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Drug receives breakthrough designation for relapsed/refractory AML
The US Food and Drug Administration (FDA) has granted GMI-1271 breakthrough therapy designation for the treatment of adults with relapsed/refractory acute myeloid leukemia (AML).
GMI-1271 is an E-selectin antagonist being developed by GlycoMimetics, Inc.
The product already has orphan and fast track designations from the FDA for the treatment of AML.
GMI-1271 is currently being evaluated in a phase 1/2 trial of patients with relapsed or refractory AML and patients age 60 and older with newly diagnosed AML.
The patients are receiving GM-1271 in combination with chemotherapy. The relapsed/refractory group is receiving mitoxantrone, etoposide, and cytarabine. The newly diagnosed patients are receiving cytarabine and idarubicin (7+3).
GlycoMimetics plans to present data from this trial at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting as abstracts 2520 and 2560.
The company also plans to present the research at the 22nd Congress of the European Hematology Association (EHA) as abstracts P547 and P203.
About breakthrough designation
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved. 
The US Food and Drug Administration (FDA) has granted GMI-1271 breakthrough therapy designation for the treatment of adults with relapsed/refractory acute myeloid leukemia (AML).
GMI-1271 is an E-selectin antagonist being developed by GlycoMimetics, Inc.
The product already has orphan and fast track designations from the FDA for the treatment of AML.
GMI-1271 is currently being evaluated in a phase 1/2 trial of patients with relapsed or refractory AML and patients age 60 and older with newly diagnosed AML.
The patients are receiving GM-1271 in combination with chemotherapy. The relapsed/refractory group is receiving mitoxantrone, etoposide, and cytarabine. The newly diagnosed patients are receiving cytarabine and idarubicin (7+3).
GlycoMimetics plans to present data from this trial at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting as abstracts 2520 and 2560.
The company also plans to present the research at the 22nd Congress of the European Hematology Association (EHA) as abstracts P547 and P203.
About breakthrough designation
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted GMI-1271 breakthrough therapy designation for the treatment of adults with relapsed/refractory acute myeloid leukemia (AML).
GMI-1271 is an E-selectin antagonist being developed by GlycoMimetics, Inc.
The product already has orphan and fast track designations from the FDA for the treatment of AML.
GMI-1271 is currently being evaluated in a phase 1/2 trial of patients with relapsed or refractory AML and patients age 60 and older with newly diagnosed AML.
The patients are receiving GM-1271 in combination with chemotherapy. The relapsed/refractory group is receiving mitoxantrone, etoposide, and cytarabine. The newly diagnosed patients are receiving cytarabine and idarubicin (7+3).
GlycoMimetics plans to present data from this trial at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting as abstracts 2520 and 2560.
The company also plans to present the research at the 22nd Congress of the European Hematology Association (EHA) as abstracts P547 and P203.
About breakthrough designation
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Antibody shows potential for treating AML, B-ALL
Endoglin may be a promising therapeutic target in acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL), according to researchers.
The group identified endoglin expression on the majority of blasts from patients with AML and B-ALL.
The team also found that an endoglin antibody, TRC105 (carotuximab), exhibited activity against AML and B-ALL in vivo, and combining the drug with chemotherapeutic agents enhanced this activity.
Rita Perlingeiro, PhD, of the University of Minnesota in Minneapolis, and her colleagues reported these findings in Blood.
The researchers first discovered that endoglin, which is also known as CD105, was “highly expressed” in leukemic blasts.
In samples from AML patients, 47.6% to 98.5% of blasts were CD105+. In samples from B-ALL patients, 92.6% to 99% of blasts were CD105+.
“We have been studying the function of endoglin in hematopoiesis for more than a decade, and the consistent expression of this receptor in the majority of acute leukemias was intriguing,” Dr Perlingeiro said.
She and her colleagues also found that CD105+ blasts had superior leukemogenic activity and reduced survival in mice when compared to CD105- blasts.
Mice injected with AML CD105+ blasts had all died at day 110 after injection, but mice injected with CD105- AML blasts survived until day 140.
Mice injected with CD105+ ALL blasts died 3 months after injection, but mice injected with CD105- ALL blasts were still alive and showed no signs of disease at the time of sacrifice, which was 5 months after injection.
TRC105 monotherapy
Several experiments showed that TRC105 could reduce leukemic activity in vivo.
TRC105 reduced blast counts in the peripheral blood of mice that had been injected with AML blasts. The drug also reduced blasts in the bone marrow initially, though blast counts were comparable in treated mice and controls by week 12.
On the other hand, mice treated with TRC105 did not experience the weight loss and splenomegaly observed in control mice. And TRC105 suppressed the ability of AML blasts to give rise to leukemia in secondary recipient mice.
In mice injected with ALL blasts, TRC105 initially decreased blast counts. However, by week 8, blast counts in the peripheral blood, bone marrow, and spleen of treated mice were similar to those observed in controls. The researchers said this suggests that TRC105 only slows the development of ALL.
The team then evaluated the effects of TRC105 after disease had been established. Mice with established AML received TRC105 for 8 weeks, and mice with established ALL received TRC105 for 4 weeks.
In mice with AML, TRC105 reduced blasts in the peripheral blood and spleen but not the bone marrow. The treatment also prevented splenomegaly and weight loss and prolonged survival.
“Our hypothesis that endoglin expression was linked to leukemia-forming activity was proven to be true, and it was even more rewarding to witness the robust anti-leukemogenic effect of blocking endoglin signaling with TRC105, even when leukemia had already been established in the mouse,” Dr Perlingeiro said.
However, in mice with established ALL, TRC105 had no effect on leukemia progression.
The researchers said this could be due to expression of soluble endoglin (sENG), which would titrate the TRC105 antibody, limiting its ability to bind to membrane-bound endoglin on leukemic cells. Results of additional experiments supported this idea.
TRC105 in combination
The researchers also tested TRC105 in combination with chemotherapy in the mouse models. The team combined the antibody with cytarabine to treat AML and cyclophosphamide to treat ALL.
In mice with AML, cytarabine and TRC105 significantly reduced levels of leukemic cells in the peripheral blood.
In mice with ALL, cyclophosphamide and TRC105 suppressed leukemia development more effectively and more quickly than cyclophosphamide alone.
The researchers detected high levels of sENG in untreated mice with ALL, but levels were lower in the TRC105-treated mice. And there was “no significant detection” of sENG in mice that received cyclophosphamide and TRC105 or cyclophosphamide alone.
Dr Perlingeiro and her colleagues said this suggests the inhibitory effects of sENG can be circumvented by suppressing tumor burden, which results in the combination therapy demonstrating potent antileukemic activity.
Endoglin may be a promising therapeutic target in acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL), according to researchers.
The group identified endoglin expression on the majority of blasts from patients with AML and B-ALL.
The team also found that an endoglin antibody, TRC105 (carotuximab), exhibited activity against AML and B-ALL in vivo, and combining the drug with chemotherapeutic agents enhanced this activity.
Rita Perlingeiro, PhD, of the University of Minnesota in Minneapolis, and her colleagues reported these findings in Blood.
The researchers first discovered that endoglin, which is also known as CD105, was “highly expressed” in leukemic blasts.
In samples from AML patients, 47.6% to 98.5% of blasts were CD105+. In samples from B-ALL patients, 92.6% to 99% of blasts were CD105+.
“We have been studying the function of endoglin in hematopoiesis for more than a decade, and the consistent expression of this receptor in the majority of acute leukemias was intriguing,” Dr Perlingeiro said.
She and her colleagues also found that CD105+ blasts had superior leukemogenic activity and reduced survival in mice when compared to CD105- blasts.
Mice injected with AML CD105+ blasts had all died at day 110 after injection, but mice injected with CD105- AML blasts survived until day 140.
Mice injected with CD105+ ALL blasts died 3 months after injection, but mice injected with CD105- ALL blasts were still alive and showed no signs of disease at the time of sacrifice, which was 5 months after injection.
TRC105 monotherapy
Several experiments showed that TRC105 could reduce leukemic activity in vivo.
TRC105 reduced blast counts in the peripheral blood of mice that had been injected with AML blasts. The drug also reduced blasts in the bone marrow initially, though blast counts were comparable in treated mice and controls by week 12.
On the other hand, mice treated with TRC105 did not experience the weight loss and splenomegaly observed in control mice. And TRC105 suppressed the ability of AML blasts to give rise to leukemia in secondary recipient mice.
In mice injected with ALL blasts, TRC105 initially decreased blast counts. However, by week 8, blast counts in the peripheral blood, bone marrow, and spleen of treated mice were similar to those observed in controls. The researchers said this suggests that TRC105 only slows the development of ALL.
The team then evaluated the effects of TRC105 after disease had been established. Mice with established AML received TRC105 for 8 weeks, and mice with established ALL received TRC105 for 4 weeks.
In mice with AML, TRC105 reduced blasts in the peripheral blood and spleen but not the bone marrow. The treatment also prevented splenomegaly and weight loss and prolonged survival.
“Our hypothesis that endoglin expression was linked to leukemia-forming activity was proven to be true, and it was even more rewarding to witness the robust anti-leukemogenic effect of blocking endoglin signaling with TRC105, even when leukemia had already been established in the mouse,” Dr Perlingeiro said.
However, in mice with established ALL, TRC105 had no effect on leukemia progression.
The researchers said this could be due to expression of soluble endoglin (sENG), which would titrate the TRC105 antibody, limiting its ability to bind to membrane-bound endoglin on leukemic cells. Results of additional experiments supported this idea.
TRC105 in combination
The researchers also tested TRC105 in combination with chemotherapy in the mouse models. The team combined the antibody with cytarabine to treat AML and cyclophosphamide to treat ALL.
In mice with AML, cytarabine and TRC105 significantly reduced levels of leukemic cells in the peripheral blood.
In mice with ALL, cyclophosphamide and TRC105 suppressed leukemia development more effectively and more quickly than cyclophosphamide alone.
The researchers detected high levels of sENG in untreated mice with ALL, but levels were lower in the TRC105-treated mice. And there was “no significant detection” of sENG in mice that received cyclophosphamide and TRC105 or cyclophosphamide alone.
Dr Perlingeiro and her colleagues said this suggests the inhibitory effects of sENG can be circumvented by suppressing tumor burden, which results in the combination therapy demonstrating potent antileukemic activity.
Endoglin may be a promising therapeutic target in acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL), according to researchers.
The group identified endoglin expression on the majority of blasts from patients with AML and B-ALL.
The team also found that an endoglin antibody, TRC105 (carotuximab), exhibited activity against AML and B-ALL in vivo, and combining the drug with chemotherapeutic agents enhanced this activity.
Rita Perlingeiro, PhD, of the University of Minnesota in Minneapolis, and her colleagues reported these findings in Blood.
The researchers first discovered that endoglin, which is also known as CD105, was “highly expressed” in leukemic blasts.
In samples from AML patients, 47.6% to 98.5% of blasts were CD105+. In samples from B-ALL patients, 92.6% to 99% of blasts were CD105+.
“We have been studying the function of endoglin in hematopoiesis for more than a decade, and the consistent expression of this receptor in the majority of acute leukemias was intriguing,” Dr Perlingeiro said.
She and her colleagues also found that CD105+ blasts had superior leukemogenic activity and reduced survival in mice when compared to CD105- blasts.
Mice injected with AML CD105+ blasts had all died at day 110 after injection, but mice injected with CD105- AML blasts survived until day 140.
Mice injected with CD105+ ALL blasts died 3 months after injection, but mice injected with CD105- ALL blasts were still alive and showed no signs of disease at the time of sacrifice, which was 5 months after injection.
TRC105 monotherapy
Several experiments showed that TRC105 could reduce leukemic activity in vivo.
TRC105 reduced blast counts in the peripheral blood of mice that had been injected with AML blasts. The drug also reduced blasts in the bone marrow initially, though blast counts were comparable in treated mice and controls by week 12.
On the other hand, mice treated with TRC105 did not experience the weight loss and splenomegaly observed in control mice. And TRC105 suppressed the ability of AML blasts to give rise to leukemia in secondary recipient mice.
In mice injected with ALL blasts, TRC105 initially decreased blast counts. However, by week 8, blast counts in the peripheral blood, bone marrow, and spleen of treated mice were similar to those observed in controls. The researchers said this suggests that TRC105 only slows the development of ALL.
The team then evaluated the effects of TRC105 after disease had been established. Mice with established AML received TRC105 for 8 weeks, and mice with established ALL received TRC105 for 4 weeks.
In mice with AML, TRC105 reduced blasts in the peripheral blood and spleen but not the bone marrow. The treatment also prevented splenomegaly and weight loss and prolonged survival.
“Our hypothesis that endoglin expression was linked to leukemia-forming activity was proven to be true, and it was even more rewarding to witness the robust anti-leukemogenic effect of blocking endoglin signaling with TRC105, even when leukemia had already been established in the mouse,” Dr Perlingeiro said.
However, in mice with established ALL, TRC105 had no effect on leukemia progression.
The researchers said this could be due to expression of soluble endoglin (sENG), which would titrate the TRC105 antibody, limiting its ability to bind to membrane-bound endoglin on leukemic cells. Results of additional experiments supported this idea.
TRC105 in combination
The researchers also tested TRC105 in combination with chemotherapy in the mouse models. The team combined the antibody with cytarabine to treat AML and cyclophosphamide to treat ALL.
In mice with AML, cytarabine and TRC105 significantly reduced levels of leukemic cells in the peripheral blood.
In mice with ALL, cyclophosphamide and TRC105 suppressed leukemia development more effectively and more quickly than cyclophosphamide alone.
The researchers detected high levels of sENG in untreated mice with ALL, but levels were lower in the TRC105-treated mice. And there was “no significant detection” of sENG in mice that received cyclophosphamide and TRC105 or cyclophosphamide alone.
Dr Perlingeiro and her colleagues said this suggests the inhibitory effects of sENG can be circumvented by suppressing tumor burden, which results in the combination therapy demonstrating potent antileukemic activity.
Novel inhibitor proves ‘potent’ in hematologic malignancies
BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.
In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.
In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).
Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).
Both studies involved researchers from Aptose Biosciences, the company developing CG’806.
Poster 25
Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”
The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.
Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.
With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).
The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).
The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.
Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.
This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.
Poster 44
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”
The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).
The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.
Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).
The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.
“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said.
BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.
In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.
In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).
Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).
Both studies involved researchers from Aptose Biosciences, the company developing CG’806.
Poster 25
Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”
The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.
Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.
With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).
The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).
The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.
Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.
This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.
Poster 44
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”
The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).
The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.
Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).
The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.
“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said.
BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.
In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.
In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).
Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).
Both studies involved researchers from Aptose Biosciences, the company developing CG’806.
Poster 25
Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”
The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.
Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.
With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).
The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).
The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.
Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.
This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.
Poster 44
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”
The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).
The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.
Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).
The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.
“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said.
Formaldehyde probably doesn’t cause leukemia, team says
There is little or no evidence to suggest that exposure to formaldehyde causes leukemia, according to a group of researchers.
The team reanalyzed data from a study published in 2010 that suggested a possible link between formaldehyde exposure and myeloid leukemia.
They also reviewed other recent studies investigating the health effects of formaldehyde.
“The weight of scientific evidence does not support a causal association between formaldehyde and leukemia,” said Kenneth A. Mundt, PhD, of Ramboll Environ, a consulting firm focused on environmental, health, and social issues.
Dr Mundt and his colleagues detailed the evidence in the Journal of Critical Reviews in Toxicology.
The team’s research was supported by the Foundation for Chemistry Research and Initiatives (formerly the Research Foundation for Health and Environmental Effects), an organization established by the American Chemistry Council (an industry trade association for American chemical companies).
The study that suggested a possible link between formaldehyde and myeloid leukemia, particularly acute myeloid leukemia (AML), was published in January 2010 in Cancer Epidemiology, Biomarkers & Prevention.
In this study, Luoping Zhang, PhD, of the University of California at Berkeley, and her colleagues compared 2 groups of workers in China—43 workers with occupational exposure to formaldehyde and 51 without such exposure.
The researchers looked at complete blood counts and peripheral stem/progenitor cell colony formation. They also cultured myeloid progenitor cells, aiming to determine the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in these cells.
The team found that workers exposed to formaldehyde had significantly lower peripheral blood cell counts and significantly elevated leukemia-specific chromosome changes in myeloid progenitor cells.
Dr Zhang and her colleagues said these results suggest “formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible.”
Dr Mundt and his colleagues reanalyzed raw data from this study, including previously unavailable data on individual workers’ exposure to formaldehyde. Those data were recently released by the National Cancer Institute, which co-funded Dr Zhang’s study.
The reanalysis indicated that the observed differences in blood cell counts were not dependent on formaldehyde exposure. And the researchers found no association between the individual average formaldehyde exposure estimates and chromosomal abnormalities.
Dr Mundt’s team also reviewed several other publications on the health effects of formaldehyde, and they said the data, as a whole, provide “little if any evidence of a causal association between formaldehyde exposure and AML.”
There is little or no evidence to suggest that exposure to formaldehyde causes leukemia, according to a group of researchers.
The team reanalyzed data from a study published in 2010 that suggested a possible link between formaldehyde exposure and myeloid leukemia.
They also reviewed other recent studies investigating the health effects of formaldehyde.
“The weight of scientific evidence does not support a causal association between formaldehyde and leukemia,” said Kenneth A. Mundt, PhD, of Ramboll Environ, a consulting firm focused on environmental, health, and social issues.
Dr Mundt and his colleagues detailed the evidence in the Journal of Critical Reviews in Toxicology.
The team’s research was supported by the Foundation for Chemistry Research and Initiatives (formerly the Research Foundation for Health and Environmental Effects), an organization established by the American Chemistry Council (an industry trade association for American chemical companies).
The study that suggested a possible link between formaldehyde and myeloid leukemia, particularly acute myeloid leukemia (AML), was published in January 2010 in Cancer Epidemiology, Biomarkers & Prevention.
In this study, Luoping Zhang, PhD, of the University of California at Berkeley, and her colleagues compared 2 groups of workers in China—43 workers with occupational exposure to formaldehyde and 51 without such exposure.
The researchers looked at complete blood counts and peripheral stem/progenitor cell colony formation. They also cultured myeloid progenitor cells, aiming to determine the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in these cells.
The team found that workers exposed to formaldehyde had significantly lower peripheral blood cell counts and significantly elevated leukemia-specific chromosome changes in myeloid progenitor cells.
Dr Zhang and her colleagues said these results suggest “formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible.”
Dr Mundt and his colleagues reanalyzed raw data from this study, including previously unavailable data on individual workers’ exposure to formaldehyde. Those data were recently released by the National Cancer Institute, which co-funded Dr Zhang’s study.
The reanalysis indicated that the observed differences in blood cell counts were not dependent on formaldehyde exposure. And the researchers found no association between the individual average formaldehyde exposure estimates and chromosomal abnormalities.
Dr Mundt’s team also reviewed several other publications on the health effects of formaldehyde, and they said the data, as a whole, provide “little if any evidence of a causal association between formaldehyde exposure and AML.”
There is little or no evidence to suggest that exposure to formaldehyde causes leukemia, according to a group of researchers.
The team reanalyzed data from a study published in 2010 that suggested a possible link between formaldehyde exposure and myeloid leukemia.
They also reviewed other recent studies investigating the health effects of formaldehyde.
“The weight of scientific evidence does not support a causal association between formaldehyde and leukemia,” said Kenneth A. Mundt, PhD, of Ramboll Environ, a consulting firm focused on environmental, health, and social issues.
Dr Mundt and his colleagues detailed the evidence in the Journal of Critical Reviews in Toxicology.
The team’s research was supported by the Foundation for Chemistry Research and Initiatives (formerly the Research Foundation for Health and Environmental Effects), an organization established by the American Chemistry Council (an industry trade association for American chemical companies).
The study that suggested a possible link between formaldehyde and myeloid leukemia, particularly acute myeloid leukemia (AML), was published in January 2010 in Cancer Epidemiology, Biomarkers & Prevention.
In this study, Luoping Zhang, PhD, of the University of California at Berkeley, and her colleagues compared 2 groups of workers in China—43 workers with occupational exposure to formaldehyde and 51 without such exposure.
The researchers looked at complete blood counts and peripheral stem/progenitor cell colony formation. They also cultured myeloid progenitor cells, aiming to determine the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in these cells.
The team found that workers exposed to formaldehyde had significantly lower peripheral blood cell counts and significantly elevated leukemia-specific chromosome changes in myeloid progenitor cells.
Dr Zhang and her colleagues said these results suggest “formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible.”
Dr Mundt and his colleagues reanalyzed raw data from this study, including previously unavailable data on individual workers’ exposure to formaldehyde. Those data were recently released by the National Cancer Institute, which co-funded Dr Zhang’s study.
The reanalysis indicated that the observed differences in blood cell counts were not dependent on formaldehyde exposure. And the researchers found no association between the individual average formaldehyde exposure estimates and chromosomal abnormalities.
Dr Mundt’s team also reviewed several other publications on the health effects of formaldehyde, and they said the data, as a whole, provide “little if any evidence of a causal association between formaldehyde exposure and AML.”
Company withdraws MAA for vosaroxin in AML
Sunesis Pharmaceuticals, Inc. is withdrawing its European Marketing Authorization Application (MAA) for the anticancer quinolone derivative vosaroxin.
The MAA was for vosaroxin as a treatment for relapsed/refractory acute myeloid leukemia (AML) in patients age 60 years and older.
Along with the MAA withdrawal, Sunesis has decided to scale back its investment in vosaroxin.
However, the company said it will continue developing the drug.
These decisions were made after Sunesis learned the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) was unlikely to recommend approval for vosaroxin.
“We are disappointed to not achieve approval for vosaroxin’s MAA, given its reported efficacy in a patient population with such poor outcomes,” said Daniel Swisher, president and chief executive officer of Sunesis.
“Although we did not receive a definitive CHMP opinion, we believed that a positive opinion was unlikely. Following our appearances before the committee’s Scientific Advisory Group on Oncology and CHMP, we carefully considered feedback from our rapporteurs and input from retained regulatory experts to make our decision to notify EMA to withdraw vosaroxin’s MAA, as our assessment concluded it was unlikely we could achieve a majority vote of CHMP members at this time or upon an immediate re-examination for our proposed indication based on VALOR data from a subgroup of a single pivotal trial that had missed reaching full statistical significance in its primary analysis.”
“In light of this, we are significantly reducing our investment in the AML program and shifting an increasing portion of resources to our kinase inhibitor pipeline . . . . We expect to continue to advance the development of vosaroxin through a modest investment in investigator-sponsored group trials and will carefully assess business development alternatives to support the conduct of another pivotal trial to achieve future regulatory approval of vosaroxin. We expect that our current cash resources are sufficient to fund the company beyond Q1 2018.”
Sunesis Pharmaceuticals, Inc. is withdrawing its European Marketing Authorization Application (MAA) for the anticancer quinolone derivative vosaroxin.
The MAA was for vosaroxin as a treatment for relapsed/refractory acute myeloid leukemia (AML) in patients age 60 years and older.
Along with the MAA withdrawal, Sunesis has decided to scale back its investment in vosaroxin.
However, the company said it will continue developing the drug.
These decisions were made after Sunesis learned the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) was unlikely to recommend approval for vosaroxin.
“We are disappointed to not achieve approval for vosaroxin’s MAA, given its reported efficacy in a patient population with such poor outcomes,” said Daniel Swisher, president and chief executive officer of Sunesis.
“Although we did not receive a definitive CHMP opinion, we believed that a positive opinion was unlikely. Following our appearances before the committee’s Scientific Advisory Group on Oncology and CHMP, we carefully considered feedback from our rapporteurs and input from retained regulatory experts to make our decision to notify EMA to withdraw vosaroxin’s MAA, as our assessment concluded it was unlikely we could achieve a majority vote of CHMP members at this time or upon an immediate re-examination for our proposed indication based on VALOR data from a subgroup of a single pivotal trial that had missed reaching full statistical significance in its primary analysis.”
“In light of this, we are significantly reducing our investment in the AML program and shifting an increasing portion of resources to our kinase inhibitor pipeline . . . . We expect to continue to advance the development of vosaroxin through a modest investment in investigator-sponsored group trials and will carefully assess business development alternatives to support the conduct of another pivotal trial to achieve future regulatory approval of vosaroxin. We expect that our current cash resources are sufficient to fund the company beyond Q1 2018.”
Sunesis Pharmaceuticals, Inc. is withdrawing its European Marketing Authorization Application (MAA) for the anticancer quinolone derivative vosaroxin.
The MAA was for vosaroxin as a treatment for relapsed/refractory acute myeloid leukemia (AML) in patients age 60 years and older.
Along with the MAA withdrawal, Sunesis has decided to scale back its investment in vosaroxin.
However, the company said it will continue developing the drug.
These decisions were made after Sunesis learned the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) was unlikely to recommend approval for vosaroxin.
“We are disappointed to not achieve approval for vosaroxin’s MAA, given its reported efficacy in a patient population with such poor outcomes,” said Daniel Swisher, president and chief executive officer of Sunesis.
“Although we did not receive a definitive CHMP opinion, we believed that a positive opinion was unlikely. Following our appearances before the committee’s Scientific Advisory Group on Oncology and CHMP, we carefully considered feedback from our rapporteurs and input from retained regulatory experts to make our decision to notify EMA to withdraw vosaroxin’s MAA, as our assessment concluded it was unlikely we could achieve a majority vote of CHMP members at this time or upon an immediate re-examination for our proposed indication based on VALOR data from a subgroup of a single pivotal trial that had missed reaching full statistical significance in its primary analysis.”
“In light of this, we are significantly reducing our investment in the AML program and shifting an increasing portion of resources to our kinase inhibitor pipeline . . . . We expect to continue to advance the development of vosaroxin through a modest investment in investigator-sponsored group trials and will carefully assess business development alternatives to support the conduct of another pivotal trial to achieve future regulatory approval of vosaroxin. We expect that our current cash resources are sufficient to fund the company beyond Q1 2018.”
Drug receives orphan designation for AML
The US Food and Drug Administration (FDA) has granted orphan drug designation for PTX-200 for the treatment of acute myeloid leukemia (AML).
PTX-200, or triciribine phosphate monohydrate, is a small-molecule Akt inhibitor being developed by Prescient Therapeutics Ltd.
PTX-200 is currently being tested in combination with cytarabine in a phase 1b/2 trial of patients with relapsed or refractory AML.
PTX-200 was previously tested as monotherapy in a phase 1 trial of patients with relapsed or refractory hematologic malignancies.
Results from this trial were published in Leukemia Research in November 2013.
The trial included 41 patients who received at least 1 dose of PTX-200. The patients’ median age was 70 (range, of 23–83), and most (77%) were male.
Thirty-six patients (84%) had AML, 3 had myelodysplastic syndromes/chronic myelomonocytic leukemia (CMML), 2 had chronic lymphocytic leukemia, and 2 had acute lymphoblastic leukemia.
The patients had received a median of 2 prior therapies (range, 0–11), and they received a median of 1 cycle (range, 0–3) of PTX-200 at varying doses.
The maximum-tolerated dose of PTX-200 was 55 mg/m2. Two dose-limiting toxicities (DLTs) occurred in 3 patients in the 65 mg/m2 cohort (2 cases of lipase elevation and 1 case of triglyceride elevation).
One dose-limiting toxicity (mucositis) occurred in the 35 mg/m2 cohort. All DLTs resolved after patients stopped taking PTX-200.
Common treatment-emergent grade 3/4 adverse events included infection/febrile neutropenia (24%), bleeding (2%), mucositis (2%), and elevated lipase (5%).
Thirty-two patients were evaluable for response. There were no responses, but 17 patients had stable disease. The remaining 15 patients progressed.
Three patients with stable disease (all with AML) achieved at least a 50% reduction in bone marrow blasts, and a patient with CMML experienced spleen reduction and resolution of leukocytosis.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.
Orphan designation provides companies with certain incentives to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation for PTX-200 for the treatment of acute myeloid leukemia (AML).
PTX-200, or triciribine phosphate monohydrate, is a small-molecule Akt inhibitor being developed by Prescient Therapeutics Ltd.
PTX-200 is currently being tested in combination with cytarabine in a phase 1b/2 trial of patients with relapsed or refractory AML.
PTX-200 was previously tested as monotherapy in a phase 1 trial of patients with relapsed or refractory hematologic malignancies.
Results from this trial were published in Leukemia Research in November 2013.
The trial included 41 patients who received at least 1 dose of PTX-200. The patients’ median age was 70 (range, of 23–83), and most (77%) were male.
Thirty-six patients (84%) had AML, 3 had myelodysplastic syndromes/chronic myelomonocytic leukemia (CMML), 2 had chronic lymphocytic leukemia, and 2 had acute lymphoblastic leukemia.
The patients had received a median of 2 prior therapies (range, 0–11), and they received a median of 1 cycle (range, 0–3) of PTX-200 at varying doses.
The maximum-tolerated dose of PTX-200 was 55 mg/m2. Two dose-limiting toxicities (DLTs) occurred in 3 patients in the 65 mg/m2 cohort (2 cases of lipase elevation and 1 case of triglyceride elevation).
One dose-limiting toxicity (mucositis) occurred in the 35 mg/m2 cohort. All DLTs resolved after patients stopped taking PTX-200.
Common treatment-emergent grade 3/4 adverse events included infection/febrile neutropenia (24%), bleeding (2%), mucositis (2%), and elevated lipase (5%).
Thirty-two patients were evaluable for response. There were no responses, but 17 patients had stable disease. The remaining 15 patients progressed.
Three patients with stable disease (all with AML) achieved at least a 50% reduction in bone marrow blasts, and a patient with CMML experienced spleen reduction and resolution of leukocytosis.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.
Orphan designation provides companies with certain incentives to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation for PTX-200 for the treatment of acute myeloid leukemia (AML).
PTX-200, or triciribine phosphate monohydrate, is a small-molecule Akt inhibitor being developed by Prescient Therapeutics Ltd.
PTX-200 is currently being tested in combination with cytarabine in a phase 1b/2 trial of patients with relapsed or refractory AML.
PTX-200 was previously tested as monotherapy in a phase 1 trial of patients with relapsed or refractory hematologic malignancies.
Results from this trial were published in Leukemia Research in November 2013.
The trial included 41 patients who received at least 1 dose of PTX-200. The patients’ median age was 70 (range, of 23–83), and most (77%) were male.
Thirty-six patients (84%) had AML, 3 had myelodysplastic syndromes/chronic myelomonocytic leukemia (CMML), 2 had chronic lymphocytic leukemia, and 2 had acute lymphoblastic leukemia.
The patients had received a median of 2 prior therapies (range, 0–11), and they received a median of 1 cycle (range, 0–3) of PTX-200 at varying doses.
The maximum-tolerated dose of PTX-200 was 55 mg/m2. Two dose-limiting toxicities (DLTs) occurred in 3 patients in the 65 mg/m2 cohort (2 cases of lipase elevation and 1 case of triglyceride elevation).
One dose-limiting toxicity (mucositis) occurred in the 35 mg/m2 cohort. All DLTs resolved after patients stopped taking PTX-200.
Common treatment-emergent grade 3/4 adverse events included infection/febrile neutropenia (24%), bleeding (2%), mucositis (2%), and elevated lipase (5%).
Thirty-two patients were evaluable for response. There were no responses, but 17 patients had stable disease. The remaining 15 patients progressed.
Three patients with stable disease (all with AML) achieved at least a 50% reduction in bone marrow blasts, and a patient with CMML experienced spleen reduction and resolution of leukocytosis.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.
Orphan designation provides companies with certain incentives to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.
FDA approves midostaurin to treat FLT3+ AML, advanced SM
The US Food and Drug Administration (FDA) has granted approval for the oral, multi-targeted kinase inhibitor midostaurin (Rydapt).
The drug is now approved for the treatment of adults with advanced systemic mastocytosis (SM), including aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL).
Midostaurin is also approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test.
The FDA approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, for use with midostaurin to test AML patients for the FLT3 mutation.
Midostaurin is a product of Novartis. The companion diagnostic was developed by Novartis and Invivoscribe Technologies, Inc.
Midostaurin in AML
The FDA’s approval of midostaurin in AML is based on results from the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.
In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.
Patients in the midostaurin arm experienced a statistically significant improvement in overall survival, with a 23% reduction in risk of death compared to the placebo arm (hazard ratio=0.77, P=0.016).
The median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).
The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.
The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.
Midostaurin in advanced SM
The FDA’s approval of midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.
Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.
Study 2 included 116 patients, 115 of whom were evaluable for response.
The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.
Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.
Among the 17 patients with SM-AHN, there were 10 response (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.
In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.
The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.
The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.
Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.
The US Food and Drug Administration (FDA) has granted approval for the oral, multi-targeted kinase inhibitor midostaurin (Rydapt).
The drug is now approved for the treatment of adults with advanced systemic mastocytosis (SM), including aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL).
Midostaurin is also approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test.
The FDA approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, for use with midostaurin to test AML patients for the FLT3 mutation.
Midostaurin is a product of Novartis. The companion diagnostic was developed by Novartis and Invivoscribe Technologies, Inc.
Midostaurin in AML
The FDA’s approval of midostaurin in AML is based on results from the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.
In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.
Patients in the midostaurin arm experienced a statistically significant improvement in overall survival, with a 23% reduction in risk of death compared to the placebo arm (hazard ratio=0.77, P=0.016).
The median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).
The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.
The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.
Midostaurin in advanced SM
The FDA’s approval of midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.
Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.
Study 2 included 116 patients, 115 of whom were evaluable for response.
The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.
Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.
Among the 17 patients with SM-AHN, there were 10 response (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.
In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.
The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.
The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.
Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.
The US Food and Drug Administration (FDA) has granted approval for the oral, multi-targeted kinase inhibitor midostaurin (Rydapt).
The drug is now approved for the treatment of adults with advanced systemic mastocytosis (SM), including aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL).
Midostaurin is also approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test.
The FDA approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, for use with midostaurin to test AML patients for the FLT3 mutation.
Midostaurin is a product of Novartis. The companion diagnostic was developed by Novartis and Invivoscribe Technologies, Inc.
Midostaurin in AML
The FDA’s approval of midostaurin in AML is based on results from the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.
In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.
Patients in the midostaurin arm experienced a statistically significant improvement in overall survival, with a 23% reduction in risk of death compared to the placebo arm (hazard ratio=0.77, P=0.016).
The median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).
The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.
The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.
Midostaurin in advanced SM
The FDA’s approval of midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.
Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.
Study 2 included 116 patients, 115 of whom were evaluable for response.
The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.
Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.
Among the 17 patients with SM-AHN, there were 10 response (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.
In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.
The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.
The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.
Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.
FDA approves test to detect FLT3 mutations
The US Food and Drug Administration (FDA) has approved use of the LeukoStrat® CDx FLT3 Mutation Assay as a companion diagnostic test.
The LeukoStrat® CDx FLT3 Mutation Assay is a signal ratio assay that identifies both internal tandem duplication and tyrosine kinase domain mutations.
The assay is the first FDA-approved companion diagnostic for acute myeloid leukemia (AML).
It is approved for use in patients newly diagnosed with AML to determine if they have FLT3 mutations and are therefore eligible to receive treatment with midostaurin (Rydapt).
The FDA granted approval for the LeukoStrat® CDx FLT3 Mutation Assay and midostaurin simultaneously.
The assay was developed by Invivoscribe Technologies, Inc. and Novartis. Midostaurin is a product of Novartis.
Under the current labeling, FLT3 mutation testing with the LeukoStrat® CDx FLT3 Mutation Assay is exclusively performed by The Laboratory for Personalized Molecular Medicine, a subsidiary of Invivoscribe Technologies, Inc.
Under terms of a previously announced agreement with Thermo Fisher, Invivoscribe will also seek FDA approval of the LeukoStrat® CDx FLT3 Mutation Assay that will allow the sale of kits to other laboratories.
The US Food and Drug Administration (FDA) has approved use of the LeukoStrat® CDx FLT3 Mutation Assay as a companion diagnostic test.
The LeukoStrat® CDx FLT3 Mutation Assay is a signal ratio assay that identifies both internal tandem duplication and tyrosine kinase domain mutations.
The assay is the first FDA-approved companion diagnostic for acute myeloid leukemia (AML).
It is approved for use in patients newly diagnosed with AML to determine if they have FLT3 mutations and are therefore eligible to receive treatment with midostaurin (Rydapt).
The FDA granted approval for the LeukoStrat® CDx FLT3 Mutation Assay and midostaurin simultaneously.
The assay was developed by Invivoscribe Technologies, Inc. and Novartis. Midostaurin is a product of Novartis.
Under the current labeling, FLT3 mutation testing with the LeukoStrat® CDx FLT3 Mutation Assay is exclusively performed by The Laboratory for Personalized Molecular Medicine, a subsidiary of Invivoscribe Technologies, Inc.
Under terms of a previously announced agreement with Thermo Fisher, Invivoscribe will also seek FDA approval of the LeukoStrat® CDx FLT3 Mutation Assay that will allow the sale of kits to other laboratories.
The US Food and Drug Administration (FDA) has approved use of the LeukoStrat® CDx FLT3 Mutation Assay as a companion diagnostic test.
The LeukoStrat® CDx FLT3 Mutation Assay is a signal ratio assay that identifies both internal tandem duplication and tyrosine kinase domain mutations.
The assay is the first FDA-approved companion diagnostic for acute myeloid leukemia (AML).
It is approved for use in patients newly diagnosed with AML to determine if they have FLT3 mutations and are therefore eligible to receive treatment with midostaurin (Rydapt).
The FDA granted approval for the LeukoStrat® CDx FLT3 Mutation Assay and midostaurin simultaneously.
The assay was developed by Invivoscribe Technologies, Inc. and Novartis. Midostaurin is a product of Novartis.
Under the current labeling, FLT3 mutation testing with the LeukoStrat® CDx FLT3 Mutation Assay is exclusively performed by The Laboratory for Personalized Molecular Medicine, a subsidiary of Invivoscribe Technologies, Inc.
Under terms of a previously announced agreement with Thermo Fisher, Invivoscribe will also seek FDA approval of the LeukoStrat® CDx FLT3 Mutation Assay that will allow the sale of kits to other laboratories.
Longer course of idarubicin consolidation increases leukemia-free survival
In adults with acute myeloid leukemia who achieve complete remission with one to two cycles of induction therapy, a slightly longer course of idarubicin during consolidation therapy increases leukemia-free survival without increasing nonhematologic toxicity, according to new findings.
The optimal dose of anthracyclines, such as idarubicin, during consolidation therapy in this patient population has not been explored to date. Researchers performed a randomized phase III clinical trial, comparing standard (2-day) idarubicin with increased (3-day) idarubicin during consolidation therapy with cytarabine and etoposide.
The 7-year trial involved 293 patients, aged 15-60 years (median age, 45 years), who were treated at 23 Australian hospitals after achieving complete remission with one to two courses of intensive cytarabine-based induction therapy. Study participants were randomly assigned to receive either standard or intensive idarubicin, said Kenneth F. Bradstock, MB, PhD, of the University of Sydney, Australia, and his associates.
More patients who were receiving the higher cumulative dose of idarubicin had leukemia-free survival at 3 years (47%), compared with the standard-dose group (35%), for a hazard ratio of 0.74 favoring intensive idarubicin. The estimated median leukemia-free survival was 2.13 years for intensified idarubicin, compared with 0.93 years for standard idarubicin (J Clin Oncol. 2017 Apr 3. doi: 10.1200/JCO.2016.70.6374).
Additionally, the time to relapse was significantly longer for intensive idarubicin (17 months) than for standard idarubicin (10 months). This study was not powered to detect a difference between the two groups in overall survival.
There was no significant difference between the two study groups in the incidence of serious nonhematologic toxicities or in the rate of treatment-related death, even though the patients receiving intensive idarubicin showed a clear increase in myelotoxicity, as expected.
In exploratory analyses, the researchers could not detect a specific benefit of increased idarubicin dose in any patient subgroups, in particular, younger versus older ages, adverse versus intermediate karyotypes, and mutations in the FLT3 and NPM1 genes. However, they were limited because of the low number of cases in some subgroups.
The trial was supported by the National Health and Medical Research Council of Australia, Pfizer Australia, and Amgen Australia. Dr. Bradstock reported ties to Amgen Australia. His is associates reported ties to numerous industry sources.
In adults with acute myeloid leukemia who achieve complete remission with one to two cycles of induction therapy, a slightly longer course of idarubicin during consolidation therapy increases leukemia-free survival without increasing nonhematologic toxicity, according to new findings.
The optimal dose of anthracyclines, such as idarubicin, during consolidation therapy in this patient population has not been explored to date. Researchers performed a randomized phase III clinical trial, comparing standard (2-day) idarubicin with increased (3-day) idarubicin during consolidation therapy with cytarabine and etoposide.
The 7-year trial involved 293 patients, aged 15-60 years (median age, 45 years), who were treated at 23 Australian hospitals after achieving complete remission with one to two courses of intensive cytarabine-based induction therapy. Study participants were randomly assigned to receive either standard or intensive idarubicin, said Kenneth F. Bradstock, MB, PhD, of the University of Sydney, Australia, and his associates.
More patients who were receiving the higher cumulative dose of idarubicin had leukemia-free survival at 3 years (47%), compared with the standard-dose group (35%), for a hazard ratio of 0.74 favoring intensive idarubicin. The estimated median leukemia-free survival was 2.13 years for intensified idarubicin, compared with 0.93 years for standard idarubicin (J Clin Oncol. 2017 Apr 3. doi: 10.1200/JCO.2016.70.6374).
Additionally, the time to relapse was significantly longer for intensive idarubicin (17 months) than for standard idarubicin (10 months). This study was not powered to detect a difference between the two groups in overall survival.
There was no significant difference between the two study groups in the incidence of serious nonhematologic toxicities or in the rate of treatment-related death, even though the patients receiving intensive idarubicin showed a clear increase in myelotoxicity, as expected.
In exploratory analyses, the researchers could not detect a specific benefit of increased idarubicin dose in any patient subgroups, in particular, younger versus older ages, adverse versus intermediate karyotypes, and mutations in the FLT3 and NPM1 genes. However, they were limited because of the low number of cases in some subgroups.
The trial was supported by the National Health and Medical Research Council of Australia, Pfizer Australia, and Amgen Australia. Dr. Bradstock reported ties to Amgen Australia. His is associates reported ties to numerous industry sources.
In adults with acute myeloid leukemia who achieve complete remission with one to two cycles of induction therapy, a slightly longer course of idarubicin during consolidation therapy increases leukemia-free survival without increasing nonhematologic toxicity, according to new findings.
The optimal dose of anthracyclines, such as idarubicin, during consolidation therapy in this patient population has not been explored to date. Researchers performed a randomized phase III clinical trial, comparing standard (2-day) idarubicin with increased (3-day) idarubicin during consolidation therapy with cytarabine and etoposide.
The 7-year trial involved 293 patients, aged 15-60 years (median age, 45 years), who were treated at 23 Australian hospitals after achieving complete remission with one to two courses of intensive cytarabine-based induction therapy. Study participants were randomly assigned to receive either standard or intensive idarubicin, said Kenneth F. Bradstock, MB, PhD, of the University of Sydney, Australia, and his associates.
More patients who were receiving the higher cumulative dose of idarubicin had leukemia-free survival at 3 years (47%), compared with the standard-dose group (35%), for a hazard ratio of 0.74 favoring intensive idarubicin. The estimated median leukemia-free survival was 2.13 years for intensified idarubicin, compared with 0.93 years for standard idarubicin (J Clin Oncol. 2017 Apr 3. doi: 10.1200/JCO.2016.70.6374).
Additionally, the time to relapse was significantly longer for intensive idarubicin (17 months) than for standard idarubicin (10 months). This study was not powered to detect a difference between the two groups in overall survival.
There was no significant difference between the two study groups in the incidence of serious nonhematologic toxicities or in the rate of treatment-related death, even though the patients receiving intensive idarubicin showed a clear increase in myelotoxicity, as expected.
In exploratory analyses, the researchers could not detect a specific benefit of increased idarubicin dose in any patient subgroups, in particular, younger versus older ages, adverse versus intermediate karyotypes, and mutations in the FLT3 and NPM1 genes. However, they were limited because of the low number of cases in some subgroups.
The trial was supported by the National Health and Medical Research Council of Australia, Pfizer Australia, and Amgen Australia. Dr. Bradstock reported ties to Amgen Australia. His is associates reported ties to numerous industry sources.
Key clinical point:
Major finding: The median leukemia-free survival was 2.13 years for intensified idarubicin, compared with 0.93 years for standard idarubicin.
Data source: A multicenter randomized phase III trial involving 293 patients.
Disclosures: The trial was supported by the National Health and Medical Research Council of Australia, Pfizer Australia, and Amgen Australia. Dr. Bradstock reported ties to Amgen Australis. His associates reported ties to numerous industry sources.
Treatment-related hypertension, kidney injury are undertreated in kids with leukemia
MONTREAL – Hypertension is a frequent, but underrecognized and undertreated, complication of chemotherapy for acute lymphoblastic leukemia (ALL), the most common childhood malignancy, investigators in a single-center U.S. study reported.
Additionally, there is a “concerningly high” incidence of acute kidney injury among children and young adults who undergo multiagent chemotherapy for acute myeloid leukemia (AML), said the authors of a study conducted in Canada.
Both studies were reported in a scientific poster session at the annual meeting of the American Society for Pediatric Hematology/Oncology.
Hypertension in ALL
Although standard induction regimens for childhood ALL contain high-dose steroids, which are known to be associated with increased risk for hypertension, the incidence of hypertension throughout induction, consolidation, and maintenance for ALL in children has not been adequately evaluated, according to Andrew S. Freiberg, MD, and his colleagues at Penn State Children’s Hospital in Hershey, Penn.
“The incidence of hypertension was much higher than the under 5% expected for a healthy pediatric population,” the investigators found.
Of 562 total readings taken during induction, 56% were in the normo- or prehypertensive range, but 30% were classified as stage 1 and 14% as stage II hypertension.
The combined percentage of stage 1 and 2 readings declined slightly over the year from 44% during induction to 35% during Q4 “but remained well above expected for the pediatric population,” the investigators reported.
Despite the high incidence, “I was surprised at how few of the patients with hypertension we actually treated,” Dr. Freiberg said in an interview.
Just 3 of the 36 patients studied received treatment for hypertension, he said, possibly because clinicians assumed that the effect was steroid related and transient.
“Now that we’re paying attention, however, we’re treating more of these patients,” Dr. Freiberg said.
The electronic record system used at his institution now alerts clinicians to hypertensive episodes during treatment, he added.
Kidney injury in AML
Like Dr. Freiberg and his colleagues, Liezl du Plessis, MBChB, from the British Columbia Children’s Hospital in Vancouver, Canada, and her colleagues were similarly taken aback when they looked into the incidence of acute kidney injury (AKI) in children and adolescents undergoing multidrug chemotherapy for AML.
“Chemotherapy agents that are used in acute myeloid leukemia are not considered to be nephrotoxic, so it was quite alarming to us to see that there is such a high rate of kidney injury in these patients,” Dr. du Plessis said in an interview.
They found that 34 of the 53 patients (64%) had AKI, with 11 patients having stage 1 (rise in serum creatinine of 1.5 or more times the baseline level), 11 having stage 2 (SCr 2 or more times baseline), and 12 having stage 3 AKI (SCr 3 or more times baseline or the need for dialysis).
Creatinine changes were counted only if they occurred within 7 days from nadir to peak.
AKI occurred in all chemotherapy cycles, with severe injury having the highest frequency in cycle 1.
In a logistical regression model, factors significantly associated with risk for AKI were male sex (odds ratio, 0.2; P = .03) and age 10 years or older (OR, 17.3; P less than .01). Neither sepsis nor aminoglycoside or vancomycin use for more than 3 days was significantly associated with risk for AKI, however.
“I think people need to realize that many of these injuries are happening on the oncology ward, and some of these kids may not even look acutely unwell, so people need to take note.” Dr. du Plessis said.
She recommended curtailing use of nephrotoxic agents whenever possible, and emphasized that clinicians need to document AKI in the medical record.
“A big portion of our AML population goes on to bone marrow transplant, and that is known to be a high risk for further kidney injury. So, I think it would be important to know that before your patient goes for his transplant that he already has certain toxicities and organ injury, so that you can limit things like fluids and get the nephrology team on board to help with the management of these patients,” she said.
The study by Dr. Freiberg was supported by the Four Diamonds Fund. The study by Dr. du Plessis was internally funded. The investigators for each study reported having no relevant financial disclosures.
MONTREAL – Hypertension is a frequent, but underrecognized and undertreated, complication of chemotherapy for acute lymphoblastic leukemia (ALL), the most common childhood malignancy, investigators in a single-center U.S. study reported.
Additionally, there is a “concerningly high” incidence of acute kidney injury among children and young adults who undergo multiagent chemotherapy for acute myeloid leukemia (AML), said the authors of a study conducted in Canada.
Both studies were reported in a scientific poster session at the annual meeting of the American Society for Pediatric Hematology/Oncology.
Hypertension in ALL
Although standard induction regimens for childhood ALL contain high-dose steroids, which are known to be associated with increased risk for hypertension, the incidence of hypertension throughout induction, consolidation, and maintenance for ALL in children has not been adequately evaluated, according to Andrew S. Freiberg, MD, and his colleagues at Penn State Children’s Hospital in Hershey, Penn.
“The incidence of hypertension was much higher than the under 5% expected for a healthy pediatric population,” the investigators found.
Of 562 total readings taken during induction, 56% were in the normo- or prehypertensive range, but 30% were classified as stage 1 and 14% as stage II hypertension.
The combined percentage of stage 1 and 2 readings declined slightly over the year from 44% during induction to 35% during Q4 “but remained well above expected for the pediatric population,” the investigators reported.
Despite the high incidence, “I was surprised at how few of the patients with hypertension we actually treated,” Dr. Freiberg said in an interview.
Just 3 of the 36 patients studied received treatment for hypertension, he said, possibly because clinicians assumed that the effect was steroid related and transient.
“Now that we’re paying attention, however, we’re treating more of these patients,” Dr. Freiberg said.
The electronic record system used at his institution now alerts clinicians to hypertensive episodes during treatment, he added.
Kidney injury in AML
Like Dr. Freiberg and his colleagues, Liezl du Plessis, MBChB, from the British Columbia Children’s Hospital in Vancouver, Canada, and her colleagues were similarly taken aback when they looked into the incidence of acute kidney injury (AKI) in children and adolescents undergoing multidrug chemotherapy for AML.
“Chemotherapy agents that are used in acute myeloid leukemia are not considered to be nephrotoxic, so it was quite alarming to us to see that there is such a high rate of kidney injury in these patients,” Dr. du Plessis said in an interview.
They found that 34 of the 53 patients (64%) had AKI, with 11 patients having stage 1 (rise in serum creatinine of 1.5 or more times the baseline level), 11 having stage 2 (SCr 2 or more times baseline), and 12 having stage 3 AKI (SCr 3 or more times baseline or the need for dialysis).
Creatinine changes were counted only if they occurred within 7 days from nadir to peak.
AKI occurred in all chemotherapy cycles, with severe injury having the highest frequency in cycle 1.
In a logistical regression model, factors significantly associated with risk for AKI were male sex (odds ratio, 0.2; P = .03) and age 10 years or older (OR, 17.3; P less than .01). Neither sepsis nor aminoglycoside or vancomycin use for more than 3 days was significantly associated with risk for AKI, however.
“I think people need to realize that many of these injuries are happening on the oncology ward, and some of these kids may not even look acutely unwell, so people need to take note.” Dr. du Plessis said.
She recommended curtailing use of nephrotoxic agents whenever possible, and emphasized that clinicians need to document AKI in the medical record.
“A big portion of our AML population goes on to bone marrow transplant, and that is known to be a high risk for further kidney injury. So, I think it would be important to know that before your patient goes for his transplant that he already has certain toxicities and organ injury, so that you can limit things like fluids and get the nephrology team on board to help with the management of these patients,” she said.
The study by Dr. Freiberg was supported by the Four Diamonds Fund. The study by Dr. du Plessis was internally funded. The investigators for each study reported having no relevant financial disclosures.
MONTREAL – Hypertension is a frequent, but underrecognized and undertreated, complication of chemotherapy for acute lymphoblastic leukemia (ALL), the most common childhood malignancy, investigators in a single-center U.S. study reported.
Additionally, there is a “concerningly high” incidence of acute kidney injury among children and young adults who undergo multiagent chemotherapy for acute myeloid leukemia (AML), said the authors of a study conducted in Canada.
Both studies were reported in a scientific poster session at the annual meeting of the American Society for Pediatric Hematology/Oncology.
Hypertension in ALL
Although standard induction regimens for childhood ALL contain high-dose steroids, which are known to be associated with increased risk for hypertension, the incidence of hypertension throughout induction, consolidation, and maintenance for ALL in children has not been adequately evaluated, according to Andrew S. Freiberg, MD, and his colleagues at Penn State Children’s Hospital in Hershey, Penn.
“The incidence of hypertension was much higher than the under 5% expected for a healthy pediatric population,” the investigators found.
Of 562 total readings taken during induction, 56% were in the normo- or prehypertensive range, but 30% were classified as stage 1 and 14% as stage II hypertension.
The combined percentage of stage 1 and 2 readings declined slightly over the year from 44% during induction to 35% during Q4 “but remained well above expected for the pediatric population,” the investigators reported.
Despite the high incidence, “I was surprised at how few of the patients with hypertension we actually treated,” Dr. Freiberg said in an interview.
Just 3 of the 36 patients studied received treatment for hypertension, he said, possibly because clinicians assumed that the effect was steroid related and transient.
“Now that we’re paying attention, however, we’re treating more of these patients,” Dr. Freiberg said.
The electronic record system used at his institution now alerts clinicians to hypertensive episodes during treatment, he added.
Kidney injury in AML
Like Dr. Freiberg and his colleagues, Liezl du Plessis, MBChB, from the British Columbia Children’s Hospital in Vancouver, Canada, and her colleagues were similarly taken aback when they looked into the incidence of acute kidney injury (AKI) in children and adolescents undergoing multidrug chemotherapy for AML.
“Chemotherapy agents that are used in acute myeloid leukemia are not considered to be nephrotoxic, so it was quite alarming to us to see that there is such a high rate of kidney injury in these patients,” Dr. du Plessis said in an interview.
They found that 34 of the 53 patients (64%) had AKI, with 11 patients having stage 1 (rise in serum creatinine of 1.5 or more times the baseline level), 11 having stage 2 (SCr 2 or more times baseline), and 12 having stage 3 AKI (SCr 3 or more times baseline or the need for dialysis).
Creatinine changes were counted only if they occurred within 7 days from nadir to peak.
AKI occurred in all chemotherapy cycles, with severe injury having the highest frequency in cycle 1.
In a logistical regression model, factors significantly associated with risk for AKI were male sex (odds ratio, 0.2; P = .03) and age 10 years or older (OR, 17.3; P less than .01). Neither sepsis nor aminoglycoside or vancomycin use for more than 3 days was significantly associated with risk for AKI, however.
“I think people need to realize that many of these injuries are happening on the oncology ward, and some of these kids may not even look acutely unwell, so people need to take note.” Dr. du Plessis said.
She recommended curtailing use of nephrotoxic agents whenever possible, and emphasized that clinicians need to document AKI in the medical record.
“A big portion of our AML population goes on to bone marrow transplant, and that is known to be a high risk for further kidney injury. So, I think it would be important to know that before your patient goes for his transplant that he already has certain toxicities and organ injury, so that you can limit things like fluids and get the nephrology team on board to help with the management of these patients,” she said.
The study by Dr. Freiberg was supported by the Four Diamonds Fund. The study by Dr. du Plessis was internally funded. The investigators for each study reported having no relevant financial disclosures.
At ASPHO 2017
Key clinical point:
Major finding: The combined incidence of stage 1 or 2 hypertension in children during induction therapy for acute lymphoblastic leukemia was 44%.
Data source: Two retrospective institutional studies.
Disclosures: The study by Dr. Freiberg was supported by the Four Diamonds Fund. The study by Dr. du Plessis was internally funded. The investigators for each study reported having no relevant financial disclosures.
