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The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.
Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.1 With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.2
In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.
AML: Historical perspective
AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.2 These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.
Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.1 In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.
However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.2 These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.
Novel therapeutics in AML
Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.2 Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.
Acute promyelocytic leukemia
APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.2 Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.
Core binding factor AML
CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.
Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).
Intensive chemotherapy in younger/fit AML
Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.
Older/unfit patients with AML: Low-intensity therapy
Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.
Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.
Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.
Other FDA-approved therapies in AML
CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.
Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.
Expert perspectives: Future of AML therapy
Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.1
“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”
Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.
“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.
“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.
They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.
Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.
References
1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.
2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.
The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.
Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.1 With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.2
In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.
AML: Historical perspective
AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.2 These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.
Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.1 In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.
However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.2 These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.
Novel therapeutics in AML
Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.2 Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.
Acute promyelocytic leukemia
APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.2 Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.
Core binding factor AML
CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.
Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).
Intensive chemotherapy in younger/fit AML
Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.
Older/unfit patients with AML: Low-intensity therapy
Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.
Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.
Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.
Other FDA-approved therapies in AML
CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.
Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.
Expert perspectives: Future of AML therapy
Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.1
“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”
Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.
“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.
“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.
They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.
Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.
References
1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.
2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.
The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.
Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.1 With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.2
In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.
AML: Historical perspective
AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.2 These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.
Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.1 In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.
However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.2 These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.
Novel therapeutics in AML
Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.2 Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.
Acute promyelocytic leukemia
APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.2 Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.
Core binding factor AML
CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.
Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).
Intensive chemotherapy in younger/fit AML
Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.
Older/unfit patients with AML: Low-intensity therapy
Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.
Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.
Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.
Other FDA-approved therapies in AML
CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.
Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.
Expert perspectives: Future of AML therapy
Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.1
“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”
Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.
“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.
“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.
They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.
Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.
References
1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.
2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.
