AML

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to SY-1425 for the treatment of acute myeloid leukemia (AML).

SY-1425 is an oral, first-in-class, selective retinoic acid receptor alpha (RARα) agonist. It is currently under investigation in a phase 2 trial of patients with AML and myelodysplastic syndromes (MDS).

“We believe that SY-1425 may provide a meaningful benefit for subsets of AML patients whose disease is driven by abnormally high expression of the RARA or IRF8 genes,” said David A. Roth, MD, chief medical officer at Syros Pharmaceuticals, the company developing SY-1425.

“Receiving orphan drug designation is an important regulatory milestone in the development of SY-1425. We’re pleased with the continued progress of the ongoing phase 2 clinical trial, and we look forward to presenting initial clinical data in the fourth quarter of this year.”

Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8. These super-enhancers are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated, and proliferative state and leading to disease.

In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.

In the ongoing phase 2 trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

All patients are prospectively selected using biomarkers for high expression of RARA or IRF8. Additional details about the trial can be found at https://clinicaltrials.gov/ct2/show/NCT02807558.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to SY-1425 for the treatment of acute myeloid leukemia (AML).

SY-1425 is an oral, first-in-class, selective retinoic acid receptor alpha (RARα) agonist. It is currently under investigation in a phase 2 trial of patients with AML and myelodysplastic syndromes (MDS).

“We believe that SY-1425 may provide a meaningful benefit for subsets of AML patients whose disease is driven by abnormally high expression of the RARA or IRF8 genes,” said David A. Roth, MD, chief medical officer at Syros Pharmaceuticals, the company developing SY-1425.

“Receiving orphan drug designation is an important regulatory milestone in the development of SY-1425. We’re pleased with the continued progress of the ongoing phase 2 clinical trial, and we look forward to presenting initial clinical data in the fourth quarter of this year.”

Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8. These super-enhancers are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated, and proliferative state and leading to disease.

In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.

In the ongoing phase 2 trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

All patients are prospectively selected using biomarkers for high expression of RARA or IRF8. Additional details about the trial can be found at https://clinicaltrials.gov/ct2/show/NCT02807558.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to SY-1425 for the treatment of acute myeloid leukemia (AML).

SY-1425 is an oral, first-in-class, selective retinoic acid receptor alpha (RARα) agonist. It is currently under investigation in a phase 2 trial of patients with AML and myelodysplastic syndromes (MDS).

“We believe that SY-1425 may provide a meaningful benefit for subsets of AML patients whose disease is driven by abnormally high expression of the RARA or IRF8 genes,” said David A. Roth, MD, chief medical officer at Syros Pharmaceuticals, the company developing SY-1425.

“Receiving orphan drug designation is an important regulatory milestone in the development of SY-1425. We’re pleased with the continued progress of the ongoing phase 2 clinical trial, and we look forward to presenting initial clinical data in the fourth quarter of this year.”

Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8. These super-enhancers are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated, and proliferative state and leading to disease.

In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.

In the ongoing phase 2 trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

All patients are prospectively selected using biomarkers for high expression of RARA or IRF8. Additional details about the trial can be found at https://clinicaltrials.gov/ct2/show/NCT02807558.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

About H3B-8800

H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.

Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.

Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.

Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).

H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.

H3B-8800 is being developed by H3 Biomedicine Inc.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

About H3B-8800

H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.

Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.

Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.

Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).

H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.

H3B-8800 is being developed by H3 Biomedicine Inc.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

About H3B-8800

H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.

Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.

Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.

Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).

H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.

H3B-8800 is being developed by H3 Biomedicine Inc.

Although adults older than 65 newly diagnosed with acute myeloid leukemia (AML) have a generally poor prognosis and short life expectancy, fewer than half were enrolled in hospice, and of those patients who were enrolled, two-thirds entered hospice within the last week of life, results of a retrospective cohort study show.

The findings suggest that there is substantial room for improvement in the care of older patients with AML in their last days of life, said investigators led by Rong Wang, PhD, and colleagues from Yale University in New Haven, Connecticut.

“[We] found that the current end-of-life care for older patients with AML is suboptimal, as reflected by low hospice enrollment and high use of potentially aggressive treatment. Transfer in and out of hospice was associated with the receipt of transfusions. Changes to current hospice services, such as enabling the provision of transfusion support, and improvements in physician-patient communications, may help facilitate better end-of-life care in this patient population,” they wrote (J Clin Oncol. 2017 Aug 7. doi: 10.1200/JCO.2017.72.7149)

Patients aged 65 and over with AML have a median overall survival (OS) of only about 2 months, and the older the patient, the worse the survival, with patients 85 and older having a median OS of just 1 month, the investigators noted.

“Hence, end-of-life care is particularly relevant for this patient population,” they wrote.

To get a better idea of how clinicians prescribe hospice and palliative care for older patients with AML, Dr. Wang and colleagues conducted a population-based, retrospective cohort study of patients with AML who were 66 or older at diagnosis, received a diagnosis from 1999 through 2011, and died before the end of 2012.

They reviewed Medicare claims data on 13,156 patients to see whether patients were receiving aggressive care such as chemotherapy and whether and when they were enrolled in hospice.

The investigators found that the proportion of patients who were enrolled in hospice after an AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012 (P for trend less than .01).

They also discovered, however, that most of the increase was attributable to patients who were enrolled within the last week of life.

When they compared patients who died within 30 days of diagnosis to those who lived longer than 30 days after diagnosis, they found that the longer-lived patients were significantly more likely to have been enrolled in hospice (48.1% vs. 30.7%, P less than .01). Additionally, of those patients who were enrolled in hospice, 51.2% of those who died within 30 days of entering hospice had been enrolled in the last 3 days of life, compared with 24.9% of those who survived for more than a month after entering hospice (P value not shown).

Over the course of the study 1,528 patients (11.6%) had chemotherapy within their last two weeks of life. The proportion of patients undergoing chemotherapy within their last 14 days increased from 7.7% in 1999 to 18.8% in 2012 (P for trend less than .01).

Patients who had end-of-life chemotherapy were significantly more likely to have had an ICU stay in the last month of life (43.0% vs. 28.4%; P less than .01) and were significantly more likely to be enrolled in hospice (22.1% vs. 47.4%, P less than .01) than patients who did not get chemotherapy with the last 14 days of life.

Predictors for end-of-life chemotherapy were male sex, being married, and dying in more recent years. Patients who were older, had state Medicaid buy-in (an optional program for workers with disabilities), or who lived outside the Northeast or major metropolitan areas were less likely to be subjected to chemotherapy in their final days.

Overall, 3,956 patients (30.1%) were admitted to the ICU within 30 days of their deaths. The percentage of ICU admissions just before death increased from 25.2% in 1999 to 31.3% in 2012 (P for trend .01).

Predictors for late-life ICU admission were similar to those for chemotherapy, except that patients with state Medicaid buy-in had 19% greater odds of being admitted to an ICU within 30 days of death (P less than .01).

The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.

hematologynews@frontlinemedcom.com

Although adults older than 65 newly diagnosed with acute myeloid leukemia (AML) have a generally poor prognosis and short life expectancy, fewer than half were enrolled in hospice, and of those patients who were enrolled, two-thirds entered hospice within the last week of life, results of a retrospective cohort study show.

The findings suggest that there is substantial room for improvement in the care of older patients with AML in their last days of life, said investigators led by Rong Wang, PhD, and colleagues from Yale University in New Haven, Connecticut.

“[We] found that the current end-of-life care for older patients with AML is suboptimal, as reflected by low hospice enrollment and high use of potentially aggressive treatment. Transfer in and out of hospice was associated with the receipt of transfusions. Changes to current hospice services, such as enabling the provision of transfusion support, and improvements in physician-patient communications, may help facilitate better end-of-life care in this patient population,” they wrote (J Clin Oncol. 2017 Aug 7. doi: 10.1200/JCO.2017.72.7149)

Patients aged 65 and over with AML have a median overall survival (OS) of only about 2 months, and the older the patient, the worse the survival, with patients 85 and older having a median OS of just 1 month, the investigators noted.

“Hence, end-of-life care is particularly relevant for this patient population,” they wrote.

To get a better idea of how clinicians prescribe hospice and palliative care for older patients with AML, Dr. Wang and colleagues conducted a population-based, retrospective cohort study of patients with AML who were 66 or older at diagnosis, received a diagnosis from 1999 through 2011, and died before the end of 2012.

They reviewed Medicare claims data on 13,156 patients to see whether patients were receiving aggressive care such as chemotherapy and whether and when they were enrolled in hospice.

The investigators found that the proportion of patients who were enrolled in hospice after an AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012 (P for trend less than .01).

They also discovered, however, that most of the increase was attributable to patients who were enrolled within the last week of life.

When they compared patients who died within 30 days of diagnosis to those who lived longer than 30 days after diagnosis, they found that the longer-lived patients were significantly more likely to have been enrolled in hospice (48.1% vs. 30.7%, P less than .01). Additionally, of those patients who were enrolled in hospice, 51.2% of those who died within 30 days of entering hospice had been enrolled in the last 3 days of life, compared with 24.9% of those who survived for more than a month after entering hospice (P value not shown).

Over the course of the study 1,528 patients (11.6%) had chemotherapy within their last two weeks of life. The proportion of patients undergoing chemotherapy within their last 14 days increased from 7.7% in 1999 to 18.8% in 2012 (P for trend less than .01).

Patients who had end-of-life chemotherapy were significantly more likely to have had an ICU stay in the last month of life (43.0% vs. 28.4%; P less than .01) and were significantly more likely to be enrolled in hospice (22.1% vs. 47.4%, P less than .01) than patients who did not get chemotherapy with the last 14 days of life.

Predictors for end-of-life chemotherapy were male sex, being married, and dying in more recent years. Patients who were older, had state Medicaid buy-in (an optional program for workers with disabilities), or who lived outside the Northeast or major metropolitan areas were less likely to be subjected to chemotherapy in their final days.

Overall, 3,956 patients (30.1%) were admitted to the ICU within 30 days of their deaths. The percentage of ICU admissions just before death increased from 25.2% in 1999 to 31.3% in 2012 (P for trend .01).

Predictors for late-life ICU admission were similar to those for chemotherapy, except that patients with state Medicaid buy-in had 19% greater odds of being admitted to an ICU within 30 days of death (P less than .01).

The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.

hematologynews@frontlinemedcom.com

Although adults older than 65 newly diagnosed with acute myeloid leukemia (AML) have a generally poor prognosis and short life expectancy, fewer than half were enrolled in hospice, and of those patients who were enrolled, two-thirds entered hospice within the last week of life, results of a retrospective cohort study show.

The findings suggest that there is substantial room for improvement in the care of older patients with AML in their last days of life, said investigators led by Rong Wang, PhD, and colleagues from Yale University in New Haven, Connecticut.

“[We] found that the current end-of-life care for older patients with AML is suboptimal, as reflected by low hospice enrollment and high use of potentially aggressive treatment. Transfer in and out of hospice was associated with the receipt of transfusions. Changes to current hospice services, such as enabling the provision of transfusion support, and improvements in physician-patient communications, may help facilitate better end-of-life care in this patient population,” they wrote (J Clin Oncol. 2017 Aug 7. doi: 10.1200/JCO.2017.72.7149)

Patients aged 65 and over with AML have a median overall survival (OS) of only about 2 months, and the older the patient, the worse the survival, with patients 85 and older having a median OS of just 1 month, the investigators noted.

“Hence, end-of-life care is particularly relevant for this patient population,” they wrote.

To get a better idea of how clinicians prescribe hospice and palliative care for older patients with AML, Dr. Wang and colleagues conducted a population-based, retrospective cohort study of patients with AML who were 66 or older at diagnosis, received a diagnosis from 1999 through 2011, and died before the end of 2012.

They reviewed Medicare claims data on 13,156 patients to see whether patients were receiving aggressive care such as chemotherapy and whether and when they were enrolled in hospice.

The investigators found that the proportion of patients who were enrolled in hospice after an AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012 (P for trend less than .01).

They also discovered, however, that most of the increase was attributable to patients who were enrolled within the last week of life.

When they compared patients who died within 30 days of diagnosis to those who lived longer than 30 days after diagnosis, they found that the longer-lived patients were significantly more likely to have been enrolled in hospice (48.1% vs. 30.7%, P less than .01). Additionally, of those patients who were enrolled in hospice, 51.2% of those who died within 30 days of entering hospice had been enrolled in the last 3 days of life, compared with 24.9% of those who survived for more than a month after entering hospice (P value not shown).

Over the course of the study 1,528 patients (11.6%) had chemotherapy within their last two weeks of life. The proportion of patients undergoing chemotherapy within their last 14 days increased from 7.7% in 1999 to 18.8% in 2012 (P for trend less than .01).

Patients who had end-of-life chemotherapy were significantly more likely to have had an ICU stay in the last month of life (43.0% vs. 28.4%; P less than .01) and were significantly more likely to be enrolled in hospice (22.1% vs. 47.4%, P less than .01) than patients who did not get chemotherapy with the last 14 days of life.

Predictors for end-of-life chemotherapy were male sex, being married, and dying in more recent years. Patients who were older, had state Medicaid buy-in (an optional program for workers with disabilities), or who lived outside the Northeast or major metropolitan areas were less likely to be subjected to chemotherapy in their final days.

Overall, 3,956 patients (30.1%) were admitted to the ICU within 30 days of their deaths. The percentage of ICU admissions just before death increased from 25.2% in 1999 to 31.3% in 2012 (P for trend .01).

Predictors for late-life ICU admission were similar to those for chemotherapy, except that patients with state Medicaid buy-in had 19% greater odds of being admitted to an ICU within 30 days of death (P less than .01).

The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.

hematologynews@frontlinemedcom.com

College of Medicine

New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).

The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).

Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.

“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”

“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.

“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”

The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.

“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.

“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”

“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”

Patients

The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).

These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).

Response

The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.

Six weeks after the first VST infusion, the overall response rate was 91.9%.

Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).

Two patients received VSTs for EBV, and both achieved a virologic CR.

Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.

Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.

Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).

All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.

A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.

Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.

Toxicity

One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.

One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.

Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.

One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).

Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.

“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”

College of Medicine

New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).

The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).

Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.

“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”

“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.

“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”

The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.

“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.

“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”

“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”

Patients

The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).

These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).

Response

The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.

Six weeks after the first VST infusion, the overall response rate was 91.9%.

Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).

Two patients received VSTs for EBV, and both achieved a virologic CR.

Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.

Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.

Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).

All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.

A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.

Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.

Toxicity

One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.

One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.

Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.

One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).

Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.

“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”

College of Medicine

New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).

The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).

Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.

“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”

“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.

“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”

The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.

“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.

“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”

“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”

Patients

The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).

These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).

Response

The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.

Six weeks after the first VST infusion, the overall response rate was 91.9%.

Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).

Two patients received VSTs for EBV, and both achieved a virologic CR.

Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.

Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.

Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).

All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.

A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.

Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.

Toxicity

One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.

One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.

Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.

One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).

Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.

“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”

Lab mouse

Researchers believe they may have found a way to prevent chemotherapy-induced myelosuppression in acute myeloid leukemia (AML).

The team found that priming mice with the FLT3 inhibitor quizartinib protected multipotent progenitor cells (MPPs) from subsequent treatment with fluorouracil (5-FU) or gemcitabine.

And treatment with quizartinib followed by 5-FU proved more effective against AML than standard induction with cytarabine and doxorubicin.

Samuel Taylor, of the University of Western Australia in Crawley, Australia, and his colleagues reported these results in Science Translational Medicine.

The researchers first found that quizartinib induced “rapid and transient” quiescence of MPPs in C57BL/6 mice.

Quizartinib also provided MPPs with “marked protection” from 5-FU. In these experiments, a 10 mg/kg dose of quizartinib was given to mice at the same time as a 150 mg/kg dose of 5-FU. This treatment provided MPPs with 4- to 5-fold greater protection than vehicle control.

Subsequent experiments revealed the optimal dose and schedule for quizartinib. A priming dose of 30 mg/kg given 6 hours before 5-FU provided “slightly greater” protection to hematopoietic stem and progenitor cells than a 10 mg/kg dose, with significantly greater protection observed for short-term hematopoietic stem cells.

The researchers then showed that priming with quizartinib allowed for “rapid recovery of bone marrow cellularity” after treatment with 5-FU. Bone marrow cells were fully restored by day 8 after treatment in quizartinib-primed mice but not in vehicle-primed mice.

Quizartinib priming also protected mice from multiple rounds of treatment with 5-FU (15 cycles in some mice) and from myelosuppression induced by gemcitabine.

Finally, the researchers tested quizartinib followed by 5-FU in mouse models of AML. They found the treatment was more effective than treatment with cytarabine and doxorubicin in both FLT3-ITD(F692L)/NPM1c AML and NPM1c/Nras^G12D AML.

FLT3-ITD(F692L)/NPM1c AML

The researchers transplanted 15 non-irradiated B6.CD45.1 mice with 3 × 10⁵ spleen cells each from a FLT3-ITD(F691L)/NPM1c mouse that succumbed to AML at 6 weeks of age. Sixteen days after transplant, the mice were given one of the following:

• No treatment
• 10-day cycles of quizartinib (30 mg/kg) followed 6 hours later by 5-FU (150 mg/kg)
• Cytarabine plus doxorubicin (5+3).

All 5 of the untreated mice died within 30 days of transplantation, exhibiting high white blood cell (WBC) counts and splenomegaly.

The 5+3 mice received 2 cycles of treatment (days 16 to 21 and 36 to 41). All 5 had died by day 56 after transplantation, with high WBC counts and splenomegaly.

One the other hand, 4 of the 5 mice in the quizartinib/5-FU arm were still healthy at 176 days after transplantation and 80 days after stopping treatment. There were no detectable CD45.2+ AML cells when the mice were last bled on day 160, and they had normal WBC counts. There were no AML cells detectable in the animals’ bone marrow after they were killed at day 176.

The quizartinib/5-FU mouse that died before day 176 is believed to have developed resistance to 5-FU. This animal died 121 days after transplantation.

NPM1c/ Nras^G12D AML

For another AML model, the researchers crossed NPM1c-mutant mice with Nras^G12D-mutant mice. The team transplanted spleen cells from NPM1c/Nras^G12D leukemic mice into 15 non-irradiated B6.CD45.1 recipient mice.

Fifteen days after transplantation, the NPM1c/ Nras^G12D mice received one of the following:

• No treatment
• Quizartinib and 5-FU as above
• Cytarabine plus doxorubicin (5+3).

All 5 untreated mice died by day 32 after transplantation, and all 5 mice that received 5+3 died by day 35. Both groups of mice had high WBC counts and splenomegaly.

Mice in the quizartinib/5-FU arm initially received 4 cycles of treatment, starting on days 15, 25, 35, and 45 after transplantation. On day 53, they had minimal or undetectable numbers of CD45.2+ AML cells, and WBC counts were normal or slightly below normal.

At day 81—a month after stopping treatment—4 of the mice had detectable CD45.2+ AML cells in their blood. So they restarted treatment the next day. After 4 additional cycles, AML cells were undetectable in all 5 mice. At day 146—a month after stopping the second round of treatment—AML cells again became detectable in the blood.

The mice did not receive any additional treatment. One died at day 196, and 1 was killed at day 197 due to weight loss related to feeding difficulties (but this mouse did not show signs of AML).

The other 3 mice were “active and healthy” until they were killed at day 214. However, they had “high proportions” of CD45.2+ myeloid cells in their blood since day 183. And 2 of the mice had increased WBC counts from day 197.

Lab mouse

Researchers believe they may have found a way to prevent chemotherapy-induced myelosuppression in acute myeloid leukemia (AML).

The team found that priming mice with the FLT3 inhibitor quizartinib protected multipotent progenitor cells (MPPs) from subsequent treatment with fluorouracil (5-FU) or gemcitabine.

And treatment with quizartinib followed by 5-FU proved more effective against AML than standard induction with cytarabine and doxorubicin.

Samuel Taylor, of the University of Western Australia in Crawley, Australia, and his colleagues reported these results in Science Translational Medicine.

The researchers first found that quizartinib induced “rapid and transient” quiescence of MPPs in C57BL/6 mice.

Quizartinib also provided MPPs with “marked protection” from 5-FU. In these experiments, a 10 mg/kg dose of quizartinib was given to mice at the same time as a 150 mg/kg dose of 5-FU. This treatment provided MPPs with 4- to 5-fold greater protection than vehicle control.

Subsequent experiments revealed the optimal dose and schedule for quizartinib. A priming dose of 30 mg/kg given 6 hours before 5-FU provided “slightly greater” protection to hematopoietic stem and progenitor cells than a 10 mg/kg dose, with significantly greater protection observed for short-term hematopoietic stem cells.

The researchers then showed that priming with quizartinib allowed for “rapid recovery of bone marrow cellularity” after treatment with 5-FU. Bone marrow cells were fully restored by day 8 after treatment in quizartinib-primed mice but not in vehicle-primed mice.

Quizartinib priming also protected mice from multiple rounds of treatment with 5-FU (15 cycles in some mice) and from myelosuppression induced by gemcitabine.

Finally, the researchers tested quizartinib followed by 5-FU in mouse models of AML. They found the treatment was more effective than treatment with cytarabine and doxorubicin in both FLT3-ITD(F692L)/NPM1c AML and NPM1c/Nras^G12D AML.

FLT3-ITD(F692L)/NPM1c AML

The researchers transplanted 15 non-irradiated B6.CD45.1 mice with 3 × 10⁵ spleen cells each from a FLT3-ITD(F691L)/NPM1c mouse that succumbed to AML at 6 weeks of age. Sixteen days after transplant, the mice were given one of the following:

• No treatment
• 10-day cycles of quizartinib (30 mg/kg) followed 6 hours later by 5-FU (150 mg/kg)
• Cytarabine plus doxorubicin (5+3).

All 5 of the untreated mice died within 30 days of transplantation, exhibiting high white blood cell (WBC) counts and splenomegaly.

The 5+3 mice received 2 cycles of treatment (days 16 to 21 and 36 to 41). All 5 had died by day 56 after transplantation, with high WBC counts and splenomegaly.

One the other hand, 4 of the 5 mice in the quizartinib/5-FU arm were still healthy at 176 days after transplantation and 80 days after stopping treatment. There were no detectable CD45.2+ AML cells when the mice were last bled on day 160, and they had normal WBC counts. There were no AML cells detectable in the animals’ bone marrow after they were killed at day 176.

The quizartinib/5-FU mouse that died before day 176 is believed to have developed resistance to 5-FU. This animal died 121 days after transplantation.

NPM1c/ Nras^G12D AML

For another AML model, the researchers crossed NPM1c-mutant mice with Nras^G12D-mutant mice. The team transplanted spleen cells from NPM1c/Nras^G12D leukemic mice into 15 non-irradiated B6.CD45.1 recipient mice.

Fifteen days after transplantation, the NPM1c/ Nras^G12D mice received one of the following:

• No treatment
• Quizartinib and 5-FU as above
• Cytarabine plus doxorubicin (5+3).

All 5 untreated mice died by day 32 after transplantation, and all 5 mice that received 5+3 died by day 35. Both groups of mice had high WBC counts and splenomegaly.

Mice in the quizartinib/5-FU arm initially received 4 cycles of treatment, starting on days 15, 25, 35, and 45 after transplantation. On day 53, they had minimal or undetectable numbers of CD45.2+ AML cells, and WBC counts were normal or slightly below normal.

At day 81—a month after stopping treatment—4 of the mice had detectable CD45.2+ AML cells in their blood. So they restarted treatment the next day. After 4 additional cycles, AML cells were undetectable in all 5 mice. At day 146—a month after stopping the second round of treatment—AML cells again became detectable in the blood.

The mice did not receive any additional treatment. One died at day 196, and 1 was killed at day 197 due to weight loss related to feeding difficulties (but this mouse did not show signs of AML).

The other 3 mice were “active and healthy” until they were killed at day 214. However, they had “high proportions” of CD45.2+ myeloid cells in their blood since day 183. And 2 of the mice had increased WBC counts from day 197.

Lab mouse

Researchers believe they may have found a way to prevent chemotherapy-induced myelosuppression in acute myeloid leukemia (AML).

The team found that priming mice with the FLT3 inhibitor quizartinib protected multipotent progenitor cells (MPPs) from subsequent treatment with fluorouracil (5-FU) or gemcitabine.

And treatment with quizartinib followed by 5-FU proved more effective against AML than standard induction with cytarabine and doxorubicin.

Samuel Taylor, of the University of Western Australia in Crawley, Australia, and his colleagues reported these results in Science Translational Medicine.

The researchers first found that quizartinib induced “rapid and transient” quiescence of MPPs in C57BL/6 mice.

Quizartinib also provided MPPs with “marked protection” from 5-FU. In these experiments, a 10 mg/kg dose of quizartinib was given to mice at the same time as a 150 mg/kg dose of 5-FU. This treatment provided MPPs with 4- to 5-fold greater protection than vehicle control.

Subsequent experiments revealed the optimal dose and schedule for quizartinib. A priming dose of 30 mg/kg given 6 hours before 5-FU provided “slightly greater” protection to hematopoietic stem and progenitor cells than a 10 mg/kg dose, with significantly greater protection observed for short-term hematopoietic stem cells.

The researchers then showed that priming with quizartinib allowed for “rapid recovery of bone marrow cellularity” after treatment with 5-FU. Bone marrow cells were fully restored by day 8 after treatment in quizartinib-primed mice but not in vehicle-primed mice.

Quizartinib priming also protected mice from multiple rounds of treatment with 5-FU (15 cycles in some mice) and from myelosuppression induced by gemcitabine.

Finally, the researchers tested quizartinib followed by 5-FU in mouse models of AML. They found the treatment was more effective than treatment with cytarabine and doxorubicin in both FLT3-ITD(F692L)/NPM1c AML and NPM1c/Nras^G12D AML.

FLT3-ITD(F692L)/NPM1c AML

The researchers transplanted 15 non-irradiated B6.CD45.1 mice with 3 × 10⁵ spleen cells each from a FLT3-ITD(F691L)/NPM1c mouse that succumbed to AML at 6 weeks of age. Sixteen days after transplant, the mice were given one of the following:

• No treatment
• 10-day cycles of quizartinib (30 mg/kg) followed 6 hours later by 5-FU (150 mg/kg)
• Cytarabine plus doxorubicin (5+3).

All 5 of the untreated mice died within 30 days of transplantation, exhibiting high white blood cell (WBC) counts and splenomegaly.

The 5+3 mice received 2 cycles of treatment (days 16 to 21 and 36 to 41). All 5 had died by day 56 after transplantation, with high WBC counts and splenomegaly.

One the other hand, 4 of the 5 mice in the quizartinib/5-FU arm were still healthy at 176 days after transplantation and 80 days after stopping treatment. There were no detectable CD45.2+ AML cells when the mice were last bled on day 160, and they had normal WBC counts. There were no AML cells detectable in the animals’ bone marrow after they were killed at day 176.

The quizartinib/5-FU mouse that died before day 176 is believed to have developed resistance to 5-FU. This animal died 121 days after transplantation.

NPM1c/ Nras^G12D AML

For another AML model, the researchers crossed NPM1c-mutant mice with Nras^G12D-mutant mice. The team transplanted spleen cells from NPM1c/Nras^G12D leukemic mice into 15 non-irradiated B6.CD45.1 recipient mice.

Fifteen days after transplantation, the NPM1c/ Nras^G12D mice received one of the following:

• No treatment
• Quizartinib and 5-FU as above
• Cytarabine plus doxorubicin (5+3).

All 5 untreated mice died by day 32 after transplantation, and all 5 mice that received 5+3 died by day 35. Both groups of mice had high WBC counts and splenomegaly.

Mice in the quizartinib/5-FU arm initially received 4 cycles of treatment, starting on days 15, 25, 35, and 45 after transplantation. On day 53, they had minimal or undetectable numbers of CD45.2+ AML cells, and WBC counts were normal or slightly below normal.

At day 81—a month after stopping treatment—4 of the mice had detectable CD45.2+ AML cells in their blood. So they restarted treatment the next day. After 4 additional cycles, AML cells were undetectable in all 5 mice. At day 146—a month after stopping the second round of treatment—AML cells again became detectable in the blood.

The mice did not receive any additional treatment. One died at day 196, and 1 was killed at day 197 due to weight loss related to feeding difficulties (but this mouse did not show signs of AML).

The other 3 mice were “active and healthy” until they were killed at day 214. However, they had “high proportions” of CD45.2+ myeloid cells in their blood since day 183. And 2 of the mice had increased WBC counts from day 197.

Henrique Orlandi Mourao

Researchers have found evidence to suggest that a type of acute myeloid leukemia (AML) depends on the production of heme.

The group’s work has revealed 2 ways to target heme synthesis that might be used to treat this type of AML, which is driven by the oncogene MYCN.

John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleague described this research in JCI Insight.

Previous research had suggested that heme production was affected in leukemia.

However, Dr Schuetz said, “Absolutely nothing was known about the role of heme biosynthesis [in AML] before our work.”

The researchers’ first clue regarding heme’s role in AML arose from a computer search. The team searched a genomic database for other genes that were abnormally switched on in MYCN-driven AML.

They found that UROD was highly activated and noted that UROD is part of the molecular machinery that synthesizes heme.

Especially significant, Dr Schuetz said, was the finding that MYCN-driven AML with the most over-activated UROD was far more lethal than other AMLs.

The researchers found that cells with over-activated MYCN consumed more oxygen and depended on the production of heme for self-renewal and oncogenic transformation. But the team was able to block cancer cell self-renewal in the MYCN cells by blocking heme synthesis.

The researchers also found they could suppress self-renewal by blocking ABCG2, a “relief-valve” molecule that rids the cells of porphyrin, a building-block molecule of heme.

Blocking ABCG2 caused the buildup of porphyrin, which is toxic to the leukemia cells. However, blocking ABCG2 in normal cells produced no ill effects.

In mouse models of MYCN leukemia, the researchers tested a strategy of knocking out ABCG2. These knockout mice had significantly slower disease progression and longer survival.

What’s more, the team found they could cure leukemia in these mice by inhibiting ABCG2 and ramping up the heme machinery.

“Our findings suggest 2 drug strategies to treat AML,” Dr Schuetz said. “One would be to target UROD, which would reduce heme biosynthesis. Such drugs would selectively affect leukemia cells because they are so dependent on heme.”

“The other strategy would be to use drugs to inhibit the relief-valve protein and, at the same time, administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway.”

Dr Schuetz said other cancers with an over-activated heme pathway might also be vulnerable to such a treatment strategy.

He and his colleagues plan to extend their understanding of the heme machinery in AML with further studies. For example, they don’t know whether heme’s role in cell respiration is the only important one in supporting AML progression, since heme plays a wide range of roles in cells.

The researchers are also planning to test whether drugs that suppress UROD function in the heme-production machinery can effectively battle AML.

Henrique Orlandi Mourao

Researchers have found evidence to suggest that a type of acute myeloid leukemia (AML) depends on the production of heme.

The group’s work has revealed 2 ways to target heme synthesis that might be used to treat this type of AML, which is driven by the oncogene MYCN.

John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleague described this research in JCI Insight.

Previous research had suggested that heme production was affected in leukemia.

However, Dr Schuetz said, “Absolutely nothing was known about the role of heme biosynthesis [in AML] before our work.”

The researchers’ first clue regarding heme’s role in AML arose from a computer search. The team searched a genomic database for other genes that were abnormally switched on in MYCN-driven AML.

They found that UROD was highly activated and noted that UROD is part of the molecular machinery that synthesizes heme.

Especially significant, Dr Schuetz said, was the finding that MYCN-driven AML with the most over-activated UROD was far more lethal than other AMLs.

The researchers found that cells with over-activated MYCN consumed more oxygen and depended on the production of heme for self-renewal and oncogenic transformation. But the team was able to block cancer cell self-renewal in the MYCN cells by blocking heme synthesis.

The researchers also found they could suppress self-renewal by blocking ABCG2, a “relief-valve” molecule that rids the cells of porphyrin, a building-block molecule of heme.

Blocking ABCG2 caused the buildup of porphyrin, which is toxic to the leukemia cells. However, blocking ABCG2 in normal cells produced no ill effects.

In mouse models of MYCN leukemia, the researchers tested a strategy of knocking out ABCG2. These knockout mice had significantly slower disease progression and longer survival.

What’s more, the team found they could cure leukemia in these mice by inhibiting ABCG2 and ramping up the heme machinery.

“Our findings suggest 2 drug strategies to treat AML,” Dr Schuetz said. “One would be to target UROD, which would reduce heme biosynthesis. Such drugs would selectively affect leukemia cells because they are so dependent on heme.”

“The other strategy would be to use drugs to inhibit the relief-valve protein and, at the same time, administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway.”

Dr Schuetz said other cancers with an over-activated heme pathway might also be vulnerable to such a treatment strategy.

He and his colleagues plan to extend their understanding of the heme machinery in AML with further studies. For example, they don’t know whether heme’s role in cell respiration is the only important one in supporting AML progression, since heme plays a wide range of roles in cells.

The researchers are also planning to test whether drugs that suppress UROD function in the heme-production machinery can effectively battle AML.

Henrique Orlandi Mourao

Researchers have found evidence to suggest that a type of acute myeloid leukemia (AML) depends on the production of heme.

The group’s work has revealed 2 ways to target heme synthesis that might be used to treat this type of AML, which is driven by the oncogene MYCN.

John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleague described this research in JCI Insight.

Previous research had suggested that heme production was affected in leukemia.

However, Dr Schuetz said, “Absolutely nothing was known about the role of heme biosynthesis [in AML] before our work.”

The researchers’ first clue regarding heme’s role in AML arose from a computer search. The team searched a genomic database for other genes that were abnormally switched on in MYCN-driven AML.

They found that UROD was highly activated and noted that UROD is part of the molecular machinery that synthesizes heme.

Especially significant, Dr Schuetz said, was the finding that MYCN-driven AML with the most over-activated UROD was far more lethal than other AMLs.

The researchers found that cells with over-activated MYCN consumed more oxygen and depended on the production of heme for self-renewal and oncogenic transformation. But the team was able to block cancer cell self-renewal in the MYCN cells by blocking heme synthesis.

The researchers also found they could suppress self-renewal by blocking ABCG2, a “relief-valve” molecule that rids the cells of porphyrin, a building-block molecule of heme.

Blocking ABCG2 caused the buildup of porphyrin, which is toxic to the leukemia cells. However, blocking ABCG2 in normal cells produced no ill effects.

In mouse models of MYCN leukemia, the researchers tested a strategy of knocking out ABCG2. These knockout mice had significantly slower disease progression and longer survival.

What’s more, the team found they could cure leukemia in these mice by inhibiting ABCG2 and ramping up the heme machinery.

“Our findings suggest 2 drug strategies to treat AML,” Dr Schuetz said. “One would be to target UROD, which would reduce heme biosynthesis. Such drugs would selectively affect leukemia cells because they are so dependent on heme.”

“The other strategy would be to use drugs to inhibit the relief-valve protein and, at the same time, administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway.”

Dr Schuetz said other cancers with an over-activated heme pathway might also be vulnerable to such a treatment strategy.

He and his colleagues plan to extend their understanding of the heme machinery in AML with further studies. For example, they don’t know whether heme’s role in cell respiration is the only important one in supporting AML progression, since heme plays a wide range of roles in cells.

The researchers are also planning to test whether drugs that suppress UROD function in the heme-production machinery can effectively battle AML.

AML cells

The US Food and Drug Administration (FDA) has granted approval for CPX-351 (Vyxeos™), a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.

CPX-351 is approved to treat adults with 2 types of acute myeloid leukemia (AML)—AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML.

The FDA granted the approval of CPX-351 to Jazz Pharmaceuticals.

The company says the drug will be commercially available within a week.

The FDA approval of CPX-351 is based on data from a phase 3 trial in which researchers compared CPX-351 to cytarabine and daunorubicin (7+3) in 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).

The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.

The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).

All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.

Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.

The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.

The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.

The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.

For more information on CPX-351, visit http://www.vyxeos.com.

AML cells

The US Food and Drug Administration (FDA) has granted approval for CPX-351 (Vyxeos™), a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.

CPX-351 is approved to treat adults with 2 types of acute myeloid leukemia (AML)—AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML.

The FDA granted the approval of CPX-351 to Jazz Pharmaceuticals.

The company says the drug will be commercially available within a week.

The FDA approval of CPX-351 is based on data from a phase 3 trial in which researchers compared CPX-351 to cytarabine and daunorubicin (7+3) in 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).

The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.

The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).

All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.

Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.

The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.

The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.

The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.

For more information on CPX-351, visit http://www.vyxeos.com.

AML cells

The US Food and Drug Administration (FDA) has granted approval for CPX-351 (Vyxeos™), a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.

CPX-351 is approved to treat adults with 2 types of acute myeloid leukemia (AML)—AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML.

The FDA granted the approval of CPX-351 to Jazz Pharmaceuticals.

The company says the drug will be commercially available within a week.

The FDA approval of CPX-351 is based on data from a phase 3 trial in which researchers compared CPX-351 to cytarabine and daunorubicin (7+3) in 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).

The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.

The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).

All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.

Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.

The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.

The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.

The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.

For more information on CPX-351, visit http://www.vyxeos.com.

Vyxeos, a liposome-encapsulated combination of daunorubicin and cytarabine, has been approved for the treatment of adults with newly-diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC), the Food and Drug Administration announced on Aug. 3.

Vyxeos is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC, the FDA said in its press release announcing the approval.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Vyxeos, a liposome-encapsulated combination of daunorubicin and cytarabine, has been approved for the treatment of adults with newly-diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC), the Food and Drug Administration announced on Aug. 3.

Vyxeos is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC, the FDA said in its press release announcing the approval.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Vyxeos, a liposome-encapsulated combination of daunorubicin and cytarabine, has been approved for the treatment of adults with newly-diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC), the Food and Drug Administration announced on Aug. 3.

Vyxeos is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC, the FDA said in its press release announcing the approval.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Photo from Business Wire

The US Food and Drug Administration (FDA) has approved marketing of the oral IDH2 inhibitor enasidenib (IDHIFA®).

The drug is now approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation, as detected by an FDA-approved test.

Enasidenib is available in 50 mg and 100 mg tablets. The recommended dose is 100 mg once daily until disease progression or unacceptable toxicity.

The prescribing information for enasidenib includes a boxed warning that the drug may cause differentiation syndrome, and this adverse event (AE) can be fatal if not treated.

Signs and symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, and hepatic, renal, or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms resolve.

Companion diagnostic

Enasidenib was approved concurrently with the Abbott RealTime™ IDH2 companion diagnostic test, which was approved as an aid in identifying AML patients for treatment with enasidenib.

The FDA granted approval of enasidenib to Celgene Corporation and approval of the RealTime IDH2 Assay to Abbott Laboratories.

Enasidenib is licensed from Agios Pharmaceuticals.

Trial results

The FDA’s approval of enasidenib and the companion diagnostic test was based on data from a phase 1/2 trial (Study AG221-C-001, NCT01915498).

Data from this trial were recently presented at the ASCO 2017 Annual Meeting. However, the definitive data are included in the prescribing information for enasidenib.

The prescribing information includes efficacy data for 199 adults with relapsed/refractory AML and an IDH2 mutation. IDH2 mutations were identified or confirmed by the Abbott RealTime™ IDH2 test.

The 199 patients received enasidenib at a starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage side effects.

The patients’ median age was 68 (range, 19 to 100). They received a median of 2 prior anticancer regimens (range, 1 to 6). More than half (52%) were refractory to previous therapy.

The rate of complete response (CR) or CR with partial hematologic improvement (CRh) was 23% (n=46). The median duration of CR/CRh was 8.2 months (range, 4.3 to 19.4).

For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, 0.5 to 7.5), and the median time to best response of CR/CRh was 3.7 months (range, 0.6 to 11.2).

Among the 157 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 53 (34%) became independent of RBC and platelet transfusions during any 56-day period post-baseline.

Of the 42 patients who were independent of both RBC and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post-baseline period.

Researchers evaluated the safety of enasidenib in 214 patients. The median duration of exposure to enasidenib was 4.3 months (range, 0.3 to 23.6).

The most common AEs of any grade (≥20%) were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite.

Serious AEs were reported in 77.1% of patients. The most frequent serious AEs (≥2%) were leukocytosis, diarrhea, nausea, vomiting, decreased appetite, tumor lysis syndrome, and differentiation syndrome.

The 30-day and 60-day mortality rates were 4.2% (9/214) and 11.7% (25/214), respectively.

Photo from Business Wire

The US Food and Drug Administration (FDA) has approved marketing of the oral IDH2 inhibitor enasidenib (IDHIFA®).

The drug is now approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation, as detected by an FDA-approved test.

Enasidenib is available in 50 mg and 100 mg tablets. The recommended dose is 100 mg once daily until disease progression or unacceptable toxicity.

The prescribing information for enasidenib includes a boxed warning that the drug may cause differentiation syndrome, and this adverse event (AE) can be fatal if not treated.

Signs and symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, and hepatic, renal, or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms resolve.

Companion diagnostic

Enasidenib was approved concurrently with the Abbott RealTime™ IDH2 companion diagnostic test, which was approved as an aid in identifying AML patients for treatment with enasidenib.

The FDA granted approval of enasidenib to Celgene Corporation and approval of the RealTime IDH2 Assay to Abbott Laboratories.

Enasidenib is licensed from Agios Pharmaceuticals.

Trial results

The FDA’s approval of enasidenib and the companion diagnostic test was based on data from a phase 1/2 trial (Study AG221-C-001, NCT01915498).

Data from this trial were recently presented at the ASCO 2017 Annual Meeting. However, the definitive data are included in the prescribing information for enasidenib.

The prescribing information includes efficacy data for 199 adults with relapsed/refractory AML and an IDH2 mutation. IDH2 mutations were identified or confirmed by the Abbott RealTime™ IDH2 test.

The 199 patients received enasidenib at a starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage side effects.

The patients’ median age was 68 (range, 19 to 100). They received a median of 2 prior anticancer regimens (range, 1 to 6). More than half (52%) were refractory to previous therapy.

The rate of complete response (CR) or CR with partial hematologic improvement (CRh) was 23% (n=46). The median duration of CR/CRh was 8.2 months (range, 4.3 to 19.4).

For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, 0.5 to 7.5), and the median time to best response of CR/CRh was 3.7 months (range, 0.6 to 11.2).

Among the 157 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 53 (34%) became independent of RBC and platelet transfusions during any 56-day period post-baseline.

Of the 42 patients who were independent of both RBC and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post-baseline period.

Researchers evaluated the safety of enasidenib in 214 patients. The median duration of exposure to enasidenib was 4.3 months (range, 0.3 to 23.6).

The most common AEs of any grade (≥20%) were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite.

Serious AEs were reported in 77.1% of patients. The most frequent serious AEs (≥2%) were leukocytosis, diarrhea, nausea, vomiting, decreased appetite, tumor lysis syndrome, and differentiation syndrome.

The 30-day and 60-day mortality rates were 4.2% (9/214) and 11.7% (25/214), respectively.

Photo from Business Wire

The US Food and Drug Administration (FDA) has approved marketing of the oral IDH2 inhibitor enasidenib (IDHIFA®).

The drug is now approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation, as detected by an FDA-approved test.

Enasidenib is available in 50 mg and 100 mg tablets. The recommended dose is 100 mg once daily until disease progression or unacceptable toxicity.

The prescribing information for enasidenib includes a boxed warning that the drug may cause differentiation syndrome, and this adverse event (AE) can be fatal if not treated.

Signs and symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, and hepatic, renal, or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms resolve.

Companion diagnostic

Enasidenib was approved concurrently with the Abbott RealTime™ IDH2 companion diagnostic test, which was approved as an aid in identifying AML patients for treatment with enasidenib.

The FDA granted approval of enasidenib to Celgene Corporation and approval of the RealTime IDH2 Assay to Abbott Laboratories.

Enasidenib is licensed from Agios Pharmaceuticals.

Trial results

The FDA’s approval of enasidenib and the companion diagnostic test was based on data from a phase 1/2 trial (Study AG221-C-001, NCT01915498).

Data from this trial were recently presented at the ASCO 2017 Annual Meeting. However, the definitive data are included in the prescribing information for enasidenib.

The prescribing information includes efficacy data for 199 adults with relapsed/refractory AML and an IDH2 mutation. IDH2 mutations were identified or confirmed by the Abbott RealTime™ IDH2 test.

The 199 patients received enasidenib at a starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage side effects.

The patients’ median age was 68 (range, 19 to 100). They received a median of 2 prior anticancer regimens (range, 1 to 6). More than half (52%) were refractory to previous therapy.

The rate of complete response (CR) or CR with partial hematologic improvement (CRh) was 23% (n=46). The median duration of CR/CRh was 8.2 months (range, 4.3 to 19.4).

For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, 0.5 to 7.5), and the median time to best response of CR/CRh was 3.7 months (range, 0.6 to 11.2).

Among the 157 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 53 (34%) became independent of RBC and platelet transfusions during any 56-day period post-baseline.

Of the 42 patients who were independent of both RBC and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post-baseline period.

Researchers evaluated the safety of enasidenib in 214 patients. The median duration of exposure to enasidenib was 4.3 months (range, 0.3 to 23.6).

The most common AEs of any grade (≥20%) were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite.

Serious AEs were reported in 77.1% of patients. The most frequent serious AEs (≥2%) were leukocytosis, diarrhea, nausea, vomiting, decreased appetite, tumor lysis syndrome, and differentiation syndrome.

The 30-day and 60-day mortality rates were 4.2% (9/214) and 11.7% (25/214), respectively.