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MDM2 inhibitors could treat resistant AML
Preclinical research has revealed a potential treatment for chemotherapy-resistant acute myeloid leukemia (AML).
Researchers characterized a mechanism of chemotherapy resistance in AML and found that MDM2 is a key player in this dysregulated signaling pathway.
They tested MDM2 inhibitors and found these drugs could sensitize resistant AML to chemotherapy in vitro and in vivo.
In fact, mice with refractory AML responded to standard induction therapy when combined with an MDM2 inhibitor, showing no signs of disease and prolonged survival.
These results were published in Cancer Discovery.
“We were blown away when we saw the results,” said study author William Stanford, PhD, of Ottawa Hospital Research Institute in Ontario, Canada.
“If these findings hold up in clinical trials, we could have a new treatment for people who would almost certainly die of their disease today.”
Mechanism of resistance
Dr. Stanford’s research began with the protein MTF2. He and his colleagues previously found that MTF2 plays a role in erythropoiesis, and the team wanted to determine if MTF2 also plays a role in AML.
Using AML samples from patients treated at The Ottawa Hospital, the researchers found the mean survival was three times longer in patients with normal MTF2 activity than in patients with low MTF2 activity.
“Initially, we thought that MTF2 could be an important biomarker to identify patients who might benefit from experimental therapies,” Dr. Stanford said. “But then we started thinking that if we could understand what MTF2 was doing, maybe we could use this information to develop a new treatment.”
Dr. Stanford and his colleagues discovered that MTF2 represses MDM2, a protein that helps cells resist chemotherapy.
The team found that MTF2-deficient cells overexpress MDM2, which inhibits p53, and this leads to defects in cell-cycle regulation and apoptosis that enable resistance to chemotherapy.
Testing MDM2 inhibitors
Since MDM2 inhibitors are already being tested in clinical trials for other cancers, Dr. Stanford and his colleagues tested these inhibitors in vitro and in mouse models of chemotherapy-resistant AML.
The in vitro experiments included two MDM2 inhibitors—Nutlin3A and MI-773—combined with daunorubicin or cytarabine.
The researchers found that refractory, MTF2-deficient AML cells underwent apoptosis when treated with either daunorubicin or cytarabine in combination with Nutlin3A or MI-773. The effect was comparable to that observed in AML cells with normal MTF2.
The team found that Nutlin3A was more efficient at sensitizing refractory, MTF2-deficient AML cells to daunorubicin, so they used Nutlin3A in the in vivo experiments.
For these experiments, the researchers tested Nutlin3A in mice injected with either chemotherapy-responsive AML cells (with normal MTF2) or refractory, MTF2-deficient AML cells.
Once the mice had “a substantial leukemic burden” (≥ 20% CD45+CD33+ leukemic blasts in their peripheral blood), they were randomized to receive vehicle control, Nutlin3A, standard induction therapy, or induction plus Nutlin3A.
The mice engrafted with chemotherapy-responsive AML cells did not respond to vehicle control or Nutlin3A alone. However, they did respond to standard induction and induction plus Nutlin3A, surviving until the end of the experiment at 16 weeks.
Among the mice engrafted with refractory, MTF2-deficient AML cells, only those animals treated with induction plus Nutlin3A survived until the end of the experiment.
The researchers also noted a “dramatic loss” in the blast-containing CD45+CD33+ and CD34+CD38− populations in mice treated with induction plus Nutlin3A.
To assess residual disease, the researchers performed secondary transplants with cells from mice that had engrafted with refractory, MTF2-deficient AML cells but responded to induction plus Nutlin3A.
The recipient mice had no evidence of AML at 16 weeks after transplant when the experiment ended.
Dr. Stanford and his colleagues are now trying to obtain pharmaceutical-grade MDM2 inhibitors to conduct trials in AML patients at The Ottawa Hospital.
The researchers are also screening libraries of approved drugs to see if any of these can block MDM2, and they are working with a biotech company to develop a test to identify chemotherapy-resistant AML patients who would respond to MDM2 inhibitors.
The current research was supported by grants from the Canadian Cancer Society Research Institute, Canadian Institutes of Health Research, Cancer Research Society, National Institutes of Health, and a Tier 1 Canada Research Chair in Integrative Stem Cell Biology. One study author reported a relationship with Epicypher, Inc. No other conflicts of interest were reported.
Preclinical research has revealed a potential treatment for chemotherapy-resistant acute myeloid leukemia (AML).
Researchers characterized a mechanism of chemotherapy resistance in AML and found that MDM2 is a key player in this dysregulated signaling pathway.
They tested MDM2 inhibitors and found these drugs could sensitize resistant AML to chemotherapy in vitro and in vivo.
In fact, mice with refractory AML responded to standard induction therapy when combined with an MDM2 inhibitor, showing no signs of disease and prolonged survival.
These results were published in Cancer Discovery.
“We were blown away when we saw the results,” said study author William Stanford, PhD, of Ottawa Hospital Research Institute in Ontario, Canada.
“If these findings hold up in clinical trials, we could have a new treatment for people who would almost certainly die of their disease today.”
Mechanism of resistance
Dr. Stanford’s research began with the protein MTF2. He and his colleagues previously found that MTF2 plays a role in erythropoiesis, and the team wanted to determine if MTF2 also plays a role in AML.
Using AML samples from patients treated at The Ottawa Hospital, the researchers found the mean survival was three times longer in patients with normal MTF2 activity than in patients with low MTF2 activity.
“Initially, we thought that MTF2 could be an important biomarker to identify patients who might benefit from experimental therapies,” Dr. Stanford said. “But then we started thinking that if we could understand what MTF2 was doing, maybe we could use this information to develop a new treatment.”
Dr. Stanford and his colleagues discovered that MTF2 represses MDM2, a protein that helps cells resist chemotherapy.
The team found that MTF2-deficient cells overexpress MDM2, which inhibits p53, and this leads to defects in cell-cycle regulation and apoptosis that enable resistance to chemotherapy.
Testing MDM2 inhibitors
Since MDM2 inhibitors are already being tested in clinical trials for other cancers, Dr. Stanford and his colleagues tested these inhibitors in vitro and in mouse models of chemotherapy-resistant AML.
The in vitro experiments included two MDM2 inhibitors—Nutlin3A and MI-773—combined with daunorubicin or cytarabine.
The researchers found that refractory, MTF2-deficient AML cells underwent apoptosis when treated with either daunorubicin or cytarabine in combination with Nutlin3A or MI-773. The effect was comparable to that observed in AML cells with normal MTF2.
The team found that Nutlin3A was more efficient at sensitizing refractory, MTF2-deficient AML cells to daunorubicin, so they used Nutlin3A in the in vivo experiments.
For these experiments, the researchers tested Nutlin3A in mice injected with either chemotherapy-responsive AML cells (with normal MTF2) or refractory, MTF2-deficient AML cells.
Once the mice had “a substantial leukemic burden” (≥ 20% CD45+CD33+ leukemic blasts in their peripheral blood), they were randomized to receive vehicle control, Nutlin3A, standard induction therapy, or induction plus Nutlin3A.
The mice engrafted with chemotherapy-responsive AML cells did not respond to vehicle control or Nutlin3A alone. However, they did respond to standard induction and induction plus Nutlin3A, surviving until the end of the experiment at 16 weeks.
Among the mice engrafted with refractory, MTF2-deficient AML cells, only those animals treated with induction plus Nutlin3A survived until the end of the experiment.
The researchers also noted a “dramatic loss” in the blast-containing CD45+CD33+ and CD34+CD38− populations in mice treated with induction plus Nutlin3A.
To assess residual disease, the researchers performed secondary transplants with cells from mice that had engrafted with refractory, MTF2-deficient AML cells but responded to induction plus Nutlin3A.
The recipient mice had no evidence of AML at 16 weeks after transplant when the experiment ended.
Dr. Stanford and his colleagues are now trying to obtain pharmaceutical-grade MDM2 inhibitors to conduct trials in AML patients at The Ottawa Hospital.
The researchers are also screening libraries of approved drugs to see if any of these can block MDM2, and they are working with a biotech company to develop a test to identify chemotherapy-resistant AML patients who would respond to MDM2 inhibitors.
The current research was supported by grants from the Canadian Cancer Society Research Institute, Canadian Institutes of Health Research, Cancer Research Society, National Institutes of Health, and a Tier 1 Canada Research Chair in Integrative Stem Cell Biology. One study author reported a relationship with Epicypher, Inc. No other conflicts of interest were reported.
Preclinical research has revealed a potential treatment for chemotherapy-resistant acute myeloid leukemia (AML).
Researchers characterized a mechanism of chemotherapy resistance in AML and found that MDM2 is a key player in this dysregulated signaling pathway.
They tested MDM2 inhibitors and found these drugs could sensitize resistant AML to chemotherapy in vitro and in vivo.
In fact, mice with refractory AML responded to standard induction therapy when combined with an MDM2 inhibitor, showing no signs of disease and prolonged survival.
These results were published in Cancer Discovery.
“We were blown away when we saw the results,” said study author William Stanford, PhD, of Ottawa Hospital Research Institute in Ontario, Canada.
“If these findings hold up in clinical trials, we could have a new treatment for people who would almost certainly die of their disease today.”
Mechanism of resistance
Dr. Stanford’s research began with the protein MTF2. He and his colleagues previously found that MTF2 plays a role in erythropoiesis, and the team wanted to determine if MTF2 also plays a role in AML.
Using AML samples from patients treated at The Ottawa Hospital, the researchers found the mean survival was three times longer in patients with normal MTF2 activity than in patients with low MTF2 activity.
“Initially, we thought that MTF2 could be an important biomarker to identify patients who might benefit from experimental therapies,” Dr. Stanford said. “But then we started thinking that if we could understand what MTF2 was doing, maybe we could use this information to develop a new treatment.”
Dr. Stanford and his colleagues discovered that MTF2 represses MDM2, a protein that helps cells resist chemotherapy.
The team found that MTF2-deficient cells overexpress MDM2, which inhibits p53, and this leads to defects in cell-cycle regulation and apoptosis that enable resistance to chemotherapy.
Testing MDM2 inhibitors
Since MDM2 inhibitors are already being tested in clinical trials for other cancers, Dr. Stanford and his colleagues tested these inhibitors in vitro and in mouse models of chemotherapy-resistant AML.
The in vitro experiments included two MDM2 inhibitors—Nutlin3A and MI-773—combined with daunorubicin or cytarabine.
The researchers found that refractory, MTF2-deficient AML cells underwent apoptosis when treated with either daunorubicin or cytarabine in combination with Nutlin3A or MI-773. The effect was comparable to that observed in AML cells with normal MTF2.
The team found that Nutlin3A was more efficient at sensitizing refractory, MTF2-deficient AML cells to daunorubicin, so they used Nutlin3A in the in vivo experiments.
For these experiments, the researchers tested Nutlin3A in mice injected with either chemotherapy-responsive AML cells (with normal MTF2) or refractory, MTF2-deficient AML cells.
Once the mice had “a substantial leukemic burden” (≥ 20% CD45+CD33+ leukemic blasts in their peripheral blood), they were randomized to receive vehicle control, Nutlin3A, standard induction therapy, or induction plus Nutlin3A.
The mice engrafted with chemotherapy-responsive AML cells did not respond to vehicle control or Nutlin3A alone. However, they did respond to standard induction and induction plus Nutlin3A, surviving until the end of the experiment at 16 weeks.
Among the mice engrafted with refractory, MTF2-deficient AML cells, only those animals treated with induction plus Nutlin3A survived until the end of the experiment.
The researchers also noted a “dramatic loss” in the blast-containing CD45+CD33+ and CD34+CD38− populations in mice treated with induction plus Nutlin3A.
To assess residual disease, the researchers performed secondary transplants with cells from mice that had engrafted with refractory, MTF2-deficient AML cells but responded to induction plus Nutlin3A.
The recipient mice had no evidence of AML at 16 weeks after transplant when the experiment ended.
Dr. Stanford and his colleagues are now trying to obtain pharmaceutical-grade MDM2 inhibitors to conduct trials in AML patients at The Ottawa Hospital.
The researchers are also screening libraries of approved drugs to see if any of these can block MDM2, and they are working with a biotech company to develop a test to identify chemotherapy-resistant AML patients who would respond to MDM2 inhibitors.
The current research was supported by grants from the Canadian Cancer Society Research Institute, Canadian Institutes of Health Research, Cancer Research Society, National Institutes of Health, and a Tier 1 Canada Research Chair in Integrative Stem Cell Biology. One study author reported a relationship with Epicypher, Inc. No other conflicts of interest were reported.
CDK8 inhibitor shows activity against AML
DUBROVNIK, CROATIA – The (AML), but the agent’s mechanism of action is still unclear.
Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples. SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.
The researchers suggest that SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.
Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research on SEL120 at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.
Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research indicated that CDK8 drives oncogenic transcription in AML (Nature. 2015 Oct 8;526[7572]:273-6).
In a prior study, researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation (Oncotarget. 2017 May 16;8[20]:33779-95).
Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.
“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.
In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.
Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.
After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.
SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).
In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.
Toxicities observed in the mice included weight loss and upregulation of inflammation.
The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.
Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from three of four patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.
Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.
“The mechanism of action ... is, in our mind – at least in some cases – linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.
“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”
Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.
The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
DUBROVNIK, CROATIA – The (AML), but the agent’s mechanism of action is still unclear.
Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples. SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.
The researchers suggest that SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.
Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research on SEL120 at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.
Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research indicated that CDK8 drives oncogenic transcription in AML (Nature. 2015 Oct 8;526[7572]:273-6).
In a prior study, researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation (Oncotarget. 2017 May 16;8[20]:33779-95).
Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.
“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.
In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.
Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.
After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.
SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).
In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.
Toxicities observed in the mice included weight loss and upregulation of inflammation.
The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.
Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from three of four patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.
Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.
“The mechanism of action ... is, in our mind – at least in some cases – linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.
“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”
Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.
The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
DUBROVNIK, CROATIA – The (AML), but the agent’s mechanism of action is still unclear.
Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples. SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.
The researchers suggest that SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.
Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research on SEL120 at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.
Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research indicated that CDK8 drives oncogenic transcription in AML (Nature. 2015 Oct 8;526[7572]:273-6).
In a prior study, researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation (Oncotarget. 2017 May 16;8[20]:33779-95).
Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.
“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.
In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.
Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.
After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.
SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).
In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.
Toxicities observed in the mice included weight loss and upregulation of inflammation.
The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.
Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from three of four patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.
Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.
“The mechanism of action ... is, in our mind – at least in some cases – linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.
“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”
Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.
The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
EXPERT ANALYSIS FROM LEUKEMIA AND LYMPHOMA 2018
‘Intense’ end-of-life care may be common in HSCT recipients
Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.
Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).
However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.
For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.
Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.
The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.
Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.
Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.
Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.
Factors associated with intense care
The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.
Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:
- Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
- Ages 30 to 39—OR=1.8 (P<0.01)
- Ages 40 to 49—OR=1.4 (P<0.05).
Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.
Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).
Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).
Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).
Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).
“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.
“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”
This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.
Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.
Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).
However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.
For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.
Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.
The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.
Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.
Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.
Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.
Factors associated with intense care
The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.
Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:
- Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
- Ages 30 to 39—OR=1.8 (P<0.01)
- Ages 40 to 49—OR=1.4 (P<0.05).
Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.
Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).
Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).
Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).
Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).
“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.
“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”
This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.
Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.
Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).
However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.
For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.
Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.
The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.
Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.
Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.
Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.
Factors associated with intense care
The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.
Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:
- Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
- Ages 30 to 39—OR=1.8 (P<0.01)
- Ages 40 to 49—OR=1.4 (P<0.05).
Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.
Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).
Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).
Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).
Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).
“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.
“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”
This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.
Adoptive T-cell therapy treats PML
Adoptive T-cell therapy has proven effective for treating progressive multifocal leukoencephalopathy (PML), according to research published in The New England Journal of Medicine.
Researchers observed substantial improvements in three PML patients infused with donor T cells targeting the BK virus.
Although one patient ultimately died, two had complete clearance of the JC virus and no clinical signs of PML after treatment.
“The JC and BK viruses are genetically similar and share proteins that can be targeted by the immune system,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“Because of these similarities, we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
Dr. Rezvani’s team developed a novel approach for the generation of BK virus-specific T cells from healthy donors and established a bank of viral-specific T cells for immediate clinical use.
The researchers treated three patients with third-party, partially human leukocyte antigen (HLA)-matched, BK virus-specific T cells.
Patient 1 was a 32-year-old female with acute myeloid leukemia (AML) who previously received a double cord blood transplant.
Patient 2 was a 73-year-old female with JAK2-positive polycythemia rubra vera (PV) who had been treated with ruxolitinib.
Patient 3 was a 35-year-old man with AIDS who had discontinued highly active antiretroviral therapy due to side effects and who was no longer able to walk.
Following the first infusion, all three patients had a reduction in JC viral load in their cerebrospinal fluid. Viral loads dropped from:
- 700 to 78 copies in the AML patient
- 230,000 to 5,200 in the PV patient
- 4,300 to 1,300 in the AIDS patient.
“After infusion of viral-specific T cells, patients 1 and 3 had clinical improvement with significant reduction in JC virus in their cerebrospinal fluid,” Dr. Rezvani said.
“Both patients responded despite persistent T-cell immunodeficiency, supporting the concept that the response was mediated by the adoptively infused viral-specific T cells, and there were no infusion-related reactions.”
The AML patient received two additional infusions, which resulted in clearance of the virus in the cerebrospinal fluid and no signs of PML 27 months after the first infusion.
The PV patient received a second infusion that further reduced JC viral load, but no additional improvement was seen. The patient died 8 months after the first infusion.
The AIDS patient received additional infusions, resulting in complete clearance of the JC virus. This patient has regained mobility, and, 9 months after the first infusion, he is able to walk with a cane.
“We are encouraged that off-the-shelf, third-party, partially HLA-matched BK viral-specific T cells may provide a therapy for PML,” Dr. Rezvani said. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events with this treatment.”
This study was supported with funding from the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot, part of MD Anderson’s Moon Shots Program, as well as the National Institutes of Health.
Adoptive T-cell therapy has proven effective for treating progressive multifocal leukoencephalopathy (PML), according to research published in The New England Journal of Medicine.
Researchers observed substantial improvements in three PML patients infused with donor T cells targeting the BK virus.
Although one patient ultimately died, two had complete clearance of the JC virus and no clinical signs of PML after treatment.
“The JC and BK viruses are genetically similar and share proteins that can be targeted by the immune system,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“Because of these similarities, we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
Dr. Rezvani’s team developed a novel approach for the generation of BK virus-specific T cells from healthy donors and established a bank of viral-specific T cells for immediate clinical use.
The researchers treated three patients with third-party, partially human leukocyte antigen (HLA)-matched, BK virus-specific T cells.
Patient 1 was a 32-year-old female with acute myeloid leukemia (AML) who previously received a double cord blood transplant.
Patient 2 was a 73-year-old female with JAK2-positive polycythemia rubra vera (PV) who had been treated with ruxolitinib.
Patient 3 was a 35-year-old man with AIDS who had discontinued highly active antiretroviral therapy due to side effects and who was no longer able to walk.
Following the first infusion, all three patients had a reduction in JC viral load in their cerebrospinal fluid. Viral loads dropped from:
- 700 to 78 copies in the AML patient
- 230,000 to 5,200 in the PV patient
- 4,300 to 1,300 in the AIDS patient.
“After infusion of viral-specific T cells, patients 1 and 3 had clinical improvement with significant reduction in JC virus in their cerebrospinal fluid,” Dr. Rezvani said.
“Both patients responded despite persistent T-cell immunodeficiency, supporting the concept that the response was mediated by the adoptively infused viral-specific T cells, and there were no infusion-related reactions.”
The AML patient received two additional infusions, which resulted in clearance of the virus in the cerebrospinal fluid and no signs of PML 27 months after the first infusion.
The PV patient received a second infusion that further reduced JC viral load, but no additional improvement was seen. The patient died 8 months after the first infusion.
The AIDS patient received additional infusions, resulting in complete clearance of the JC virus. This patient has regained mobility, and, 9 months after the first infusion, he is able to walk with a cane.
“We are encouraged that off-the-shelf, third-party, partially HLA-matched BK viral-specific T cells may provide a therapy for PML,” Dr. Rezvani said. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events with this treatment.”
This study was supported with funding from the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot, part of MD Anderson’s Moon Shots Program, as well as the National Institutes of Health.
Adoptive T-cell therapy has proven effective for treating progressive multifocal leukoencephalopathy (PML), according to research published in The New England Journal of Medicine.
Researchers observed substantial improvements in three PML patients infused with donor T cells targeting the BK virus.
Although one patient ultimately died, two had complete clearance of the JC virus and no clinical signs of PML after treatment.
“The JC and BK viruses are genetically similar and share proteins that can be targeted by the immune system,” said study author Katy Rezvani, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.
“Because of these similarities, we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
Dr. Rezvani’s team developed a novel approach for the generation of BK virus-specific T cells from healthy donors and established a bank of viral-specific T cells for immediate clinical use.
The researchers treated three patients with third-party, partially human leukocyte antigen (HLA)-matched, BK virus-specific T cells.
Patient 1 was a 32-year-old female with acute myeloid leukemia (AML) who previously received a double cord blood transplant.
Patient 2 was a 73-year-old female with JAK2-positive polycythemia rubra vera (PV) who had been treated with ruxolitinib.
Patient 3 was a 35-year-old man with AIDS who had discontinued highly active antiretroviral therapy due to side effects and who was no longer able to walk.
Following the first infusion, all three patients had a reduction in JC viral load in their cerebrospinal fluid. Viral loads dropped from:
- 700 to 78 copies in the AML patient
- 230,000 to 5,200 in the PV patient
- 4,300 to 1,300 in the AIDS patient.
“After infusion of viral-specific T cells, patients 1 and 3 had clinical improvement with significant reduction in JC virus in their cerebrospinal fluid,” Dr. Rezvani said.
“Both patients responded despite persistent T-cell immunodeficiency, supporting the concept that the response was mediated by the adoptively infused viral-specific T cells, and there were no infusion-related reactions.”
The AML patient received two additional infusions, which resulted in clearance of the virus in the cerebrospinal fluid and no signs of PML 27 months after the first infusion.
The PV patient received a second infusion that further reduced JC viral load, but no additional improvement was seen. The patient died 8 months after the first infusion.
The AIDS patient received additional infusions, resulting in complete clearance of the JC virus. This patient has regained mobility, and, 9 months after the first infusion, he is able to walk with a cane.
“We are encouraged that off-the-shelf, third-party, partially HLA-matched BK viral-specific T cells may provide a therapy for PML,” Dr. Rezvani said. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events with this treatment.”
This study was supported with funding from the Myelodysplastic Syndromes and Acute Myeloid Leukemia Moon Shot, part of MD Anderson’s Moon Shots Program, as well as the National Institutes of Health.
Dataset could reveal better therapies for AML
Researchers have released a dataset detailing the molecular makeup of tumor cells from more than 500 patients with acute myeloid leukemia (AML).
The team discovered mutations not previously observed in AML and found associations between mutations and responses to certain therapies.
For instance, AML cases with FLT3, NPM1, and DNMT3A mutations proved sensitive to the BTK inhibitor ibrutinib.
The researchers described their findings in Nature.
The team also made their dataset available via Vizome, an online data viewer. Other researchers can use Vizome to find out which targeted therapies might be most effective against specific subsets of AML cells.
“People can get online, search our database, and very quickly get answers to ‘Is this a good drug?’ or ‘Is there a patient population my drug can work in?’” said study author Brian Druker, MD, of Oregon Health & Science University (OHSU) in Portland, Oregon.
Newly identified mutations
For this study, part of the Beat AML initiative, Dr. Druker and his colleagues performed whole-exome and RNA sequencing on 672 samples from 562 AML patients.
The team identified mutations in 11 genes that were called in 1% or more of patients in this dataset but had not been observed in previous AML sequencing studies. The genes were:
- CUB and Sushi multiple domains 2 (CSMD2)
- NAC alpha domain containing (NACAD)
- Teneurin transmembrane protein 2 (TENM2)
- Aggrecan (ACAN)
- ADAM metallopeptidase with thrombospondin type 1 motif 7 (ADAMTS7)
- Immunoglobulin-like and fibronectin type III domain containing 1 (IGFN1)
- Neurobeachin-like 2 (NBEAL2)
- Poly(U) binding splicing factor 60 (PUF60)
- Zinc-finger protein 687 (ZNF687)
- Cadherin EGF LAG sevenpass G-type receptor 2 (CELSR2)
- Glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B).
Testing therapies
The researchers also assessed how AML cells from 409 of the patient samples responded to each of 122 targeted therapies.
The team found that mutations in TP53, ASXL1, NRAS, and KRAS caused “a broad pattern of drug resistance.”
However, cases with TP53 mutations were sensitive to elesclomol (a drug that targets cancer cell metabolism), cases with ASXL1 mutations were sensitive to the HDAC inhibitor panobinostat, and cases with KRAS/NRAS mutations were sensitive to MAPK inhibitors (with NRAS-mutated cases demonstrating greater sensitivity).
The researchers also found that IDH2 mutations “conferred sensitivity to a broad spectrum of drugs,” but IDH1 mutations were associated with resistance to most drugs.
As previously mentioned, the researchers found a significant association between mutations in FLT3, NPM1, and DNMT3A and sensitivity to ibrutinib. However, the team found that cases with DNMT3A mutations alone or mutations in DNMT3A and FLT3 were not significantly different from cases with wild-type genes.
On the other hand, cases with FLT3-ITD alone or any combination with a mutation in NPM1 (including mutations in all three genes) were significantly more sensitive to ibrutinib than cases with wild-type genes.
Cases with FLT3-ITD and mutations in NPM1 were sensitive to another kinase inhibitor, entospletinib, as well.
The researchers also found that mutations in both BCOR and RUNX1 correlated with increased sensitivity to four JAK inhibitors—momelotinib, ruxolitinib, tofacitinib, and JAK inhibitor I.
However, cases with BCOR mutations alone or mutations in BCOR and DNMT3A or SRSF2 showed no difference in sensitivity to the JAK inhibitors from cases with wild-type genes.
Next steps
“We’re just starting to scratch the surface of what we can do when we analyze the data,” Dr. Druker said. “The real power comes when you start to integrate all that data. You can analyze what drug worked and why it worked.”
In fact, the researchers are already developing and initiating clinical trials to test hypotheses generated by this study.
“You can start to sense some momentum building with new, better therapeutics for AML patients, and, hopefully, this dataset will help fuel that momentum even further,” said study author Jeff Tyner, PhD, of the OHSU School of Medicine.
“We want to parlay this information into clinical trials as much as we can, and we also want the broader community to use this dataset to accelerate their own work.”
Funding for the current study was provided by grants from The Leukemia & Lymphoma Society, the National Cancer Institute, the National Library of Medicine, and other groups.
Researchers have released a dataset detailing the molecular makeup of tumor cells from more than 500 patients with acute myeloid leukemia (AML).
The team discovered mutations not previously observed in AML and found associations between mutations and responses to certain therapies.
For instance, AML cases with FLT3, NPM1, and DNMT3A mutations proved sensitive to the BTK inhibitor ibrutinib.
The researchers described their findings in Nature.
The team also made their dataset available via Vizome, an online data viewer. Other researchers can use Vizome to find out which targeted therapies might be most effective against specific subsets of AML cells.
“People can get online, search our database, and very quickly get answers to ‘Is this a good drug?’ or ‘Is there a patient population my drug can work in?’” said study author Brian Druker, MD, of Oregon Health & Science University (OHSU) in Portland, Oregon.
Newly identified mutations
For this study, part of the Beat AML initiative, Dr. Druker and his colleagues performed whole-exome and RNA sequencing on 672 samples from 562 AML patients.
The team identified mutations in 11 genes that were called in 1% or more of patients in this dataset but had not been observed in previous AML sequencing studies. The genes were:
- CUB and Sushi multiple domains 2 (CSMD2)
- NAC alpha domain containing (NACAD)
- Teneurin transmembrane protein 2 (TENM2)
- Aggrecan (ACAN)
- ADAM metallopeptidase with thrombospondin type 1 motif 7 (ADAMTS7)
- Immunoglobulin-like and fibronectin type III domain containing 1 (IGFN1)
- Neurobeachin-like 2 (NBEAL2)
- Poly(U) binding splicing factor 60 (PUF60)
- Zinc-finger protein 687 (ZNF687)
- Cadherin EGF LAG sevenpass G-type receptor 2 (CELSR2)
- Glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B).
Testing therapies
The researchers also assessed how AML cells from 409 of the patient samples responded to each of 122 targeted therapies.
The team found that mutations in TP53, ASXL1, NRAS, and KRAS caused “a broad pattern of drug resistance.”
However, cases with TP53 mutations were sensitive to elesclomol (a drug that targets cancer cell metabolism), cases with ASXL1 mutations were sensitive to the HDAC inhibitor panobinostat, and cases with KRAS/NRAS mutations were sensitive to MAPK inhibitors (with NRAS-mutated cases demonstrating greater sensitivity).
The researchers also found that IDH2 mutations “conferred sensitivity to a broad spectrum of drugs,” but IDH1 mutations were associated with resistance to most drugs.
As previously mentioned, the researchers found a significant association between mutations in FLT3, NPM1, and DNMT3A and sensitivity to ibrutinib. However, the team found that cases with DNMT3A mutations alone or mutations in DNMT3A and FLT3 were not significantly different from cases with wild-type genes.
On the other hand, cases with FLT3-ITD alone or any combination with a mutation in NPM1 (including mutations in all three genes) were significantly more sensitive to ibrutinib than cases with wild-type genes.
Cases with FLT3-ITD and mutations in NPM1 were sensitive to another kinase inhibitor, entospletinib, as well.
The researchers also found that mutations in both BCOR and RUNX1 correlated with increased sensitivity to four JAK inhibitors—momelotinib, ruxolitinib, tofacitinib, and JAK inhibitor I.
However, cases with BCOR mutations alone or mutations in BCOR and DNMT3A or SRSF2 showed no difference in sensitivity to the JAK inhibitors from cases with wild-type genes.
Next steps
“We’re just starting to scratch the surface of what we can do when we analyze the data,” Dr. Druker said. “The real power comes when you start to integrate all that data. You can analyze what drug worked and why it worked.”
In fact, the researchers are already developing and initiating clinical trials to test hypotheses generated by this study.
“You can start to sense some momentum building with new, better therapeutics for AML patients, and, hopefully, this dataset will help fuel that momentum even further,” said study author Jeff Tyner, PhD, of the OHSU School of Medicine.
“We want to parlay this information into clinical trials as much as we can, and we also want the broader community to use this dataset to accelerate their own work.”
Funding for the current study was provided by grants from The Leukemia & Lymphoma Society, the National Cancer Institute, the National Library of Medicine, and other groups.
Researchers have released a dataset detailing the molecular makeup of tumor cells from more than 500 patients with acute myeloid leukemia (AML).
The team discovered mutations not previously observed in AML and found associations between mutations and responses to certain therapies.
For instance, AML cases with FLT3, NPM1, and DNMT3A mutations proved sensitive to the BTK inhibitor ibrutinib.
The researchers described their findings in Nature.
The team also made their dataset available via Vizome, an online data viewer. Other researchers can use Vizome to find out which targeted therapies might be most effective against specific subsets of AML cells.
“People can get online, search our database, and very quickly get answers to ‘Is this a good drug?’ or ‘Is there a patient population my drug can work in?’” said study author Brian Druker, MD, of Oregon Health & Science University (OHSU) in Portland, Oregon.
Newly identified mutations
For this study, part of the Beat AML initiative, Dr. Druker and his colleagues performed whole-exome and RNA sequencing on 672 samples from 562 AML patients.
The team identified mutations in 11 genes that were called in 1% or more of patients in this dataset but had not been observed in previous AML sequencing studies. The genes were:
- CUB and Sushi multiple domains 2 (CSMD2)
- NAC alpha domain containing (NACAD)
- Teneurin transmembrane protein 2 (TENM2)
- Aggrecan (ACAN)
- ADAM metallopeptidase with thrombospondin type 1 motif 7 (ADAMTS7)
- Immunoglobulin-like and fibronectin type III domain containing 1 (IGFN1)
- Neurobeachin-like 2 (NBEAL2)
- Poly(U) binding splicing factor 60 (PUF60)
- Zinc-finger protein 687 (ZNF687)
- Cadherin EGF LAG sevenpass G-type receptor 2 (CELSR2)
- Glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B).
Testing therapies
The researchers also assessed how AML cells from 409 of the patient samples responded to each of 122 targeted therapies.
The team found that mutations in TP53, ASXL1, NRAS, and KRAS caused “a broad pattern of drug resistance.”
However, cases with TP53 mutations were sensitive to elesclomol (a drug that targets cancer cell metabolism), cases with ASXL1 mutations were sensitive to the HDAC inhibitor panobinostat, and cases with KRAS/NRAS mutations were sensitive to MAPK inhibitors (with NRAS-mutated cases demonstrating greater sensitivity).
The researchers also found that IDH2 mutations “conferred sensitivity to a broad spectrum of drugs,” but IDH1 mutations were associated with resistance to most drugs.
As previously mentioned, the researchers found a significant association between mutations in FLT3, NPM1, and DNMT3A and sensitivity to ibrutinib. However, the team found that cases with DNMT3A mutations alone or mutations in DNMT3A and FLT3 were not significantly different from cases with wild-type genes.
On the other hand, cases with FLT3-ITD alone or any combination with a mutation in NPM1 (including mutations in all three genes) were significantly more sensitive to ibrutinib than cases with wild-type genes.
Cases with FLT3-ITD and mutations in NPM1 were sensitive to another kinase inhibitor, entospletinib, as well.
The researchers also found that mutations in both BCOR and RUNX1 correlated with increased sensitivity to four JAK inhibitors—momelotinib, ruxolitinib, tofacitinib, and JAK inhibitor I.
However, cases with BCOR mutations alone or mutations in BCOR and DNMT3A or SRSF2 showed no difference in sensitivity to the JAK inhibitors from cases with wild-type genes.
Next steps
“We’re just starting to scratch the surface of what we can do when we analyze the data,” Dr. Druker said. “The real power comes when you start to integrate all that data. You can analyze what drug worked and why it worked.”
In fact, the researchers are already developing and initiating clinical trials to test hypotheses generated by this study.
“You can start to sense some momentum building with new, better therapeutics for AML patients, and, hopefully, this dataset will help fuel that momentum even further,” said study author Jeff Tyner, PhD, of the OHSU School of Medicine.
“We want to parlay this information into clinical trials as much as we can, and we also want the broader community to use this dataset to accelerate their own work.”
Funding for the current study was provided by grants from The Leukemia & Lymphoma Society, the National Cancer Institute, the National Library of Medicine, and other groups.
FDA issues draft guidance on MRD
The U.S. Food and Drug Administration (FDA) has issued a draft guidance on the use of minimal residual disease (MRD) assessment in trials of patients with hematologic malignancies.
The FDA said it developed this guidance to assist sponsors who are planning to use MRD as a biomarker in clinical trials conducted under an investigational new drug application or to support FDA approval of products intended to treat hematologic malignancies.
“As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of MRD data, the FDA identified a need to provide sponsors with guidance on the use of MRD as a biomarker in regulatory submissions,” said FDA Commissioner Scott Gottlieb, MD.
The guidance explains how MRD might be used in clinical trials, highlights considerations for MRD assessment that are specific to certain hematologic malignancies, and lists requirements for regulatory submissions that utilize MRD.
The full document, “Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment,” is available for download from the FDA website.
How MRD can be used
The guidance notes that MRD could potentially be used as a biomarker in clinical trials, specifically, as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker.
MRD could also be used as a surrogate endpoint, and there are two mechanisms for obtaining FDA feedback on the use of a novel surrogate endpoint to support approval of a product:
- The drug development tool qualification process
- Discussions with the specific Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research review division.
Furthermore, a sponsor can use MRD “to select patients at high risk or to enrich the trial population,” according to the guidance.
Disease specifics
The guidance also details specific considerations for MRD assessment in individual hematologic malignancies. For example:
- In acute lymphoblastic leukemia, a patient with an MRD level of 0.1% or more in first or second complete remission has a high risk of relapse.
- In trials of acute myeloid leukemia, the sponsor should provide data showing that the marker selected to assess MRD “reflects the leukemia and not underlying clonal hematopoiesis.”
- Patients with low-risk acute promyelocytic leukemia who achieve MRD negativity after arsenic/tretinoin-based therapy are generally considered cured.
- In chronic lymphocytic leukemia, MRD can be assessed in the peripheral blood or bone marrow, but the sample source should remain the same throughout a trial.
- In chronic myeloid leukemia, MRD can be used to select and monitor patients who are eligible to discontinue treatment with tyrosine kinase inhibitors.
- In multiple myeloma, imaging techniques may be combined with MRD assessment of the bone marrow to assess patient response to treatment.
Types of technology
The guidance lists the four general technologies used for MRD assessment in hematologic malignancies:
- Multiparametric flow cytometry
- Next-generation sequencing
- Quantitative reverse transcription polymerase chain reaction of specific gene fusions
- Allele-specific oligonucleotide polymerase chain reaction.
The FDA said it does not have a preference as to which technology is used in a trial. However, the sponsor must pre-specify the technology used and should utilize the same technology throughout a trial.
The FDA also said it “does not foresee the need for co-development of an MRD assay with a drug product.” However, the assay must be analytically valid for results important to the trial, and MRD assessment must be a clinically valid biomarker in the context in which it’s used.
If the MRD assay used is not FDA-cleared or -approved, additional information about the assay must be provided to the FDA.
The U.S. Food and Drug Administration (FDA) has issued a draft guidance on the use of minimal residual disease (MRD) assessment in trials of patients with hematologic malignancies.
The FDA said it developed this guidance to assist sponsors who are planning to use MRD as a biomarker in clinical trials conducted under an investigational new drug application or to support FDA approval of products intended to treat hematologic malignancies.
“As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of MRD data, the FDA identified a need to provide sponsors with guidance on the use of MRD as a biomarker in regulatory submissions,” said FDA Commissioner Scott Gottlieb, MD.
The guidance explains how MRD might be used in clinical trials, highlights considerations for MRD assessment that are specific to certain hematologic malignancies, and lists requirements for regulatory submissions that utilize MRD.
The full document, “Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment,” is available for download from the FDA website.
How MRD can be used
The guidance notes that MRD could potentially be used as a biomarker in clinical trials, specifically, as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker.
MRD could also be used as a surrogate endpoint, and there are two mechanisms for obtaining FDA feedback on the use of a novel surrogate endpoint to support approval of a product:
- The drug development tool qualification process
- Discussions with the specific Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research review division.
Furthermore, a sponsor can use MRD “to select patients at high risk or to enrich the trial population,” according to the guidance.
Disease specifics
The guidance also details specific considerations for MRD assessment in individual hematologic malignancies. For example:
- In acute lymphoblastic leukemia, a patient with an MRD level of 0.1% or more in first or second complete remission has a high risk of relapse.
- In trials of acute myeloid leukemia, the sponsor should provide data showing that the marker selected to assess MRD “reflects the leukemia and not underlying clonal hematopoiesis.”
- Patients with low-risk acute promyelocytic leukemia who achieve MRD negativity after arsenic/tretinoin-based therapy are generally considered cured.
- In chronic lymphocytic leukemia, MRD can be assessed in the peripheral blood or bone marrow, but the sample source should remain the same throughout a trial.
- In chronic myeloid leukemia, MRD can be used to select and monitor patients who are eligible to discontinue treatment with tyrosine kinase inhibitors.
- In multiple myeloma, imaging techniques may be combined with MRD assessment of the bone marrow to assess patient response to treatment.
Types of technology
The guidance lists the four general technologies used for MRD assessment in hematologic malignancies:
- Multiparametric flow cytometry
- Next-generation sequencing
- Quantitative reverse transcription polymerase chain reaction of specific gene fusions
- Allele-specific oligonucleotide polymerase chain reaction.
The FDA said it does not have a preference as to which technology is used in a trial. However, the sponsor must pre-specify the technology used and should utilize the same technology throughout a trial.
The FDA also said it “does not foresee the need for co-development of an MRD assay with a drug product.” However, the assay must be analytically valid for results important to the trial, and MRD assessment must be a clinically valid biomarker in the context in which it’s used.
If the MRD assay used is not FDA-cleared or -approved, additional information about the assay must be provided to the FDA.
The U.S. Food and Drug Administration (FDA) has issued a draft guidance on the use of minimal residual disease (MRD) assessment in trials of patients with hematologic malignancies.
The FDA said it developed this guidance to assist sponsors who are planning to use MRD as a biomarker in clinical trials conducted under an investigational new drug application or to support FDA approval of products intended to treat hematologic malignancies.
“As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of MRD data, the FDA identified a need to provide sponsors with guidance on the use of MRD as a biomarker in regulatory submissions,” said FDA Commissioner Scott Gottlieb, MD.
The guidance explains how MRD might be used in clinical trials, highlights considerations for MRD assessment that are specific to certain hematologic malignancies, and lists requirements for regulatory submissions that utilize MRD.
The full document, “Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment,” is available for download from the FDA website.
How MRD can be used
The guidance notes that MRD could potentially be used as a biomarker in clinical trials, specifically, as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker.
MRD could also be used as a surrogate endpoint, and there are two mechanisms for obtaining FDA feedback on the use of a novel surrogate endpoint to support approval of a product:
- The drug development tool qualification process
- Discussions with the specific Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research review division.
Furthermore, a sponsor can use MRD “to select patients at high risk or to enrich the trial population,” according to the guidance.
Disease specifics
The guidance also details specific considerations for MRD assessment in individual hematologic malignancies. For example:
- In acute lymphoblastic leukemia, a patient with an MRD level of 0.1% or more in first or second complete remission has a high risk of relapse.
- In trials of acute myeloid leukemia, the sponsor should provide data showing that the marker selected to assess MRD “reflects the leukemia and not underlying clonal hematopoiesis.”
- Patients with low-risk acute promyelocytic leukemia who achieve MRD negativity after arsenic/tretinoin-based therapy are generally considered cured.
- In chronic lymphocytic leukemia, MRD can be assessed in the peripheral blood or bone marrow, but the sample source should remain the same throughout a trial.
- In chronic myeloid leukemia, MRD can be used to select and monitor patients who are eligible to discontinue treatment with tyrosine kinase inhibitors.
- In multiple myeloma, imaging techniques may be combined with MRD assessment of the bone marrow to assess patient response to treatment.
Types of technology
The guidance lists the four general technologies used for MRD assessment in hematologic malignancies:
- Multiparametric flow cytometry
- Next-generation sequencing
- Quantitative reverse transcription polymerase chain reaction of specific gene fusions
- Allele-specific oligonucleotide polymerase chain reaction.
The FDA said it does not have a preference as to which technology is used in a trial. However, the sponsor must pre-specify the technology used and should utilize the same technology throughout a trial.
The FDA also said it “does not foresee the need for co-development of an MRD assay with a drug product.” However, the assay must be analytically valid for results important to the trial, and MRD assessment must be a clinically valid biomarker in the context in which it’s used.
If the MRD assay used is not FDA-cleared or -approved, additional information about the assay must be provided to the FDA.
Virus-specific T-cell infusion may resolve progressive multifocal leukoencephalopathy
, according to investigators from the University of Texas MD Anderson Cancer Center, Houston.
The infusion cleared JC virus from the cerebrospinal fluid (CSF) of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of MD Anderson’s department of stem cell transplantation and cellular therapy and colleagues. One of the patients completely recovered and returned to work.
“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators wrote in the New England Journal of Medicine. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions.
“Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators wrote. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
This hypothesis proved accurate. The investigators infused three PML patients with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib (Jakafi) therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.
T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees: The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about 8 months later.
No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within 4 weeks of treatment. Still, the investigators were optimistic about future potential.
“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”
The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.
SOURCE: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51
This article was updated 3/22/19.
, according to investigators from the University of Texas MD Anderson Cancer Center, Houston.
The infusion cleared JC virus from the cerebrospinal fluid (CSF) of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of MD Anderson’s department of stem cell transplantation and cellular therapy and colleagues. One of the patients completely recovered and returned to work.
“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators wrote in the New England Journal of Medicine. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions.
“Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators wrote. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
This hypothesis proved accurate. The investigators infused three PML patients with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib (Jakafi) therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.
T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees: The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about 8 months later.
No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within 4 weeks of treatment. Still, the investigators were optimistic about future potential.
“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”
The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.
SOURCE: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51
This article was updated 3/22/19.
, according to investigators from the University of Texas MD Anderson Cancer Center, Houston.
The infusion cleared JC virus from the cerebrospinal fluid (CSF) of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of MD Anderson’s department of stem cell transplantation and cellular therapy and colleagues. One of the patients completely recovered and returned to work.
“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators wrote in the New England Journal of Medicine. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions.
“Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators wrote. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
This hypothesis proved accurate. The investigators infused three PML patients with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib (Jakafi) therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.
T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees: The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about 8 months later.
No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within 4 weeks of treatment. Still, the investigators were optimistic about future potential.
“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”
The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.
SOURCE: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51
This article was updated 3/22/19.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Infusion of allogeneic BK virus-specific T cells may be an effective treatment for patients with PML.
Major finding: Two of three patients cleared JC virus from cerebrospinal fluid after infusion.
Study details: A case series involving three patients with PML.
Disclosures: The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.
Source: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51.
Genomic profiling predicts outcomes in patients with MPN
Genomic characteristics of patients with myeloproliferative neoplasms (MPN) can predict clinical outcomes, a recent study found.
Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts, according to Jacob Grinfeld, MD, of the Wellcome-MRC Cambridge (England) Stem Cell Institute and Cambridge Institute for Medical Research and his colleagues.
“Current classification schemes distinguish among the subtypes of myeloproliferative neoplasms according to clinical and laboratory features, but uncertainty clouds where and how to draw dividing lines among them,” the investigators wrote in the New England Journal of Medicine. “In blood cancers, a progressive shift is under way, from clinical and morphologic classification schemes to those that are based on genomics.”
MPNs are often driven by mutations in CALR, MPL, or JAK2 genes, but classification is not confined to just three genomic types; many patients have additional driver mutations throughout a variety of cancer genes, and it is these additional mutations that are responsible for the wide range of disease phenotypes and clinical outcomes.
This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other MPN diagnoses. The investigators performed targeted sequencing for the full coding sequence of 69 genes and genomewide copy-number information in 1,887 patients. Another 148 patients underwent whole-exome sequencing.
By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across a population of patients with MPNs and identify mutation-associated clinical outcomes.
The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations. In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.
Further analysis identified eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations. For example, one subgroup included patients with TP53 mutations; these individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia (AML), compared with the JAK2-heterozygous subgroup (P less than .001).
Because prognosis is “a key determinant of the treatment of patients with MPNs,” genomic subgrouping may one day guide clinical decision making, the investigators concluded.
To further this cause, the investigators have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.
The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.
SOURCE: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.
Genomic characteristics of patients with myeloproliferative neoplasms (MPN) can predict clinical outcomes, a recent study found.
Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts, according to Jacob Grinfeld, MD, of the Wellcome-MRC Cambridge (England) Stem Cell Institute and Cambridge Institute for Medical Research and his colleagues.
“Current classification schemes distinguish among the subtypes of myeloproliferative neoplasms according to clinical and laboratory features, but uncertainty clouds where and how to draw dividing lines among them,” the investigators wrote in the New England Journal of Medicine. “In blood cancers, a progressive shift is under way, from clinical and morphologic classification schemes to those that are based on genomics.”
MPNs are often driven by mutations in CALR, MPL, or JAK2 genes, but classification is not confined to just three genomic types; many patients have additional driver mutations throughout a variety of cancer genes, and it is these additional mutations that are responsible for the wide range of disease phenotypes and clinical outcomes.
This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other MPN diagnoses. The investigators performed targeted sequencing for the full coding sequence of 69 genes and genomewide copy-number information in 1,887 patients. Another 148 patients underwent whole-exome sequencing.
By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across a population of patients with MPNs and identify mutation-associated clinical outcomes.
The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations. In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.
Further analysis identified eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations. For example, one subgroup included patients with TP53 mutations; these individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia (AML), compared with the JAK2-heterozygous subgroup (P less than .001).
Because prognosis is “a key determinant of the treatment of patients with MPNs,” genomic subgrouping may one day guide clinical decision making, the investigators concluded.
To further this cause, the investigators have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.
The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.
SOURCE: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.
Genomic characteristics of patients with myeloproliferative neoplasms (MPN) can predict clinical outcomes, a recent study found.
Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts, according to Jacob Grinfeld, MD, of the Wellcome-MRC Cambridge (England) Stem Cell Institute and Cambridge Institute for Medical Research and his colleagues.
“Current classification schemes distinguish among the subtypes of myeloproliferative neoplasms according to clinical and laboratory features, but uncertainty clouds where and how to draw dividing lines among them,” the investigators wrote in the New England Journal of Medicine. “In blood cancers, a progressive shift is under way, from clinical and morphologic classification schemes to those that are based on genomics.”
MPNs are often driven by mutations in CALR, MPL, or JAK2 genes, but classification is not confined to just three genomic types; many patients have additional driver mutations throughout a variety of cancer genes, and it is these additional mutations that are responsible for the wide range of disease phenotypes and clinical outcomes.
This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other MPN diagnoses. The investigators performed targeted sequencing for the full coding sequence of 69 genes and genomewide copy-number information in 1,887 patients. Another 148 patients underwent whole-exome sequencing.
By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across a population of patients with MPNs and identify mutation-associated clinical outcomes.
The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations. In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.
Further analysis identified eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations. For example, one subgroup included patients with TP53 mutations; these individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia (AML), compared with the JAK2-heterozygous subgroup (P less than .001).
Because prognosis is “a key determinant of the treatment of patients with MPNs,” genomic subgrouping may one day guide clinical decision making, the investigators concluded.
To further this cause, the investigators have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.
The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.
SOURCE: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts.
Study details: A gene sequencing study involving 2,035 patients with MPN.
Disclosures: The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.
Source: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.
CDK8 inhibitor can fight AML, though it’s unclear how
DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.
Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.
SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.
The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.
Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.
Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research1 indicated that CDK8 drives oncogenic transcription in AML.
In a prior study2, researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.
Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.
“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.
In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.
Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.
After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.
SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).
In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.
Toxicities observed in the mice included weight loss and upregulation of inflammation.
The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.
Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.
Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.
“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.
“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”
Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.
1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904
2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.
DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.
Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.
SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.
The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.
Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.
Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research1 indicated that CDK8 drives oncogenic transcription in AML.
In a prior study2, researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.
Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.
“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.
In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.
Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.
After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.
SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).
In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.
Toxicities observed in the mice included weight loss and upregulation of inflammation.
The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.
Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.
Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.
“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.
“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”
Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.
1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904
2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.
DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.
Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.
SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.
The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.
Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.
Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research1 indicated that CDK8 drives oncogenic transcription in AML.
In a prior study2, researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.
Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.
“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.
In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.
Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.
After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.
SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).
In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.
Toxicities observed in the mice included weight loss and upregulation of inflammation.
The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.
Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.
Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.
“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.
“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”
Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.
1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904
2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.
Five “can’t miss” oncologic emergencies
SAN DIEGO – Acute promyelocytic leukemia is one of five “can’t miss” oncologic emergencies, Megan Boysen Osborn, MD, MHPE, told a standing-room-only crowd at the annual meeting of the American College of Emergency Physicians.
In our exclusive video interview, Dr. Osborn, vice chair of education and the residency program director in the department of emergency medicine at the University of California, Irvine, offered tips on how to recognize acute promyelocytic leukemia, leukostasis, neutropenic fever, tumor lysis syndrome, and disseminated intravascular coagulation.
“All patients with suspected leukemias should be admitted,” she said. “Time is of the essence.”
Dr. Osborn reported having no financial disclosures related to her presentation.
SAN DIEGO – Acute promyelocytic leukemia is one of five “can’t miss” oncologic emergencies, Megan Boysen Osborn, MD, MHPE, told a standing-room-only crowd at the annual meeting of the American College of Emergency Physicians.
In our exclusive video interview, Dr. Osborn, vice chair of education and the residency program director in the department of emergency medicine at the University of California, Irvine, offered tips on how to recognize acute promyelocytic leukemia, leukostasis, neutropenic fever, tumor lysis syndrome, and disseminated intravascular coagulation.
“All patients with suspected leukemias should be admitted,” she said. “Time is of the essence.”
Dr. Osborn reported having no financial disclosures related to her presentation.
SAN DIEGO – Acute promyelocytic leukemia is one of five “can’t miss” oncologic emergencies, Megan Boysen Osborn, MD, MHPE, told a standing-room-only crowd at the annual meeting of the American College of Emergency Physicians.
In our exclusive video interview, Dr. Osborn, vice chair of education and the residency program director in the department of emergency medicine at the University of California, Irvine, offered tips on how to recognize acute promyelocytic leukemia, leukostasis, neutropenic fever, tumor lysis syndrome, and disseminated intravascular coagulation.
“All patients with suspected leukemias should be admitted,” she said. “Time is of the essence.”
Dr. Osborn reported having no financial disclosures related to her presentation.
REPORTING FROM ACEP18
