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FDA to review FLT3 agent for refractory AML
The Food and Drug Administration has granted priority review to an FMS-like tyrosine kinase 3 (FLT3)–targeting agent for the treatment of adults with relapsed or refractory acute myeloid leukemia (AML).
If approved, it would be the first FLT3 inhibitor available for this indication.
The application is based on the ongoing ADMIRAL trial, a phase 3, open-label, randomized study of gilteritinib versus salvage chemotherapy. The trial is designed to enroll 369 patients with FLT3 mutations present in bone marrow or whole blood who are refractory or have relapsed on first-line therapy. The primary endpoints are overall survival and rates of complete remission and complete remission with partial hematologic recovery.
The FDA has set Nov. 29 as a target date for reaching a decision on approval of the drug.
The Food and Drug Administration has granted priority review to an FMS-like tyrosine kinase 3 (FLT3)–targeting agent for the treatment of adults with relapsed or refractory acute myeloid leukemia (AML).
If approved, it would be the first FLT3 inhibitor available for this indication.
The application is based on the ongoing ADMIRAL trial, a phase 3, open-label, randomized study of gilteritinib versus salvage chemotherapy. The trial is designed to enroll 369 patients with FLT3 mutations present in bone marrow or whole blood who are refractory or have relapsed on first-line therapy. The primary endpoints are overall survival and rates of complete remission and complete remission with partial hematologic recovery.
The FDA has set Nov. 29 as a target date for reaching a decision on approval of the drug.
The Food and Drug Administration has granted priority review to an FMS-like tyrosine kinase 3 (FLT3)–targeting agent for the treatment of adults with relapsed or refractory acute myeloid leukemia (AML).
If approved, it would be the first FLT3 inhibitor available for this indication.
The application is based on the ongoing ADMIRAL trial, a phase 3, open-label, randomized study of gilteritinib versus salvage chemotherapy. The trial is designed to enroll 369 patients with FLT3 mutations present in bone marrow or whole blood who are refractory or have relapsed on first-line therapy. The primary endpoints are overall survival and rates of complete remission and complete remission with partial hematologic recovery.
The FDA has set Nov. 29 as a target date for reaching a decision on approval of the drug.
Protein may be therapeutic target for AML
A signaling protein may be a “potent” therapeutic target for acute myeloid leukemia (AML), according to a paper published in the Journal of Experimental Medicine.
The protein, interleukin-1 receptor accessory protein (IL1RAP), is often highly expressed on the surface of leukemic stem cells (LSCs) but largely absent from normal hematopoietic stem cells.
Despite this, it wasn’t known whether LSCs require IL1RAP to survive and proliferate and whether inhibiting IL1RAP could be a successful way to treat AML.
Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York, and his colleagues conducted research to find out.
The team found that targeting IL1RAP via RNA interference, genetic deletion, or antibodies induced the death of AML cells, including LSCs, in vitro. These effects were seen in the absence of immune effector cells, indicating that AML cells intrinsically depend on IL1RAP.
In contrast, antibodies targeting IL1RAP had no effect on the growth and survival of normal hematopoietic cells.
In mice, IL1RAP antibody treatment inhibited the proliferation of AML cells without causing any negative side effects.
The researchers also found that IL1RAP’s role in AML is not restricted to the IL-1 receptor pathway.
The team found that IL1RAP enhances the activity of 2 other membrane receptor proteins, FLT3 and c-KIT, which are known to stimulate the proliferation of LSCs when activated by their ligands. IL1RAP antibodies inhibited the ability of these ligands to induce proliferation in AML cells.
“Our findings show that IL1RAP can amplify multiple key pathways in AML, demonstrating a much broader role for this protein in disease pathogenesis than previously appreciated,” Dr Steidl noted.
“Importantly, as IL1RAP is also overexpressed in the stem cells of chronic myeloid leukemia and high-risk myelodysplastic syndromes, there is significant therapeutic potential in further developing IL1RAP-directed targeting strategies.”
A signaling protein may be a “potent” therapeutic target for acute myeloid leukemia (AML), according to a paper published in the Journal of Experimental Medicine.
The protein, interleukin-1 receptor accessory protein (IL1RAP), is often highly expressed on the surface of leukemic stem cells (LSCs) but largely absent from normal hematopoietic stem cells.
Despite this, it wasn’t known whether LSCs require IL1RAP to survive and proliferate and whether inhibiting IL1RAP could be a successful way to treat AML.
Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York, and his colleagues conducted research to find out.
The team found that targeting IL1RAP via RNA interference, genetic deletion, or antibodies induced the death of AML cells, including LSCs, in vitro. These effects were seen in the absence of immune effector cells, indicating that AML cells intrinsically depend on IL1RAP.
In contrast, antibodies targeting IL1RAP had no effect on the growth and survival of normal hematopoietic cells.
In mice, IL1RAP antibody treatment inhibited the proliferation of AML cells without causing any negative side effects.
The researchers also found that IL1RAP’s role in AML is not restricted to the IL-1 receptor pathway.
The team found that IL1RAP enhances the activity of 2 other membrane receptor proteins, FLT3 and c-KIT, which are known to stimulate the proliferation of LSCs when activated by their ligands. IL1RAP antibodies inhibited the ability of these ligands to induce proliferation in AML cells.
“Our findings show that IL1RAP can amplify multiple key pathways in AML, demonstrating a much broader role for this protein in disease pathogenesis than previously appreciated,” Dr Steidl noted.
“Importantly, as IL1RAP is also overexpressed in the stem cells of chronic myeloid leukemia and high-risk myelodysplastic syndromes, there is significant therapeutic potential in further developing IL1RAP-directed targeting strategies.”
A signaling protein may be a “potent” therapeutic target for acute myeloid leukemia (AML), according to a paper published in the Journal of Experimental Medicine.
The protein, interleukin-1 receptor accessory protein (IL1RAP), is often highly expressed on the surface of leukemic stem cells (LSCs) but largely absent from normal hematopoietic stem cells.
Despite this, it wasn’t known whether LSCs require IL1RAP to survive and proliferate and whether inhibiting IL1RAP could be a successful way to treat AML.
Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York, and his colleagues conducted research to find out.
The team found that targeting IL1RAP via RNA interference, genetic deletion, or antibodies induced the death of AML cells, including LSCs, in vitro. These effects were seen in the absence of immune effector cells, indicating that AML cells intrinsically depend on IL1RAP.
In contrast, antibodies targeting IL1RAP had no effect on the growth and survival of normal hematopoietic cells.
In mice, IL1RAP antibody treatment inhibited the proliferation of AML cells without causing any negative side effects.
The researchers also found that IL1RAP’s role in AML is not restricted to the IL-1 receptor pathway.
The team found that IL1RAP enhances the activity of 2 other membrane receptor proteins, FLT3 and c-KIT, which are known to stimulate the proliferation of LSCs when activated by their ligands. IL1RAP antibodies inhibited the ability of these ligands to induce proliferation in AML cells.
“Our findings show that IL1RAP can amplify multiple key pathways in AML, demonstrating a much broader role for this protein in disease pathogenesis than previously appreciated,” Dr Steidl noted.
“Importantly, as IL1RAP is also overexpressed in the stem cells of chronic myeloid leukemia and high-risk myelodysplastic syndromes, there is significant therapeutic potential in further developing IL1RAP-directed targeting strategies.”
NCCN releases guidelines for AML patients
The National Comprehensive Cancer Network (NCCN) has released guidelines for patients with acute myeloid leukemia (AML).
The guidelines are intended to help patients make better informed decision about their care.
The guidelines explain what AML is, describe testing procedures and treatment options, and provide tips to help patients choose the best treatment.
The guidelines also include a list of suggested questions for patients to bring up with their doctors, illustrations, and a glossary of key terms and acronyms.
“People with AML often aren’t aware that this isn’t a single disease but many different diseases that share fundamental characteristics,” said Martin Tallman, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and vice-chair of the NCCN Guidelines Panel for AML.
“The good news is that the future for AML is getting a lot brighter. After 40 years without much progress, 4 new medications were just approved last year*, and more new treatment courses are in development as we speak.”
The guidelines are available for free on the NCCN website or via the NCCN Patient Guides for Cancer app. Printed versions of the guidelines can be purchased at Amazon.com.
NCCN also has guidelines for patients with acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, multiple myeloma, myelodysplastic syndromes, myeloproliferative neoplasms, non-Hodgkin lymphomas, and Waldenström’s macroglobulinemia, as well as solid tumor malignancies.
There are patient guidelines for adolescents and young adults with cancer and guidelines on distress/supportive care, and nausea and vomiting/supportive care as well.
*(1) Midostaurin (Rydapt) was approved for adults with newly diagnosed, FLT3-positive AML
(2) Gemtuzumab ozogamicin (Mylotarg) was approved for adults with newly diagnosed AML and patients age 2 and older with relapsed/refractory AML
(3) Liposomal daunorubicin/cytarabine (Vyxeos) was approved for AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML
(4) Enasidenib (Idhifa) was approved for adults with relapsed/refractory AML and an IDH2 mutation.
The National Comprehensive Cancer Network (NCCN) has released guidelines for patients with acute myeloid leukemia (AML).
The guidelines are intended to help patients make better informed decision about their care.
The guidelines explain what AML is, describe testing procedures and treatment options, and provide tips to help patients choose the best treatment.
The guidelines also include a list of suggested questions for patients to bring up with their doctors, illustrations, and a glossary of key terms and acronyms.
“People with AML often aren’t aware that this isn’t a single disease but many different diseases that share fundamental characteristics,” said Martin Tallman, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and vice-chair of the NCCN Guidelines Panel for AML.
“The good news is that the future for AML is getting a lot brighter. After 40 years without much progress, 4 new medications were just approved last year*, and more new treatment courses are in development as we speak.”
The guidelines are available for free on the NCCN website or via the NCCN Patient Guides for Cancer app. Printed versions of the guidelines can be purchased at Amazon.com.
NCCN also has guidelines for patients with acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, multiple myeloma, myelodysplastic syndromes, myeloproliferative neoplasms, non-Hodgkin lymphomas, and Waldenström’s macroglobulinemia, as well as solid tumor malignancies.
There are patient guidelines for adolescents and young adults with cancer and guidelines on distress/supportive care, and nausea and vomiting/supportive care as well.
*(1) Midostaurin (Rydapt) was approved for adults with newly diagnosed, FLT3-positive AML
(2) Gemtuzumab ozogamicin (Mylotarg) was approved for adults with newly diagnosed AML and patients age 2 and older with relapsed/refractory AML
(3) Liposomal daunorubicin/cytarabine (Vyxeos) was approved for AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML
(4) Enasidenib (Idhifa) was approved for adults with relapsed/refractory AML and an IDH2 mutation.
The National Comprehensive Cancer Network (NCCN) has released guidelines for patients with acute myeloid leukemia (AML).
The guidelines are intended to help patients make better informed decision about their care.
The guidelines explain what AML is, describe testing procedures and treatment options, and provide tips to help patients choose the best treatment.
The guidelines also include a list of suggested questions for patients to bring up with their doctors, illustrations, and a glossary of key terms and acronyms.
“People with AML often aren’t aware that this isn’t a single disease but many different diseases that share fundamental characteristics,” said Martin Tallman, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and vice-chair of the NCCN Guidelines Panel for AML.
“The good news is that the future for AML is getting a lot brighter. After 40 years without much progress, 4 new medications were just approved last year*, and more new treatment courses are in development as we speak.”
The guidelines are available for free on the NCCN website or via the NCCN Patient Guides for Cancer app. Printed versions of the guidelines can be purchased at Amazon.com.
NCCN also has guidelines for patients with acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, multiple myeloma, myelodysplastic syndromes, myeloproliferative neoplasms, non-Hodgkin lymphomas, and Waldenström’s macroglobulinemia, as well as solid tumor malignancies.
There are patient guidelines for adolescents and young adults with cancer and guidelines on distress/supportive care, and nausea and vomiting/supportive care as well.
*(1) Midostaurin (Rydapt) was approved for adults with newly diagnosed, FLT3-positive AML
(2) Gemtuzumab ozogamicin (Mylotarg) was approved for adults with newly diagnosed AML and patients age 2 and older with relapsed/refractory AML
(3) Liposomal daunorubicin/cytarabine (Vyxeos) was approved for AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML
(4) Enasidenib (Idhifa) was approved for adults with relapsed/refractory AML and an IDH2 mutation.
CAR T-cell therapy bridges to HSCT in AML patient
A case report suggests an investigational chimeric antigen receptor (CAR) T-cell therapy can provide a bridge to transplant in relapsed/refractory acute myeloid leukemia (AML).
The therapy, known as CYAD-01, prompted a morphologic leukemia-free state in an AML patient.
This patient went on to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) and achieve a complete molecular remission, which was ongoing 6 months after transplant.
Investigators reported no adverse events related to CYAD-01.
This report was published in haematologica.
The patient is enrolled in the THINK trial (NCT03018405), which is sponsored by Celyad SA, the company developing CYAD-01.
According to Celyad, CYAD-01 consists of autologous T cells expressing a CAR based on the natural killer group 2 member D receptor (NKG2D), a transmembrane receptor expressed by natural killer cells and some T-cell subsets.
The AML patient who received CYAD-01 was 52 years old at trial enrollment. He had +8/del(7)(q22q36), FLT3/NPM1 wild-type AML.
The patient’s disease was primary refractory to 7+3 induction, so he went on to receive salvage chemotherapy with cladribine, cytarabine, G-CSF, and mitoxantrone. He achieved a complete response to this treatment and received 2 cycles of consolidation with cladribine and cytarabine.
The patient’s subsequent allo-HSCT was delayed to allow for pulmonary function test recovery. In the meantime, he relapsed.
At this point, the patient enrolled in the THINK trial. He underwent apheresis and received CYAD-01 infusions at the initial dose level of 3 x 108 cells every 2 weeks for 3 administrations.
The patient achieved a morphologic leukemia-free state at 3 months, which enabled him to undergo allo-HSCT.
The patient achieved a complete molecular remission after transplant. He remained in remission at last follow-up—9 months after his first CYAD-01 infusion and 6 months after allo-HSCT.
The investigators said CYAD-01 was well tolerated in this patient. He did not develop cytokine release syndrome or experience neurotoxic effects. The patient had only non-related grade 1 adverse events.
“The THINK study case report provides the first clinical validity of CYAD-01 as a tumor-specific antigen-receptor and AML as a disease sensitive to gene-engineered cell therapies,” said study investigator David Sallman, MD, of Moffitt Cancer Center in Tampa, Florida.
“As antigen targeting offers significant challenges in AML, this outcome brings hope for the further use of gene-engineered T cells for patients with AML [who] have run out of therapeutic options. It’s all the more striking that this outcome was observed without any prior lymphodepletion, highlighting the potential of using a physiologic antigen-receptor.”
A case report suggests an investigational chimeric antigen receptor (CAR) T-cell therapy can provide a bridge to transplant in relapsed/refractory acute myeloid leukemia (AML).
The therapy, known as CYAD-01, prompted a morphologic leukemia-free state in an AML patient.
This patient went on to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) and achieve a complete molecular remission, which was ongoing 6 months after transplant.
Investigators reported no adverse events related to CYAD-01.
This report was published in haematologica.
The patient is enrolled in the THINK trial (NCT03018405), which is sponsored by Celyad SA, the company developing CYAD-01.
According to Celyad, CYAD-01 consists of autologous T cells expressing a CAR based on the natural killer group 2 member D receptor (NKG2D), a transmembrane receptor expressed by natural killer cells and some T-cell subsets.
The AML patient who received CYAD-01 was 52 years old at trial enrollment. He had +8/del(7)(q22q36), FLT3/NPM1 wild-type AML.
The patient’s disease was primary refractory to 7+3 induction, so he went on to receive salvage chemotherapy with cladribine, cytarabine, G-CSF, and mitoxantrone. He achieved a complete response to this treatment and received 2 cycles of consolidation with cladribine and cytarabine.
The patient’s subsequent allo-HSCT was delayed to allow for pulmonary function test recovery. In the meantime, he relapsed.
At this point, the patient enrolled in the THINK trial. He underwent apheresis and received CYAD-01 infusions at the initial dose level of 3 x 108 cells every 2 weeks for 3 administrations.
The patient achieved a morphologic leukemia-free state at 3 months, which enabled him to undergo allo-HSCT.
The patient achieved a complete molecular remission after transplant. He remained in remission at last follow-up—9 months after his first CYAD-01 infusion and 6 months after allo-HSCT.
The investigators said CYAD-01 was well tolerated in this patient. He did not develop cytokine release syndrome or experience neurotoxic effects. The patient had only non-related grade 1 adverse events.
“The THINK study case report provides the first clinical validity of CYAD-01 as a tumor-specific antigen-receptor and AML as a disease sensitive to gene-engineered cell therapies,” said study investigator David Sallman, MD, of Moffitt Cancer Center in Tampa, Florida.
“As antigen targeting offers significant challenges in AML, this outcome brings hope for the further use of gene-engineered T cells for patients with AML [who] have run out of therapeutic options. It’s all the more striking that this outcome was observed without any prior lymphodepletion, highlighting the potential of using a physiologic antigen-receptor.”
A case report suggests an investigational chimeric antigen receptor (CAR) T-cell therapy can provide a bridge to transplant in relapsed/refractory acute myeloid leukemia (AML).
The therapy, known as CYAD-01, prompted a morphologic leukemia-free state in an AML patient.
This patient went on to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) and achieve a complete molecular remission, which was ongoing 6 months after transplant.
Investigators reported no adverse events related to CYAD-01.
This report was published in haematologica.
The patient is enrolled in the THINK trial (NCT03018405), which is sponsored by Celyad SA, the company developing CYAD-01.
According to Celyad, CYAD-01 consists of autologous T cells expressing a CAR based on the natural killer group 2 member D receptor (NKG2D), a transmembrane receptor expressed by natural killer cells and some T-cell subsets.
The AML patient who received CYAD-01 was 52 years old at trial enrollment. He had +8/del(7)(q22q36), FLT3/NPM1 wild-type AML.
The patient’s disease was primary refractory to 7+3 induction, so he went on to receive salvage chemotherapy with cladribine, cytarabine, G-CSF, and mitoxantrone. He achieved a complete response to this treatment and received 2 cycles of consolidation with cladribine and cytarabine.
The patient’s subsequent allo-HSCT was delayed to allow for pulmonary function test recovery. In the meantime, he relapsed.
At this point, the patient enrolled in the THINK trial. He underwent apheresis and received CYAD-01 infusions at the initial dose level of 3 x 108 cells every 2 weeks for 3 administrations.
The patient achieved a morphologic leukemia-free state at 3 months, which enabled him to undergo allo-HSCT.
The patient achieved a complete molecular remission after transplant. He remained in remission at last follow-up—9 months after his first CYAD-01 infusion and 6 months after allo-HSCT.
The investigators said CYAD-01 was well tolerated in this patient. He did not develop cytokine release syndrome or experience neurotoxic effects. The patient had only non-related grade 1 adverse events.
“The THINK study case report provides the first clinical validity of CYAD-01 as a tumor-specific antigen-receptor and AML as a disease sensitive to gene-engineered cell therapies,” said study investigator David Sallman, MD, of Moffitt Cancer Center in Tampa, Florida.
“As antigen targeting offers significant challenges in AML, this outcome brings hope for the further use of gene-engineered T cells for patients with AML [who] have run out of therapeutic options. It’s all the more striking that this outcome was observed without any prior lymphodepletion, highlighting the potential of using a physiologic antigen-receptor.”
Y chromosome gene protects against AML
Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.
The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).
However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.
The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.
“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.
“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”
For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.
In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.
They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.
Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.
“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.
“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”
Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.
The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).
However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.
The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.
“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.
“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”
For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.
In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.
They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.
Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.
“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.
“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”
Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.
The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).
However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.
The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.
“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.
“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”
For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.
In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.
They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.
Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.
“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.
“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”
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.”