AML

MADRID – Flotetuzumab, a novel bispecific monoclonal antibody that employs a proprietary technology to redirect T lymphocytes to kill CD123-expressing cells, was safe and demonstrated efficacy in patients with acute myeloid leukemia in a phase 1 trial, based on data presented at the European Society for Medical Oncology (ESMO) Congress.

Flotetuzumab combines a portion of antibody recognizing CD3, which is an activating molecule expressed by T cells, and an arm that recognizes CD123 on the cancer cell, explained Norbert Vey, MD, PhD, Head, Leukemia Treatment Unit, Institut Paoli-Calmettes, Marseille, France. This bispecific quality, produced through a proprietary technology called Dual-Affinity ReTargeting, is considered promising because CD123 is expressed by more than 90% of AML cells and is highly expressed on stem cells involved in initiating myelodysplastic syndrome (MDS).

In this dose-ranging study (NCT02152956), 42 patients with AML and 5 patients with MDS were treated in the first cycle with infusions of flotetuzumab on either a continuous 7-day or a 4-days-on, 3-days-off schedule. For subsequent cycles, patients received the 4-days-on, 3-days-off schedule. Continuous infusion is employed due to the short half-life of flotetuzumab.

The most common adverse events were infusion-related reactions, which were observed in 76.6% of patients. Pyrexia, a potential sign of cytokine release syndrome (CRS), was observed in 23.4% of patients, who were given tocilizumab at the earliest sign of CRS. Two patients had grade 3 CRS, and one discontinued therapy. There was also one case of grade 3 myalgia. Dr. Vey characterized the overall level of adverse events as “acceptable.”

In addition to its relative safety, flotetuzumab was associated with “encouraging antileukemic activity,” Dr. Vey said. Six of 14 patients receiving doses that exceeded 500 ng/kg per day had objective responses and two of these patients had complete responses. Again, toxicity at these dose levels was considered manageable.

“This rate of clinical response is exciting,” commented Tim Somervaille, MD, Senior Group Leader, Leukemia Biology Laboratory, Cancer Research UK Institute, Manchester (England). An ESMO-invited discussant on this paper, Dr. Somervaille expressed enthusiasm in general about a growing role for bispecific T-cell engagers. Blinatumomab, the first of these agents, received regulatory approval for refractory AML in 2014.

“There are a number of these bispecific T cell antibodies that are in early-phase trials,” said Dr. Somervaille, citing several that also target CD123 within the context of a different partner antigen than that employed by flotetuzumab. He also mentioned ongoing efforts to develop bispecific natural killer cell engagers that target malignant cells through immune activation.

As for flotetuzumab, the phase 1 trial provided adequate data to encourage further development.

“A cohort expansion is now ongoing and enrolling patients at 11 sites in the United States and Europe,” Dr. Vey reported. “A clinical update on these results is expected by the end of the year.”

Dr. Vey reported financial relationships with Bristol-Myers Squibb, Novartis, and Servier.

MacroGenics retains full development and commercialization rights to flotetuzumab in the United States, Canada, Mexico, Japan, South Korea, and India. Servier participates in the development and has rights to flotetuzumab in all other countries. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the investigational treatment of AML, according to a press release from MacroGenics.

MADRID – Flotetuzumab, a novel bispecific monoclonal antibody that employs a proprietary technology to redirect T lymphocytes to kill CD123-expressing cells, was safe and demonstrated efficacy in patients with acute myeloid leukemia in a phase 1 trial, based on data presented at the European Society for Medical Oncology (ESMO) Congress.

Flotetuzumab combines a portion of antibody recognizing CD3, which is an activating molecule expressed by T cells, and an arm that recognizes CD123 on the cancer cell, explained Norbert Vey, MD, PhD, Head, Leukemia Treatment Unit, Institut Paoli-Calmettes, Marseille, France. This bispecific quality, produced through a proprietary technology called Dual-Affinity ReTargeting, is considered promising because CD123 is expressed by more than 90% of AML cells and is highly expressed on stem cells involved in initiating myelodysplastic syndrome (MDS).

In this dose-ranging study (NCT02152956), 42 patients with AML and 5 patients with MDS were treated in the first cycle with infusions of flotetuzumab on either a continuous 7-day or a 4-days-on, 3-days-off schedule. For subsequent cycles, patients received the 4-days-on, 3-days-off schedule. Continuous infusion is employed due to the short half-life of flotetuzumab.

The most common adverse events were infusion-related reactions, which were observed in 76.6% of patients. Pyrexia, a potential sign of cytokine release syndrome (CRS), was observed in 23.4% of patients, who were given tocilizumab at the earliest sign of CRS. Two patients had grade 3 CRS, and one discontinued therapy. There was also one case of grade 3 myalgia. Dr. Vey characterized the overall level of adverse events as “acceptable.”

In addition to its relative safety, flotetuzumab was associated with “encouraging antileukemic activity,” Dr. Vey said. Six of 14 patients receiving doses that exceeded 500 ng/kg per day had objective responses and two of these patients had complete responses. Again, toxicity at these dose levels was considered manageable.

“This rate of clinical response is exciting,” commented Tim Somervaille, MD, Senior Group Leader, Leukemia Biology Laboratory, Cancer Research UK Institute, Manchester (England). An ESMO-invited discussant on this paper, Dr. Somervaille expressed enthusiasm in general about a growing role for bispecific T-cell engagers. Blinatumomab, the first of these agents, received regulatory approval for refractory AML in 2014.

“There are a number of these bispecific T cell antibodies that are in early-phase trials,” said Dr. Somervaille, citing several that also target CD123 within the context of a different partner antigen than that employed by flotetuzumab. He also mentioned ongoing efforts to develop bispecific natural killer cell engagers that target malignant cells through immune activation.

As for flotetuzumab, the phase 1 trial provided adequate data to encourage further development.

“A cohort expansion is now ongoing and enrolling patients at 11 sites in the United States and Europe,” Dr. Vey reported. “A clinical update on these results is expected by the end of the year.”

Dr. Vey reported financial relationships with Bristol-Myers Squibb, Novartis, and Servier.

MacroGenics retains full development and commercialization rights to flotetuzumab in the United States, Canada, Mexico, Japan, South Korea, and India. Servier participates in the development and has rights to flotetuzumab in all other countries. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the investigational treatment of AML, according to a press release from MacroGenics.

MADRID – Flotetuzumab, a novel bispecific monoclonal antibody that employs a proprietary technology to redirect T lymphocytes to kill CD123-expressing cells, was safe and demonstrated efficacy in patients with acute myeloid leukemia in a phase 1 trial, based on data presented at the European Society for Medical Oncology (ESMO) Congress.

Flotetuzumab combines a portion of antibody recognizing CD3, which is an activating molecule expressed by T cells, and an arm that recognizes CD123 on the cancer cell, explained Norbert Vey, MD, PhD, Head, Leukemia Treatment Unit, Institut Paoli-Calmettes, Marseille, France. This bispecific quality, produced through a proprietary technology called Dual-Affinity ReTargeting, is considered promising because CD123 is expressed by more than 90% of AML cells and is highly expressed on stem cells involved in initiating myelodysplastic syndrome (MDS).

In this dose-ranging study (NCT02152956), 42 patients with AML and 5 patients with MDS were treated in the first cycle with infusions of flotetuzumab on either a continuous 7-day or a 4-days-on, 3-days-off schedule. For subsequent cycles, patients received the 4-days-on, 3-days-off schedule. Continuous infusion is employed due to the short half-life of flotetuzumab.

The most common adverse events were infusion-related reactions, which were observed in 76.6% of patients. Pyrexia, a potential sign of cytokine release syndrome (CRS), was observed in 23.4% of patients, who were given tocilizumab at the earliest sign of CRS. Two patients had grade 3 CRS, and one discontinued therapy. There was also one case of grade 3 myalgia. Dr. Vey characterized the overall level of adverse events as “acceptable.”

In addition to its relative safety, flotetuzumab was associated with “encouraging antileukemic activity,” Dr. Vey said. Six of 14 patients receiving doses that exceeded 500 ng/kg per day had objective responses and two of these patients had complete responses. Again, toxicity at these dose levels was considered manageable.

“This rate of clinical response is exciting,” commented Tim Somervaille, MD, Senior Group Leader, Leukemia Biology Laboratory, Cancer Research UK Institute, Manchester (England). An ESMO-invited discussant on this paper, Dr. Somervaille expressed enthusiasm in general about a growing role for bispecific T-cell engagers. Blinatumomab, the first of these agents, received regulatory approval for refractory AML in 2014.

“There are a number of these bispecific T cell antibodies that are in early-phase trials,” said Dr. Somervaille, citing several that also target CD123 within the context of a different partner antigen than that employed by flotetuzumab. He also mentioned ongoing efforts to develop bispecific natural killer cell engagers that target malignant cells through immune activation.

As for flotetuzumab, the phase 1 trial provided adequate data to encourage further development.

“A cohort expansion is now ongoing and enrolling patients at 11 sites in the United States and Europe,” Dr. Vey reported. “A clinical update on these results is expected by the end of the year.”

Dr. Vey reported financial relationships with Bristol-Myers Squibb, Novartis, and Servier.

MacroGenics retains full development and commercialization rights to flotetuzumab in the United States, Canada, Mexico, Japan, South Korea, and India. Servier participates in the development and has rights to flotetuzumab in all other countries. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the investigational treatment of AML, according to a press release from MacroGenics.

Photo courtesy of Novartis

The European Commission has approved the multi-targeted kinase inhibitor midostaurin (Rydapt®) to treat acute myeloid leukemia (AML) and 3 types of advanced systemic mastocytosis (SM).

Midostaurin is approved to treat adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive. In these patients, midostaurin can be used in combination with standard daunorubicin and cytarabine induction, followed by high-dose cytarabine consolidation. Patients who achieve a complete response can then receive midostaurin as maintenance therapy.

Midostaurin is also approved as monotherapy for adults with aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

Midostaurin in AML

The approval of midostaurin in AML is based on results from the phase 3 RATIFY trial, which were published in NEJM last month.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).

And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infection.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Midostaurin in advanced SM

The approval of midostaurin in advanced SM is based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3. Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.

Study 2 included 116 patients, 115 of whom were evaluable for response.

The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.

Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.

Among the 17 patients with SM-AHN, there were 10 responses (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.

In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.

The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.

The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.

Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders.

Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.

Photo courtesy of Novartis

The European Commission has approved the multi-targeted kinase inhibitor midostaurin (Rydapt®) to treat acute myeloid leukemia (AML) and 3 types of advanced systemic mastocytosis (SM).

Midostaurin is approved to treat adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive. In these patients, midostaurin can be used in combination with standard daunorubicin and cytarabine induction, followed by high-dose cytarabine consolidation. Patients who achieve a complete response can then receive midostaurin as maintenance therapy.

Midostaurin is also approved as monotherapy for adults with aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

Midostaurin in AML

The approval of midostaurin in AML is based on results from the phase 3 RATIFY trial, which were published in NEJM last month.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).

And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infection.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Midostaurin in advanced SM

The approval of midostaurin in advanced SM is based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3. Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.

Study 2 included 116 patients, 115 of whom were evaluable for response.

The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.

Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.

Among the 17 patients with SM-AHN, there were 10 responses (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.

In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.

The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.

The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.

Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders.

Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.

Photo courtesy of Novartis

The European Commission has approved the multi-targeted kinase inhibitor midostaurin (Rydapt®) to treat acute myeloid leukemia (AML) and 3 types of advanced systemic mastocytosis (SM).

Midostaurin is approved to treat adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive. In these patients, midostaurin can be used in combination with standard daunorubicin and cytarabine induction, followed by high-dose cytarabine consolidation. Patients who achieve a complete response can then receive midostaurin as maintenance therapy.

Midostaurin is also approved as monotherapy for adults with aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

Midostaurin in AML

The approval of midostaurin in AML is based on results from the phase 3 RATIFY trial, which were published in NEJM last month.

In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.

The median overall survival was significantly longer in the midostaurin arm than the placebo arm—74.7 months and 25.6 months, respectively (hazard ratio=0.77, P=0.016).

And the median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).

The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infection.

The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.

Midostaurin in advanced SM

The approval of midostaurin in advanced SM is based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3. Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.

Study 2 included 116 patients, 115 of whom were evaluable for response.

The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.

Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.

Among the 17 patients with SM-AHN, there were 10 responses (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.

In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.

The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.

The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.

Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders.

Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.

Image from NIAID

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).

ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.

Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.

About RMAT designation

The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.

Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.

A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.

“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.

“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”

ATIR101 trials

Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.

Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.

A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.

Image from NIAID

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).

ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.

Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.

About RMAT designation

The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.

Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.

A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.

“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.

“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”

ATIR101 trials

Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.

Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.

A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.

Image from NIAID

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).

ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.

Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.

About RMAT designation

The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.

Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.

A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.

“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.

“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”

ATIR101 trials

Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.

Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.

A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.

Anderson Cancer Center

Researchers say they have created guidelines for managing the unique toxicities associated with chimeric antigen receptor (CAR) T-cell therapy.

The guidelines focus on cytokine release syndrome (CRS); neurological toxicity, which the researchers have dubbed “CAR-T-cell-related encephalopathy syndrome (CRES);” and adverse effects related to these syndromes.

“The toxicities are unique, and every member of the care team needs to be trained to recognize them and act accordingly,” said Sattva Neelapu, MD, of University of Texas MD Anderson Cancer Center in Houston.

Dr Neelapu and his colleagues described the toxicities and related recommendations in Nature Reviews Clinical Oncology.

The team’s guidelines include supportive-care considerations for patients receiving CAR T‑cell therapy. For example, they recommend:

• Baseline brain MRI to rule out central nervous system disease
• Cardiac monitoring starting on the day of CAR T‑cell infusion
• Assessing a patient’s vital signs every 4 hours after CAR T-cell infusion
• Assessing and grading CRS at least twice daily and whenever the patient’s status changes
• Assessing and grading CRES at least every 8 hours.

CRS

One section of the guidelines is dedicated to CRS, with subsections on pathophysiology, precautions and supportive care, the use of corticosteroids and IL‑6/IL‑6R antagonists, and grading CRS.

The researchers noted that CRS typically manifests with constitutional symptoms, such as fever, malaise, anorexia, and myalgias. However, CRS can affect any organ system in the body.

The team recommends managing CRS according to grade. For example, patients with grade 1 CRS should typically receive supportive care. However, physicians should consider giving tocilizumab or siltuximab to grade 1 patients who have a refractory fever lasting more than 3 days.

The researchers also noted that CRS can evolve into fulminant hemophagocytic lymphohistiocytosis (HLH), also known as macrophage-activation syndrome (MAS).

The team said HLH/MAS encompasses a group of severe immunological disorders characterized by hyperactivation of macrophages and lymphocytes, proinflammatory cytokine production, lymphohistiocytic tissue infiltration, and immune-mediated multi-organ failure.

The guidelines include diagnostic criteria for CAR T‑cell-related HLH/MAS and recommendations for managing the condition.

CRES

One section of the guidelines is dedicated to the grading and treatment of CRES, which typically mani­fests as a toxic encephalopathy.

The researchers said the earliest signs of CRES are diminished attention, language disturbance, and impaired handwriting. Other symptoms include confusion, disorientation, agitation, apha­sia, somnolence, and tremors.

Patients with severe CRES (grade >2) may experience seizures, motor weakness, incontinence, mental obtundation, increased intracra­nial pressure, papilledema, and cerebral edema.

Therefore, the guidelines include recommendations for the management of status epilepticus and raised intracranial pressure after CAR T‑cell therapy.

The researchers also devised an algorithm, known as CARTOX-10, for identifying neurotoxicity. (An existing general method didn’t effectively quantify the neurological effects caused by CAR T-cell therapies.)

CARTOX-10 is a 10-point test in which patients are asked to do the following:

• Name the current month (1 point) and year (1 point)
• Name the city (1 point) and hospital they are in (1 point)
• Name the president/prime minister of their home country (1 point)
• Name 3 nearby objects (3 points)
• Write a standard sentence (1 point)
• Count backward from 100 by tens (1 point).

A perfect score indicates normal cognitive function. A patient has mild to severe impairment depending on the number of questions or activities missed.

Dr Neelapu and his colleagues believe their recommendations will be applicable to other types of cell-based immunotherapy as well, including CAR natural killer cells, T-cell receptor engineered T cells, and combination drugs that use an antibody to connect T cells to targets on cancer cells.

Researchers involved in this work have received funding from companies developing/marketing CAR T-cell therapies.

Anderson Cancer Center

Researchers say they have created guidelines for managing the unique toxicities associated with chimeric antigen receptor (CAR) T-cell therapy.

The guidelines focus on cytokine release syndrome (CRS); neurological toxicity, which the researchers have dubbed “CAR-T-cell-related encephalopathy syndrome (CRES);” and adverse effects related to these syndromes.

“The toxicities are unique, and every member of the care team needs to be trained to recognize them and act accordingly,” said Sattva Neelapu, MD, of University of Texas MD Anderson Cancer Center in Houston.

Dr Neelapu and his colleagues described the toxicities and related recommendations in Nature Reviews Clinical Oncology.

The team’s guidelines include supportive-care considerations for patients receiving CAR T‑cell therapy. For example, they recommend:

• Baseline brain MRI to rule out central nervous system disease
• Cardiac monitoring starting on the day of CAR T‑cell infusion
• Assessing a patient’s vital signs every 4 hours after CAR T-cell infusion
• Assessing and grading CRS at least twice daily and whenever the patient’s status changes
• Assessing and grading CRES at least every 8 hours.

CRS

One section of the guidelines is dedicated to CRS, with subsections on pathophysiology, precautions and supportive care, the use of corticosteroids and IL‑6/IL‑6R antagonists, and grading CRS.

The researchers noted that CRS typically manifests with constitutional symptoms, such as fever, malaise, anorexia, and myalgias. However, CRS can affect any organ system in the body.

The team recommends managing CRS according to grade. For example, patients with grade 1 CRS should typically receive supportive care. However, physicians should consider giving tocilizumab or siltuximab to grade 1 patients who have a refractory fever lasting more than 3 days.

The researchers also noted that CRS can evolve into fulminant hemophagocytic lymphohistiocytosis (HLH), also known as macrophage-activation syndrome (MAS).

The team said HLH/MAS encompasses a group of severe immunological disorders characterized by hyperactivation of macrophages and lymphocytes, proinflammatory cytokine production, lymphohistiocytic tissue infiltration, and immune-mediated multi-organ failure.

The guidelines include diagnostic criteria for CAR T‑cell-related HLH/MAS and recommendations for managing the condition.

CRES

One section of the guidelines is dedicated to the grading and treatment of CRES, which typically mani­fests as a toxic encephalopathy.

The researchers said the earliest signs of CRES are diminished attention, language disturbance, and impaired handwriting. Other symptoms include confusion, disorientation, agitation, apha­sia, somnolence, and tremors.

Patients with severe CRES (grade >2) may experience seizures, motor weakness, incontinence, mental obtundation, increased intracra­nial pressure, papilledema, and cerebral edema.

Therefore, the guidelines include recommendations for the management of status epilepticus and raised intracranial pressure after CAR T‑cell therapy.

The researchers also devised an algorithm, known as CARTOX-10, for identifying neurotoxicity. (An existing general method didn’t effectively quantify the neurological effects caused by CAR T-cell therapies.)

CARTOX-10 is a 10-point test in which patients are asked to do the following:

• Name the current month (1 point) and year (1 point)
• Name the city (1 point) and hospital they are in (1 point)
• Name the president/prime minister of their home country (1 point)
• Name 3 nearby objects (3 points)
• Write a standard sentence (1 point)
• Count backward from 100 by tens (1 point).

A perfect score indicates normal cognitive function. A patient has mild to severe impairment depending on the number of questions or activities missed.

Dr Neelapu and his colleagues believe their recommendations will be applicable to other types of cell-based immunotherapy as well, including CAR natural killer cells, T-cell receptor engineered T cells, and combination drugs that use an antibody to connect T cells to targets on cancer cells.

Researchers involved in this work have received funding from companies developing/marketing CAR T-cell therapies.

Anderson Cancer Center

Researchers say they have created guidelines for managing the unique toxicities associated with chimeric antigen receptor (CAR) T-cell therapy.

The guidelines focus on cytokine release syndrome (CRS); neurological toxicity, which the researchers have dubbed “CAR-T-cell-related encephalopathy syndrome (CRES);” and adverse effects related to these syndromes.

“The toxicities are unique, and every member of the care team needs to be trained to recognize them and act accordingly,” said Sattva Neelapu, MD, of University of Texas MD Anderson Cancer Center in Houston.

Dr Neelapu and his colleagues described the toxicities and related recommendations in Nature Reviews Clinical Oncology.

The team’s guidelines include supportive-care considerations for patients receiving CAR T‑cell therapy. For example, they recommend:

• Baseline brain MRI to rule out central nervous system disease
• Cardiac monitoring starting on the day of CAR T‑cell infusion
• Assessing a patient’s vital signs every 4 hours after CAR T-cell infusion
• Assessing and grading CRS at least twice daily and whenever the patient’s status changes
• Assessing and grading CRES at least every 8 hours.

CRS

One section of the guidelines is dedicated to CRS, with subsections on pathophysiology, precautions and supportive care, the use of corticosteroids and IL‑6/IL‑6R antagonists, and grading CRS.

The researchers noted that CRS typically manifests with constitutional symptoms, such as fever, malaise, anorexia, and myalgias. However, CRS can affect any organ system in the body.

The team recommends managing CRS according to grade. For example, patients with grade 1 CRS should typically receive supportive care. However, physicians should consider giving tocilizumab or siltuximab to grade 1 patients who have a refractory fever lasting more than 3 days.

The researchers also noted that CRS can evolve into fulminant hemophagocytic lymphohistiocytosis (HLH), also known as macrophage-activation syndrome (MAS).

The team said HLH/MAS encompasses a group of severe immunological disorders characterized by hyperactivation of macrophages and lymphocytes, proinflammatory cytokine production, lymphohistiocytic tissue infiltration, and immune-mediated multi-organ failure.

The guidelines include diagnostic criteria for CAR T‑cell-related HLH/MAS and recommendations for managing the condition.

CRES

One section of the guidelines is dedicated to the grading and treatment of CRES, which typically mani­fests as a toxic encephalopathy.

The researchers said the earliest signs of CRES are diminished attention, language disturbance, and impaired handwriting. Other symptoms include confusion, disorientation, agitation, apha­sia, somnolence, and tremors.

Patients with severe CRES (grade >2) may experience seizures, motor weakness, incontinence, mental obtundation, increased intracra­nial pressure, papilledema, and cerebral edema.

Therefore, the guidelines include recommendations for the management of status epilepticus and raised intracranial pressure after CAR T‑cell therapy.

The researchers also devised an algorithm, known as CARTOX-10, for identifying neurotoxicity. (An existing general method didn’t effectively quantify the neurological effects caused by CAR T-cell therapies.)

CARTOX-10 is a 10-point test in which patients are asked to do the following:

• Name the current month (1 point) and year (1 point)
• Name the city (1 point) and hospital they are in (1 point)
• Name the president/prime minister of their home country (1 point)
• Name 3 nearby objects (3 points)
• Write a standard sentence (1 point)
• Count backward from 100 by tens (1 point).

A perfect score indicates normal cognitive function. A patient has mild to severe impairment depending on the number of questions or activities missed.

Dr Neelapu and his colleagues believe their recommendations will be applicable to other types of cell-based immunotherapy as well, including CAR natural killer cells, T-cell receptor engineered T cells, and combination drugs that use an antibody to connect T cells to targets on cancer cells.

Researchers involved in this work have received funding from companies developing/marketing CAR T-cell therapies.

Micrograph showing MDS

MADRID—Interim results of a phase 1 study suggest flotetuzumab, a CD123 and CD3 bispecific antibody, may be a feasible treatment option for relapsed or refractory acute myeloid leukemia (AML) or intermediate/high-risk myelodysplastic syndromes (MDS).

Researchers said flotetuzumab demonstrated acceptable tolerability in the dose-escalation portion of the study, with infusion-related reactions (IRRs) and cytokine release syndrome (CRS) being the most common adverse events (AEs).

In addition, flotetuzumab exhibited anti-leukemic activity in 8 of 14 response-evaluable patients, with 6 patients achieving a response.

Norbert Vey, MD, of Institut Paoli-Calmettes in Marseille, France, presented these results at the ESMO 2017 Congress (abstract 995O*). The study is sponsored by MacroGenics, Inc., the company developing flotetuzumab.

Flotetuzumab (MGD006) recognizes CD123 and CD3. The primary mechanism of flotetuzumab is thought to be its ability to redirect T cells to kill CD123-expressing cells. To achieve this, the molecule combines a portion of an antibody recognizing CD3 (an activating molecule expressed by T cells) with an arm that recognizes CD123 on the target cancer cells.

In this ongoing phase 1 study of flotetuzumab, researchers have enrolled 47 patients with a median age of 64 (range, 29-84). About 89% of these patients had AML (n=42), and the rest (n=5) had MDS.

Twenty-four percent had relapsed AML (n=10), 55% had refractory AML (n=23), and 21% had failed treatment with hypomethylating agents (n=9). One patient had intermediate-1-risk MDS, 2 had intermediate-2-risk, and 2 had high-risk MDS.

Treatment

The study began with single patients receiving flotetuzumab at escalating doses—3 ng/kg/day, 10 ng/kg/day, 30 ng/kg/day, and 100 ng/kg/day.

Then, patients received a range of doses on 2 different schedules for cycle 1. One group received treatment 7 days a week. The other had a 4-days-on/3-days-off schedule.

All patients received a lead-in dose during the first week of cycle 1. They received 30 ng/kg/day for 3 days, then 100 ng/kg/day for 4 days.

For the rest of cycle 1, patients in the 4 days/3 days group received doses of 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg. Patients in the daily dosing group received doses of 300 ng/kg, 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg.

For cycle 2 and beyond, all patients were on the 4-days-on/3-days-off schedule.

Safety

The maximum tolerated dose and schedule was 500 ng/kg/day for 7 days.

Dose-limiting toxicities occurring at the 700 ng/kg/day dose included grade 2 IRRs/CRS in 2 patients and grade 3 myalgia in 1 patient. There was 1 drug-related central nervous system AE that led to treatment discontinuation.

IRRs/CRS occurred in 77% of patients, with 13% of patients having grade 3 events and 8.5% of patients discontinuing treatment due to IRRs/CRS.

The researchers said they found ways to decrease the incidence and severity of CRS. One is early intervention with tocilizumab. The other is a 2-step lead-in dose during week 1. So patients first receive 30 ng/kg, then 100 ng/kg, and then their target dose.

Other grade 3 AEs occurring in this trial include febrile neutropenia (11%), anemia (11%), and decreases in platelets (13%), white blood cells (11%), and lymphocytes (13%).

Efficacy

The researchers said they observed encouraging anti-leukemic activity in patients treated at 500 ng/kg/day or greater.

As of the data cut-off, 14 patients treated at this dose were evaluable for response. Eight (57%) patients had anti-leukemic activity, with 6 (43%) of these patients experiencing an objective response.

One patient achieved a complete response (CR), 2 had a CR with incomplete count recovery, and 1 had a molecular CR.

In most responders, anti-leukemic activity was observed after a single cycle of therapy.

MacroGenics is currently enrolling patients in dose-expansion cohorts. The company plans to present updated results from this trial at another scientific conference later this year.

*Slides from this presentation are available on the MacroGenics website at http://ir.macrogenics.com/events.cfm.

Micrograph showing MDS

MADRID—Interim results of a phase 1 study suggest flotetuzumab, a CD123 and CD3 bispecific antibody, may be a feasible treatment option for relapsed or refractory acute myeloid leukemia (AML) or intermediate/high-risk myelodysplastic syndromes (MDS).

Researchers said flotetuzumab demonstrated acceptable tolerability in the dose-escalation portion of the study, with infusion-related reactions (IRRs) and cytokine release syndrome (CRS) being the most common adverse events (AEs).

In addition, flotetuzumab exhibited anti-leukemic activity in 8 of 14 response-evaluable patients, with 6 patients achieving a response.

Norbert Vey, MD, of Institut Paoli-Calmettes in Marseille, France, presented these results at the ESMO 2017 Congress (abstract 995O*). The study is sponsored by MacroGenics, Inc., the company developing flotetuzumab.

Flotetuzumab (MGD006) recognizes CD123 and CD3. The primary mechanism of flotetuzumab is thought to be its ability to redirect T cells to kill CD123-expressing cells. To achieve this, the molecule combines a portion of an antibody recognizing CD3 (an activating molecule expressed by T cells) with an arm that recognizes CD123 on the target cancer cells.

In this ongoing phase 1 study of flotetuzumab, researchers have enrolled 47 patients with a median age of 64 (range, 29-84). About 89% of these patients had AML (n=42), and the rest (n=5) had MDS.

Twenty-four percent had relapsed AML (n=10), 55% had refractory AML (n=23), and 21% had failed treatment with hypomethylating agents (n=9). One patient had intermediate-1-risk MDS, 2 had intermediate-2-risk, and 2 had high-risk MDS.

Treatment

The study began with single patients receiving flotetuzumab at escalating doses—3 ng/kg/day, 10 ng/kg/day, 30 ng/kg/day, and 100 ng/kg/day.

Then, patients received a range of doses on 2 different schedules for cycle 1. One group received treatment 7 days a week. The other had a 4-days-on/3-days-off schedule.

All patients received a lead-in dose during the first week of cycle 1. They received 30 ng/kg/day for 3 days, then 100 ng/kg/day for 4 days.

For the rest of cycle 1, patients in the 4 days/3 days group received doses of 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg. Patients in the daily dosing group received doses of 300 ng/kg, 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg.

For cycle 2 and beyond, all patients were on the 4-days-on/3-days-off schedule.

Safety

The maximum tolerated dose and schedule was 500 ng/kg/day for 7 days.

Dose-limiting toxicities occurring at the 700 ng/kg/day dose included grade 2 IRRs/CRS in 2 patients and grade 3 myalgia in 1 patient. There was 1 drug-related central nervous system AE that led to treatment discontinuation.

IRRs/CRS occurred in 77% of patients, with 13% of patients having grade 3 events and 8.5% of patients discontinuing treatment due to IRRs/CRS.

The researchers said they found ways to decrease the incidence and severity of CRS. One is early intervention with tocilizumab. The other is a 2-step lead-in dose during week 1. So patients first receive 30 ng/kg, then 100 ng/kg, and then their target dose.

Other grade 3 AEs occurring in this trial include febrile neutropenia (11%), anemia (11%), and decreases in platelets (13%), white blood cells (11%), and lymphocytes (13%).

Efficacy

The researchers said they observed encouraging anti-leukemic activity in patients treated at 500 ng/kg/day or greater.

As of the data cut-off, 14 patients treated at this dose were evaluable for response. Eight (57%) patients had anti-leukemic activity, with 6 (43%) of these patients experiencing an objective response.

One patient achieved a complete response (CR), 2 had a CR with incomplete count recovery, and 1 had a molecular CR.

In most responders, anti-leukemic activity was observed after a single cycle of therapy.

MacroGenics is currently enrolling patients in dose-expansion cohorts. The company plans to present updated results from this trial at another scientific conference later this year.

*Slides from this presentation are available on the MacroGenics website at http://ir.macrogenics.com/events.cfm.

Micrograph showing MDS

MADRID—Interim results of a phase 1 study suggest flotetuzumab, a CD123 and CD3 bispecific antibody, may be a feasible treatment option for relapsed or refractory acute myeloid leukemia (AML) or intermediate/high-risk myelodysplastic syndromes (MDS).

Researchers said flotetuzumab demonstrated acceptable tolerability in the dose-escalation portion of the study, with infusion-related reactions (IRRs) and cytokine release syndrome (CRS) being the most common adverse events (AEs).

In addition, flotetuzumab exhibited anti-leukemic activity in 8 of 14 response-evaluable patients, with 6 patients achieving a response.

Norbert Vey, MD, of Institut Paoli-Calmettes in Marseille, France, presented these results at the ESMO 2017 Congress (abstract 995O*). The study is sponsored by MacroGenics, Inc., the company developing flotetuzumab.

Flotetuzumab (MGD006) recognizes CD123 and CD3. The primary mechanism of flotetuzumab is thought to be its ability to redirect T cells to kill CD123-expressing cells. To achieve this, the molecule combines a portion of an antibody recognizing CD3 (an activating molecule expressed by T cells) with an arm that recognizes CD123 on the target cancer cells.

In this ongoing phase 1 study of flotetuzumab, researchers have enrolled 47 patients with a median age of 64 (range, 29-84). About 89% of these patients had AML (n=42), and the rest (n=5) had MDS.

Twenty-four percent had relapsed AML (n=10), 55% had refractory AML (n=23), and 21% had failed treatment with hypomethylating agents (n=9). One patient had intermediate-1-risk MDS, 2 had intermediate-2-risk, and 2 had high-risk MDS.

Treatment

The study began with single patients receiving flotetuzumab at escalating doses—3 ng/kg/day, 10 ng/kg/day, 30 ng/kg/day, and 100 ng/kg/day.

Then, patients received a range of doses on 2 different schedules for cycle 1. One group received treatment 7 days a week. The other had a 4-days-on/3-days-off schedule.

All patients received a lead-in dose during the first week of cycle 1. They received 30 ng/kg/day for 3 days, then 100 ng/kg/day for 4 days.

For the rest of cycle 1, patients in the 4 days/3 days group received doses of 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg. Patients in the daily dosing group received doses of 300 ng/kg, 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg.

For cycle 2 and beyond, all patients were on the 4-days-on/3-days-off schedule.

Safety

The maximum tolerated dose and schedule was 500 ng/kg/day for 7 days.

Dose-limiting toxicities occurring at the 700 ng/kg/day dose included grade 2 IRRs/CRS in 2 patients and grade 3 myalgia in 1 patient. There was 1 drug-related central nervous system AE that led to treatment discontinuation.

IRRs/CRS occurred in 77% of patients, with 13% of patients having grade 3 events and 8.5% of patients discontinuing treatment due to IRRs/CRS.

The researchers said they found ways to decrease the incidence and severity of CRS. One is early intervention with tocilizumab. The other is a 2-step lead-in dose during week 1. So patients first receive 30 ng/kg, then 100 ng/kg, and then their target dose.

Other grade 3 AEs occurring in this trial include febrile neutropenia (11%), anemia (11%), and decreases in platelets (13%), white blood cells (11%), and lymphocytes (13%).

Efficacy

The researchers said they observed encouraging anti-leukemic activity in patients treated at 500 ng/kg/day or greater.

As of the data cut-off, 14 patients treated at this dose were evaluable for response. Eight (57%) patients had anti-leukemic activity, with 6 (43%) of these patients experiencing an objective response.

One patient achieved a complete response (CR), 2 had a CR with incomplete count recovery, and 1 had a molecular CR.

In most responders, anti-leukemic activity was observed after a single cycle of therapy.

MacroGenics is currently enrolling patients in dose-expansion cohorts. The company plans to present updated results from this trial at another scientific conference later this year.

*Slides from this presentation are available on the MacroGenics website at http://ir.macrogenics.com/events.cfm.

MADRID – Radioactive iodine treatment is associated with nearly twice the risk of developing acute myeloid leukemia (AML) in patients with well-differentiated thyroid cancer, based on data from the Surveillance Epidemiology and End Results (SEER) registry.

Up to 40% of patients in Europe and North America with well-differentiated thyroid cancer still receive radioactive iodine treatment “even though RAI has no proven benefit in this population,” Remco Molenaar, MD, PhD, of the University of Amsterdam reported at the European Society of Medical Oncology Congress.

Of 148,215 patients treated for well-differentiated thyroid cancer between 1973 and 2014, 55% had surgery only and 45% received surgery plus radioactive iodine treatment. After a median 4.3 years of follow-up, 44 patients developed AML. When cases in those exposed to RAI were cross-referenced to those who were not, the relative risk was increased more than fivefold. When the analysis controlled for an extensive list of potentially confounding variables, the hazard ratio of 1.79 remained statistically significant (P = .03).

“There is a nearly twofold increased risk even though radioactive iodine treatment is not indicated in this population,” Dr. Molenaar said. Moreover, AML following treatment for well-differentiated thyroid cancer was associated with a substantial reduction in expected overall survival, falling from a median 24.4 years to 7.5 years.

Compared with other AML patients, “those who develop AML after RAI also have a worse prognosis,” added Dr. Molenaar, noting the difference in overall survival is highly statistically significant (1.2 vs. 3.5 years; P = .004).

The ESMO-invited discussant, Tim Somervaille, MD, senior group leader of the Leukemia Biology Laboratory at the Cancer Research UK Manchester Institute, called this analysis “a more thorough and detailed study” than previous retrospective analyses, but he added a note of caution: Despite the almost twofold increase in risk, AML remains a rare iatrogenic event in thyroid cancer patients even if it is avoidable by withholding RAI therapy.

“These data do suggest that the risk is measurable and will further provide some downward pressure on the numbers of patients having unnecessary RAI therapy for well-differentiated thyroid cancer,” he said.

In the discussion that followed the presentation, one audience member suggested that telling patients they have a twofold increased risk of AML after RAI therapy is misleading. It was emphasized that a twofold increase of a very small number is still a very small number, but Dr. Molenaar suggested that this misses the point.

“I don’t think this is something that you need to discuss with patients, because you should not be giving RAI therapy to thyroid cancer patients with low- or intermediate-risk disease,” he said. Any AML case caused “by a therapy with no proven benefit is one too many,” especially since unnecessary RAI adds inconvenience and cost to treatment.

[email protected]

MADRID – Radioactive iodine treatment is associated with nearly twice the risk of developing acute myeloid leukemia (AML) in patients with well-differentiated thyroid cancer, based on data from the Surveillance Epidemiology and End Results (SEER) registry.

Up to 40% of patients in Europe and North America with well-differentiated thyroid cancer still receive radioactive iodine treatment “even though RAI has no proven benefit in this population,” Remco Molenaar, MD, PhD, of the University of Amsterdam reported at the European Society of Medical Oncology Congress.

Of 148,215 patients treated for well-differentiated thyroid cancer between 1973 and 2014, 55% had surgery only and 45% received surgery plus radioactive iodine treatment. After a median 4.3 years of follow-up, 44 patients developed AML. When cases in those exposed to RAI were cross-referenced to those who were not, the relative risk was increased more than fivefold. When the analysis controlled for an extensive list of potentially confounding variables, the hazard ratio of 1.79 remained statistically significant (P = .03).

“There is a nearly twofold increased risk even though radioactive iodine treatment is not indicated in this population,” Dr. Molenaar said. Moreover, AML following treatment for well-differentiated thyroid cancer was associated with a substantial reduction in expected overall survival, falling from a median 24.4 years to 7.5 years.

Compared with other AML patients, “those who develop AML after RAI also have a worse prognosis,” added Dr. Molenaar, noting the difference in overall survival is highly statistically significant (1.2 vs. 3.5 years; P = .004).

The ESMO-invited discussant, Tim Somervaille, MD, senior group leader of the Leukemia Biology Laboratory at the Cancer Research UK Manchester Institute, called this analysis “a more thorough and detailed study” than previous retrospective analyses, but he added a note of caution: Despite the almost twofold increase in risk, AML remains a rare iatrogenic event in thyroid cancer patients even if it is avoidable by withholding RAI therapy.

“These data do suggest that the risk is measurable and will further provide some downward pressure on the numbers of patients having unnecessary RAI therapy for well-differentiated thyroid cancer,” he said.

In the discussion that followed the presentation, one audience member suggested that telling patients they have a twofold increased risk of AML after RAI therapy is misleading. It was emphasized that a twofold increase of a very small number is still a very small number, but Dr. Molenaar suggested that this misses the point.

“I don’t think this is something that you need to discuss with patients, because you should not be giving RAI therapy to thyroid cancer patients with low- or intermediate-risk disease,” he said. Any AML case caused “by a therapy with no proven benefit is one too many,” especially since unnecessary RAI adds inconvenience and cost to treatment.

[email protected]

MADRID – Radioactive iodine treatment is associated with nearly twice the risk of developing acute myeloid leukemia (AML) in patients with well-differentiated thyroid cancer, based on data from the Surveillance Epidemiology and End Results (SEER) registry.

Up to 40% of patients in Europe and North America with well-differentiated thyroid cancer still receive radioactive iodine treatment “even though RAI has no proven benefit in this population,” Remco Molenaar, MD, PhD, of the University of Amsterdam reported at the European Society of Medical Oncology Congress.

Of 148,215 patients treated for well-differentiated thyroid cancer between 1973 and 2014, 55% had surgery only and 45% received surgery plus radioactive iodine treatment. After a median 4.3 years of follow-up, 44 patients developed AML. When cases in those exposed to RAI were cross-referenced to those who were not, the relative risk was increased more than fivefold. When the analysis controlled for an extensive list of potentially confounding variables, the hazard ratio of 1.79 remained statistically significant (P = .03).

“There is a nearly twofold increased risk even though radioactive iodine treatment is not indicated in this population,” Dr. Molenaar said. Moreover, AML following treatment for well-differentiated thyroid cancer was associated with a substantial reduction in expected overall survival, falling from a median 24.4 years to 7.5 years.

Compared with other AML patients, “those who develop AML after RAI also have a worse prognosis,” added Dr. Molenaar, noting the difference in overall survival is highly statistically significant (1.2 vs. 3.5 years; P = .004).

The ESMO-invited discussant, Tim Somervaille, MD, senior group leader of the Leukemia Biology Laboratory at the Cancer Research UK Manchester Institute, called this analysis “a more thorough and detailed study” than previous retrospective analyses, but he added a note of caution: Despite the almost twofold increase in risk, AML remains a rare iatrogenic event in thyroid cancer patients even if it is avoidable by withholding RAI therapy.

“These data do suggest that the risk is measurable and will further provide some downward pressure on the numbers of patients having unnecessary RAI therapy for well-differentiated thyroid cancer,” he said.

In the discussion that followed the presentation, one audience member suggested that telling patients they have a twofold increased risk of AML after RAI therapy is misleading. It was emphasized that a twofold increase of a very small number is still a very small number, but Dr. Molenaar suggested that this misses the point.

“I don’t think this is something that you need to discuss with patients, because you should not be giving RAI therapy to thyroid cancer patients with low- or intermediate-risk disease,” he said. Any AML case caused “by a therapy with no proven benefit is one too many,” especially since unnecessary RAI adds inconvenience and cost to treatment.

[email protected]

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Photo courtesy of ESMO

MADRID—New research suggests patients with well-differentiated thyroid cancer (WDTC) are more likely to develop acute myeloid leukemia (AML) if they receive radioactive iodine (RAI) after surgery.

Of the WDTC patients studied, those who only underwent surgery were less likely to develop AML.

WDTC patients who did develop AML had a far worse prognosis than WDTC patients without AML and patients with de novo AML.

These results were presented at the ESMO 2017 Congress (abstract 996O).

Researchers already knew that the risk of developing leukemia is increased after radiation and RAI treatment for WDTC.

However, the risk of AML following RAI treatment in WDTC survivors had not been fully characterized, according to Remco J. Molenaar, an MD/PhD candidate at Academic Medical Centre in Amsterdam, Netherlands.

Therefore, Molenaar and colleagues reviewed data from all 18 registries in the Surveillance Epidemiology and End Results database for WDTC cases treated solely with surgery or by surgery and RAI.

The researchers identified 148,215 patients who were diagnosed with WDTC from 1973 to 2014. Fifty-five percent were treated with surgery alone, and 45% were treated with surgery and RAI.

The median follow-up was 4.3 person-years. AML occurred in 44 patients in the surgery-only arm and 56 patients in the RAI arm.

A comparison to the background rates in the general population showed that patients receiving surgery plus RAI had an increased risk of developing AML (relative risk=5.6; 95% confidence interval [CI] 3.8, 8.1; P<0.0001), after correcting for age, sex, and year of WDTC diagnosis.

This risk peaked within the first 3 years following RAI and subsequently regressed to baseline rates.

In multivariate analysis that corrected for sex and WDTC tumor size, 3 variables emerged as independent predictors of AML development. There was an increased risk of AML associated with:

• Patient age (hazard ratio [HR]=1.03; 95% CI 1.02, 1.05; P<0.001)
• WDTC tumor stage (HR=1.36; 95% CI 1.04, 1.79; P=0.03)
• Receiving RAI after thyroidectomy vs thyroidectomy alone (HR=1.38; 95% CI 1.09, 1.75; P=0.007).

The researchers also found prognosis is significantly poorer in WDTC patients who develop AML following RAI and in patients with spontaneous AML development.

Case-control analyses revealed that WDTC patients who developed AML after surgery and RAI survived one-third as long as matched control patients who were successfully treated for WDTC but did not develop AML. The median overall survival was 7.4 years and 24.4 years, respectively (P<0.0001).

Patients who were diagnosed with AML after RAI treatment also had a significantly worse prognosis than patients with de novo AML. The median overall survival was 1.2 years and 3.5 years, respectively (P=0.004).

The researchers noted that rates of AML in WDTC survivors will likely continue to rise due to the increasing incidence of WDTC, the young ages at which most WDTC diagnoses are made, and the otherwise high survival rates of patients with WDTC.

Photo courtesy of ESMO

MADRID—New research suggests patients with well-differentiated thyroid cancer (WDTC) are more likely to develop acute myeloid leukemia (AML) if they receive radioactive iodine (RAI) after surgery.

Of the WDTC patients studied, those who only underwent surgery were less likely to develop AML.

WDTC patients who did develop AML had a far worse prognosis than WDTC patients without AML and patients with de novo AML.

These results were presented at the ESMO 2017 Congress (abstract 996O).

Researchers already knew that the risk of developing leukemia is increased after radiation and RAI treatment for WDTC.

However, the risk of AML following RAI treatment in WDTC survivors had not been fully characterized, according to Remco J. Molenaar, an MD/PhD candidate at Academic Medical Centre in Amsterdam, Netherlands.

Therefore, Molenaar and colleagues reviewed data from all 18 registries in the Surveillance Epidemiology and End Results database for WDTC cases treated solely with surgery or by surgery and RAI.

The researchers identified 148,215 patients who were diagnosed with WDTC from 1973 to 2014. Fifty-five percent were treated with surgery alone, and 45% were treated with surgery and RAI.

The median follow-up was 4.3 person-years. AML occurred in 44 patients in the surgery-only arm and 56 patients in the RAI arm.

A comparison to the background rates in the general population showed that patients receiving surgery plus RAI had an increased risk of developing AML (relative risk=5.6; 95% confidence interval [CI] 3.8, 8.1; P<0.0001), after correcting for age, sex, and year of WDTC diagnosis.

This risk peaked within the first 3 years following RAI and subsequently regressed to baseline rates.

In multivariate analysis that corrected for sex and WDTC tumor size, 3 variables emerged as independent predictors of AML development. There was an increased risk of AML associated with:

• Patient age (hazard ratio [HR]=1.03; 95% CI 1.02, 1.05; P<0.001)
• WDTC tumor stage (HR=1.36; 95% CI 1.04, 1.79; P=0.03)
• Receiving RAI after thyroidectomy vs thyroidectomy alone (HR=1.38; 95% CI 1.09, 1.75; P=0.007).

The researchers also found prognosis is significantly poorer in WDTC patients who develop AML following RAI and in patients with spontaneous AML development.

Case-control analyses revealed that WDTC patients who developed AML after surgery and RAI survived one-third as long as matched control patients who were successfully treated for WDTC but did not develop AML. The median overall survival was 7.4 years and 24.4 years, respectively (P<0.0001).

Patients who were diagnosed with AML after RAI treatment also had a significantly worse prognosis than patients with de novo AML. The median overall survival was 1.2 years and 3.5 years, respectively (P=0.004).

The researchers noted that rates of AML in WDTC survivors will likely continue to rise due to the increasing incidence of WDTC, the young ages at which most WDTC diagnoses are made, and the otherwise high survival rates of patients with WDTC.

Photo courtesy of ESMO

MADRID—New research suggests patients with well-differentiated thyroid cancer (WDTC) are more likely to develop acute myeloid leukemia (AML) if they receive radioactive iodine (RAI) after surgery.

Of the WDTC patients studied, those who only underwent surgery were less likely to develop AML.

WDTC patients who did develop AML had a far worse prognosis than WDTC patients without AML and patients with de novo AML.

These results were presented at the ESMO 2017 Congress (abstract 996O).

Researchers already knew that the risk of developing leukemia is increased after radiation and RAI treatment for WDTC.

However, the risk of AML following RAI treatment in WDTC survivors had not been fully characterized, according to Remco J. Molenaar, an MD/PhD candidate at Academic Medical Centre in Amsterdam, Netherlands.

Therefore, Molenaar and colleagues reviewed data from all 18 registries in the Surveillance Epidemiology and End Results database for WDTC cases treated solely with surgery or by surgery and RAI.

The researchers identified 148,215 patients who were diagnosed with WDTC from 1973 to 2014. Fifty-five percent were treated with surgery alone, and 45% were treated with surgery and RAI.

The median follow-up was 4.3 person-years. AML occurred in 44 patients in the surgery-only arm and 56 patients in the RAI arm.

A comparison to the background rates in the general population showed that patients receiving surgery plus RAI had an increased risk of developing AML (relative risk=5.6; 95% confidence interval [CI] 3.8, 8.1; P<0.0001), after correcting for age, sex, and year of WDTC diagnosis.

This risk peaked within the first 3 years following RAI and subsequently regressed to baseline rates.

In multivariate analysis that corrected for sex and WDTC tumor size, 3 variables emerged as independent predictors of AML development. There was an increased risk of AML associated with:

• Patient age (hazard ratio [HR]=1.03; 95% CI 1.02, 1.05; P<0.001)
• WDTC tumor stage (HR=1.36; 95% CI 1.04, 1.79; P=0.03)
• Receiving RAI after thyroidectomy vs thyroidectomy alone (HR=1.38; 95% CI 1.09, 1.75; P=0.007).

The researchers also found prognosis is significantly poorer in WDTC patients who develop AML following RAI and in patients with spontaneous AML development.

Case-control analyses revealed that WDTC patients who developed AML after surgery and RAI survived one-third as long as matched control patients who were successfully treated for WDTC but did not develop AML. The median overall survival was 7.4 years and 24.4 years, respectively (P<0.0001).

Patients who were diagnosed with AML after RAI treatment also had a significantly worse prognosis than patients with de novo AML. The median overall survival was 1.2 years and 3.5 years, respectively (P=0.004).

The researchers noted that rates of AML in WDTC survivors will likely continue to rise due to the increasing incidence of WDTC, the young ages at which most WDTC diagnoses are made, and the otherwise high survival rates of patients with WDTC.

Photo courtesy of NIH

Adult survivors of childhood cancer have a greater cumulative burden of chronic health conditions than the general public, according to research published in The Lancet.

The study showed that, by age 50, childhood cancer survivors (CCSs) had experienced, on average, 17.1 chronic health conditions, and matched control subjects had experienced 9.2.

“The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

For this study, Dr Bhakta and his colleagues assessed the lifelong impact of 168 chronic health conditions—such as hepatic, thyroid, ocular, and reproductive disorders—on CCSs and control subjects.

The 3010 evaluable CCSs had survived 10 years or longer from their initial cancer diagnosis and were 18 years or older as of June 30, 2015. The 272 controls had no history of pediatric cancer and were matched to CCSs by age and sex.

At age 50, the cumulative incidence of chronic health conditions (of any grade) was 99.9% in CCSs and 96.0% in controls (P<0.0001). The cumulative incidence of grade 3 to 5 chronic health conditions was 96.0% and 84.9%, respectively (P<0.0001).

The cumulative burden for CCSs was 17.1 chronic health conditions, including 4.7 that were grade 3 to 5. For controls, the cumulative burden was 9.2 chronic health conditions, including 2.3 that were grade 3 to 5 (P<0.0001 for both comparisons).

The researchers said second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden observed in CCSs. However, there was “notable heterogeneity” in burden according to the patients’ primary cancer diagnosis.

For instance, growth hormone deficiency was in the top 10th percentile of chronic health conditions for survivors of acute lymphoblastic leukemia but not for controls.

And pulmonary function deficits were in the top 10th percentile for survivors of acute myeloid leukemia and Hodgkin lymphoma but not for controls or survivors of acute lymphoblastic leukemia or non-Hodgkin lymphoma.

“This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by healthcare providers to disentangle and manage—time that community providers are unlikely to have,” Dr Bhakta said.

“The results suggest that childhood cancer survivors may benefit from the integrated, specialized healthcare delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems.”

Photo courtesy of NIH

Adult survivors of childhood cancer have a greater cumulative burden of chronic health conditions than the general public, according to research published in The Lancet.

The study showed that, by age 50, childhood cancer survivors (CCSs) had experienced, on average, 17.1 chronic health conditions, and matched control subjects had experienced 9.2.

“The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

For this study, Dr Bhakta and his colleagues assessed the lifelong impact of 168 chronic health conditions—such as hepatic, thyroid, ocular, and reproductive disorders—on CCSs and control subjects.

The 3010 evaluable CCSs had survived 10 years or longer from their initial cancer diagnosis and were 18 years or older as of June 30, 2015. The 272 controls had no history of pediatric cancer and were matched to CCSs by age and sex.

At age 50, the cumulative incidence of chronic health conditions (of any grade) was 99.9% in CCSs and 96.0% in controls (P<0.0001). The cumulative incidence of grade 3 to 5 chronic health conditions was 96.0% and 84.9%, respectively (P<0.0001).

The cumulative burden for CCSs was 17.1 chronic health conditions, including 4.7 that were grade 3 to 5. For controls, the cumulative burden was 9.2 chronic health conditions, including 2.3 that were grade 3 to 5 (P<0.0001 for both comparisons).

The researchers said second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden observed in CCSs. However, there was “notable heterogeneity” in burden according to the patients’ primary cancer diagnosis.

For instance, growth hormone deficiency was in the top 10th percentile of chronic health conditions for survivors of acute lymphoblastic leukemia but not for controls.

And pulmonary function deficits were in the top 10th percentile for survivors of acute myeloid leukemia and Hodgkin lymphoma but not for controls or survivors of acute lymphoblastic leukemia or non-Hodgkin lymphoma.

“This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by healthcare providers to disentangle and manage—time that community providers are unlikely to have,” Dr Bhakta said.

“The results suggest that childhood cancer survivors may benefit from the integrated, specialized healthcare delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems.”

Photo courtesy of NIH

Adult survivors of childhood cancer have a greater cumulative burden of chronic health conditions than the general public, according to research published in The Lancet.

The study showed that, by age 50, childhood cancer survivors (CCSs) had experienced, on average, 17.1 chronic health conditions, and matched control subjects had experienced 9.2.

“The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

For this study, Dr Bhakta and his colleagues assessed the lifelong impact of 168 chronic health conditions—such as hepatic, thyroid, ocular, and reproductive disorders—on CCSs and control subjects.

The 3010 evaluable CCSs had survived 10 years or longer from their initial cancer diagnosis and were 18 years or older as of June 30, 2015. The 272 controls had no history of pediatric cancer and were matched to CCSs by age and sex.

At age 50, the cumulative incidence of chronic health conditions (of any grade) was 99.9% in CCSs and 96.0% in controls (P<0.0001). The cumulative incidence of grade 3 to 5 chronic health conditions was 96.0% and 84.9%, respectively (P<0.0001).

The cumulative burden for CCSs was 17.1 chronic health conditions, including 4.7 that were grade 3 to 5. For controls, the cumulative burden was 9.2 chronic health conditions, including 2.3 that were grade 3 to 5 (P<0.0001 for both comparisons).

The researchers said second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden observed in CCSs. However, there was “notable heterogeneity” in burden according to the patients’ primary cancer diagnosis.

For instance, growth hormone deficiency was in the top 10th percentile of chronic health conditions for survivors of acute lymphoblastic leukemia but not for controls.

And pulmonary function deficits were in the top 10th percentile for survivors of acute myeloid leukemia and Hodgkin lymphoma but not for controls or survivors of acute lymphoblastic leukemia or non-Hodgkin lymphoma.

“This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by healthcare providers to disentangle and manage—time that community providers are unlikely to have,” Dr Bhakta said.

“The results suggest that childhood cancer survivors may benefit from the integrated, specialized healthcare delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems.”

With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.

Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.

“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.

In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.

Vyxeos

The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.

In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).

“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.

Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.

The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”

“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”

The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.

Oral targeted therapies

Enasidenib (Idhifa) was approved under priority review in August in conjunction with a companion diagnostic IDH2 assay for patients with relapsed or refractory disease and specific mutations in the IDH2 gene. Midostaurin (Rydapt) was approved in April for use in conjunction with standard daunorubicin and cytarabine induction and cytarabine consolidation in adults with FLT3 mutation-positive AML.

In a phase 1 dose escalation study reported at the annual meeting of the European Hematology Association, enasidenib was associated with an overall response rate of 37% in patients with relapsed/refractory AML, including 20.1% complete responses and 7.9% complete responses with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state. Patients who had a CR had a median overall survival of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months, Dr. Eytan M. Stein, of Memorial Sloan Kettering Cancer Center in New York, reported.

Additionally, need for transfusions was reduced in 34% of 157 patients who required transfusions at study entry.

“In a relapsed or refractory group of patients where there’s no true standard of care, this drug definitely represents a major breakthrough and has a lot of utility as a single agent, as a potential bridge to a transplant, and in combination with new or even old drugs – including regular old induction chemotherapy as a way to improve responses and outcomes in the future,” Dr. Lancet said, adding that as an oral agent it has potential for development as a maintenance strategy.

This agent could have a large impact, he said, adding: “I think this sets the paradigm for novel targeted therapies.”

Midostaurin has also emerged as a new standard of care, particularly for younger patients, Dr. Lancet said.

The approval of the multitargeted kinase inhibitor was based on the results of the randomized, placebo-controlled phase 3 RATIFY trial, which demonstrated significantly longer overall and event-free survival vs. placebo and standard chemotherapy in newly diagnosed AML patients with FLT3 gene mutations.

“I think this will be the new comparator for future studies, whatever they may be, for this patient population,” he said.

Dr. Capozzi noted that she has had some difficulty obtaining prior authorization for enasidenib due to its high cost (about $1,000/day).

The drug is taken orally on days 8-21 of a 28-day treatment cycle. In RATIFY, patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy.

Dr. Capozzi noted that the dosing regimen can be confusing, as it changes depending on whether it is used for induction or consolidation. It remains to be seen how these agents will fit into the treatment setting, she said.

Targeted therapies in development

Other targeted therapies in development for AML include an IDH1 inhibitor, the BCL2 inhibitor venetoclax, and several second-generation FLT3 inhibitors such as gilteritinib, Dr. Lancet said.

Venetoclax, which is currently approved for chronic lymphocytic leukemia, has shown single agent activity, but is even more promising in combination with low-dose cytarabine or aza-nucleosides, he noted.

For example, in one recent study reported at the annual congress of the European Hematology Association, response rates in older, newly diagnosed AML patients were as high as 72% for azacitidine plus venetoclax, and 76% for decitabine plus venetoclax.

“So there’s a lot of interest and promise,” Dr. Lancet said, adding that venetoclax may have broad application in AML. “We’ll be seeing a lot more data in the next year or two.”

An unusual aspect of venetoclax, which is used often for CLL, is the need for observation during dose escalation, Dr. Capozzi noted. Patients tend to question the need for admission for observation with the use of an oral agent, thus efforts are underway to develop criteria for outpatient observation.

Otherwise, venetoclax is fairly easy to access and use, and is well tolerated, she said.

“I expect as we learn more about where (venetoclax) fits in, it will be a much more commonplace agent” as part of AML therapy, she said.

Gilteritinib, as well as the second generation FLT3 inhibitors quizartinib and crenolanib, are also of interest in AML. With midostaurin already on the market, however, different strategies are being pursued, Dr. Lancet said.

“I believe gilteritinib is entering the fray in relapsed/refractory disease, and crenolanib is being looked at in the upfront FLT3 AML-positive setting and ultimately will be compared to midostaurin in combination with chemotherapy in that setting,” he added, noting that these drugs have the advantage of being more potent and selective inhibitors of FLT3, and some appear to have the ability to target resistance-conferring mutations.

“It still remains to be determined what the ultimate role will be, especially now that midostaurin is approved as frontline therapy and, in my opinion, will likely be entrenched there for awhile,” he said. “It’s a fairly competitive field right now, but certainly one where there’s a lot of excitement. The encouraging part is the second generation inhibitors, especially crenolanib and gilteritinib, are able to rescue some patients who may have failed primary therapy with an FLT3 inhibitor.”

Future direction and outcomes

So how should one go about selecting therapies, in the absence of data on combining therapies, for patients with multiple mutations?

Ideally, that means teasing out which of the AML patient’s mutations is clonal and the driver of their disease, and which one is subclonal. There are no guarantees, but that seems like a rational way to begin and move the field forward to studies of combination therapies, Dr. Lancet said.

“I think with the right combinations that target leukemias that are mutationally driven, there is potential to treat subsets of patient with very targeted therapies that will lead to prolonged survival. Right now, for the most part, we don’t have drugs for many of the targets that are very important in AML, and we don’t always know which target is driving the disease ... these are considerations that remain to be discovered,” he said. “But I do think that in 10 years we will have the ability with novel drugs and increased understanding of the clinical relevance of these targets to really personalize the approach more so than we are today, and to increase response rates significantly and improve survival as a result.”

Dr. Lancet is a consultant for Jazz Pharmaceuticals, Daiichi Sankyo, and Celgene. Dr. Capozzi reported having no disclosures.

[email protected]

With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.

Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.

“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.

In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.

Vyxeos

The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.

In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).

“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.

Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.

The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”

“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”

The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.

Oral targeted therapies

Enasidenib (Idhifa) was approved under priority review in August in conjunction with a companion diagnostic IDH2 assay for patients with relapsed or refractory disease and specific mutations in the IDH2 gene. Midostaurin (Rydapt) was approved in April for use in conjunction with standard daunorubicin and cytarabine induction and cytarabine consolidation in adults with FLT3 mutation-positive AML.

In a phase 1 dose escalation study reported at the annual meeting of the European Hematology Association, enasidenib was associated with an overall response rate of 37% in patients with relapsed/refractory AML, including 20.1% complete responses and 7.9% complete responses with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state. Patients who had a CR had a median overall survival of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months, Dr. Eytan M. Stein, of Memorial Sloan Kettering Cancer Center in New York, reported.

Additionally, need for transfusions was reduced in 34% of 157 patients who required transfusions at study entry.

“In a relapsed or refractory group of patients where there’s no true standard of care, this drug definitely represents a major breakthrough and has a lot of utility as a single agent, as a potential bridge to a transplant, and in combination with new or even old drugs – including regular old induction chemotherapy as a way to improve responses and outcomes in the future,” Dr. Lancet said, adding that as an oral agent it has potential for development as a maintenance strategy.

This agent could have a large impact, he said, adding: “I think this sets the paradigm for novel targeted therapies.”

Midostaurin has also emerged as a new standard of care, particularly for younger patients, Dr. Lancet said.

The approval of the multitargeted kinase inhibitor was based on the results of the randomized, placebo-controlled phase 3 RATIFY trial, which demonstrated significantly longer overall and event-free survival vs. placebo and standard chemotherapy in newly diagnosed AML patients with FLT3 gene mutations.

“I think this will be the new comparator for future studies, whatever they may be, for this patient population,” he said.

Dr. Capozzi noted that she has had some difficulty obtaining prior authorization for enasidenib due to its high cost (about $1,000/day).

The drug is taken orally on days 8-21 of a 28-day treatment cycle. In RATIFY, patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy.

Dr. Capozzi noted that the dosing regimen can be confusing, as it changes depending on whether it is used for induction or consolidation. It remains to be seen how these agents will fit into the treatment setting, she said.

Targeted therapies in development

Other targeted therapies in development for AML include an IDH1 inhibitor, the BCL2 inhibitor venetoclax, and several second-generation FLT3 inhibitors such as gilteritinib, Dr. Lancet said.

Venetoclax, which is currently approved for chronic lymphocytic leukemia, has shown single agent activity, but is even more promising in combination with low-dose cytarabine or aza-nucleosides, he noted.

For example, in one recent study reported at the annual congress of the European Hematology Association, response rates in older, newly diagnosed AML patients were as high as 72% for azacitidine plus venetoclax, and 76% for decitabine plus venetoclax.

“So there’s a lot of interest and promise,” Dr. Lancet said, adding that venetoclax may have broad application in AML. “We’ll be seeing a lot more data in the next year or two.”

An unusual aspect of venetoclax, which is used often for CLL, is the need for observation during dose escalation, Dr. Capozzi noted. Patients tend to question the need for admission for observation with the use of an oral agent, thus efforts are underway to develop criteria for outpatient observation.

Otherwise, venetoclax is fairly easy to access and use, and is well tolerated, she said.

“I expect as we learn more about where (venetoclax) fits in, it will be a much more commonplace agent” as part of AML therapy, she said.

Gilteritinib, as well as the second generation FLT3 inhibitors quizartinib and crenolanib, are also of interest in AML. With midostaurin already on the market, however, different strategies are being pursued, Dr. Lancet said.

“I believe gilteritinib is entering the fray in relapsed/refractory disease, and crenolanib is being looked at in the upfront FLT3 AML-positive setting and ultimately will be compared to midostaurin in combination with chemotherapy in that setting,” he added, noting that these drugs have the advantage of being more potent and selective inhibitors of FLT3, and some appear to have the ability to target resistance-conferring mutations.

“It still remains to be determined what the ultimate role will be, especially now that midostaurin is approved as frontline therapy and, in my opinion, will likely be entrenched there for awhile,” he said. “It’s a fairly competitive field right now, but certainly one where there’s a lot of excitement. The encouraging part is the second generation inhibitors, especially crenolanib and gilteritinib, are able to rescue some patients who may have failed primary therapy with an FLT3 inhibitor.”

Future direction and outcomes

So how should one go about selecting therapies, in the absence of data on combining therapies, for patients with multiple mutations?

Ideally, that means teasing out which of the AML patient’s mutations is clonal and the driver of their disease, and which one is subclonal. There are no guarantees, but that seems like a rational way to begin and move the field forward to studies of combination therapies, Dr. Lancet said.

“I think with the right combinations that target leukemias that are mutationally driven, there is potential to treat subsets of patient with very targeted therapies that will lead to prolonged survival. Right now, for the most part, we don’t have drugs for many of the targets that are very important in AML, and we don’t always know which target is driving the disease ... these are considerations that remain to be discovered,” he said. “But I do think that in 10 years we will have the ability with novel drugs and increased understanding of the clinical relevance of these targets to really personalize the approach more so than we are today, and to increase response rates significantly and improve survival as a result.”

Dr. Lancet is a consultant for Jazz Pharmaceuticals, Daiichi Sankyo, and Celgene. Dr. Capozzi reported having no disclosures.

[email protected]

With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.

Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.

“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.

In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.

Vyxeos

The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.

In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).

“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.

Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.

The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”

“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”

The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.

Oral targeted therapies

Enasidenib (Idhifa) was approved under priority review in August in conjunction with a companion diagnostic IDH2 assay for patients with relapsed or refractory disease and specific mutations in the IDH2 gene. Midostaurin (Rydapt) was approved in April for use in conjunction with standard daunorubicin and cytarabine induction and cytarabine consolidation in adults with FLT3 mutation-positive AML.

In a phase 1 dose escalation study reported at the annual meeting of the European Hematology Association, enasidenib was associated with an overall response rate of 37% in patients with relapsed/refractory AML, including 20.1% complete responses and 7.9% complete responses with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state. Patients who had a CR had a median overall survival of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months, Dr. Eytan M. Stein, of Memorial Sloan Kettering Cancer Center in New York, reported.

Additionally, need for transfusions was reduced in 34% of 157 patients who required transfusions at study entry.

“In a relapsed or refractory group of patients where there’s no true standard of care, this drug definitely represents a major breakthrough and has a lot of utility as a single agent, as a potential bridge to a transplant, and in combination with new or even old drugs – including regular old induction chemotherapy as a way to improve responses and outcomes in the future,” Dr. Lancet said, adding that as an oral agent it has potential for development as a maintenance strategy.

This agent could have a large impact, he said, adding: “I think this sets the paradigm for novel targeted therapies.”

Midostaurin has also emerged as a new standard of care, particularly for younger patients, Dr. Lancet said.

The approval of the multitargeted kinase inhibitor was based on the results of the randomized, placebo-controlled phase 3 RATIFY trial, which demonstrated significantly longer overall and event-free survival vs. placebo and standard chemotherapy in newly diagnosed AML patients with FLT3 gene mutations.

“I think this will be the new comparator for future studies, whatever they may be, for this patient population,” he said.

Dr. Capozzi noted that she has had some difficulty obtaining prior authorization for enasidenib due to its high cost (about $1,000/day).

The drug is taken orally on days 8-21 of a 28-day treatment cycle. In RATIFY, patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy.

Dr. Capozzi noted that the dosing regimen can be confusing, as it changes depending on whether it is used for induction or consolidation. It remains to be seen how these agents will fit into the treatment setting, she said.

Targeted therapies in development

Other targeted therapies in development for AML include an IDH1 inhibitor, the BCL2 inhibitor venetoclax, and several second-generation FLT3 inhibitors such as gilteritinib, Dr. Lancet said.

Venetoclax, which is currently approved for chronic lymphocytic leukemia, has shown single agent activity, but is even more promising in combination with low-dose cytarabine or aza-nucleosides, he noted.

For example, in one recent study reported at the annual congress of the European Hematology Association, response rates in older, newly diagnosed AML patients were as high as 72% for azacitidine plus venetoclax, and 76% for decitabine plus venetoclax.

“So there’s a lot of interest and promise,” Dr. Lancet said, adding that venetoclax may have broad application in AML. “We’ll be seeing a lot more data in the next year or two.”

An unusual aspect of venetoclax, which is used often for CLL, is the need for observation during dose escalation, Dr. Capozzi noted. Patients tend to question the need for admission for observation with the use of an oral agent, thus efforts are underway to develop criteria for outpatient observation.

Otherwise, venetoclax is fairly easy to access and use, and is well tolerated, she said.

“I expect as we learn more about where (venetoclax) fits in, it will be a much more commonplace agent” as part of AML therapy, she said.

Gilteritinib, as well as the second generation FLT3 inhibitors quizartinib and crenolanib, are also of interest in AML. With midostaurin already on the market, however, different strategies are being pursued, Dr. Lancet said.

“I believe gilteritinib is entering the fray in relapsed/refractory disease, and crenolanib is being looked at in the upfront FLT3 AML-positive setting and ultimately will be compared to midostaurin in combination with chemotherapy in that setting,” he added, noting that these drugs have the advantage of being more potent and selective inhibitors of FLT3, and some appear to have the ability to target resistance-conferring mutations.

“It still remains to be determined what the ultimate role will be, especially now that midostaurin is approved as frontline therapy and, in my opinion, will likely be entrenched there for awhile,” he said. “It’s a fairly competitive field right now, but certainly one where there’s a lot of excitement. The encouraging part is the second generation inhibitors, especially crenolanib and gilteritinib, are able to rescue some patients who may have failed primary therapy with an FLT3 inhibitor.”

Future direction and outcomes

So how should one go about selecting therapies, in the absence of data on combining therapies, for patients with multiple mutations?

Ideally, that means teasing out which of the AML patient’s mutations is clonal and the driver of their disease, and which one is subclonal. There are no guarantees, but that seems like a rational way to begin and move the field forward to studies of combination therapies, Dr. Lancet said.

“I think with the right combinations that target leukemias that are mutationally driven, there is potential to treat subsets of patient with very targeted therapies that will lead to prolonged survival. Right now, for the most part, we don’t have drugs for many of the targets that are very important in AML, and we don’t always know which target is driving the disease ... these are considerations that remain to be discovered,” he said. “But I do think that in 10 years we will have the ability with novel drugs and increased understanding of the clinical relevance of these targets to really personalize the approach more so than we are today, and to increase response rates significantly and improve survival as a result.”

Dr. Lancet is a consultant for Jazz Pharmaceuticals, Daiichi Sankyo, and Celgene. Dr. Capozzi reported having no disclosures.

[email protected]