Leukemia, Myelodysplasia, Transplantation

ATLANTA – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.

At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.

SOURCE: Röllig C et al. ASH 2017 Abstract 721.

ATLANTA – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.

At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.

SOURCE: Röllig C et al. ASH 2017 Abstract 721.

ATLANTA – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.

At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.

SOURCE: Röllig C et al. ASH 2017 Abstract 721.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).

Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.

The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.

The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.

The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.

In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.

The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.

The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.

The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.

The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.

In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.

The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.

Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).

Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.

The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.

The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.

The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.

In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.

The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.

The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.

The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.

The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.

In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.

The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.

Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).

Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.

The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.

The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.

The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.

In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.

The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.

The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.

The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.

The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.

In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.

The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.

Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.

Bosutinib is now approved for the treatment of adults with newly diagnosed chronic phase Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML).

The Food and Drug Administration granted accelerated approval for bosutinib (Bosulif), which is marketed by Pfizer. The approval is based on data from the randomized, multicenter phase 3 BFORE trial of 487 patients with Ph+ newly diagnosed chronic phase CML who received either bosutinib or imatinib 400 mg once daily. Major molecular response at 12 months was 47.2% (95% confidence interval, 40.9-53.4) in the bosutinib arm and 36.9% (95% CI, 30.8-43.0) in the imatinib arm (two-sided P = .0200).

[email protected]

Bosutinib is now approved for the treatment of adults with newly diagnosed chronic phase Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML).

The Food and Drug Administration granted accelerated approval for bosutinib (Bosulif), which is marketed by Pfizer. The approval is based on data from the randomized, multicenter phase 3 BFORE trial of 487 patients with Ph+ newly diagnosed chronic phase CML who received either bosutinib or imatinib 400 mg once daily. Major molecular response at 12 months was 47.2% (95% confidence interval, 40.9-53.4) in the bosutinib arm and 36.9% (95% CI, 30.8-43.0) in the imatinib arm (two-sided P = .0200).

[email protected]

Bosutinib is now approved for the treatment of adults with newly diagnosed chronic phase Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML).

The Food and Drug Administration granted accelerated approval for bosutinib (Bosulif), which is marketed by Pfizer. The approval is based on data from the randomized, multicenter phase 3 BFORE trial of 487 patients with Ph+ newly diagnosed chronic phase CML who received either bosutinib or imatinib 400 mg once daily. Major molecular response at 12 months was 47.2% (95% confidence interval, 40.9-53.4) in the bosutinib arm and 36.9% (95% CI, 30.8-43.0) in the imatinib arm (two-sided P = .0200).

[email protected]

Lab mouse

Chemotherapy for acute myeloid leukemia (AML) might be improved by the addition of deferoxamine, according to preclinical research published in Cell Stem Cell.

Researchers found that, when certain areas of the bone marrow are overtaken by AML cells, hematopoietic stem cells (HSCs) are lost, and the delivery of chemotherapy may be compromised.

However, the team also discovered that deferoxamine, a drug already approved to treat iron overload, can protect these areas of the bone marrow, allowing HSCs to survive and improving the efficacy of chemotherapy.

“Since the drug is already approved for human use for a different condition, we already know that it is safe,” said study author Cristina Lo Celso, PhD, of Imperial College London in the UK.

“We still need to test it in the context of leukemia and chemotherapy, but, because it is already in use, we can progress to clinical trials much quicker than we could with a brand-new drug.”

For the current study, Dr Lo Celso and her colleagues used intravital microscopy to study AML cells, healthy hematopoietic cells, and the bone marrow microenvironment in mice.

The researchers found the endosteal microenvironment was hit particularly hard by AML. Specifically, AML progression led to endosteal remodeling, with AML cells degrading endosteal endothelium, stromal cells, and osteoblastic cells.

This remodeling resulted in the loss of nonleukemic HSCs, which hindered hematopoiesis. However, preserving endosteal vessels prevented the loss of HSCs.

Previous research had shown that deferoxamine could induce endosteal vessel expansion through enhancement of hypoxia-inducible factor 1a stability and activity. So the researchers administered deferoxamine to mice with AML.

The drug had a protective effect on endosteal vessels, which were able to support healthy HSCs and improve HSC homing.

The researchers also found that enhanced endosteal vessels improved the efficacy of chemotherapy (cytarabine and doxorubicin) in mice with AML.

The team compared Fbxw7^iΔEC-mutant mice, in which the administration of tamoxifen increases the number of endosteal vessels and arterioles, to control mice. Both sets of mice had AML.

After confirming the mutant mice had increased numbers of endosteal vessels, the researchers treated the mutant mice and controls with cytarabine and doxorubicin.

Both sets of mice had significant chemotherapy-induced damage to the bone marrow vasculature, including endosteal vessels.

However, after treatment, the Fbxw7^iΔEC-mutant mice had lower numbers of surviving AML cells in the bone marrow, delayed relapse, and longer survival than control mice.

The researchers therefore concluded that rescuing endosteal vessels before starting chemotherapy can improve the efficacy of treatment in AML.

“Our work suggests that therapies targeting these blood vessels may improve existing therapeutic regimens for AML and perhaps other leukemias too,” said study author Delfim Duarte, MD, of Imperial College London.

Based on this work, the researchers are hoping to start trials of deferoxamine in patients with AML.

Lab mouse

Chemotherapy for acute myeloid leukemia (AML) might be improved by the addition of deferoxamine, according to preclinical research published in Cell Stem Cell.

Researchers found that, when certain areas of the bone marrow are overtaken by AML cells, hematopoietic stem cells (HSCs) are lost, and the delivery of chemotherapy may be compromised.

However, the team also discovered that deferoxamine, a drug already approved to treat iron overload, can protect these areas of the bone marrow, allowing HSCs to survive and improving the efficacy of chemotherapy.

“Since the drug is already approved for human use for a different condition, we already know that it is safe,” said study author Cristina Lo Celso, PhD, of Imperial College London in the UK.

“We still need to test it in the context of leukemia and chemotherapy, but, because it is already in use, we can progress to clinical trials much quicker than we could with a brand-new drug.”

For the current study, Dr Lo Celso and her colleagues used intravital microscopy to study AML cells, healthy hematopoietic cells, and the bone marrow microenvironment in mice.

The researchers found the endosteal microenvironment was hit particularly hard by AML. Specifically, AML progression led to endosteal remodeling, with AML cells degrading endosteal endothelium, stromal cells, and osteoblastic cells.

This remodeling resulted in the loss of nonleukemic HSCs, which hindered hematopoiesis. However, preserving endosteal vessels prevented the loss of HSCs.

Previous research had shown that deferoxamine could induce endosteal vessel expansion through enhancement of hypoxia-inducible factor 1a stability and activity. So the researchers administered deferoxamine to mice with AML.

The drug had a protective effect on endosteal vessels, which were able to support healthy HSCs and improve HSC homing.

The researchers also found that enhanced endosteal vessels improved the efficacy of chemotherapy (cytarabine and doxorubicin) in mice with AML.

The team compared Fbxw7^iΔEC-mutant mice, in which the administration of tamoxifen increases the number of endosteal vessels and arterioles, to control mice. Both sets of mice had AML.

After confirming the mutant mice had increased numbers of endosteal vessels, the researchers treated the mutant mice and controls with cytarabine and doxorubicin.

Both sets of mice had significant chemotherapy-induced damage to the bone marrow vasculature, including endosteal vessels.

However, after treatment, the Fbxw7^iΔEC-mutant mice had lower numbers of surviving AML cells in the bone marrow, delayed relapse, and longer survival than control mice.

The researchers therefore concluded that rescuing endosteal vessels before starting chemotherapy can improve the efficacy of treatment in AML.

“Our work suggests that therapies targeting these blood vessels may improve existing therapeutic regimens for AML and perhaps other leukemias too,” said study author Delfim Duarte, MD, of Imperial College London.

Based on this work, the researchers are hoping to start trials of deferoxamine in patients with AML.

Lab mouse

Chemotherapy for acute myeloid leukemia (AML) might be improved by the addition of deferoxamine, according to preclinical research published in Cell Stem Cell.

Researchers found that, when certain areas of the bone marrow are overtaken by AML cells, hematopoietic stem cells (HSCs) are lost, and the delivery of chemotherapy may be compromised.

However, the team also discovered that deferoxamine, a drug already approved to treat iron overload, can protect these areas of the bone marrow, allowing HSCs to survive and improving the efficacy of chemotherapy.

“Since the drug is already approved for human use for a different condition, we already know that it is safe,” said study author Cristina Lo Celso, PhD, of Imperial College London in the UK.

“We still need to test it in the context of leukemia and chemotherapy, but, because it is already in use, we can progress to clinical trials much quicker than we could with a brand-new drug.”

For the current study, Dr Lo Celso and her colleagues used intravital microscopy to study AML cells, healthy hematopoietic cells, and the bone marrow microenvironment in mice.

The researchers found the endosteal microenvironment was hit particularly hard by AML. Specifically, AML progression led to endosteal remodeling, with AML cells degrading endosteal endothelium, stromal cells, and osteoblastic cells.

This remodeling resulted in the loss of nonleukemic HSCs, which hindered hematopoiesis. However, preserving endosteal vessels prevented the loss of HSCs.

Previous research had shown that deferoxamine could induce endosteal vessel expansion through enhancement of hypoxia-inducible factor 1a stability and activity. So the researchers administered deferoxamine to mice with AML.

The drug had a protective effect on endosteal vessels, which were able to support healthy HSCs and improve HSC homing.

The researchers also found that enhanced endosteal vessels improved the efficacy of chemotherapy (cytarabine and doxorubicin) in mice with AML.

The team compared Fbxw7^iΔEC-mutant mice, in which the administration of tamoxifen increases the number of endosteal vessels and arterioles, to control mice. Both sets of mice had AML.

After confirming the mutant mice had increased numbers of endosteal vessels, the researchers treated the mutant mice and controls with cytarabine and doxorubicin.

Both sets of mice had significant chemotherapy-induced damage to the bone marrow vasculature, including endosteal vessels.

However, after treatment, the Fbxw7^iΔEC-mutant mice had lower numbers of surviving AML cells in the bone marrow, delayed relapse, and longer survival than control mice.

The researchers therefore concluded that rescuing endosteal vessels before starting chemotherapy can improve the efficacy of treatment in AML.

“Our work suggests that therapies targeting these blood vessels may improve existing therapeutic regimens for AML and perhaps other leukemias too,” said study author Delfim Duarte, MD, of Imperial College London.

Based on this work, the researchers are hoping to start trials of deferoxamine in patients with AML.

ATLANTA – In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.

An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.

SOURCE: Seymour J et al. ASH 2017 LBA-2.

ATLANTA – In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.

An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.

SOURCE: Seymour J et al. ASH 2017 LBA-2.

ATLANTA – In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.

An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.

SOURCE: Seymour J et al. ASH 2017 LBA-2.

The Food and Drug Administration has updated the label of nilotinib (Tasigna) with information on how to discontinue use of the drug for patients who meet certain criteria. Nilotinib, a kinase inhibitor that blocks the BCR-ABL protein that promotes abnormal cell growth, was originally approved in 2007 and was indicated for use in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). In accordance with the new label update, patients who have early phase CML, have been using nilotinib for 3 years or more, and whose leukemia has responded to treatment according to a test that has received FDA marketing authorization, may be eligible to discontinue use of nilotinib.

The information that led to the FDA approved label update was based on two single-arm trials of patients with chronic phase Ph+ CML. The trial measured the length of time patients were able to discontinue use of nilotinib without leukemia returning, and who had entered treatment-free remission (TFR). In the first trial, among 190 newly diagnosed CML patients who discontinued taking nilotinib after using the drug for 3 or more years, 51.6% were still in TFR after about 1 year (48 weeks) and 48.9% were still in TFR after nearly 2 years (96 weeks). Similar results were seen in the second trial, among 126 patients, with 57.9% in TFR after about a year (48 weeks) and 53.2% in TFR after approximately 2 years (96 weeks).

An important element of these trials was regular monitoring of specific RNA information that specifies the level of BCR-ABL protein in the blood using a diagnostic test that has received FDA marketing authorization. Monitoring with a test that accurately detects the reductions of RNA information in the blood with accuracy and precision is critical in discontinuing the use of nilotinib. This monitoring will allow physicians to detect the first signs of relapse.

“Patients diagnosed with CML generally face a lifetime of treatment to keep their leukemia from growing or recurring,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval shows that some patients may be able to stop treatment with Tasigna altogether if they are showing a strong response to therapy. While we welcome this progress in patient care, it’s important to note that any discontinuation of treatment still means patients must be regularly monitored for disease recurrence,” Dr. Pazdur said in the FDA statement.

Common side effects after discontinuing use of nilotinib include body aches and pain in the bones and extremities. Severe side effects of taking nilotinib can include myelosuppression, blockages in the heart and arteries, and inflammation of the pancreas. Severe liver damage can also occur.

Severe side effects typically associated with nilotinib administration occurred less frequently in patients who discontinued the drug. However, the long-term outcomes of patients discontinuing versus continuing treatment are unknown at this time, the FDA noted.

[email protected]

The Food and Drug Administration has updated the label of nilotinib (Tasigna) with information on how to discontinue use of the drug for patients who meet certain criteria. Nilotinib, a kinase inhibitor that blocks the BCR-ABL protein that promotes abnormal cell growth, was originally approved in 2007 and was indicated for use in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). In accordance with the new label update, patients who have early phase CML, have been using nilotinib for 3 years or more, and whose leukemia has responded to treatment according to a test that has received FDA marketing authorization, may be eligible to discontinue use of nilotinib.

The information that led to the FDA approved label update was based on two single-arm trials of patients with chronic phase Ph+ CML. The trial measured the length of time patients were able to discontinue use of nilotinib without leukemia returning, and who had entered treatment-free remission (TFR). In the first trial, among 190 newly diagnosed CML patients who discontinued taking nilotinib after using the drug for 3 or more years, 51.6% were still in TFR after about 1 year (48 weeks) and 48.9% were still in TFR after nearly 2 years (96 weeks). Similar results were seen in the second trial, among 126 patients, with 57.9% in TFR after about a year (48 weeks) and 53.2% in TFR after approximately 2 years (96 weeks).

An important element of these trials was regular monitoring of specific RNA information that specifies the level of BCR-ABL protein in the blood using a diagnostic test that has received FDA marketing authorization. Monitoring with a test that accurately detects the reductions of RNA information in the blood with accuracy and precision is critical in discontinuing the use of nilotinib. This monitoring will allow physicians to detect the first signs of relapse.

“Patients diagnosed with CML generally face a lifetime of treatment to keep their leukemia from growing or recurring,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval shows that some patients may be able to stop treatment with Tasigna altogether if they are showing a strong response to therapy. While we welcome this progress in patient care, it’s important to note that any discontinuation of treatment still means patients must be regularly monitored for disease recurrence,” Dr. Pazdur said in the FDA statement.

Common side effects after discontinuing use of nilotinib include body aches and pain in the bones and extremities. Severe side effects of taking nilotinib can include myelosuppression, blockages in the heart and arteries, and inflammation of the pancreas. Severe liver damage can also occur.

Severe side effects typically associated with nilotinib administration occurred less frequently in patients who discontinued the drug. However, the long-term outcomes of patients discontinuing versus continuing treatment are unknown at this time, the FDA noted.

[email protected]

The Food and Drug Administration has updated the label of nilotinib (Tasigna) with information on how to discontinue use of the drug for patients who meet certain criteria. Nilotinib, a kinase inhibitor that blocks the BCR-ABL protein that promotes abnormal cell growth, was originally approved in 2007 and was indicated for use in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). In accordance with the new label update, patients who have early phase CML, have been using nilotinib for 3 years or more, and whose leukemia has responded to treatment according to a test that has received FDA marketing authorization, may be eligible to discontinue use of nilotinib.

The information that led to the FDA approved label update was based on two single-arm trials of patients with chronic phase Ph+ CML. The trial measured the length of time patients were able to discontinue use of nilotinib without leukemia returning, and who had entered treatment-free remission (TFR). In the first trial, among 190 newly diagnosed CML patients who discontinued taking nilotinib after using the drug for 3 or more years, 51.6% were still in TFR after about 1 year (48 weeks) and 48.9% were still in TFR after nearly 2 years (96 weeks). Similar results were seen in the second trial, among 126 patients, with 57.9% in TFR after about a year (48 weeks) and 53.2% in TFR after approximately 2 years (96 weeks).

An important element of these trials was regular monitoring of specific RNA information that specifies the level of BCR-ABL protein in the blood using a diagnostic test that has received FDA marketing authorization. Monitoring with a test that accurately detects the reductions of RNA information in the blood with accuracy and precision is critical in discontinuing the use of nilotinib. This monitoring will allow physicians to detect the first signs of relapse.

“Patients diagnosed with CML generally face a lifetime of treatment to keep their leukemia from growing or recurring,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval shows that some patients may be able to stop treatment with Tasigna altogether if they are showing a strong response to therapy. While we welcome this progress in patient care, it’s important to note that any discontinuation of treatment still means patients must be regularly monitored for disease recurrence,” Dr. Pazdur said in the FDA statement.

Common side effects after discontinuing use of nilotinib include body aches and pain in the bones and extremities. Severe side effects of taking nilotinib can include myelosuppression, blockages in the heart and arteries, and inflammation of the pancreas. Severe liver damage can also occur.

Severe side effects typically associated with nilotinib administration occurred less frequently in patients who discontinued the drug. However, the long-term outcomes of patients discontinuing versus continuing treatment are unknown at this time, the FDA noted.

[email protected]

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to CG’806 for the treatment of patients with acute myeloid leukemia (AML).

CG’806 is an oral, first-in-class pan-FLT3/pan-BTK inhibitor being developed by Aptose Biosciences Inc.

In preclinical studies, CG’806 inhibited all wild-type and mutant forms of FLT3 tested, suppressed multiple oncogenic pathways operative in AML, and eliminated AML tumors (without toxicity) in murine xenograft models.

In addition, CG’806 demonstrated non-covalent inhibition of the wild-type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinases operative in B-cell malignancies.

Preclinical results with CG’806 were presented as posters at the AACR conference “Hematologic Malignancies: Translating Discoveries to Novel Therapies,” which took place last May.

“Results from non-clinical studies that we and our research collaborators have generated are promising and give reason for our eagerness to begin clinical trials in both AML and B-cell malignancies in 2018,” said William G. Rice, PhD, chairman, president, and chief executive officer at Aptose.

“We are pleased that the FDA has recognized the unique potential of CG’806 to address AML and has assigned CG’806 the status of orphan drug designation.”

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.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to CG’806 for the treatment of patients with acute myeloid leukemia (AML).

CG’806 is an oral, first-in-class pan-FLT3/pan-BTK inhibitor being developed by Aptose Biosciences Inc.

In preclinical studies, CG’806 inhibited all wild-type and mutant forms of FLT3 tested, suppressed multiple oncogenic pathways operative in AML, and eliminated AML tumors (without toxicity) in murine xenograft models.

In addition, CG’806 demonstrated non-covalent inhibition of the wild-type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinases operative in B-cell malignancies.

Preclinical results with CG’806 were presented as posters at the AACR conference “Hematologic Malignancies: Translating Discoveries to Novel Therapies,” which took place last May.

“Results from non-clinical studies that we and our research collaborators have generated are promising and give reason for our eagerness to begin clinical trials in both AML and B-cell malignancies in 2018,” said William G. Rice, PhD, chairman, president, and chief executive officer at Aptose.

“We are pleased that the FDA has recognized the unique potential of CG’806 to address AML and has assigned CG’806 the status of orphan drug designation.”

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.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to CG’806 for the treatment of patients with acute myeloid leukemia (AML).

CG’806 is an oral, first-in-class pan-FLT3/pan-BTK inhibitor being developed by Aptose Biosciences Inc.

In preclinical studies, CG’806 inhibited all wild-type and mutant forms of FLT3 tested, suppressed multiple oncogenic pathways operative in AML, and eliminated AML tumors (without toxicity) in murine xenograft models.

In addition, CG’806 demonstrated non-covalent inhibition of the wild-type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinases operative in B-cell malignancies.

Preclinical results with CG’806 were presented as posters at the AACR conference “Hematologic Malignancies: Translating Discoveries to Novel Therapies,” which took place last May.

“Results from non-clinical studies that we and our research collaborators have generated are promising and give reason for our eagerness to begin clinical trials in both AML and B-cell malignancies in 2018,” said William G. Rice, PhD, chairman, president, and chief executive officer at Aptose.

“We are pleased that the FDA has recognized the unique potential of CG’806 to address AML and has assigned CG’806 the status of orphan drug designation.”

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.

Image by Difu Wu

The US Food and Drug Administration (FDA) has approved an update to the product label for nilotinib (Tasigna) that includes information about how to discontinue the drug in certain patients.

Nilotinib, which was first approved by the FDA in 2007, is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML).

The updated prescribing information for the drug now outlines which of these patients may be eligible to stop receiving nilotinib.

Patients with chronic phase, Ph+ CML who have been taking nilotinib for 3 years or more (as first-line treatment or after failure with imatinib) and have achieved a sustained deep molecular response may be eligible to stop treatment.

Patients must have maintained a molecular response of at least MR4.0 for 1 year prior to discontinuation and achieved an MR4.5 at their last assessment.

Patients must have typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), no history of accelerated phase or blast crisis, and no past attempts at treatment discontinuation that resulted in relapse.

After discontinuation, patients must be monitored for possible loss of major molecular response (MMR). BCR-ABL transcript levels must be assessed and a complete blood count with differential performed monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter.

BCR-ABL transcript levels should be measured using the MolecularMD MRDxTM BCR-ABL test, an FDA-authorized companion diagnostic validated to measure down to MR4.5.

If patients lose MMR, they must restart nilotinib within 4 weeks and receive the dose level they were receiving prior to discontinuation.

BCR-ABL transcript levels should be monitored every 2 weeks until they are lower than MMR for 4 consecutive measurements. Patients can then return to the original monitoring schedule.

The update of nilotinib’s label to include this information was based on results from 2 single-arm trials—ENESTfreedom and ENESTop.

ENESTfreedom

This phase 2 trial included 215 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 190 patients who had achieved a response of MR4.5 with nilotinib as first-line treatment. The patients had sustained deep molecular response for 1 year prior to treatment discontinuation.

Ninety-six weeks after stopping treatment, 48.9% of patients were still in MMR, also known as treatment-free remission (TFR).

Of the 88 patients who restarted nilotinib due to loss of MMR by the cut-off date, 98.9% were able to regain MMR (n=87). One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with nilotinib. Eighty-one patients (92.0%) regained MR4.5 by the cut-off date.

Common adverse events (AEs) in patients who discontinued nilotinib included musculoskeletal symptoms such as body aches, bone pain, and pain in extremities. However, these AEs decreased over time.

The incidence of musculoskeletal pain-related AEs decreased from 34.0% to 9.0% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 17.0% during the treatment consolidation phase.

ENESTop

This phase 2 trial included 163 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 126 patients who had previously received imatinib, then switched to nilotinib and sustained a molecular response for 1 year prior to stopping nilotinib.

At 96 weeks, 53.2% of patients were still in TFR.

Fifty-six patients with confirmed loss of MR4.0 or loss of MMR restarted nilotinib by the cut-off date. Of these patients, 92.9% (n=52) regained both MR4.0 and MR4.5.

As in ENESTfreedom, patients who discontinued nilotinib had musculoskeletal symptoms that decreased over time.

The incidence of musculoskeletal pain-related AEs decreased from 47.9% to 15.1% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 13.7% during the treatment consolidation phase.

Additional data from ENESTop and ENESTfreedom, as well as the recommendations for stopping nilotinib, are included in the updated prescribing information, which is available at https://www.us.tasigna.com/.

Image by Difu Wu

The US Food and Drug Administration (FDA) has approved an update to the product label for nilotinib (Tasigna) that includes information about how to discontinue the drug in certain patients.

Nilotinib, which was first approved by the FDA in 2007, is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML).

The updated prescribing information for the drug now outlines which of these patients may be eligible to stop receiving nilotinib.

Patients with chronic phase, Ph+ CML who have been taking nilotinib for 3 years or more (as first-line treatment or after failure with imatinib) and have achieved a sustained deep molecular response may be eligible to stop treatment.

Patients must have maintained a molecular response of at least MR4.0 for 1 year prior to discontinuation and achieved an MR4.5 at their last assessment.

Patients must have typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), no history of accelerated phase or blast crisis, and no past attempts at treatment discontinuation that resulted in relapse.

After discontinuation, patients must be monitored for possible loss of major molecular response (MMR). BCR-ABL transcript levels must be assessed and a complete blood count with differential performed monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter.

BCR-ABL transcript levels should be measured using the MolecularMD MRDxTM BCR-ABL test, an FDA-authorized companion diagnostic validated to measure down to MR4.5.

If patients lose MMR, they must restart nilotinib within 4 weeks and receive the dose level they were receiving prior to discontinuation.

BCR-ABL transcript levels should be monitored every 2 weeks until they are lower than MMR for 4 consecutive measurements. Patients can then return to the original monitoring schedule.

The update of nilotinib’s label to include this information was based on results from 2 single-arm trials—ENESTfreedom and ENESTop.

ENESTfreedom

This phase 2 trial included 215 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 190 patients who had achieved a response of MR4.5 with nilotinib as first-line treatment. The patients had sustained deep molecular response for 1 year prior to treatment discontinuation.

Ninety-six weeks after stopping treatment, 48.9% of patients were still in MMR, also known as treatment-free remission (TFR).

Of the 88 patients who restarted nilotinib due to loss of MMR by the cut-off date, 98.9% were able to regain MMR (n=87). One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with nilotinib. Eighty-one patients (92.0%) regained MR4.5 by the cut-off date.

Common adverse events (AEs) in patients who discontinued nilotinib included musculoskeletal symptoms such as body aches, bone pain, and pain in extremities. However, these AEs decreased over time.

The incidence of musculoskeletal pain-related AEs decreased from 34.0% to 9.0% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 17.0% during the treatment consolidation phase.

ENESTop

This phase 2 trial included 163 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 126 patients who had previously received imatinib, then switched to nilotinib and sustained a molecular response for 1 year prior to stopping nilotinib.

At 96 weeks, 53.2% of patients were still in TFR.

Fifty-six patients with confirmed loss of MR4.0 or loss of MMR restarted nilotinib by the cut-off date. Of these patients, 92.9% (n=52) regained both MR4.0 and MR4.5.

As in ENESTfreedom, patients who discontinued nilotinib had musculoskeletal symptoms that decreased over time.

The incidence of musculoskeletal pain-related AEs decreased from 47.9% to 15.1% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 13.7% during the treatment consolidation phase.

Additional data from ENESTop and ENESTfreedom, as well as the recommendations for stopping nilotinib, are included in the updated prescribing information, which is available at https://www.us.tasigna.com/.

Image by Difu Wu

The US Food and Drug Administration (FDA) has approved an update to the product label for nilotinib (Tasigna) that includes information about how to discontinue the drug in certain patients.

Nilotinib, which was first approved by the FDA in 2007, is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML).

The updated prescribing information for the drug now outlines which of these patients may be eligible to stop receiving nilotinib.

Patients with chronic phase, Ph+ CML who have been taking nilotinib for 3 years or more (as first-line treatment or after failure with imatinib) and have achieved a sustained deep molecular response may be eligible to stop treatment.

Patients must have maintained a molecular response of at least MR4.0 for 1 year prior to discontinuation and achieved an MR4.5 at their last assessment.

Patients must have typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), no history of accelerated phase or blast crisis, and no past attempts at treatment discontinuation that resulted in relapse.

After discontinuation, patients must be monitored for possible loss of major molecular response (MMR). BCR-ABL transcript levels must be assessed and a complete blood count with differential performed monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter.

BCR-ABL transcript levels should be measured using the MolecularMD MRDxTM BCR-ABL test, an FDA-authorized companion diagnostic validated to measure down to MR4.5.

If patients lose MMR, they must restart nilotinib within 4 weeks and receive the dose level they were receiving prior to discontinuation.

BCR-ABL transcript levels should be monitored every 2 weeks until they are lower than MMR for 4 consecutive measurements. Patients can then return to the original monitoring schedule.

The update of nilotinib’s label to include this information was based on results from 2 single-arm trials—ENESTfreedom and ENESTop.

ENESTfreedom

This phase 2 trial included 215 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 190 patients who had achieved a response of MR4.5 with nilotinib as first-line treatment. The patients had sustained deep molecular response for 1 year prior to treatment discontinuation.

Ninety-six weeks after stopping treatment, 48.9% of patients were still in MMR, also known as treatment-free remission (TFR).

Of the 88 patients who restarted nilotinib due to loss of MMR by the cut-off date, 98.9% were able to regain MMR (n=87). One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with nilotinib. Eighty-one patients (92.0%) regained MR4.5 by the cut-off date.

Common adverse events (AEs) in patients who discontinued nilotinib included musculoskeletal symptoms such as body aches, bone pain, and pain in extremities. However, these AEs decreased over time.

The incidence of musculoskeletal pain-related AEs decreased from 34.0% to 9.0% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 17.0% during the treatment consolidation phase.

ENESTop

This phase 2 trial included 163 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 126 patients who had previously received imatinib, then switched to nilotinib and sustained a molecular response for 1 year prior to stopping nilotinib.

At 96 weeks, 53.2% of patients were still in TFR.

Fifty-six patients with confirmed loss of MR4.0 or loss of MMR restarted nilotinib by the cut-off date. Of these patients, 92.9% (n=52) regained both MR4.0 and MR4.5.

As in ENESTfreedom, patients who discontinued nilotinib had musculoskeletal symptoms that decreased over time.

The incidence of musculoskeletal pain-related AEs decreased from 47.9% to 15.1% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 13.7% during the treatment consolidation phase.

Additional data from ENESTop and ENESTfreedom, as well as the recommendations for stopping nilotinib, are included in the updated prescribing information, which is available at https://www.us.tasigna.com/.

John F. Seymour, MBBS, PhD

ATLANTA—The combination of venetoclax and rituximab (VR) should be a standard treatment option for adults with relapsed/refractory chronic lymphocytic leukemia (CLL), according to a speaker at the 2017 ASH Annual Meeting.

Data from the phase 3 MURANO study showed that patients with relapsed/refractory CLL who received VR had significantly longer progression-free survival (PFS) than those who received bendamustine and rituximab (BR).

In addition, “secondary endpoints were consistently in favor of venetoclax-rituximab,” said study investigator John F. Seymour, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Adverse events (AEs) were largely consistent with the known safety profiles of the drugs studied, but tumor lysis syndrome (TLS) was infrequent and occurred at a similar frequency in both treatment arms.

“Thus, overall, I believe venetoclax and rituximab should be considered as a suitable standard therapeutic option in patients with relapsed/refractory CLL,” Dr Seymour said.

It is important to note, however, that patients in the VR arm of this study could receive venetoclax for up to 2 years, whereas patients in the BR arm received study treatment for a maximum of six 28-day cycles.

Dr Seymour presented results from MURANO as a late-breaking abstract at ASH (LBA-2). The study was sponsored by Hoffman-La Roche and AbbVie.

MURANO enrolled 389 CLL patients who had received 1 to 3 prior therapies. Patients were randomized to receive VR (n=194) or BR (n=195). Baseline characteristics were similar between the treatment arms.

In both arms, patients received a single monthly dose of rituximab for 6 cycles. The first dose was 375 mg/m², and all subsequent doses were 500 mg/m².

In the VR arm, patients received a 4-week or 5-week dose ramp-up of venetoclax from 20 mg to 400 mg daily. This was intended to mitigate the risk of TLS, which has been observed in previous studies of venetoclax.

Patients in the VR arm continued with daily venetoclax at 400 mg for a maximum of 2 years or until disease progression or cessation due to toxicity. They started receiving rituximab after the ramp-up period (at week 6).

In the BR arm, patients received bendamustine at 70 mg/m² on days 1 and 2 of each 28-day cycle for 6 cycles. Patients could proceed to subsequent therapy if they progressed.

The median follow-up was 23.8 months (range, 0-37.4 months).

Twenty-five percent of patients in the VR arm and 17% in the BR arm discontinued treatment ahead of schedule. Reasons for discontinuation (in the VR and BR arms, respectively) were disease progression (5% and 3%), AEs (12% and 6%), death (1% and 2%), and “other” (6% and 7%).

Survival

The study’s primary endpoint was investigator-assessed PFS. PFS according to an independent review committee (IRC) was a secondary endpoint.

According to investigators, the median PFS was not reached in the VR arm and was 17.0 months in the BR arm (hazard ratio [HR]=0.17, P<0.0001). According to the IRC, the median PFS was not reached in the VR arm and was 18.1 months in the BR arm (HR=0.17, P<0.0001).

According to investigators, the estimated PFS at 24 months was 84.9% in the VR arm and 36.3% in the BR arm. According to the IRC, the 24-month PFS was 82.8% and 37.4%, respectively.

The benefit with VR was consistent across subgroups. Patients had a PFS benefit regardless of their number of prior therapies, deletion 17p status, TP53 mutational status, baseline IGHV mutational status, and whether they had relapsed or refractory disease.

Dr Seymour acknowledged that the differences in treatment duration between the BR and VR arms may have affected the interpretation of these results.

“[T]he treatment duration differed, although, of course, the capacity to deliver more than 6 cycles of bendamustine-rituximab would have been problematic,” he said. “There is some data that antibody treatment may prolong progression-free survival. However, when this study was designed, in 2013, that data was certainly not available. And I believe, currently, maintenance antibody is not an accepted standard of treatment.”

The median overall survival (OS) was not reached in either treatment arm. The 1-year OS rate was 95.9% in the VR arm and 91.1% in the BR arm. The 2-year OS rate was 91.9% and 86.6%, respectively (HR=0.48, P=0.0186).

“[W]ith median follow-up of just on 2 years, there is already a clinically meaningful difference [in OS between the treatment arms],” Dr Seymour said.

“This is not attributable to any difference in availability of novel therapies. Of the 54 patients who received subsequent therapy after progression on the bendamustine-rituximab arm, 40 of those received novel targeted agents.”

Response and MRD

According to investigators, the overall response rate was 93.3% (181/194) in the VR arm and 67.7% (312/195) in the BR arm (P<0.0001). According to the IRC, the overall response rate was 92.3% (179/194) and 72.3% (141/195), respectively (P<0.0001).

According to investigators, the rate of complete response (CR) or CR with incomplete marrow recovery (CRi) was 26.8% (n=52) in the VR arm and 8.2% (n=16) in the BR arm. According to the IRC, the CR/CRi rate was 8.2% (n=16) and 3.6% (n=7), respectively.

Dr Seymour acknowledged the differences in CR/CRi between investigator and IRC assessments. He said 28 of the 42 discrepancies in the VR arm “were attributable to residual CT scan nodal abnormalities in the 16- to 30-mm size.” However, he also noted that 88% of these patients were negative for minimal residual disease (MRD) in the peripheral blood at that time point.

MRD was assessed every 3 months. Patients were counted as MRD-positive if they were positive by either allele-specific oligonucleotide polymerase chain reaction or multicolor flow cytometry. Patients were also counted as MRD-positive if there was a failure to collect a sample.

The proportion of patients who were MRD-negative in the VR and BR arms, respectively, was:

• 45% and 6% at 4 months
• 62% and 13% at 9 months
• 60% and 10% at 12 months
• 57% and 9% at 15 months
• 60% and 5% at 18 months.

Dr Seymour pointed out that 65 patients in the VR arm surpassed the maximum treatment duration for venetoclax (2 years) and therefore stopped receiving the drug, but only 12 of these patients have follow-up beyond 3 months.

“So information about the durability of response after cessation remains immature at the moment,” he said.

Safety

All patients in the VR arm and 98% in the BR arm had at least 1 AE. The rate of serious AEs was 46% and 43%, respectively. The rate of grade 3/4 AEs was 82% and 70%, respectively.

Grade 3/4 AEs with at least a 2% difference in incidence between the treatment arms (in the VR and BR arms, respectively) were neutropenia (58% and 39%), anemia (11% and 14%), thrombocytopenia (6% and 10%), febrile neutropenia (4% and 10%), pneumonia (5% and 8%), infusion-related reactions (2% and 5%), TLS (3% and 1%), hypotension (0% and 3%), hyperglycemia (2% and 0%), and hypogammaglobulinemia (2% and 0%).

The rate of grade 5 AEs was 5% in the VR arm and 6% in the BR arm.

Grade 5 AEs in the VR arm were pneumonia (n=3), sepsis (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1).

Grade 5 AEs in the BR arm included sepsis (n=2), lung cancer (n=2), Listeria sepsis (n=1), Scedosporium infection (n=1), lymphoma (n=1), hemorrhagic stroke (n=1), pulmonary embolism (n=1), acute myeloid leukemia (n=1), and sudden death (n=1).

John F. Seymour, MBBS, PhD

ATLANTA—The combination of venetoclax and rituximab (VR) should be a standard treatment option for adults with relapsed/refractory chronic lymphocytic leukemia (CLL), according to a speaker at the 2017 ASH Annual Meeting.

Data from the phase 3 MURANO study showed that patients with relapsed/refractory CLL who received VR had significantly longer progression-free survival (PFS) than those who received bendamustine and rituximab (BR).

In addition, “secondary endpoints were consistently in favor of venetoclax-rituximab,” said study investigator John F. Seymour, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Adverse events (AEs) were largely consistent with the known safety profiles of the drugs studied, but tumor lysis syndrome (TLS) was infrequent and occurred at a similar frequency in both treatment arms.

“Thus, overall, I believe venetoclax and rituximab should be considered as a suitable standard therapeutic option in patients with relapsed/refractory CLL,” Dr Seymour said.

It is important to note, however, that patients in the VR arm of this study could receive venetoclax for up to 2 years, whereas patients in the BR arm received study treatment for a maximum of six 28-day cycles.

Dr Seymour presented results from MURANO as a late-breaking abstract at ASH (LBA-2). The study was sponsored by Hoffman-La Roche and AbbVie.

MURANO enrolled 389 CLL patients who had received 1 to 3 prior therapies. Patients were randomized to receive VR (n=194) or BR (n=195). Baseline characteristics were similar between the treatment arms.

In both arms, patients received a single monthly dose of rituximab for 6 cycles. The first dose was 375 mg/m², and all subsequent doses were 500 mg/m².

In the VR arm, patients received a 4-week or 5-week dose ramp-up of venetoclax from 20 mg to 400 mg daily. This was intended to mitigate the risk of TLS, which has been observed in previous studies of venetoclax.

Patients in the VR arm continued with daily venetoclax at 400 mg for a maximum of 2 years or until disease progression or cessation due to toxicity. They started receiving rituximab after the ramp-up period (at week 6).

In the BR arm, patients received bendamustine at 70 mg/m² on days 1 and 2 of each 28-day cycle for 6 cycles. Patients could proceed to subsequent therapy if they progressed.

The median follow-up was 23.8 months (range, 0-37.4 months).

Twenty-five percent of patients in the VR arm and 17% in the BR arm discontinued treatment ahead of schedule. Reasons for discontinuation (in the VR and BR arms, respectively) were disease progression (5% and 3%), AEs (12% and 6%), death (1% and 2%), and “other” (6% and 7%).

Survival

The study’s primary endpoint was investigator-assessed PFS. PFS according to an independent review committee (IRC) was a secondary endpoint.

According to investigators, the median PFS was not reached in the VR arm and was 17.0 months in the BR arm (hazard ratio [HR]=0.17, P<0.0001). According to the IRC, the median PFS was not reached in the VR arm and was 18.1 months in the BR arm (HR=0.17, P<0.0001).

According to investigators, the estimated PFS at 24 months was 84.9% in the VR arm and 36.3% in the BR arm. According to the IRC, the 24-month PFS was 82.8% and 37.4%, respectively.

The benefit with VR was consistent across subgroups. Patients had a PFS benefit regardless of their number of prior therapies, deletion 17p status, TP53 mutational status, baseline IGHV mutational status, and whether they had relapsed or refractory disease.

Dr Seymour acknowledged that the differences in treatment duration between the BR and VR arms may have affected the interpretation of these results.

“[T]he treatment duration differed, although, of course, the capacity to deliver more than 6 cycles of bendamustine-rituximab would have been problematic,” he said. “There is some data that antibody treatment may prolong progression-free survival. However, when this study was designed, in 2013, that data was certainly not available. And I believe, currently, maintenance antibody is not an accepted standard of treatment.”

The median overall survival (OS) was not reached in either treatment arm. The 1-year OS rate was 95.9% in the VR arm and 91.1% in the BR arm. The 2-year OS rate was 91.9% and 86.6%, respectively (HR=0.48, P=0.0186).

“[W]ith median follow-up of just on 2 years, there is already a clinically meaningful difference [in OS between the treatment arms],” Dr Seymour said.

“This is not attributable to any difference in availability of novel therapies. Of the 54 patients who received subsequent therapy after progression on the bendamustine-rituximab arm, 40 of those received novel targeted agents.”

Response and MRD

According to investigators, the overall response rate was 93.3% (181/194) in the VR arm and 67.7% (312/195) in the BR arm (P<0.0001). According to the IRC, the overall response rate was 92.3% (179/194) and 72.3% (141/195), respectively (P<0.0001).

According to investigators, the rate of complete response (CR) or CR with incomplete marrow recovery (CRi) was 26.8% (n=52) in the VR arm and 8.2% (n=16) in the BR arm. According to the IRC, the CR/CRi rate was 8.2% (n=16) and 3.6% (n=7), respectively.

Dr Seymour acknowledged the differences in CR/CRi between investigator and IRC assessments. He said 28 of the 42 discrepancies in the VR arm “were attributable to residual CT scan nodal abnormalities in the 16- to 30-mm size.” However, he also noted that 88% of these patients were negative for minimal residual disease (MRD) in the peripheral blood at that time point.

MRD was assessed every 3 months. Patients were counted as MRD-positive if they were positive by either allele-specific oligonucleotide polymerase chain reaction or multicolor flow cytometry. Patients were also counted as MRD-positive if there was a failure to collect a sample.

The proportion of patients who were MRD-negative in the VR and BR arms, respectively, was:

• 45% and 6% at 4 months
• 62% and 13% at 9 months
• 60% and 10% at 12 months
• 57% and 9% at 15 months
• 60% and 5% at 18 months.

Dr Seymour pointed out that 65 patients in the VR arm surpassed the maximum treatment duration for venetoclax (2 years) and therefore stopped receiving the drug, but only 12 of these patients have follow-up beyond 3 months.

“So information about the durability of response after cessation remains immature at the moment,” he said.

Safety

All patients in the VR arm and 98% in the BR arm had at least 1 AE. The rate of serious AEs was 46% and 43%, respectively. The rate of grade 3/4 AEs was 82% and 70%, respectively.

Grade 3/4 AEs with at least a 2% difference in incidence between the treatment arms (in the VR and BR arms, respectively) were neutropenia (58% and 39%), anemia (11% and 14%), thrombocytopenia (6% and 10%), febrile neutropenia (4% and 10%), pneumonia (5% and 8%), infusion-related reactions (2% and 5%), TLS (3% and 1%), hypotension (0% and 3%), hyperglycemia (2% and 0%), and hypogammaglobulinemia (2% and 0%).

The rate of grade 5 AEs was 5% in the VR arm and 6% in the BR arm.

Grade 5 AEs in the VR arm were pneumonia (n=3), sepsis (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1).

Grade 5 AEs in the BR arm included sepsis (n=2), lung cancer (n=2), Listeria sepsis (n=1), Scedosporium infection (n=1), lymphoma (n=1), hemorrhagic stroke (n=1), pulmonary embolism (n=1), acute myeloid leukemia (n=1), and sudden death (n=1).

John F. Seymour, MBBS, PhD

ATLANTA—The combination of venetoclax and rituximab (VR) should be a standard treatment option for adults with relapsed/refractory chronic lymphocytic leukemia (CLL), according to a speaker at the 2017 ASH Annual Meeting.

Data from the phase 3 MURANO study showed that patients with relapsed/refractory CLL who received VR had significantly longer progression-free survival (PFS) than those who received bendamustine and rituximab (BR).

In addition, “secondary endpoints were consistently in favor of venetoclax-rituximab,” said study investigator John F. Seymour, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Adverse events (AEs) were largely consistent with the known safety profiles of the drugs studied, but tumor lysis syndrome (TLS) was infrequent and occurred at a similar frequency in both treatment arms.

“Thus, overall, I believe venetoclax and rituximab should be considered as a suitable standard therapeutic option in patients with relapsed/refractory CLL,” Dr Seymour said.

It is important to note, however, that patients in the VR arm of this study could receive venetoclax for up to 2 years, whereas patients in the BR arm received study treatment for a maximum of six 28-day cycles.

Dr Seymour presented results from MURANO as a late-breaking abstract at ASH (LBA-2). The study was sponsored by Hoffman-La Roche and AbbVie.

MURANO enrolled 389 CLL patients who had received 1 to 3 prior therapies. Patients were randomized to receive VR (n=194) or BR (n=195). Baseline characteristics were similar between the treatment arms.

In both arms, patients received a single monthly dose of rituximab for 6 cycles. The first dose was 375 mg/m², and all subsequent doses were 500 mg/m².

In the VR arm, patients received a 4-week or 5-week dose ramp-up of venetoclax from 20 mg to 400 mg daily. This was intended to mitigate the risk of TLS, which has been observed in previous studies of venetoclax.

Patients in the VR arm continued with daily venetoclax at 400 mg for a maximum of 2 years or until disease progression or cessation due to toxicity. They started receiving rituximab after the ramp-up period (at week 6).

In the BR arm, patients received bendamustine at 70 mg/m² on days 1 and 2 of each 28-day cycle for 6 cycles. Patients could proceed to subsequent therapy if they progressed.

The median follow-up was 23.8 months (range, 0-37.4 months).

Twenty-five percent of patients in the VR arm and 17% in the BR arm discontinued treatment ahead of schedule. Reasons for discontinuation (in the VR and BR arms, respectively) were disease progression (5% and 3%), AEs (12% and 6%), death (1% and 2%), and “other” (6% and 7%).

Survival

The study’s primary endpoint was investigator-assessed PFS. PFS according to an independent review committee (IRC) was a secondary endpoint.

According to investigators, the median PFS was not reached in the VR arm and was 17.0 months in the BR arm (hazard ratio [HR]=0.17, P<0.0001). According to the IRC, the median PFS was not reached in the VR arm and was 18.1 months in the BR arm (HR=0.17, P<0.0001).

According to investigators, the estimated PFS at 24 months was 84.9% in the VR arm and 36.3% in the BR arm. According to the IRC, the 24-month PFS was 82.8% and 37.4%, respectively.

The benefit with VR was consistent across subgroups. Patients had a PFS benefit regardless of their number of prior therapies, deletion 17p status, TP53 mutational status, baseline IGHV mutational status, and whether they had relapsed or refractory disease.

Dr Seymour acknowledged that the differences in treatment duration between the BR and VR arms may have affected the interpretation of these results.

“[T]he treatment duration differed, although, of course, the capacity to deliver more than 6 cycles of bendamustine-rituximab would have been problematic,” he said. “There is some data that antibody treatment may prolong progression-free survival. However, when this study was designed, in 2013, that data was certainly not available. And I believe, currently, maintenance antibody is not an accepted standard of treatment.”

The median overall survival (OS) was not reached in either treatment arm. The 1-year OS rate was 95.9% in the VR arm and 91.1% in the BR arm. The 2-year OS rate was 91.9% and 86.6%, respectively (HR=0.48, P=0.0186).

“[W]ith median follow-up of just on 2 years, there is already a clinically meaningful difference [in OS between the treatment arms],” Dr Seymour said.

“This is not attributable to any difference in availability of novel therapies. Of the 54 patients who received subsequent therapy after progression on the bendamustine-rituximab arm, 40 of those received novel targeted agents.”

Response and MRD

According to investigators, the overall response rate was 93.3% (181/194) in the VR arm and 67.7% (312/195) in the BR arm (P<0.0001). According to the IRC, the overall response rate was 92.3% (179/194) and 72.3% (141/195), respectively (P<0.0001).

According to investigators, the rate of complete response (CR) or CR with incomplete marrow recovery (CRi) was 26.8% (n=52) in the VR arm and 8.2% (n=16) in the BR arm. According to the IRC, the CR/CRi rate was 8.2% (n=16) and 3.6% (n=7), respectively.

Dr Seymour acknowledged the differences in CR/CRi between investigator and IRC assessments. He said 28 of the 42 discrepancies in the VR arm “were attributable to residual CT scan nodal abnormalities in the 16- to 30-mm size.” However, he also noted that 88% of these patients were negative for minimal residual disease (MRD) in the peripheral blood at that time point.

MRD was assessed every 3 months. Patients were counted as MRD-positive if they were positive by either allele-specific oligonucleotide polymerase chain reaction or multicolor flow cytometry. Patients were also counted as MRD-positive if there was a failure to collect a sample.

The proportion of patients who were MRD-negative in the VR and BR arms, respectively, was:

• 45% and 6% at 4 months
• 62% and 13% at 9 months
• 60% and 10% at 12 months
• 57% and 9% at 15 months
• 60% and 5% at 18 months.

Dr Seymour pointed out that 65 patients in the VR arm surpassed the maximum treatment duration for venetoclax (2 years) and therefore stopped receiving the drug, but only 12 of these patients have follow-up beyond 3 months.

“So information about the durability of response after cessation remains immature at the moment,” he said.

Safety

All patients in the VR arm and 98% in the BR arm had at least 1 AE. The rate of serious AEs was 46% and 43%, respectively. The rate of grade 3/4 AEs was 82% and 70%, respectively.

Grade 3/4 AEs with at least a 2% difference in incidence between the treatment arms (in the VR and BR arms, respectively) were neutropenia (58% and 39%), anemia (11% and 14%), thrombocytopenia (6% and 10%), febrile neutropenia (4% and 10%), pneumonia (5% and 8%), infusion-related reactions (2% and 5%), TLS (3% and 1%), hypotension (0% and 3%), hyperglycemia (2% and 0%), and hypogammaglobulinemia (2% and 0%).

The rate of grade 5 AEs was 5% in the VR arm and 6% in the BR arm.

Grade 5 AEs in the VR arm were pneumonia (n=3), sepsis (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1).

Grade 5 AEs in the BR arm included sepsis (n=2), lung cancer (n=2), Listeria sepsis (n=1), Scedosporium infection (n=1), lymphoma (n=1), hemorrhagic stroke (n=1), pulmonary embolism (n=1), acute myeloid leukemia (n=1), and sudden death (n=1).

Image by Difu Wu

The US Food and Drug Administration (FDA) has expanded the approved indication for bosutinib (BOSULIF®).

The tyrosine kinase inhibitor (TKI) is now approved to treat adults with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).

Bosutinib has accelerated approval for this indication. The approval was based on molecular and cytogenetic response rates.

Continued approval may be contingent upon verification and confirmation of clinical benefit in an ongoing, long-term follow-up trial.

Bosutinib was first approved by the FDA in September 2012. At that time, the TKI was approved to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

A 400 mg tablet of bosutinib was recently approved by the FDA, adding to the previously approved 100 mg and 500 mg strengths.

The recommended dose of bosutinib for newly diagnosed patients is 400 mg orally once daily with food.

For patients who are resistant or intolerant to prior TKI therapy, the recommended dose is 500 mg orally once daily with food.

BFORE trial

The approval of bosutinib in adults with newly diagnosed, chronic phase, Ph+ CML was based on the phase 3 BFORE trial. Results from the trial were presented at the 2017 ASCO Annual Meeting.

In this ongoing study, researchers are comparing bosutinib and imatinib as first-line treatment of chronic phase CML.

As of the ASCO presentation, the trial had enrolled 536 patients who were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).

The presentation included results in a modified intent-to-treat population of Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.

Most of the patients were still on therapy at the 12-month mark or beyond—78% in the bosutinib arm and 73.2% in the imatinib arm. The median treatment duration was 14.1 months and 13.8 months, respectively.

At 12 months, the rate of major molecular response was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P=0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).

One patient in the bosutinib arm and 4 in the imatinib arm discontinued treatment due to disease progression, while 12.7% and 8.7%, respectively, discontinued treatment due to drug-related toxicity.

Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%).

Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).

Pfizer and Avillion entered into an exclusive collaborative development agreement in 2014 to conduct the BFORE trial.

Under the terms of the agreement, Avillion provided funding and conducted the trial to generate the clinical data used to support regulatory filings for marketing authorization for bosutinib as first-line treatment for patients with chronic phase, Ph+ CML.

With this approval, Avillion is eligible to receive milestone payments from Pfizer. Pfizer retains all rights to commercialize bosutinib globally.

Image by Difu Wu

The US Food and Drug Administration (FDA) has expanded the approved indication for bosutinib (BOSULIF®).

The tyrosine kinase inhibitor (TKI) is now approved to treat adults with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).

Bosutinib has accelerated approval for this indication. The approval was based on molecular and cytogenetic response rates.

Continued approval may be contingent upon verification and confirmation of clinical benefit in an ongoing, long-term follow-up trial.

Bosutinib was first approved by the FDA in September 2012. At that time, the TKI was approved to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

A 400 mg tablet of bosutinib was recently approved by the FDA, adding to the previously approved 100 mg and 500 mg strengths.

The recommended dose of bosutinib for newly diagnosed patients is 400 mg orally once daily with food.

For patients who are resistant or intolerant to prior TKI therapy, the recommended dose is 500 mg orally once daily with food.

BFORE trial

The approval of bosutinib in adults with newly diagnosed, chronic phase, Ph+ CML was based on the phase 3 BFORE trial. Results from the trial were presented at the 2017 ASCO Annual Meeting.

In this ongoing study, researchers are comparing bosutinib and imatinib as first-line treatment of chronic phase CML.

As of the ASCO presentation, the trial had enrolled 536 patients who were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).

The presentation included results in a modified intent-to-treat population of Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.

Most of the patients were still on therapy at the 12-month mark or beyond—78% in the bosutinib arm and 73.2% in the imatinib arm. The median treatment duration was 14.1 months and 13.8 months, respectively.

At 12 months, the rate of major molecular response was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P=0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).

One patient in the bosutinib arm and 4 in the imatinib arm discontinued treatment due to disease progression, while 12.7% and 8.7%, respectively, discontinued treatment due to drug-related toxicity.

Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%).

Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).

Pfizer and Avillion entered into an exclusive collaborative development agreement in 2014 to conduct the BFORE trial.

Under the terms of the agreement, Avillion provided funding and conducted the trial to generate the clinical data used to support regulatory filings for marketing authorization for bosutinib as first-line treatment for patients with chronic phase, Ph+ CML.

With this approval, Avillion is eligible to receive milestone payments from Pfizer. Pfizer retains all rights to commercialize bosutinib globally.

Image by Difu Wu

The US Food and Drug Administration (FDA) has expanded the approved indication for bosutinib (BOSULIF®).

The tyrosine kinase inhibitor (TKI) is now approved to treat adults with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).

Bosutinib has accelerated approval for this indication. The approval was based on molecular and cytogenetic response rates.

Continued approval may be contingent upon verification and confirmation of clinical benefit in an ongoing, long-term follow-up trial.

Bosutinib was first approved by the FDA in September 2012. At that time, the TKI was approved to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

A 400 mg tablet of bosutinib was recently approved by the FDA, adding to the previously approved 100 mg and 500 mg strengths.

The recommended dose of bosutinib for newly diagnosed patients is 400 mg orally once daily with food.

For patients who are resistant or intolerant to prior TKI therapy, the recommended dose is 500 mg orally once daily with food.

BFORE trial

The approval of bosutinib in adults with newly diagnosed, chronic phase, Ph+ CML was based on the phase 3 BFORE trial. Results from the trial were presented at the 2017 ASCO Annual Meeting.

In this ongoing study, researchers are comparing bosutinib and imatinib as first-line treatment of chronic phase CML.

As of the ASCO presentation, the trial had enrolled 536 patients who were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).

The presentation included results in a modified intent-to-treat population of Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.

Most of the patients were still on therapy at the 12-month mark or beyond—78% in the bosutinib arm and 73.2% in the imatinib arm. The median treatment duration was 14.1 months and 13.8 months, respectively.

At 12 months, the rate of major molecular response was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P=0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).

One patient in the bosutinib arm and 4 in the imatinib arm discontinued treatment due to disease progression, while 12.7% and 8.7%, respectively, discontinued treatment due to drug-related toxicity.

Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%).

Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).

Pfizer and Avillion entered into an exclusive collaborative development agreement in 2014 to conduct the BFORE trial.

Under the terms of the agreement, Avillion provided funding and conducted the trial to generate the clinical data used to support regulatory filings for marketing authorization for bosutinib as first-line treatment for patients with chronic phase, Ph+ CML.

With this approval, Avillion is eligible to receive milestone payments from Pfizer. Pfizer retains all rights to commercialize bosutinib globally.