Leukemia, Myelodysplasia, Transplantation

Caregiver holding

patient’s hand

Choosing to die at home does not hasten death for patients with terminal cancer, according to a study published in Cancer.

The research showed that cancer patients who died at home lived at least as long as patients who spent their last days in hospitals.

Investigators say these results suggest oncologists should not hesitate to refer patients for home-based palliative care simply because less medical treatment may be provided.

“The cancer patient and family tend to be concerned that the quality of medical treatment provided at home will be inferior to that given in a hospital and that survival might be shortened,” said study author Jun Hamano, MD, of the University of Tsukuba in Japan.

“However, our finding—that home death does not actually have a negative influence on the survival of cancer patients at all and, rather, may have a positive influence—could suggest that the patient and family can choose the place of death in terms of their preference and values.”

Dr Hamano and his colleagues conducted this research by prospectively studying 2069 patients—1582 receiving hospital-based palliative care and 487 receiving home-based palliative care.

In all, 1607 patients died in the hospital, and 462 died at home.

Among patients thought to have only days to live, the survival of those who died at home was significantly longer than the survival of those who died in a hospital. The estimated median survival times were 13 days and 9 days, respectively (P<0.006).

Similarly, survival was significantly longer in the home group than the hospital group among patients thought to have weeks to live. The estimated median survival times were 36 days and 29 days, respectively (P<0.007).

There was no significant difference between the home and hospital groups among patients thought to have months to live. The estimated median survival times were 59 days and 62 days, respectively (P=0.925).

Finally, analyses suggested the place of death had a significant influence on the survival time in both unadjusted and adjusted models. The hazard ratios were 0.86 (P<0.01) and 0.87 (P=0.01), respectively.

Based on these findings, Dr Hamano concluded that, “Patients, families, and clinicians should be reassured that good home hospice care does not shorten patient life and even may achieve longer survival.”

Caregiver holding

patient’s hand

Choosing to die at home does not hasten death for patients with terminal cancer, according to a study published in Cancer.

The research showed that cancer patients who died at home lived at least as long as patients who spent their last days in hospitals.

Investigators say these results suggest oncologists should not hesitate to refer patients for home-based palliative care simply because less medical treatment may be provided.

“The cancer patient and family tend to be concerned that the quality of medical treatment provided at home will be inferior to that given in a hospital and that survival might be shortened,” said study author Jun Hamano, MD, of the University of Tsukuba in Japan.

“However, our finding—that home death does not actually have a negative influence on the survival of cancer patients at all and, rather, may have a positive influence—could suggest that the patient and family can choose the place of death in terms of their preference and values.”

Dr Hamano and his colleagues conducted this research by prospectively studying 2069 patients—1582 receiving hospital-based palliative care and 487 receiving home-based palliative care.

In all, 1607 patients died in the hospital, and 462 died at home.

Among patients thought to have only days to live, the survival of those who died at home was significantly longer than the survival of those who died in a hospital. The estimated median survival times were 13 days and 9 days, respectively (P<0.006).

Similarly, survival was significantly longer in the home group than the hospital group among patients thought to have weeks to live. The estimated median survival times were 36 days and 29 days, respectively (P<0.007).

There was no significant difference between the home and hospital groups among patients thought to have months to live. The estimated median survival times were 59 days and 62 days, respectively (P=0.925).

Finally, analyses suggested the place of death had a significant influence on the survival time in both unadjusted and adjusted models. The hazard ratios were 0.86 (P<0.01) and 0.87 (P=0.01), respectively.

Based on these findings, Dr Hamano concluded that, “Patients, families, and clinicians should be reassured that good home hospice care does not shorten patient life and even may achieve longer survival.”

Caregiver holding

patient’s hand

Choosing to die at home does not hasten death for patients with terminal cancer, according to a study published in Cancer.

The research showed that cancer patients who died at home lived at least as long as patients who spent their last days in hospitals.

Investigators say these results suggest oncologists should not hesitate to refer patients for home-based palliative care simply because less medical treatment may be provided.

“The cancer patient and family tend to be concerned that the quality of medical treatment provided at home will be inferior to that given in a hospital and that survival might be shortened,” said study author Jun Hamano, MD, of the University of Tsukuba in Japan.

“However, our finding—that home death does not actually have a negative influence on the survival of cancer patients at all and, rather, may have a positive influence—could suggest that the patient and family can choose the place of death in terms of their preference and values.”

Dr Hamano and his colleagues conducted this research by prospectively studying 2069 patients—1582 receiving hospital-based palliative care and 487 receiving home-based palliative care.

In all, 1607 patients died in the hospital, and 462 died at home.

Among patients thought to have only days to live, the survival of those who died at home was significantly longer than the survival of those who died in a hospital. The estimated median survival times were 13 days and 9 days, respectively (P<0.006).

Similarly, survival was significantly longer in the home group than the hospital group among patients thought to have weeks to live. The estimated median survival times were 36 days and 29 days, respectively (P<0.007).

There was no significant difference between the home and hospital groups among patients thought to have months to live. The estimated median survival times were 59 days and 62 days, respectively (P=0.925).

Finally, analyses suggested the place of death had a significant influence on the survival time in both unadjusted and adjusted models. The hazard ratios were 0.86 (P<0.01) and 0.87 (P=0.01), respectively.

Based on these findings, Dr Hamano concluded that, “Patients, families, and clinicians should be reassured that good home hospice care does not shorten patient life and even may achieve longer survival.”

Micrograph showing MDS

Researchers have found the fusion protein APG101 can rescue erythropoiesis in bone marrow samples from patients with lower-risk myelodysplastic syndromes (MDS).

Previous research suggested that CD95—a receptor that can induce apoptosis when triggered by the CD95 ligand—is overexpressed in two-thirds of patients with lower-risk MDS, and overexpression of CD95 is predictive of a lower response to erythropoiesis-stimulating agents (ESAs).

APG101, which consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG antibody, is designed to block the CD95 ligand.

The new study showed that APG101 can inhibit apoptosis in erythrocyte precursor cells and improve their overall proliferation rate. The drug increased the number of burst-forming unit-erythroid (BFU-E) progenitors in samples from MDS patients with low BFU-E numbers at baseline.

“APG101 added to cellular assays efficiently rescued the growth of erythroid progenitors in MDS patients harboring a profound defect of erythropoiesis, independent of the expression level of CD95 or CD95 ligand,” said Michaela Fontenay, MD, PhD, of the Institut Cochin in Paris, France.

Dr Fontenay and her colleagues described these results in Oncotarget. The research was funded by Apogenix, the company developing APG101.

By comparing bone marrow samples from MDS patients and healthy control subjects, the researchers found that CD95, but not CD95 ligand, was overexpressed in patients with lower-risk MDS.

Further analysis revealed that a patient’s CD95 expression level at diagnosis could predict response to an ESA. Specifically, CD95 overexpression was predictive of a lower response rate to ESAs in patients with low- or intermediate-1-risk MDS.

Next, the researchers tested bone marrow erythroid progenitors from 3 control subjects and 5 patients with MDS and found that CD95 expression increased during MDS erythroid progenitor amplification but remained lower in control cultures.

On day 5 of culture, the mean number of BFU-Es was significantly lower in MDS patient samples than in controls. And treatment with APG101 prompted a dose-dependent increase in BFU-E growth in MDS samples but not in controls.

When the researchers added APG101 (at 10 μg/mL) to the cultures over 7 days, they observed an improvement in the proliferation of erythroblasts but no significant effect on the kinetics of differentiation.

They also found that APG101 reduced apoptosis in immature precursors by 30% but had no effect on apoptosis in mature precursors.

Baseline BFU-E number affects response

The researchers then assessed the effects of APG101 in samples from 5 control subjects and 20 MDS patients with varying responses to ESAs and varying baseline levels of BFU-Es.

Fifteen of the MDS patients had a significantly lower number of baseline BFU-Es than controls (P=0.005), but 5 MDS patients had a mean number of BFU-Es that was comparable to controls (P=0.429). There was no significant difference in WHO classification or CD95 expression between the 2 groups of MDS patients (P=0.612).

However, 11 of the 15 patients with low erythropoiesis had received an ESA, and all of them were resistant to this treatment. In all, 15 of the MDS patients had received an ESA, and 14 were resistant to it (6 primary and 8 secondary).

The researchers found that APG101 induced a dose-dependent increase of BFU-Es in samples from the 15 MDS patients with low erythropoiesis but not in samples from the 5 patients with normal erythropoiesis or in the control samples (P<0.001).

The team said that a low BFU-E number at baseline was significantly associated with in vitro response to APG101 among the 20 MDS patients (P=0.031) and the 14 ESA-resistant patients (P=0.027).

Further investigation confirmed that a low clonogenic progenitor number at baseline, but not the level of CD95 or CD95 ligand expression, was predictive of the response to APG101.

“This study provides a rationale for further clinical investigation of this potential new therapeutic option in patients with severely impaired erythropoiesis who are resistant to erythropoiesis-stimulating agents,” Dr Fontenay said.

Apogenix has conducted a phase 1 trial of APG101 in transfusion-dependent patients with low- to intermediate-1-risk MDS. The company expects the results of this trial will be available in the coming months.

Micrograph showing MDS

Researchers have found the fusion protein APG101 can rescue erythropoiesis in bone marrow samples from patients with lower-risk myelodysplastic syndromes (MDS).

Previous research suggested that CD95—a receptor that can induce apoptosis when triggered by the CD95 ligand—is overexpressed in two-thirds of patients with lower-risk MDS, and overexpression of CD95 is predictive of a lower response to erythropoiesis-stimulating agents (ESAs).

APG101, which consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG antibody, is designed to block the CD95 ligand.

The new study showed that APG101 can inhibit apoptosis in erythrocyte precursor cells and improve their overall proliferation rate. The drug increased the number of burst-forming unit-erythroid (BFU-E) progenitors in samples from MDS patients with low BFU-E numbers at baseline.

“APG101 added to cellular assays efficiently rescued the growth of erythroid progenitors in MDS patients harboring a profound defect of erythropoiesis, independent of the expression level of CD95 or CD95 ligand,” said Michaela Fontenay, MD, PhD, of the Institut Cochin in Paris, France.

Dr Fontenay and her colleagues described these results in Oncotarget. The research was funded by Apogenix, the company developing APG101.

By comparing bone marrow samples from MDS patients and healthy control subjects, the researchers found that CD95, but not CD95 ligand, was overexpressed in patients with lower-risk MDS.

Further analysis revealed that a patient’s CD95 expression level at diagnosis could predict response to an ESA. Specifically, CD95 overexpression was predictive of a lower response rate to ESAs in patients with low- or intermediate-1-risk MDS.

Next, the researchers tested bone marrow erythroid progenitors from 3 control subjects and 5 patients with MDS and found that CD95 expression increased during MDS erythroid progenitor amplification but remained lower in control cultures.

On day 5 of culture, the mean number of BFU-Es was significantly lower in MDS patient samples than in controls. And treatment with APG101 prompted a dose-dependent increase in BFU-E growth in MDS samples but not in controls.

When the researchers added APG101 (at 10 μg/mL) to the cultures over 7 days, they observed an improvement in the proliferation of erythroblasts but no significant effect on the kinetics of differentiation.

They also found that APG101 reduced apoptosis in immature precursors by 30% but had no effect on apoptosis in mature precursors.

Baseline BFU-E number affects response

The researchers then assessed the effects of APG101 in samples from 5 control subjects and 20 MDS patients with varying responses to ESAs and varying baseline levels of BFU-Es.

Fifteen of the MDS patients had a significantly lower number of baseline BFU-Es than controls (P=0.005), but 5 MDS patients had a mean number of BFU-Es that was comparable to controls (P=0.429). There was no significant difference in WHO classification or CD95 expression between the 2 groups of MDS patients (P=0.612).

However, 11 of the 15 patients with low erythropoiesis had received an ESA, and all of them were resistant to this treatment. In all, 15 of the MDS patients had received an ESA, and 14 were resistant to it (6 primary and 8 secondary).

The researchers found that APG101 induced a dose-dependent increase of BFU-Es in samples from the 15 MDS patients with low erythropoiesis but not in samples from the 5 patients with normal erythropoiesis or in the control samples (P<0.001).

The team said that a low BFU-E number at baseline was significantly associated with in vitro response to APG101 among the 20 MDS patients (P=0.031) and the 14 ESA-resistant patients (P=0.027).

Further investigation confirmed that a low clonogenic progenitor number at baseline, but not the level of CD95 or CD95 ligand expression, was predictive of the response to APG101.

“This study provides a rationale for further clinical investigation of this potential new therapeutic option in patients with severely impaired erythropoiesis who are resistant to erythropoiesis-stimulating agents,” Dr Fontenay said.

Apogenix has conducted a phase 1 trial of APG101 in transfusion-dependent patients with low- to intermediate-1-risk MDS. The company expects the results of this trial will be available in the coming months.

Micrograph showing MDS

Researchers have found the fusion protein APG101 can rescue erythropoiesis in bone marrow samples from patients with lower-risk myelodysplastic syndromes (MDS).

Previous research suggested that CD95—a receptor that can induce apoptosis when triggered by the CD95 ligand—is overexpressed in two-thirds of patients with lower-risk MDS, and overexpression of CD95 is predictive of a lower response to erythropoiesis-stimulating agents (ESAs).

APG101, which consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG antibody, is designed to block the CD95 ligand.

The new study showed that APG101 can inhibit apoptosis in erythrocyte precursor cells and improve their overall proliferation rate. The drug increased the number of burst-forming unit-erythroid (BFU-E) progenitors in samples from MDS patients with low BFU-E numbers at baseline.

“APG101 added to cellular assays efficiently rescued the growth of erythroid progenitors in MDS patients harboring a profound defect of erythropoiesis, independent of the expression level of CD95 or CD95 ligand,” said Michaela Fontenay, MD, PhD, of the Institut Cochin in Paris, France.

Dr Fontenay and her colleagues described these results in Oncotarget. The research was funded by Apogenix, the company developing APG101.

By comparing bone marrow samples from MDS patients and healthy control subjects, the researchers found that CD95, but not CD95 ligand, was overexpressed in patients with lower-risk MDS.

Further analysis revealed that a patient’s CD95 expression level at diagnosis could predict response to an ESA. Specifically, CD95 overexpression was predictive of a lower response rate to ESAs in patients with low- or intermediate-1-risk MDS.

Next, the researchers tested bone marrow erythroid progenitors from 3 control subjects and 5 patients with MDS and found that CD95 expression increased during MDS erythroid progenitor amplification but remained lower in control cultures.

On day 5 of culture, the mean number of BFU-Es was significantly lower in MDS patient samples than in controls. And treatment with APG101 prompted a dose-dependent increase in BFU-E growth in MDS samples but not in controls.

When the researchers added APG101 (at 10 μg/mL) to the cultures over 7 days, they observed an improvement in the proliferation of erythroblasts but no significant effect on the kinetics of differentiation.

They also found that APG101 reduced apoptosis in immature precursors by 30% but had no effect on apoptosis in mature precursors.

Baseline BFU-E number affects response

The researchers then assessed the effects of APG101 in samples from 5 control subjects and 20 MDS patients with varying responses to ESAs and varying baseline levels of BFU-Es.

Fifteen of the MDS patients had a significantly lower number of baseline BFU-Es than controls (P=0.005), but 5 MDS patients had a mean number of BFU-Es that was comparable to controls (P=0.429). There was no significant difference in WHO classification or CD95 expression between the 2 groups of MDS patients (P=0.612).

However, 11 of the 15 patients with low erythropoiesis had received an ESA, and all of them were resistant to this treatment. In all, 15 of the MDS patients had received an ESA, and 14 were resistant to it (6 primary and 8 secondary).

The researchers found that APG101 induced a dose-dependent increase of BFU-Es in samples from the 15 MDS patients with low erythropoiesis but not in samples from the 5 patients with normal erythropoiesis or in the control samples (P<0.001).

The team said that a low BFU-E number at baseline was significantly associated with in vitro response to APG101 among the 20 MDS patients (P=0.031) and the 14 ESA-resistant patients (P=0.027).

Further investigation confirmed that a low clonogenic progenitor number at baseline, but not the level of CD95 or CD95 ligand expression, was predictive of the response to APG101.

“This study provides a rationale for further clinical investigation of this potential new therapeutic option in patients with severely impaired erythropoiesis who are resistant to erythropoiesis-stimulating agents,” Dr Fontenay said.

Apogenix has conducted a phase 1 trial of APG101 in transfusion-dependent patients with low- to intermediate-1-risk MDS. The company expects the results of this trial will be available in the coming months.

Click on the PDF icon at the top of this introduction to read the full article. 

Click on the PDF icon at the top of this introduction to read the full article. 

Click on the PDF icon at the top of this introduction to read the full article. 

 

 

Follicular lymphoma

 

Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.

Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.

However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.

Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.

The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).

The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).

The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).

Dosing, toxicity, and discontinuation

This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m²/day to 90 μg/m²/day.

The researchers found that neurologic events were dose-limiting, and 60 μg/m²/day was the MTD.

Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m²/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m²/day), 2 cases of grade 3 encephalopathy (90 μg/m²/day), and 1 case of grade 3 seizure and aphasia (90 μg/m²/day).

Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.

The researchers found that stepwise dosing (5 μg/m²/day to 60 μg/m²/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.

However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.

The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.

Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.

Response

Among patients treated at the MTD (60 μg/m²/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m²/day (2/4), 20% at 15 μg/m²/day (3/15), and 17% at 30 μg/m²/day (1/6).

Complete responses (CRs) occurred in 1 patient at the 15 μg/m²/day dose, 1 at the 30 μg/m²/day dose, 1 at the 90 μg/m²/day dose, and 8 at the 60 μg/m²/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m²/day dose.

Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.

The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).

Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.

“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”

 

 

Follicular lymphoma

 

Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.

Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.

However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.

Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.

The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).

The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).

The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).

Dosing, toxicity, and discontinuation

This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m²/day to 90 μg/m²/day.

The researchers found that neurologic events were dose-limiting, and 60 μg/m²/day was the MTD.

Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m²/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m²/day), 2 cases of grade 3 encephalopathy (90 μg/m²/day), and 1 case of grade 3 seizure and aphasia (90 μg/m²/day).

Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.

The researchers found that stepwise dosing (5 μg/m²/day to 60 μg/m²/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.

However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.

The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.

Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.

Response

Among patients treated at the MTD (60 μg/m²/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m²/day (2/4), 20% at 15 μg/m²/day (3/15), and 17% at 30 μg/m²/day (1/6).

Complete responses (CRs) occurred in 1 patient at the 15 μg/m²/day dose, 1 at the 30 μg/m²/day dose, 1 at the 90 μg/m²/day dose, and 8 at the 60 μg/m²/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m²/day dose.

Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.

The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).

Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.

“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”

 

 

Follicular lymphoma

 

Blinatumomab, a CD19/CD3 bispecific T-cell engager antibody construct, can produce durable responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to a phase 1 study.

Among patients who received the maximum-tolerated dose (MTD) of blinatumomab, the overall response rate (ORR) was nearly 70%, and the median duration of response was more than 400 days.

However, there was a high rate of neurologic events, particularly among patients who received higher doses of the drug.

Ralph Bargou, MD, of Wuerzburg University Hospital in Germany, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was supported by Amgen (and Micromet before its acquisition by Amgen), the companies developing blinatumomab.

The study enrolled 76 patients with relapsed/refractory NHL. Most patients (n=52) had indolent NHL. Subtypes included follicular lymphoma (FL, n=28), mantle cell lymphoma (MCL, n=24), diffuse large B-cell lymphoma (DLBCL, n=14), and “other” (n=10).

The “other” category included lymphoplasmacytic lymphoma (n=2), small lymphoplasmacytic lymphoma (n=1), immunocytoma (n=1), Waldenstrom’s macroglobulinemia (n=1), marginal zone NHL (n=1), marginal zone B-cell lymphoma (n=1), marginal zone lymphoma (n=1), chronic lymphocytic leukemia (n=1), and small lymphoplasmacytic lymphoma/chronic lymphocytic leukemia (n=1).

The patients’ median age was 65 (range, 20-80), and the median number of prior treatment regimens was 3 (range, 1-10).

Dosing, toxicity, and discontinuation

This phase 1, dose-escalation study had a 3 + 3 design. Blinatumomab was given over 4 or 8 weeks at 7 different dose levels, ranging from 0.5 μg/m²/day to 90 μg/m²/day.

The researchers found that neurologic events were dose-limiting, and 60 μg/m²/day was the MTD.

Five patients experienced dose-limiting toxicities, including a grade 2 mental disorder (15 μg/m²/day), a case of grade 4 metabolic acidosis due to grand mal seizure (30 μg/m²/day), 2 cases of grade 3 encephalopathy (90 μg/m²/day), and 1 case of grade 3 seizure and aphasia (90 μg/m²/day).

Forty-two patients received treatment in the formal dose-escalation phase. Thirty-four additional patients were recruited to evaluate the antilymphoma activity of blinatumomab and test strategies for mitigating neurologic events at the MTD.

The researchers found that stepwise dosing (5 μg/m²/day to 60 μg/m²/day) plus pentosan polysulfate SP54 (n=3) prompted no treatment discontinuations.

However, single-step (n=5) dosing led to 2 discontinuations, and double-step (n=24) dosing led to 7 discontinuations. All were due to neurologic events.

The most clinically relevant adverse events were neurologic in nature. The overall incidence of these events, regardless of causality, was 71%. The incidence of grade 3 neurologic events was 22%.

Twenty percent of patients experienced serious neurologic events, including encephalopathy (8%), aphasia (4%), and headache (3%). There were no grade 4 or 5 neurologic events.

Response

Among patients treated at the MTD (60 μg/m²/day), the ORR was 69% (24/35). The ORR was 50% at 90 μg/m²/day (2/4), 20% at 15 μg/m²/day (3/15), and 17% at 30 μg/m²/day (1/6).

Complete responses (CRs) occurred in 1 patient at the 15 μg/m²/day dose, 1 at the 30 μg/m²/day dose, 1 at the 90 μg/m²/day dose, and 8 at the 60 μg/m²/day dose. Unconfirmed CRs (CRus) occurred in 5 patients at the 60 μg/m²/day dose.

Among patients who received the MTD, the ORR was 80% in FL patients, 71% in MCL patients, 55% in DLBCL patients, and 50% in the “other” category. There were 6 CR/CRus among FL patients, 3 CR/CRus among MCL patients, and 4 CR/CRus among DLBCL patients.

The median duration of response for patients who received the MTD was 404 days (95% CI, 207 to 1129). The median duration of CR/CRu was 508 days (95% CI, 213 to not estimable). And the median duration of partial response was 185 days (95% CI, 28 to 754).

Nine patients were still in remission at the time of the analysis, and 12 patients had remissions lasting more than 1 year.

“Blinatumomab continues to demonstrate a long duration of response in heavily pretreated non-Hodgkin lymphoma patients,” Dr Bargou said. “Results of the expanded phase 1 experience suggest that blinatumomab has the potential to alter the clinical course of disease in patients with a variety of NHL subtypes.”

Pregnant woman

Photo by Nina Matthews

Results of a large study suggest that female survivors of childhood cancer may have more luck than their male peers when it comes to conceiving a child.

Both male and female childhood cancer survivors (CCSs) reported fewer pregnancies and live births than their healthy siblings.

However, chemotherapeutic agents appeared to have a much greater impact on the fertility of male CCSs than female CCSs.

Eric Chow, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues reported these findings in The Lancet Oncology.

Previous research has shown that fertility can be compromised by several types of chemotherapy, mainly alkylating drugs. However, little is known about the dose effects on pregnancy from newer drugs, such as ifosfamide and cisplatin, in CCSs.

With this in mind, Dr Chow and his colleagues analyzed data from the Childhood Cancer Survivor Study, which tracks subjects who were diagnosed with the most common types of childhood cancer before the age of 21 and treated at 27 institutions across the US and Canada between 1970 and 1999.

Patients had been diagnosed with leukemias, lymphomas, and neuroblastoma, as well as kidney, brain, soft tissue, and bone tumors. All had survived at least 5 years after diagnosis.

The researchers examined the impact of various doses of 14 commonly used chemotherapy drugs on pregnancy and live birth in 10,938 male and female CCSs, compared with 3949 siblings.

The team specifically focused on CCSs who were treated with chemotherapy and did not receive any radiotherapy to the pelvis or the brain.

The drugs the researchers evaluated were busulfan, carboplatin, carmustine, chlorambucil, chlormethine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, procarbazine, temozolomide, and thiotepa.

Outcomes

Multivariable analysis showed that CCSs were significantly less likely than their siblings to have or sire a pregnancy. For male CCSs, the hazard ratio (HR) was 0.63 (P<0.0001). For female CCSs, the HR was 0.87 (P<0.0001).

CCSs were also significantly less likely to have a live birth. For male CCSs, the HR was 0.63 (P<0.0001). For female CCSs, the HR was 0.82 (P<0.0001).

The researchers noted that, overall, female CCSs were less likely to conceive and have a child when compared to their siblings, but the effect was much smaller than that observed among the men.

In addition, the difference between CCSs and siblings was more pronounced for women who delayed pregnancy until they were 30 or older, possibly because chemotherapy exposure might accelerate the natural depletion of eggs and hasten menopause.

Impact of specific drugs

In male CCSs, the reduced likelihood of siring a pregnancy was associated with upper tertile doses of cyclophosphamide (HR=0.60, P<0.0001), ifosfamide (HR=0.42, P=0.0069), procarbazine (HR=0.30, P<0.0001), and cisplatin (HR=0.56, P=0.0023).

Cyclophosphamide-equivalent dose in male CCSs was significantly associated with a decreased likelihood of siring a pregnancy per 5000 mg/m² increments (HR=0.82, P<0.0001).

In female CCSs, the reduced likelihood of becoming pregnant was associated with busulfan—both at doses less than 450 mg/m² (HR=0.22, P=0.020) and at doses of 450 mg/m² or higher (HR=0.14, P=0.0051)—and with doses of lomustine at 411 mg/m² or greater (HR=0.41, P=0.046).

Cyclophosphamide-equivalent dose in female CCSs was associated with risk only at the highest doses in analyses categorized by quartile (upper quartile vs no exposure, HR=0.85, P=0.023).

Limitations and implications

The researchers noted that a limitation of this study is that it relied on self-reported pregnancy and live birth, and some pregnancies may go unrecognized.

And although the findings are consistent with others in the field, this study did not account for other factors such as marital or cohabitation status, the intention to conceive, or length of time attempting to conceive.

The researchers also noted that, although the total number of CCSs in this study is large, the number of patients who were exposed to individual drugs varied significantly. So while the overall conclusions of the study are consistent with previous studies, more research is needed to estimate the exact risk of some less commonly used drugs.

“We think these results will be encouraging for most women who were treated with chemotherapy in childhood,” Dr Chow said. “However, I think we, as pediatric oncologists, still need to do a better job discussing fertility and fertility preservation options with patients and families upfront before starting cancer treatment.”

“In particular, all boys diagnosed post-puberty should be encouraged to bank their sperm to maximize their reproductive options in the future. The current options for post-pubertal girls remain more complicated but include oocyte and embryo cryopreservation.”

Pregnant woman

Photo by Nina Matthews

Results of a large study suggest that female survivors of childhood cancer may have more luck than their male peers when it comes to conceiving a child.

Both male and female childhood cancer survivors (CCSs) reported fewer pregnancies and live births than their healthy siblings.

However, chemotherapeutic agents appeared to have a much greater impact on the fertility of male CCSs than female CCSs.

Eric Chow, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues reported these findings in The Lancet Oncology.

Previous research has shown that fertility can be compromised by several types of chemotherapy, mainly alkylating drugs. However, little is known about the dose effects on pregnancy from newer drugs, such as ifosfamide and cisplatin, in CCSs.

With this in mind, Dr Chow and his colleagues analyzed data from the Childhood Cancer Survivor Study, which tracks subjects who were diagnosed with the most common types of childhood cancer before the age of 21 and treated at 27 institutions across the US and Canada between 1970 and 1999.

Patients had been diagnosed with leukemias, lymphomas, and neuroblastoma, as well as kidney, brain, soft tissue, and bone tumors. All had survived at least 5 years after diagnosis.

The researchers examined the impact of various doses of 14 commonly used chemotherapy drugs on pregnancy and live birth in 10,938 male and female CCSs, compared with 3949 siblings.

The team specifically focused on CCSs who were treated with chemotherapy and did not receive any radiotherapy to the pelvis or the brain.

The drugs the researchers evaluated were busulfan, carboplatin, carmustine, chlorambucil, chlormethine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, procarbazine, temozolomide, and thiotepa.

Outcomes

Multivariable analysis showed that CCSs were significantly less likely than their siblings to have or sire a pregnancy. For male CCSs, the hazard ratio (HR) was 0.63 (P<0.0001). For female CCSs, the HR was 0.87 (P<0.0001).

CCSs were also significantly less likely to have a live birth. For male CCSs, the HR was 0.63 (P<0.0001). For female CCSs, the HR was 0.82 (P<0.0001).

The researchers noted that, overall, female CCSs were less likely to conceive and have a child when compared to their siblings, but the effect was much smaller than that observed among the men.

In addition, the difference between CCSs and siblings was more pronounced for women who delayed pregnancy until they were 30 or older, possibly because chemotherapy exposure might accelerate the natural depletion of eggs and hasten menopause.

Impact of specific drugs

In male CCSs, the reduced likelihood of siring a pregnancy was associated with upper tertile doses of cyclophosphamide (HR=0.60, P<0.0001), ifosfamide (HR=0.42, P=0.0069), procarbazine (HR=0.30, P<0.0001), and cisplatin (HR=0.56, P=0.0023).

Cyclophosphamide-equivalent dose in male CCSs was significantly associated with a decreased likelihood of siring a pregnancy per 5000 mg/m² increments (HR=0.82, P<0.0001).

In female CCSs, the reduced likelihood of becoming pregnant was associated with busulfan—both at doses less than 450 mg/m² (HR=0.22, P=0.020) and at doses of 450 mg/m² or higher (HR=0.14, P=0.0051)—and with doses of lomustine at 411 mg/m² or greater (HR=0.41, P=0.046).

Cyclophosphamide-equivalent dose in female CCSs was associated with risk only at the highest doses in analyses categorized by quartile (upper quartile vs no exposure, HR=0.85, P=0.023).

Limitations and implications

The researchers noted that a limitation of this study is that it relied on self-reported pregnancy and live birth, and some pregnancies may go unrecognized.

And although the findings are consistent with others in the field, this study did not account for other factors such as marital or cohabitation status, the intention to conceive, or length of time attempting to conceive.

The researchers also noted that, although the total number of CCSs in this study is large, the number of patients who were exposed to individual drugs varied significantly. So while the overall conclusions of the study are consistent with previous studies, more research is needed to estimate the exact risk of some less commonly used drugs.

“We think these results will be encouraging for most women who were treated with chemotherapy in childhood,” Dr Chow said. “However, I think we, as pediatric oncologists, still need to do a better job discussing fertility and fertility preservation options with patients and families upfront before starting cancer treatment.”

“In particular, all boys diagnosed post-puberty should be encouraged to bank their sperm to maximize their reproductive options in the future. The current options for post-pubertal girls remain more complicated but include oocyte and embryo cryopreservation.”

Pregnant woman

Photo by Nina Matthews

Results of a large study suggest that female survivors of childhood cancer may have more luck than their male peers when it comes to conceiving a child.

Both male and female childhood cancer survivors (CCSs) reported fewer pregnancies and live births than their healthy siblings.

However, chemotherapeutic agents appeared to have a much greater impact on the fertility of male CCSs than female CCSs.

Eric Chow, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues reported these findings in The Lancet Oncology.

Previous research has shown that fertility can be compromised by several types of chemotherapy, mainly alkylating drugs. However, little is known about the dose effects on pregnancy from newer drugs, such as ifosfamide and cisplatin, in CCSs.

With this in mind, Dr Chow and his colleagues analyzed data from the Childhood Cancer Survivor Study, which tracks subjects who were diagnosed with the most common types of childhood cancer before the age of 21 and treated at 27 institutions across the US and Canada between 1970 and 1999.

Patients had been diagnosed with leukemias, lymphomas, and neuroblastoma, as well as kidney, brain, soft tissue, and bone tumors. All had survived at least 5 years after diagnosis.

The researchers examined the impact of various doses of 14 commonly used chemotherapy drugs on pregnancy and live birth in 10,938 male and female CCSs, compared with 3949 siblings.

The team specifically focused on CCSs who were treated with chemotherapy and did not receive any radiotherapy to the pelvis or the brain.

The drugs the researchers evaluated were busulfan, carboplatin, carmustine, chlorambucil, chlormethine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, procarbazine, temozolomide, and thiotepa.

Outcomes

Multivariable analysis showed that CCSs were significantly less likely than their siblings to have or sire a pregnancy. For male CCSs, the hazard ratio (HR) was 0.63 (P<0.0001). For female CCSs, the HR was 0.87 (P<0.0001).

CCSs were also significantly less likely to have a live birth. For male CCSs, the HR was 0.63 (P<0.0001). For female CCSs, the HR was 0.82 (P<0.0001).

The researchers noted that, overall, female CCSs were less likely to conceive and have a child when compared to their siblings, but the effect was much smaller than that observed among the men.

In addition, the difference between CCSs and siblings was more pronounced for women who delayed pregnancy until they were 30 or older, possibly because chemotherapy exposure might accelerate the natural depletion of eggs and hasten menopause.

Impact of specific drugs

In male CCSs, the reduced likelihood of siring a pregnancy was associated with upper tertile doses of cyclophosphamide (HR=0.60, P<0.0001), ifosfamide (HR=0.42, P=0.0069), procarbazine (HR=0.30, P<0.0001), and cisplatin (HR=0.56, P=0.0023).

Cyclophosphamide-equivalent dose in male CCSs was significantly associated with a decreased likelihood of siring a pregnancy per 5000 mg/m² increments (HR=0.82, P<0.0001).

In female CCSs, the reduced likelihood of becoming pregnant was associated with busulfan—both at doses less than 450 mg/m² (HR=0.22, P=0.020) and at doses of 450 mg/m² or higher (HR=0.14, P=0.0051)—and with doses of lomustine at 411 mg/m² or greater (HR=0.41, P=0.046).

Cyclophosphamide-equivalent dose in female CCSs was associated with risk only at the highest doses in analyses categorized by quartile (upper quartile vs no exposure, HR=0.85, P=0.023).

Limitations and implications

The researchers noted that a limitation of this study is that it relied on self-reported pregnancy and live birth, and some pregnancies may go unrecognized.

And although the findings are consistent with others in the field, this study did not account for other factors such as marital or cohabitation status, the intention to conceive, or length of time attempting to conceive.

The researchers also noted that, although the total number of CCSs in this study is large, the number of patients who were exposed to individual drugs varied significantly. So while the overall conclusions of the study are consistent with previous studies, more research is needed to estimate the exact risk of some less commonly used drugs.

“We think these results will be encouraging for most women who were treated with chemotherapy in childhood,” Dr Chow said. “However, I think we, as pediatric oncologists, still need to do a better job discussing fertility and fertility preservation options with patients and families upfront before starting cancer treatment.”

“In particular, all boys diagnosed post-puberty should be encouraged to bank their sperm to maximize their reproductive options in the future. The current options for post-pubertal girls remain more complicated but include oocyte and embryo cryopreservation.”

Men install laminate flooring

while woman looks on

US government agencies have released a revised report on the health risks associated with formaldehyde in certain types of laminate flooring.

The new report corrects a previous error and reveals an increase in the estimated lifetime risk of cancers, including leukemias, for individuals who regularly breathe in formaldehyde from the flooring.

The report also suggests that irritation and breathing problems can result in anyone exposed to the flooring.

The report was compiled by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control and Prevention’s National Center for Environmental Health (NCEH).

About the report

On March 1, 2015, the CBS news program 60 Minutes reported that an American company, Lumber Liquidators®, was selling laminate wood flooring produced in China that released elevated levels of formaldehyde.

Based on this allegation, the US Consumer Product Safety Commission (CPSC) tested laminate flooring samples manufactured in China from 2012 to 2014 that were sold at Lumber Liquidators® stores. The CPSC then requested that the NCEH and ATSDR evaluate the test results for possible health effects.

The NCEH and ATSDR published a report detailing the possible health effects on February 10, 2016. But the report was pulled on February 19, 2016, after the agencies were informed that the report’s indoor air model incorporated an incorrect value for ceiling height.

As a result, the health risks were calculated using airborne concentration estimates about 3 times lower than they should have been.

Since the discovery of the error, the NCEH and ATSDR revised the value in the model, conducted a review of the revised results, and re-evaluated the possible health implications.

In addition, the revised report has been reviewed by outside experts and experts from the CPSC, the US Environmental Protection Agency, and the US Department of Housing and Urban Development.

Results 

The revised report concludes that irritation and breathing problems could occur in everyone exposed to formaldehyde in the tested flooring.

The previous report suggested such problems might only occur in sensitive groups (eg, children) and people with pre-existing health conditions (eg, asthma).

The new report also increased the estimated lifetime cancer risk from breathing the highest levels of formaldehyde from the affected flooring all day, every day for 2 years.

The previous estimate of lifetime cancer risk was 2 to 9 extra cases for every 100,000 people.

The new estimate is 6 to 30 extra cases per 100,000 people.

There is conflicting data regarding the types of cancers associated with formaldehyde exposure, but many studies have suggested that formaldehyde causes cancer of the nasopharynx, sinuses, and nasal cavity, as well as leukemia, particularly myeloid leukemia.

Recommendations

Although the revised report shows an increase in health risks associated with the flooring, the NCEH and ATSDR said their recommendations remain the same.

They recommend that people with the affected flooring:

• Reduce their exposure to formaldehyde in their homes by opening windows, running exhaust fans, avoiding use of other products containing formaldehyde, etc.
• See a doctor for ongoing health symptoms such as breathing problems or irritation of the eyes, nose, or throat
• Weigh the pros and cons of professional air testing
• Consult a professional before removing the flooring, as removing it may release more formaldehyde into the home.
  

Men install laminate flooring

while woman looks on

US government agencies have released a revised report on the health risks associated with formaldehyde in certain types of laminate flooring.

The new report corrects a previous error and reveals an increase in the estimated lifetime risk of cancers, including leukemias, for individuals who regularly breathe in formaldehyde from the flooring.

The report also suggests that irritation and breathing problems can result in anyone exposed to the flooring.

The report was compiled by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control and Prevention’s National Center for Environmental Health (NCEH).

About the report

On March 1, 2015, the CBS news program 60 Minutes reported that an American company, Lumber Liquidators®, was selling laminate wood flooring produced in China that released elevated levels of formaldehyde.

Based on this allegation, the US Consumer Product Safety Commission (CPSC) tested laminate flooring samples manufactured in China from 2012 to 2014 that were sold at Lumber Liquidators® stores. The CPSC then requested that the NCEH and ATSDR evaluate the test results for possible health effects.

The NCEH and ATSDR published a report detailing the possible health effects on February 10, 2016. But the report was pulled on February 19, 2016, after the agencies were informed that the report’s indoor air model incorporated an incorrect value for ceiling height.

As a result, the health risks were calculated using airborne concentration estimates about 3 times lower than they should have been.

Since the discovery of the error, the NCEH and ATSDR revised the value in the model, conducted a review of the revised results, and re-evaluated the possible health implications.

In addition, the revised report has been reviewed by outside experts and experts from the CPSC, the US Environmental Protection Agency, and the US Department of Housing and Urban Development.

Results 

The revised report concludes that irritation and breathing problems could occur in everyone exposed to formaldehyde in the tested flooring.

The previous report suggested such problems might only occur in sensitive groups (eg, children) and people with pre-existing health conditions (eg, asthma).

The new report also increased the estimated lifetime cancer risk from breathing the highest levels of formaldehyde from the affected flooring all day, every day for 2 years.

The previous estimate of lifetime cancer risk was 2 to 9 extra cases for every 100,000 people.

The new estimate is 6 to 30 extra cases per 100,000 people.

There is conflicting data regarding the types of cancers associated with formaldehyde exposure, but many studies have suggested that formaldehyde causes cancer of the nasopharynx, sinuses, and nasal cavity, as well as leukemia, particularly myeloid leukemia.

Recommendations

Although the revised report shows an increase in health risks associated with the flooring, the NCEH and ATSDR said their recommendations remain the same.

They recommend that people with the affected flooring:

• Reduce their exposure to formaldehyde in their homes by opening windows, running exhaust fans, avoiding use of other products containing formaldehyde, etc.
• See a doctor for ongoing health symptoms such as breathing problems or irritation of the eyes, nose, or throat
• Weigh the pros and cons of professional air testing
• Consult a professional before removing the flooring, as removing it may release more formaldehyde into the home.
  

Men install laminate flooring

while woman looks on

US government agencies have released a revised report on the health risks associated with formaldehyde in certain types of laminate flooring.

The new report corrects a previous error and reveals an increase in the estimated lifetime risk of cancers, including leukemias, for individuals who regularly breathe in formaldehyde from the flooring.

The report also suggests that irritation and breathing problems can result in anyone exposed to the flooring.

The report was compiled by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control and Prevention’s National Center for Environmental Health (NCEH).

About the report

On March 1, 2015, the CBS news program 60 Minutes reported that an American company, Lumber Liquidators®, was selling laminate wood flooring produced in China that released elevated levels of formaldehyde.

Based on this allegation, the US Consumer Product Safety Commission (CPSC) tested laminate flooring samples manufactured in China from 2012 to 2014 that were sold at Lumber Liquidators® stores. The CPSC then requested that the NCEH and ATSDR evaluate the test results for possible health effects.

The NCEH and ATSDR published a report detailing the possible health effects on February 10, 2016. But the report was pulled on February 19, 2016, after the agencies were informed that the report’s indoor air model incorporated an incorrect value for ceiling height.

As a result, the health risks were calculated using airborne concentration estimates about 3 times lower than they should have been.

Since the discovery of the error, the NCEH and ATSDR revised the value in the model, conducted a review of the revised results, and re-evaluated the possible health implications.

In addition, the revised report has been reviewed by outside experts and experts from the CPSC, the US Environmental Protection Agency, and the US Department of Housing and Urban Development.

Results 

The revised report concludes that irritation and breathing problems could occur in everyone exposed to formaldehyde in the tested flooring.

The previous report suggested such problems might only occur in sensitive groups (eg, children) and people with pre-existing health conditions (eg, asthma).

The new report also increased the estimated lifetime cancer risk from breathing the highest levels of formaldehyde from the affected flooring all day, every day for 2 years.

The previous estimate of lifetime cancer risk was 2 to 9 extra cases for every 100,000 people.

The new estimate is 6 to 30 extra cases per 100,000 people.

There is conflicting data regarding the types of cancers associated with formaldehyde exposure, but many studies have suggested that formaldehyde causes cancer of the nasopharynx, sinuses, and nasal cavity, as well as leukemia, particularly myeloid leukemia.

Recommendations

Although the revised report shows an increase in health risks associated with the flooring, the NCEH and ATSDR said their recommendations remain the same.

They recommend that people with the affected flooring:

• Reduce their exposure to formaldehyde in their homes by opening windows, running exhaust fans, avoiding use of other products containing formaldehyde, etc.
• See a doctor for ongoing health symptoms such as breathing problems or irritation of the eyes, nose, or throat
• Weigh the pros and cons of professional air testing
• Consult a professional before removing the flooring, as removing it may release more formaldehyde into the home.
  

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

In light of recently reported safety concerns, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has issued provisional advice for doctors and patients using idelalisib (Zydelig).

The EMA recently began reviewing the safety of idelalisib because of serious adverse events, most of which were infection-related, that were reported in 3 clinical trials investigating idelalisib in combination with other drugs.

These trials have since been stopped.

Now, the PRAC is making provisional recommendations to ensure idelalisib is used as safely as possible outside of clinical trials.

These recommendations will be forwarded to the European Commission, which will issue a provisional legally binding decision applicable in all European Union (EU) member states.

In the EU, idelalisib is approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

Idelalisib is also approved for use in combination with rituximab to treat adults with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients considered unsuitable for chemo-immunotherapy.

Recommendations

The PRAC is recommending that previously untreated CLL patients with 17p deletion or TP53 mutation do not begin treatment with idelalisib. In addition, doctors should re-evaluate each patient taking idelalisib as first-line treatment for CLL and only continue treatment if the benefits outweigh the risks.

Idelalisib can continue to be used in combination, only with rituximab, in CLL patients who have received at least 1 prior therapy and as monotherapy in patients with follicular lymphoma that is refractory to 2 lines of treatment.

Patients with any evidence of ongoing systemic infection should not be started on treatment with idelalisib.

And patients should be informed about the risk of serious infections with idelalisib.

All patients who do receive idelalisib should take antibiotics to prevent Pneumocystis jirovecii pneumonia, and they should be monitored for respiratory signs and symptoms. Regular clinical and laboratory monitoring for cytomegalovirus infection is also recommended.

Patients should have regular blood tests to detect neutropenia. In case a patient has moderate or severe neutropenia, treatment with idelalisib may have to be interrupted, in line with the updated summary of product characteristics.

The EMA said further details on these provisional measures will be provided in writing to healthcare professionals, and the product information will be updated accordingly.

Likewise, further information on the review of idelalisib will be provided as necessary and once the review is finished.

About the review

The EMA’s review of idelalisib started after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indication for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

At present, the PRAC is conducting the review. Once the PRAC is finished, its recommendations will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt a final opinion.

The European Commission will take this opinion into account and adopt a legally binding decision that is applicable in all EU member states.

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

In light of recently reported safety concerns, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has issued provisional advice for doctors and patients using idelalisib (Zydelig).

The EMA recently began reviewing the safety of idelalisib because of serious adverse events, most of which were infection-related, that were reported in 3 clinical trials investigating idelalisib in combination with other drugs.

These trials have since been stopped.

Now, the PRAC is making provisional recommendations to ensure idelalisib is used as safely as possible outside of clinical trials.

These recommendations will be forwarded to the European Commission, which will issue a provisional legally binding decision applicable in all European Union (EU) member states.

In the EU, idelalisib is approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

Idelalisib is also approved for use in combination with rituximab to treat adults with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients considered unsuitable for chemo-immunotherapy.

Recommendations

The PRAC is recommending that previously untreated CLL patients with 17p deletion or TP53 mutation do not begin treatment with idelalisib. In addition, doctors should re-evaluate each patient taking idelalisib as first-line treatment for CLL and only continue treatment if the benefits outweigh the risks.

Idelalisib can continue to be used in combination, only with rituximab, in CLL patients who have received at least 1 prior therapy and as monotherapy in patients with follicular lymphoma that is refractory to 2 lines of treatment.

Patients with any evidence of ongoing systemic infection should not be started on treatment with idelalisib.

And patients should be informed about the risk of serious infections with idelalisib.

All patients who do receive idelalisib should take antibiotics to prevent Pneumocystis jirovecii pneumonia, and they should be monitored for respiratory signs and symptoms. Regular clinical and laboratory monitoring for cytomegalovirus infection is also recommended.

Patients should have regular blood tests to detect neutropenia. In case a patient has moderate or severe neutropenia, treatment with idelalisib may have to be interrupted, in line with the updated summary of product characteristics.

The EMA said further details on these provisional measures will be provided in writing to healthcare professionals, and the product information will be updated accordingly.

Likewise, further information on the review of idelalisib will be provided as necessary and once the review is finished.

About the review

The EMA’s review of idelalisib started after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indication for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

At present, the PRAC is conducting the review. Once the PRAC is finished, its recommendations will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt a final opinion.

The European Commission will take this opinion into account and adopt a legally binding decision that is applicable in all EU member states.

 

 

Idelalisib (Zydelig)

Photo courtesy of

Gilead Sciences, Inc.

 

In light of recently reported safety concerns, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has issued provisional advice for doctors and patients using idelalisib (Zydelig).

The EMA recently began reviewing the safety of idelalisib because of serious adverse events, most of which were infection-related, that were reported in 3 clinical trials investigating idelalisib in combination with other drugs.

These trials have since been stopped.

Now, the PRAC is making provisional recommendations to ensure idelalisib is used as safely as possible outside of clinical trials.

These recommendations will be forwarded to the European Commission, which will issue a provisional legally binding decision applicable in all European Union (EU) member states.

In the EU, idelalisib is approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.

Idelalisib is also approved for use in combination with rituximab to treat adults with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients considered unsuitable for chemo-immunotherapy.

Recommendations

The PRAC is recommending that previously untreated CLL patients with 17p deletion or TP53 mutation do not begin treatment with idelalisib. In addition, doctors should re-evaluate each patient taking idelalisib as first-line treatment for CLL and only continue treatment if the benefits outweigh the risks.

Idelalisib can continue to be used in combination, only with rituximab, in CLL patients who have received at least 1 prior therapy and as monotherapy in patients with follicular lymphoma that is refractory to 2 lines of treatment.

Patients with any evidence of ongoing systemic infection should not be started on treatment with idelalisib.

And patients should be informed about the risk of serious infections with idelalisib.

All patients who do receive idelalisib should take antibiotics to prevent Pneumocystis jirovecii pneumonia, and they should be monitored for respiratory signs and symptoms. Regular clinical and laboratory monitoring for cytomegalovirus infection is also recommended.

Patients should have regular blood tests to detect neutropenia. In case a patient has moderate or severe neutropenia, treatment with idelalisib may have to be interrupted, in line with the updated summary of product characteristics.

The EMA said further details on these provisional measures will be provided in writing to healthcare professionals, and the product information will be updated accordingly.

Likewise, further information on the review of idelalisib will be provided as necessary and once the review is finished.

About the review

The EMA’s review of idelalisib started after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).

Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.

The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indication for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.

The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.

At present, the PRAC is conducting the review. Once the PRAC is finished, its recommendations will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt a final opinion.

The European Commission will take this opinion into account and adopt a legally binding decision that is applicable in all EU member states.

Micrograph showing MDS

Results of a phase 3 trial suggest the small-molecule inhibitor rigosertib may improve overall survival (OS) in some patients with higher-risk myelodysplastic syndromes (HR-MDS).

Overall, researchers found no significant difference in OS between patients who received rigosertib and those who received best supportive care (BSC).

However, the data indicate that rigosertib can confer a survival benefit in certain subgroups of HR-MDS patients.

The results of this trial, known as ONTIME, were published in The Lancet Oncology. The trial was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.

The trial enrolled 299 HR-MDS patients. They had refractory anemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia based on local site assessment. They had all failed treatment with a hypomethylating agent (HMA) in the past 2 years.

The patients were randomized (2:1) to receive rigosertib at 1800 mg per 24 hours via 72-hour continuous intravenous (IV) infusion, administered every other week (n=199), or BSC with or without low-dose cytarabine (n=100).

At a median follow-up of 19.5 months, there was no significant difference in OS between the treatment arms. The median OS was 8.2 months in the rigosertib arm and 5.9 months in the BSC arm. The hazard ratio (HR) was 0.87 (P=0.33).

However, the researchers said that subgroup analyses suggested rigosertib may provide a survival benefit over BSC in some HR-MDS patients. This includes:

• Patients younger than 75 years of age (HR=0.55, P=0.0010)
• Patients who received HMA therapy for 9 months or fewer (HR=0.54, P=0.0016)
• Patients with primary, rather than secondary, HMA failure (HR=0.72, P=0.060)
• Patients who were classified as “very high risk” according to the Revised International Prognostic Scoring System (HR=0.61, P=0.015)
• Patients with monosomy 7 (HR=0.26, P=0.0041)
• Patients with trisomy 8 (HR=0.28, P=0.0083).

The most common grade 3 or higher adverse events—in the rigosertib and BSC arms, respectively—were anemia (18% vs 8%), thrombocytopenia (19% vs 7%), neutropenia (17% vs 8%), febrile neutropenia (12% vs 11%), and pneumonia (12% vs 11%).

Twenty-two percent of patients in the rigosertib arm and 33% in the BSC arm died due to adverse events. Three deaths were attributed to rigosertib.

“Rigosertib was well-tolerated in patients with a high unmet medical need who have no approved therapeutic options,” said study author Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“We are impressed by the trend to notable efficacy in well-defined, well-balanced subgroups of HR-MDS patients with very poor prognosis. Based on these findings, we have designed the new phase 3 INSPIRE study with IV rigosertib, which is currently enrolling patients.”

INSPIRE is a randomized, controlled study designed to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first 9 months of HMA treatment initiation.

The trial is expected to enroll approximately 225 patients, who will be randomized at a 2:1 ratio into 2 treatment arms: IV rigosertib plus BSC versus physician’s choice plus BSC. The primary endpoint is OS. Full details on the trial can be found on clinicaltrials.gov (NCT02562443).

Micrograph showing MDS

Results of a phase 3 trial suggest the small-molecule inhibitor rigosertib may improve overall survival (OS) in some patients with higher-risk myelodysplastic syndromes (HR-MDS).

Overall, researchers found no significant difference in OS between patients who received rigosertib and those who received best supportive care (BSC).

However, the data indicate that rigosertib can confer a survival benefit in certain subgroups of HR-MDS patients.

The results of this trial, known as ONTIME, were published in The Lancet Oncology. The trial was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.

The trial enrolled 299 HR-MDS patients. They had refractory anemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia based on local site assessment. They had all failed treatment with a hypomethylating agent (HMA) in the past 2 years.

The patients were randomized (2:1) to receive rigosertib at 1800 mg per 24 hours via 72-hour continuous intravenous (IV) infusion, administered every other week (n=199), or BSC with or without low-dose cytarabine (n=100).

At a median follow-up of 19.5 months, there was no significant difference in OS between the treatment arms. The median OS was 8.2 months in the rigosertib arm and 5.9 months in the BSC arm. The hazard ratio (HR) was 0.87 (P=0.33).

However, the researchers said that subgroup analyses suggested rigosertib may provide a survival benefit over BSC in some HR-MDS patients. This includes:

• Patients younger than 75 years of age (HR=0.55, P=0.0010)
• Patients who received HMA therapy for 9 months or fewer (HR=0.54, P=0.0016)
• Patients with primary, rather than secondary, HMA failure (HR=0.72, P=0.060)
• Patients who were classified as “very high risk” according to the Revised International Prognostic Scoring System (HR=0.61, P=0.015)
• Patients with monosomy 7 (HR=0.26, P=0.0041)
• Patients with trisomy 8 (HR=0.28, P=0.0083).

The most common grade 3 or higher adverse events—in the rigosertib and BSC arms, respectively—were anemia (18% vs 8%), thrombocytopenia (19% vs 7%), neutropenia (17% vs 8%), febrile neutropenia (12% vs 11%), and pneumonia (12% vs 11%).

Twenty-two percent of patients in the rigosertib arm and 33% in the BSC arm died due to adverse events. Three deaths were attributed to rigosertib.

“Rigosertib was well-tolerated in patients with a high unmet medical need who have no approved therapeutic options,” said study author Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“We are impressed by the trend to notable efficacy in well-defined, well-balanced subgroups of HR-MDS patients with very poor prognosis. Based on these findings, we have designed the new phase 3 INSPIRE study with IV rigosertib, which is currently enrolling patients.”

INSPIRE is a randomized, controlled study designed to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first 9 months of HMA treatment initiation.

The trial is expected to enroll approximately 225 patients, who will be randomized at a 2:1 ratio into 2 treatment arms: IV rigosertib plus BSC versus physician’s choice plus BSC. The primary endpoint is OS. Full details on the trial can be found on clinicaltrials.gov (NCT02562443).

Micrograph showing MDS

Results of a phase 3 trial suggest the small-molecule inhibitor rigosertib may improve overall survival (OS) in some patients with higher-risk myelodysplastic syndromes (HR-MDS).

Overall, researchers found no significant difference in OS between patients who received rigosertib and those who received best supportive care (BSC).

However, the data indicate that rigosertib can confer a survival benefit in certain subgroups of HR-MDS patients.

The results of this trial, known as ONTIME, were published in The Lancet Oncology. The trial was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.

The trial enrolled 299 HR-MDS patients. They had refractory anemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia based on local site assessment. They had all failed treatment with a hypomethylating agent (HMA) in the past 2 years.

The patients were randomized (2:1) to receive rigosertib at 1800 mg per 24 hours via 72-hour continuous intravenous (IV) infusion, administered every other week (n=199), or BSC with or without low-dose cytarabine (n=100).

At a median follow-up of 19.5 months, there was no significant difference in OS between the treatment arms. The median OS was 8.2 months in the rigosertib arm and 5.9 months in the BSC arm. The hazard ratio (HR) was 0.87 (P=0.33).

However, the researchers said that subgroup analyses suggested rigosertib may provide a survival benefit over BSC in some HR-MDS patients. This includes:

• Patients younger than 75 years of age (HR=0.55, P=0.0010)
• Patients who received HMA therapy for 9 months or fewer (HR=0.54, P=0.0016)
• Patients with primary, rather than secondary, HMA failure (HR=0.72, P=0.060)
• Patients who were classified as “very high risk” according to the Revised International Prognostic Scoring System (HR=0.61, P=0.015)
• Patients with monosomy 7 (HR=0.26, P=0.0041)
• Patients with trisomy 8 (HR=0.28, P=0.0083).

The most common grade 3 or higher adverse events—in the rigosertib and BSC arms, respectively—were anemia (18% vs 8%), thrombocytopenia (19% vs 7%), neutropenia (17% vs 8%), febrile neutropenia (12% vs 11%), and pneumonia (12% vs 11%).

Twenty-two percent of patients in the rigosertib arm and 33% in the BSC arm died due to adverse events. Three deaths were attributed to rigosertib.

“Rigosertib was well-tolerated in patients with a high unmet medical need who have no approved therapeutic options,” said study author Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“We are impressed by the trend to notable efficacy in well-defined, well-balanced subgroups of HR-MDS patients with very poor prognosis. Based on these findings, we have designed the new phase 3 INSPIRE study with IV rigosertib, which is currently enrolling patients.”

INSPIRE is a randomized, controlled study designed to assess the efficacy and safety of IV rigosertib in HR-MDS patients under 80 years of age who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first 9 months of HMA treatment initiation.

The trial is expected to enroll approximately 225 patients, who will be randomized at a 2:1 ratio into 2 treatment arms: IV rigosertib plus BSC versus physician’s choice plus BSC. The primary endpoint is OS. Full details on the trial can be found on clinicaltrials.gov (NCT02562443).