50 values were 0.114 µM for CG’806 and 4.09 µM for ibrutinib.
The researchers said this greater potency of CG’806 may be due to the activity of CG’806 on CSF1R, which has been identified as a therapeutic target in CLL.
“The clinical benefit of current FLT3 inhibitors in AML is transient, as resistance develops after several months of treatment,” Dr Kurtz noted. “Similarly, ibrutinib . . . is limited by acquired resistance as well as refractory disease and tolerance challenges. As a pan-FLT3/pan-BTK inhibitor . . ., CG’806 offers important potential to address these limitations.”
Hongying Zhang, MD, PhD, of Aptose Biosciences, and her colleagues presented results with CG’806 in malignant B-cell and AML cell lines.
The researchers found that CG’806 inhibited FLT3-ITD signaling and induced apoptosis more effectively than quizartinib in FLT3-ITD AML cells (MV4-11). The team noted that CG’806 caused G0/G1 cell-cycle arrest in the cells.
CG’806 also exhibited greater cytotoxic activity than quizartinib in FLT3-WT AML cell lines (KG-1 and NOMO-1).
In addition, CG’806 was more potent than quizartinib, gilteritinib, and crenolanib in Ba/F3 cells transfected with FLT3-WT, ITD, D835Y, and ITD-F691. CG’806 was more potent than quizartinib and crenolanib—but not gilteritinib—in Ba/F3 cells transfected with FLT3-ITD-D835Y.
The researchers said they found that CG’806 inhibits BTK, AURK, and downstream signals in FLT3-WT AML cells.
The team also found that CG’806 decreased BTK phosphorylation in all tested cell lines of B-cell malignancies. This included acute lymphoblastic leukemia, mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma cell lines.
Across all cell lines, CG’806 killed malignant B cells more effectively than ibrutinib. And CG’806 was “equally potent” against WT and C481S-mutant BTK, according to the researchers.
The team also said CG’806 inhibited AURK and induced polyploidy in B-cell malignancies.
“[C]G’806 has demonstrated the ability to kill a broad range of AML and B-cell malignancies through inhibition of multiple oncogenic pathways,” said William G. Rice, PhD, chairman and chief executive officer of Aptose.
“These studies are critical for understanding how to develop and position CG’806 as we prepare for clinical development in these challenging hematologic malignancies.”
CHICAGO—Preclinical research suggests the pan-FLT3/pan-BTK inhibitor CG’806 is more effective than other kinase inhibitors in fighting certain hematologic malignancies.
In one study, CG’806 proved more potent than comparator drugs in primary samples of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL).
In another study, CG’806 demonstrated greater cytotoxicity than comparators in a range of malignant B cell lines.
Data from both studies were presented at the AACR Annual Meeting 2018 (abstracts 791 and 794).
The research was supported by Aptose Biosciences, Inc., the company developing CG’806.
CG’806 is a small molecule that inhibits wild-type (WT) FLT3, as well as FLT3 housing the ITD mutation or with point mutations in the tyrosine kinase domain (TKD, including D835G, D835Y, D835H) or in the gatekeeper region (F691L). CG’806 also inhibits BTK-WT and BTK-C481S.
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented results with CG’806 in primary patient samples.
The team found that CG’806 demonstrated greater potency against AML samples relative to other FLT3 inhibitors.
Median IC50 values in 188 AML patient samples were 0.0765 µM for CG’806, 0.125 µM for gilteritinib, 0.199 µM for quizartinib, 0.551 µM for dovitinib, 2.25 µM for midostaurin, 2.93 µM for sorafenib, and 5.01 µM for crenolanib.
The researchers said CG’806 sensitivity was enhanced in FLT3-ITD and FLT3-TKD positive cases.
In CLL patient samples, CG’806 exhibited greater potency and a greater range of activity than the BTK inhibitor ibrutinib. Across 95 CLL samples, the median IC50 values were 0.114 µM for CG’806 and 4.09 µM for ibrutinib.
The researchers said this greater potency of CG’806 may be due to the activity of CG’806 on CSF1R, which has been identified as a therapeutic target in CLL.
“The clinical benefit of current FLT3 inhibitors in AML is transient, as resistance develops after several months of treatment,” Dr Kurtz noted. “Similarly, ibrutinib . . . is limited by acquired resistance as well as refractory disease and tolerance challenges. As a pan-FLT3/pan-BTK inhibitor . . ., CG’806 offers important potential to address these limitations.”
Hongying Zhang, MD, PhD, of Aptose Biosciences, and her colleagues presented results with CG’806 in malignant B-cell and AML cell lines.
The researchers found that CG’806 inhibited FLT3-ITD signaling and induced apoptosis more effectively than quizartinib in FLT3-ITD AML cells (MV4-11). The team noted that CG’806 caused G0/G1 cell-cycle arrest in the cells.
CG’806 also exhibited greater cytotoxic activity than quizartinib in FLT3-WT AML cell lines (KG-1 and NOMO-1).
In addition, CG’806 was more potent than quizartinib, gilteritinib, and crenolanib in Ba/F3 cells transfected with FLT3-WT, ITD, D835Y, and ITD-F691. CG’806 was more potent than quizartinib and crenolanib—but not gilteritinib—in Ba/F3 cells transfected with FLT3-ITD-D835Y.
The researchers said they found that CG’806 inhibits BTK, AURK, and downstream signals in FLT3-WT AML cells.
The team also found that CG’806 decreased BTK phosphorylation in all tested cell lines of B-cell malignancies. This included acute lymphoblastic leukemia, mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma cell lines.
Across all cell lines, CG’806 killed malignant B cells more effectively than ibrutinib. And CG’806 was “equally potent” against WT and C481S-mutant BTK, according to the researchers.
The team also said CG’806 inhibited AURK and induced polyploidy in B-cell malignancies.
“[C]G’806 has demonstrated the ability to kill a broad range of AML and B-cell malignancies through inhibition of multiple oncogenic pathways,” said William G. Rice, PhD, chairman and chief executive officer of Aptose.
“These studies are critical for understanding how to develop and position CG’806 as we prepare for clinical development in these challenging hematologic malignancies.”
CHICAGO—Preclinical research suggests the pan-FLT3/pan-BTK inhibitor CG’806 is more effective than other kinase inhibitors in fighting certain hematologic malignancies.
In one study, CG’806 proved more potent than comparator drugs in primary samples of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL).
In another study, CG’806 demonstrated greater cytotoxicity than comparators in a range of malignant B cell lines.
Data from both studies were presented at the AACR Annual Meeting 2018 (abstracts 791 and 794).
The research was supported by Aptose Biosciences, Inc., the company developing CG’806.
CG’806 is a small molecule that inhibits wild-type (WT) FLT3, as well as FLT3 housing the ITD mutation or with point mutations in the tyrosine kinase domain (TKD, including D835G, D835Y, D835H) or in the gatekeeper region (F691L). CG’806 also inhibits BTK-WT and BTK-C481S.
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented results with CG’806 in primary patient samples.
The team found that CG’806 demonstrated greater potency against AML samples relative to other FLT3 inhibitors.
Median IC50 values in 188 AML patient samples were 0.0765 µM for CG’806, 0.125 µM for gilteritinib, 0.199 µM for quizartinib, 0.551 µM for dovitinib, 2.25 µM for midostaurin, 2.93 µM for sorafenib, and 5.01 µM for crenolanib.
The researchers said CG’806 sensitivity was enhanced in FLT3-ITD and FLT3-TKD positive cases.
In CLL patient samples, CG’806 exhibited greater potency and a greater range of activity than the BTK inhibitor ibrutinib. Across 95 CLL samples, the median IC50 values were 0.114 µM for CG’806 and 4.09 µM for ibrutinib.
The researchers said this greater potency of CG’806 may be due to the activity of CG’806 on CSF1R, which has been identified as a therapeutic target in CLL.
“The clinical benefit of current FLT3 inhibitors in AML is transient, as resistance develops after several months of treatment,” Dr Kurtz noted. “Similarly, ibrutinib . . . is limited by acquired resistance as well as refractory disease and tolerance challenges. As a pan-FLT3/pan-BTK inhibitor . . ., CG’806 offers important potential to address these limitations.”
Hongying Zhang, MD, PhD, of Aptose Biosciences, and her colleagues presented results with CG’806 in malignant B-cell and AML cell lines.
The researchers found that CG’806 inhibited FLT3-ITD signaling and induced apoptosis more effectively than quizartinib in FLT3-ITD AML cells (MV4-11). The team noted that CG’806 caused G0/G1 cell-cycle arrest in the cells.
CG’806 also exhibited greater cytotoxic activity than quizartinib in FLT3-WT AML cell lines (KG-1 and NOMO-1).
In addition, CG’806 was more potent than quizartinib, gilteritinib, and crenolanib in Ba/F3 cells transfected with FLT3-WT, ITD, D835Y, and ITD-F691. CG’806 was more potent than quizartinib and crenolanib—but not gilteritinib—in Ba/F3 cells transfected with FLT3-ITD-D835Y.
The researchers said they found that CG’806 inhibits BTK, AURK, and downstream signals in FLT3-WT AML cells.
The team also found that CG’806 decreased BTK phosphorylation in all tested cell lines of B-cell malignancies. This included acute lymphoblastic leukemia, mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma cell lines.
Across all cell lines, CG’806 killed malignant B cells more effectively than ibrutinib. And CG’806 was “equally potent” against WT and C481S-mutant BTK, according to the researchers.
The team also said CG’806 inhibited AURK and induced polyploidy in B-cell malignancies.
“[C]G’806 has demonstrated the ability to kill a broad range of AML and B-cell malignancies through inhibition of multiple oncogenic pathways,” said William G. Rice, PhD, chairman and chief executive officer of Aptose.
“These studies are critical for understanding how to develop and position CG’806 as we prepare for clinical development in these challenging hematologic malignancies.”
Antibody has ‘potent’ effects against AML
CHICAGO—The bispecific antibody APVO436 has demonstrated robust T-cell activation with limited cytokine release in acute myeloid leukemia (AML), according to researchers.
APVO436 binds CD123 and CD3 to redirect T-cell cytotoxicity against CD123-expressing tumor cells.
Researchers found that APVO436 induced T-cell cytotoxicity in AML cells in vitro and in mouse models.
In addition, levels of several cytokines were lower in experiments with APVO436 than in experiments with a comparator antibody.
These findings were presented in a poster at the AACR Annual Meeting 2018 (abstract 1786).
The research was conducted by employees of Aptevo Therapeutics Inc., the company developing APVO436.
“We are especially excited about these latest data for APVO436, which continue to show robust T-cell engagement and cytotoxic activity with reduced levels of cytokine release,” said Jane Gross, PhD, senior vice president and chief scientific officer for Aptevo.
Dr Gross and her colleagues found that APVO436 binds human CD123 and CD3-expressing cells and has “potent” target-specific activity against CD123-expressing AML cell lines (Molm-13 and KG-1a).
In addition, APVO436 induced endogenous T-cell activation and proliferation, accompanied by depletion of CD123-expressing cells, in samples from AML patients and healthy donors.
T cells from these cultures (both AML and non-AML) were expanded and co-cultured with Molm-13 cells and APVO436 or a control antibody. Again, the researchers observed “potent” cytotoxic activity in the presence of APVO436.
Dr Gross and her colleagues also tested APVO436, co-administered with human T cells, in mice with established disseminated Molm-13 tumors. The treatment resulted in a “rapid and significant” reduction in skeletal tumor burden.
Finally, the team compared APVO436 with an Aptevo-generated version of MGD006, a CD123 x CD3 dual-affinity re-targeting molecule being developed by Macrogenics, Inc.
The researchers took purified T cells from healthy donors and cultured them with Molm-13 cells, as well as APVO436, Aptevo’s version of MGD006, and a control antibody.
Both APVO436 and Aptevo’s version of MGD006 were effective at stimulating a tumor-directed immune response, inducing comparable levels of T-cell activation, proliferation, and cytotoxicity.
However, APVO436 induced lower levels of several cytokines—including IFNγ, IL-2, IL-6, and TNFα.
“Importantly, IFNγ, IL-6, and TNFα are considered to be the most relevant cytokines responsible for dosing toxicities observed in clinical studies with T-cell engaging molecules, which suggests that APVO436 could offer the potential for reduced toxicities compared to other CD123 x CD3 T-cell engagers at comparable or higher doses,” Dr Gross said.
She added that Aptevo is planning to launch a phase 1 trial of APVO436 in patients with AML and myelodysplastic syndromes later this year.
CHICAGO—The bispecific antibody APVO436 has demonstrated robust T-cell activation with limited cytokine release in acute myeloid leukemia (AML), according to researchers.
APVO436 binds CD123 and CD3 to redirect T-cell cytotoxicity against CD123-expressing tumor cells.
Researchers found that APVO436 induced T-cell cytotoxicity in AML cells in vitro and in mouse models.
In addition, levels of several cytokines were lower in experiments with APVO436 than in experiments with a comparator antibody.
These findings were presented in a poster at the AACR Annual Meeting 2018 (abstract 1786).
The research was conducted by employees of Aptevo Therapeutics Inc., the company developing APVO436.
“We are especially excited about these latest data for APVO436, which continue to show robust T-cell engagement and cytotoxic activity with reduced levels of cytokine release,” said Jane Gross, PhD, senior vice president and chief scientific officer for Aptevo.
Dr Gross and her colleagues found that APVO436 binds human CD123 and CD3-expressing cells and has “potent” target-specific activity against CD123-expressing AML cell lines (Molm-13 and KG-1a).
In addition, APVO436 induced endogenous T-cell activation and proliferation, accompanied by depletion of CD123-expressing cells, in samples from AML patients and healthy donors.
T cells from these cultures (both AML and non-AML) were expanded and co-cultured with Molm-13 cells and APVO436 or a control antibody. Again, the researchers observed “potent” cytotoxic activity in the presence of APVO436.
Dr Gross and her colleagues also tested APVO436, co-administered with human T cells, in mice with established disseminated Molm-13 tumors. The treatment resulted in a “rapid and significant” reduction in skeletal tumor burden.
Finally, the team compared APVO436 with an Aptevo-generated version of MGD006, a CD123 x CD3 dual-affinity re-targeting molecule being developed by Macrogenics, Inc.
The researchers took purified T cells from healthy donors and cultured them with Molm-13 cells, as well as APVO436, Aptevo’s version of MGD006, and a control antibody.
Both APVO436 and Aptevo’s version of MGD006 were effective at stimulating a tumor-directed immune response, inducing comparable levels of T-cell activation, proliferation, and cytotoxicity.
However, APVO436 induced lower levels of several cytokines—including IFNγ, IL-2, IL-6, and TNFα.
“Importantly, IFNγ, IL-6, and TNFα are considered to be the most relevant cytokines responsible for dosing toxicities observed in clinical studies with T-cell engaging molecules, which suggests that APVO436 could offer the potential for reduced toxicities compared to other CD123 x CD3 T-cell engagers at comparable or higher doses,” Dr Gross said.
She added that Aptevo is planning to launch a phase 1 trial of APVO436 in patients with AML and myelodysplastic syndromes later this year.
CHICAGO—The bispecific antibody APVO436 has demonstrated robust T-cell activation with limited cytokine release in acute myeloid leukemia (AML), according to researchers.
APVO436 binds CD123 and CD3 to redirect T-cell cytotoxicity against CD123-expressing tumor cells.
Researchers found that APVO436 induced T-cell cytotoxicity in AML cells in vitro and in mouse models.
In addition, levels of several cytokines were lower in experiments with APVO436 than in experiments with a comparator antibody.
These findings were presented in a poster at the AACR Annual Meeting 2018 (abstract 1786).
The research was conducted by employees of Aptevo Therapeutics Inc., the company developing APVO436.
“We are especially excited about these latest data for APVO436, which continue to show robust T-cell engagement and cytotoxic activity with reduced levels of cytokine release,” said Jane Gross, PhD, senior vice president and chief scientific officer for Aptevo.
Dr Gross and her colleagues found that APVO436 binds human CD123 and CD3-expressing cells and has “potent” target-specific activity against CD123-expressing AML cell lines (Molm-13 and KG-1a).
In addition, APVO436 induced endogenous T-cell activation and proliferation, accompanied by depletion of CD123-expressing cells, in samples from AML patients and healthy donors.
T cells from these cultures (both AML and non-AML) were expanded and co-cultured with Molm-13 cells and APVO436 or a control antibody. Again, the researchers observed “potent” cytotoxic activity in the presence of APVO436.
Dr Gross and her colleagues also tested APVO436, co-administered with human T cells, in mice with established disseminated Molm-13 tumors. The treatment resulted in a “rapid and significant” reduction in skeletal tumor burden.
Finally, the team compared APVO436 with an Aptevo-generated version of MGD006, a CD123 x CD3 dual-affinity re-targeting molecule being developed by Macrogenics, Inc.
The researchers took purified T cells from healthy donors and cultured them with Molm-13 cells, as well as APVO436, Aptevo’s version of MGD006, and a control antibody.
Both APVO436 and Aptevo’s version of MGD006 were effective at stimulating a tumor-directed immune response, inducing comparable levels of T-cell activation, proliferation, and cytotoxicity.
However, APVO436 induced lower levels of several cytokines—including IFNγ, IL-2, IL-6, and TNFα.
“Importantly, IFNγ, IL-6, and TNFα are considered to be the most relevant cytokines responsible for dosing toxicities observed in clinical studies with T-cell engaging molecules, which suggests that APVO436 could offer the potential for reduced toxicities compared to other CD123 x CD3 T-cell engagers at comparable or higher doses,” Dr Gross said.
She added that Aptevo is planning to launch a phase 1 trial of APVO436 in patients with AML and myelodysplastic syndromes later this year.
Checkpoint inhibition after HiDAC shows promise in AML
NEWPORT BEACH, CALIF. – Adding pembrolizumab after high-dose cytarabine in patients with relapsed or refractory acute myeloid leukemia (AML) appears safe and feasible and shows promising efficacy, according to early results from a multicenter phase 2 study.
The overall response rate to this novel treatment approach in 19 evaluable patients (of 20 enrolled to date) was 42%, with 7 patients (37%) achieving a complete response or complete response with incomplete blood count recovery, and 1 (5%) achieving a partial response, reported Joshua Zeidner, MD, in a poster at the Acute Leukemia Forum of Hemedicus.
Those who went on to allogeneic stem cell transplant included three patients in complete response and one of the five who received pembrolizumab maintenance. That patient on pembrolizumab maintenance went to transplant after two cycles, three others on it relapsed after a median duration of 2.8 months in complete response, and one initially achieved a partial response and had stable disease for a “pretty remarkable” 12 cycles before progressing, he said.
Preliminary analyses in the first six patients, including three with complete response and three nonresponders, showed increased posttreatment diversity of the T-cell receptor repertoire versus baseline in peripheral blood CD8+ T cells in the complete response patients, compared with nonresponders. This suggests that T-cell diversity at baseline is a promising biomarker for programmed death-1 (PD-1) blockade response, Dr. Zeidner noted.
PD-1 suppresses immune activation, and the PD-1 pathway is exploited by AML cells to evade immune surveillance, Dr. Zeidner explained. PD-1 blockade has been shown to have antileukemic effects in vivo, there is expression of multiple coinhibitory receptors in AML patients at the time of diagnosis (that persists in refractory AML), and the ligand for PD-1 is up-regulated on AML blasts, particularly in relapsed/refractory disease, he added.
He and his colleagues hypothesized that targeting PD-1 with pembrolizumab after high-dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T cell–mediated antileukemic immune response and lead to improved efficacy in patients with relapsed or refractory AML.
The ongoing study, with planned enrollment of 37 patients, includes patients aged 18-70 years with relapsed/refractory AML (median age of first 20 enrolled is 54 years). Those under age 60 years receive 2 g/m2 of intravenous HiDAC every 12 hours on days 1-5, and those over age 60 years receive 1.5 g/m2 every 12 hours on days 1-5. In both age groups, this is followed by intravenous pembrolizumab given at 200 mg on day 14.
Overall responders receive maintenance phase intravenous pembrolizumab at 200 mg every 3 weeks for up to 2 years until relapse or progression. Patients are allowed to proceed to stem cell transplant before or after the maintenance phase.
A number of correlative studies, including serial peripheral blood and bone marrow flow cytometry and T-cell receptor clonality studies, also are being conducted to look for predictive biomarkers of response, Dr. Zeidner said.
The study population to date is a relatively young, very-high-risk subgroup of AML patients; European LeukemiaNet-2017 genetic risk status was favorable in only 3 of the first 20 patients (15%), intermediate in 7 (35%), and adverse in 10 (50%). Treatment has been well tolerated; toxicities have been rare and manageable. “Overall, there have been no unexpected toxicities,” he said.
The most common overall toxicities included febrile neutropenia in 70% of patients; transaminitis (including one grade 3 case) in 50%, hyperbilirubinemia in 35%, and fatigue, increased alkaline phosphatase, and rash in 25% each.
Novel therapies for relapsed/refractory AML are urgently needed, and these early results demonstrated the safety and feasibility of adding pembrolizumab after HiDAC chemotherapy in relapsed/refractory AML patients. The preliminary finding that broadening of the immune repertoire, which may occur via increasing T-cell responses beyond endogenous viral responses, was associated with complete response was particularly encouraging, Dr. Zeidner said. The investigators hope to determine predictors of response to immune checkpoint blockade in AML through a comprehensive immune biomarker discovery approach, he added.
This study was funded by Merck. Dr. Zeidner reported having no financial disclosures. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
SOURCE: Zeidner J et al. ALF 2018, Poster Session.
NEWPORT BEACH, CALIF. – Adding pembrolizumab after high-dose cytarabine in patients with relapsed or refractory acute myeloid leukemia (AML) appears safe and feasible and shows promising efficacy, according to early results from a multicenter phase 2 study.
The overall response rate to this novel treatment approach in 19 evaluable patients (of 20 enrolled to date) was 42%, with 7 patients (37%) achieving a complete response or complete response with incomplete blood count recovery, and 1 (5%) achieving a partial response, reported Joshua Zeidner, MD, in a poster at the Acute Leukemia Forum of Hemedicus.
Those who went on to allogeneic stem cell transplant included three patients in complete response and one of the five who received pembrolizumab maintenance. That patient on pembrolizumab maintenance went to transplant after two cycles, three others on it relapsed after a median duration of 2.8 months in complete response, and one initially achieved a partial response and had stable disease for a “pretty remarkable” 12 cycles before progressing, he said.
Preliminary analyses in the first six patients, including three with complete response and three nonresponders, showed increased posttreatment diversity of the T-cell receptor repertoire versus baseline in peripheral blood CD8+ T cells in the complete response patients, compared with nonresponders. This suggests that T-cell diversity at baseline is a promising biomarker for programmed death-1 (PD-1) blockade response, Dr. Zeidner noted.
PD-1 suppresses immune activation, and the PD-1 pathway is exploited by AML cells to evade immune surveillance, Dr. Zeidner explained. PD-1 blockade has been shown to have antileukemic effects in vivo, there is expression of multiple coinhibitory receptors in AML patients at the time of diagnosis (that persists in refractory AML), and the ligand for PD-1 is up-regulated on AML blasts, particularly in relapsed/refractory disease, he added.
He and his colleagues hypothesized that targeting PD-1 with pembrolizumab after high-dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T cell–mediated antileukemic immune response and lead to improved efficacy in patients with relapsed or refractory AML.
The ongoing study, with planned enrollment of 37 patients, includes patients aged 18-70 years with relapsed/refractory AML (median age of first 20 enrolled is 54 years). Those under age 60 years receive 2 g/m2 of intravenous HiDAC every 12 hours on days 1-5, and those over age 60 years receive 1.5 g/m2 every 12 hours on days 1-5. In both age groups, this is followed by intravenous pembrolizumab given at 200 mg on day 14.
Overall responders receive maintenance phase intravenous pembrolizumab at 200 mg every 3 weeks for up to 2 years until relapse or progression. Patients are allowed to proceed to stem cell transplant before or after the maintenance phase.
A number of correlative studies, including serial peripheral blood and bone marrow flow cytometry and T-cell receptor clonality studies, also are being conducted to look for predictive biomarkers of response, Dr. Zeidner said.
The study population to date is a relatively young, very-high-risk subgroup of AML patients; European LeukemiaNet-2017 genetic risk status was favorable in only 3 of the first 20 patients (15%), intermediate in 7 (35%), and adverse in 10 (50%). Treatment has been well tolerated; toxicities have been rare and manageable. “Overall, there have been no unexpected toxicities,” he said.
The most common overall toxicities included febrile neutropenia in 70% of patients; transaminitis (including one grade 3 case) in 50%, hyperbilirubinemia in 35%, and fatigue, increased alkaline phosphatase, and rash in 25% each.
Novel therapies for relapsed/refractory AML are urgently needed, and these early results demonstrated the safety and feasibility of adding pembrolizumab after HiDAC chemotherapy in relapsed/refractory AML patients. The preliminary finding that broadening of the immune repertoire, which may occur via increasing T-cell responses beyond endogenous viral responses, was associated with complete response was particularly encouraging, Dr. Zeidner said. The investigators hope to determine predictors of response to immune checkpoint blockade in AML through a comprehensive immune biomarker discovery approach, he added.
This study was funded by Merck. Dr. Zeidner reported having no financial disclosures. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
SOURCE: Zeidner J et al. ALF 2018, Poster Session.
NEWPORT BEACH, CALIF. – Adding pembrolizumab after high-dose cytarabine in patients with relapsed or refractory acute myeloid leukemia (AML) appears safe and feasible and shows promising efficacy, according to early results from a multicenter phase 2 study.
The overall response rate to this novel treatment approach in 19 evaluable patients (of 20 enrolled to date) was 42%, with 7 patients (37%) achieving a complete response or complete response with incomplete blood count recovery, and 1 (5%) achieving a partial response, reported Joshua Zeidner, MD, in a poster at the Acute Leukemia Forum of Hemedicus.
Those who went on to allogeneic stem cell transplant included three patients in complete response and one of the five who received pembrolizumab maintenance. That patient on pembrolizumab maintenance went to transplant after two cycles, three others on it relapsed after a median duration of 2.8 months in complete response, and one initially achieved a partial response and had stable disease for a “pretty remarkable” 12 cycles before progressing, he said.
Preliminary analyses in the first six patients, including three with complete response and three nonresponders, showed increased posttreatment diversity of the T-cell receptor repertoire versus baseline in peripheral blood CD8+ T cells in the complete response patients, compared with nonresponders. This suggests that T-cell diversity at baseline is a promising biomarker for programmed death-1 (PD-1) blockade response, Dr. Zeidner noted.
PD-1 suppresses immune activation, and the PD-1 pathway is exploited by AML cells to evade immune surveillance, Dr. Zeidner explained. PD-1 blockade has been shown to have antileukemic effects in vivo, there is expression of multiple coinhibitory receptors in AML patients at the time of diagnosis (that persists in refractory AML), and the ligand for PD-1 is up-regulated on AML blasts, particularly in relapsed/refractory disease, he added.
He and his colleagues hypothesized that targeting PD-1 with pembrolizumab after high-dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T cell–mediated antileukemic immune response and lead to improved efficacy in patients with relapsed or refractory AML.
The ongoing study, with planned enrollment of 37 patients, includes patients aged 18-70 years with relapsed/refractory AML (median age of first 20 enrolled is 54 years). Those under age 60 years receive 2 g/m2 of intravenous HiDAC every 12 hours on days 1-5, and those over age 60 years receive 1.5 g/m2 every 12 hours on days 1-5. In both age groups, this is followed by intravenous pembrolizumab given at 200 mg on day 14.
Overall responders receive maintenance phase intravenous pembrolizumab at 200 mg every 3 weeks for up to 2 years until relapse or progression. Patients are allowed to proceed to stem cell transplant before or after the maintenance phase.
A number of correlative studies, including serial peripheral blood and bone marrow flow cytometry and T-cell receptor clonality studies, also are being conducted to look for predictive biomarkers of response, Dr. Zeidner said.
The study population to date is a relatively young, very-high-risk subgroup of AML patients; European LeukemiaNet-2017 genetic risk status was favorable in only 3 of the first 20 patients (15%), intermediate in 7 (35%), and adverse in 10 (50%). Treatment has been well tolerated; toxicities have been rare and manageable. “Overall, there have been no unexpected toxicities,” he said.
The most common overall toxicities included febrile neutropenia in 70% of patients; transaminitis (including one grade 3 case) in 50%, hyperbilirubinemia in 35%, and fatigue, increased alkaline phosphatase, and rash in 25% each.
Novel therapies for relapsed/refractory AML are urgently needed, and these early results demonstrated the safety and feasibility of adding pembrolizumab after HiDAC chemotherapy in relapsed/refractory AML patients. The preliminary finding that broadening of the immune repertoire, which may occur via increasing T-cell responses beyond endogenous viral responses, was associated with complete response was particularly encouraging, Dr. Zeidner said. The investigators hope to determine predictors of response to immune checkpoint blockade in AML through a comprehensive immune biomarker discovery approach, he added.
This study was funded by Merck. Dr. Zeidner reported having no financial disclosures. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
SOURCE: Zeidner J et al. ALF 2018, Poster Session.
REPORTING FROM ALF 2018
Key clinical point:
Major finding: The overall response rate was 42%; 37% of patients achieved complete response or CR with incomplete blood count recovery, and 5% achieved partial response.
Study details: A multicenter, phase 2 study with early results from the first 20 patients enrolled.
Disclosures: This study was funded by Merck. Dr. Zeidner reported having no financial disclosures. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
Source: Zeidner J et al. ALF 2018, Poster Session.
5- and 10-day decitabine go head-to-head in poor-risk AML
NEWPORT BEACH, CALIF. – Response and survival rates are similar with 5- and 10-day dosing of decitabine in poor-risk older adults with previously untreated acute myeloid leukemia, according to findings from a randomized phase 2 trial.
The overall response rates in 25 patients randomized to receive 5 days of decitabine and 40 patients randomized to receive 10 days of decitabine were 44% and 38%, respectively. Complete response rates were 28% and 30%, respectively, and the median number of cycles to best response was two in both arms, Nicholas J. Short, MD, reported in a poster at the Acute Leukemia Forum of Hemedicus.
Patients were followed for a median of 38 months. Median remission duration was 9.4 months in 11 responders who received 5 days of decitabine, and 6.4 months in 15 responders in the 10-day treatment arm. The 1-year continued remission rates were 25% and 30%, respectively (P = .85). Median overall survival was 4.9 and 7.1 months, respectively, and 1-year overall survival rates were 27% and 25%, respectively, he said, adding that none of the differences in the groups were statistically significant.
Further, no differences in survival were seen when patients in the two treatment arms were stratified by cytogenetics, de novo versus secondary or treatment-related disease, or TP53 mutations; however, these subgroups were small, he noted.
Study subjects were adults aged 60 years or older (median, 77 and 78 years) with newly diagnosed and untreated acute myeloid leukemia (AML), and adults under age 60 years who were not suitable candidates for intensive chemotherapy. They were enrolled between February 2013 and July 2017. About 30% of patients had performance status scores of 2-3, and 45% of patients had secondary AML.
“About 40% of patients in the 5-day arm had poor-risk cytogenetics, and about half in the 10-day arm had poor-risk cytogenetics,” Dr. Short said in an interview, adding that 6 of 21 tested patients in the 5-day arm and 16 of 38 tested patients in the 10-day arm had a TP53 mutation.
Patients received intravenous decitabine at a dose of 20 mg/m2 for the assigned duration of either 5 or 10 consecutive days for the first three cycles of induction, and those who responded to treatment received additional consolidation cycles every 4-8 weeks for up to 24 total cycles. Patients in the 10-day arm were switched to 5-day dosing after achieving complete response or complete response with incomplete blood count recovery.
The groups were well balanced with respect to baseline characteristics and the imbalance in patient numbers in the arms was mainly because of adaptive randomization; the 10-day patients had better responses during the early part of the study, Dr. Short explained.
None of the patients underwent allogeneic stem cell transplantation, he added.
Older patients with acute AML often have poor tolerance for intensive chemotherapy, but decitabine has been shown to improve survival when compared with supportive care or low-dose cytarabine in these patients. However, while some single-arm studies have suggested that 5- and 10-day dosing may result in similar outcomes, and another suggested that 10-day dosing may be superior in TP53-mutated AML, no studies have directly compared 5- and 10-day dosing, he said.
“In this relatively poor-risk cohort of older adults with newly diagnosed AML, decitabine for 5 and 10 days resulted in similar response rates, survival, and early mortality,” he concluded.
This study was funded by a University of Texas MD Anderson Cancer Center support grant. Dr. Short reported having no financial disclosures.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
SOURCE: Short NJ et al. ALF 2018, Poster Session.
NEWPORT BEACH, CALIF. – Response and survival rates are similar with 5- and 10-day dosing of decitabine in poor-risk older adults with previously untreated acute myeloid leukemia, according to findings from a randomized phase 2 trial.
The overall response rates in 25 patients randomized to receive 5 days of decitabine and 40 patients randomized to receive 10 days of decitabine were 44% and 38%, respectively. Complete response rates were 28% and 30%, respectively, and the median number of cycles to best response was two in both arms, Nicholas J. Short, MD, reported in a poster at the Acute Leukemia Forum of Hemedicus.
Patients were followed for a median of 38 months. Median remission duration was 9.4 months in 11 responders who received 5 days of decitabine, and 6.4 months in 15 responders in the 10-day treatment arm. The 1-year continued remission rates were 25% and 30%, respectively (P = .85). Median overall survival was 4.9 and 7.1 months, respectively, and 1-year overall survival rates were 27% and 25%, respectively, he said, adding that none of the differences in the groups were statistically significant.
Further, no differences in survival were seen when patients in the two treatment arms were stratified by cytogenetics, de novo versus secondary or treatment-related disease, or TP53 mutations; however, these subgroups were small, he noted.
Study subjects were adults aged 60 years or older (median, 77 and 78 years) with newly diagnosed and untreated acute myeloid leukemia (AML), and adults under age 60 years who were not suitable candidates for intensive chemotherapy. They were enrolled between February 2013 and July 2017. About 30% of patients had performance status scores of 2-3, and 45% of patients had secondary AML.
“About 40% of patients in the 5-day arm had poor-risk cytogenetics, and about half in the 10-day arm had poor-risk cytogenetics,” Dr. Short said in an interview, adding that 6 of 21 tested patients in the 5-day arm and 16 of 38 tested patients in the 10-day arm had a TP53 mutation.
Patients received intravenous decitabine at a dose of 20 mg/m2 for the assigned duration of either 5 or 10 consecutive days for the first three cycles of induction, and those who responded to treatment received additional consolidation cycles every 4-8 weeks for up to 24 total cycles. Patients in the 10-day arm were switched to 5-day dosing after achieving complete response or complete response with incomplete blood count recovery.
The groups were well balanced with respect to baseline characteristics and the imbalance in patient numbers in the arms was mainly because of adaptive randomization; the 10-day patients had better responses during the early part of the study, Dr. Short explained.
None of the patients underwent allogeneic stem cell transplantation, he added.
Older patients with acute AML often have poor tolerance for intensive chemotherapy, but decitabine has been shown to improve survival when compared with supportive care or low-dose cytarabine in these patients. However, while some single-arm studies have suggested that 5- and 10-day dosing may result in similar outcomes, and another suggested that 10-day dosing may be superior in TP53-mutated AML, no studies have directly compared 5- and 10-day dosing, he said.
“In this relatively poor-risk cohort of older adults with newly diagnosed AML, decitabine for 5 and 10 days resulted in similar response rates, survival, and early mortality,” he concluded.
This study was funded by a University of Texas MD Anderson Cancer Center support grant. Dr. Short reported having no financial disclosures.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
SOURCE: Short NJ et al. ALF 2018, Poster Session.
NEWPORT BEACH, CALIF. – Response and survival rates are similar with 5- and 10-day dosing of decitabine in poor-risk older adults with previously untreated acute myeloid leukemia, according to findings from a randomized phase 2 trial.
The overall response rates in 25 patients randomized to receive 5 days of decitabine and 40 patients randomized to receive 10 days of decitabine were 44% and 38%, respectively. Complete response rates were 28% and 30%, respectively, and the median number of cycles to best response was two in both arms, Nicholas J. Short, MD, reported in a poster at the Acute Leukemia Forum of Hemedicus.
Patients were followed for a median of 38 months. Median remission duration was 9.4 months in 11 responders who received 5 days of decitabine, and 6.4 months in 15 responders in the 10-day treatment arm. The 1-year continued remission rates were 25% and 30%, respectively (P = .85). Median overall survival was 4.9 and 7.1 months, respectively, and 1-year overall survival rates were 27% and 25%, respectively, he said, adding that none of the differences in the groups were statistically significant.
Further, no differences in survival were seen when patients in the two treatment arms were stratified by cytogenetics, de novo versus secondary or treatment-related disease, or TP53 mutations; however, these subgroups were small, he noted.
Study subjects were adults aged 60 years or older (median, 77 and 78 years) with newly diagnosed and untreated acute myeloid leukemia (AML), and adults under age 60 years who were not suitable candidates for intensive chemotherapy. They were enrolled between February 2013 and July 2017. About 30% of patients had performance status scores of 2-3, and 45% of patients had secondary AML.
“About 40% of patients in the 5-day arm had poor-risk cytogenetics, and about half in the 10-day arm had poor-risk cytogenetics,” Dr. Short said in an interview, adding that 6 of 21 tested patients in the 5-day arm and 16 of 38 tested patients in the 10-day arm had a TP53 mutation.
Patients received intravenous decitabine at a dose of 20 mg/m2 for the assigned duration of either 5 or 10 consecutive days for the first three cycles of induction, and those who responded to treatment received additional consolidation cycles every 4-8 weeks for up to 24 total cycles. Patients in the 10-day arm were switched to 5-day dosing after achieving complete response or complete response with incomplete blood count recovery.
The groups were well balanced with respect to baseline characteristics and the imbalance in patient numbers in the arms was mainly because of adaptive randomization; the 10-day patients had better responses during the early part of the study, Dr. Short explained.
None of the patients underwent allogeneic stem cell transplantation, he added.
Older patients with acute AML often have poor tolerance for intensive chemotherapy, but decitabine has been shown to improve survival when compared with supportive care or low-dose cytarabine in these patients. However, while some single-arm studies have suggested that 5- and 10-day dosing may result in similar outcomes, and another suggested that 10-day dosing may be superior in TP53-mutated AML, no studies have directly compared 5- and 10-day dosing, he said.
“In this relatively poor-risk cohort of older adults with newly diagnosed AML, decitabine for 5 and 10 days resulted in similar response rates, survival, and early mortality,” he concluded.
This study was funded by a University of Texas MD Anderson Cancer Center support grant. Dr. Short reported having no financial disclosures.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
SOURCE: Short NJ et al. ALF 2018, Poster Session.
REPORTING FROM ALF 2018
Key clinical point:
Major finding: Overall response rates were 44% with 5-day dosing and 38% with 10-day dosing.
Study details: A randomized phase 2 study of 65 patients.
Disclosures: This study was funded by an University of Texas MD Anderson Cancer Center support grant. Dr. Short reported having no financial disclosures.
Source: Short NJ et al. ALF 2018, Poster Session.
Statin plus chemo yields encouraging results in poor-risk AML
Patients with poor-risk acute myelogenous leukemia (AML) had promising rates of response and survival following treatment with a statin added to standard chemotherapy, researchers reported.
Pravastatin in combination with idarubicin and cytarabine had a 30% response rate in poor-risk AML patients, according to Anjali S. Advani, MD, of the Taussig Cancer Institute at the Cleveland Clinic, and her coauthors.
Although that response rate did not meet a prespecified threshold for statistical significance, results of the phase 2 study were nevertheless “encouraging” for a group of patients with unfavorable cytogenetics and poor-risk molecular mutations, the researchers wrote. The study was published in Leukemia Research.
The estimated median overall survival was 4.1 months in the phase 2 trial, known as SWOG S0919. About one-quarter of the patients were able to proceed to allogeneic hematopoietic stem cell transplant, and for that group, median overall survival was 27.1 months.
These findings appear to provide further support for the hypothesis that targeting the cholesterol pathway may be a promising approach in patients with AML.
Some previous investigations suggested that AML blasts overexpress genes for lipoprotein receptors and regulatory enzymes, while others showed that these cells import and synthesize cholesterol at levels higher than what is seen in normal progenitor cells. In addition, some AML patients have hypocholesterolemia that usually resolves when they achieve a complete remission.
“These observations suggest that AML cells may require high levels of cholesterol for their survival and that abnormalities in cholesterol homeostasis are necessary for AML cell survival,” the researchers wrote.
This led to a phase 1 trial of pravastatin plus idarubicin/cytarabine, followed by the phase 2 SWOG S0919 trial, which demonstrated a 75% rate of complete response (CR) or complete response with incomplete count recovery (CRi) for the regimen.
The SWOG S0919 study was amended to include the poor-risk AML patients described in the present study. That cohort of 46 patients had a CR/CRi of less than 6 months after their last induction regimen or refractory disease. Many had poor-risk cytogenetics (43%) or one of a number of poor-risk mutations, according to the study report.
Pravastatin, in addition to working on the cholesterol pathway in AML, may also have a therapeutic advantage in patients with FLT3 mutations. Three out of six patients with FLT3 mutations achieved CR/CRi, corroborating earlier preclinical studies and suggesting further study of this specific patient population would be worthwhile, the researchers noted.
The study was supported in part by the National Institutes of Health and Bristol-Myers Squibb. Dr. Advani reported having no financial disclosures but other study authors reported relationships with various pharmaceutical companies.
SOURCE: Advani AS et al. Leuk Res. 2018 Apr;67:17-20.
Patients with poor-risk acute myelogenous leukemia (AML) had promising rates of response and survival following treatment with a statin added to standard chemotherapy, researchers reported.
Pravastatin in combination with idarubicin and cytarabine had a 30% response rate in poor-risk AML patients, according to Anjali S. Advani, MD, of the Taussig Cancer Institute at the Cleveland Clinic, and her coauthors.
Although that response rate did not meet a prespecified threshold for statistical significance, results of the phase 2 study were nevertheless “encouraging” for a group of patients with unfavorable cytogenetics and poor-risk molecular mutations, the researchers wrote. The study was published in Leukemia Research.
The estimated median overall survival was 4.1 months in the phase 2 trial, known as SWOG S0919. About one-quarter of the patients were able to proceed to allogeneic hematopoietic stem cell transplant, and for that group, median overall survival was 27.1 months.
These findings appear to provide further support for the hypothesis that targeting the cholesterol pathway may be a promising approach in patients with AML.
Some previous investigations suggested that AML blasts overexpress genes for lipoprotein receptors and regulatory enzymes, while others showed that these cells import and synthesize cholesterol at levels higher than what is seen in normal progenitor cells. In addition, some AML patients have hypocholesterolemia that usually resolves when they achieve a complete remission.
“These observations suggest that AML cells may require high levels of cholesterol for their survival and that abnormalities in cholesterol homeostasis are necessary for AML cell survival,” the researchers wrote.
This led to a phase 1 trial of pravastatin plus idarubicin/cytarabine, followed by the phase 2 SWOG S0919 trial, which demonstrated a 75% rate of complete response (CR) or complete response with incomplete count recovery (CRi) for the regimen.
The SWOG S0919 study was amended to include the poor-risk AML patients described in the present study. That cohort of 46 patients had a CR/CRi of less than 6 months after their last induction regimen or refractory disease. Many had poor-risk cytogenetics (43%) or one of a number of poor-risk mutations, according to the study report.
Pravastatin, in addition to working on the cholesterol pathway in AML, may also have a therapeutic advantage in patients with FLT3 mutations. Three out of six patients with FLT3 mutations achieved CR/CRi, corroborating earlier preclinical studies and suggesting further study of this specific patient population would be worthwhile, the researchers noted.
The study was supported in part by the National Institutes of Health and Bristol-Myers Squibb. Dr. Advani reported having no financial disclosures but other study authors reported relationships with various pharmaceutical companies.
SOURCE: Advani AS et al. Leuk Res. 2018 Apr;67:17-20.
Patients with poor-risk acute myelogenous leukemia (AML) had promising rates of response and survival following treatment with a statin added to standard chemotherapy, researchers reported.
Pravastatin in combination with idarubicin and cytarabine had a 30% response rate in poor-risk AML patients, according to Anjali S. Advani, MD, of the Taussig Cancer Institute at the Cleveland Clinic, and her coauthors.
Although that response rate did not meet a prespecified threshold for statistical significance, results of the phase 2 study were nevertheless “encouraging” for a group of patients with unfavorable cytogenetics and poor-risk molecular mutations, the researchers wrote. The study was published in Leukemia Research.
The estimated median overall survival was 4.1 months in the phase 2 trial, known as SWOG S0919. About one-quarter of the patients were able to proceed to allogeneic hematopoietic stem cell transplant, and for that group, median overall survival was 27.1 months.
These findings appear to provide further support for the hypothesis that targeting the cholesterol pathway may be a promising approach in patients with AML.
Some previous investigations suggested that AML blasts overexpress genes for lipoprotein receptors and regulatory enzymes, while others showed that these cells import and synthesize cholesterol at levels higher than what is seen in normal progenitor cells. In addition, some AML patients have hypocholesterolemia that usually resolves when they achieve a complete remission.
“These observations suggest that AML cells may require high levels of cholesterol for their survival and that abnormalities in cholesterol homeostasis are necessary for AML cell survival,” the researchers wrote.
This led to a phase 1 trial of pravastatin plus idarubicin/cytarabine, followed by the phase 2 SWOG S0919 trial, which demonstrated a 75% rate of complete response (CR) or complete response with incomplete count recovery (CRi) for the regimen.
The SWOG S0919 study was amended to include the poor-risk AML patients described in the present study. That cohort of 46 patients had a CR/CRi of less than 6 months after their last induction regimen or refractory disease. Many had poor-risk cytogenetics (43%) or one of a number of poor-risk mutations, according to the study report.
Pravastatin, in addition to working on the cholesterol pathway in AML, may also have a therapeutic advantage in patients with FLT3 mutations. Three out of six patients with FLT3 mutations achieved CR/CRi, corroborating earlier preclinical studies and suggesting further study of this specific patient population would be worthwhile, the researchers noted.
The study was supported in part by the National Institutes of Health and Bristol-Myers Squibb. Dr. Advani reported having no financial disclosures but other study authors reported relationships with various pharmaceutical companies.
SOURCE: Advani AS et al. Leuk Res. 2018 Apr;67:17-20.
FROM LEUKEMIA RESEARCH
Key clinical point:
Major finding: Pravastatin in combination with idarubicin and cytarabine had a 30% response rate in poor risk AML patients.
Study details: Results from the poor-risk cohort (n = 46) in SWOG S0919, a phase 2 study.
Disclosures: The research was supported in part by the National Institutes of Health and Bristol-Myers Squibb. Dr. Advani reported having no financial disclosures but other study authors reported relationships with various pharmaceutical companies.
Source: Advani AS et al. Leuk Res. 2018 Apr;67:17-20.