AML

HOUSTON – Midostaurin maintenance therapy along with standard-of-care treatment after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) appears to reduce the risk of relapse, according to findings from the randomized, phase 2 RADIUS trial.

Sharon Worcester/MDedge News

Notably, the effect of midostaurin in this open-label, exploratory trial was most pronounced in patients with high levels of phosphorylated FLT3 (pFLT3) inhibition as assessed by plasma inhibitor activity assay, Richard T. Maziarz, MD, reported at the Transplantation & Cellular Therapy Meetings.

“The median [pFLT3 reduction] was less than 70% ... those patients who had the deepest level inhibition maintained the highest likelihood of staying free of disease,” Dr. Maziarz, a professor of medicine at Oregon Health & Science University, Portland, said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).


Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that was shown in the pivotal RATIFY trial to significantly improve event-free and overall survival versus placebo when interspersed with induction and consolidation chemotherapy and also when used for maintenance in adults with newly diagnosed FLT3-mutated AML, Dr. Maziarz explained. He noted that patients in the RATIFY study who underwent alloSCT did not receive midostaurin maintenance (N Engl J Med. 2017; 377:454-64).

Although alloSCT provides the greatest likelihood of sustained remission in AML, relapse rates remain high at 30%-59%, he said, adding that, “in the setting of transplantation, FLT3 expression, or FLT3-ITD [internal tandem duplication] ... is a poor risk feature.”

[email protected]

HOUSTON – Midostaurin maintenance therapy along with standard-of-care treatment after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) appears to reduce the risk of relapse, according to findings from the randomized, phase 2 RADIUS trial.

Sharon Worcester/MDedge News

Notably, the effect of midostaurin in this open-label, exploratory trial was most pronounced in patients with high levels of phosphorylated FLT3 (pFLT3) inhibition as assessed by plasma inhibitor activity assay, Richard T. Maziarz, MD, reported at the Transplantation & Cellular Therapy Meetings.

“The median [pFLT3 reduction] was less than 70% ... those patients who had the deepest level inhibition maintained the highest likelihood of staying free of disease,” Dr. Maziarz, a professor of medicine at Oregon Health & Science University, Portland, said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).


Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that was shown in the pivotal RATIFY trial to significantly improve event-free and overall survival versus placebo when interspersed with induction and consolidation chemotherapy and also when used for maintenance in adults with newly diagnosed FLT3-mutated AML, Dr. Maziarz explained. He noted that patients in the RATIFY study who underwent alloSCT did not receive midostaurin maintenance (N Engl J Med. 2017; 377:454-64).

Although alloSCT provides the greatest likelihood of sustained remission in AML, relapse rates remain high at 30%-59%, he said, adding that, “in the setting of transplantation, FLT3 expression, or FLT3-ITD [internal tandem duplication] ... is a poor risk feature.”

[email protected]

HOUSTON – Midostaurin maintenance therapy along with standard-of-care treatment after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) appears to reduce the risk of relapse, according to findings from the randomized, phase 2 RADIUS trial.

Sharon Worcester/MDedge News

Notably, the effect of midostaurin in this open-label, exploratory trial was most pronounced in patients with high levels of phosphorylated FLT3 (pFLT3) inhibition as assessed by plasma inhibitor activity assay, Richard T. Maziarz, MD, reported at the Transplantation & Cellular Therapy Meetings.

“The median [pFLT3 reduction] was less than 70% ... those patients who had the deepest level inhibition maintained the highest likelihood of staying free of disease,” Dr. Maziarz, a professor of medicine at Oregon Health & Science University, Portland, said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).


Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that was shown in the pivotal RATIFY trial to significantly improve event-free and overall survival versus placebo when interspersed with induction and consolidation chemotherapy and also when used for maintenance in adults with newly diagnosed FLT3-mutated AML, Dr. Maziarz explained. He noted that patients in the RATIFY study who underwent alloSCT did not receive midostaurin maintenance (N Engl J Med. 2017; 377:454-64).

Although alloSCT provides the greatest likelihood of sustained remission in AML, relapse rates remain high at 30%-59%, he said, adding that, “in the setting of transplantation, FLT3 expression, or FLT3-ITD [internal tandem duplication] ... is a poor risk feature.”

[email protected]

HOUSTON – A treosulfan-based conditioning regimen could become standard prior to allogeneic transplant in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndromes, according to the lead investigator in a phase 3 trial.

The treosulfan/fludarabine myeloablative conditioning regimen had noninferior event-free survival, compared with a reduced-intensity busulfan-based regimen in the large, randomized trial that included elderly patients and those with multiple comorbidities, said researcher Dietrich Wilhelm Beelen, MD, PhD.

The experimental regimen was superior to busulfan in overall survival, nonrelapse mortality, and complete donor chimerism in the trial, added Dr. Beelen, who is with the department of bone marrow transplantation at the West German Cancer Center, University Hospital of Essen, Germany.

“The study results point to a potential benefit of the treosulfan/fludarabine regimen, while the early safety profile, engraftment kinetics, acute or chronic graft-versus-host-disease (GvHD), and the relapse risk of both regimens appear comparable,” Dr. Beelen said at the Transplantation & Cellular Therapy Meetings.

Allogeneic hematopoietic cell transplantation (HCT) is challenging in elderly and comorbid patients, who have an increased risk of nonrelapse mortality with standard myeloablative regimens, according to Dr. Beelen, who presented results on behalf of investigators from the international MC-FludT.14/L Study Group.

SOURCE: Beelen DW et al. TCT 2019, Abstract 4.

HOUSTON – A treosulfan-based conditioning regimen could become standard prior to allogeneic transplant in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndromes, according to the lead investigator in a phase 3 trial.

The treosulfan/fludarabine myeloablative conditioning regimen had noninferior event-free survival, compared with a reduced-intensity busulfan-based regimen in the large, randomized trial that included elderly patients and those with multiple comorbidities, said researcher Dietrich Wilhelm Beelen, MD, PhD.

The experimental regimen was superior to busulfan in overall survival, nonrelapse mortality, and complete donor chimerism in the trial, added Dr. Beelen, who is with the department of bone marrow transplantation at the West German Cancer Center, University Hospital of Essen, Germany.

“The study results point to a potential benefit of the treosulfan/fludarabine regimen, while the early safety profile, engraftment kinetics, acute or chronic graft-versus-host-disease (GvHD), and the relapse risk of both regimens appear comparable,” Dr. Beelen said at the Transplantation & Cellular Therapy Meetings.

Allogeneic hematopoietic cell transplantation (HCT) is challenging in elderly and comorbid patients, who have an increased risk of nonrelapse mortality with standard myeloablative regimens, according to Dr. Beelen, who presented results on behalf of investigators from the international MC-FludT.14/L Study Group.

SOURCE: Beelen DW et al. TCT 2019, Abstract 4.

HOUSTON – A treosulfan-based conditioning regimen could become standard prior to allogeneic transplant in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndromes, according to the lead investigator in a phase 3 trial.

The treosulfan/fludarabine myeloablative conditioning regimen had noninferior event-free survival, compared with a reduced-intensity busulfan-based regimen in the large, randomized trial that included elderly patients and those with multiple comorbidities, said researcher Dietrich Wilhelm Beelen, MD, PhD.

The experimental regimen was superior to busulfan in overall survival, nonrelapse mortality, and complete donor chimerism in the trial, added Dr. Beelen, who is with the department of bone marrow transplantation at the West German Cancer Center, University Hospital of Essen, Germany.

“The study results point to a potential benefit of the treosulfan/fludarabine regimen, while the early safety profile, engraftment kinetics, acute or chronic graft-versus-host-disease (GvHD), and the relapse risk of both regimens appear comparable,” Dr. Beelen said at the Transplantation & Cellular Therapy Meetings.

Allogeneic hematopoietic cell transplantation (HCT) is challenging in elderly and comorbid patients, who have an increased risk of nonrelapse mortality with standard myeloablative regimens, according to Dr. Beelen, who presented results on behalf of investigators from the international MC-FludT.14/L Study Group.

SOURCE: Beelen DW et al. TCT 2019, Abstract 4.

The thrombopoietic agent eltrombopag (Promacta) did more harm than good when given to adults with acute myeloid leukemia (AML) during standard induction chemotherapy, results of a randomized phase 2 trial show.

Patients who were randomly assigned to receive standard induction chemotherapy with daunorubicin and cytarabine plus eltrombopag had a higher incidence of serious adverse events and death from hemorrhage within 30 days of the last eltrombopag dose, compared with patients who received chemotherapy and placebo, reported Noelle Frey, MD, from the University of Pennsylvania in Philadelphia, and colleagues.

“Overall survival was also numerically longer in the placebo group, compared with the eltrombopag group. It remains unclear why there were more deaths, particularly due to hemorrhage within 30 days after the last dose of treatment, in the eltrombopag group,” they wrote in the Lancet Haematology.

The investigators had expected better results, based on eltrombopag’s demonstrated efficacy against thrombocytopenia (a common feature of AML, exacerbated by chemotherapy), and because of evidence suggesting that the thrombopoietin-receptor agonist might also have antileukemic properties.

They set out to test the safety, tolerability, and efficacy of eltrombopag added to standard induction therapy in patients with treatment-naive AML of any subtype except M3 (acute promyelocytic leukemia) or M7 (acute megakaryocytic leukemia).

Patients received chemotherapy with daunorubicin in a bolus intravenous infusion at a dose of 90 mg/m² on days 1-3 for patients 18-60 years of age, or 60 mg/m² for patients older than 60 years, plus cytarabine continuous intravenous infusion at a dose of 100 mg/m² on days 1-7. The 148 patients were randomized in groups of 74 each to receive either eltrombopag 200 mg (100 mg for patients of east Asian heritage) or placebo, once daily.

Eltrombopag was continued until platelet counts were 200 × 10⁹/L or higher, remission, or 42 days after the start of induction chemotherapy.

Grade 3 or 4 adverse events occurring in 10% or more of patients – a primary endpoint – were febrile neutropenia, which occurred in 42% of patients receiving eltrombopag, compared with 39% receiving placebo, decreased white blood cell count in 11% vs. 7%, and hypophosphatemia in 4% and 13%, respectively,

Serious adverse events occurred in 34% of patients on eltrombopag, compared with 20% on placebo. Similarly, 53% of patients receiving eltrombopag died, compared with 41% of patients receiving the placebo.

Most of the deaths were attributable to AML, including 19 patients (26%) on eltrombopag and 10 (14%) on placebo. Eleven patients on eltrombopag and four on placebo died within 30 days of the last dose of study treatment.

Hemorrhage accounted for the deaths of five patients on eltrombopag and three on placebo, and sepsis accounted for the deaths of five and six patients, respectively.

Both the incidence of thromboembolic events and mean change in left ventricular ejection fraction were similar between the groups.

Median overall survival was 15.4 months in the eltrombopag group vs. 25.7 months in the placebo group, although this difference was not statistically significant, likely because of the sample size.

The investigators were at a loss to explain why the eltrombopag-treated patients had numerically worse outcomes.

“In the present study, eltrombopag did not improve the time to platelet recovery or the incidences of grade 3-4 thrombocytopenia, neutropenia, or anemia, compared with placebo. Furthermore, the study did not reveal any differences in investigator-assessed response to treatment. These findings were unexpected given outcomes from previous studies of eltrombopag monotherapy in patients with myelodysplastic syndromes or acute myeloid leukemia,” they wrote.

Although the reasons behind the findings are unclear, “the data from this trial do not support a favorable benefit-risk profile for eltrombopag in combination with induction chemotherapy in patients with acute myeloid leukemia,” the investigators wrote.

The study was funded by Novartis. Dr. Frey reported nonfinancial support from Novartis during the conduct of the study and consultancy fees from Novartis outside of the submitted work. Multiple coauthors reported similar relationships with Novartis and/or other companies.

SOURCE: Frey N et al. Lancet Haematol. 2019 Jan 28. doi: 10.1016/S2352-3026(18)30231-X.

The thrombopoietic agent eltrombopag (Promacta) did more harm than good when given to adults with acute myeloid leukemia (AML) during standard induction chemotherapy, results of a randomized phase 2 trial show.

Patients who were randomly assigned to receive standard induction chemotherapy with daunorubicin and cytarabine plus eltrombopag had a higher incidence of serious adverse events and death from hemorrhage within 30 days of the last eltrombopag dose, compared with patients who received chemotherapy and placebo, reported Noelle Frey, MD, from the University of Pennsylvania in Philadelphia, and colleagues.

“Overall survival was also numerically longer in the placebo group, compared with the eltrombopag group. It remains unclear why there were more deaths, particularly due to hemorrhage within 30 days after the last dose of treatment, in the eltrombopag group,” they wrote in the Lancet Haematology.

The investigators had expected better results, based on eltrombopag’s demonstrated efficacy against thrombocytopenia (a common feature of AML, exacerbated by chemotherapy), and because of evidence suggesting that the thrombopoietin-receptor agonist might also have antileukemic properties.

They set out to test the safety, tolerability, and efficacy of eltrombopag added to standard induction therapy in patients with treatment-naive AML of any subtype except M3 (acute promyelocytic leukemia) or M7 (acute megakaryocytic leukemia).

Patients received chemotherapy with daunorubicin in a bolus intravenous infusion at a dose of 90 mg/m² on days 1-3 for patients 18-60 years of age, or 60 mg/m² for patients older than 60 years, plus cytarabine continuous intravenous infusion at a dose of 100 mg/m² on days 1-7. The 148 patients were randomized in groups of 74 each to receive either eltrombopag 200 mg (100 mg for patients of east Asian heritage) or placebo, once daily.

Eltrombopag was continued until platelet counts were 200 × 10⁹/L or higher, remission, or 42 days after the start of induction chemotherapy.

Grade 3 or 4 adverse events occurring in 10% or more of patients – a primary endpoint – were febrile neutropenia, which occurred in 42% of patients receiving eltrombopag, compared with 39% receiving placebo, decreased white blood cell count in 11% vs. 7%, and hypophosphatemia in 4% and 13%, respectively,

Serious adverse events occurred in 34% of patients on eltrombopag, compared with 20% on placebo. Similarly, 53% of patients receiving eltrombopag died, compared with 41% of patients receiving the placebo.

Most of the deaths were attributable to AML, including 19 patients (26%) on eltrombopag and 10 (14%) on placebo. Eleven patients on eltrombopag and four on placebo died within 30 days of the last dose of study treatment.

Hemorrhage accounted for the deaths of five patients on eltrombopag and three on placebo, and sepsis accounted for the deaths of five and six patients, respectively.

Both the incidence of thromboembolic events and mean change in left ventricular ejection fraction were similar between the groups.

Median overall survival was 15.4 months in the eltrombopag group vs. 25.7 months in the placebo group, although this difference was not statistically significant, likely because of the sample size.

The investigators were at a loss to explain why the eltrombopag-treated patients had numerically worse outcomes.

“In the present study, eltrombopag did not improve the time to platelet recovery or the incidences of grade 3-4 thrombocytopenia, neutropenia, or anemia, compared with placebo. Furthermore, the study did not reveal any differences in investigator-assessed response to treatment. These findings were unexpected given outcomes from previous studies of eltrombopag monotherapy in patients with myelodysplastic syndromes or acute myeloid leukemia,” they wrote.

Although the reasons behind the findings are unclear, “the data from this trial do not support a favorable benefit-risk profile for eltrombopag in combination with induction chemotherapy in patients with acute myeloid leukemia,” the investigators wrote.

The study was funded by Novartis. Dr. Frey reported nonfinancial support from Novartis during the conduct of the study and consultancy fees from Novartis outside of the submitted work. Multiple coauthors reported similar relationships with Novartis and/or other companies.

SOURCE: Frey N et al. Lancet Haematol. 2019 Jan 28. doi: 10.1016/S2352-3026(18)30231-X.

The thrombopoietic agent eltrombopag (Promacta) did more harm than good when given to adults with acute myeloid leukemia (AML) during standard induction chemotherapy, results of a randomized phase 2 trial show.

Patients who were randomly assigned to receive standard induction chemotherapy with daunorubicin and cytarabine plus eltrombopag had a higher incidence of serious adverse events and death from hemorrhage within 30 days of the last eltrombopag dose, compared with patients who received chemotherapy and placebo, reported Noelle Frey, MD, from the University of Pennsylvania in Philadelphia, and colleagues.

“Overall survival was also numerically longer in the placebo group, compared with the eltrombopag group. It remains unclear why there were more deaths, particularly due to hemorrhage within 30 days after the last dose of treatment, in the eltrombopag group,” they wrote in the Lancet Haematology.

The investigators had expected better results, based on eltrombopag’s demonstrated efficacy against thrombocytopenia (a common feature of AML, exacerbated by chemotherapy), and because of evidence suggesting that the thrombopoietin-receptor agonist might also have antileukemic properties.

They set out to test the safety, tolerability, and efficacy of eltrombopag added to standard induction therapy in patients with treatment-naive AML of any subtype except M3 (acute promyelocytic leukemia) or M7 (acute megakaryocytic leukemia).

Patients received chemotherapy with daunorubicin in a bolus intravenous infusion at a dose of 90 mg/m² on days 1-3 for patients 18-60 years of age, or 60 mg/m² for patients older than 60 years, plus cytarabine continuous intravenous infusion at a dose of 100 mg/m² on days 1-7. The 148 patients were randomized in groups of 74 each to receive either eltrombopag 200 mg (100 mg for patients of east Asian heritage) or placebo, once daily.

Eltrombopag was continued until platelet counts were 200 × 10⁹/L or higher, remission, or 42 days after the start of induction chemotherapy.

Grade 3 or 4 adverse events occurring in 10% or more of patients – a primary endpoint – were febrile neutropenia, which occurred in 42% of patients receiving eltrombopag, compared with 39% receiving placebo, decreased white blood cell count in 11% vs. 7%, and hypophosphatemia in 4% and 13%, respectively,

Serious adverse events occurred in 34% of patients on eltrombopag, compared with 20% on placebo. Similarly, 53% of patients receiving eltrombopag died, compared with 41% of patients receiving the placebo.

Most of the deaths were attributable to AML, including 19 patients (26%) on eltrombopag and 10 (14%) on placebo. Eleven patients on eltrombopag and four on placebo died within 30 days of the last dose of study treatment.

Hemorrhage accounted for the deaths of five patients on eltrombopag and three on placebo, and sepsis accounted for the deaths of five and six patients, respectively.

Both the incidence of thromboembolic events and mean change in left ventricular ejection fraction were similar between the groups.

Median overall survival was 15.4 months in the eltrombopag group vs. 25.7 months in the placebo group, although this difference was not statistically significant, likely because of the sample size.

The investigators were at a loss to explain why the eltrombopag-treated patients had numerically worse outcomes.

“In the present study, eltrombopag did not improve the time to platelet recovery or the incidences of grade 3-4 thrombocytopenia, neutropenia, or anemia, compared with placebo. Furthermore, the study did not reveal any differences in investigator-assessed response to treatment. These findings were unexpected given outcomes from previous studies of eltrombopag monotherapy in patients with myelodysplastic syndromes or acute myeloid leukemia,” they wrote.

Although the reasons behind the findings are unclear, “the data from this trial do not support a favorable benefit-risk profile for eltrombopag in combination with induction chemotherapy in patients with acute myeloid leukemia,” the investigators wrote.

The study was funded by Novartis. Dr. Frey reported nonfinancial support from Novartis during the conduct of the study and consultancy fees from Novartis outside of the submitted work. Multiple coauthors reported similar relationships with Novartis and/or other companies.

SOURCE: Frey N et al. Lancet Haematol. 2019 Jan 28. doi: 10.1016/S2352-3026(18)30231-X.

Breast cancer survivors should continue to be monitored for hematologic malignancies, especially acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), results of a population-based study from France suggest.

Among nearly 440,000 women with an incident breast cancer diagnosis, the incidence of AML was nearly three times higher and the incidence of MDS was five times higher than that of women in the general population. Women with breast cancer also were at higher risk for multiple myeloma (MM) and acute lymphoblastic leukemia/lymphocytic lymphoma (ALL/LL) compared with the background population, reported Marie Joelle Jabagi, PharmD, MPH, of the University of Paris Sud, France, and her colleagues.

“These findings serve to better inform practicing oncologists, and breast cancer survivors should be advised of the increased risk of developing certain hematologic malignant neoplasms after their first cancer diagnosis,” they wrote in JAMA Network Open.

Breast cancers are the malignant solid tumors most frequently associated with risk for myeloid neoplasms, but there is little information on the risk for secondary lymphoid malignancies among breast cancer patients, the investigators stated.

“In addition, real-life data on secondary hematologic malignant neoplasm incidence are scarce, especially in the recent period marked by major advances in breast cancer treatments,” they wrote.

To get better estimates of the incidence of myeloid and lymphoid neoplasms in this population, they conducted a retrospective review of information from the French National Health Data System on all French women from the ages of 20 to 85 years who had an incident breast cancer diagnosis from July 1, 2006, through Dec. 31, 2015.

In all, 439,704 women with a median age of 59 years were identified. They were followed until a diagnosis of a hematologic malignancy, death, or loss to follow-up, or until Dec. 31, 2016.

Data on the breast cancer patients were compared with those for all French women in the general population who were registered in the general national health insurance program from January 2007 through the end of 2016.

During a median follow-up of 5 years, there were 3,046 cases of hematologic neoplasms among the breast cancer patients, including 509 cases of AML, for a crude incidence rate (CIR) of 24.5 per 100,000 person-years (py); 832 cases of MDS for a CIR of 40.1/100,000 py; and 267 cases of myeloproliferative neoplasms (MPN), for a CIR of 12.8/100,000 py.

In addition, there were 420 cases of MM for a CIR of 20.3/100,000 py; 912 cases of Hodgkin or non-Hodgkin lymphoma (HL/NHL) for a CIR of 44.4/100,000 py, and 106 cases of ALL/LL for a CIR of 5.1/100,000 py.

Breast cancer survivors had significantly higher incidences, compared with the general population, of AML (standardized incidence ratio [SIR] 2.8, 95% confidence interval [CI], 2.5-3.2), MDS (SIR 5.0, CI, 4.4-5.7), MM (SIR 1.5, CI, 1.3-17), and ALL/LL (SIR 2.0, CI, 1.3-3.0). There was a trend toward significance for both MPN and HL/NHL, but the lower limit of the confidence intervals for these conditions either crossed or touched 1.

In a review of the literature, the authors found that “[s]everal studies linked AML and MDS to chemotherapeutic agents, radiation treatment, and supportive treatment with granulocyte colony-stimulating factor. These results are consistent with other available data showing a 2½-fold to 3½-fold increased risk of AML.”

They noted that their estimate of a five-fold increase in risk for MDS was higher than the 3.7-fold risk reported in a previous registry cohort analysis, suggesting that risk for MDS among breast cancer patients may be underestimated.

“The recent discovery of the gene signatures that guide treatment decisions in early-stage breast cancer might reduce the number of patients exposed to cytotoxic chemotherapy and its complications, including hematologic malignant neoplasm. Therefore, continuing to monitor hematologic malignant neoplasm trends is necessary, especially given that approaches to cancer treatment are rapidly evolving. Further research is also required to assess the modality of treatment for and the genetic predisposition to these secondary malignant neoplasms,” the authors concluded.

SOURCE: Jabagi MJ et al. JAMA Network Open. 2019 Jan 18. doi: 10.1001/jamanetworkopen.2018.7147.

Breast cancer survivors should continue to be monitored for hematologic malignancies, especially acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), results of a population-based study from France suggest.

Among nearly 440,000 women with an incident breast cancer diagnosis, the incidence of AML was nearly three times higher and the incidence of MDS was five times higher than that of women in the general population. Women with breast cancer also were at higher risk for multiple myeloma (MM) and acute lymphoblastic leukemia/lymphocytic lymphoma (ALL/LL) compared with the background population, reported Marie Joelle Jabagi, PharmD, MPH, of the University of Paris Sud, France, and her colleagues.

“These findings serve to better inform practicing oncologists, and breast cancer survivors should be advised of the increased risk of developing certain hematologic malignant neoplasms after their first cancer diagnosis,” they wrote in JAMA Network Open.

Breast cancers are the malignant solid tumors most frequently associated with risk for myeloid neoplasms, but there is little information on the risk for secondary lymphoid malignancies among breast cancer patients, the investigators stated.

“In addition, real-life data on secondary hematologic malignant neoplasm incidence are scarce, especially in the recent period marked by major advances in breast cancer treatments,” they wrote.

To get better estimates of the incidence of myeloid and lymphoid neoplasms in this population, they conducted a retrospective review of information from the French National Health Data System on all French women from the ages of 20 to 85 years who had an incident breast cancer diagnosis from July 1, 2006, through Dec. 31, 2015.

In all, 439,704 women with a median age of 59 years were identified. They were followed until a diagnosis of a hematologic malignancy, death, or loss to follow-up, or until Dec. 31, 2016.

Data on the breast cancer patients were compared with those for all French women in the general population who were registered in the general national health insurance program from January 2007 through the end of 2016.

During a median follow-up of 5 years, there were 3,046 cases of hematologic neoplasms among the breast cancer patients, including 509 cases of AML, for a crude incidence rate (CIR) of 24.5 per 100,000 person-years (py); 832 cases of MDS for a CIR of 40.1/100,000 py; and 267 cases of myeloproliferative neoplasms (MPN), for a CIR of 12.8/100,000 py.

In addition, there were 420 cases of MM for a CIR of 20.3/100,000 py; 912 cases of Hodgkin or non-Hodgkin lymphoma (HL/NHL) for a CIR of 44.4/100,000 py, and 106 cases of ALL/LL for a CIR of 5.1/100,000 py.

Breast cancer survivors had significantly higher incidences, compared with the general population, of AML (standardized incidence ratio [SIR] 2.8, 95% confidence interval [CI], 2.5-3.2), MDS (SIR 5.0, CI, 4.4-5.7), MM (SIR 1.5, CI, 1.3-17), and ALL/LL (SIR 2.0, CI, 1.3-3.0). There was a trend toward significance for both MPN and HL/NHL, but the lower limit of the confidence intervals for these conditions either crossed or touched 1.

In a review of the literature, the authors found that “[s]everal studies linked AML and MDS to chemotherapeutic agents, radiation treatment, and supportive treatment with granulocyte colony-stimulating factor. These results are consistent with other available data showing a 2½-fold to 3½-fold increased risk of AML.”

They noted that their estimate of a five-fold increase in risk for MDS was higher than the 3.7-fold risk reported in a previous registry cohort analysis, suggesting that risk for MDS among breast cancer patients may be underestimated.

“The recent discovery of the gene signatures that guide treatment decisions in early-stage breast cancer might reduce the number of patients exposed to cytotoxic chemotherapy and its complications, including hematologic malignant neoplasm. Therefore, continuing to monitor hematologic malignant neoplasm trends is necessary, especially given that approaches to cancer treatment are rapidly evolving. Further research is also required to assess the modality of treatment for and the genetic predisposition to these secondary malignant neoplasms,” the authors concluded.

SOURCE: Jabagi MJ et al. JAMA Network Open. 2019 Jan 18. doi: 10.1001/jamanetworkopen.2018.7147.

Breast cancer survivors should continue to be monitored for hematologic malignancies, especially acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), results of a population-based study from France suggest.

Among nearly 440,000 women with an incident breast cancer diagnosis, the incidence of AML was nearly three times higher and the incidence of MDS was five times higher than that of women in the general population. Women with breast cancer also were at higher risk for multiple myeloma (MM) and acute lymphoblastic leukemia/lymphocytic lymphoma (ALL/LL) compared with the background population, reported Marie Joelle Jabagi, PharmD, MPH, of the University of Paris Sud, France, and her colleagues.

“These findings serve to better inform practicing oncologists, and breast cancer survivors should be advised of the increased risk of developing certain hematologic malignant neoplasms after their first cancer diagnosis,” they wrote in JAMA Network Open.

Breast cancers are the malignant solid tumors most frequently associated with risk for myeloid neoplasms, but there is little information on the risk for secondary lymphoid malignancies among breast cancer patients, the investigators stated.

“In addition, real-life data on secondary hematologic malignant neoplasm incidence are scarce, especially in the recent period marked by major advances in breast cancer treatments,” they wrote.

To get better estimates of the incidence of myeloid and lymphoid neoplasms in this population, they conducted a retrospective review of information from the French National Health Data System on all French women from the ages of 20 to 85 years who had an incident breast cancer diagnosis from July 1, 2006, through Dec. 31, 2015.

In all, 439,704 women with a median age of 59 years were identified. They were followed until a diagnosis of a hematologic malignancy, death, or loss to follow-up, or until Dec. 31, 2016.

Data on the breast cancer patients were compared with those for all French women in the general population who were registered in the general national health insurance program from January 2007 through the end of 2016.

During a median follow-up of 5 years, there were 3,046 cases of hematologic neoplasms among the breast cancer patients, including 509 cases of AML, for a crude incidence rate (CIR) of 24.5 per 100,000 person-years (py); 832 cases of MDS for a CIR of 40.1/100,000 py; and 267 cases of myeloproliferative neoplasms (MPN), for a CIR of 12.8/100,000 py.

In addition, there were 420 cases of MM for a CIR of 20.3/100,000 py; 912 cases of Hodgkin or non-Hodgkin lymphoma (HL/NHL) for a CIR of 44.4/100,000 py, and 106 cases of ALL/LL for a CIR of 5.1/100,000 py.

Breast cancer survivors had significantly higher incidences, compared with the general population, of AML (standardized incidence ratio [SIR] 2.8, 95% confidence interval [CI], 2.5-3.2), MDS (SIR 5.0, CI, 4.4-5.7), MM (SIR 1.5, CI, 1.3-17), and ALL/LL (SIR 2.0, CI, 1.3-3.0). There was a trend toward significance for both MPN and HL/NHL, but the lower limit of the confidence intervals for these conditions either crossed or touched 1.

In a review of the literature, the authors found that “[s]everal studies linked AML and MDS to chemotherapeutic agents, radiation treatment, and supportive treatment with granulocyte colony-stimulating factor. These results are consistent with other available data showing a 2½-fold to 3½-fold increased risk of AML.”

They noted that their estimate of a five-fold increase in risk for MDS was higher than the 3.7-fold risk reported in a previous registry cohort analysis, suggesting that risk for MDS among breast cancer patients may be underestimated.

“The recent discovery of the gene signatures that guide treatment decisions in early-stage breast cancer might reduce the number of patients exposed to cytotoxic chemotherapy and its complications, including hematologic malignant neoplasm. Therefore, continuing to monitor hematologic malignant neoplasm trends is necessary, especially given that approaches to cancer treatment are rapidly evolving. Further research is also required to assess the modality of treatment for and the genetic predisposition to these secondary malignant neoplasms,” the authors concluded.

SOURCE: Jabagi MJ et al. JAMA Network Open. 2019 Jan 18. doi: 10.1001/jamanetworkopen.2018.7147.

The University of Texas MD Anderson Cancer Center, Houston, and Ascentage Pharma of Suzhou, China, recently formed a 5-year strategic alliance to advance the development of novel cancer therapeutics, primarily for leukemia.

The collaboration, led by Hagop Kantarjian, MD, chair of leukemia at MD Anderson, will use Ascentage’s proprietary Protein-Protein Interaction drug discovery technology platform to develop the company’s apoptosis-targeted and tyrosine kinase inhibitor drug candidates.

The drug candidates will be studied as single-agent therapies and in combinations with other approved or investigational therapeutics. The candidates, chosen for their potential to treat acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms, and myelofibrosis, include:

• HQP1351, a third-generation BCR-ABL inhibitor that has been shown to be safe and “highly active” in treating patients with chronic- or accelerated-phase CML, with or without the T3151 mutation. Preliminary results of the phase 1 study were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 791).
• APG-1252, a highly potent Bcl-2 family inhibitor, has high binding affinities to Bcl-2, Bcl-xL and Bcl-w. It has achieved tumor regression in small cell lung cancer, colon, breast, and ALL xenografts. A phase 1, dose-escalating study is currently being conducted (NCT03387332).
• APG-2575, a selective Bcl-2 inhibitor, is being studied in a phase 1, multicenter, single-agent trial in patients with B-cell hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, non-Hodgkin lymphomas, and AML (NCT03537482).
• APG-1387, an inhibitor of apoptosis protein, is being studied in solid tumors and hematologic malignancies (NCT03386526). Investigators asserted that combining it with an anti–programmed death 1 antibody would be “a very attractive approach” for cancer therapy. In advanced solid tumors it has been well tolerated with manageable adverse events, according to a study presented at the 2018 annual meeting of the American Society of Clinical Oncology (Abstract 2593).
• APG-115 is an MDM2-p53 inhibitor that, when combined with radiotherapy, has been shown to enhance the antitumor effect in gastric adenocarcinoma, according to a paper published in the Journal of Experimental & Clinical Cancer Research.

“We will be investigating this pipeline of candidate therapies, and we are interested in the novel mechanism of their actions,” Dr. Kantarjian said in a statement.

[email protected]

The University of Texas MD Anderson Cancer Center, Houston, and Ascentage Pharma of Suzhou, China, recently formed a 5-year strategic alliance to advance the development of novel cancer therapeutics, primarily for leukemia.

The collaboration, led by Hagop Kantarjian, MD, chair of leukemia at MD Anderson, will use Ascentage’s proprietary Protein-Protein Interaction drug discovery technology platform to develop the company’s apoptosis-targeted and tyrosine kinase inhibitor drug candidates.

The drug candidates will be studied as single-agent therapies and in combinations with other approved or investigational therapeutics. The candidates, chosen for their potential to treat acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms, and myelofibrosis, include:

• HQP1351, a third-generation BCR-ABL inhibitor that has been shown to be safe and “highly active” in treating patients with chronic- or accelerated-phase CML, with or without the T3151 mutation. Preliminary results of the phase 1 study were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 791).
• APG-1252, a highly potent Bcl-2 family inhibitor, has high binding affinities to Bcl-2, Bcl-xL and Bcl-w. It has achieved tumor regression in small cell lung cancer, colon, breast, and ALL xenografts. A phase 1, dose-escalating study is currently being conducted (NCT03387332).
• APG-2575, a selective Bcl-2 inhibitor, is being studied in a phase 1, multicenter, single-agent trial in patients with B-cell hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, non-Hodgkin lymphomas, and AML (NCT03537482).
• APG-1387, an inhibitor of apoptosis protein, is being studied in solid tumors and hematologic malignancies (NCT03386526). Investigators asserted that combining it with an anti–programmed death 1 antibody would be “a very attractive approach” for cancer therapy. In advanced solid tumors it has been well tolerated with manageable adverse events, according to a study presented at the 2018 annual meeting of the American Society of Clinical Oncology (Abstract 2593).
• APG-115 is an MDM2-p53 inhibitor that, when combined with radiotherapy, has been shown to enhance the antitumor effect in gastric adenocarcinoma, according to a paper published in the Journal of Experimental & Clinical Cancer Research.

“We will be investigating this pipeline of candidate therapies, and we are interested in the novel mechanism of their actions,” Dr. Kantarjian said in a statement.

[email protected]

The University of Texas MD Anderson Cancer Center, Houston, and Ascentage Pharma of Suzhou, China, recently formed a 5-year strategic alliance to advance the development of novel cancer therapeutics, primarily for leukemia.

The collaboration, led by Hagop Kantarjian, MD, chair of leukemia at MD Anderson, will use Ascentage’s proprietary Protein-Protein Interaction drug discovery technology platform to develop the company’s apoptosis-targeted and tyrosine kinase inhibitor drug candidates.

The drug candidates will be studied as single-agent therapies and in combinations with other approved or investigational therapeutics. The candidates, chosen for their potential to treat acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms, and myelofibrosis, include:

• HQP1351, a third-generation BCR-ABL inhibitor that has been shown to be safe and “highly active” in treating patients with chronic- or accelerated-phase CML, with or without the T3151 mutation. Preliminary results of the phase 1 study were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 791).
• APG-1252, a highly potent Bcl-2 family inhibitor, has high binding affinities to Bcl-2, Bcl-xL and Bcl-w. It has achieved tumor regression in small cell lung cancer, colon, breast, and ALL xenografts. A phase 1, dose-escalating study is currently being conducted (NCT03387332).
• APG-2575, a selective Bcl-2 inhibitor, is being studied in a phase 1, multicenter, single-agent trial in patients with B-cell hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, non-Hodgkin lymphomas, and AML (NCT03537482).
• APG-1387, an inhibitor of apoptosis protein, is being studied in solid tumors and hematologic malignancies (NCT03386526). Investigators asserted that combining it with an anti–programmed death 1 antibody would be “a very attractive approach” for cancer therapy. In advanced solid tumors it has been well tolerated with manageable adverse events, according to a study presented at the 2018 annual meeting of the American Society of Clinical Oncology (Abstract 2593).
• APG-115 is an MDM2-p53 inhibitor that, when combined with radiotherapy, has been shown to enhance the antitumor effect in gastric adenocarcinoma, according to a paper published in the Journal of Experimental & Clinical Cancer Research.

“We will be investigating this pipeline of candidate therapies, and we are interested in the novel mechanism of their actions,” Dr. Kantarjian said in a statement.

[email protected]

SAN DIEGO – Research into hundreds of babies with Down syndrome is providing valuable insight into the genetic roots of leukemia and offering a route to identify newborns at high risk.

“We can now identify children at high risk of developing myeloid leukemia within 4 years” through blood or genetic tests, Irene Roberts, MD, a pediatric hematologist at the University of Oxford’s (England) MRC Weatherall Institute of Molecular Medicine, said at the annual meeting of the American Society of Hematology.

About 2%-3% of children with Down syndrome will develop acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML), according to the National Cancer Institute, rates that are much higher than in the general population.

Research suggests that among children aged 0-4 years with Down syndrome, the standardized incidence ratio (SIR) of AML is 114, compared with other children, Dr. Roberts said. The SIR of ALL is 27 in children aged 1-4 years, she said.

For people with Down syndrome aged 0-60 years, the SIRs are 12 and 13 in AML and ALL, respectively, she said.

In her presentation, Dr. Roberts focused on AML that appears before age 4 years and is preceded by a neonatal preleukemia – transient abnormal myelopoiesis (TAM) – that only occurs in Down syndrome. In most cases, TAM, which occurs with GATA1 mutations, resolves on its own after birth, she said. But in others, the GATA1 mutations continue and cause AML to develop.

Dr. Roberts highlighted her institution’s Oxford Down Syndrome Cohort Study and offered an update to a 2013 report (Blood. 2013 Dec 5;122[24]:3908–17). The study recruited 471 neonates with Down syndrome and followed them for up to 4 years: 341 with no GATA1 mutation and 130 (28%) with the mutation. Dr. Roberts called the latter number a “very high frequency.”

Of those with the mutation, 7 patients (5%) developed AML at a median age of 16 months. None of those without the mutation developed AML.

Also, among the 130 neonates with the mutation, 42% were considered to have “clinical” TAM (more than 10% blasts) and 58% were considered to have “silent” TAM (fewer than 10% blasts).

“We predicted that these babies with clinical TAM would have more severe clinical disease ... and that in fact turned out to be the case,” Dr. Roberts said.

Why is the GATA1 mutation so significant? Research suggests that platelet production is abnormal in neonates with Down syndrome, compared with neonates without it, regardless of whether they have the mutation, Dr. Roberts said.

The mutation doesn’t reduce further platelet count, but does disrupt megakaryopoiesis – the process of the production of platelets. As a result, giant platelets and megakaryocyte fragments are more common, she explained.

Moving forward, research data can be used to identify which children are most at risk, Dr. Roberts said. Newborns with Down syndrome are more likely to survive without leukemia if they have silent TAM, compared with those who have clinical TAM, and if they have an estimated variant allele frequency above 15%, according to findings from the Oxford study.

Children at high risk of AML before age 4 years can be identified by analyzing the percentage of blasts on a smear and/or by analyzing mutation of GATA1, according to Dr. Roberts. However, this cannot be accomplished by the use of a complete blood count (CBC) test, she said, which is used to check for leukemia.

Dr. Roberts called for the development of more guidelines for screening newborns with Down syndrome for leukemia risk. The British Society for Haematology issued testing guidelines, coauthored by Dr. Roberts, in 2018 (Br J Haematol. 2018 Jul;182[2]:200-11).

Dr. Roberts reported having no financial disclosures.

SAN DIEGO – Research into hundreds of babies with Down syndrome is providing valuable insight into the genetic roots of leukemia and offering a route to identify newborns at high risk.

“We can now identify children at high risk of developing myeloid leukemia within 4 years” through blood or genetic tests, Irene Roberts, MD, a pediatric hematologist at the University of Oxford’s (England) MRC Weatherall Institute of Molecular Medicine, said at the annual meeting of the American Society of Hematology.

About 2%-3% of children with Down syndrome will develop acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML), according to the National Cancer Institute, rates that are much higher than in the general population.

Research suggests that among children aged 0-4 years with Down syndrome, the standardized incidence ratio (SIR) of AML is 114, compared with other children, Dr. Roberts said. The SIR of ALL is 27 in children aged 1-4 years, she said.

For people with Down syndrome aged 0-60 years, the SIRs are 12 and 13 in AML and ALL, respectively, she said.

In her presentation, Dr. Roberts focused on AML that appears before age 4 years and is preceded by a neonatal preleukemia – transient abnormal myelopoiesis (TAM) – that only occurs in Down syndrome. In most cases, TAM, which occurs with GATA1 mutations, resolves on its own after birth, she said. But in others, the GATA1 mutations continue and cause AML to develop.

Dr. Roberts highlighted her institution’s Oxford Down Syndrome Cohort Study and offered an update to a 2013 report (Blood. 2013 Dec 5;122[24]:3908–17). The study recruited 471 neonates with Down syndrome and followed them for up to 4 years: 341 with no GATA1 mutation and 130 (28%) with the mutation. Dr. Roberts called the latter number a “very high frequency.”

Of those with the mutation, 7 patients (5%) developed AML at a median age of 16 months. None of those without the mutation developed AML.

Also, among the 130 neonates with the mutation, 42% were considered to have “clinical” TAM (more than 10% blasts) and 58% were considered to have “silent” TAM (fewer than 10% blasts).

“We predicted that these babies with clinical TAM would have more severe clinical disease ... and that in fact turned out to be the case,” Dr. Roberts said.

Why is the GATA1 mutation so significant? Research suggests that platelet production is abnormal in neonates with Down syndrome, compared with neonates without it, regardless of whether they have the mutation, Dr. Roberts said.

The mutation doesn’t reduce further platelet count, but does disrupt megakaryopoiesis – the process of the production of platelets. As a result, giant platelets and megakaryocyte fragments are more common, she explained.

Moving forward, research data can be used to identify which children are most at risk, Dr. Roberts said. Newborns with Down syndrome are more likely to survive without leukemia if they have silent TAM, compared with those who have clinical TAM, and if they have an estimated variant allele frequency above 15%, according to findings from the Oxford study.

Children at high risk of AML before age 4 years can be identified by analyzing the percentage of blasts on a smear and/or by analyzing mutation of GATA1, according to Dr. Roberts. However, this cannot be accomplished by the use of a complete blood count (CBC) test, she said, which is used to check for leukemia.

Dr. Roberts called for the development of more guidelines for screening newborns with Down syndrome for leukemia risk. The British Society for Haematology issued testing guidelines, coauthored by Dr. Roberts, in 2018 (Br J Haematol. 2018 Jul;182[2]:200-11).

Dr. Roberts reported having no financial disclosures.

SAN DIEGO – Research into hundreds of babies with Down syndrome is providing valuable insight into the genetic roots of leukemia and offering a route to identify newborns at high risk.

“We can now identify children at high risk of developing myeloid leukemia within 4 years” through blood or genetic tests, Irene Roberts, MD, a pediatric hematologist at the University of Oxford’s (England) MRC Weatherall Institute of Molecular Medicine, said at the annual meeting of the American Society of Hematology.

About 2%-3% of children with Down syndrome will develop acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML), according to the National Cancer Institute, rates that are much higher than in the general population.

Research suggests that among children aged 0-4 years with Down syndrome, the standardized incidence ratio (SIR) of AML is 114, compared with other children, Dr. Roberts said. The SIR of ALL is 27 in children aged 1-4 years, she said.

For people with Down syndrome aged 0-60 years, the SIRs are 12 and 13 in AML and ALL, respectively, she said.

In her presentation, Dr. Roberts focused on AML that appears before age 4 years and is preceded by a neonatal preleukemia – transient abnormal myelopoiesis (TAM) – that only occurs in Down syndrome. In most cases, TAM, which occurs with GATA1 mutations, resolves on its own after birth, she said. But in others, the GATA1 mutations continue and cause AML to develop.

Dr. Roberts highlighted her institution’s Oxford Down Syndrome Cohort Study and offered an update to a 2013 report (Blood. 2013 Dec 5;122[24]:3908–17). The study recruited 471 neonates with Down syndrome and followed them for up to 4 years: 341 with no GATA1 mutation and 130 (28%) with the mutation. Dr. Roberts called the latter number a “very high frequency.”

Of those with the mutation, 7 patients (5%) developed AML at a median age of 16 months. None of those without the mutation developed AML.

Also, among the 130 neonates with the mutation, 42% were considered to have “clinical” TAM (more than 10% blasts) and 58% were considered to have “silent” TAM (fewer than 10% blasts).

“We predicted that these babies with clinical TAM would have more severe clinical disease ... and that in fact turned out to be the case,” Dr. Roberts said.

Why is the GATA1 mutation so significant? Research suggests that platelet production is abnormal in neonates with Down syndrome, compared with neonates without it, regardless of whether they have the mutation, Dr. Roberts said.

The mutation doesn’t reduce further platelet count, but does disrupt megakaryopoiesis – the process of the production of platelets. As a result, giant platelets and megakaryocyte fragments are more common, she explained.

Moving forward, research data can be used to identify which children are most at risk, Dr. Roberts said. Newborns with Down syndrome are more likely to survive without leukemia if they have silent TAM, compared with those who have clinical TAM, and if they have an estimated variant allele frequency above 15%, according to findings from the Oxford study.

Children at high risk of AML before age 4 years can be identified by analyzing the percentage of blasts on a smear and/or by analyzing mutation of GATA1, according to Dr. Roberts. However, this cannot be accomplished by the use of a complete blood count (CBC) test, she said, which is used to check for leukemia.

Dr. Roberts called for the development of more guidelines for screening newborns with Down syndrome for leukemia risk. The British Society for Haematology issued testing guidelines, coauthored by Dr. Roberts, in 2018 (Br J Haematol. 2018 Jul;182[2]:200-11).

Dr. Roberts reported having no financial disclosures.

Photo by Rhoda Baer

Chemotherapy for solid tumors is associated with an increased risk of therapy-related myelodysplastic syndromes or acute myeloid leukemia (tMDS/AML), according to a retrospective analysis.

Long-term, population-based cohort data showed the risk of tMDS/AML was significantly elevated after chemotherapy for 22 solid tumor types.

The relative risk of tMDS/AML was 1.5- to 39.0-fold greater among patients treated for these tumors than among the general population.

Lindsay M. Morton, PhD, of the National Institutes of Health in Rockville, Maryland, and her colleagues reported these findings in JAMA Oncology.

“We undertook an investigation to quantify tMDS/AML risks after chemotherapy for solid tumors in the modern treatment era, 2000-2014, using United States cancer registry data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program,” the investigators wrote.

They retrospectively analyzed data from 1619 patients with tMDS/AML who were diagnosed with an initial primary solid tumor from 2000 to 2013.

Patients were given initial chemotherapy and lived for at least 1 year after treatment. Subsequently, Dr. Morton and her colleagues linked patient database records with Medicare insurance claim information to confirm the accuracy of chemotherapy data.

“Because registry data do not include treatment details, we used an alternative database to provide descriptive information on population-based patterns of chemotherapeutic drug use,” the investigators noted.

The team found the risk of developing tMDS/AML was significantly increased following chemotherapy administration for 22 of 23 solid tumor types, excluding colon cancer.

The standardized incidence ratio (SIR) for tMDS/AML ranged from 1.5 to 39.0, and the excess absolute risk (EAR) ranged from 1.4 to 23.6 cases per 10,000 person-years.

SIRs were greatest in patients who received chemotherapy for malignancy of the bone (SIR=39.0, EAR=23.6), testis (SIR, 12.3, EAR=4.4), soft tissue (SIR=10.4, EAR=12.6), fallopian tube (SIR=8.7, EAR=16.0), small cell lung (SIR=8.1, EAR=19.9), peritoneum (SIR=7.5, EAR=15.8), brain or central nervous system (SIR=7.2, EAR=6.0), and ovary (SIR=5.8, EAR=8.2).

The investigators also found that patients who were given chemotherapy at a young age had the highest risk of developing tMDS/AML.

“For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy,” the investigators said.

They acknowledged a key limitation of this study was the limited data on patient-specific chemotherapy and dosing information. Given these limitations, Dr. Morton and her colleagues said, “the exact magnitude of our risk estimates, including the proportions of excess cases, should therefore be interpreted cautiously.”

This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the California Department of Public Health. The authors reported no conflicts of interest.

Photo by Rhoda Baer

Chemotherapy for solid tumors is associated with an increased risk of therapy-related myelodysplastic syndromes or acute myeloid leukemia (tMDS/AML), according to a retrospective analysis.

Long-term, population-based cohort data showed the risk of tMDS/AML was significantly elevated after chemotherapy for 22 solid tumor types.

The relative risk of tMDS/AML was 1.5- to 39.0-fold greater among patients treated for these tumors than among the general population.

Lindsay M. Morton, PhD, of the National Institutes of Health in Rockville, Maryland, and her colleagues reported these findings in JAMA Oncology.

“We undertook an investigation to quantify tMDS/AML risks after chemotherapy for solid tumors in the modern treatment era, 2000-2014, using United States cancer registry data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program,” the investigators wrote.

They retrospectively analyzed data from 1619 patients with tMDS/AML who were diagnosed with an initial primary solid tumor from 2000 to 2013.

Patients were given initial chemotherapy and lived for at least 1 year after treatment. Subsequently, Dr. Morton and her colleagues linked patient database records with Medicare insurance claim information to confirm the accuracy of chemotherapy data.

“Because registry data do not include treatment details, we used an alternative database to provide descriptive information on population-based patterns of chemotherapeutic drug use,” the investigators noted.

The team found the risk of developing tMDS/AML was significantly increased following chemotherapy administration for 22 of 23 solid tumor types, excluding colon cancer.

The standardized incidence ratio (SIR) for tMDS/AML ranged from 1.5 to 39.0, and the excess absolute risk (EAR) ranged from 1.4 to 23.6 cases per 10,000 person-years.

SIRs were greatest in patients who received chemotherapy for malignancy of the bone (SIR=39.0, EAR=23.6), testis (SIR, 12.3, EAR=4.4), soft tissue (SIR=10.4, EAR=12.6), fallopian tube (SIR=8.7, EAR=16.0), small cell lung (SIR=8.1, EAR=19.9), peritoneum (SIR=7.5, EAR=15.8), brain or central nervous system (SIR=7.2, EAR=6.0), and ovary (SIR=5.8, EAR=8.2).

The investigators also found that patients who were given chemotherapy at a young age had the highest risk of developing tMDS/AML.

“For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy,” the investigators said.

They acknowledged a key limitation of this study was the limited data on patient-specific chemotherapy and dosing information. Given these limitations, Dr. Morton and her colleagues said, “the exact magnitude of our risk estimates, including the proportions of excess cases, should therefore be interpreted cautiously.”

This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the California Department of Public Health. The authors reported no conflicts of interest.

Photo by Rhoda Baer

Chemotherapy for solid tumors is associated with an increased risk of therapy-related myelodysplastic syndromes or acute myeloid leukemia (tMDS/AML), according to a retrospective analysis.

Long-term, population-based cohort data showed the risk of tMDS/AML was significantly elevated after chemotherapy for 22 solid tumor types.

The relative risk of tMDS/AML was 1.5- to 39.0-fold greater among patients treated for these tumors than among the general population.

Lindsay M. Morton, PhD, of the National Institutes of Health in Rockville, Maryland, and her colleagues reported these findings in JAMA Oncology.

“We undertook an investigation to quantify tMDS/AML risks after chemotherapy for solid tumors in the modern treatment era, 2000-2014, using United States cancer registry data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program,” the investigators wrote.

They retrospectively analyzed data from 1619 patients with tMDS/AML who were diagnosed with an initial primary solid tumor from 2000 to 2013.

Patients were given initial chemotherapy and lived for at least 1 year after treatment. Subsequently, Dr. Morton and her colleagues linked patient database records with Medicare insurance claim information to confirm the accuracy of chemotherapy data.

“Because registry data do not include treatment details, we used an alternative database to provide descriptive information on population-based patterns of chemotherapeutic drug use,” the investigators noted.

The team found the risk of developing tMDS/AML was significantly increased following chemotherapy administration for 22 of 23 solid tumor types, excluding colon cancer.

The standardized incidence ratio (SIR) for tMDS/AML ranged from 1.5 to 39.0, and the excess absolute risk (EAR) ranged from 1.4 to 23.6 cases per 10,000 person-years.

SIRs were greatest in patients who received chemotherapy for malignancy of the bone (SIR=39.0, EAR=23.6), testis (SIR, 12.3, EAR=4.4), soft tissue (SIR=10.4, EAR=12.6), fallopian tube (SIR=8.7, EAR=16.0), small cell lung (SIR=8.1, EAR=19.9), peritoneum (SIR=7.5, EAR=15.8), brain or central nervous system (SIR=7.2, EAR=6.0), and ovary (SIR=5.8, EAR=8.2).

The investigators also found that patients who were given chemotherapy at a young age had the highest risk of developing tMDS/AML.

“For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy,” the investigators said.

They acknowledged a key limitation of this study was the limited data on patient-specific chemotherapy and dosing information. Given these limitations, Dr. Morton and her colleagues said, “the exact magnitude of our risk estimates, including the proportions of excess cases, should therefore be interpreted cautiously.”

This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the California Department of Public Health. The authors reported no conflicts of interest.

There is an increased risk for therapy-related myelodysplastic syndrome or acute myeloid leukemia (tMDS/AML) following chemotherapy for the majority of solid tumor types, according to an analysis of cancer registry data.

These findings suggest a substantial expansion in the patients at risk for tMDS/AML because, in the past, excess risks were established only after chemotherapy for cancers of the lung, ovary, breast, soft tissue, testis, and brain or central nervous system,” Lindsay M. Morton, PhD, of the National Institutes of Health, and her colleagues wrote in JAMA Oncology.

The researchers retrospectively analyzed data from 1,619 patients with tMDS/AML who were diagnosed with an initial primary solid tumor from 2000 to 2013. Data came from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program and Medicare claims.

Study participants were given initial chemotherapy and lived for at least 1 year after treatment. Subsequently, Dr. Morton and her colleagues linked patient database records with Medicare insurance claim information to confirm the accuracy of chemotherapy data.

“Because registry data [does] not include treatment details, we used an alternative database to provide descriptive information on population-based patterns of chemotherapeutic drug use,” the researchers wrote in JAMA Oncology.

After statistical analysis, the researchers found that the risk of developing tMDS/AML was significantly elevated following chemotherapy administration for 22 of 23 solid tumor types, excluding colon cancer. They reported a 1.5-fold to more than 10-fold increased relative risk for tMDS/AML in those patients who received chemotherapy for those 22 solid cancer types, compared with the general population.

The relative risks were highest after chemotherapy for bone, soft-tissue, and testis cancers.

The researchers found that the absolute risk of developing tMDS/AML was low. Excess absolute risks ranged from 1.4 to greater than 15 cases per 10,000 person-years, compared with the general population, in those 22 solid cancer types. The greatest absolute risks were for peritoneum, small-cell lung, bone, soft-tissue, and fallopian tube cancers.

“For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy,” they added.

The researchers acknowledged a key limitation of the study was the limited data on dosing and patient-specific chemotherapy. As a result, Dr. Morton and her colleagues called for a cautious interpretation of the magnitude of the risk.

The study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the California Department of Public Health. The authors reported having no conflicts of interest.

SOURCE: Morton LM et al. JAMA Oncol. 2018 Dec 20. doi: 10.1001/jamaoncol.2018.5625.

There is an increased risk for therapy-related myelodysplastic syndrome or acute myeloid leukemia (tMDS/AML) following chemotherapy for the majority of solid tumor types, according to an analysis of cancer registry data.

These findings suggest a substantial expansion in the patients at risk for tMDS/AML because, in the past, excess risks were established only after chemotherapy for cancers of the lung, ovary, breast, soft tissue, testis, and brain or central nervous system,” Lindsay M. Morton, PhD, of the National Institutes of Health, and her colleagues wrote in JAMA Oncology.

The researchers retrospectively analyzed data from 1,619 patients with tMDS/AML who were diagnosed with an initial primary solid tumor from 2000 to 2013. Data came from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program and Medicare claims.

Study participants were given initial chemotherapy and lived for at least 1 year after treatment. Subsequently, Dr. Morton and her colleagues linked patient database records with Medicare insurance claim information to confirm the accuracy of chemotherapy data.

“Because registry data [does] not include treatment details, we used an alternative database to provide descriptive information on population-based patterns of chemotherapeutic drug use,” the researchers wrote in JAMA Oncology.

After statistical analysis, the researchers found that the risk of developing tMDS/AML was significantly elevated following chemotherapy administration for 22 of 23 solid tumor types, excluding colon cancer. They reported a 1.5-fold to more than 10-fold increased relative risk for tMDS/AML in those patients who received chemotherapy for those 22 solid cancer types, compared with the general population.

The relative risks were highest after chemotherapy for bone, soft-tissue, and testis cancers.

The researchers found that the absolute risk of developing tMDS/AML was low. Excess absolute risks ranged from 1.4 to greater than 15 cases per 10,000 person-years, compared with the general population, in those 22 solid cancer types. The greatest absolute risks were for peritoneum, small-cell lung, bone, soft-tissue, and fallopian tube cancers.

“For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy,” they added.

The researchers acknowledged a key limitation of the study was the limited data on dosing and patient-specific chemotherapy. As a result, Dr. Morton and her colleagues called for a cautious interpretation of the magnitude of the risk.

The study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the California Department of Public Health. The authors reported having no conflicts of interest.

SOURCE: Morton LM et al. JAMA Oncol. 2018 Dec 20. doi: 10.1001/jamaoncol.2018.5625.

There is an increased risk for therapy-related myelodysplastic syndrome or acute myeloid leukemia (tMDS/AML) following chemotherapy for the majority of solid tumor types, according to an analysis of cancer registry data.

These findings suggest a substantial expansion in the patients at risk for tMDS/AML because, in the past, excess risks were established only after chemotherapy for cancers of the lung, ovary, breast, soft tissue, testis, and brain or central nervous system,” Lindsay M. Morton, PhD, of the National Institutes of Health, and her colleagues wrote in JAMA Oncology.

The researchers retrospectively analyzed data from 1,619 patients with tMDS/AML who were diagnosed with an initial primary solid tumor from 2000 to 2013. Data came from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program and Medicare claims.

Study participants were given initial chemotherapy and lived for at least 1 year after treatment. Subsequently, Dr. Morton and her colleagues linked patient database records with Medicare insurance claim information to confirm the accuracy of chemotherapy data.

“Because registry data [does] not include treatment details, we used an alternative database to provide descriptive information on population-based patterns of chemotherapeutic drug use,” the researchers wrote in JAMA Oncology.

After statistical analysis, the researchers found that the risk of developing tMDS/AML was significantly elevated following chemotherapy administration for 22 of 23 solid tumor types, excluding colon cancer. They reported a 1.5-fold to more than 10-fold increased relative risk for tMDS/AML in those patients who received chemotherapy for those 22 solid cancer types, compared with the general population.

The relative risks were highest after chemotherapy for bone, soft-tissue, and testis cancers.

The researchers found that the absolute risk of developing tMDS/AML was low. Excess absolute risks ranged from 1.4 to greater than 15 cases per 10,000 person-years, compared with the general population, in those 22 solid cancer types. The greatest absolute risks were for peritoneum, small-cell lung, bone, soft-tissue, and fallopian tube cancers.

“For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy,” they added.

The researchers acknowledged a key limitation of the study was the limited data on dosing and patient-specific chemotherapy. As a result, Dr. Morton and her colleagues called for a cautious interpretation of the magnitude of the risk.

The study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the California Department of Public Health. The authors reported having no conflicts of interest.

SOURCE: Morton LM et al. JAMA Oncol. 2018 Dec 20. doi: 10.1001/jamaoncol.2018.5625.

Single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – for patients with relapsed/refractory acute myeloid leukemia (AML) bearing the FLT3-ITD mutation, results of the phase 3 randomized QuANTUM-R trial showed.

Neil Osterweil/MDedge News

Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177), reported Jorge E. Cortes, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“This study is the first study that demonstrates in a randomized fashion an overall survival benefit in the salvage setting for patients with FLT-3 mutated refractory or relapsed AML,” he said at the annual meeting of the American Society of Hematology. “I will also add that these results you saw here are very consistent with all the trials previously with quizartinib with more than 1,000 patients treated.”

Quizartinib, a tyrosine kinase inhibitor (TKI), has previously been shown to be associated with higher response rates among patients with AML bearing the FLT3-ITD mutation than in patients with AML without the deleterious mutation.

Investigators in the QuANTUM-R trial enrolled 367 adults with FTL3-ITD mutated AML that was refractory to the most recent line of therapy or had relapsed within 6 months of first remission, with or without hematopoietic stem cell transplant (HSCT).

The patients had all received at least one cycle of standard-dose induction therapy containing an anthracycline or mitoxantrone, and had a 3% or greater FLT3-ITD allelic ratio in their AML cells.

The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.

Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to two cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to HSCT.

The analysis was by intention-to-treat. In the quizartinib arm, 241 of the 245 randomized patients (98.4%) received treatment. In the chemotherapy arm, 94 of 122 randomized patients (77%) received chemotherapy. Of this group, 22 received LoDAC, 25 received MEC, and 47 received FLAG-IDA.

The median treatment duration was 97 days in the quizartinib arm versus 28 days (one cycle) in the chemotherapy arm.

The 1-year overall survival rate was 27% for patients assigned to quizartinib, compared with 20% for patients assigned to chemotherapy.

An analysis of OS by subgroup indicated a trend or significant benefit for quizartinib in all categories, including age over or under 65 years, sex, low or high-intensity chemotherapy, response to prior therapy, FLT3 variant allele frequency, prior allogenic HSCT, and AML risk score.

For the secondary endpoint of event-free survival in the ITT population, there was no significant difference between the study arms. In a per-protocol analysis, however, median event-free survival was better with quizartinib, at 1.4 months versus 0.0 months (P = .006).

In all, 32% of patients assigned to quizartinib went on to HSCT, compared with 12% of patients randomized to chemotherapy.

Rates of treatment-emergent adverse events (TEAEs) were similar between the study arms, despite higher total drug exposure in patients randomized to quizartinib. The most frequent grade 3 or greater TEAEs in each arm were infections and cytopenia-related events.

Two patients discontinued quizartinib due to QTcF prolongation. Grade 3 QTcF (greater than 500 ms) occurred in 3% of patients treated with quizartinib, but no grade 4 cases were seen.

The adverse event profile for patients who resumed quizartinib following HSCT was similar to that of patients who received the drug pretransplant.

The combination of standard chemotherapy, with or without quizartinib, is currently being explored in the phase 3 QuANTUM-First trial, Dr. Cortes said.

Daiichi Sankyo sponsored the trial. Dr. Cortes reported financial relationships with Daiichi Sankyo, Pfizer, Arog, Astellas Pharma, and Novartis.

SOURCE: Cortes JE et al. ASH 2018, Abstract 563.

Single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – for patients with relapsed/refractory acute myeloid leukemia (AML) bearing the FLT3-ITD mutation, results of the phase 3 randomized QuANTUM-R trial showed.

Neil Osterweil/MDedge News

Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177), reported Jorge E. Cortes, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“This study is the first study that demonstrates in a randomized fashion an overall survival benefit in the salvage setting for patients with FLT-3 mutated refractory or relapsed AML,” he said at the annual meeting of the American Society of Hematology. “I will also add that these results you saw here are very consistent with all the trials previously with quizartinib with more than 1,000 patients treated.”

Quizartinib, a tyrosine kinase inhibitor (TKI), has previously been shown to be associated with higher response rates among patients with AML bearing the FLT3-ITD mutation than in patients with AML without the deleterious mutation.

Investigators in the QuANTUM-R trial enrolled 367 adults with FTL3-ITD mutated AML that was refractory to the most recent line of therapy or had relapsed within 6 months of first remission, with or without hematopoietic stem cell transplant (HSCT).

The patients had all received at least one cycle of standard-dose induction therapy containing an anthracycline or mitoxantrone, and had a 3% or greater FLT3-ITD allelic ratio in their AML cells.

The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.

Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to two cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to HSCT.

The analysis was by intention-to-treat. In the quizartinib arm, 241 of the 245 randomized patients (98.4%) received treatment. In the chemotherapy arm, 94 of 122 randomized patients (77%) received chemotherapy. Of this group, 22 received LoDAC, 25 received MEC, and 47 received FLAG-IDA.

The median treatment duration was 97 days in the quizartinib arm versus 28 days (one cycle) in the chemotherapy arm.

The 1-year overall survival rate was 27% for patients assigned to quizartinib, compared with 20% for patients assigned to chemotherapy.

An analysis of OS by subgroup indicated a trend or significant benefit for quizartinib in all categories, including age over or under 65 years, sex, low or high-intensity chemotherapy, response to prior therapy, FLT3 variant allele frequency, prior allogenic HSCT, and AML risk score.

For the secondary endpoint of event-free survival in the ITT population, there was no significant difference between the study arms. In a per-protocol analysis, however, median event-free survival was better with quizartinib, at 1.4 months versus 0.0 months (P = .006).

In all, 32% of patients assigned to quizartinib went on to HSCT, compared with 12% of patients randomized to chemotherapy.

Rates of treatment-emergent adverse events (TEAEs) were similar between the study arms, despite higher total drug exposure in patients randomized to quizartinib. The most frequent grade 3 or greater TEAEs in each arm were infections and cytopenia-related events.

Two patients discontinued quizartinib due to QTcF prolongation. Grade 3 QTcF (greater than 500 ms) occurred in 3% of patients treated with quizartinib, but no grade 4 cases were seen.

The adverse event profile for patients who resumed quizartinib following HSCT was similar to that of patients who received the drug pretransplant.

The combination of standard chemotherapy, with or without quizartinib, is currently being explored in the phase 3 QuANTUM-First trial, Dr. Cortes said.

Daiichi Sankyo sponsored the trial. Dr. Cortes reported financial relationships with Daiichi Sankyo, Pfizer, Arog, Astellas Pharma, and Novartis.

SOURCE: Cortes JE et al. ASH 2018, Abstract 563.

Single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – for patients with relapsed/refractory acute myeloid leukemia (AML) bearing the FLT3-ITD mutation, results of the phase 3 randomized QuANTUM-R trial showed.

Neil Osterweil/MDedge News

Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177), reported Jorge E. Cortes, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“This study is the first study that demonstrates in a randomized fashion an overall survival benefit in the salvage setting for patients with FLT-3 mutated refractory or relapsed AML,” he said at the annual meeting of the American Society of Hematology. “I will also add that these results you saw here are very consistent with all the trials previously with quizartinib with more than 1,000 patients treated.”

Quizartinib, a tyrosine kinase inhibitor (TKI), has previously been shown to be associated with higher response rates among patients with AML bearing the FLT3-ITD mutation than in patients with AML without the deleterious mutation.

Investigators in the QuANTUM-R trial enrolled 367 adults with FTL3-ITD mutated AML that was refractory to the most recent line of therapy or had relapsed within 6 months of first remission, with or without hematopoietic stem cell transplant (HSCT).

The patients had all received at least one cycle of standard-dose induction therapy containing an anthracycline or mitoxantrone, and had a 3% or greater FLT3-ITD allelic ratio in their AML cells.

The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.

Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to two cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to HSCT.

The analysis was by intention-to-treat. In the quizartinib arm, 241 of the 245 randomized patients (98.4%) received treatment. In the chemotherapy arm, 94 of 122 randomized patients (77%) received chemotherapy. Of this group, 22 received LoDAC, 25 received MEC, and 47 received FLAG-IDA.

The median treatment duration was 97 days in the quizartinib arm versus 28 days (one cycle) in the chemotherapy arm.

The 1-year overall survival rate was 27% for patients assigned to quizartinib, compared with 20% for patients assigned to chemotherapy.

An analysis of OS by subgroup indicated a trend or significant benefit for quizartinib in all categories, including age over or under 65 years, sex, low or high-intensity chemotherapy, response to prior therapy, FLT3 variant allele frequency, prior allogenic HSCT, and AML risk score.

For the secondary endpoint of event-free survival in the ITT population, there was no significant difference between the study arms. In a per-protocol analysis, however, median event-free survival was better with quizartinib, at 1.4 months versus 0.0 months (P = .006).

In all, 32% of patients assigned to quizartinib went on to HSCT, compared with 12% of patients randomized to chemotherapy.

Rates of treatment-emergent adverse events (TEAEs) were similar between the study arms, despite higher total drug exposure in patients randomized to quizartinib. The most frequent grade 3 or greater TEAEs in each arm were infections and cytopenia-related events.

Two patients discontinued quizartinib due to QTcF prolongation. Grade 3 QTcF (greater than 500 ms) occurred in 3% of patients treated with quizartinib, but no grade 4 cases were seen.

The adverse event profile for patients who resumed quizartinib following HSCT was similar to that of patients who received the drug pretransplant.

The combination of standard chemotherapy, with or without quizartinib, is currently being explored in the phase 3 QuANTUM-First trial, Dr. Cortes said.

Daiichi Sankyo sponsored the trial. Dr. Cortes reported financial relationships with Daiichi Sankyo, Pfizer, Arog, Astellas Pharma, and Novartis.

SOURCE: Cortes JE et al. ASH 2018, Abstract 563.

Photo by Daniel Sone

The U.S. Food and Drug Administration (FDA) has approved tagraxofusp-erzs (Elzonris) to treat patients age 2 and older who have blastic plasmacytoid dendritic cell neoplasm (BPDCN).

Tagraxofusp-erzs (formerly SL-401) is a CD123-directed cytotoxin that is the first FDA-approved treatment for BPDCN.

Tagraxofusp-erzs will be commercially available in early 2019, according to Stemline Therapeutics, makers of the drug.

The prescribing information for tagraxofusp-erzs contains a boxed warning noting that the drug is associated with an increased risk of capillary leak syndrome (CLS), which may be life-threatening or fatal.

The FDA previously granted tagraxofusp-erzs breakthrough therapy and orphan drug designations and assessed the drug under priority review.

The FDA’s approval of tagraxofusp-erzs was based on a phase 1 trial (STML-401-0114; NCT02113982).

The trial enrolled 47 patients with BPDCN, including 32 who were treatment-naïve and 15 who were previously treated.

Patients received tagraxofusp-erzs intravenously on days 1-5 of a 21-day cycle for multiple consecutive cycles. The trial had a dose-escalation stage (stage 1), an expansion stage (stage 2), a confirmatory stage (stage 3), and a stage that enabled uninterrupted access to tagraxofusp-erzs (stage 4).

In the confirmatory stage, 13 patients with treatment-naïve BPDCN received tagraxofusp-erzs at the recommended dose and schedule—12 mcg/kg daily for 5 days of a 21-day cycle.

Efficacy was based on the rate of complete response (CR) or clinical complete response (CRc). CRc was defined as CR with residual skin abnormality not indicative of active disease.

The CR/CRc rate was 53.8% (7/13), and the median duration of CR/CRc was not reached (range, 3.9 to 12.2 months).

The safety of tagraxofusp-erzs was assessed in 94 adults with treatment-naïve or previously treated myeloid malignancies, including 58 patients with BPDCN, who were treated at the recommended dose and schedule.

There were two fatal adverse events—both CLS. Eleven percent of patients discontinued treatment with tagraxofusp-erzs due to an adverse event. The most common of these were hepatic toxicities and CLS.

The most common adverse events overall were CLS (55%), nausea (49%), fatigue (45%), peripheral edema (43%), pyrexia (43%), and weight increase (31%).

The most common laboratory abnormalities were decreases in albumin (77%), platelets (67%), hemoglobin (60%), calcium (57%), and sodium (50%), as well as increases in glucose (87%), alanine aminotransferase (82%), and aspartate aminotransferase (79%).

Photo by Daniel Sone

The U.S. Food and Drug Administration (FDA) has approved tagraxofusp-erzs (Elzonris) to treat patients age 2 and older who have blastic plasmacytoid dendritic cell neoplasm (BPDCN).

Tagraxofusp-erzs (formerly SL-401) is a CD123-directed cytotoxin that is the first FDA-approved treatment for BPDCN.

Tagraxofusp-erzs will be commercially available in early 2019, according to Stemline Therapeutics, makers of the drug.

The prescribing information for tagraxofusp-erzs contains a boxed warning noting that the drug is associated with an increased risk of capillary leak syndrome (CLS), which may be life-threatening or fatal.

The FDA previously granted tagraxofusp-erzs breakthrough therapy and orphan drug designations and assessed the drug under priority review.

The FDA’s approval of tagraxofusp-erzs was based on a phase 1 trial (STML-401-0114; NCT02113982).

The trial enrolled 47 patients with BPDCN, including 32 who were treatment-naïve and 15 who were previously treated.

Patients received tagraxofusp-erzs intravenously on days 1-5 of a 21-day cycle for multiple consecutive cycles. The trial had a dose-escalation stage (stage 1), an expansion stage (stage 2), a confirmatory stage (stage 3), and a stage that enabled uninterrupted access to tagraxofusp-erzs (stage 4).

In the confirmatory stage, 13 patients with treatment-naïve BPDCN received tagraxofusp-erzs at the recommended dose and schedule—12 mcg/kg daily for 5 days of a 21-day cycle.

Efficacy was based on the rate of complete response (CR) or clinical complete response (CRc). CRc was defined as CR with residual skin abnormality not indicative of active disease.

The CR/CRc rate was 53.8% (7/13), and the median duration of CR/CRc was not reached (range, 3.9 to 12.2 months).

The safety of tagraxofusp-erzs was assessed in 94 adults with treatment-naïve or previously treated myeloid malignancies, including 58 patients with BPDCN, who were treated at the recommended dose and schedule.

There were two fatal adverse events—both CLS. Eleven percent of patients discontinued treatment with tagraxofusp-erzs due to an adverse event. The most common of these were hepatic toxicities and CLS.

The most common adverse events overall were CLS (55%), nausea (49%), fatigue (45%), peripheral edema (43%), pyrexia (43%), and weight increase (31%).

The most common laboratory abnormalities were decreases in albumin (77%), platelets (67%), hemoglobin (60%), calcium (57%), and sodium (50%), as well as increases in glucose (87%), alanine aminotransferase (82%), and aspartate aminotransferase (79%).

Photo by Daniel Sone

The U.S. Food and Drug Administration (FDA) has approved tagraxofusp-erzs (Elzonris) to treat patients age 2 and older who have blastic plasmacytoid dendritic cell neoplasm (BPDCN).

Tagraxofusp-erzs (formerly SL-401) is a CD123-directed cytotoxin that is the first FDA-approved treatment for BPDCN.

Tagraxofusp-erzs will be commercially available in early 2019, according to Stemline Therapeutics, makers of the drug.

The prescribing information for tagraxofusp-erzs contains a boxed warning noting that the drug is associated with an increased risk of capillary leak syndrome (CLS), which may be life-threatening or fatal.

The FDA previously granted tagraxofusp-erzs breakthrough therapy and orphan drug designations and assessed the drug under priority review.

The FDA’s approval of tagraxofusp-erzs was based on a phase 1 trial (STML-401-0114; NCT02113982).

The trial enrolled 47 patients with BPDCN, including 32 who were treatment-naïve and 15 who were previously treated.

Patients received tagraxofusp-erzs intravenously on days 1-5 of a 21-day cycle for multiple consecutive cycles. The trial had a dose-escalation stage (stage 1), an expansion stage (stage 2), a confirmatory stage (stage 3), and a stage that enabled uninterrupted access to tagraxofusp-erzs (stage 4).

In the confirmatory stage, 13 patients with treatment-naïve BPDCN received tagraxofusp-erzs at the recommended dose and schedule—12 mcg/kg daily for 5 days of a 21-day cycle.

Efficacy was based on the rate of complete response (CR) or clinical complete response (CRc). CRc was defined as CR with residual skin abnormality not indicative of active disease.

The CR/CRc rate was 53.8% (7/13), and the median duration of CR/CRc was not reached (range, 3.9 to 12.2 months).

The safety of tagraxofusp-erzs was assessed in 94 adults with treatment-naïve or previously treated myeloid malignancies, including 58 patients with BPDCN, who were treated at the recommended dose and schedule.

There were two fatal adverse events—both CLS. Eleven percent of patients discontinued treatment with tagraxofusp-erzs due to an adverse event. The most common of these were hepatic toxicities and CLS.

The most common adverse events overall were CLS (55%), nausea (49%), fatigue (45%), peripheral edema (43%), pyrexia (43%), and weight increase (31%).

The most common laboratory abnormalities were decreases in albumin (77%), platelets (67%), hemoglobin (60%), calcium (57%), and sodium (50%), as well as increases in glucose (87%), alanine aminotransferase (82%), and aspartate aminotransferase (79%).