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Jennifer Smith is the editor of Oncology Practice, part of MDedge Hematology/Oncology. She was previously the editor of Hematology Times, an editor at Principal Investigators Association, and a reporter at The Oneida Daily Dispatch. She has a BS in journalism.
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
When is it CMML?
DUBROVNIK, CROATIA – in 2018.
Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Durakovic, MD, PhD, of the University Hospital Centre Zagreb (Croatia).
However, there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML), Dr. Durakovic said 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.
Studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.
According to the 2016 WHO classification, patients have CMML if:
- They have persistent peripheral blood monocytosis (1×109/L), with monocytes accounting for 10% of the white blood cell count.
- They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia.
- There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement.
- They have fewer than 20% blasts in the blood and bone marrow they have dysplasia in one or more myeloid lineages.
If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present. Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Durakovic said.
Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions, such as pregnancy.
However, Dr. Durakovic pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.
“There are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Durakovic said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”
Differential diagnosis
“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Durakovic said. “There are dysplastic features that are present in CMML ... but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”
The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.
Dr. Durakovic noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.
She noted that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).
Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.
Dr. Durakovic also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.
Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Durakovic said.
It can also be difficult to differentiate CMML from atypical CML.
“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Durakovic explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”
Karyotyping, genotyping, and immunophenotyping
“There is no disease-defining karyotype abnormality [in CMML],” Dr. Durakovic said.
She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.
Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Durakovic said.
For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Durakovic said.
In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes – SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood. 2012;120:3080-8).
However, Dr. Durakovic noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.
A 2015 study revealed a technique that does appear useful for identifying CMML – monocyte subset distribution analysis. For this analysis, monocytes are divided into the following categories:
- Classical/MO1 (CD14bright/CD16−).
- Intermediate/MO2 (CD14bright/CD16+).
- Nonclassical/MO3 (CD14dim/CD16+).
The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis (Blood. 2015 Jun 4;125[23]:3618-26).
A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML. This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes (Am J Clin Pathol. 2018 Aug 30;150[4]:293-302).
Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Durakovic said.
She added that the technique can be implemented in clinical practice using the Hematoflow solution.
Dr. Durakovic did not report any conflicts of interest.
The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
DUBROVNIK, CROATIA – in 2018.
Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Durakovic, MD, PhD, of the University Hospital Centre Zagreb (Croatia).
However, there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML), Dr. Durakovic said 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.
Studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.
According to the 2016 WHO classification, patients have CMML if:
- They have persistent peripheral blood monocytosis (1×109/L), with monocytes accounting for 10% of the white blood cell count.
- They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia.
- There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement.
- They have fewer than 20% blasts in the blood and bone marrow they have dysplasia in one or more myeloid lineages.
If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present. Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Durakovic said.
Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions, such as pregnancy.
However, Dr. Durakovic pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.
“There are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Durakovic said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”
Differential diagnosis
“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Durakovic said. “There are dysplastic features that are present in CMML ... but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”
The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.
Dr. Durakovic noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.
She noted that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).
Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.
Dr. Durakovic also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.
Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Durakovic said.
It can also be difficult to differentiate CMML from atypical CML.
“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Durakovic explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”
Karyotyping, genotyping, and immunophenotyping
“There is no disease-defining karyotype abnormality [in CMML],” Dr. Durakovic said.
She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.
Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Durakovic said.
For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Durakovic said.
In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes – SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood. 2012;120:3080-8).
However, Dr. Durakovic noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.
A 2015 study revealed a technique that does appear useful for identifying CMML – monocyte subset distribution analysis. For this analysis, monocytes are divided into the following categories:
- Classical/MO1 (CD14bright/CD16−).
- Intermediate/MO2 (CD14bright/CD16+).
- Nonclassical/MO3 (CD14dim/CD16+).
The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis (Blood. 2015 Jun 4;125[23]:3618-26).
A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML. This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes (Am J Clin Pathol. 2018 Aug 30;150[4]:293-302).
Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Durakovic said.
She added that the technique can be implemented in clinical practice using the Hematoflow solution.
Dr. Durakovic did not report any conflicts of interest.
The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
DUBROVNIK, CROATIA – in 2018.
Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Durakovic, MD, PhD, of the University Hospital Centre Zagreb (Croatia).
However, there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML), Dr. Durakovic said 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.
Studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.
According to the 2016 WHO classification, patients have CMML if:
- They have persistent peripheral blood monocytosis (1×109/L), with monocytes accounting for 10% of the white blood cell count.
- They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia.
- There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement.
- They have fewer than 20% blasts in the blood and bone marrow they have dysplasia in one or more myeloid lineages.
If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present. Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Durakovic said.
Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions, such as pregnancy.
However, Dr. Durakovic pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.
“There are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Durakovic said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”
Differential diagnosis
“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Durakovic said. “There are dysplastic features that are present in CMML ... but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”
The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.
Dr. Durakovic noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.
She noted that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).
Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.
Dr. Durakovic also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.
Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Durakovic said.
It can also be difficult to differentiate CMML from atypical CML.
“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Durakovic explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”
Karyotyping, genotyping, and immunophenotyping
“There is no disease-defining karyotype abnormality [in CMML],” Dr. Durakovic said.
She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.
Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Durakovic said.
For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Durakovic said.
In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes – SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood. 2012;120:3080-8).
However, Dr. Durakovic noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.
A 2015 study revealed a technique that does appear useful for identifying CMML – monocyte subset distribution analysis. For this analysis, monocytes are divided into the following categories:
- Classical/MO1 (CD14bright/CD16−).
- Intermediate/MO2 (CD14bright/CD16+).
- Nonclassical/MO3 (CD14dim/CD16+).
The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis (Blood. 2015 Jun 4;125[23]:3618-26).
A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML. This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes (Am J Clin Pathol. 2018 Aug 30;150[4]:293-302).
Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Durakovic said.
She added that the technique can be implemented in clinical practice using the Hematoflow solution.
Dr. Durakovic did not report any conflicts of interest.
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
FDA offers guidance on MRD assessment in blood cancer trials
The of patients with hematologic malignancies.
The FDA said it developed the document to assist drug sponsors who are planning to use minimal residual disease (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,” FDA Commissioner Scott Gottlieb, MD, said in a statement.
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.
MRD could potentially be used as a biomarker in clinical trials – specifically as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker, according to the draft guidance. Additionally, MRD could be used as a surrogate endpoint or “to select patients at high risk or to enrich the trial population.”
The draft guidance also provides specific considerations for MRD assessment in individual hematologic malignancies, including acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and multiple myeloma.
The full document is available on the FDA website.
The of patients with hematologic malignancies.
The FDA said it developed the document to assist drug sponsors who are planning to use minimal residual disease (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,” FDA Commissioner Scott Gottlieb, MD, said in a statement.
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.
MRD could potentially be used as a biomarker in clinical trials – specifically as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker, according to the draft guidance. Additionally, MRD could be used as a surrogate endpoint or “to select patients at high risk or to enrich the trial population.”
The draft guidance also provides specific considerations for MRD assessment in individual hematologic malignancies, including acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and multiple myeloma.
The full document is available on the FDA website.
The of patients with hematologic malignancies.
The FDA said it developed the document to assist drug sponsors who are planning to use minimal residual disease (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,” FDA Commissioner Scott Gottlieb, MD, said in a statement.
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.
MRD could potentially be used as a biomarker in clinical trials – specifically as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker, according to the draft guidance. Additionally, MRD could be used as a surrogate endpoint or “to select patients at high risk or to enrich the trial population.”
The draft guidance also provides specific considerations for MRD assessment in individual hematologic malignancies, including acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and multiple myeloma.
The full document is available on the FDA website.
Optimizing use of TKIs in chronic leukemia
DUBROVNIK, CROATIA – Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to one expert.
Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs. But the newer TKIs pose a higher risk of uncommon toxicities, Hagop M. Kantarjian, MD, said during the keynote presentation 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. Kantarjian, a professor at MD Anderson Cancer Center in Houston, said most CML patients should receive daily treatment with TKIs – even if they are in complete cytogenetic response or 100% Philadelphia chromosome positive – because they will live longer.
Frontline treatment options for CML that are approved by the Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.
Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.
Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial (J Clin Oncol. 2016 Jul 10;34[20]:2333-40).
In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib (Leukemia. 2016 May;30[5]:1044-54).
However, the higher incidence of uncommon toxicities with the newer TKIs must be taken into account, Dr. Kantarjian said.
Choosing a TKI
Dr. Kantarjian recommends frontline imatinib for older patients (aged 65-70) and those who are low risk based on their Sokal score.
Second-generation TKIs should be given up front to patients who are at higher risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” he said.
“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”
A TKI should not be discarded unless there is loss of complete cytogenetic response – not major molecular response – at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities, Dr. Kantarjian added.
“We have to remember that we can go down on the dosages of, for example, imatinib, down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” he said. “So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”
Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20-mg dose can be used.
Vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. For that reason, Dr. Kantarjian said he prefers to forgo up-front nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.
“The incidence of vaso-occlusive and vasospastic reactions is now close to 10%-15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”
For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.
For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib), as well as omacetaxine or allogeneic stem cell transplant.
“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.
Ponatinib is not used up front because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension, he added.
Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.
Discontinuing a TKI
Dr. Kantarjian said patients can discontinue TKI therapy if they:
- Are low- or intermediate-risk by Sokal.
- Have quantifiable BCR-ABL transcripts.
- Are in chronic phase.
- Achieved an optimal response to their first TKI.
- Have been on TKI therapy for more than 8 years.
- Achieved a complete molecular response.
- Have had a molecular response for more than 2-3 years.
- Are available for monitoring every other month for the first 2 years.
Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis, Bristol-Myers Squibb, Pfizer, and Ariad Pharmaceuticals.
The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
DUBROVNIK, CROATIA – Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to one expert.
Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs. But the newer TKIs pose a higher risk of uncommon toxicities, Hagop M. Kantarjian, MD, said during the keynote presentation 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. Kantarjian, a professor at MD Anderson Cancer Center in Houston, said most CML patients should receive daily treatment with TKIs – even if they are in complete cytogenetic response or 100% Philadelphia chromosome positive – because they will live longer.
Frontline treatment options for CML that are approved by the Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.
Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.
Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial (J Clin Oncol. 2016 Jul 10;34[20]:2333-40).
In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib (Leukemia. 2016 May;30[5]:1044-54).
However, the higher incidence of uncommon toxicities with the newer TKIs must be taken into account, Dr. Kantarjian said.
Choosing a TKI
Dr. Kantarjian recommends frontline imatinib for older patients (aged 65-70) and those who are low risk based on their Sokal score.
Second-generation TKIs should be given up front to patients who are at higher risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” he said.
“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”
A TKI should not be discarded unless there is loss of complete cytogenetic response – not major molecular response – at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities, Dr. Kantarjian added.
“We have to remember that we can go down on the dosages of, for example, imatinib, down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” he said. “So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”
Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20-mg dose can be used.
Vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. For that reason, Dr. Kantarjian said he prefers to forgo up-front nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.
“The incidence of vaso-occlusive and vasospastic reactions is now close to 10%-15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”
For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.
For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib), as well as omacetaxine or allogeneic stem cell transplant.
“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.
Ponatinib is not used up front because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension, he added.
Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.
Discontinuing a TKI
Dr. Kantarjian said patients can discontinue TKI therapy if they:
- Are low- or intermediate-risk by Sokal.
- Have quantifiable BCR-ABL transcripts.
- Are in chronic phase.
- Achieved an optimal response to their first TKI.
- Have been on TKI therapy for more than 8 years.
- Achieved a complete molecular response.
- Have had a molecular response for more than 2-3 years.
- Are available for monitoring every other month for the first 2 years.
Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis, Bristol-Myers Squibb, Pfizer, and Ariad Pharmaceuticals.
The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
DUBROVNIK, CROATIA – Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to one expert.
Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs. But the newer TKIs pose a higher risk of uncommon toxicities, Hagop M. Kantarjian, MD, said during the keynote presentation 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. Kantarjian, a professor at MD Anderson Cancer Center in Houston, said most CML patients should receive daily treatment with TKIs – even if they are in complete cytogenetic response or 100% Philadelphia chromosome positive – because they will live longer.
Frontline treatment options for CML that are approved by the Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.
Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.
Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial (J Clin Oncol. 2016 Jul 10;34[20]:2333-40).
In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib (Leukemia. 2016 May;30[5]:1044-54).
However, the higher incidence of uncommon toxicities with the newer TKIs must be taken into account, Dr. Kantarjian said.
Choosing a TKI
Dr. Kantarjian recommends frontline imatinib for older patients (aged 65-70) and those who are low risk based on their Sokal score.
Second-generation TKIs should be given up front to patients who are at higher risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” he said.
“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”
A TKI should not be discarded unless there is loss of complete cytogenetic response – not major molecular response – at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities, Dr. Kantarjian added.
“We have to remember that we can go down on the dosages of, for example, imatinib, down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” he said. “So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”
Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20-mg dose can be used.
Vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. For that reason, Dr. Kantarjian said he prefers to forgo up-front nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.
“The incidence of vaso-occlusive and vasospastic reactions is now close to 10%-15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”
For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.
For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib), as well as omacetaxine or allogeneic stem cell transplant.
“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.
Ponatinib is not used up front because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension, he added.
Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.
Discontinuing a TKI
Dr. Kantarjian said patients can discontinue TKI therapy if they:
- Are low- or intermediate-risk by Sokal.
- Have quantifiable BCR-ABL transcripts.
- Are in chronic phase.
- Achieved an optimal response to their first TKI.
- Have been on TKI therapy for more than 8 years.
- Achieved a complete molecular response.
- Have had a molecular response for more than 2-3 years.
- Are available for monitoring every other month for the first 2 years.
Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis, Bristol-Myers Squibb, Pfizer, and Ariad Pharmaceuticals.
The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
REPORTING FROM LEUKEMIA AND LYMPHOMA 2018
Updated ThroLy system predicts need for thromboprophylaxis
DUBROVNIK, CROATIA – An updated scoring system can more accurately identify lymphoma patients who may require thromboprophylaxis, according to researchers.
The revised scoring system, ThroLy, proved more effective than other systems for predicting thromboembolic events in lymphoma patients, with a positive predictive value of 22%-25%, a negative predictive value of 96%, sensitivity of 56%-57%, and specificity of 85%-87%.
Darko Antic, MD, PhD, of the University of Belgrade in Serbia, presented these findings 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. Antic said that he and his colleagues developed ThroLy because other systems used to predict venous thromboembolism (VTE) are not quite right for lymphoma. He noted that the Padua score is not designed for cancer patients and the Khorana score is predominantly used for solid tumor malignancies.
The ThroLy scoring system is based on variables used in the Padua and Khorana systems, as well as variables that are specific to lymphoma patients.
In a previous study, the researchers found several variables that were independently associated with risk for VTE in lymphoma, including previous VTE, previous acute MI or stroke, mediastinal involvement, high body mass index, reduced mobility, extranodal localization, neutropenia, and hemoglobin less than 100 g/L (Am J Hematol. 2016 Oct;91[10]:1014-9).
In an initial version of the ThroLy scoring system, previous VTE, previous acute MI/stroke, obesity, and mediastinal involvement were all worth two points, and the other factors were worth a single point in the ThroLy system.
Patients with scores of 0 to 1 were considered low risk, patients with scores of 2 to 3 were considered intermediate risk, and patients with scores of 4 or greater were considered high risk.
To validate and refine ThroLy, Dr. Antic and his colleagues used it to assess 1,723 lymphoma patients treated at eight institutions in Austria, Croatia, France, Jordan, Macedonia, Spain, Switzerland, and the United States.
Patients had indolent non-Hodgkin lymphoma, aggressive non-Hodgkin lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and Hodgkin lymphoma. Most subjects (84%) were outpatients. A total of 9%of patients had thrombosis, with 7% having VTE.
ThroLy had a positive predictive value of 17%, compared with 11% with Khorana and 13% with Padua. The negative predictive value was 93%, 92%, and 95%, respectively. The sensitivity was 51% with ThroLy, 42% with Khorana, and 70% with Padua; specificity was 72%, 64%, and 52%, respectively.
“The positive predictive value was low [with ThroLy] but definitely higher than the positive predictive value of the other two [scoring systems],” Dr. Antic noted.
Updated models
To further improve ThroLy, the researchers updated the system, creating two new models. Model 1 included the type of lymphoma/clinical stage (1 point), previous VTE (5 points), reduced mobility (2 points), hemoglobin less than 100 g/L (1 point), and the presence of vascular devices (1 point). Model 2 included all of the variables in Model 1 plus the thrombophilic condition, which was worth 1 point.
Patients were considered low risk if they scored 2 points or lower and high risk if they scored more than 2 points.
For Model 1, the positive predictive value was 22%, the negative predictive value was 96%, the sensitivity was 56%, and the specificity was 85%. For Model 2, the positive predictive value was 25%, the negative predictive value was 96%, the sensitivity was 57%, and the specificity was 87%.
There were no major differences in model discrimination and calibration based on the country in which a patient was treated or whether the patient was treated in an inpatient or outpatient setting.
Dr. Antic did not report any conflicts of interest. The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
DUBROVNIK, CROATIA – An updated scoring system can more accurately identify lymphoma patients who may require thromboprophylaxis, according to researchers.
The revised scoring system, ThroLy, proved more effective than other systems for predicting thromboembolic events in lymphoma patients, with a positive predictive value of 22%-25%, a negative predictive value of 96%, sensitivity of 56%-57%, and specificity of 85%-87%.
Darko Antic, MD, PhD, of the University of Belgrade in Serbia, presented these findings 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. Antic said that he and his colleagues developed ThroLy because other systems used to predict venous thromboembolism (VTE) are not quite right for lymphoma. He noted that the Padua score is not designed for cancer patients and the Khorana score is predominantly used for solid tumor malignancies.
The ThroLy scoring system is based on variables used in the Padua and Khorana systems, as well as variables that are specific to lymphoma patients.
In a previous study, the researchers found several variables that were independently associated with risk for VTE in lymphoma, including previous VTE, previous acute MI or stroke, mediastinal involvement, high body mass index, reduced mobility, extranodal localization, neutropenia, and hemoglobin less than 100 g/L (Am J Hematol. 2016 Oct;91[10]:1014-9).
In an initial version of the ThroLy scoring system, previous VTE, previous acute MI/stroke, obesity, and mediastinal involvement were all worth two points, and the other factors were worth a single point in the ThroLy system.
Patients with scores of 0 to 1 were considered low risk, patients with scores of 2 to 3 were considered intermediate risk, and patients with scores of 4 or greater were considered high risk.
To validate and refine ThroLy, Dr. Antic and his colleagues used it to assess 1,723 lymphoma patients treated at eight institutions in Austria, Croatia, France, Jordan, Macedonia, Spain, Switzerland, and the United States.
Patients had indolent non-Hodgkin lymphoma, aggressive non-Hodgkin lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and Hodgkin lymphoma. Most subjects (84%) were outpatients. A total of 9%of patients had thrombosis, with 7% having VTE.
ThroLy had a positive predictive value of 17%, compared with 11% with Khorana and 13% with Padua. The negative predictive value was 93%, 92%, and 95%, respectively. The sensitivity was 51% with ThroLy, 42% with Khorana, and 70% with Padua; specificity was 72%, 64%, and 52%, respectively.
“The positive predictive value was low [with ThroLy] but definitely higher than the positive predictive value of the other two [scoring systems],” Dr. Antic noted.
Updated models
To further improve ThroLy, the researchers updated the system, creating two new models. Model 1 included the type of lymphoma/clinical stage (1 point), previous VTE (5 points), reduced mobility (2 points), hemoglobin less than 100 g/L (1 point), and the presence of vascular devices (1 point). Model 2 included all of the variables in Model 1 plus the thrombophilic condition, which was worth 1 point.
Patients were considered low risk if they scored 2 points or lower and high risk if they scored more than 2 points.
For Model 1, the positive predictive value was 22%, the negative predictive value was 96%, the sensitivity was 56%, and the specificity was 85%. For Model 2, the positive predictive value was 25%, the negative predictive value was 96%, the sensitivity was 57%, and the specificity was 87%.
There were no major differences in model discrimination and calibration based on the country in which a patient was treated or whether the patient was treated in an inpatient or outpatient setting.
Dr. Antic did not report any conflicts of interest. The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
DUBROVNIK, CROATIA – An updated scoring system can more accurately identify lymphoma patients who may require thromboprophylaxis, according to researchers.
The revised scoring system, ThroLy, proved more effective than other systems for predicting thromboembolic events in lymphoma patients, with a positive predictive value of 22%-25%, a negative predictive value of 96%, sensitivity of 56%-57%, and specificity of 85%-87%.
Darko Antic, MD, PhD, of the University of Belgrade in Serbia, presented these findings 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. Antic said that he and his colleagues developed ThroLy because other systems used to predict venous thromboembolism (VTE) are not quite right for lymphoma. He noted that the Padua score is not designed for cancer patients and the Khorana score is predominantly used for solid tumor malignancies.
The ThroLy scoring system is based on variables used in the Padua and Khorana systems, as well as variables that are specific to lymphoma patients.
In a previous study, the researchers found several variables that were independently associated with risk for VTE in lymphoma, including previous VTE, previous acute MI or stroke, mediastinal involvement, high body mass index, reduced mobility, extranodal localization, neutropenia, and hemoglobin less than 100 g/L (Am J Hematol. 2016 Oct;91[10]:1014-9).
In an initial version of the ThroLy scoring system, previous VTE, previous acute MI/stroke, obesity, and mediastinal involvement were all worth two points, and the other factors were worth a single point in the ThroLy system.
Patients with scores of 0 to 1 were considered low risk, patients with scores of 2 to 3 were considered intermediate risk, and patients with scores of 4 or greater were considered high risk.
To validate and refine ThroLy, Dr. Antic and his colleagues used it to assess 1,723 lymphoma patients treated at eight institutions in Austria, Croatia, France, Jordan, Macedonia, Spain, Switzerland, and the United States.
Patients had indolent non-Hodgkin lymphoma, aggressive non-Hodgkin lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and Hodgkin lymphoma. Most subjects (84%) were outpatients. A total of 9%of patients had thrombosis, with 7% having VTE.
ThroLy had a positive predictive value of 17%, compared with 11% with Khorana and 13% with Padua. The negative predictive value was 93%, 92%, and 95%, respectively. The sensitivity was 51% with ThroLy, 42% with Khorana, and 70% with Padua; specificity was 72%, 64%, and 52%, respectively.
“The positive predictive value was low [with ThroLy] but definitely higher than the positive predictive value of the other two [scoring systems],” Dr. Antic noted.
Updated models
To further improve ThroLy, the researchers updated the system, creating two new models. Model 1 included the type of lymphoma/clinical stage (1 point), previous VTE (5 points), reduced mobility (2 points), hemoglobin less than 100 g/L (1 point), and the presence of vascular devices (1 point). Model 2 included all of the variables in Model 1 plus the thrombophilic condition, which was worth 1 point.
Patients were considered low risk if they scored 2 points or lower and high risk if they scored more than 2 points.
For Model 1, the positive predictive value was 22%, the negative predictive value was 96%, the sensitivity was 56%, and the specificity was 85%. For Model 2, the positive predictive value was 25%, the negative predictive value was 96%, the sensitivity was 57%, and the specificity was 87%.
There were no major differences in model discrimination and calibration based on the country in which a patient was treated or whether the patient was treated in an inpatient or outpatient setting.
Dr. Antic did not report any conflicts of interest. The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
REPORTING FROM LEUKEMIA AND LYMPHOMA 2018
Key clinical point:
Major finding: The updated ThroLy had a positive predictive value of 22%-25%, a negative predictive value of 96%, sensitivity of 56%-57%, and specificity of 85%-87%.
Study details: The scoring system was validated on 1,723 lymphoma patients treated at eight institutions worldwide.
Disclosures: Dr. Antic reported having no conflicts of interest.
FDA lifts partial hold on tazemetostat trials
The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.
The patient had been on study for approximately 15 months and had achieved a confirmed partial response. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.
“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” Robert Bazemore, president and chief executive officer of Epizyme, said in a webcast on Sept. 24.
Epizyme assessed the risk of secondary malignancies, including T-LBL, as well as the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials. A panel of external scientific and medical experts who reviewed the findings concluded that T-LBL risks appear to be confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.
“The team at Epizyme has worked diligently in collaboration with external experts and the FDA over the past several months,” Mr. Bazemore said.
The company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials. However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies. Mr. Bazemore said Epizyme hopes to submit a New Drug Application for tazemetostat in the treatment of epithelioid sarcoma.
Tazemetostat is under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid-tumor malignancies. The drug is also being studied as part of combination therapy for non–small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).
In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.
Epizyme is now working to resolve partial clinical holds placed on tazemetostat in France and Germany in order to resume trial enrollment in those countries.
The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.
The patient had been on study for approximately 15 months and had achieved a confirmed partial response. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.
“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” Robert Bazemore, president and chief executive officer of Epizyme, said in a webcast on Sept. 24.
Epizyme assessed the risk of secondary malignancies, including T-LBL, as well as the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials. A panel of external scientific and medical experts who reviewed the findings concluded that T-LBL risks appear to be confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.
“The team at Epizyme has worked diligently in collaboration with external experts and the FDA over the past several months,” Mr. Bazemore said.
The company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials. However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies. Mr. Bazemore said Epizyme hopes to submit a New Drug Application for tazemetostat in the treatment of epithelioid sarcoma.
Tazemetostat is under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid-tumor malignancies. The drug is also being studied as part of combination therapy for non–small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).
In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.
Epizyme is now working to resolve partial clinical holds placed on tazemetostat in France and Germany in order to resume trial enrollment in those countries.
The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.
The patient had been on study for approximately 15 months and had achieved a confirmed partial response. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.
“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” Robert Bazemore, president and chief executive officer of Epizyme, said in a webcast on Sept. 24.
Epizyme assessed the risk of secondary malignancies, including T-LBL, as well as the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials. A panel of external scientific and medical experts who reviewed the findings concluded that T-LBL risks appear to be confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.
“The team at Epizyme has worked diligently in collaboration with external experts and the FDA over the past several months,” Mr. Bazemore said.
The company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials. However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies. Mr. Bazemore said Epizyme hopes to submit a New Drug Application for tazemetostat in the treatment of epithelioid sarcoma.
Tazemetostat is under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid-tumor malignancies. The drug is also being studied as part of combination therapy for non–small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).
In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.
Epizyme is now working to resolve partial clinical holds placed on tazemetostat in France and Germany in order to resume trial enrollment in those countries.
FDA approves new drug for CLL/SLL and follicular lymphoma
The Food and Drug Administration has approved duvelisib (Copiktra), a dual PI3K delta/gamma inhibitor, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma.
who have received at least two prior therapies. Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.
Accelerated approval is based on a surrogate or intermediate endpoint – in this case, overall response rate – that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.
Duvelisib will be available in the U.S. immediately, according to Verastem, the company marketing the drug. The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug – infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.
The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.
The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. The DUO trial included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2,000 mg).
Efficacy results are based on patients who had received at least two prior therapies, including 95 patients in the duvelisib arm and 101 in the ofatumumab arm. The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.
The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab.
The safety results include all patients treated with duvelisib or ofatumumab in this trial. In the duvelisib arm, 12% of patients had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab. Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection and diarrhea/colitis. The DYNAMO trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy. There were 83 patients with FL.
Patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.
The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.
Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.
Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.
The Food and Drug Administration has approved duvelisib (Copiktra), a dual PI3K delta/gamma inhibitor, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma.
who have received at least two prior therapies. Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.
Accelerated approval is based on a surrogate or intermediate endpoint – in this case, overall response rate – that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.
Duvelisib will be available in the U.S. immediately, according to Verastem, the company marketing the drug. The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug – infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.
The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.
The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. The DUO trial included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2,000 mg).
Efficacy results are based on patients who had received at least two prior therapies, including 95 patients in the duvelisib arm and 101 in the ofatumumab arm. The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.
The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab.
The safety results include all patients treated with duvelisib or ofatumumab in this trial. In the duvelisib arm, 12% of patients had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab. Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection and diarrhea/colitis. The DYNAMO trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy. There were 83 patients with FL.
Patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.
The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.
Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.
Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.
The Food and Drug Administration has approved duvelisib (Copiktra), a dual PI3K delta/gamma inhibitor, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma.
who have received at least two prior therapies. Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.
Accelerated approval is based on a surrogate or intermediate endpoint – in this case, overall response rate – that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.
Duvelisib will be available in the U.S. immediately, according to Verastem, the company marketing the drug. The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug – infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.
The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.
The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. The DUO trial included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2,000 mg).
Efficacy results are based on patients who had received at least two prior therapies, including 95 patients in the duvelisib arm and 101 in the ofatumumab arm. The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.
The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab.
The safety results include all patients treated with duvelisib or ofatumumab in this trial. In the duvelisib arm, 12% of patients had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab. Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection and diarrhea/colitis. The DYNAMO trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy. There were 83 patients with FL.
Patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.
The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.
Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.
Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.
NICE looks likely to reject use of Kymriah for DLBCL
The National Institute for Health and Care Excellence (NICE) has issued draft guidance recommending against tisagenlecleucel (Kymriah) as a treatment for adults with diffuse large B-cell lymphoma (DLBCL).
Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that was recently approved by the European Commission to treat adults with relapsed or refractory DLBCL who have received two or more lines of systemic therapy.
Tisagenlecleucel is also European Commission–approved to treat patients up to age 25 years who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse posttransplant, or in second or later relapse.
In September 2018, the National Health Service (NHS) in England announced tisagenlecleucel will be made available for these ALL patients through the Cancer Drugs Fund.
However, in who have received two or more lines of systemic therapy. NICE noted that there is no standard treatment for this patient group, and that salvage chemotherapy is the most common treatment option.
Although the latest results from the JULIET trial suggest tisagenlecleucel can produce responses in patients with relapsed/refractory DLBCL, there are no data comparing tisagenlecleucel with salvage chemotherapy. Additionally, tisagenlecleucel cannot be considered a life-extending treatment at the end of life, according to NICE criteria.
All cost-effectiveness estimates for tisagenlecleucel are above the range NICE normally considers acceptable, and tisagenlecleucel does not meet criteria for inclusion in the Cancer Drugs Fund.
The list price for tisagenlecleucel is 282,000 pounds. However, Novartis, the company developing tisagenlecleucel, has a confidential commercial arrangement with the NHS that lowers the price of tisagenlecleucel for the ALL indication. This arrangement would apply if tisagenlecleucel were recommended for the DLBCL indication.
In August, NICE issued a similar draft guidance document recommending against use of another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta). Axicabtagene ciloleucel is approved in Europe for the treatment of patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.
The National Institute for Health and Care Excellence (NICE) has issued draft guidance recommending against tisagenlecleucel (Kymriah) as a treatment for adults with diffuse large B-cell lymphoma (DLBCL).
Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that was recently approved by the European Commission to treat adults with relapsed or refractory DLBCL who have received two or more lines of systemic therapy.
Tisagenlecleucel is also European Commission–approved to treat patients up to age 25 years who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse posttransplant, or in second or later relapse.
In September 2018, the National Health Service (NHS) in England announced tisagenlecleucel will be made available for these ALL patients through the Cancer Drugs Fund.
However, in who have received two or more lines of systemic therapy. NICE noted that there is no standard treatment for this patient group, and that salvage chemotherapy is the most common treatment option.
Although the latest results from the JULIET trial suggest tisagenlecleucel can produce responses in patients with relapsed/refractory DLBCL, there are no data comparing tisagenlecleucel with salvage chemotherapy. Additionally, tisagenlecleucel cannot be considered a life-extending treatment at the end of life, according to NICE criteria.
All cost-effectiveness estimates for tisagenlecleucel are above the range NICE normally considers acceptable, and tisagenlecleucel does not meet criteria for inclusion in the Cancer Drugs Fund.
The list price for tisagenlecleucel is 282,000 pounds. However, Novartis, the company developing tisagenlecleucel, has a confidential commercial arrangement with the NHS that lowers the price of tisagenlecleucel for the ALL indication. This arrangement would apply if tisagenlecleucel were recommended for the DLBCL indication.
In August, NICE issued a similar draft guidance document recommending against use of another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta). Axicabtagene ciloleucel is approved in Europe for the treatment of patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.
The National Institute for Health and Care Excellence (NICE) has issued draft guidance recommending against tisagenlecleucel (Kymriah) as a treatment for adults with diffuse large B-cell lymphoma (DLBCL).
Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that was recently approved by the European Commission to treat adults with relapsed or refractory DLBCL who have received two or more lines of systemic therapy.
Tisagenlecleucel is also European Commission–approved to treat patients up to age 25 years who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse posttransplant, or in second or later relapse.
In September 2018, the National Health Service (NHS) in England announced tisagenlecleucel will be made available for these ALL patients through the Cancer Drugs Fund.
However, in who have received two or more lines of systemic therapy. NICE noted that there is no standard treatment for this patient group, and that salvage chemotherapy is the most common treatment option.
Although the latest results from the JULIET trial suggest tisagenlecleucel can produce responses in patients with relapsed/refractory DLBCL, there are no data comparing tisagenlecleucel with salvage chemotherapy. Additionally, tisagenlecleucel cannot be considered a life-extending treatment at the end of life, according to NICE criteria.
All cost-effectiveness estimates for tisagenlecleucel are above the range NICE normally considers acceptable, and tisagenlecleucel does not meet criteria for inclusion in the Cancer Drugs Fund.
The list price for tisagenlecleucel is 282,000 pounds. However, Novartis, the company developing tisagenlecleucel, has a confidential commercial arrangement with the NHS that lowers the price of tisagenlecleucel for the ALL indication. This arrangement would apply if tisagenlecleucel were recommended for the DLBCL indication.
In August, NICE issued a similar draft guidance document recommending against use of another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta). Axicabtagene ciloleucel is approved in Europe for the treatment of patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.
FDA grants OBI-3424 orphan designation for ALL
The Food and Drug Administration has granted orphan drug designation to OBI-3424 for the treatment of acute lymphoblastic leukemia (ALL).
OBI-3424 is a small-molecule prodrug that targets cancers overexpressing aldo-keto reductase 1C3 (AKR1C3) and selectively releases a DNA alkylating agent in the presence of the AKR1C3 enzyme.
AKR1C3 overexpression has been observed in ALL, particularly T-cell ALL.
OBI-3424 demonstrated activity against T-ALL in preclinical research presented as a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2017.
Researchers reported that OBI-3424 “exerted profound in vivo efficacy” against T-ALL xenografts derived mainly from patients with aggressive and fatal T-ALL. In addition, OBI-3424 significantly reduced leukemia bone marrow infiltration in four of six evaluable T-ALL xenografts, and OBI-3424 was considered well tolerated.
The poster presentation describing this research is available for download from the website of OBI Pharma, the company developing OBI-3424 in cooperation with Ascenta Pharma.
OBI-3424 also has orphan drug designation from the FDA as a treatment for hepatocellular carcinoma.
The Food and Drug Administration has granted orphan drug designation to OBI-3424 for the treatment of acute lymphoblastic leukemia (ALL).
OBI-3424 is a small-molecule prodrug that targets cancers overexpressing aldo-keto reductase 1C3 (AKR1C3) and selectively releases a DNA alkylating agent in the presence of the AKR1C3 enzyme.
AKR1C3 overexpression has been observed in ALL, particularly T-cell ALL.
OBI-3424 demonstrated activity against T-ALL in preclinical research presented as a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2017.
Researchers reported that OBI-3424 “exerted profound in vivo efficacy” against T-ALL xenografts derived mainly from patients with aggressive and fatal T-ALL. In addition, OBI-3424 significantly reduced leukemia bone marrow infiltration in four of six evaluable T-ALL xenografts, and OBI-3424 was considered well tolerated.
The poster presentation describing this research is available for download from the website of OBI Pharma, the company developing OBI-3424 in cooperation with Ascenta Pharma.
OBI-3424 also has orphan drug designation from the FDA as a treatment for hepatocellular carcinoma.
The Food and Drug Administration has granted orphan drug designation to OBI-3424 for the treatment of acute lymphoblastic leukemia (ALL).
OBI-3424 is a small-molecule prodrug that targets cancers overexpressing aldo-keto reductase 1C3 (AKR1C3) and selectively releases a DNA alkylating agent in the presence of the AKR1C3 enzyme.
AKR1C3 overexpression has been observed in ALL, particularly T-cell ALL.
OBI-3424 demonstrated activity against T-ALL in preclinical research presented as a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2017.
Researchers reported that OBI-3424 “exerted profound in vivo efficacy” against T-ALL xenografts derived mainly from patients with aggressive and fatal T-ALL. In addition, OBI-3424 significantly reduced leukemia bone marrow infiltration in four of six evaluable T-ALL xenografts, and OBI-3424 was considered well tolerated.
The poster presentation describing this research is available for download from the website of OBI Pharma, the company developing OBI-3424 in cooperation with Ascenta Pharma.
OBI-3424 also has orphan drug designation from the FDA as a treatment for hepatocellular carcinoma.
Researchers propose new acute leukemia subtypes
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.
Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.
This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.
In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.
WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.
SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.
Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.
This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.
In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.
WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.
SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.
Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.
This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.
In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.
WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.
SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
FROM NATURE
Key clinical point:
Major finding: In total, 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL.
Study details: Whole-genome, -exome, and RNA sequencing of 115 samples from pediatric patients with MPAL.
Disclosures: This research was supported by the National Cancer Institute and other organizations. The researchers reported having no competing interests.
Source: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.