Leukemia, Myelodysplasia, Transplantation

 

 

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).

Lab mouse

Preclinical research indicates that a novel inhibitor can overcome resistance-conferring FLT3 mutations in acute myeloid leukemia (AML).

The MERTK/FLT3 inhibitor MRX-2843 induced apoptosis and inhibited colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD.

MRX-2843 also improved survival in mouse models of AML, including cases where tumors were resistant to the FLT3 inhibitor quizartinib.

Douglas Graham, MD, PhD, of the University of Colorado in Aurora, and his colleagues conducted this research and reported the results in JCI Insight.

The researchers previously showed that the receptor tyrosine kinase MERTK is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis.

With the current study, they showed that MRX-2843 abrogates activation of MERTK, FLT3, and their downstream effectors. And this translates to antileukemic activity in vitro and in vivo.

MRX-2843 inhibited MERTK signaling, induced cell death, and abolished oncogenic phenotypes in AML cells. The drug also exhibited therapeutic activity in a MERTK-dependent xenograft model.

MRX-2843 was able to stop the activation of FLT3 and its signaling pathways almost completely. The researchers said this suggests the drug has somewhat higher cellular potency against FLT3 relative to MERTK.

In mouse models of FLT3-ITD AML, MRX-2843 significantly prolonged survival when compared to vehicle control.

The researchers also said MRX-2843 selectively inhibited colony formation in primary AML patient samples. Primary human MERTK-expressing leukemic blasts, with or without FLT3-ITD mutations, proved sensitive to treatment with MRX-2843.

In addition, MRX-2843 increased survival and decreased peripheral disease burden in patient-derived xenograft models of AML—both MERTK⁺FLT3-WT and MERTK⁺FLT3-ITD models.

Finally, the researchers found that MRX-2843 was active against quizartinib-resistant FLT3-mutant proteins, induced apoptosis and inhibited colony formation in quizartinib-resistant FLT3-ITD cell lines, and prolonged survival in quizartinib-resistant FLT3-ITD xenograft models.

Lab mouse

Preclinical research indicates that a novel inhibitor can overcome resistance-conferring FLT3 mutations in acute myeloid leukemia (AML).

The MERTK/FLT3 inhibitor MRX-2843 induced apoptosis and inhibited colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD.

MRX-2843 also improved survival in mouse models of AML, including cases where tumors were resistant to the FLT3 inhibitor quizartinib.

Douglas Graham, MD, PhD, of the University of Colorado in Aurora, and his colleagues conducted this research and reported the results in JCI Insight.

The researchers previously showed that the receptor tyrosine kinase MERTK is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis.

With the current study, they showed that MRX-2843 abrogates activation of MERTK, FLT3, and their downstream effectors. And this translates to antileukemic activity in vitro and in vivo.

MRX-2843 inhibited MERTK signaling, induced cell death, and abolished oncogenic phenotypes in AML cells. The drug also exhibited therapeutic activity in a MERTK-dependent xenograft model.

MRX-2843 was able to stop the activation of FLT3 and its signaling pathways almost completely. The researchers said this suggests the drug has somewhat higher cellular potency against FLT3 relative to MERTK.

In mouse models of FLT3-ITD AML, MRX-2843 significantly prolonged survival when compared to vehicle control.

The researchers also said MRX-2843 selectively inhibited colony formation in primary AML patient samples. Primary human MERTK-expressing leukemic blasts, with or without FLT3-ITD mutations, proved sensitive to treatment with MRX-2843.

In addition, MRX-2843 increased survival and decreased peripheral disease burden in patient-derived xenograft models of AML—both MERTK⁺FLT3-WT and MERTK⁺FLT3-ITD models.

Finally, the researchers found that MRX-2843 was active against quizartinib-resistant FLT3-mutant proteins, induced apoptosis and inhibited colony formation in quizartinib-resistant FLT3-ITD cell lines, and prolonged survival in quizartinib-resistant FLT3-ITD xenograft models.

Lab mouse

Preclinical research indicates that a novel inhibitor can overcome resistance-conferring FLT3 mutations in acute myeloid leukemia (AML).

The MERTK/FLT3 inhibitor MRX-2843 induced apoptosis and inhibited colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD.

MRX-2843 also improved survival in mouse models of AML, including cases where tumors were resistant to the FLT3 inhibitor quizartinib.

Douglas Graham, MD, PhD, of the University of Colorado in Aurora, and his colleagues conducted this research and reported the results in JCI Insight.

The researchers previously showed that the receptor tyrosine kinase MERTK is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis.

With the current study, they showed that MRX-2843 abrogates activation of MERTK, FLT3, and their downstream effectors. And this translates to antileukemic activity in vitro and in vivo.

MRX-2843 inhibited MERTK signaling, induced cell death, and abolished oncogenic phenotypes in AML cells. The drug also exhibited therapeutic activity in a MERTK-dependent xenograft model.

MRX-2843 was able to stop the activation of FLT3 and its signaling pathways almost completely. The researchers said this suggests the drug has somewhat higher cellular potency against FLT3 relative to MERTK.

In mouse models of FLT3-ITD AML, MRX-2843 significantly prolonged survival when compared to vehicle control.

The researchers also said MRX-2843 selectively inhibited colony formation in primary AML patient samples. Primary human MERTK-expressing leukemic blasts, with or without FLT3-ITD mutations, proved sensitive to treatment with MRX-2843.

In addition, MRX-2843 increased survival and decreased peripheral disease burden in patient-derived xenograft models of AML—both MERTK⁺FLT3-WT and MERTK⁺FLT3-ITD models.

Finally, the researchers found that MRX-2843 was active against quizartinib-resistant FLT3-mutant proteins, induced apoptosis and inhibited colony formation in quizartinib-resistant FLT3-ITD cell lines, and prolonged survival in quizartinib-resistant FLT3-ITD xenograft models.

Cancer patient

receiving treatment

Photo by Rhoda Baer

An analysis of nearly 20 million cancer survivors showed that almost 29% had financial burdens as a result of their cancer diagnosis and/or treatment.

In other words, they borrowed money, declared bankruptcy, worried about paying large medical bills, were unable to cover the cost of medical visits, or made other financial sacrifices.

Furthermore, such hardships could have lasting effects on a cancer survivor’s quality of life (QOL).

Hrishikesh Kale and Norman Carroll, PhD, both of Virginia Commonwealth University School of Pharmacy in Richmond, reported these findings in Cancer.

The pair analyzed 2011 Medical Expenditure Panel Survey data on 19.6 million cancer survivors, assessing financial burden and QOL.

Subjects were considered to have financial burden if they reported 1 of the following problems: borrowed money/declared bankruptcy, worried about paying large medical bills, unable to cover the cost of medical care visits, or other financial sacrifices.

Nearly 29% of the cancer survivors reported at least 1 financial problem resulting from cancer diagnosis, treatment, or lasting effects of that treatment.

Of all the cancer survivors in the analysis, 20.9% worried about paying large medical bills, 11.5% were unable to cover the cost of medical care visits, 7.6% reported borrowing money or going into debt, 1.4% declared bankruptcy, and 8.6% reported other financial sacrifices.

Cancer survivors who faced such financial difficulties had lower physical and mental health-related QOL, higher risk for depressed mood and psychological distress, and were more likely to worry about cancer recurrence, when compared with cancer survivors who did not face financial problems.

In addition, as the number of financial problems reported by cancer survivors increased, their QOL continued to decrease. And their risk for depressed mood, psychological distress, and worries about cancer recurrence continued to increase.

“Our results suggest that policies and practices that minimize cancer patients’ out-of-pocket costs can improve survivors’ health-related quality of life and psychological health,” Dr Carroll said.

“Reducing the financial burden of cancer care requires integrated efforts, and the study findings are useful for survivorship care programs, oncologists, payers, pharmaceutical companies, and patients and their family members.”

Cancer patient

receiving treatment

Photo by Rhoda Baer

An analysis of nearly 20 million cancer survivors showed that almost 29% had financial burdens as a result of their cancer diagnosis and/or treatment.

In other words, they borrowed money, declared bankruptcy, worried about paying large medical bills, were unable to cover the cost of medical visits, or made other financial sacrifices.

Furthermore, such hardships could have lasting effects on a cancer survivor’s quality of life (QOL).

Hrishikesh Kale and Norman Carroll, PhD, both of Virginia Commonwealth University School of Pharmacy in Richmond, reported these findings in Cancer.

The pair analyzed 2011 Medical Expenditure Panel Survey data on 19.6 million cancer survivors, assessing financial burden and QOL.

Subjects were considered to have financial burden if they reported 1 of the following problems: borrowed money/declared bankruptcy, worried about paying large medical bills, unable to cover the cost of medical care visits, or other financial sacrifices.

Nearly 29% of the cancer survivors reported at least 1 financial problem resulting from cancer diagnosis, treatment, or lasting effects of that treatment.

Of all the cancer survivors in the analysis, 20.9% worried about paying large medical bills, 11.5% were unable to cover the cost of medical care visits, 7.6% reported borrowing money or going into debt, 1.4% declared bankruptcy, and 8.6% reported other financial sacrifices.

Cancer survivors who faced such financial difficulties had lower physical and mental health-related QOL, higher risk for depressed mood and psychological distress, and were more likely to worry about cancer recurrence, when compared with cancer survivors who did not face financial problems.

In addition, as the number of financial problems reported by cancer survivors increased, their QOL continued to decrease. And their risk for depressed mood, psychological distress, and worries about cancer recurrence continued to increase.

“Our results suggest that policies and practices that minimize cancer patients’ out-of-pocket costs can improve survivors’ health-related quality of life and psychological health,” Dr Carroll said.

“Reducing the financial burden of cancer care requires integrated efforts, and the study findings are useful for survivorship care programs, oncologists, payers, pharmaceutical companies, and patients and their family members.”

Cancer patient

receiving treatment

Photo by Rhoda Baer

An analysis of nearly 20 million cancer survivors showed that almost 29% had financial burdens as a result of their cancer diagnosis and/or treatment.

In other words, they borrowed money, declared bankruptcy, worried about paying large medical bills, were unable to cover the cost of medical visits, or made other financial sacrifices.

Furthermore, such hardships could have lasting effects on a cancer survivor’s quality of life (QOL).

Hrishikesh Kale and Norman Carroll, PhD, both of Virginia Commonwealth University School of Pharmacy in Richmond, reported these findings in Cancer.

The pair analyzed 2011 Medical Expenditure Panel Survey data on 19.6 million cancer survivors, assessing financial burden and QOL.

Subjects were considered to have financial burden if they reported 1 of the following problems: borrowed money/declared bankruptcy, worried about paying large medical bills, unable to cover the cost of medical care visits, or other financial sacrifices.

Nearly 29% of the cancer survivors reported at least 1 financial problem resulting from cancer diagnosis, treatment, or lasting effects of that treatment.

Of all the cancer survivors in the analysis, 20.9% worried about paying large medical bills, 11.5% were unable to cover the cost of medical care visits, 7.6% reported borrowing money or going into debt, 1.4% declared bankruptcy, and 8.6% reported other financial sacrifices.

Cancer survivors who faced such financial difficulties had lower physical and mental health-related QOL, higher risk for depressed mood and psychological distress, and were more likely to worry about cancer recurrence, when compared with cancer survivors who did not face financial problems.

In addition, as the number of financial problems reported by cancer survivors increased, their QOL continued to decrease. And their risk for depressed mood, psychological distress, and worries about cancer recurrence continued to increase.

“Our results suggest that policies and practices that minimize cancer patients’ out-of-pocket costs can improve survivors’ health-related quality of life and psychological health,” Dr Carroll said.

“Reducing the financial burden of cancer care requires integrated efforts, and the study findings are useful for survivorship care programs, oncologists, payers, pharmaceutical companies, and patients and their family members.”

Mutations in the RPS15 gene occurred in 8 of 41 patients with relapsing chronic lymphocytic leukemia (CLL), and the mutations were present before treatment in 7 of the 8, a possible indication that the aberrations are early genetic events in aggressive CLL pathobiology.

RPS15 mutations may lead to defective p53 stability and increased degradation, representing a potential novel mechanism in CLL pathobiology. The findings suggest “RPS15-mutant cases should be treated with alternative regimens that act independently of the p53 pathway,” wrote Dr. Viktor Ljungström of the department of immunology, genetics, and pathology, Uppsala (Sweden) University, and colleagues (Blood 2016 Feb 25. doi: 10.1182/blood-2015-10-674572).

©SilverV/thinkstockphotos.com

In their study, the researchers performed whole exome sequencing of 110 samples collected before and after treatment from 41 patients with aggressive CLL that relapsed after a median of 2 years; 7 patients had mutations in RPS15 before treatment, and 8 had RPS15 mutations after treatment. The findings suggest that standard therapy with fludarabine, cyclophosphamide, and rituximab was not intrinsically mutagenic.

High frequencies of mutations were linked to poor outcome in both pretreated and relapse samples. These mutations included NOTCH1, TP53, ATM, SF3B1, MGA, and BIRC3. At least one mutation was seen before treatment in 26 of the 41 patients, and that rate rose to 33 of 41 patients at relapse. Two or more mutations were noted before treatment in 12 of 41 patients, and that rose to 15 of 41 at relapse.

In response to their findings, the researchers next performed targeted resequencing of the RPS15 hot spot (exon 4) in an extended series of 790 patients with CLL, intentionally enriched with 605 cases with adverse prognostic profiles. They found an additional 36 mutations in RPS15 (36/605, 6%). In contrast, none of the 185 patients with more favorable prognostic, IGHV-mutated CLL carried RPS15 mutations. RPS15-mutant patients without concomitant TP53 aberrations had an overall survival similar to other aggressive CLL subgroups, but none of the patients with both mutations survived at 10 years, compared with 59% of patients with wild-type RPS15 and wild-type TP53, “pointing to a dismal prognosis for RPS15-mutated CLL,” they wrote.

They also analyzed 30 cases with Richter syndrome (CLL transformed into diffuse large B-cell lymphoma), and only a single case was found to carry an RPS15 mutation, and the mutation was also observed in the preceding CLL phase. This finding indicates that RPS15 mutation probably does not underlie the transformation of CLL to Richter syndrome, according to the researchers.

Dr. Ljungström and coauthors reported having no relevant financial disclosures.

Mutations in the RPS15 gene occurred in 8 of 41 patients with relapsing chronic lymphocytic leukemia (CLL), and the mutations were present before treatment in 7 of the 8, a possible indication that the aberrations are early genetic events in aggressive CLL pathobiology.

RPS15 mutations may lead to defective p53 stability and increased degradation, representing a potential novel mechanism in CLL pathobiology. The findings suggest “RPS15-mutant cases should be treated with alternative regimens that act independently of the p53 pathway,” wrote Dr. Viktor Ljungström of the department of immunology, genetics, and pathology, Uppsala (Sweden) University, and colleagues (Blood 2016 Feb 25. doi: 10.1182/blood-2015-10-674572).

©SilverV/thinkstockphotos.com

In their study, the researchers performed whole exome sequencing of 110 samples collected before and after treatment from 41 patients with aggressive CLL that relapsed after a median of 2 years; 7 patients had mutations in RPS15 before treatment, and 8 had RPS15 mutations after treatment. The findings suggest that standard therapy with fludarabine, cyclophosphamide, and rituximab was not intrinsically mutagenic.

High frequencies of mutations were linked to poor outcome in both pretreated and relapse samples. These mutations included NOTCH1, TP53, ATM, SF3B1, MGA, and BIRC3. At least one mutation was seen before treatment in 26 of the 41 patients, and that rate rose to 33 of 41 patients at relapse. Two or more mutations were noted before treatment in 12 of 41 patients, and that rose to 15 of 41 at relapse.

In response to their findings, the researchers next performed targeted resequencing of the RPS15 hot spot (exon 4) in an extended series of 790 patients with CLL, intentionally enriched with 605 cases with adverse prognostic profiles. They found an additional 36 mutations in RPS15 (36/605, 6%). In contrast, none of the 185 patients with more favorable prognostic, IGHV-mutated CLL carried RPS15 mutations. RPS15-mutant patients without concomitant TP53 aberrations had an overall survival similar to other aggressive CLL subgroups, but none of the patients with both mutations survived at 10 years, compared with 59% of patients with wild-type RPS15 and wild-type TP53, “pointing to a dismal prognosis for RPS15-mutated CLL,” they wrote.

They also analyzed 30 cases with Richter syndrome (CLL transformed into diffuse large B-cell lymphoma), and only a single case was found to carry an RPS15 mutation, and the mutation was also observed in the preceding CLL phase. This finding indicates that RPS15 mutation probably does not underlie the transformation of CLL to Richter syndrome, according to the researchers.

Dr. Ljungström and coauthors reported having no relevant financial disclosures.

Mutations in the RPS15 gene occurred in 8 of 41 patients with relapsing chronic lymphocytic leukemia (CLL), and the mutations were present before treatment in 7 of the 8, a possible indication that the aberrations are early genetic events in aggressive CLL pathobiology.

RPS15 mutations may lead to defective p53 stability and increased degradation, representing a potential novel mechanism in CLL pathobiology. The findings suggest “RPS15-mutant cases should be treated with alternative regimens that act independently of the p53 pathway,” wrote Dr. Viktor Ljungström of the department of immunology, genetics, and pathology, Uppsala (Sweden) University, and colleagues (Blood 2016 Feb 25. doi: 10.1182/blood-2015-10-674572).

©SilverV/thinkstockphotos.com

In their study, the researchers performed whole exome sequencing of 110 samples collected before and after treatment from 41 patients with aggressive CLL that relapsed after a median of 2 years; 7 patients had mutations in RPS15 before treatment, and 8 had RPS15 mutations after treatment. The findings suggest that standard therapy with fludarabine, cyclophosphamide, and rituximab was not intrinsically mutagenic.

High frequencies of mutations were linked to poor outcome in both pretreated and relapse samples. These mutations included NOTCH1, TP53, ATM, SF3B1, MGA, and BIRC3. At least one mutation was seen before treatment in 26 of the 41 patients, and that rate rose to 33 of 41 patients at relapse. Two or more mutations were noted before treatment in 12 of 41 patients, and that rose to 15 of 41 at relapse.

In response to their findings, the researchers next performed targeted resequencing of the RPS15 hot spot (exon 4) in an extended series of 790 patients with CLL, intentionally enriched with 605 cases with adverse prognostic profiles. They found an additional 36 mutations in RPS15 (36/605, 6%). In contrast, none of the 185 patients with more favorable prognostic, IGHV-mutated CLL carried RPS15 mutations. RPS15-mutant patients without concomitant TP53 aberrations had an overall survival similar to other aggressive CLL subgroups, but none of the patients with both mutations survived at 10 years, compared with 59% of patients with wild-type RPS15 and wild-type TP53, “pointing to a dismal prognosis for RPS15-mutated CLL,” they wrote.

They also analyzed 30 cases with Richter syndrome (CLL transformed into diffuse large B-cell lymphoma), and only a single case was found to carry an RPS15 mutation, and the mutation was also observed in the preceding CLL phase. This finding indicates that RPS15 mutation probably does not underlie the transformation of CLL to Richter syndrome, according to the researchers.

Dr. Ljungström and coauthors reported having no relevant financial disclosures.