Anemia

Red blood cells

The European Medicines Agency (EMA) has recommended orphan drug designation for the complement C3 inhibitor APL-2 as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).

APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).

This comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH, according to Apellis Pharmaceuticals, Inc., the company developing APL-2.

APL-2 has been evaluated in a pair of phase 1 studies of healthy volunteers. Results from these studies were presented at the 2016 ASH Annual Meeting (abstract 1251).

Now, Apellis is evaluating APL-2 in PNH patients in a pair of phase 1b trials.

In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.

In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days. 

Red blood cells

The European Medicines Agency (EMA) has recommended orphan drug designation for the complement C3 inhibitor APL-2 as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).

APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).

This comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH, according to Apellis Pharmaceuticals, Inc., the company developing APL-2.

APL-2 has been evaluated in a pair of phase 1 studies of healthy volunteers. Results from these studies were presented at the 2016 ASH Annual Meeting (abstract 1251).

Now, Apellis is evaluating APL-2 in PNH patients in a pair of phase 1b trials.

In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.

In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days. 

Red blood cells

The European Medicines Agency (EMA) has recommended orphan drug designation for the complement C3 inhibitor APL-2 as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).

APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).

This comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH, according to Apellis Pharmaceuticals, Inc., the company developing APL-2.

APL-2 has been evaluated in a pair of phase 1 studies of healthy volunteers. Results from these studies were presented at the 2016 ASH Annual Meeting (abstract 1251).

Now, Apellis is evaluating APL-2 in PNH patients in a pair of phase 1b trials.

In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.

In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days. 

PARIS – Unwarranted prescriptions for proton pump inhibitors tripled the rate at which patients with atrial fibrillation needed hospitalization for a first episode of acute heart failure, in a retrospective study of 172 patients at a single center in Portugal.

About a third of the atrial fibrillation patients received a proton pump inhibitor (PPI) without a clear indication, and the PPI recipients developed heart failure at 2.9 times the rate as patients not on a PPI, a statistically significant difference, João B. Augusto, MD, reported at a meeting held by the Heart Failure Association of the European Society of Cardiology. Dr. Augusto believes that these patients largely had no need for PPI treatment, and the drug may have cut iron and vitamin B12 absorption by lowering gastric acid, resulting in deficiencies that produced anemia, and following that, heart failure, he suggested.

Mitchel L. Zoler/Frontline Medical News

PARIS – Unwarranted prescriptions for proton pump inhibitors tripled the rate at which patients with atrial fibrillation needed hospitalization for a first episode of acute heart failure, in a retrospective study of 172 patients at a single center in Portugal.

About a third of the atrial fibrillation patients received a proton pump inhibitor (PPI) without a clear indication, and the PPI recipients developed heart failure at 2.9 times the rate as patients not on a PPI, a statistically significant difference, João B. Augusto, MD, reported at a meeting held by the Heart Failure Association of the European Society of Cardiology. Dr. Augusto believes that these patients largely had no need for PPI treatment, and the drug may have cut iron and vitamin B12 absorption by lowering gastric acid, resulting in deficiencies that produced anemia, and following that, heart failure, he suggested.

Mitchel L. Zoler/Frontline Medical News

PARIS – Unwarranted prescriptions for proton pump inhibitors tripled the rate at which patients with atrial fibrillation needed hospitalization for a first episode of acute heart failure, in a retrospective study of 172 patients at a single center in Portugal.

About a third of the atrial fibrillation patients received a proton pump inhibitor (PPI) without a clear indication, and the PPI recipients developed heart failure at 2.9 times the rate as patients not on a PPI, a statistically significant difference, João B. Augusto, MD, reported at a meeting held by the Heart Failure Association of the European Society of Cardiology. Dr. Augusto believes that these patients largely had no need for PPI treatment, and the drug may have cut iron and vitamin B12 absorption by lowering gastric acid, resulting in deficiencies that produced anemia, and following that, heart failure, he suggested.

Mitchel L. Zoler/Frontline Medical News

Micrograph showing MDS

VALENCIA, SPAIN—Phase 2 results suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with myelodysplastic syndromes (MDS).

Erythroid response rates were similar whether or not patients had received prior treatment with erythropoiesis-stimulating agents (ESAs).

However, patients without prior ESA exposure were more likely to achieve transfusion independence.

Most adverse events (AEs) considered possibly or probably related to luspatercept were grade 1 or 2.

Uwe Platzbecker, MD, of Universitätsklinikum Carl Gustav Carus in Dresden, Germany, presented these results at the 14th International Symposium on MDS.

The research was sponsored by Acceleron Pharma Inc., the company developing luspatercept in collaboration with Celgene Corporation.

Dr Platzbecker explained that luspatercept, formerly ACE-536, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for GDF11 and other TGF-βfamily ligands to suppress Smad2/3 signaling.

He presented data from a phase 2 base study and an extension study of luspatercept. The base study included 89 patients who received luspatercept for 3 months. The long-term extension study included 52 patients who may receive luspatercept for an additional 5 years.

The patients received luspatercept at doses ranging from 0.125 mg/kg to 1.75 mg/kg in the base study and 1.0 mg/kg to 1.75 mg/kg in the extension study. They received the drug subcutaneously every 3 weeks.

There were 82 patients evaluable for efficacy. They were a median of 2.3 years from diagnosis (range, 0-14). Their median age was 72 (range, 29-90), 63% were male, and 52% had prior treatment with ESAs.

The outcome measures used in these studies were clinically meaningful erythroid hematologic improvement per the International Working Group’s criteria (IWG HI-E) and red blood cell transfusion independence (RBC-TI).

IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with a transfusion burden at baseline of less than 4 RBC units every 8 weeks and baseline hemoglobin levels below 10 g/dL. For patients with a greater transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 RBC units sustained for ≥ 8 weeks.

RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a baseline transfusion burden of at least 2 RBC units every 8 weeks.

Response data

In ESA-naïve patients, 48% (11/23) achieved RBC-TI with luspatercept, and 51% (20/39) achieved an IWG HI-E response.

Among patients with prior ESA treatment, 33% (11/33) achieved RBC-TI with luspatercept, and 51% (22/43) achieved an IWG HI-E response.

In patients with baseline erythropoietin (EPO) levels ≤ 500 international units per liter (IU/L), RBC-TI and IWG HI-E response rates were positive in both ring sideroblast-positive (RS+) and RS-negative (RS-) patients, according to the researchers.

*Table includes ESA-refractory and ESA-naïve patients. Patients treated at dose levels ≥ 0.75 mg/kg.

Safety data

All 89 patients were evaluable for safety. Common AEs (occurring in at least 3 patients) that were considered possibly or probably related to study drug were fatigue (6.7%), headache (6.7%), hypertension (5.6%), diarrhea (4.5%), arthralgia (3.4%), bone pain (3.4%), injection site erythema (3.4%), myalgia (3.4%), and peripheral edema (3.4%).

Grade 3 AEs possibly or probably related to study drug were ascites, blast cell count increase, blood bilirubin increase, hypertension, platelet count increase, and pleural effusion.

Grade 3 serious AEs possibly or probably related to study drug were general physical health deterioration and myalgia. 

Micrograph showing MDS

VALENCIA, SPAIN—Phase 2 results suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with myelodysplastic syndromes (MDS).

Erythroid response rates were similar whether or not patients had received prior treatment with erythropoiesis-stimulating agents (ESAs).

However, patients without prior ESA exposure were more likely to achieve transfusion independence.

Most adverse events (AEs) considered possibly or probably related to luspatercept were grade 1 or 2.

Uwe Platzbecker, MD, of Universitätsklinikum Carl Gustav Carus in Dresden, Germany, presented these results at the 14th International Symposium on MDS.

The research was sponsored by Acceleron Pharma Inc., the company developing luspatercept in collaboration with Celgene Corporation.

Dr Platzbecker explained that luspatercept, formerly ACE-536, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for GDF11 and other TGF-βfamily ligands to suppress Smad2/3 signaling.

He presented data from a phase 2 base study and an extension study of luspatercept. The base study included 89 patients who received luspatercept for 3 months. The long-term extension study included 52 patients who may receive luspatercept for an additional 5 years.

The patients received luspatercept at doses ranging from 0.125 mg/kg to 1.75 mg/kg in the base study and 1.0 mg/kg to 1.75 mg/kg in the extension study. They received the drug subcutaneously every 3 weeks.

There were 82 patients evaluable for efficacy. They were a median of 2.3 years from diagnosis (range, 0-14). Their median age was 72 (range, 29-90), 63% were male, and 52% had prior treatment with ESAs.

The outcome measures used in these studies were clinically meaningful erythroid hematologic improvement per the International Working Group’s criteria (IWG HI-E) and red blood cell transfusion independence (RBC-TI).

IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with a transfusion burden at baseline of less than 4 RBC units every 8 weeks and baseline hemoglobin levels below 10 g/dL. For patients with a greater transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 RBC units sustained for ≥ 8 weeks.

RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a baseline transfusion burden of at least 2 RBC units every 8 weeks.

Response data

In ESA-naïve patients, 48% (11/23) achieved RBC-TI with luspatercept, and 51% (20/39) achieved an IWG HI-E response.

Among patients with prior ESA treatment, 33% (11/33) achieved RBC-TI with luspatercept, and 51% (22/43) achieved an IWG HI-E response.

In patients with baseline erythropoietin (EPO) levels ≤ 500 international units per liter (IU/L), RBC-TI and IWG HI-E response rates were positive in both ring sideroblast-positive (RS+) and RS-negative (RS-) patients, according to the researchers.

*Table includes ESA-refractory and ESA-naïve patients. Patients treated at dose levels ≥ 0.75 mg/kg.

Safety data

All 89 patients were evaluable for safety. Common AEs (occurring in at least 3 patients) that were considered possibly or probably related to study drug were fatigue (6.7%), headache (6.7%), hypertension (5.6%), diarrhea (4.5%), arthralgia (3.4%), bone pain (3.4%), injection site erythema (3.4%), myalgia (3.4%), and peripheral edema (3.4%).

Grade 3 AEs possibly or probably related to study drug were ascites, blast cell count increase, blood bilirubin increase, hypertension, platelet count increase, and pleural effusion.

Grade 3 serious AEs possibly or probably related to study drug were general physical health deterioration and myalgia. 

Micrograph showing MDS

VALENCIA, SPAIN—Phase 2 results suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with myelodysplastic syndromes (MDS).

Erythroid response rates were similar whether or not patients had received prior treatment with erythropoiesis-stimulating agents (ESAs).

However, patients without prior ESA exposure were more likely to achieve transfusion independence.

Most adverse events (AEs) considered possibly or probably related to luspatercept were grade 1 or 2.

Uwe Platzbecker, MD, of Universitätsklinikum Carl Gustav Carus in Dresden, Germany, presented these results at the 14th International Symposium on MDS.

The research was sponsored by Acceleron Pharma Inc., the company developing luspatercept in collaboration with Celgene Corporation.

Dr Platzbecker explained that luspatercept, formerly ACE-536, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for GDF11 and other TGF-βfamily ligands to suppress Smad2/3 signaling.

He presented data from a phase 2 base study and an extension study of luspatercept. The base study included 89 patients who received luspatercept for 3 months. The long-term extension study included 52 patients who may receive luspatercept for an additional 5 years.

The patients received luspatercept at doses ranging from 0.125 mg/kg to 1.75 mg/kg in the base study and 1.0 mg/kg to 1.75 mg/kg in the extension study. They received the drug subcutaneously every 3 weeks.

There were 82 patients evaluable for efficacy. They were a median of 2.3 years from diagnosis (range, 0-14). Their median age was 72 (range, 29-90), 63% were male, and 52% had prior treatment with ESAs.

The outcome measures used in these studies were clinically meaningful erythroid hematologic improvement per the International Working Group’s criteria (IWG HI-E) and red blood cell transfusion independence (RBC-TI).

IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with a transfusion burden at baseline of less than 4 RBC units every 8 weeks and baseline hemoglobin levels below 10 g/dL. For patients with a greater transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 RBC units sustained for ≥ 8 weeks.

RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a baseline transfusion burden of at least 2 RBC units every 8 weeks.

Response data

In ESA-naïve patients, 48% (11/23) achieved RBC-TI with luspatercept, and 51% (20/39) achieved an IWG HI-E response.

Among patients with prior ESA treatment, 33% (11/33) achieved RBC-TI with luspatercept, and 51% (22/43) achieved an IWG HI-E response.

In patients with baseline erythropoietin (EPO) levels ≤ 500 international units per liter (IU/L), RBC-TI and IWG HI-E response rates were positive in both ring sideroblast-positive (RS+) and RS-negative (RS-) patients, according to the researchers.

*Table includes ESA-refractory and ESA-naïve patients. Patients treated at dose levels ≥ 0.75 mg/kg.

Safety data

All 89 patients were evaluable for safety. Common AEs (occurring in at least 3 patients) that were considered possibly or probably related to study drug were fatigue (6.7%), headache (6.7%), hypertension (5.6%), diarrhea (4.5%), arthralgia (3.4%), bone pain (3.4%), injection site erythema (3.4%), myalgia (3.4%), and peripheral edema (3.4%).

Grade 3 AEs possibly or probably related to study drug were ascites, blast cell count increase, blood bilirubin increase, hypertension, platelet count increase, and pleural effusion.

Grade 3 serious AEs possibly or probably related to study drug were general physical health deterioration and myalgia. 

Photo by Rhoda Baer

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. 

Photo by Rhoda Baer

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. 

Photo by Rhoda Baer

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. 

Photo by Chad McNeeley

Results of a phase 3 trial revealed similar outcomes in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) to treat myelodysplastic syndromes (MDS), regardless of the conditioning regimen they received.

Rates of engraftment, graft-vs-host disease (GVHD), relapse, and survival were similar between patients who received reduced-intensity conditioning (RIC) and those who received standard myeloablative conditioning (MAC) before HSCT.

Researchers reported these results in the Journal of Clinical Oncology.

“Our study shed new light on expected benefits of a reduced-intensity conditioning regimen that can be offered as a curative treatment approach, especially in older patients with MDS,” said study author Nicolaus Kröger, MD, of University Hospital Eppendorf in Hamburg, Germany.

Patient characteristics

The study, known as RICMAC, involved 129 patients who underwent HSCT between May 2004 and December 2012 at 18 transplant units in 7 countries.

Patients were randomized in a 1:1 ratio to RIC (n=65) or MAC (n=64) and were stratified according to donor type, age, and blast count.

The median age was 50 (range, 19-64) in the MAC arm and 51 (range, 22-63) in the RIC arm. The median blast percentage was 4% (range, 0-18) and 5% (range, 0-18), respectively.

According to IPSS, most patients in both arms had intermediate-I-risk disease (28 MAC, 25 RIC) or intermediate-II-risk disease (18 MAC, 24 RIC).

Similar numbers of patients in each arm had low cytogenetic risk (24 MAC, 28 RIC), intermediate cytogenetic risk (17 MAC, 13 RIC), and high cytogenetic risk (17 MAC, 18 RIC).

Thirty-three patients in the MAC arm and 32 in the RIC arm received ATG as GVHD prophylaxis.

Patients received grafts from matched related donors (17 MAC, 16 RIC), matched unrelated donors (36 MAC, 38 RIC), or mismatched related/unrelated donors (11 in both arms).

Most patients received peripheral blood stem cell grafts—61 in the MAC arm and 59 in the RIC arm.

Results

The researchers said engraftment was comparable between the arms. There were 4 graft failures in the MAC arm and 3 in the RIC arm (P=0.72). The median time to leukocyte engraftment was 15 days in both arms. The median time to platelet engraftment was 15 days in the RIC arm and 16 in the MAC arm (P=0.33).

There was no significant difference in the cumulative incidence of GVHD between the RIC and MAC arms:

• Grade 2-4 acute GVHD—32.3% and 37.5%, respectively
• Grade 3-4 acute GVHD—15% and 14%, respectively (P=0.35 for between-arm difference for all acute GVHD)
• Chronic GVHD—61.6% and 64.7%, respectively (P=0.76).

Though the occurrence of infection was similar between the MAC and RIC arms (48 and 44, respectively), the rate of infection was higher in the MAC arm than the RIC arm.

The rate of infection in the first 100 days was 6.9 per 100 person-years in the MAC arm and 4.3 in the RIC arm (P=0.002). The rate of infection during the total follow-up was 2.0 per 100 person-years in the MAC arm and 1.4 in the RIC arm (P=0.002).

There was no significant difference between the RIC and MAC arms with regard to the cumulative incidence of nonrelapse mortality after 1 year—16.9% and 25.3%, respectively (P=0.29).

And there was no significant difference in the cumulative incidence of relapse at 2 years—17% and 14.8%, respectively (P=0.6).

The 2-year relapse-free survival rate was similar in the MAC and RIC arms—58.3% and 62.4% (P=0.58)—as was the 2-year overall survival rate—63.2% and 76.3%, respectively (P=0.08). 

Photo by Chad McNeeley

Results of a phase 3 trial revealed similar outcomes in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) to treat myelodysplastic syndromes (MDS), regardless of the conditioning regimen they received.

Rates of engraftment, graft-vs-host disease (GVHD), relapse, and survival were similar between patients who received reduced-intensity conditioning (RIC) and those who received standard myeloablative conditioning (MAC) before HSCT.

Researchers reported these results in the Journal of Clinical Oncology.

“Our study shed new light on expected benefits of a reduced-intensity conditioning regimen that can be offered as a curative treatment approach, especially in older patients with MDS,” said study author Nicolaus Kröger, MD, of University Hospital Eppendorf in Hamburg, Germany.

Patient characteristics

The study, known as RICMAC, involved 129 patients who underwent HSCT between May 2004 and December 2012 at 18 transplant units in 7 countries.

Patients were randomized in a 1:1 ratio to RIC (n=65) or MAC (n=64) and were stratified according to donor type, age, and blast count.

The median age was 50 (range, 19-64) in the MAC arm and 51 (range, 22-63) in the RIC arm. The median blast percentage was 4% (range, 0-18) and 5% (range, 0-18), respectively.

According to IPSS, most patients in both arms had intermediate-I-risk disease (28 MAC, 25 RIC) or intermediate-II-risk disease (18 MAC, 24 RIC).

Similar numbers of patients in each arm had low cytogenetic risk (24 MAC, 28 RIC), intermediate cytogenetic risk (17 MAC, 13 RIC), and high cytogenetic risk (17 MAC, 18 RIC).

Thirty-three patients in the MAC arm and 32 in the RIC arm received ATG as GVHD prophylaxis.

Patients received grafts from matched related donors (17 MAC, 16 RIC), matched unrelated donors (36 MAC, 38 RIC), or mismatched related/unrelated donors (11 in both arms).

Most patients received peripheral blood stem cell grafts—61 in the MAC arm and 59 in the RIC arm.

Results

The researchers said engraftment was comparable between the arms. There were 4 graft failures in the MAC arm and 3 in the RIC arm (P=0.72). The median time to leukocyte engraftment was 15 days in both arms. The median time to platelet engraftment was 15 days in the RIC arm and 16 in the MAC arm (P=0.33).

There was no significant difference in the cumulative incidence of GVHD between the RIC and MAC arms:

• Grade 2-4 acute GVHD—32.3% and 37.5%, respectively
• Grade 3-4 acute GVHD—15% and 14%, respectively (P=0.35 for between-arm difference for all acute GVHD)
• Chronic GVHD—61.6% and 64.7%, respectively (P=0.76).

Though the occurrence of infection was similar between the MAC and RIC arms (48 and 44, respectively), the rate of infection was higher in the MAC arm than the RIC arm.

The rate of infection in the first 100 days was 6.9 per 100 person-years in the MAC arm and 4.3 in the RIC arm (P=0.002). The rate of infection during the total follow-up was 2.0 per 100 person-years in the MAC arm and 1.4 in the RIC arm (P=0.002).

There was no significant difference between the RIC and MAC arms with regard to the cumulative incidence of nonrelapse mortality after 1 year—16.9% and 25.3%, respectively (P=0.29).

And there was no significant difference in the cumulative incidence of relapse at 2 years—17% and 14.8%, respectively (P=0.6).

The 2-year relapse-free survival rate was similar in the MAC and RIC arms—58.3% and 62.4% (P=0.58)—as was the 2-year overall survival rate—63.2% and 76.3%, respectively (P=0.08). 

Photo by Chad McNeeley

Results of a phase 3 trial revealed similar outcomes in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) to treat myelodysplastic syndromes (MDS), regardless of the conditioning regimen they received.

Rates of engraftment, graft-vs-host disease (GVHD), relapse, and survival were similar between patients who received reduced-intensity conditioning (RIC) and those who received standard myeloablative conditioning (MAC) before HSCT.

Researchers reported these results in the Journal of Clinical Oncology.

“Our study shed new light on expected benefits of a reduced-intensity conditioning regimen that can be offered as a curative treatment approach, especially in older patients with MDS,” said study author Nicolaus Kröger, MD, of University Hospital Eppendorf in Hamburg, Germany.

Patient characteristics

The study, known as RICMAC, involved 129 patients who underwent HSCT between May 2004 and December 2012 at 18 transplant units in 7 countries.

Patients were randomized in a 1:1 ratio to RIC (n=65) or MAC (n=64) and were stratified according to donor type, age, and blast count.

The median age was 50 (range, 19-64) in the MAC arm and 51 (range, 22-63) in the RIC arm. The median blast percentage was 4% (range, 0-18) and 5% (range, 0-18), respectively.

According to IPSS, most patients in both arms had intermediate-I-risk disease (28 MAC, 25 RIC) or intermediate-II-risk disease (18 MAC, 24 RIC).

Similar numbers of patients in each arm had low cytogenetic risk (24 MAC, 28 RIC), intermediate cytogenetic risk (17 MAC, 13 RIC), and high cytogenetic risk (17 MAC, 18 RIC).

Thirty-three patients in the MAC arm and 32 in the RIC arm received ATG as GVHD prophylaxis.

Patients received grafts from matched related donors (17 MAC, 16 RIC), matched unrelated donors (36 MAC, 38 RIC), or mismatched related/unrelated donors (11 in both arms).

Most patients received peripheral blood stem cell grafts—61 in the MAC arm and 59 in the RIC arm.

Results

The researchers said engraftment was comparable between the arms. There were 4 graft failures in the MAC arm and 3 in the RIC arm (P=0.72). The median time to leukocyte engraftment was 15 days in both arms. The median time to platelet engraftment was 15 days in the RIC arm and 16 in the MAC arm (P=0.33).

There was no significant difference in the cumulative incidence of GVHD between the RIC and MAC arms:

• Grade 2-4 acute GVHD—32.3% and 37.5%, respectively
• Grade 3-4 acute GVHD—15% and 14%, respectively (P=0.35 for between-arm difference for all acute GVHD)
• Chronic GVHD—61.6% and 64.7%, respectively (P=0.76).

Though the occurrence of infection was similar between the MAC and RIC arms (48 and 44, respectively), the rate of infection was higher in the MAC arm than the RIC arm.

The rate of infection in the first 100 days was 6.9 per 100 person-years in the MAC arm and 4.3 in the RIC arm (P=0.002). The rate of infection during the total follow-up was 2.0 per 100 person-years in the MAC arm and 1.4 in the RIC arm (P=0.002).

There was no significant difference between the RIC and MAC arms with regard to the cumulative incidence of nonrelapse mortality after 1 year—16.9% and 25.3%, respectively (P=0.29).

And there was no significant difference in the cumulative incidence of relapse at 2 years—17% and 14.8%, respectively (P=0.6).

The 2-year relapse-free survival rate was similar in the MAC and RIC arms—58.3% and 62.4% (P=0.58)—as was the 2-year overall survival rate—63.2% and 76.3%, respectively (P=0.08). 

MONTREAL – Osteomyelitis is an especially challenging diagnosis in children with sickle cell disease (SCD) because the bone and joint signs, elevated white cell counts, and C-reactive protein levels that are commonly used to diagnose bone infection are frequently features of SCD as well.

As a result, most patients with SCD and suspected osteomyelitis are treated without a confirmation of the diagnosis.

A decade of data

The researchers set out to get a better handle on the characteristics and outcomes of osteomyelitis in patients with SCD and to see which laboratory and imaging findings might prove most useful for diagnosing osteomyelitis in this population. They reviewed data on 59 patients who were identified with indeterminate or likely osteomyelitis over a 10-year span. Of those, 30 were diagnosed and treated for osteomyelitis, and 29 were tentatively diagnosed but not treated. The latter group likely had symptoms caused by a bone infarction or vaso-occlusive crisis, Dr. Weisman said.

Among the 30 treated patients, osteomyelitis was confirmed by bone biopsy in 3, and an organism was isolated from blood or an abscess in 6. In the other 21, osteomyelitis was presumed based on clinical, laboratory, and MRI findings.

The median patient age was 12 years (range, 8 months to 18 years), 18 were male, and all but three patients have the HbSS genotype. Of the remaining patients, two had the HbSC and one the HbSF genotypes.

Infections occurred in the lower extremities in 11 patients, in the upper extremities in 10, in the pelvis or vertebrae in 2 each, and in the scapula, clavicle, hand, rib, or mandible in 1 patient each.

Just 13 of the 30 patients (43%) had lab findings of leukocytosis (more than 15,000 cells/mm²), and an equal number had elevated CRP (greater than 10 mg/L).

In contrast, 29 patients had an ESR above 20 mm/hour, and, in three of these patients, the rate was higher than 100 mm/hour.

When the researchers compared white blood cell counts and CRP levels between the treated patients and the 29 untreated controls, they found no significant differences for either measure of inflammation. In contrast, ESR was significantly higher among treated patients (P = .03).

Looking at the receiver operating characteristic curve for ESR, they found that an ESR of more than 100 mm/hour had 100% specificity for osteomyelitis in this group of patients.

Only 6 of the 30 (20%) had bacteremia. In 9 patients, nontyphoidal salmonella was isolated from cultures of either bone biopsy (3), abscess (3), or blood (6), but no possible causative organism could be isolated in the remaining 21 patients.

All patients were treated with prolonged antibiotic therapy. Surgical drainage and/or debridement were required in 6 patients. Two patients developed chronic osteomyelitis, but infection eventually resolved in all patients.

Recommendations

Dr. Weisman recommended early consultation with infectious disease experts and orthopedists; labs studies with complete blood counts, CRP, and ESR; and imaging studies with MRI when there is clinical suspicion of osteomyelitis in patients with SCD.

When an SCD patient has indeterminate findings, a blood culture can be performed. If it is positive for salmonella and the ESR is above 100 mm/hour, the patient can then go on to treatment. If the blood culture is negative and the ESR is below 100 mm hour but the suspicion of osteomyelitis remains high, a bone biopsy can be considered, they concluded.

The study was internally funded. Dr. Weisman reported no conflicts of interest to disclose.

MONTREAL – Osteomyelitis is an especially challenging diagnosis in children with sickle cell disease (SCD) because the bone and joint signs, elevated white cell counts, and C-reactive protein levels that are commonly used to diagnose bone infection are frequently features of SCD as well.

As a result, most patients with SCD and suspected osteomyelitis are treated without a confirmation of the diagnosis.

A decade of data

The researchers set out to get a better handle on the characteristics and outcomes of osteomyelitis in patients with SCD and to see which laboratory and imaging findings might prove most useful for diagnosing osteomyelitis in this population. They reviewed data on 59 patients who were identified with indeterminate or likely osteomyelitis over a 10-year span. Of those, 30 were diagnosed and treated for osteomyelitis, and 29 were tentatively diagnosed but not treated. The latter group likely had symptoms caused by a bone infarction or vaso-occlusive crisis, Dr. Weisman said.

Among the 30 treated patients, osteomyelitis was confirmed by bone biopsy in 3, and an organism was isolated from blood or an abscess in 6. In the other 21, osteomyelitis was presumed based on clinical, laboratory, and MRI findings.

The median patient age was 12 years (range, 8 months to 18 years), 18 were male, and all but three patients have the HbSS genotype. Of the remaining patients, two had the HbSC and one the HbSF genotypes.

Infections occurred in the lower extremities in 11 patients, in the upper extremities in 10, in the pelvis or vertebrae in 2 each, and in the scapula, clavicle, hand, rib, or mandible in 1 patient each.

Just 13 of the 30 patients (43%) had lab findings of leukocytosis (more than 15,000 cells/mm²), and an equal number had elevated CRP (greater than 10 mg/L).

In contrast, 29 patients had an ESR above 20 mm/hour, and, in three of these patients, the rate was higher than 100 mm/hour.

When the researchers compared white blood cell counts and CRP levels between the treated patients and the 29 untreated controls, they found no significant differences for either measure of inflammation. In contrast, ESR was significantly higher among treated patients (P = .03).

Looking at the receiver operating characteristic curve for ESR, they found that an ESR of more than 100 mm/hour had 100% specificity for osteomyelitis in this group of patients.

Only 6 of the 30 (20%) had bacteremia. In 9 patients, nontyphoidal salmonella was isolated from cultures of either bone biopsy (3), abscess (3), or blood (6), but no possible causative organism could be isolated in the remaining 21 patients.

All patients were treated with prolonged antibiotic therapy. Surgical drainage and/or debridement were required in 6 patients. Two patients developed chronic osteomyelitis, but infection eventually resolved in all patients.

Recommendations

Dr. Weisman recommended early consultation with infectious disease experts and orthopedists; labs studies with complete blood counts, CRP, and ESR; and imaging studies with MRI when there is clinical suspicion of osteomyelitis in patients with SCD.

When an SCD patient has indeterminate findings, a blood culture can be performed. If it is positive for salmonella and the ESR is above 100 mm/hour, the patient can then go on to treatment. If the blood culture is negative and the ESR is below 100 mm hour but the suspicion of osteomyelitis remains high, a bone biopsy can be considered, they concluded.

The study was internally funded. Dr. Weisman reported no conflicts of interest to disclose.

MONTREAL – Osteomyelitis is an especially challenging diagnosis in children with sickle cell disease (SCD) because the bone and joint signs, elevated white cell counts, and C-reactive protein levels that are commonly used to diagnose bone infection are frequently features of SCD as well.

As a result, most patients with SCD and suspected osteomyelitis are treated without a confirmation of the diagnosis.

A decade of data

The researchers set out to get a better handle on the characteristics and outcomes of osteomyelitis in patients with SCD and to see which laboratory and imaging findings might prove most useful for diagnosing osteomyelitis in this population. They reviewed data on 59 patients who were identified with indeterminate or likely osteomyelitis over a 10-year span. Of those, 30 were diagnosed and treated for osteomyelitis, and 29 were tentatively diagnosed but not treated. The latter group likely had symptoms caused by a bone infarction or vaso-occlusive crisis, Dr. Weisman said.

Among the 30 treated patients, osteomyelitis was confirmed by bone biopsy in 3, and an organism was isolated from blood or an abscess in 6. In the other 21, osteomyelitis was presumed based on clinical, laboratory, and MRI findings.

The median patient age was 12 years (range, 8 months to 18 years), 18 were male, and all but three patients have the HbSS genotype. Of the remaining patients, two had the HbSC and one the HbSF genotypes.

Infections occurred in the lower extremities in 11 patients, in the upper extremities in 10, in the pelvis or vertebrae in 2 each, and in the scapula, clavicle, hand, rib, or mandible in 1 patient each.

Just 13 of the 30 patients (43%) had lab findings of leukocytosis (more than 15,000 cells/mm²), and an equal number had elevated CRP (greater than 10 mg/L).

In contrast, 29 patients had an ESR above 20 mm/hour, and, in three of these patients, the rate was higher than 100 mm/hour.

When the researchers compared white blood cell counts and CRP levels between the treated patients and the 29 untreated controls, they found no significant differences for either measure of inflammation. In contrast, ESR was significantly higher among treated patients (P = .03).

Looking at the receiver operating characteristic curve for ESR, they found that an ESR of more than 100 mm/hour had 100% specificity for osteomyelitis in this group of patients.

Only 6 of the 30 (20%) had bacteremia. In 9 patients, nontyphoidal salmonella was isolated from cultures of either bone biopsy (3), abscess (3), or blood (6), but no possible causative organism could be isolated in the remaining 21 patients.

All patients were treated with prolonged antibiotic therapy. Surgical drainage and/or debridement were required in 6 patients. Two patients developed chronic osteomyelitis, but infection eventually resolved in all patients.

Recommendations

Dr. Weisman recommended early consultation with infectious disease experts and orthopedists; labs studies with complete blood counts, CRP, and ESR; and imaging studies with MRI when there is clinical suspicion of osteomyelitis in patients with SCD.

When an SCD patient has indeterminate findings, a blood culture can be performed. If it is positive for salmonella and the ESR is above 100 mm/hour, the patient can then go on to treatment. If the blood culture is negative and the ESR is below 100 mm hour but the suspicion of osteomyelitis remains high, a bone biopsy can be considered, they concluded.

The study was internally funded. Dr. Weisman reported no conflicts of interest to disclose.

The Food and Drug Administration’s 2007 “boxed warning” about serious adverse events associated with the use of erythropoietin-stimulating agents (ESAs) was followed by a substantial reduction in their use among patients recovering from colorectal, breast, or lung cancer, according to a new report.

Boxed warnings are considered one of the strongest mechanisms with which the FDA can communicate concerns about drug safety to the public. However, some critics have questioned the effectiveness of these warnings, and the available evidence “remains inconclusive, largely because almost all of [the data] were drawn from observational studies using pre-post designs without control groups,” said John Bian, PhD, of the University of South Carolina College of Pharmacy and Hollings Cancer Center, Columbia, and his associates.

The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.

[email protected]

The Food and Drug Administration’s 2007 “boxed warning” about serious adverse events associated with the use of erythropoietin-stimulating agents (ESAs) was followed by a substantial reduction in their use among patients recovering from colorectal, breast, or lung cancer, according to a new report.

Boxed warnings are considered one of the strongest mechanisms with which the FDA can communicate concerns about drug safety to the public. However, some critics have questioned the effectiveness of these warnings, and the available evidence “remains inconclusive, largely because almost all of [the data] were drawn from observational studies using pre-post designs without control groups,” said John Bian, PhD, of the University of South Carolina College of Pharmacy and Hollings Cancer Center, Columbia, and his associates.

The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.

[email protected]

The Food and Drug Administration’s 2007 “boxed warning” about serious adverse events associated with the use of erythropoietin-stimulating agents (ESAs) was followed by a substantial reduction in their use among patients recovering from colorectal, breast, or lung cancer, according to a new report.

Boxed warnings are considered one of the strongest mechanisms with which the FDA can communicate concerns about drug safety to the public. However, some critics have questioned the effectiveness of these warnings, and the available evidence “remains inconclusive, largely because almost all of [the data] were drawn from observational studies using pre-post designs without control groups,” said John Bian, PhD, of the University of South Carolina College of Pharmacy and Hollings Cancer Center, Columbia, and his associates.

The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.

[email protected]

Comprehensive Cancer Center

New research appears to explain how TET2 mutations increase the risk of hematologic malignancies.

In studying mouse models and patient samples, researchers found evidence to suggest that loss of TET2 opens the door for mutations that drive lymphoid and myeloid malignancies.

The researchers said loss of TET2 leads to hypermutagenicity in hematopoietic stem and progenitor cells (HSPCs), and although TET2-deficient HSPCs are likely not malignant, the higher mutation rates in these cells may result in additional driver mutations in TET2 target genes over time.

“If you lose TET2, it’s not a malignant state per se,” said Mingjiang Xu, MD, PhD, of the University of Miami Miller School of Medicine in Florida.

“But it’s creating a situation for other mutations to happen, leading to all types of blood cancer.”

Dr Xu and his colleagues reported these findings in Nature Communications.

The researchers found that Tet2-knockout mice developed spontaneous, lethal hematologic malignancies. Most (92%) developed myeloid malignancies, but 3.5% developed T-cell malignancies, and 4.5% developed B-cell malignancies.

In sequencing tumor and non-tumor cells from the Tet2-knockout mice, the researchers observed that loss of Tet2 leads to hypermutagenicity in HSPCs.

The team identified 190 genes with recurrent single-nucleotide variants. This included genes that are recurrently altered in human hematologic malignancies—Apc, Nf1, Flt3, Cbl, Notch1, and Mll2.

The researchers also analyzed samples from patients with acute myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic syndromes.

The team found that patients with TET2 mutations had “significantly more mutational events than patients with wild-type TET2.” And TET2 mutations were associated with subclonal events in APC, NF1, ASXL1, CBL, and ZRSR2, among other genes.

These findings suggest that targeting TET2 could potentially prevent the development of hematologic malignancies.

The researchers noted that TET2 mutations occur in healthy elderly individuals with clonal hematopoiesis, and these individuals would be ideal candidates for a preventive therapy targeting TET2.

“We are developing a method to target TET2,” Dr Xu said. “If we target that population [with TET2 mutations] for early therapy, we could potentially prevent those downstream mutations from happening.”

Comprehensive Cancer Center

New research appears to explain how TET2 mutations increase the risk of hematologic malignancies.

In studying mouse models and patient samples, researchers found evidence to suggest that loss of TET2 opens the door for mutations that drive lymphoid and myeloid malignancies.

The researchers said loss of TET2 leads to hypermutagenicity in hematopoietic stem and progenitor cells (HSPCs), and although TET2-deficient HSPCs are likely not malignant, the higher mutation rates in these cells may result in additional driver mutations in TET2 target genes over time.

“If you lose TET2, it’s not a malignant state per se,” said Mingjiang Xu, MD, PhD, of the University of Miami Miller School of Medicine in Florida.

“But it’s creating a situation for other mutations to happen, leading to all types of blood cancer.”

Dr Xu and his colleagues reported these findings in Nature Communications.

The researchers found that Tet2-knockout mice developed spontaneous, lethal hematologic malignancies. Most (92%) developed myeloid malignancies, but 3.5% developed T-cell malignancies, and 4.5% developed B-cell malignancies.

In sequencing tumor and non-tumor cells from the Tet2-knockout mice, the researchers observed that loss of Tet2 leads to hypermutagenicity in HSPCs.

The team identified 190 genes with recurrent single-nucleotide variants. This included genes that are recurrently altered in human hematologic malignancies—Apc, Nf1, Flt3, Cbl, Notch1, and Mll2.

The researchers also analyzed samples from patients with acute myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic syndromes.

The team found that patients with TET2 mutations had “significantly more mutational events than patients with wild-type TET2.” And TET2 mutations were associated with subclonal events in APC, NF1, ASXL1, CBL, and ZRSR2, among other genes.

These findings suggest that targeting TET2 could potentially prevent the development of hematologic malignancies.

The researchers noted that TET2 mutations occur in healthy elderly individuals with clonal hematopoiesis, and these individuals would be ideal candidates for a preventive therapy targeting TET2.

“We are developing a method to target TET2,” Dr Xu said. “If we target that population [with TET2 mutations] for early therapy, we could potentially prevent those downstream mutations from happening.”

Comprehensive Cancer Center

New research appears to explain how TET2 mutations increase the risk of hematologic malignancies.

In studying mouse models and patient samples, researchers found evidence to suggest that loss of TET2 opens the door for mutations that drive lymphoid and myeloid malignancies.

The researchers said loss of TET2 leads to hypermutagenicity in hematopoietic stem and progenitor cells (HSPCs), and although TET2-deficient HSPCs are likely not malignant, the higher mutation rates in these cells may result in additional driver mutations in TET2 target genes over time.

“If you lose TET2, it’s not a malignant state per se,” said Mingjiang Xu, MD, PhD, of the University of Miami Miller School of Medicine in Florida.

“But it’s creating a situation for other mutations to happen, leading to all types of blood cancer.”

Dr Xu and his colleagues reported these findings in Nature Communications.

The researchers found that Tet2-knockout mice developed spontaneous, lethal hematologic malignancies. Most (92%) developed myeloid malignancies, but 3.5% developed T-cell malignancies, and 4.5% developed B-cell malignancies.

In sequencing tumor and non-tumor cells from the Tet2-knockout mice, the researchers observed that loss of Tet2 leads to hypermutagenicity in HSPCs.

The team identified 190 genes with recurrent single-nucleotide variants. This included genes that are recurrently altered in human hematologic malignancies—Apc, Nf1, Flt3, Cbl, Notch1, and Mll2.

The researchers also analyzed samples from patients with acute myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic syndromes.

The team found that patients with TET2 mutations had “significantly more mutational events than patients with wild-type TET2.” And TET2 mutations were associated with subclonal events in APC, NF1, ASXL1, CBL, and ZRSR2, among other genes.

These findings suggest that targeting TET2 could potentially prevent the development of hematologic malignancies.

The researchers noted that TET2 mutations occur in healthy elderly individuals with clonal hematopoiesis, and these individuals would be ideal candidates for a preventive therapy targeting TET2.

“We are developing a method to target TET2,” Dr Xu said. “If we target that population [with TET2 mutations] for early therapy, we could potentially prevent those downstream mutations from happening.”

Adding the thrombopoietin-receptor agonist eltrombopag to standard immunosuppressive therapy markedly improved the frequency, speed, and robustness of hematologic recovery in a phase I-II trial of patients with severe aplastic anemia, according to a report published online April 20 in the New England Journal of Medicine.

Previously, researchers found that eltrombopag was effective against aplastic anemia that was refractory to immunosuppression, inducing higher platelet counts, hemoglobin levels, and neutrophil numbers when used as a single agent. They then examined whether adding the drug to immunosuppression in treatment-naive patients would improve the response in this nonrandomized prospective trial, said Danielle M. Townsley, MD, of the hematology branch, National Heart, Lung, and Blood Institute, and her associates.

Ninety-two consecutive patients aged 3-82 years were divided into three cohorts with different timing and duration of treatment. Cohort 1 (30 patients) received eltrombopag from day 14 to 6 months; cohort 2 (31 patients) received it from day 14 to 3 months; and cohort 3 (31 patients) received it from day 1 to 6 months.

The primary efficacy endpoint – the rate of complete hematologic response at 6 months – was highest, at 58%, in cohort 3, which had the earliest initiation and the longest duration of eltrombopag treatment. It was lowest, at 26%, in cohort 2, which had the shortest duration of eltrombopag treatment. The rate of complete hematologic response was intermediate in cohort 1, at 33% (N Engl J Med. 2017 Apr 20. doi:10.1056/NEJMoa1613878).

These complete response rates all exceeded those reported historically, which range from 10% to 20%. Moreover, the rate of partial or complete hematologic response was 87% across all three cohorts, compared with the 66% partial or complete response rate that would be expected with standard immunosuppression alone. Absolute neutrophil counts and platelet counts in all three cohorts also were higher at both 3 and 6 months than were those that have been reported historically.

The average time to independence from transfusions in the entire study population was 1 month, and clinically meaningful improvements in neutrophil levels were seen within a few weeks of initiating eltrombopag.

Two cases of severe cutaneous eruptions led to discontinuation of the study drug. Liver abnormalities were frequent but transient and did not limit the use of eltrombopag.

If these results are validated in future studies, and if no unexpected late complications are identified, adding eltrombopag to standard immunosuppressive therapy “may help patients optimize the timing of allogeneic stem-cell transplantation or avoid it. Of particular interest would be use of eltrombopag in combination with less toxic immunosuppressive regimens that omit antithymocyte globulin, particularly in older patients, in patients with coexisting conditions, and in developing countries where aplastic anemia is prevalent and conventional therapies [are] extremely costly,” Dr. Townsley and her associates noted.

One such confirmatory study, a large randomized placebo-controlled trial (NCT02099747), is now underway in Europe, they wrote.

This trial was supported by the National Heart, Lung, and Blood Institute. Dr. Townsley and her associates reported ties to GlaxoSmithKline and Novartis, makers of eltrombopag.

Adding the thrombopoietin-receptor agonist eltrombopag to standard immunosuppressive therapy markedly improved the frequency, speed, and robustness of hematologic recovery in a phase I-II trial of patients with severe aplastic anemia, according to a report published online April 20 in the New England Journal of Medicine.

Previously, researchers found that eltrombopag was effective against aplastic anemia that was refractory to immunosuppression, inducing higher platelet counts, hemoglobin levels, and neutrophil numbers when used as a single agent. They then examined whether adding the drug to immunosuppression in treatment-naive patients would improve the response in this nonrandomized prospective trial, said Danielle M. Townsley, MD, of the hematology branch, National Heart, Lung, and Blood Institute, and her associates.

Ninety-two consecutive patients aged 3-82 years were divided into three cohorts with different timing and duration of treatment. Cohort 1 (30 patients) received eltrombopag from day 14 to 6 months; cohort 2 (31 patients) received it from day 14 to 3 months; and cohort 3 (31 patients) received it from day 1 to 6 months.

The primary efficacy endpoint – the rate of complete hematologic response at 6 months – was highest, at 58%, in cohort 3, which had the earliest initiation and the longest duration of eltrombopag treatment. It was lowest, at 26%, in cohort 2, which had the shortest duration of eltrombopag treatment. The rate of complete hematologic response was intermediate in cohort 1, at 33% (N Engl J Med. 2017 Apr 20. doi:10.1056/NEJMoa1613878).

These complete response rates all exceeded those reported historically, which range from 10% to 20%. Moreover, the rate of partial or complete hematologic response was 87% across all three cohorts, compared with the 66% partial or complete response rate that would be expected with standard immunosuppression alone. Absolute neutrophil counts and platelet counts in all three cohorts also were higher at both 3 and 6 months than were those that have been reported historically.

The average time to independence from transfusions in the entire study population was 1 month, and clinically meaningful improvements in neutrophil levels were seen within a few weeks of initiating eltrombopag.

Two cases of severe cutaneous eruptions led to discontinuation of the study drug. Liver abnormalities were frequent but transient and did not limit the use of eltrombopag.

If these results are validated in future studies, and if no unexpected late complications are identified, adding eltrombopag to standard immunosuppressive therapy “may help patients optimize the timing of allogeneic stem-cell transplantation or avoid it. Of particular interest would be use of eltrombopag in combination with less toxic immunosuppressive regimens that omit antithymocyte globulin, particularly in older patients, in patients with coexisting conditions, and in developing countries where aplastic anemia is prevalent and conventional therapies [are] extremely costly,” Dr. Townsley and her associates noted.

One such confirmatory study, a large randomized placebo-controlled trial (NCT02099747), is now underway in Europe, they wrote.

This trial was supported by the National Heart, Lung, and Blood Institute. Dr. Townsley and her associates reported ties to GlaxoSmithKline and Novartis, makers of eltrombopag.

Adding the thrombopoietin-receptor agonist eltrombopag to standard immunosuppressive therapy markedly improved the frequency, speed, and robustness of hematologic recovery in a phase I-II trial of patients with severe aplastic anemia, according to a report published online April 20 in the New England Journal of Medicine.

Previously, researchers found that eltrombopag was effective against aplastic anemia that was refractory to immunosuppression, inducing higher platelet counts, hemoglobin levels, and neutrophil numbers when used as a single agent. They then examined whether adding the drug to immunosuppression in treatment-naive patients would improve the response in this nonrandomized prospective trial, said Danielle M. Townsley, MD, of the hematology branch, National Heart, Lung, and Blood Institute, and her associates.

Ninety-two consecutive patients aged 3-82 years were divided into three cohorts with different timing and duration of treatment. Cohort 1 (30 patients) received eltrombopag from day 14 to 6 months; cohort 2 (31 patients) received it from day 14 to 3 months; and cohort 3 (31 patients) received it from day 1 to 6 months.

The primary efficacy endpoint – the rate of complete hematologic response at 6 months – was highest, at 58%, in cohort 3, which had the earliest initiation and the longest duration of eltrombopag treatment. It was lowest, at 26%, in cohort 2, which had the shortest duration of eltrombopag treatment. The rate of complete hematologic response was intermediate in cohort 1, at 33% (N Engl J Med. 2017 Apr 20. doi:10.1056/NEJMoa1613878).

These complete response rates all exceeded those reported historically, which range from 10% to 20%. Moreover, the rate of partial or complete hematologic response was 87% across all three cohorts, compared with the 66% partial or complete response rate that would be expected with standard immunosuppression alone. Absolute neutrophil counts and platelet counts in all three cohorts also were higher at both 3 and 6 months than were those that have been reported historically.

The average time to independence from transfusions in the entire study population was 1 month, and clinically meaningful improvements in neutrophil levels were seen within a few weeks of initiating eltrombopag.

Two cases of severe cutaneous eruptions led to discontinuation of the study drug. Liver abnormalities were frequent but transient and did not limit the use of eltrombopag.

If these results are validated in future studies, and if no unexpected late complications are identified, adding eltrombopag to standard immunosuppressive therapy “may help patients optimize the timing of allogeneic stem-cell transplantation or avoid it. Of particular interest would be use of eltrombopag in combination with less toxic immunosuppressive regimens that omit antithymocyte globulin, particularly in older patients, in patients with coexisting conditions, and in developing countries where aplastic anemia is prevalent and conventional therapies [are] extremely costly,” Dr. Townsley and her associates noted.

One such confirmatory study, a large randomized placebo-controlled trial (NCT02099747), is now underway in Europe, they wrote.

This trial was supported by the National Heart, Lung, and Blood Institute. Dr. Townsley and her associates reported ties to GlaxoSmithKline and Novartis, makers of eltrombopag.

Photo courtesy of GSK

Adding eltrombopag to immunosuppressive therapy (IST) can produce high rates of response in treatment-naïve severe aplastic anemia (SAA), according to research published in NEJM.

In patients who received eltrombopag for 6 months, the overall response rate (ORR) was 94%, and the complete response (CR) rate was 58%.

Researchers noted that these rates are “markedly higher” than response rates observed in historical controls who received IST alone.

The team also said the safety profile of eltrombopag in this study was consistent with the known safety profile of the drug.

“[E]ltrombopag plus standard immunosuppressive therapy appeared to increase the overall response rate and substantially increase the frequency, speed, and robustness of hematologic recovery in patients with SAA compared to historical controls,” said study author Danielle Townsley, MD, of the National Heart, Lung and Blood Institute (NHLBI).

She and her colleagues at NHLBI conducted this research through a Cooperative Research and Development Agreement with Novartis, the company that markets eltrombopag as Promacta/Revolade.

Patients and treatment

This phase 1/2 trial included 92 patients with treatment-naïve SAA. The patients’ median age was 32 (range, 3-82), and 54% of them were male.

At baseline, the patients’ median neutrophil count was 310/mm³ (range, 0-1810), their median reticulocyte count was 19,950/mm³ (range, 1600-60,400), and their median platelet count was 9000/mm³ (range, 0-37,000). Their median thrombopoietin level was 3163 pg/ml (range, 1806-4955).

All patients received horse antithymocyte globulin on days 1 to 4 and cyclosporine from day 1 to 6 months. The patients also received eltrombopag at an age-dependent dose.

They received eltrombopag at 150 mg daily if they were 12 years or older, 75 mg daily if they were 6 to 11, and 2.5 mg/kg/day if they were 2 to 5 years of age.

Patients were also split into 3 cohorts according to treatment duration:

• Cohort 1 received eltrombopag from day 14 to the 6-month mark.
• Cohort 2 received eltrombopag from day 14 to the 3-month mark.
• Cohort 3 received eltrombopag from day 1 to 6 months.

Response

The study’s primary efficacy endpoint was hematologic CR at 6 months. CR was defined as an absolute neutrophil count of at least 1000/mm³, a hemoglobin level of at least 10 g/dL, and a platelet count of at least 100,000/mm³.

Secondary endpoints included partial response (PR) and ORR, among other endpoints. ORR was the rate of CR plus PR. Patients had a PR if they had blood counts that no longer met the criteria for SAA but they did not meet criteria for CR.

For all cohorts, at 6 months, the ORR was 87%, and the CR rate was 39%.

In cohort 1, the ORR was 80%, and the CR rate was 33%.

In cohort 2, the ORR was 87%, and the CR rate was 26%.

In cohort 3, the ORR was 94%, and the CR rate was 58%.

The researchers noted that ORRs were higher across all cohorts than the ORR observed in a historical cohort (66%). The cohort consisted of 102 patients who had received standard IST while serving as controls in 1 of 2 recent NHLBI clinical trials.

Relapse

Thirty-two percent of responding patients (25/78) relapsed after 6 months.

After the study protocol was amended to allow the continuation of low-dose cyclosporine from 6 months to 2 years, the frequency of relapse decreased.

Fourteen percent of responders receiving low-dose cyclosporine beyond 6 months relapsed (6/43), compared to 54% of patients who stopped cyclosporine at 6 months (19/35).

Restarting full-dose cyclosporine reversed relapse and increased blood counts in 13 of 25 patients. Adding eltrombopag reversed relapse in an additional 10 patients.

Survival

The 2-year overall survival rate was 97% for the entire study population and 99% when data were censored for transplant.

Twelve patients under went transplant after eltrombopag. Six of them had not responded or were still transfusion-dependent, 3 relapsed, and 3 had clonal evolution.

Three patients died—1 while on study and 2 after transplant.

Clonal evolution and PNH

The researchers said the frequency of clonal evolution in this study was similar to that observed in the historical cohort of patients who received standard IST. The rate of clonal evolution at 2 years was 8% in both groups.

In the current study, 7 patients had clonal evolution at 2 years. Five patients had loss of chromosome 7, which was associated with dysplastic bone marrow changes in 3 patients.

One patient with a complex karyotype progressed to acute myeloid leukemia.

Two patients developed hemolytic paroxysmal nocturnal hemoglobinuria (PNH).

Safety

Two severe adverse events (AEs) were attributed to eltrombopag. Both were cutaneous eruptions—a grade 2 and a grade 3 event. Both AEs led to discontinuation of the drug.

Seven patients briefly stopped taking eltrombopag during the first 2 weeks of treatment due to transient elevations in liver enzymes.

AEs not attributed to eltrombopag were neutropenic infections and AEs known to be associated with IST.

The single patient who died on study was a non-responder who died 3 months after starting treatment. The death was due to paraneoplastic encephalopathy, which was attributed to thymoma that predated study entry.

Photo courtesy of GSK

Adding eltrombopag to immunosuppressive therapy (IST) can produce high rates of response in treatment-naïve severe aplastic anemia (SAA), according to research published in NEJM.

In patients who received eltrombopag for 6 months, the overall response rate (ORR) was 94%, and the complete response (CR) rate was 58%.

Researchers noted that these rates are “markedly higher” than response rates observed in historical controls who received IST alone.

The team also said the safety profile of eltrombopag in this study was consistent with the known safety profile of the drug.

“[E]ltrombopag plus standard immunosuppressive therapy appeared to increase the overall response rate and substantially increase the frequency, speed, and robustness of hematologic recovery in patients with SAA compared to historical controls,” said study author Danielle Townsley, MD, of the National Heart, Lung and Blood Institute (NHLBI).

She and her colleagues at NHLBI conducted this research through a Cooperative Research and Development Agreement with Novartis, the company that markets eltrombopag as Promacta/Revolade.

Patients and treatment

This phase 1/2 trial included 92 patients with treatment-naïve SAA. The patients’ median age was 32 (range, 3-82), and 54% of them were male.

At baseline, the patients’ median neutrophil count was 310/mm³ (range, 0-1810), their median reticulocyte count was 19,950/mm³ (range, 1600-60,400), and their median platelet count was 9000/mm³ (range, 0-37,000). Their median thrombopoietin level was 3163 pg/ml (range, 1806-4955).

All patients received horse antithymocyte globulin on days 1 to 4 and cyclosporine from day 1 to 6 months. The patients also received eltrombopag at an age-dependent dose.

They received eltrombopag at 150 mg daily if they were 12 years or older, 75 mg daily if they were 6 to 11, and 2.5 mg/kg/day if they were 2 to 5 years of age.

Patients were also split into 3 cohorts according to treatment duration:

• Cohort 1 received eltrombopag from day 14 to the 6-month mark.
• Cohort 2 received eltrombopag from day 14 to the 3-month mark.
• Cohort 3 received eltrombopag from day 1 to 6 months.

Response

The study’s primary efficacy endpoint was hematologic CR at 6 months. CR was defined as an absolute neutrophil count of at least 1000/mm³, a hemoglobin level of at least 10 g/dL, and a platelet count of at least 100,000/mm³.

Secondary endpoints included partial response (PR) and ORR, among other endpoints. ORR was the rate of CR plus PR. Patients had a PR if they had blood counts that no longer met the criteria for SAA but they did not meet criteria for CR.

For all cohorts, at 6 months, the ORR was 87%, and the CR rate was 39%.

In cohort 1, the ORR was 80%, and the CR rate was 33%.

In cohort 2, the ORR was 87%, and the CR rate was 26%.

In cohort 3, the ORR was 94%, and the CR rate was 58%.

The researchers noted that ORRs were higher across all cohorts than the ORR observed in a historical cohort (66%). The cohort consisted of 102 patients who had received standard IST while serving as controls in 1 of 2 recent NHLBI clinical trials.

Relapse

Thirty-two percent of responding patients (25/78) relapsed after 6 months.

After the study protocol was amended to allow the continuation of low-dose cyclosporine from 6 months to 2 years, the frequency of relapse decreased.

Fourteen percent of responders receiving low-dose cyclosporine beyond 6 months relapsed (6/43), compared to 54% of patients who stopped cyclosporine at 6 months (19/35).

Restarting full-dose cyclosporine reversed relapse and increased blood counts in 13 of 25 patients. Adding eltrombopag reversed relapse in an additional 10 patients.

Survival

The 2-year overall survival rate was 97% for the entire study population and 99% when data were censored for transplant.

Twelve patients under went transplant after eltrombopag. Six of them had not responded or were still transfusion-dependent, 3 relapsed, and 3 had clonal evolution.

Three patients died—1 while on study and 2 after transplant.

Clonal evolution and PNH

The researchers said the frequency of clonal evolution in this study was similar to that observed in the historical cohort of patients who received standard IST. The rate of clonal evolution at 2 years was 8% in both groups.

In the current study, 7 patients had clonal evolution at 2 years. Five patients had loss of chromosome 7, which was associated with dysplastic bone marrow changes in 3 patients.

One patient with a complex karyotype progressed to acute myeloid leukemia.

Two patients developed hemolytic paroxysmal nocturnal hemoglobinuria (PNH).

Safety

Two severe adverse events (AEs) were attributed to eltrombopag. Both were cutaneous eruptions—a grade 2 and a grade 3 event. Both AEs led to discontinuation of the drug.

Seven patients briefly stopped taking eltrombopag during the first 2 weeks of treatment due to transient elevations in liver enzymes.

AEs not attributed to eltrombopag were neutropenic infections and AEs known to be associated with IST.

The single patient who died on study was a non-responder who died 3 months after starting treatment. The death was due to paraneoplastic encephalopathy, which was attributed to thymoma that predated study entry.

Photo courtesy of GSK

Adding eltrombopag to immunosuppressive therapy (IST) can produce high rates of response in treatment-naïve severe aplastic anemia (SAA), according to research published in NEJM.

In patients who received eltrombopag for 6 months, the overall response rate (ORR) was 94%, and the complete response (CR) rate was 58%.

Researchers noted that these rates are “markedly higher” than response rates observed in historical controls who received IST alone.

The team also said the safety profile of eltrombopag in this study was consistent with the known safety profile of the drug.

“[E]ltrombopag plus standard immunosuppressive therapy appeared to increase the overall response rate and substantially increase the frequency, speed, and robustness of hematologic recovery in patients with SAA compared to historical controls,” said study author Danielle Townsley, MD, of the National Heart, Lung and Blood Institute (NHLBI).

She and her colleagues at NHLBI conducted this research through a Cooperative Research and Development Agreement with Novartis, the company that markets eltrombopag as Promacta/Revolade.

Patients and treatment

This phase 1/2 trial included 92 patients with treatment-naïve SAA. The patients’ median age was 32 (range, 3-82), and 54% of them were male.

At baseline, the patients’ median neutrophil count was 310/mm³ (range, 0-1810), their median reticulocyte count was 19,950/mm³ (range, 1600-60,400), and their median platelet count was 9000/mm³ (range, 0-37,000). Their median thrombopoietin level was 3163 pg/ml (range, 1806-4955).

All patients received horse antithymocyte globulin on days 1 to 4 and cyclosporine from day 1 to 6 months. The patients also received eltrombopag at an age-dependent dose.

They received eltrombopag at 150 mg daily if they were 12 years or older, 75 mg daily if they were 6 to 11, and 2.5 mg/kg/day if they were 2 to 5 years of age.

Patients were also split into 3 cohorts according to treatment duration:

• Cohort 1 received eltrombopag from day 14 to the 6-month mark.
• Cohort 2 received eltrombopag from day 14 to the 3-month mark.
• Cohort 3 received eltrombopag from day 1 to 6 months.

Response

The study’s primary efficacy endpoint was hematologic CR at 6 months. CR was defined as an absolute neutrophil count of at least 1000/mm³, a hemoglobin level of at least 10 g/dL, and a platelet count of at least 100,000/mm³.

Secondary endpoints included partial response (PR) and ORR, among other endpoints. ORR was the rate of CR plus PR. Patients had a PR if they had blood counts that no longer met the criteria for SAA but they did not meet criteria for CR.

For all cohorts, at 6 months, the ORR was 87%, and the CR rate was 39%.

In cohort 1, the ORR was 80%, and the CR rate was 33%.

In cohort 2, the ORR was 87%, and the CR rate was 26%.

In cohort 3, the ORR was 94%, and the CR rate was 58%.

The researchers noted that ORRs were higher across all cohorts than the ORR observed in a historical cohort (66%). The cohort consisted of 102 patients who had received standard IST while serving as controls in 1 of 2 recent NHLBI clinical trials.

Relapse

Thirty-two percent of responding patients (25/78) relapsed after 6 months.

After the study protocol was amended to allow the continuation of low-dose cyclosporine from 6 months to 2 years, the frequency of relapse decreased.

Fourteen percent of responders receiving low-dose cyclosporine beyond 6 months relapsed (6/43), compared to 54% of patients who stopped cyclosporine at 6 months (19/35).

Restarting full-dose cyclosporine reversed relapse and increased blood counts in 13 of 25 patients. Adding eltrombopag reversed relapse in an additional 10 patients.

Survival

The 2-year overall survival rate was 97% for the entire study population and 99% when data were censored for transplant.

Twelve patients under went transplant after eltrombopag. Six of them had not responded or were still transfusion-dependent, 3 relapsed, and 3 had clonal evolution.

Three patients died—1 while on study and 2 after transplant.

Clonal evolution and PNH

The researchers said the frequency of clonal evolution in this study was similar to that observed in the historical cohort of patients who received standard IST. The rate of clonal evolution at 2 years was 8% in both groups.

In the current study, 7 patients had clonal evolution at 2 years. Five patients had loss of chromosome 7, which was associated with dysplastic bone marrow changes in 3 patients.

One patient with a complex karyotype progressed to acute myeloid leukemia.

Two patients developed hemolytic paroxysmal nocturnal hemoglobinuria (PNH).

Safety

Two severe adverse events (AEs) were attributed to eltrombopag. Both were cutaneous eruptions—a grade 2 and a grade 3 event. Both AEs led to discontinuation of the drug.

Seven patients briefly stopped taking eltrombopag during the first 2 weeks of treatment due to transient elevations in liver enzymes.

AEs not attributed to eltrombopag were neutropenic infections and AEs known to be associated with IST.

The single patient who died on study was a non-responder who died 3 months after starting treatment. The death was due to paraneoplastic encephalopathy, which was attributed to thymoma that predated study entry.