User login
Strategy could reduce myelosuppression in AML
Researchers believe they may have found a way to prevent chemotherapy-induced myelosuppression in acute myeloid leukemia (AML).
The team found that priming mice with the FLT3 inhibitor quizartinib protected multipotent progenitor cells (MPPs) from subsequent treatment with fluorouracil (5-FU) or gemcitabine.
And treatment with quizartinib followed by 5-FU proved more effective against AML than standard induction with cytarabine and doxorubicin.
Samuel Taylor, of the University of Western Australia in Crawley, Australia, and his colleagues reported these results in Science Translational Medicine.
The researchers first found that quizartinib induced “rapid and transient” quiescence of MPPs in C57BL/6 mice.
Quizartinib also provided MPPs with “marked protection” from 5-FU. In these experiments, a 10 mg/kg dose of quizartinib was given to mice at the same time as a 150 mg/kg dose of 5-FU. This treatment provided MPPs with 4- to 5-fold greater protection than vehicle control.
Subsequent experiments revealed the optimal dose and schedule for quizartinib. A priming dose of 30 mg/kg given 6 hours before 5-FU provided “slightly greater” protection to hematopoietic stem and progenitor cells than a 10 mg/kg dose, with significantly greater protection observed for short-term hematopoietic stem cells.
The researchers then showed that priming with quizartinib allowed for “rapid recovery of bone marrow cellularity” after treatment with 5-FU. Bone marrow cells were fully restored by day 8 after treatment in quizartinib-primed mice but not in vehicle-primed mice.
Quizartinib priming also protected mice from multiple rounds of treatment with 5-FU (15 cycles in some mice) and from myelosuppression induced by gemcitabine.
Finally, the researchers tested quizartinib followed by 5-FU in mouse models of AML. They found the treatment was more effective than treatment with cytarabine and doxorubicin in both FLT3-ITD(F692L)/NPM1c AML and NPM1c/NrasG12D AML.
FLT3-ITD(F692L)/NPM1c AML
The researchers transplanted 15 non-irradiated B6.CD45.1 mice with 3 × 105 spleen cells each from a FLT3-ITD(F691L)/NPM1c mouse that succumbed to AML at 6 weeks of age. Sixteen days after transplant, the mice were given one of the following:
- No treatment
- 10-day cycles of quizartinib (30 mg/kg) followed 6 hours later by 5-FU (150 mg/kg)
- Cytarabine plus doxorubicin (5+3).
All 5 of the untreated mice died within 30 days of transplantation, exhibiting high white blood cell (WBC) counts and splenomegaly.
The 5+3 mice received 2 cycles of treatment (days 16 to 21 and 36 to 41). All 5 had died by day 56 after transplantation, with high WBC counts and splenomegaly.
One the other hand, 4 of the 5 mice in the quizartinib/5-FU arm were still healthy at 176 days after transplantation and 80 days after stopping treatment. There were no detectable CD45.2+ AML cells when the mice were last bled on day 160, and they had normal WBC counts. There were no AML cells detectable in the animals’ bone marrow after they were killed at day 176.
The quizartinib/5-FU mouse that died before day 176 is believed to have developed resistance to 5-FU. This animal died 121 days after transplantation.
NPM1c/ NrasG12D AML
For another AML model, the researchers crossed NPM1c-mutant mice with NrasG12D-mutant mice. The team transplanted spleen cells from NPM1c/NrasG12D leukemic mice into 15 non-irradiated B6.CD45.1 recipient mice.
Fifteen days after transplantation, the NPM1c/ NrasG12D mice received one of the following:
- No treatment
- Quizartinib and 5-FU as above
- Cytarabine plus doxorubicin (5+3).
All 5 untreated mice died by day 32 after transplantation, and all 5 mice that received 5+3 died by day 35. Both groups of mice had high WBC counts and splenomegaly.
Mice in the quizartinib/5-FU arm initially received 4 cycles of treatment, starting on days 15, 25, 35, and 45 after transplantation. On day 53, they had minimal or undetectable numbers of CD45.2+ AML cells, and WBC counts were normal or slightly below normal.
At day 81—a month after stopping treatment—4 of the mice had detectable CD45.2+ AML cells in their blood. So they restarted treatment the next day. After 4 additional cycles, AML cells were undetectable in all 5 mice. At day 146—a month after stopping the second round of treatment—AML cells again became detectable in the blood.
The mice did not receive any additional treatment. One died at day 196, and 1 was killed at day 197 due to weight loss related to feeding difficulties (but this mouse did not show signs of AML).
The other 3 mice were “active and healthy” until they were killed at day 214. However, they had “high proportions” of CD45.2+ myeloid cells in their blood since day 183. And 2 of the mice had increased WBC counts from day 197. 
Researchers believe they may have found a way to prevent chemotherapy-induced myelosuppression in acute myeloid leukemia (AML).
The team found that priming mice with the FLT3 inhibitor quizartinib protected multipotent progenitor cells (MPPs) from subsequent treatment with fluorouracil (5-FU) or gemcitabine.
And treatment with quizartinib followed by 5-FU proved more effective against AML than standard induction with cytarabine and doxorubicin.
Samuel Taylor, of the University of Western Australia in Crawley, Australia, and his colleagues reported these results in Science Translational Medicine.
The researchers first found that quizartinib induced “rapid and transient” quiescence of MPPs in C57BL/6 mice.
Quizartinib also provided MPPs with “marked protection” from 5-FU. In these experiments, a 10 mg/kg dose of quizartinib was given to mice at the same time as a 150 mg/kg dose of 5-FU. This treatment provided MPPs with 4- to 5-fold greater protection than vehicle control.
Subsequent experiments revealed the optimal dose and schedule for quizartinib. A priming dose of 30 mg/kg given 6 hours before 5-FU provided “slightly greater” protection to hematopoietic stem and progenitor cells than a 10 mg/kg dose, with significantly greater protection observed for short-term hematopoietic stem cells.
The researchers then showed that priming with quizartinib allowed for “rapid recovery of bone marrow cellularity” after treatment with 5-FU. Bone marrow cells were fully restored by day 8 after treatment in quizartinib-primed mice but not in vehicle-primed mice.
Quizartinib priming also protected mice from multiple rounds of treatment with 5-FU (15 cycles in some mice) and from myelosuppression induced by gemcitabine.
Finally, the researchers tested quizartinib followed by 5-FU in mouse models of AML. They found the treatment was more effective than treatment with cytarabine and doxorubicin in both FLT3-ITD(F692L)/NPM1c AML and NPM1c/NrasG12D AML.
FLT3-ITD(F692L)/NPM1c AML
The researchers transplanted 15 non-irradiated B6.CD45.1 mice with 3 × 105 spleen cells each from a FLT3-ITD(F691L)/NPM1c mouse that succumbed to AML at 6 weeks of age. Sixteen days after transplant, the mice were given one of the following:
- No treatment
- 10-day cycles of quizartinib (30 mg/kg) followed 6 hours later by 5-FU (150 mg/kg)
- Cytarabine plus doxorubicin (5+3).
All 5 of the untreated mice died within 30 days of transplantation, exhibiting high white blood cell (WBC) counts and splenomegaly.
The 5+3 mice received 2 cycles of treatment (days 16 to 21 and 36 to 41). All 5 had died by day 56 after transplantation, with high WBC counts and splenomegaly.
One the other hand, 4 of the 5 mice in the quizartinib/5-FU arm were still healthy at 176 days after transplantation and 80 days after stopping treatment. There were no detectable CD45.2+ AML cells when the mice were last bled on day 160, and they had normal WBC counts. There were no AML cells detectable in the animals’ bone marrow after they were killed at day 176.
The quizartinib/5-FU mouse that died before day 176 is believed to have developed resistance to 5-FU. This animal died 121 days after transplantation.
NPM1c/ NrasG12D AML
For another AML model, the researchers crossed NPM1c-mutant mice with NrasG12D-mutant mice. The team transplanted spleen cells from NPM1c/NrasG12D leukemic mice into 15 non-irradiated B6.CD45.1 recipient mice.
Fifteen days after transplantation, the NPM1c/ NrasG12D mice received one of the following:
- No treatment
- Quizartinib and 5-FU as above
- Cytarabine plus doxorubicin (5+3).
All 5 untreated mice died by day 32 after transplantation, and all 5 mice that received 5+3 died by day 35. Both groups of mice had high WBC counts and splenomegaly.
Mice in the quizartinib/5-FU arm initially received 4 cycles of treatment, starting on days 15, 25, 35, and 45 after transplantation. On day 53, they had minimal or undetectable numbers of CD45.2+ AML cells, and WBC counts were normal or slightly below normal.
At day 81—a month after stopping treatment—4 of the mice had detectable CD45.2+ AML cells in their blood. So they restarted treatment the next day. After 4 additional cycles, AML cells were undetectable in all 5 mice. At day 146—a month after stopping the second round of treatment—AML cells again became detectable in the blood.
The mice did not receive any additional treatment. One died at day 196, and 1 was killed at day 197 due to weight loss related to feeding difficulties (but this mouse did not show signs of AML).
The other 3 mice were “active and healthy” until they were killed at day 214. However, they had “high proportions” of CD45.2+ myeloid cells in their blood since day 183. And 2 of the mice had increased WBC counts from day 197.
Researchers believe they may have found a way to prevent chemotherapy-induced myelosuppression in acute myeloid leukemia (AML).
The team found that priming mice with the FLT3 inhibitor quizartinib protected multipotent progenitor cells (MPPs) from subsequent treatment with fluorouracil (5-FU) or gemcitabine.
And treatment with quizartinib followed by 5-FU proved more effective against AML than standard induction with cytarabine and doxorubicin.
Samuel Taylor, of the University of Western Australia in Crawley, Australia, and his colleagues reported these results in Science Translational Medicine.
The researchers first found that quizartinib induced “rapid and transient” quiescence of MPPs in C57BL/6 mice.
Quizartinib also provided MPPs with “marked protection” from 5-FU. In these experiments, a 10 mg/kg dose of quizartinib was given to mice at the same time as a 150 mg/kg dose of 5-FU. This treatment provided MPPs with 4- to 5-fold greater protection than vehicle control.
Subsequent experiments revealed the optimal dose and schedule for quizartinib. A priming dose of 30 mg/kg given 6 hours before 5-FU provided “slightly greater” protection to hematopoietic stem and progenitor cells than a 10 mg/kg dose, with significantly greater protection observed for short-term hematopoietic stem cells.
The researchers then showed that priming with quizartinib allowed for “rapid recovery of bone marrow cellularity” after treatment with 5-FU. Bone marrow cells were fully restored by day 8 after treatment in quizartinib-primed mice but not in vehicle-primed mice.
Quizartinib priming also protected mice from multiple rounds of treatment with 5-FU (15 cycles in some mice) and from myelosuppression induced by gemcitabine.
Finally, the researchers tested quizartinib followed by 5-FU in mouse models of AML. They found the treatment was more effective than treatment with cytarabine and doxorubicin in both FLT3-ITD(F692L)/NPM1c AML and NPM1c/NrasG12D AML.
FLT3-ITD(F692L)/NPM1c AML
The researchers transplanted 15 non-irradiated B6.CD45.1 mice with 3 × 105 spleen cells each from a FLT3-ITD(F691L)/NPM1c mouse that succumbed to AML at 6 weeks of age. Sixteen days after transplant, the mice were given one of the following:
- No treatment
- 10-day cycles of quizartinib (30 mg/kg) followed 6 hours later by 5-FU (150 mg/kg)
- Cytarabine plus doxorubicin (5+3).
All 5 of the untreated mice died within 30 days of transplantation, exhibiting high white blood cell (WBC) counts and splenomegaly.
The 5+3 mice received 2 cycles of treatment (days 16 to 21 and 36 to 41). All 5 had died by day 56 after transplantation, with high WBC counts and splenomegaly.
One the other hand, 4 of the 5 mice in the quizartinib/5-FU arm were still healthy at 176 days after transplantation and 80 days after stopping treatment. There were no detectable CD45.2+ AML cells when the mice were last bled on day 160, and they had normal WBC counts. There were no AML cells detectable in the animals’ bone marrow after they were killed at day 176.
The quizartinib/5-FU mouse that died before day 176 is believed to have developed resistance to 5-FU. This animal died 121 days after transplantation.
NPM1c/ NrasG12D AML
For another AML model, the researchers crossed NPM1c-mutant mice with NrasG12D-mutant mice. The team transplanted spleen cells from NPM1c/NrasG12D leukemic mice into 15 non-irradiated B6.CD45.1 recipient mice.
Fifteen days after transplantation, the NPM1c/ NrasG12D mice received one of the following:
- No treatment
- Quizartinib and 5-FU as above
- Cytarabine plus doxorubicin (5+3).
All 5 untreated mice died by day 32 after transplantation, and all 5 mice that received 5+3 died by day 35. Both groups of mice had high WBC counts and splenomegaly.
Mice in the quizartinib/5-FU arm initially received 4 cycles of treatment, starting on days 15, 25, 35, and 45 after transplantation. On day 53, they had minimal or undetectable numbers of CD45.2+ AML cells, and WBC counts were normal or slightly below normal.
At day 81—a month after stopping treatment—4 of the mice had detectable CD45.2+ AML cells in their blood. So they restarted treatment the next day. After 4 additional cycles, AML cells were undetectable in all 5 mice. At day 146—a month after stopping the second round of treatment—AML cells again became detectable in the blood.
The mice did not receive any additional treatment. One died at day 196, and 1 was killed at day 197 due to weight loss related to feeding difficulties (but this mouse did not show signs of AML).
The other 3 mice were “active and healthy” until they were killed at day 214. However, they had “high proportions” of CD45.2+ myeloid cells in their blood since day 183. And 2 of the mice had increased WBC counts from day 197.
Targeting heme synthesis to treat AML
Researchers have found evidence to suggest that a type of acute myeloid leukemia (AML) depends on the production of heme.
The group’s work has revealed 2 ways to target heme synthesis that might be used to treat this type of AML, which is driven by the oncogene MYCN.
John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleague described this research in JCI Insight.
Previous research had suggested that heme production was affected in leukemia.
However, Dr Schuetz said, “Absolutely nothing was known about the role of heme biosynthesis [in AML] before our work.”
The researchers’ first clue regarding heme’s role in AML arose from a computer search. The team searched a genomic database for other genes that were abnormally switched on in MYCN-driven AML.
They found that UROD was highly activated and noted that UROD is part of the molecular machinery that synthesizes heme.
Especially significant, Dr Schuetz said, was the finding that MYCN-driven AML with the most over-activated UROD was far more lethal than other AMLs.
The researchers found that cells with over-activated MYCN consumed more oxygen and depended on the production of heme for self-renewal and oncogenic transformation. But the team was able to block cancer cell self-renewal in the MYCN cells by blocking heme synthesis.
The researchers also found they could suppress self-renewal by blocking ABCG2, a “relief-valve” molecule that rids the cells of porphyrin, a building-block molecule of heme.
Blocking ABCG2 caused the buildup of porphyrin, which is toxic to the leukemia cells. However, blocking ABCG2 in normal cells produced no ill effects.
In mouse models of MYCN leukemia, the researchers tested a strategy of knocking out ABCG2. These knockout mice had significantly slower disease progression and longer survival.
What’s more, the team found they could cure leukemia in these mice by inhibiting ABCG2 and ramping up the heme machinery.
“Our findings suggest 2 drug strategies to treat AML,” Dr Schuetz said. “One would be to target UROD, which would reduce heme biosynthesis. Such drugs would selectively affect leukemia cells because they are so dependent on heme.”
“The other strategy would be to use drugs to inhibit the relief-valve protein and, at the same time, administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway.”
Dr Schuetz said other cancers with an over-activated heme pathway might also be vulnerable to such a treatment strategy.
He and his colleagues plan to extend their understanding of the heme machinery in AML with further studies. For example, they don’t know whether heme’s role in cell respiration is the only important one in supporting AML progression, since heme plays a wide range of roles in cells.
The researchers are also planning to test whether drugs that suppress UROD function in the heme-production machinery can effectively battle AML.
Researchers have found evidence to suggest that a type of acute myeloid leukemia (AML) depends on the production of heme.
The group’s work has revealed 2 ways to target heme synthesis that might be used to treat this type of AML, which is driven by the oncogene MYCN.
John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleague described this research in JCI Insight.
Previous research had suggested that heme production was affected in leukemia.
However, Dr Schuetz said, “Absolutely nothing was known about the role of heme biosynthesis [in AML] before our work.”
The researchers’ first clue regarding heme’s role in AML arose from a computer search. The team searched a genomic database for other genes that were abnormally switched on in MYCN-driven AML.
They found that UROD was highly activated and noted that UROD is part of the molecular machinery that synthesizes heme.
Especially significant, Dr Schuetz said, was the finding that MYCN-driven AML with the most over-activated UROD was far more lethal than other AMLs.
The researchers found that cells with over-activated MYCN consumed more oxygen and depended on the production of heme for self-renewal and oncogenic transformation. But the team was able to block cancer cell self-renewal in the MYCN cells by blocking heme synthesis.
The researchers also found they could suppress self-renewal by blocking ABCG2, a “relief-valve” molecule that rids the cells of porphyrin, a building-block molecule of heme.
Blocking ABCG2 caused the buildup of porphyrin, which is toxic to the leukemia cells. However, blocking ABCG2 in normal cells produced no ill effects.
In mouse models of MYCN leukemia, the researchers tested a strategy of knocking out ABCG2. These knockout mice had significantly slower disease progression and longer survival.
What’s more, the team found they could cure leukemia in these mice by inhibiting ABCG2 and ramping up the heme machinery.
“Our findings suggest 2 drug strategies to treat AML,” Dr Schuetz said. “One would be to target UROD, which would reduce heme biosynthesis. Such drugs would selectively affect leukemia cells because they are so dependent on heme.”
“The other strategy would be to use drugs to inhibit the relief-valve protein and, at the same time, administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway.”
Dr Schuetz said other cancers with an over-activated heme pathway might also be vulnerable to such a treatment strategy.
He and his colleagues plan to extend their understanding of the heme machinery in AML with further studies. For example, they don’t know whether heme’s role in cell respiration is the only important one in supporting AML progression, since heme plays a wide range of roles in cells.
The researchers are also planning to test whether drugs that suppress UROD function in the heme-production machinery can effectively battle AML.
Researchers have found evidence to suggest that a type of acute myeloid leukemia (AML) depends on the production of heme.
The group’s work has revealed 2 ways to target heme synthesis that might be used to treat this type of AML, which is driven by the oncogene MYCN.
John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleague described this research in JCI Insight.
Previous research had suggested that heme production was affected in leukemia.
However, Dr Schuetz said, “Absolutely nothing was known about the role of heme biosynthesis [in AML] before our work.”
The researchers’ first clue regarding heme’s role in AML arose from a computer search. The team searched a genomic database for other genes that were abnormally switched on in MYCN-driven AML.
They found that UROD was highly activated and noted that UROD is part of the molecular machinery that synthesizes heme.
Especially significant, Dr Schuetz said, was the finding that MYCN-driven AML with the most over-activated UROD was far more lethal than other AMLs.
The researchers found that cells with over-activated MYCN consumed more oxygen and depended on the production of heme for self-renewal and oncogenic transformation. But the team was able to block cancer cell self-renewal in the MYCN cells by blocking heme synthesis.
The researchers also found they could suppress self-renewal by blocking ABCG2, a “relief-valve” molecule that rids the cells of porphyrin, a building-block molecule of heme.
Blocking ABCG2 caused the buildup of porphyrin, which is toxic to the leukemia cells. However, blocking ABCG2 in normal cells produced no ill effects.
In mouse models of MYCN leukemia, the researchers tested a strategy of knocking out ABCG2. These knockout mice had significantly slower disease progression and longer survival.
What’s more, the team found they could cure leukemia in these mice by inhibiting ABCG2 and ramping up the heme machinery.
“Our findings suggest 2 drug strategies to treat AML,” Dr Schuetz said. “One would be to target UROD, which would reduce heme biosynthesis. Such drugs would selectively affect leukemia cells because they are so dependent on heme.”
“The other strategy would be to use drugs to inhibit the relief-valve protein and, at the same time, administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway.”
Dr Schuetz said other cancers with an over-activated heme pathway might also be vulnerable to such a treatment strategy.
He and his colleagues plan to extend their understanding of the heme machinery in AML with further studies. For example, they don’t know whether heme’s role in cell respiration is the only important one in supporting AML progression, since heme plays a wide range of roles in cells.
The researchers are also planning to test whether drugs that suppress UROD function in the heme-production machinery can effectively battle AML.
FDA approves drug to treat 2 types of AML
The US Food and Drug Administration (FDA) has granted approval for CPX-351 (Vyxeos™), a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.
CPX-351 is approved to treat adults with 2 types of acute myeloid leukemia (AML)—AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML.
The FDA granted the approval of CPX-351 to Jazz Pharmaceuticals.
The company says the drug will be commercially available within a week.
The FDA approval of CPX-351 is based on data from a phase 3 trial in which researchers compared CPX-351 to cytarabine and daunorubicin (7+3) in 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.
The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).
The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.
The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).
All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.
Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.
The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.
The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.
The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.
For more information on CPX-351, visit http://www.vyxeos.com.
The US Food and Drug Administration (FDA) has granted approval for CPX-351 (Vyxeos™), a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.
CPX-351 is approved to treat adults with 2 types of acute myeloid leukemia (AML)—AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML.
The FDA granted the approval of CPX-351 to Jazz Pharmaceuticals.
The company says the drug will be commercially available within a week.
The FDA approval of CPX-351 is based on data from a phase 3 trial in which researchers compared CPX-351 to cytarabine and daunorubicin (7+3) in 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.
The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).
The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.
The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).
All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.
Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.
The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.
The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.
The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.
For more information on CPX-351, visit http://www.vyxeos.com.
The US Food and Drug Administration (FDA) has granted approval for CPX-351 (Vyxeos™), a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.
CPX-351 is approved to treat adults with 2 types of acute myeloid leukemia (AML)—AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML.
The FDA granted the approval of CPX-351 to Jazz Pharmaceuticals.
The company says the drug will be commercially available within a week.
The FDA approval of CPX-351 is based on data from a phase 3 trial in which researchers compared CPX-351 to cytarabine and daunorubicin (7+3) in 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.
The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).
The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.
The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).
All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.
Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.
The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.
The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.
The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.
For more information on CPX-351, visit http://www.vyxeos.com.
Liposomal daunorubicin and cytarabine approved for t-AML, AML-MRC
, the Food and Drug Administration announced on Aug. 3.
Vyxeos is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC, the FDA said in its press release announcing the approval.
“Vyxeos is the first chemotherapy to demonstrate an overall survival advantage over the standard of care in a phase 3 randomized study of older adults with newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes,” Jeffrey E. Lancet, MD, an investigator in the clinical trials of Vyxeos and chair of the department of malignant hematology at the H. Lee Moffitt Cancer Center in Tampa, Fla., said in a press release.
Vyxeos was associated with a median overall survival of 9.6 months and a standard combination of cytarabine and daunorubicin (7+3) was associated with a median survival of 5.9 months in a randomized, multicenter, open-label trial of 309 patients aged 60-75 years with newly-diagnosed t-AML or AML-MRC. Data from the study, which is NCT01696084, was the basis for the drug’s approval.
Vyxeos is a fixed-dose combination with each Vyxeos vial containing 44 mg daunorubicin and 100 mg cytarabine encapsulated together in liposomes. As dosing is based on the daunorubicin component, the corresponding cytarabine dose does not need to be calculated. Daunorubicin dosing is calculated on the basis of body surface area (mg/m2).
For the first induction cycle, the recommended Vyxeos dose is daunorubicin 44 mg/m2 (cytarabine 100 mg/m2) infused intravenously over 90 minutes on days 1, 3, and 5. If a second induction cycle is needed, the same dose is administered on days 1 and 3. The recommended dose of Vyxeos for each cycle of consolidation therapy is daunorubicin 29 mg/m2 (cytarabine 65 mg/m2) liposome via intravenous infusion over 90 minutes on days 1 and 3.
Adverse reactions occurring in at least 25% of treated patients in the clinical trial included hemorrhage, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.
The prescribing information includes a boxed warning not to substitute Vyxeos with other daunorubicin- or cytarabine-containing products. Full prescribing information is available at: www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl.pdf
The maker of Vyxeos is Jazz Pharmaceuticals.
[email protected]
On Twitter @maryjodales
, the Food and Drug Administration announced on Aug. 3.
Vyxeos is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC, the FDA said in its press release announcing the approval.
“Vyxeos is the first chemotherapy to demonstrate an overall survival advantage over the standard of care in a phase 3 randomized study of older adults with newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes,” Jeffrey E. Lancet, MD, an investigator in the clinical trials of Vyxeos and chair of the department of malignant hematology at the H. Lee Moffitt Cancer Center in Tampa, Fla., said in a press release.
Vyxeos was associated with a median overall survival of 9.6 months and a standard combination of cytarabine and daunorubicin (7+3) was associated with a median survival of 5.9 months in a randomized, multicenter, open-label trial of 309 patients aged 60-75 years with newly-diagnosed t-AML or AML-MRC. Data from the study, which is NCT01696084, was the basis for the drug’s approval.
Vyxeos is a fixed-dose combination with each Vyxeos vial containing 44 mg daunorubicin and 100 mg cytarabine encapsulated together in liposomes. As dosing is based on the daunorubicin component, the corresponding cytarabine dose does not need to be calculated. Daunorubicin dosing is calculated on the basis of body surface area (mg/m2).
For the first induction cycle, the recommended Vyxeos dose is daunorubicin 44 mg/m2 (cytarabine 100 mg/m2) infused intravenously over 90 minutes on days 1, 3, and 5. If a second induction cycle is needed, the same dose is administered on days 1 and 3. The recommended dose of Vyxeos for each cycle of consolidation therapy is daunorubicin 29 mg/m2 (cytarabine 65 mg/m2) liposome via intravenous infusion over 90 minutes on days 1 and 3.
Adverse reactions occurring in at least 25% of treated patients in the clinical trial included hemorrhage, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.
The prescribing information includes a boxed warning not to substitute Vyxeos with other daunorubicin- or cytarabine-containing products. Full prescribing information is available at: www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl.pdf
The maker of Vyxeos is Jazz Pharmaceuticals.
[email protected]
On Twitter @maryjodales
, the Food and Drug Administration announced on Aug. 3.
Vyxeos is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC, the FDA said in its press release announcing the approval.
“Vyxeos is the first chemotherapy to demonstrate an overall survival advantage over the standard of care in a phase 3 randomized study of older adults with newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes,” Jeffrey E. Lancet, MD, an investigator in the clinical trials of Vyxeos and chair of the department of malignant hematology at the H. Lee Moffitt Cancer Center in Tampa, Fla., said in a press release.
Vyxeos was associated with a median overall survival of 9.6 months and a standard combination of cytarabine and daunorubicin (7+3) was associated with a median survival of 5.9 months in a randomized, multicenter, open-label trial of 309 patients aged 60-75 years with newly-diagnosed t-AML or AML-MRC. Data from the study, which is NCT01696084, was the basis for the drug’s approval.
Vyxeos is a fixed-dose combination with each Vyxeos vial containing 44 mg daunorubicin and 100 mg cytarabine encapsulated together in liposomes. As dosing is based on the daunorubicin component, the corresponding cytarabine dose does not need to be calculated. Daunorubicin dosing is calculated on the basis of body surface area (mg/m2).
For the first induction cycle, the recommended Vyxeos dose is daunorubicin 44 mg/m2 (cytarabine 100 mg/m2) infused intravenously over 90 minutes on days 1, 3, and 5. If a second induction cycle is needed, the same dose is administered on days 1 and 3. The recommended dose of Vyxeos for each cycle of consolidation therapy is daunorubicin 29 mg/m2 (cytarabine 65 mg/m2) liposome via intravenous infusion over 90 minutes on days 1 and 3.
Adverse reactions occurring in at least 25% of treated patients in the clinical trial included hemorrhage, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.
The prescribing information includes a boxed warning not to substitute Vyxeos with other daunorubicin- or cytarabine-containing products. Full prescribing information is available at: www.accessdata.fda.gov/drugsatfda_docs/label/2017/209401s000lbl.pdf
The maker of Vyxeos is Jazz Pharmaceuticals.
[email protected]
On Twitter @maryjodales
FDA approves enasidenib to treat relapsed/refractory AML
The US Food and Drug Administration (FDA) has approved marketing of the oral IDH2 inhibitor enasidenib (IDHIFA®).
The drug is now approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation, as detected by an FDA-approved test.
Enasidenib is available in 50 mg and 100 mg tablets. The recommended dose is 100 mg once daily until disease progression or unacceptable toxicity.
The prescribing information for enasidenib includes a boxed warning that the drug may cause differentiation syndrome, and this adverse event (AE) can be fatal if not treated.
Signs and symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, and hepatic, renal, or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms resolve.
Companion diagnostic
Enasidenib was approved concurrently with the Abbott RealTime™ IDH2 companion diagnostic test, which was approved as an aid in identifying AML patients for treatment with enasidenib.
The FDA granted approval of enasidenib to Celgene Corporation and approval of the RealTime IDH2 Assay to Abbott Laboratories.
Enasidenib is licensed from Agios Pharmaceuticals.
Trial results
The FDA’s approval of enasidenib and the companion diagnostic test was based on data from a phase 1/2 trial (Study AG221-C-001, NCT01915498).
Data from this trial were recently presented at the ASCO 2017 Annual Meeting. However, the definitive data are included in the prescribing information for enasidenib.
The prescribing information includes efficacy data for 199 adults with relapsed/refractory AML and an IDH2 mutation. IDH2 mutations were identified or confirmed by the Abbott RealTime™ IDH2 test.
The 199 patients received enasidenib at a starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage side effects.
The patients’ median age was 68 (range, 19 to 100). They received a median of 2 prior anticancer regimens (range, 1 to 6). More than half (52%) were refractory to previous therapy.
The rate of complete response (CR) or CR with partial hematologic improvement (CRh) was 23% (n=46). The median duration of CR/CRh was 8.2 months (range, 4.3 to 19.4).
For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, 0.5 to 7.5), and the median time to best response of CR/CRh was 3.7 months (range, 0.6 to 11.2).
Among the 157 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 53 (34%) became independent of RBC and platelet transfusions during any 56-day period post-baseline.
Of the 42 patients who were independent of both RBC and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post-baseline period.
Researchers evaluated the safety of enasidenib in 214 patients. The median duration of exposure to enasidenib was 4.3 months (range, 0.3 to 23.6).
The most common AEs of any grade (≥20%) were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite.
Serious AEs were reported in 77.1% of patients. The most frequent serious AEs (≥2%) were leukocytosis, diarrhea, nausea, vomiting, decreased appetite, tumor lysis syndrome, and differentiation syndrome.
The 30-day and 60-day mortality rates were 4.2% (9/214) and 11.7% (25/214), respectively.
The US Food and Drug Administration (FDA) has approved marketing of the oral IDH2 inhibitor enasidenib (IDHIFA®).
The drug is now approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation, as detected by an FDA-approved test.
Enasidenib is available in 50 mg and 100 mg tablets. The recommended dose is 100 mg once daily until disease progression or unacceptable toxicity.
The prescribing information for enasidenib includes a boxed warning that the drug may cause differentiation syndrome, and this adverse event (AE) can be fatal if not treated.
Signs and symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, and hepatic, renal, or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms resolve.
Companion diagnostic
Enasidenib was approved concurrently with the Abbott RealTime™ IDH2 companion diagnostic test, which was approved as an aid in identifying AML patients for treatment with enasidenib.
The FDA granted approval of enasidenib to Celgene Corporation and approval of the RealTime IDH2 Assay to Abbott Laboratories.
Enasidenib is licensed from Agios Pharmaceuticals.
Trial results
The FDA’s approval of enasidenib and the companion diagnostic test was based on data from a phase 1/2 trial (Study AG221-C-001, NCT01915498).
Data from this trial were recently presented at the ASCO 2017 Annual Meeting. However, the definitive data are included in the prescribing information for enasidenib.
The prescribing information includes efficacy data for 199 adults with relapsed/refractory AML and an IDH2 mutation. IDH2 mutations were identified or confirmed by the Abbott RealTime™ IDH2 test.
The 199 patients received enasidenib at a starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage side effects.
The patients’ median age was 68 (range, 19 to 100). They received a median of 2 prior anticancer regimens (range, 1 to 6). More than half (52%) were refractory to previous therapy.
The rate of complete response (CR) or CR with partial hematologic improvement (CRh) was 23% (n=46). The median duration of CR/CRh was 8.2 months (range, 4.3 to 19.4).
For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, 0.5 to 7.5), and the median time to best response of CR/CRh was 3.7 months (range, 0.6 to 11.2).
Among the 157 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 53 (34%) became independent of RBC and platelet transfusions during any 56-day period post-baseline.
Of the 42 patients who were independent of both RBC and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post-baseline period.
Researchers evaluated the safety of enasidenib in 214 patients. The median duration of exposure to enasidenib was 4.3 months (range, 0.3 to 23.6).
The most common AEs of any grade (≥20%) were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite.
Serious AEs were reported in 77.1% of patients. The most frequent serious AEs (≥2%) were leukocytosis, diarrhea, nausea, vomiting, decreased appetite, tumor lysis syndrome, and differentiation syndrome.
The 30-day and 60-day mortality rates were 4.2% (9/214) and 11.7% (25/214), respectively.
The US Food and Drug Administration (FDA) has approved marketing of the oral IDH2 inhibitor enasidenib (IDHIFA®).
The drug is now approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation, as detected by an FDA-approved test.
Enasidenib is available in 50 mg and 100 mg tablets. The recommended dose is 100 mg once daily until disease progression or unacceptable toxicity.
The prescribing information for enasidenib includes a boxed warning that the drug may cause differentiation syndrome, and this adverse event (AE) can be fatal if not treated.
Signs and symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, and hepatic, renal, or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms resolve.
Companion diagnostic
Enasidenib was approved concurrently with the Abbott RealTime™ IDH2 companion diagnostic test, which was approved as an aid in identifying AML patients for treatment with enasidenib.
The FDA granted approval of enasidenib to Celgene Corporation and approval of the RealTime IDH2 Assay to Abbott Laboratories.
Enasidenib is licensed from Agios Pharmaceuticals.
Trial results
The FDA’s approval of enasidenib and the companion diagnostic test was based on data from a phase 1/2 trial (Study AG221-C-001, NCT01915498).
Data from this trial were recently presented at the ASCO 2017 Annual Meeting. However, the definitive data are included in the prescribing information for enasidenib.
The prescribing information includes efficacy data for 199 adults with relapsed/refractory AML and an IDH2 mutation. IDH2 mutations were identified or confirmed by the Abbott RealTime™ IDH2 test.
The 199 patients received enasidenib at a starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage side effects.
The patients’ median age was 68 (range, 19 to 100). They received a median of 2 prior anticancer regimens (range, 1 to 6). More than half (52%) were refractory to previous therapy.
The rate of complete response (CR) or CR with partial hematologic improvement (CRh) was 23% (n=46). The median duration of CR/CRh was 8.2 months (range, 4.3 to 19.4).
For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, 0.5 to 7.5), and the median time to best response of CR/CRh was 3.7 months (range, 0.6 to 11.2).
Among the 157 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 53 (34%) became independent of RBC and platelet transfusions during any 56-day period post-baseline.
Of the 42 patients who were independent of both RBC and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post-baseline period.
Researchers evaluated the safety of enasidenib in 214 patients. The median duration of exposure to enasidenib was 4.3 months (range, 0.3 to 23.6).
The most common AEs of any grade (≥20%) were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite.
Serious AEs were reported in 77.1% of patients. The most frequent serious AEs (≥2%) were leukocytosis, diarrhea, nausea, vomiting, decreased appetite, tumor lysis syndrome, and differentiation syndrome.
The 30-day and 60-day mortality rates were 4.2% (9/214) and 11.7% (25/214), respectively.
Enasidenib gets FDA approval for AML with IDH2 mutations
Enasidenib has been approved for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) and specific mutations in the IDH2 gene, the U.S. Food and Drug Administration announced on Aug. 1.
The drug is approved for use with a companion diagnostic, the RealTime IDH2 Assay, which is used to detect IDH2 gene mutations. The FDA granted the approval of enasidenib (Idhifa) to the Celgene Corp. and the approval of the companion RealTime IDH2 Assay to Abbott Laboratories. Idhifa had Priority Review and Orphan Drug designations.
In data reported at the annual congress of the European Hematology Association, the overall response rate to enasidenib among 214 patients with IDH2 gene mutations treated at the 100-mg/day dose was 37%. This included 20.1% with a complete remission, 7.9% with complete remission with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state, according to Eytan M. Stein, MD, an internist and hematologic oncologist at the Memorial Sloan Kettering Cancer Center in New York.
According to an FDA press release, 34% of 157 patients who required transfusions of blood or platelets at the start of the study no longer required transfusions after treatment.
For 8%-19% of AML patients, the mutated IDH2 enzyme blocks normal blood cell development and results in an overabundance of immature blood cells, Celgene said in an announcement.
Common side effects of enasidenib, an isocitrate dehydrogenase-2 inhibitor, include nausea, vomiting, diarrhea, hyperbilirubinemia, and decreased appetite.
Fatal differentiation syndrome can occur and is treated with corticosteroids. The prescribing information for Idhifa includes a boxed warning regarding that risk. Symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, or hepatic, renal or multi-organ dysfunction, according to a press release issued by the FDA.
[email protected]
On Twitter @maryjodales
Enasidenib has been approved for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) and specific mutations in the IDH2 gene, the U.S. Food and Drug Administration announced on Aug. 1.
The drug is approved for use with a companion diagnostic, the RealTime IDH2 Assay, which is used to detect IDH2 gene mutations. The FDA granted the approval of enasidenib (Idhifa) to the Celgene Corp. and the approval of the companion RealTime IDH2 Assay to Abbott Laboratories. Idhifa had Priority Review and Orphan Drug designations.
In data reported at the annual congress of the European Hematology Association, the overall response rate to enasidenib among 214 patients with IDH2 gene mutations treated at the 100-mg/day dose was 37%. This included 20.1% with a complete remission, 7.9% with complete remission with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state, according to Eytan M. Stein, MD, an internist and hematologic oncologist at the Memorial Sloan Kettering Cancer Center in New York.
According to an FDA press release, 34% of 157 patients who required transfusions of blood or platelets at the start of the study no longer required transfusions after treatment.
For 8%-19% of AML patients, the mutated IDH2 enzyme blocks normal blood cell development and results in an overabundance of immature blood cells, Celgene said in an announcement.
Common side effects of enasidenib, an isocitrate dehydrogenase-2 inhibitor, include nausea, vomiting, diarrhea, hyperbilirubinemia, and decreased appetite.
Fatal differentiation syndrome can occur and is treated with corticosteroids. The prescribing information for Idhifa includes a boxed warning regarding that risk. Symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, or hepatic, renal or multi-organ dysfunction, according to a press release issued by the FDA.
[email protected]
On Twitter @maryjodales
Enasidenib has been approved for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) and specific mutations in the IDH2 gene, the U.S. Food and Drug Administration announced on Aug. 1.
The drug is approved for use with a companion diagnostic, the RealTime IDH2 Assay, which is used to detect IDH2 gene mutations. The FDA granted the approval of enasidenib (Idhifa) to the Celgene Corp. and the approval of the companion RealTime IDH2 Assay to Abbott Laboratories. Idhifa had Priority Review and Orphan Drug designations.
In data reported at the annual congress of the European Hematology Association, the overall response rate to enasidenib among 214 patients with IDH2 gene mutations treated at the 100-mg/day dose was 37%. This included 20.1% with a complete remission, 7.9% with complete remission with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state, according to Eytan M. Stein, MD, an internist and hematologic oncologist at the Memorial Sloan Kettering Cancer Center in New York.
According to an FDA press release, 34% of 157 patients who required transfusions of blood or platelets at the start of the study no longer required transfusions after treatment.
For 8%-19% of AML patients, the mutated IDH2 enzyme blocks normal blood cell development and results in an overabundance of immature blood cells, Celgene said in an announcement.
Common side effects of enasidenib, an isocitrate dehydrogenase-2 inhibitor, include nausea, vomiting, diarrhea, hyperbilirubinemia, and decreased appetite.
Fatal differentiation syndrome can occur and is treated with corticosteroids. The prescribing information for Idhifa includes a boxed warning regarding that risk. Symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, or hepatic, renal or multi-organ dysfunction, according to a press release issued by the FDA.
[email protected]
On Twitter @maryjodales
FDA grants drug breakthrough designation for AML
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to venetoclax (Venclexta®).
The designation is for venetoclax in combination with low-dose cytarabine to treat elderly patients with previously untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
About venetoclax
Venetoclax is a small molecule designed to selectively bind and inhibit the BCL-2 protein. The drug is being developed by AbbVie and Roche.
Last year, the FDA granted venetoclax accelerated approval to treat patients with chronic lymphocytic leukemia who have 17p deletion and have received at least one prior therapy. Continued approval of venetoclax for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
The FDA granted venetoclax breakthrough therapy designation for the AML indication based on data from an ongoing phase 1/2 study. Preliminary data from the study were presented at the 22nd European Hematology Association (EHA) Annual Congress.
The presentation included data on 61 elderly patients (older than 65) with previously untreated AML who were ineligible for intensive chemotherapy.
They received venetoclax in combination with low-dose cytarabine (as well as prophylaxis for tumor lysis syndrome). The patients’ median time on treatment was 6 months (range, <1 to 19 months), and 72% of patients discontinued treatment.
The overall response rate was 65%. Twenty-five percent of patients achieved a complete response, 38% had a complete response with incomplete blood count recovery, and 2% had a partial response.
The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.
The most common adverse events of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).
Grade 3/4 adverse events (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), anemia (28%), hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%).
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to venetoclax (Venclexta®).
The designation is for venetoclax in combination with low-dose cytarabine to treat elderly patients with previously untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
About venetoclax
Venetoclax is a small molecule designed to selectively bind and inhibit the BCL-2 protein. The drug is being developed by AbbVie and Roche.
Last year, the FDA granted venetoclax accelerated approval to treat patients with chronic lymphocytic leukemia who have 17p deletion and have received at least one prior therapy. Continued approval of venetoclax for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
The FDA granted venetoclax breakthrough therapy designation for the AML indication based on data from an ongoing phase 1/2 study. Preliminary data from the study were presented at the 22nd European Hematology Association (EHA) Annual Congress.
The presentation included data on 61 elderly patients (older than 65) with previously untreated AML who were ineligible for intensive chemotherapy.
They received venetoclax in combination with low-dose cytarabine (as well as prophylaxis for tumor lysis syndrome). The patients’ median time on treatment was 6 months (range, <1 to 19 months), and 72% of patients discontinued treatment.
The overall response rate was 65%. Twenty-five percent of patients achieved a complete response, 38% had a complete response with incomplete blood count recovery, and 2% had a partial response.
The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.
The most common adverse events of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).
Grade 3/4 adverse events (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), anemia (28%), hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%).
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to venetoclax (Venclexta®).
The designation is for venetoclax in combination with low-dose cytarabine to treat elderly patients with previously untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
About venetoclax
Venetoclax is a small molecule designed to selectively bind and inhibit the BCL-2 protein. The drug is being developed by AbbVie and Roche.
Last year, the FDA granted venetoclax accelerated approval to treat patients with chronic lymphocytic leukemia who have 17p deletion and have received at least one prior therapy. Continued approval of venetoclax for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
The FDA granted venetoclax breakthrough therapy designation for the AML indication based on data from an ongoing phase 1/2 study. Preliminary data from the study were presented at the 22nd European Hematology Association (EHA) Annual Congress.
The presentation included data on 61 elderly patients (older than 65) with previously untreated AML who were ineligible for intensive chemotherapy.
They received venetoclax in combination with low-dose cytarabine (as well as prophylaxis for tumor lysis syndrome). The patients’ median time on treatment was 6 months (range, <1 to 19 months), and 72% of patients discontinued treatment.
The overall response rate was 65%. Twenty-five percent of patients achieved a complete response, 38% had a complete response with incomplete blood count recovery, and 2% had a partial response.
The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.
The most common adverse events of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).
Grade 3/4 adverse events (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), anemia (28%), hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%).
Team makes ‘fundamental’ AML discovery
A newly identified pathway plays a “fundamental” role in acute myeloid leukemia (AML), according to researchers.
The team discovered that AML cells have a secretory pathway that leads to the production and release of the immune receptor Tim-3 and its ligand galectin-9, both of which prevent natural killer (NK) and other cytotoxic cells from killing the AML cells.
Vadim Sumbayev, PhD, of the University of Kent in the UK, and his colleagues recounted these findings in EBioMedicine.
The researchers found that AML cells—but not healthy blood cells—express a receptor called latrophilin 1 (LPHN1). LPHN1 induces activation of PKCα, which triggers the translation and secretion of Tim-3 and galectin-9.
Soluble Tim-3 prevents the secretion of interleukin 2, which is required for the activation of NK cells and cytotoxic T cells. Galectin-9 impairs the AML-cell-killing ability of NK cells and other cytotoxic lymphocytes.
The researchers said their work revealed both biomarkers for AML diagnostics and potential targets for AML treatment.
“Targeting this pathway will crucially enhance patients’ own immune defenses, helping them to eliminate leukemia cells,” Dr Sumbayev said.
He added that his group’s discovery might be applied to the treatment of other cancers as well.
A newly identified pathway plays a “fundamental” role in acute myeloid leukemia (AML), according to researchers.
The team discovered that AML cells have a secretory pathway that leads to the production and release of the immune receptor Tim-3 and its ligand galectin-9, both of which prevent natural killer (NK) and other cytotoxic cells from killing the AML cells.
Vadim Sumbayev, PhD, of the University of Kent in the UK, and his colleagues recounted these findings in EBioMedicine.
The researchers found that AML cells—but not healthy blood cells—express a receptor called latrophilin 1 (LPHN1). LPHN1 induces activation of PKCα, which triggers the translation and secretion of Tim-3 and galectin-9.
Soluble Tim-3 prevents the secretion of interleukin 2, which is required for the activation of NK cells and cytotoxic T cells. Galectin-9 impairs the AML-cell-killing ability of NK cells and other cytotoxic lymphocytes.
The researchers said their work revealed both biomarkers for AML diagnostics and potential targets for AML treatment.
“Targeting this pathway will crucially enhance patients’ own immune defenses, helping them to eliminate leukemia cells,” Dr Sumbayev said.
He added that his group’s discovery might be applied to the treatment of other cancers as well.
A newly identified pathway plays a “fundamental” role in acute myeloid leukemia (AML), according to researchers.
The team discovered that AML cells have a secretory pathway that leads to the production and release of the immune receptor Tim-3 and its ligand galectin-9, both of which prevent natural killer (NK) and other cytotoxic cells from killing the AML cells.
Vadim Sumbayev, PhD, of the University of Kent in the UK, and his colleagues recounted these findings in EBioMedicine.
The researchers found that AML cells—but not healthy blood cells—express a receptor called latrophilin 1 (LPHN1). LPHN1 induces activation of PKCα, which triggers the translation and secretion of Tim-3 and galectin-9.
Soluble Tim-3 prevents the secretion of interleukin 2, which is required for the activation of NK cells and cytotoxic T cells. Galectin-9 impairs the AML-cell-killing ability of NK cells and other cytotoxic lymphocytes.
The researchers said their work revealed both biomarkers for AML diagnostics and potential targets for AML treatment.
“Targeting this pathway will crucially enhance patients’ own immune defenses, helping them to eliminate leukemia cells,” Dr Sumbayev said.
He added that his group’s discovery might be applied to the treatment of other cancers as well.
Predicting response to treatment in AML, MDS
Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.
The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.
The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.
And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.
Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.
In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.
The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.
The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.
The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.
Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.
The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.
DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.
In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.
The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.
The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.
And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.
Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.
In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.
The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.
The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.
The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.
Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.
The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.
DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.
In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.
The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.
The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.
And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.
Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.
In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.
The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.
The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.
The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.
Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.
The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.
DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.
In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
CHMP recommends midostaurin for FLT3+ AML, SM
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) is recommending approval for midostaurin (Rydapt®) as a treatment for acute myeloid leukemia (AML) and systemic mastocytosis (SM).
If approved by the European Commission, midostaurin would be used in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation—followed by midostaurin maintenance for patients in complete response—in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3-mutation-positive.
Midostaurin would also be approved to treat adults with aggressive SM, SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).
If approved, midostaurin would be the first targeted treatment available in the European Union for newly diagnosed FLT3+ AML patients and advanced SM patients.
The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation. The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.
Midostaurin in AML
The CHMP’s recommendation for midostaurin in AML is based on results from the phase 3 RATIFY trial, which were recently published in NEJM.
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 infections.
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 CHMP’s recommendation for midostaurin in advanced SM was 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.
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) is recommending approval for midostaurin (Rydapt®) as a treatment for acute myeloid leukemia (AML) and systemic mastocytosis (SM).
If approved by the European Commission, midostaurin would be used in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation—followed by midostaurin maintenance for patients in complete response—in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3-mutation-positive.
Midostaurin would also be approved to treat adults with aggressive SM, SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).
If approved, midostaurin would be the first targeted treatment available in the European Union for newly diagnosed FLT3+ AML patients and advanced SM patients.
The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation. The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.
Midostaurin in AML
The CHMP’s recommendation for midostaurin in AML is based on results from the phase 3 RATIFY trial, which were recently published in NEJM.
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 infections.
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 CHMP’s recommendation for midostaurin in advanced SM was 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.
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) is recommending approval for midostaurin (Rydapt®) as a treatment for acute myeloid leukemia (AML) and systemic mastocytosis (SM).
If approved by the European Commission, midostaurin would be used in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation—followed by midostaurin maintenance for patients in complete response—in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3-mutation-positive.
Midostaurin would also be approved to treat adults with aggressive SM, SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).
If approved, midostaurin would be the first targeted treatment available in the European Union for newly diagnosed FLT3+ AML patients and advanced SM patients.
The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation. The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.
Midostaurin in AML
The CHMP’s recommendation for midostaurin in AML is based on results from the phase 3 RATIFY trial, which were recently published in NEJM.
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 infections.
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 CHMP’s recommendation for midostaurin in advanced SM was 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.