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MSC product may treat refractory aGVHD

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MSC product may treat refractory aGVHD

Mesenchymal stem cells

HONOLULU—A mesenchymal stem cell (MSC) product has shown promise for treating children with steroid-refractory acute graft-versus-host disease (aGVHD), according to researchers.

The product, remestemcel-L (MSC-100-IV, formerly Prochymal), produced an overall response rate of 65% by 28 days after treatment.

And patients who responded to remestemcel-L had significantly better survival at day 100 than patients who did not respond.

Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina, presented these data at the 2016 BMT Tandem Meetings (abstract 54). The study was sponsored by Mesoblast, the company developing remestemcel-L.

“There is a critical and urgent need for an effective and well-tolerated treatment for the very ill children who develop [GVHD] after a bone marrow transplant,” Dr Kurtzberg said. “While, historically, there is a high mortality rate associated with this complication, we are now seeing the majority of children who receive Mesoblast’s cell therapy respond and survive.”

For this study, Dr Kurtzberg and her colleagues assessed 241 children treated in Mesoblast’s Expanded Access Program, which was conducted at 50 sites in North American and Europe from 2007 to 2014.

Forty-five percent of the children received a bone marrow transplant, 31% received cord blood, and 45% had a mismatched transplant. Their median age was 9.6 (range, 2 months-18 years), 61% were male, and 60% were Caucasian.

All of the patients had steroid-refractory aGVHD. Thirty percent had grade C GVHD, 50% had grade D, 50% had multi-organ disease, and 79% were classified as “high-risk” disease.

Treatment

All 241 children received remestemcel-L, which consists of bone-marrow derived and culture-expanded human MSCs. The initial treatment was 2 million MSCs/kg twice a week for 4 weeks, at least 3 days apart.

Continued treatment consisted of 2 million MSCs/kg once a week for 4 weeks if patients achieved a partial or mixed response (improvement in one organ with deterioration in another organ) at the day-28 assessment.

The patients received a total of 2434 infusions. The median number of infusions was 11 (range, 1-24), and the median duration of treatment was 46 days (range, 1-186). Eighty-one percent (123/152) of eligible patients with a partial or mixed response at day 28 received continued therapy of 1 infusion a week for 4 weeks.

Results

Fifty-seven percent of patients (n=138) had at least 1 serious adverse event. About 5% (n=11) were considered treatment-related, and 1.7% (n=4) led to study discontinuation. There was 1 infusion reaction.

Thirty-four percent of patients (n=81) died through day 100, and 2.5% (n=6) experienced a relapse of their underlying disease.

At day 28 after treatment, the overall response rate was 65%, with a complete response rate of 14% and  partial response rate of 51%. Responses were observed for all aGVHD grades and did not differ by baseline organ involvement.

When remestemcel-L was used as front-line therapy following steroid failure, the response rate was 81%. In patients with gastrointestinal and liver disease, the overall response rates were 65% and 62%, respectively.

Children who achieved a response at day 28 had significantly improved survival, compared to those who did not—82% and 39%, respectively (P<0.0001).

Extending therapy beyond day 28 in children who had a mixed response at day 28 resulted in significantly improved survival as well. Survival was 72% for these patients, compared to 18% for patients with a mixed response who did not receive additional therapy (P=0.003).

Mesoblast is now conducting a 60-patient, open label, phase 3 trial using remestemcel-L as front-line therapy in children with steroid-refractory aGVHD.

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Mesenchymal stem cells

HONOLULU—A mesenchymal stem cell (MSC) product has shown promise for treating children with steroid-refractory acute graft-versus-host disease (aGVHD), according to researchers.

The product, remestemcel-L (MSC-100-IV, formerly Prochymal), produced an overall response rate of 65% by 28 days after treatment.

And patients who responded to remestemcel-L had significantly better survival at day 100 than patients who did not respond.

Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina, presented these data at the 2016 BMT Tandem Meetings (abstract 54). The study was sponsored by Mesoblast, the company developing remestemcel-L.

“There is a critical and urgent need for an effective and well-tolerated treatment for the very ill children who develop [GVHD] after a bone marrow transplant,” Dr Kurtzberg said. “While, historically, there is a high mortality rate associated with this complication, we are now seeing the majority of children who receive Mesoblast’s cell therapy respond and survive.”

For this study, Dr Kurtzberg and her colleagues assessed 241 children treated in Mesoblast’s Expanded Access Program, which was conducted at 50 sites in North American and Europe from 2007 to 2014.

Forty-five percent of the children received a bone marrow transplant, 31% received cord blood, and 45% had a mismatched transplant. Their median age was 9.6 (range, 2 months-18 years), 61% were male, and 60% were Caucasian.

All of the patients had steroid-refractory aGVHD. Thirty percent had grade C GVHD, 50% had grade D, 50% had multi-organ disease, and 79% were classified as “high-risk” disease.

Treatment

All 241 children received remestemcel-L, which consists of bone-marrow derived and culture-expanded human MSCs. The initial treatment was 2 million MSCs/kg twice a week for 4 weeks, at least 3 days apart.

Continued treatment consisted of 2 million MSCs/kg once a week for 4 weeks if patients achieved a partial or mixed response (improvement in one organ with deterioration in another organ) at the day-28 assessment.

The patients received a total of 2434 infusions. The median number of infusions was 11 (range, 1-24), and the median duration of treatment was 46 days (range, 1-186). Eighty-one percent (123/152) of eligible patients with a partial or mixed response at day 28 received continued therapy of 1 infusion a week for 4 weeks.

Results

Fifty-seven percent of patients (n=138) had at least 1 serious adverse event. About 5% (n=11) were considered treatment-related, and 1.7% (n=4) led to study discontinuation. There was 1 infusion reaction.

Thirty-four percent of patients (n=81) died through day 100, and 2.5% (n=6) experienced a relapse of their underlying disease.

At day 28 after treatment, the overall response rate was 65%, with a complete response rate of 14% and  partial response rate of 51%. Responses were observed for all aGVHD grades and did not differ by baseline organ involvement.

When remestemcel-L was used as front-line therapy following steroid failure, the response rate was 81%. In patients with gastrointestinal and liver disease, the overall response rates were 65% and 62%, respectively.

Children who achieved a response at day 28 had significantly improved survival, compared to those who did not—82% and 39%, respectively (P<0.0001).

Extending therapy beyond day 28 in children who had a mixed response at day 28 resulted in significantly improved survival as well. Survival was 72% for these patients, compared to 18% for patients with a mixed response who did not receive additional therapy (P=0.003).

Mesoblast is now conducting a 60-patient, open label, phase 3 trial using remestemcel-L as front-line therapy in children with steroid-refractory aGVHD.

Mesenchymal stem cells

HONOLULU—A mesenchymal stem cell (MSC) product has shown promise for treating children with steroid-refractory acute graft-versus-host disease (aGVHD), according to researchers.

The product, remestemcel-L (MSC-100-IV, formerly Prochymal), produced an overall response rate of 65% by 28 days after treatment.

And patients who responded to remestemcel-L had significantly better survival at day 100 than patients who did not respond.

Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina, presented these data at the 2016 BMT Tandem Meetings (abstract 54). The study was sponsored by Mesoblast, the company developing remestemcel-L.

“There is a critical and urgent need for an effective and well-tolerated treatment for the very ill children who develop [GVHD] after a bone marrow transplant,” Dr Kurtzberg said. “While, historically, there is a high mortality rate associated with this complication, we are now seeing the majority of children who receive Mesoblast’s cell therapy respond and survive.”

For this study, Dr Kurtzberg and her colleagues assessed 241 children treated in Mesoblast’s Expanded Access Program, which was conducted at 50 sites in North American and Europe from 2007 to 2014.

Forty-five percent of the children received a bone marrow transplant, 31% received cord blood, and 45% had a mismatched transplant. Their median age was 9.6 (range, 2 months-18 years), 61% were male, and 60% were Caucasian.

All of the patients had steroid-refractory aGVHD. Thirty percent had grade C GVHD, 50% had grade D, 50% had multi-organ disease, and 79% were classified as “high-risk” disease.

Treatment

All 241 children received remestemcel-L, which consists of bone-marrow derived and culture-expanded human MSCs. The initial treatment was 2 million MSCs/kg twice a week for 4 weeks, at least 3 days apart.

Continued treatment consisted of 2 million MSCs/kg once a week for 4 weeks if patients achieved a partial or mixed response (improvement in one organ with deterioration in another organ) at the day-28 assessment.

The patients received a total of 2434 infusions. The median number of infusions was 11 (range, 1-24), and the median duration of treatment was 46 days (range, 1-186). Eighty-one percent (123/152) of eligible patients with a partial or mixed response at day 28 received continued therapy of 1 infusion a week for 4 weeks.

Results

Fifty-seven percent of patients (n=138) had at least 1 serious adverse event. About 5% (n=11) were considered treatment-related, and 1.7% (n=4) led to study discontinuation. There was 1 infusion reaction.

Thirty-four percent of patients (n=81) died through day 100, and 2.5% (n=6) experienced a relapse of their underlying disease.

At day 28 after treatment, the overall response rate was 65%, with a complete response rate of 14% and  partial response rate of 51%. Responses were observed for all aGVHD grades and did not differ by baseline organ involvement.

When remestemcel-L was used as front-line therapy following steroid failure, the response rate was 81%. In patients with gastrointestinal and liver disease, the overall response rates were 65% and 62%, respectively.

Children who achieved a response at day 28 had significantly improved survival, compared to those who did not—82% and 39%, respectively (P<0.0001).

Extending therapy beyond day 28 in children who had a mixed response at day 28 resulted in significantly improved survival as well. Survival was 72% for these patients, compared to 18% for patients with a mixed response who did not receive additional therapy (P=0.003).

Mesoblast is now conducting a 60-patient, open label, phase 3 trial using remestemcel-L as front-line therapy in children with steroid-refractory aGVHD.

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Drug may still be viable as CMV prophylaxis

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Drug may still be viable as CMV prophylaxis

HSCT preparation

Photo by Chad McNeeley

HONOLULU—Despite disappointing results in a phase 3 trial, investigators believe the oral nucleotide analog brincidofovir may still be viable as cytomegalovirus (CMV) prophylaxis in patients undergoing hematopoietic stem cell transplant (HSCT).

As reported last December, brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, which was to prevent clinically significant CMV infection at week 24 after HSCT.

However, trial investigators said the drug did prevent CMV through week 14, which was the end of the treatment period.

The team believes they have an explanation for these findings, which were presented at the 2016 BMT Tandem Meetings (abstract 5). The trial was supported by Chimerix, the company developing brincidofovir.

The SUPPRESS trial included 452 subjects at high risk for CMV who were randomized to receive brincidofovir or placebo twice weekly for up to 14 weeks following allogeneic HSCT. They were then followed for 10 weeks after treatment.

Baseline characteristics were similar between the treatment arms, although there were more males in the placebo arm than the brincidofovir arm—66% and 54%, respectively. The median age was 56 in the brincidofovir arm and 54 in the placebo arm (overall range, 18-77).

Key results

The primary endpoint was assessed at week 24. At that time, the proportion of patients with clinically significant CMV infection was similar in the brincidofovir and placebo arms—51% and 52%, respectively.

However, the investigators did note that brincidofovir exhibited an antiviral effect during the trial. At the end of the on-treatment period at week 14, patients who received brincidofovir had fewer clinically significant CMV infections than patients in the placebo group—24% and 38%, respectively (P=0.002).

The investigators said the failure to meet the primary endpoint at week 24 appears to be associated with CMV events in the post-treatment period among subjects on the brincidofovir arm, driven by higher use of corticosteroids and other immunosuppressive therapies for the treatment of presumptive graft-versus-host disease (GVHD).

Diarrhea can be a symptom of GVHD in the gut and is also a known side effect of brincidofovir that can be managed by a temporary dose interruption, as described in the safety monitoring and management plan (SMMP) developed during the phase 2 trial of the drug (then known as CMX001).

In the SUPPRESS trial, diarrhea in brincidofovir-treated patients was more frequent and often presumed to be gut GVHD. So patients were treated with corticosteroids rather than undergoing temporary treatment interruption according to the SMMP. Among patients who were managed according to the SMMP, the investigators observed significantly fewer CMV infections (P=0.03) and lower mortality (P<0.001).

There was an 8-fold increase in the use of corticosteroids through week 14 in the brincidofovir arm compared to the placebo arm. The median cumulative dose of prednisone-equivalent corticosteroids was 26 mg/kg and 3 mg/kg, respectively.

The use of corticosteroids and other immunosuppressive therapies for the treatment of GVHD is known to increase the risk of infections, including CMV infections that occur when patients discontinue antiviral therapy.

Among patients who either underwent T-cell depletion or received alemtuzumab/ATG to decrease the risk of GVHD, those who were randomized to receive brincidofovir showed a lower incidence of CMV when compared to placebo, at a rate consistent with what was observed in the phase 2 study.

Additional endpoints

Brincidofovir did not prevent infection with non-CMV DNA viruses, such as BK virus.

And there was no significant difference between the treatment arms with regard to all-cause mortality. The rate was 15.5% in the brincidofovir arm and 10.1% in the placebo arm (P=0.12).

 

 

The investigators said the numerical differences in mortality appear to be driven by higher use of corticosteroids and other immunosuppressive therapies in the subjects who received brincidofovir.

The rate of treatment-emergent adverse events (AEs) was 100% in the brincidofovir arm and 98% in the placebo arm. The rate of grade 3 or higher AEs was 67% and 38%, respectively. The rate of serious AEs was 57% and 38%, respectively.

The rate of AEs leading to treatment discontinuation was 26% and 7%, respectively. And the rate of AEs leading to treatment change or interruption was 45% and 15%, respectively.

The most common AEs in the brincidofovir arm were diarrhea (61%), acute GVHD (57%), abdominal pain (34%), nausea (31%), vomiting (24%), peripheral edema (17%), hyperglycemia (16%), hypokalemia (16%), hypomagnesemia (13%), and ALT elevation (11%). There was no evidence of bone marrow toxicity, kidney toxicity, or viral resistance to brincidofovir.

Brincidofovir development

Chimerix said it will discuss the SUPPRESS data in full with the US Food and Drug Administration and other regulators, including the benefit-to-risk profile in specific subpopulations, as well as the current adenovirus and smallpox data, to determine next steps for the brincidofovir clinical programs.

The development of an intravenous (IV) formulation of brincidofovir is progressing toward clinical testing and has the potential to avoid the gastrointestinal side effects of orally administered brincidofovir.

Preclinical studies of IV brincidofovir have shown a lower risk of gastrointestinal effects based on maintained body weight during dosing and no evidence of injury in preliminary review of the gastrointestinal tract.

If human studies continue to support these findings, IV dosing during the first few weeks after transplant when patients are recovering from conditioning chemotherapy could be explored, with oral brincidofovir therapy available as patients are discharged home.

As there is no preventive therapy approved for CMV in HSCT recipients, Chimerix said it is committed to moving brincidofovir forward in this indication. Plans for brincidofovir in HSCT recipients will be the subject of further discussions with regulators.

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HSCT preparation

Photo by Chad McNeeley

HONOLULU—Despite disappointing results in a phase 3 trial, investigators believe the oral nucleotide analog brincidofovir may still be viable as cytomegalovirus (CMV) prophylaxis in patients undergoing hematopoietic stem cell transplant (HSCT).

As reported last December, brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, which was to prevent clinically significant CMV infection at week 24 after HSCT.

However, trial investigators said the drug did prevent CMV through week 14, which was the end of the treatment period.

The team believes they have an explanation for these findings, which were presented at the 2016 BMT Tandem Meetings (abstract 5). The trial was supported by Chimerix, the company developing brincidofovir.

The SUPPRESS trial included 452 subjects at high risk for CMV who were randomized to receive brincidofovir or placebo twice weekly for up to 14 weeks following allogeneic HSCT. They were then followed for 10 weeks after treatment.

Baseline characteristics were similar between the treatment arms, although there were more males in the placebo arm than the brincidofovir arm—66% and 54%, respectively. The median age was 56 in the brincidofovir arm and 54 in the placebo arm (overall range, 18-77).

Key results

The primary endpoint was assessed at week 24. At that time, the proportion of patients with clinically significant CMV infection was similar in the brincidofovir and placebo arms—51% and 52%, respectively.

However, the investigators did note that brincidofovir exhibited an antiviral effect during the trial. At the end of the on-treatment period at week 14, patients who received brincidofovir had fewer clinically significant CMV infections than patients in the placebo group—24% and 38%, respectively (P=0.002).

The investigators said the failure to meet the primary endpoint at week 24 appears to be associated with CMV events in the post-treatment period among subjects on the brincidofovir arm, driven by higher use of corticosteroids and other immunosuppressive therapies for the treatment of presumptive graft-versus-host disease (GVHD).

Diarrhea can be a symptom of GVHD in the gut and is also a known side effect of brincidofovir that can be managed by a temporary dose interruption, as described in the safety monitoring and management plan (SMMP) developed during the phase 2 trial of the drug (then known as CMX001).

In the SUPPRESS trial, diarrhea in brincidofovir-treated patients was more frequent and often presumed to be gut GVHD. So patients were treated with corticosteroids rather than undergoing temporary treatment interruption according to the SMMP. Among patients who were managed according to the SMMP, the investigators observed significantly fewer CMV infections (P=0.03) and lower mortality (P<0.001).

There was an 8-fold increase in the use of corticosteroids through week 14 in the brincidofovir arm compared to the placebo arm. The median cumulative dose of prednisone-equivalent corticosteroids was 26 mg/kg and 3 mg/kg, respectively.

The use of corticosteroids and other immunosuppressive therapies for the treatment of GVHD is known to increase the risk of infections, including CMV infections that occur when patients discontinue antiviral therapy.

Among patients who either underwent T-cell depletion or received alemtuzumab/ATG to decrease the risk of GVHD, those who were randomized to receive brincidofovir showed a lower incidence of CMV when compared to placebo, at a rate consistent with what was observed in the phase 2 study.

Additional endpoints

Brincidofovir did not prevent infection with non-CMV DNA viruses, such as BK virus.

And there was no significant difference between the treatment arms with regard to all-cause mortality. The rate was 15.5% in the brincidofovir arm and 10.1% in the placebo arm (P=0.12).

 

 

The investigators said the numerical differences in mortality appear to be driven by higher use of corticosteroids and other immunosuppressive therapies in the subjects who received brincidofovir.

The rate of treatment-emergent adverse events (AEs) was 100% in the brincidofovir arm and 98% in the placebo arm. The rate of grade 3 or higher AEs was 67% and 38%, respectively. The rate of serious AEs was 57% and 38%, respectively.

The rate of AEs leading to treatment discontinuation was 26% and 7%, respectively. And the rate of AEs leading to treatment change or interruption was 45% and 15%, respectively.

The most common AEs in the brincidofovir arm were diarrhea (61%), acute GVHD (57%), abdominal pain (34%), nausea (31%), vomiting (24%), peripheral edema (17%), hyperglycemia (16%), hypokalemia (16%), hypomagnesemia (13%), and ALT elevation (11%). There was no evidence of bone marrow toxicity, kidney toxicity, or viral resistance to brincidofovir.

Brincidofovir development

Chimerix said it will discuss the SUPPRESS data in full with the US Food and Drug Administration and other regulators, including the benefit-to-risk profile in specific subpopulations, as well as the current adenovirus and smallpox data, to determine next steps for the brincidofovir clinical programs.

The development of an intravenous (IV) formulation of brincidofovir is progressing toward clinical testing and has the potential to avoid the gastrointestinal side effects of orally administered brincidofovir.

Preclinical studies of IV brincidofovir have shown a lower risk of gastrointestinal effects based on maintained body weight during dosing and no evidence of injury in preliminary review of the gastrointestinal tract.

If human studies continue to support these findings, IV dosing during the first few weeks after transplant when patients are recovering from conditioning chemotherapy could be explored, with oral brincidofovir therapy available as patients are discharged home.

As there is no preventive therapy approved for CMV in HSCT recipients, Chimerix said it is committed to moving brincidofovir forward in this indication. Plans for brincidofovir in HSCT recipients will be the subject of further discussions with regulators.

HSCT preparation

Photo by Chad McNeeley

HONOLULU—Despite disappointing results in a phase 3 trial, investigators believe the oral nucleotide analog brincidofovir may still be viable as cytomegalovirus (CMV) prophylaxis in patients undergoing hematopoietic stem cell transplant (HSCT).

As reported last December, brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, which was to prevent clinically significant CMV infection at week 24 after HSCT.

However, trial investigators said the drug did prevent CMV through week 14, which was the end of the treatment period.

The team believes they have an explanation for these findings, which were presented at the 2016 BMT Tandem Meetings (abstract 5). The trial was supported by Chimerix, the company developing brincidofovir.

The SUPPRESS trial included 452 subjects at high risk for CMV who were randomized to receive brincidofovir or placebo twice weekly for up to 14 weeks following allogeneic HSCT. They were then followed for 10 weeks after treatment.

Baseline characteristics were similar between the treatment arms, although there were more males in the placebo arm than the brincidofovir arm—66% and 54%, respectively. The median age was 56 in the brincidofovir arm and 54 in the placebo arm (overall range, 18-77).

Key results

The primary endpoint was assessed at week 24. At that time, the proportion of patients with clinically significant CMV infection was similar in the brincidofovir and placebo arms—51% and 52%, respectively.

However, the investigators did note that brincidofovir exhibited an antiviral effect during the trial. At the end of the on-treatment period at week 14, patients who received brincidofovir had fewer clinically significant CMV infections than patients in the placebo group—24% and 38%, respectively (P=0.002).

The investigators said the failure to meet the primary endpoint at week 24 appears to be associated with CMV events in the post-treatment period among subjects on the brincidofovir arm, driven by higher use of corticosteroids and other immunosuppressive therapies for the treatment of presumptive graft-versus-host disease (GVHD).

Diarrhea can be a symptom of GVHD in the gut and is also a known side effect of brincidofovir that can be managed by a temporary dose interruption, as described in the safety monitoring and management plan (SMMP) developed during the phase 2 trial of the drug (then known as CMX001).

In the SUPPRESS trial, diarrhea in brincidofovir-treated patients was more frequent and often presumed to be gut GVHD. So patients were treated with corticosteroids rather than undergoing temporary treatment interruption according to the SMMP. Among patients who were managed according to the SMMP, the investigators observed significantly fewer CMV infections (P=0.03) and lower mortality (P<0.001).

There was an 8-fold increase in the use of corticosteroids through week 14 in the brincidofovir arm compared to the placebo arm. The median cumulative dose of prednisone-equivalent corticosteroids was 26 mg/kg and 3 mg/kg, respectively.

The use of corticosteroids and other immunosuppressive therapies for the treatment of GVHD is known to increase the risk of infections, including CMV infections that occur when patients discontinue antiviral therapy.

Among patients who either underwent T-cell depletion or received alemtuzumab/ATG to decrease the risk of GVHD, those who were randomized to receive brincidofovir showed a lower incidence of CMV when compared to placebo, at a rate consistent with what was observed in the phase 2 study.

Additional endpoints

Brincidofovir did not prevent infection with non-CMV DNA viruses, such as BK virus.

And there was no significant difference between the treatment arms with regard to all-cause mortality. The rate was 15.5% in the brincidofovir arm and 10.1% in the placebo arm (P=0.12).

 

 

The investigators said the numerical differences in mortality appear to be driven by higher use of corticosteroids and other immunosuppressive therapies in the subjects who received brincidofovir.

The rate of treatment-emergent adverse events (AEs) was 100% in the brincidofovir arm and 98% in the placebo arm. The rate of grade 3 or higher AEs was 67% and 38%, respectively. The rate of serious AEs was 57% and 38%, respectively.

The rate of AEs leading to treatment discontinuation was 26% and 7%, respectively. And the rate of AEs leading to treatment change or interruption was 45% and 15%, respectively.

The most common AEs in the brincidofovir arm were diarrhea (61%), acute GVHD (57%), abdominal pain (34%), nausea (31%), vomiting (24%), peripheral edema (17%), hyperglycemia (16%), hypokalemia (16%), hypomagnesemia (13%), and ALT elevation (11%). There was no evidence of bone marrow toxicity, kidney toxicity, or viral resistance to brincidofovir.

Brincidofovir development

Chimerix said it will discuss the SUPPRESS data in full with the US Food and Drug Administration and other regulators, including the benefit-to-risk profile in specific subpopulations, as well as the current adenovirus and smallpox data, to determine next steps for the brincidofovir clinical programs.

The development of an intravenous (IV) formulation of brincidofovir is progressing toward clinical testing and has the potential to avoid the gastrointestinal side effects of orally administered brincidofovir.

Preclinical studies of IV brincidofovir have shown a lower risk of gastrointestinal effects based on maintained body weight during dosing and no evidence of injury in preliminary review of the gastrointestinal tract.

If human studies continue to support these findings, IV dosing during the first few weeks after transplant when patients are recovering from conditioning chemotherapy could be explored, with oral brincidofovir therapy available as patients are discharged home.

As there is no preventive therapy approved for CMV in HSCT recipients, Chimerix said it is committed to moving brincidofovir forward in this indication. Plans for brincidofovir in HSCT recipients will be the subject of further discussions with regulators.

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Group identifies genes that may impact HSCT

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Wed, 02/17/2016 - 06:00
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Group identifies genes that may impact HSCT

Lab mice

Photo by Aaron Logan

A new screening method has revealed genes that regulate how hematopoietic stem and progenitor cells (HSPCs) grow and thrive in mice.

Researchers used this method to uncover 17 genes that are regulators of hematopoietic stem cell transplant (HSCT).

Thirteen of these genes had never before been linked to HSPC engraftment.

The researchers reported their findings in the Journal of Experimental Medicine.

“We recognized that one barrier to improving [HSCT] is a lack of understanding of how [HSPCs] successfully grow in the challenged environment of transplant, so we set out to identify the genes that control this process,” said Shannon McKinney-Freeman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr McKinney-Freeman and her colleagues transplanted more than 1300 mice with shRNA-transduced HSPCs and searched for genes that regulate HSPC repopulation.

The team identified 17 such genes—Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp251.

For most of these genes, knockdown yielded a loss of function. The exceptions were Armcx1 and Gprasp2, whose loss enhanced HSPC repopulation.

“Our functional screen in mice is a first step to enhancing [HSCT],” Dr McKinney-Freeman said. “If we are to improve transplant outcomes in patients, we next need to study these identified genes and the molecules they specify in much more detail.”

“The more we understand the full scope of the molecular mechanisms that regulate stable engraftment of [HSPCs], the better equipped we will be to develop and clinically test novel therapies to improve health outcomes.”

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Lab mice

Photo by Aaron Logan

A new screening method has revealed genes that regulate how hematopoietic stem and progenitor cells (HSPCs) grow and thrive in mice.

Researchers used this method to uncover 17 genes that are regulators of hematopoietic stem cell transplant (HSCT).

Thirteen of these genes had never before been linked to HSPC engraftment.

The researchers reported their findings in the Journal of Experimental Medicine.

“We recognized that one barrier to improving [HSCT] is a lack of understanding of how [HSPCs] successfully grow in the challenged environment of transplant, so we set out to identify the genes that control this process,” said Shannon McKinney-Freeman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr McKinney-Freeman and her colleagues transplanted more than 1300 mice with shRNA-transduced HSPCs and searched for genes that regulate HSPC repopulation.

The team identified 17 such genes—Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp251.

For most of these genes, knockdown yielded a loss of function. The exceptions were Armcx1 and Gprasp2, whose loss enhanced HSPC repopulation.

“Our functional screen in mice is a first step to enhancing [HSCT],” Dr McKinney-Freeman said. “If we are to improve transplant outcomes in patients, we next need to study these identified genes and the molecules they specify in much more detail.”

“The more we understand the full scope of the molecular mechanisms that regulate stable engraftment of [HSPCs], the better equipped we will be to develop and clinically test novel therapies to improve health outcomes.”

Lab mice

Photo by Aaron Logan

A new screening method has revealed genes that regulate how hematopoietic stem and progenitor cells (HSPCs) grow and thrive in mice.

Researchers used this method to uncover 17 genes that are regulators of hematopoietic stem cell transplant (HSCT).

Thirteen of these genes had never before been linked to HSPC engraftment.

The researchers reported their findings in the Journal of Experimental Medicine.

“We recognized that one barrier to improving [HSCT] is a lack of understanding of how [HSPCs] successfully grow in the challenged environment of transplant, so we set out to identify the genes that control this process,” said Shannon McKinney-Freeman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr McKinney-Freeman and her colleagues transplanted more than 1300 mice with shRNA-transduced HSPCs and searched for genes that regulate HSPC repopulation.

The team identified 17 such genes—Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp251.

For most of these genes, knockdown yielded a loss of function. The exceptions were Armcx1 and Gprasp2, whose loss enhanced HSPC repopulation.

“Our functional screen in mice is a first step to enhancing [HSCT],” Dr McKinney-Freeman said. “If we are to improve transplant outcomes in patients, we next need to study these identified genes and the molecules they specify in much more detail.”

“The more we understand the full scope of the molecular mechanisms that regulate stable engraftment of [HSPCs], the better equipped we will be to develop and clinically test novel therapies to improve health outcomes.”

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EBV-CTLs get orphan designation for EBV-PTLD

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An EBV-infected cell (green/red)

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Benjamin Chaigne-Delalande

The US Food and Drug Administration (FDA) has granted orphan designation for cytotoxic T lymphocytes activated against Epstein-Barr virus (EBV-CTLs) to treat EBV post-transplant lymphoproliferative disorder (EBV-PTLD) occurring after solid organ or hematopoietic stem cell transplant.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases, which may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and a 7-year period of marketing exclusivity if the product is approved.

The EBV-CTL product is under development by Atara Biotherapeutics, Inc. It is produced by collecting T cells from third-party donors and exposing the cells to EBV antigens.

The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.

In the context of EBV-PTLD, Atara’s EBV-CTLs find the cancer cells expressing EBV and kill them. EBV-CTLs are currently being studied in phase 2 trials.

Results of a phase 1/2 study were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.

The FDA previously granted EBV-CTLs breakthrough designation to treat EBV-PTLD. This designation is intended to expedite the development and review of new drugs for serious or life-threatening conditions.

To qualify for breakthrough designation, a drug must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy, or in a study that compares the new treatment plus the standard of care to the standard alone.

The designation confers several benefits, including intensive FDA guidance and eligibility for submission of a rolling biologic license application.

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An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of

Benjamin Chaigne-Delalande

The US Food and Drug Administration (FDA) has granted orphan designation for cytotoxic T lymphocytes activated against Epstein-Barr virus (EBV-CTLs) to treat EBV post-transplant lymphoproliferative disorder (EBV-PTLD) occurring after solid organ or hematopoietic stem cell transplant.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases, which may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and a 7-year period of marketing exclusivity if the product is approved.

The EBV-CTL product is under development by Atara Biotherapeutics, Inc. It is produced by collecting T cells from third-party donors and exposing the cells to EBV antigens.

The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.

In the context of EBV-PTLD, Atara’s EBV-CTLs find the cancer cells expressing EBV and kill them. EBV-CTLs are currently being studied in phase 2 trials.

Results of a phase 1/2 study were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.

The FDA previously granted EBV-CTLs breakthrough designation to treat EBV-PTLD. This designation is intended to expedite the development and review of new drugs for serious or life-threatening conditions.

To qualify for breakthrough designation, a drug must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy, or in a study that compares the new treatment plus the standard of care to the standard alone.

The designation confers several benefits, including intensive FDA guidance and eligibility for submission of a rolling biologic license application.

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of

Benjamin Chaigne-Delalande

The US Food and Drug Administration (FDA) has granted orphan designation for cytotoxic T lymphocytes activated against Epstein-Barr virus (EBV-CTLs) to treat EBV post-transplant lymphoproliferative disorder (EBV-PTLD) occurring after solid organ or hematopoietic stem cell transplant.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases, which may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and a 7-year period of marketing exclusivity if the product is approved.

The EBV-CTL product is under development by Atara Biotherapeutics, Inc. It is produced by collecting T cells from third-party donors and exposing the cells to EBV antigens.

The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.

In the context of EBV-PTLD, Atara’s EBV-CTLs find the cancer cells expressing EBV and kill them. EBV-CTLs are currently being studied in phase 2 trials.

Results of a phase 1/2 study were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.

The FDA previously granted EBV-CTLs breakthrough designation to treat EBV-PTLD. This designation is intended to expedite the development and review of new drugs for serious or life-threatening conditions.

To qualify for breakthrough designation, a drug must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy, or in a study that compares the new treatment plus the standard of care to the standard alone.

The designation confers several benefits, including intensive FDA guidance and eligibility for submission of a rolling biologic license application.

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Tandem HSCT regimen may cure MM

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Tandem HSCT regimen may cure MM

HSCT preparation

Photo by Chad McNeeley

Tandem autologous/allogeneic hematopoietic stem cell transplant (HSCT) may cure multiple myeloma (MM), according to a phase 2 study.

The study included newly diagnosed patients who received induction therapy followed by an autograft and a non-myeloablative allograft from a matched sibling donor.

The patients have been followed for a median of 8.8 years.

The probability of progression-free survival at 10 years is 41%, and the overall survival is 62%.

The rate of chronic graft-vs-host disease (GVHD) is high, but the rate of non-relapse mortality is low.

“In many hospitals, doctors have abandoned the use of allografts for multiple myeloma due to the risk of toxicity and relapse,” said study author Jean Roy, MD, of the Maisonneuve-Rosemont Hospital and University of Montreal in Quebec, Canada.

“Our results, on the other hand, have led us to offer the treatment to more patients, especially younger patients and those with poorer prognoses.”

Dr Roy and his colleagues reported these results in Bone Marrow Transplantation.

The researchers assessed 92 patients newly diagnosed with MM between 2001 and 2010. Their median age was 52 (range, 39-64), and 97% had Durie–Salmon stage II or III disease.

Patients received an induction regimen consisting of vincristine, doxorubicin, and dexamethasone (2001–2007, n=75) or a bortezomib-based regimen (2008–2010, n=17).

After induction, patients underwent autologous HSCT using melphalan 200 mg/m2.

A median of 4 months later (range, 2-13), after complete clinical recovery, the patients received an allogeneic transplant from a 6/6 HLA-matched sibling donor. Fifty-seven percent of patients had achieved at least a very good partial response before the second transplant.

The allogeneic transplant was performed on an outpatient basis. The graft consisted of G-CSF-mobilized peripheral blood stem cells (target dose ≥ 4×106 CD34+cells/kg).

The conditioning regimen consisted of fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2 for 5 days. GVHD prophylaxis was oral tacrolimus and mycophenolate mofetil.

Results

At a median follow-up of 8.8 years, 56 patients were still alive (and 36 had died).

Forty patients had no evidence of progression, including 11 patients who were still taking systemic immunosuppressive drugs for GVHD. The remaining 16 patients who were still alive had relapsed after allogeneic HSCT.

A total of 45 patients relapsed. Thirty-nine went on to receive treatment with at least 1 new drug (thalidomide, lenalidomide, bortezomib, or pomalidomide).

They received a median of 2 lines of therapy (range, 1–6), and their 5-year overall survival from first relapse was 49%. Ten of these patients were in very good partial response or greater at last follow-up.

Ten patients died from causes other than refractory MM—6 from refractory GVHD, 3 from lung adenocarcinoma (1 smoker), and 1 from invasive aspergillosis.

The cumulative incidence of extensive chronic GVHD was 79%. The cumulative incidence of grade 2-4 acute GVHD at 6 months was 9%. And 3 patients developed grade 3-4 acute GVHD.

Among the 56 patients who were still alive at last follow-up, the probability of being on any systemic immunosuppressive treatment for GVHD is 38% at 5 years and 22% at 10 years.

The probability of overall survival at 10 years is 62%, the probability of progression-free survival is 41%, and the cumulative incidence of non-relapse mortality is 10%.

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HSCT preparation

Photo by Chad McNeeley

Tandem autologous/allogeneic hematopoietic stem cell transplant (HSCT) may cure multiple myeloma (MM), according to a phase 2 study.

The study included newly diagnosed patients who received induction therapy followed by an autograft and a non-myeloablative allograft from a matched sibling donor.

The patients have been followed for a median of 8.8 years.

The probability of progression-free survival at 10 years is 41%, and the overall survival is 62%.

The rate of chronic graft-vs-host disease (GVHD) is high, but the rate of non-relapse mortality is low.

“In many hospitals, doctors have abandoned the use of allografts for multiple myeloma due to the risk of toxicity and relapse,” said study author Jean Roy, MD, of the Maisonneuve-Rosemont Hospital and University of Montreal in Quebec, Canada.

“Our results, on the other hand, have led us to offer the treatment to more patients, especially younger patients and those with poorer prognoses.”

Dr Roy and his colleagues reported these results in Bone Marrow Transplantation.

The researchers assessed 92 patients newly diagnosed with MM between 2001 and 2010. Their median age was 52 (range, 39-64), and 97% had Durie–Salmon stage II or III disease.

Patients received an induction regimen consisting of vincristine, doxorubicin, and dexamethasone (2001–2007, n=75) or a bortezomib-based regimen (2008–2010, n=17).

After induction, patients underwent autologous HSCT using melphalan 200 mg/m2.

A median of 4 months later (range, 2-13), after complete clinical recovery, the patients received an allogeneic transplant from a 6/6 HLA-matched sibling donor. Fifty-seven percent of patients had achieved at least a very good partial response before the second transplant.

The allogeneic transplant was performed on an outpatient basis. The graft consisted of G-CSF-mobilized peripheral blood stem cells (target dose ≥ 4×106 CD34+cells/kg).

The conditioning regimen consisted of fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2 for 5 days. GVHD prophylaxis was oral tacrolimus and mycophenolate mofetil.

Results

At a median follow-up of 8.8 years, 56 patients were still alive (and 36 had died).

Forty patients had no evidence of progression, including 11 patients who were still taking systemic immunosuppressive drugs for GVHD. The remaining 16 patients who were still alive had relapsed after allogeneic HSCT.

A total of 45 patients relapsed. Thirty-nine went on to receive treatment with at least 1 new drug (thalidomide, lenalidomide, bortezomib, or pomalidomide).

They received a median of 2 lines of therapy (range, 1–6), and their 5-year overall survival from first relapse was 49%. Ten of these patients were in very good partial response or greater at last follow-up.

Ten patients died from causes other than refractory MM—6 from refractory GVHD, 3 from lung adenocarcinoma (1 smoker), and 1 from invasive aspergillosis.

The cumulative incidence of extensive chronic GVHD was 79%. The cumulative incidence of grade 2-4 acute GVHD at 6 months was 9%. And 3 patients developed grade 3-4 acute GVHD.

Among the 56 patients who were still alive at last follow-up, the probability of being on any systemic immunosuppressive treatment for GVHD is 38% at 5 years and 22% at 10 years.

The probability of overall survival at 10 years is 62%, the probability of progression-free survival is 41%, and the cumulative incidence of non-relapse mortality is 10%.

HSCT preparation

Photo by Chad McNeeley

Tandem autologous/allogeneic hematopoietic stem cell transplant (HSCT) may cure multiple myeloma (MM), according to a phase 2 study.

The study included newly diagnosed patients who received induction therapy followed by an autograft and a non-myeloablative allograft from a matched sibling donor.

The patients have been followed for a median of 8.8 years.

The probability of progression-free survival at 10 years is 41%, and the overall survival is 62%.

The rate of chronic graft-vs-host disease (GVHD) is high, but the rate of non-relapse mortality is low.

“In many hospitals, doctors have abandoned the use of allografts for multiple myeloma due to the risk of toxicity and relapse,” said study author Jean Roy, MD, of the Maisonneuve-Rosemont Hospital and University of Montreal in Quebec, Canada.

“Our results, on the other hand, have led us to offer the treatment to more patients, especially younger patients and those with poorer prognoses.”

Dr Roy and his colleagues reported these results in Bone Marrow Transplantation.

The researchers assessed 92 patients newly diagnosed with MM between 2001 and 2010. Their median age was 52 (range, 39-64), and 97% had Durie–Salmon stage II or III disease.

Patients received an induction regimen consisting of vincristine, doxorubicin, and dexamethasone (2001–2007, n=75) or a bortezomib-based regimen (2008–2010, n=17).

After induction, patients underwent autologous HSCT using melphalan 200 mg/m2.

A median of 4 months later (range, 2-13), after complete clinical recovery, the patients received an allogeneic transplant from a 6/6 HLA-matched sibling donor. Fifty-seven percent of patients had achieved at least a very good partial response before the second transplant.

The allogeneic transplant was performed on an outpatient basis. The graft consisted of G-CSF-mobilized peripheral blood stem cells (target dose ≥ 4×106 CD34+cells/kg).

The conditioning regimen consisted of fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2 for 5 days. GVHD prophylaxis was oral tacrolimus and mycophenolate mofetil.

Results

At a median follow-up of 8.8 years, 56 patients were still alive (and 36 had died).

Forty patients had no evidence of progression, including 11 patients who were still taking systemic immunosuppressive drugs for GVHD. The remaining 16 patients who were still alive had relapsed after allogeneic HSCT.

A total of 45 patients relapsed. Thirty-nine went on to receive treatment with at least 1 new drug (thalidomide, lenalidomide, bortezomib, or pomalidomide).

They received a median of 2 lines of therapy (range, 1–6), and their 5-year overall survival from first relapse was 49%. Ten of these patients were in very good partial response or greater at last follow-up.

Ten patients died from causes other than refractory MM—6 from refractory GVHD, 3 from lung adenocarcinoma (1 smoker), and 1 from invasive aspergillosis.

The cumulative incidence of extensive chronic GVHD was 79%. The cumulative incidence of grade 2-4 acute GVHD at 6 months was 9%. And 3 patients developed grade 3-4 acute GVHD.

Among the 56 patients who were still alive at last follow-up, the probability of being on any systemic immunosuppressive treatment for GVHD is 38% at 5 years and 22% at 10 years.

The probability of overall survival at 10 years is 62%, the probability of progression-free survival is 41%, and the cumulative incidence of non-relapse mortality is 10%.

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Drug may improve outcomes of VOD with MOF after HSCT

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Drug may improve outcomes of VOD with MOF after HSCT

HSCT preparation

Photo by Chad McNeeley

Results of a phase 3 trial suggest defibrotide may improve survival in patients who develop hepatic veno-occlusive disease (VOD) and multi-organ failure (MOF) after hematopoietic stem cell transplant (HSCT).

The patients in this trial had a significant improvement in complete response (CR) rate and survival at day 100 after HSCT, when compared with historical controls.

The researchers said defibrotide was generally well-tolerated, and toxicity was manageable.

However, nearly all defibrotide-treated patients had at least 1 adverse event (AE), as did all historical controls. And a majority of patients in both groups had a fatal AE.

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Blood. The trial was sponsored by Jazz Pharmaceuticals, makers of defibrotide.

“Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need,” Dr Richardson said.

“Although HSCT has improved substantially over the last decade, hepatic [VOD] with MOF remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

Dr Richardson and his colleagues investigated the safety and efficacy of defibrotide in 102 adult and pediatric HSCT patients with established hepatic VOD with MOF.

The patients received defibrotide intravenously at 25 mg/kg/day for a minimum of 21 days. Treatment was scheduled to continue beyond 21 days until the resolution of VOD or the patient’s discharge from the hospital.

The researchers compared the 102 patients who received defibrotide with 32 historical controls who were treated at the same institutions. The controls were identified via a review of medical charts of HSCT patients by an independent medical review committee, which was blinded to outcomes.

Baseline characteristics

Baseline characteristics between the groups were largely well balanced. This includes underlying disease, graft source, conditioning regimen, myeloablative regimen, and VOD and MOF parameters.

However, 15% of defibrotide-treated patients received tacrolimus plus sirolimus as graft-versus-host disease prophylaxis, compared with none of the historical controls. Most patients discontinued this regimen upon diagnosis of VOD.

All patients had hyperbilirubinemia. Ascites, weight gain, and hepatomegaly were present in 72% of patients in the defibrotide group and 59% of historical controls.

Renal dysfunction was present in 78% of patients in the defibrotide group (20% dialysis-dependent) and 75% of historical controls (6% dialysis-dependent). Pulmonary dysfunction was present in 85% (26% ventilator-dependent) and 97% (19% ventilator-dependent), respectively.

Sixty-four percent of patients in the defibrotide group and 72% of historical controls had both renal and pulmonary dysfunction.

Response and survival

The primary endpoint was survival at day 100 post-HSCT, which was 38.2% in the defibrotide group and 25% in the historical control group. The estimated between-group difference, using a propensity-adjusted analysis, was 23% (P=0.0109).

The CR rate was 25.5% in the defibrotide group and 12.5% in the historical control group. The estimated difference, adjusted for propensity score, was 19% (P=0.0160).

The median time to CR was 34.5 days in the defibrotide group and 39.5 days in the control group. CR was durable for 22 of 26 patients in the defibrotide group, who still had a CR at last observation. Four patients in the defibrotide group had CR end dates before day 180. All 4 patients died of sepsis or leukemia.

In the historical control group, 1 patient had a durable CR (162 days), 2 patients had a limited CR duration (9 and 10 days, respectively), and 1 patient could not be assessed.

 

 

Safety

The median duration of defibrotide treatment was 21.5 days. Eleven patients discontinued treatment prematurely due to possible drug-related toxicity (10.7%).

All but 1 of the defibrotide-treated patients and all historical controls had at least 1 AE. Hypotension was the most common AE in both groups—39.2% with defibrotide and 50.0% for historical controls. Diarrhea was also common—23.5% and 37.5%, respectively.

Sixty-four percent of patients in the defibrotide group (n=65) and 69% of historical controls (n=22) had a fatal AE.

Fifteen patients (14.7%) in the defibrotide group and 2 (6.3%) in the historical control group had 1 or more hemorrhagic AEs leading to death.

For the defibrotide group, these were gastrointestinal hemorrhage (n=1), cerebral hemorrhage (n=2), intracranial hemorrhage (n=1), subarachnoid hemorrhage (n=1), pulmonary alveolar hemorrhage (n=7), pulmonary hemorrhage (n=2), and vascular disorders hemorrhage (n=1).

Both hemorrhagic AEs leading to death in historical controls were pulmonary alveolar hemorrhage.

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Topics

HSCT preparation

Photo by Chad McNeeley

Results of a phase 3 trial suggest defibrotide may improve survival in patients who develop hepatic veno-occlusive disease (VOD) and multi-organ failure (MOF) after hematopoietic stem cell transplant (HSCT).

The patients in this trial had a significant improvement in complete response (CR) rate and survival at day 100 after HSCT, when compared with historical controls.

The researchers said defibrotide was generally well-tolerated, and toxicity was manageable.

However, nearly all defibrotide-treated patients had at least 1 adverse event (AE), as did all historical controls. And a majority of patients in both groups had a fatal AE.

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Blood. The trial was sponsored by Jazz Pharmaceuticals, makers of defibrotide.

“Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need,” Dr Richardson said.

“Although HSCT has improved substantially over the last decade, hepatic [VOD] with MOF remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

Dr Richardson and his colleagues investigated the safety and efficacy of defibrotide in 102 adult and pediatric HSCT patients with established hepatic VOD with MOF.

The patients received defibrotide intravenously at 25 mg/kg/day for a minimum of 21 days. Treatment was scheduled to continue beyond 21 days until the resolution of VOD or the patient’s discharge from the hospital.

The researchers compared the 102 patients who received defibrotide with 32 historical controls who were treated at the same institutions. The controls were identified via a review of medical charts of HSCT patients by an independent medical review committee, which was blinded to outcomes.

Baseline characteristics

Baseline characteristics between the groups were largely well balanced. This includes underlying disease, graft source, conditioning regimen, myeloablative regimen, and VOD and MOF parameters.

However, 15% of defibrotide-treated patients received tacrolimus plus sirolimus as graft-versus-host disease prophylaxis, compared with none of the historical controls. Most patients discontinued this regimen upon diagnosis of VOD.

All patients had hyperbilirubinemia. Ascites, weight gain, and hepatomegaly were present in 72% of patients in the defibrotide group and 59% of historical controls.

Renal dysfunction was present in 78% of patients in the defibrotide group (20% dialysis-dependent) and 75% of historical controls (6% dialysis-dependent). Pulmonary dysfunction was present in 85% (26% ventilator-dependent) and 97% (19% ventilator-dependent), respectively.

Sixty-four percent of patients in the defibrotide group and 72% of historical controls had both renal and pulmonary dysfunction.

Response and survival

The primary endpoint was survival at day 100 post-HSCT, which was 38.2% in the defibrotide group and 25% in the historical control group. The estimated between-group difference, using a propensity-adjusted analysis, was 23% (P=0.0109).

The CR rate was 25.5% in the defibrotide group and 12.5% in the historical control group. The estimated difference, adjusted for propensity score, was 19% (P=0.0160).

The median time to CR was 34.5 days in the defibrotide group and 39.5 days in the control group. CR was durable for 22 of 26 patients in the defibrotide group, who still had a CR at last observation. Four patients in the defibrotide group had CR end dates before day 180. All 4 patients died of sepsis or leukemia.

In the historical control group, 1 patient had a durable CR (162 days), 2 patients had a limited CR duration (9 and 10 days, respectively), and 1 patient could not be assessed.

 

 

Safety

The median duration of defibrotide treatment was 21.5 days. Eleven patients discontinued treatment prematurely due to possible drug-related toxicity (10.7%).

All but 1 of the defibrotide-treated patients and all historical controls had at least 1 AE. Hypotension was the most common AE in both groups—39.2% with defibrotide and 50.0% for historical controls. Diarrhea was also common—23.5% and 37.5%, respectively.

Sixty-four percent of patients in the defibrotide group (n=65) and 69% of historical controls (n=22) had a fatal AE.

Fifteen patients (14.7%) in the defibrotide group and 2 (6.3%) in the historical control group had 1 or more hemorrhagic AEs leading to death.

For the defibrotide group, these were gastrointestinal hemorrhage (n=1), cerebral hemorrhage (n=2), intracranial hemorrhage (n=1), subarachnoid hemorrhage (n=1), pulmonary alveolar hemorrhage (n=7), pulmonary hemorrhage (n=2), and vascular disorders hemorrhage (n=1).

Both hemorrhagic AEs leading to death in historical controls were pulmonary alveolar hemorrhage.

HSCT preparation

Photo by Chad McNeeley

Results of a phase 3 trial suggest defibrotide may improve survival in patients who develop hepatic veno-occlusive disease (VOD) and multi-organ failure (MOF) after hematopoietic stem cell transplant (HSCT).

The patients in this trial had a significant improvement in complete response (CR) rate and survival at day 100 after HSCT, when compared with historical controls.

The researchers said defibrotide was generally well-tolerated, and toxicity was manageable.

However, nearly all defibrotide-treated patients had at least 1 adverse event (AE), as did all historical controls. And a majority of patients in both groups had a fatal AE.

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Blood. The trial was sponsored by Jazz Pharmaceuticals, makers of defibrotide.

“Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need,” Dr Richardson said.

“Although HSCT has improved substantially over the last decade, hepatic [VOD] with MOF remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

Dr Richardson and his colleagues investigated the safety and efficacy of defibrotide in 102 adult and pediatric HSCT patients with established hepatic VOD with MOF.

The patients received defibrotide intravenously at 25 mg/kg/day for a minimum of 21 days. Treatment was scheduled to continue beyond 21 days until the resolution of VOD or the patient’s discharge from the hospital.

The researchers compared the 102 patients who received defibrotide with 32 historical controls who were treated at the same institutions. The controls were identified via a review of medical charts of HSCT patients by an independent medical review committee, which was blinded to outcomes.

Baseline characteristics

Baseline characteristics between the groups were largely well balanced. This includes underlying disease, graft source, conditioning regimen, myeloablative regimen, and VOD and MOF parameters.

However, 15% of defibrotide-treated patients received tacrolimus plus sirolimus as graft-versus-host disease prophylaxis, compared with none of the historical controls. Most patients discontinued this regimen upon diagnosis of VOD.

All patients had hyperbilirubinemia. Ascites, weight gain, and hepatomegaly were present in 72% of patients in the defibrotide group and 59% of historical controls.

Renal dysfunction was present in 78% of patients in the defibrotide group (20% dialysis-dependent) and 75% of historical controls (6% dialysis-dependent). Pulmonary dysfunction was present in 85% (26% ventilator-dependent) and 97% (19% ventilator-dependent), respectively.

Sixty-four percent of patients in the defibrotide group and 72% of historical controls had both renal and pulmonary dysfunction.

Response and survival

The primary endpoint was survival at day 100 post-HSCT, which was 38.2% in the defibrotide group and 25% in the historical control group. The estimated between-group difference, using a propensity-adjusted analysis, was 23% (P=0.0109).

The CR rate was 25.5% in the defibrotide group and 12.5% in the historical control group. The estimated difference, adjusted for propensity score, was 19% (P=0.0160).

The median time to CR was 34.5 days in the defibrotide group and 39.5 days in the control group. CR was durable for 22 of 26 patients in the defibrotide group, who still had a CR at last observation. Four patients in the defibrotide group had CR end dates before day 180. All 4 patients died of sepsis or leukemia.

In the historical control group, 1 patient had a durable CR (162 days), 2 patients had a limited CR duration (9 and 10 days, respectively), and 1 patient could not be assessed.

 

 

Safety

The median duration of defibrotide treatment was 21.5 days. Eleven patients discontinued treatment prematurely due to possible drug-related toxicity (10.7%).

All but 1 of the defibrotide-treated patients and all historical controls had at least 1 AE. Hypotension was the most common AE in both groups—39.2% with defibrotide and 50.0% for historical controls. Diarrhea was also common—23.5% and 37.5%, respectively.

Sixty-four percent of patients in the defibrotide group (n=65) and 69% of historical controls (n=22) had a fatal AE.

Fifteen patients (14.7%) in the defibrotide group and 2 (6.3%) in the historical control group had 1 or more hemorrhagic AEs leading to death.

For the defibrotide group, these were gastrointestinal hemorrhage (n=1), cerebral hemorrhage (n=2), intracranial hemorrhage (n=1), subarachnoid hemorrhage (n=1), pulmonary alveolar hemorrhage (n=7), pulmonary hemorrhage (n=2), and vascular disorders hemorrhage (n=1).

Both hemorrhagic AEs leading to death in historical controls were pulmonary alveolar hemorrhage.

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EHA creates ‘roadmap’ for hematology research

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EHA creates ‘roadmap’ for hematology research

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Photo by Daniel Sone

The European Hematology Association (EHA) has created a “roadmap” for hematology research in Europe.

This guidance document summarizes the current status of basic, translational, and clinical hematology research and identifies areas of unmet scientific and medical need in Europe.

It is intended to help European and national policy makers, funding agencies, charities, research institutes, and researchers make decisions on initiating, funding, or developing research.

The guidance, “The European Hematology Association Roadmap for European Hematology Research: A Consensus Document,” is published in this month’s issue of haematologica.

“For the first time, hematologists in Europe came together to develop a roadmap to guide hematology research in Europe” said Andreas Engert, MD, chair of the EHA Research Roadmap Task Force.

“Hematology in Europe has achieved a lot, but the discipline must focus and collaborate to be efficient and remain successful in improving patient outcomes. The roadmap does just that and will determine the research agenda in Europe in the coming years.”

Roughly 300 experts from more than 20 countries—including clinicians, basic researchers, and patients—contributed to the roadmap. Stakeholders such as national hematology societies, patient organizations, hematology trial groups, and other European organizations were consulted to comment on the final draft version.

The final roadmap has 9 sections: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation.

The roadmap lists priorities and needs in these areas, including the need for targeted therapies based on genomic profiling and chemical biology, the need to eradicate minimal residual disease, and the need for treatments that are better tolerated by elderly patients.

“Now’s the time for Europe to pay attention,” said Ulrich Jäger, MD, chair of the EHA European Affairs Committee.

“With an aging population, the slow recovery from the financial and Euro crises, costly medical breakthroughs and innovations—quite a few of which involve hematology researchers—Europe faces increased health expenditures while budgets are limited.”

“Policy makers are rightfully cautious when spending the taxpayers’ money. So it is our responsibility to provide the policy makers with the information and evidence they need to decide where their support impacts knowledge and health most efficiently, to the benefit of patients and society. The Research Roadmap delivers on that. Now, it is up to the policy makers in the EU to deliver too.”

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Researcher in the lab

Photo by Daniel Sone

The European Hematology Association (EHA) has created a “roadmap” for hematology research in Europe.

This guidance document summarizes the current status of basic, translational, and clinical hematology research and identifies areas of unmet scientific and medical need in Europe.

It is intended to help European and national policy makers, funding agencies, charities, research institutes, and researchers make decisions on initiating, funding, or developing research.

The guidance, “The European Hematology Association Roadmap for European Hematology Research: A Consensus Document,” is published in this month’s issue of haematologica.

“For the first time, hematologists in Europe came together to develop a roadmap to guide hematology research in Europe” said Andreas Engert, MD, chair of the EHA Research Roadmap Task Force.

“Hematology in Europe has achieved a lot, but the discipline must focus and collaborate to be efficient and remain successful in improving patient outcomes. The roadmap does just that and will determine the research agenda in Europe in the coming years.”

Roughly 300 experts from more than 20 countries—including clinicians, basic researchers, and patients—contributed to the roadmap. Stakeholders such as national hematology societies, patient organizations, hematology trial groups, and other European organizations were consulted to comment on the final draft version.

The final roadmap has 9 sections: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation.

The roadmap lists priorities and needs in these areas, including the need for targeted therapies based on genomic profiling and chemical biology, the need to eradicate minimal residual disease, and the need for treatments that are better tolerated by elderly patients.

“Now’s the time for Europe to pay attention,” said Ulrich Jäger, MD, chair of the EHA European Affairs Committee.

“With an aging population, the slow recovery from the financial and Euro crises, costly medical breakthroughs and innovations—quite a few of which involve hematology researchers—Europe faces increased health expenditures while budgets are limited.”

“Policy makers are rightfully cautious when spending the taxpayers’ money. So it is our responsibility to provide the policy makers with the information and evidence they need to decide where their support impacts knowledge and health most efficiently, to the benefit of patients and society. The Research Roadmap delivers on that. Now, it is up to the policy makers in the EU to deliver too.”

Researcher in the lab

Photo by Daniel Sone

The European Hematology Association (EHA) has created a “roadmap” for hematology research in Europe.

This guidance document summarizes the current status of basic, translational, and clinical hematology research and identifies areas of unmet scientific and medical need in Europe.

It is intended to help European and national policy makers, funding agencies, charities, research institutes, and researchers make decisions on initiating, funding, or developing research.

The guidance, “The European Hematology Association Roadmap for European Hematology Research: A Consensus Document,” is published in this month’s issue of haematologica.

“For the first time, hematologists in Europe came together to develop a roadmap to guide hematology research in Europe” said Andreas Engert, MD, chair of the EHA Research Roadmap Task Force.

“Hematology in Europe has achieved a lot, but the discipline must focus and collaborate to be efficient and remain successful in improving patient outcomes. The roadmap does just that and will determine the research agenda in Europe in the coming years.”

Roughly 300 experts from more than 20 countries—including clinicians, basic researchers, and patients—contributed to the roadmap. Stakeholders such as national hematology societies, patient organizations, hematology trial groups, and other European organizations were consulted to comment on the final draft version.

The final roadmap has 9 sections: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation.

The roadmap lists priorities and needs in these areas, including the need for targeted therapies based on genomic profiling and chemical biology, the need to eradicate minimal residual disease, and the need for treatments that are better tolerated by elderly patients.

“Now’s the time for Europe to pay attention,” said Ulrich Jäger, MD, chair of the EHA European Affairs Committee.

“With an aging population, the slow recovery from the financial and Euro crises, costly medical breakthroughs and innovations—quite a few of which involve hematology researchers—Europe faces increased health expenditures while budgets are limited.”

“Policy makers are rightfully cautious when spending the taxpayers’ money. So it is our responsibility to provide the policy makers with the information and evidence they need to decide where their support impacts knowledge and health most efficiently, to the benefit of patients and society. The Research Roadmap delivers on that. Now, it is up to the policy makers in the EU to deliver too.”

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PBSCs used to treat BMF despite drawbacks

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PBSCs used to treat BMF despite drawbacks

PBSC collection

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District Health Board

Although studies have suggested that peripheral blood stem cells (PBSCs) are not the ideal graft source for patients with bone marrow failure (BMF), new research suggests transplant centers worldwide are still using PBSCs in these patients.

The study included data on more than 3000 hematopoietic stem cell transplants (HSCTs) performed in patients with BMF.

The numbers revealed that PBSCs were most-used in the Asia-Pacific region, Africa, and the Eastern Mediterranean region. But they were also used in Europe and the Americas.

Ayami Yoshimi, MD, PhD, of the University of Freiburg, Germany, and colleagues disclosed these findings in a letter to JAMA.

The researchers noted that bone marrow is the recommended graft source for HSCT in patients with BMF, as studies have shown that PBSCs are associated with higher rates of graft-vs-host disease and lower rates of survival.

With this in mind, the team examined the graft sources used in patients with BMF who underwent HSCTs from 2009 through 2010. The researchers looked at 194 World Health Organization member states and found that 74 had reported at least 1 HSCT during that time period.

Of the 114,217 transplants performed, there were 3282 allogeneic HSCTs in patients with BMF. Overall, the most-used graft source was bone marrow (54%), followed by PBSCs (41%), and then cord blood (5%).

Bone marrow was used most commonly in the Americas (75%) and in Europe (60%) but not in the Eastern Mediterranean region and Africa (46%) or in the Asia-Pacific region (41%; excluding Japan, 19%).

The researchers also looked at graft source according to donor type, both overall and by region, but they excluded the 180 cord blood transplants from this analysis.

The team found that, among patients who had a related donor, 57% received bone marrow and 43% received PBSCs.

For related HSCTs in the Americas, 75% of patients received bone marrow and 25% received PBSCs. In Europe, 63% received bone marrow and 37% received PBSCs. In the Eastern Mediterranean and Africa, 47% received bone marrow and 53% received PBSCs. And in the Asia-Pacific region, 37% received bone marrow and 63% received PBSCs.

Among patients who had unrelated donors, 57% received bone marrow and 43% received PBSCs.

For unrelated HSCTs in the Americas, 74% of patients received bone marrow and 26% received PBSCs. In Europe, 56% received bone marrow and 44% received PBSCs. In the Asia-Pacific region, 47% received bone marrow and 53% received PBSCs. And in the Eastern Mediterranean and Africa, 100% received PBSCs.

The use of bone marrow increased from 20% in countries with low and low-middle incomes to 50% in countries with high-middle incomes and 64% in countries with high incomes (P<0.001). There was a significant association between gross national income per capita and stem cell source (P=0.002).

The researchers speculated that PBSCs are still used in BMF patients, despite the disadvantages, because transplant centers routinely obtain PBSCs for other indications, cell separators are available at any transplant center, and PBSC transplants can be performed at a lower cost than bone marrow transplants.

The team said the association between graft source and income supports the idea that short-term financial considerations are important.

So transplant organizations and authorities should help foster regional-accredited bone marrow harvest centers for patients with nonmalignant disorders. And unrelated donor registries should provide information on the necessity of bone marrow donation for patients with BMF.

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PBSC collection

Photo from the Canterbury

District Health Board

Although studies have suggested that peripheral blood stem cells (PBSCs) are not the ideal graft source for patients with bone marrow failure (BMF), new research suggests transplant centers worldwide are still using PBSCs in these patients.

The study included data on more than 3000 hematopoietic stem cell transplants (HSCTs) performed in patients with BMF.

The numbers revealed that PBSCs were most-used in the Asia-Pacific region, Africa, and the Eastern Mediterranean region. But they were also used in Europe and the Americas.

Ayami Yoshimi, MD, PhD, of the University of Freiburg, Germany, and colleagues disclosed these findings in a letter to JAMA.

The researchers noted that bone marrow is the recommended graft source for HSCT in patients with BMF, as studies have shown that PBSCs are associated with higher rates of graft-vs-host disease and lower rates of survival.

With this in mind, the team examined the graft sources used in patients with BMF who underwent HSCTs from 2009 through 2010. The researchers looked at 194 World Health Organization member states and found that 74 had reported at least 1 HSCT during that time period.

Of the 114,217 transplants performed, there were 3282 allogeneic HSCTs in patients with BMF. Overall, the most-used graft source was bone marrow (54%), followed by PBSCs (41%), and then cord blood (5%).

Bone marrow was used most commonly in the Americas (75%) and in Europe (60%) but not in the Eastern Mediterranean region and Africa (46%) or in the Asia-Pacific region (41%; excluding Japan, 19%).

The researchers also looked at graft source according to donor type, both overall and by region, but they excluded the 180 cord blood transplants from this analysis.

The team found that, among patients who had a related donor, 57% received bone marrow and 43% received PBSCs.

For related HSCTs in the Americas, 75% of patients received bone marrow and 25% received PBSCs. In Europe, 63% received bone marrow and 37% received PBSCs. In the Eastern Mediterranean and Africa, 47% received bone marrow and 53% received PBSCs. And in the Asia-Pacific region, 37% received bone marrow and 63% received PBSCs.

Among patients who had unrelated donors, 57% received bone marrow and 43% received PBSCs.

For unrelated HSCTs in the Americas, 74% of patients received bone marrow and 26% received PBSCs. In Europe, 56% received bone marrow and 44% received PBSCs. In the Asia-Pacific region, 47% received bone marrow and 53% received PBSCs. And in the Eastern Mediterranean and Africa, 100% received PBSCs.

The use of bone marrow increased from 20% in countries with low and low-middle incomes to 50% in countries with high-middle incomes and 64% in countries with high incomes (P<0.001). There was a significant association between gross national income per capita and stem cell source (P=0.002).

The researchers speculated that PBSCs are still used in BMF patients, despite the disadvantages, because transplant centers routinely obtain PBSCs for other indications, cell separators are available at any transplant center, and PBSC transplants can be performed at a lower cost than bone marrow transplants.

The team said the association between graft source and income supports the idea that short-term financial considerations are important.

So transplant organizations and authorities should help foster regional-accredited bone marrow harvest centers for patients with nonmalignant disorders. And unrelated donor registries should provide information on the necessity of bone marrow donation for patients with BMF.

PBSC collection

Photo from the Canterbury

District Health Board

Although studies have suggested that peripheral blood stem cells (PBSCs) are not the ideal graft source for patients with bone marrow failure (BMF), new research suggests transplant centers worldwide are still using PBSCs in these patients.

The study included data on more than 3000 hematopoietic stem cell transplants (HSCTs) performed in patients with BMF.

The numbers revealed that PBSCs were most-used in the Asia-Pacific region, Africa, and the Eastern Mediterranean region. But they were also used in Europe and the Americas.

Ayami Yoshimi, MD, PhD, of the University of Freiburg, Germany, and colleagues disclosed these findings in a letter to JAMA.

The researchers noted that bone marrow is the recommended graft source for HSCT in patients with BMF, as studies have shown that PBSCs are associated with higher rates of graft-vs-host disease and lower rates of survival.

With this in mind, the team examined the graft sources used in patients with BMF who underwent HSCTs from 2009 through 2010. The researchers looked at 194 World Health Organization member states and found that 74 had reported at least 1 HSCT during that time period.

Of the 114,217 transplants performed, there were 3282 allogeneic HSCTs in patients with BMF. Overall, the most-used graft source was bone marrow (54%), followed by PBSCs (41%), and then cord blood (5%).

Bone marrow was used most commonly in the Americas (75%) and in Europe (60%) but not in the Eastern Mediterranean region and Africa (46%) or in the Asia-Pacific region (41%; excluding Japan, 19%).

The researchers also looked at graft source according to donor type, both overall and by region, but they excluded the 180 cord blood transplants from this analysis.

The team found that, among patients who had a related donor, 57% received bone marrow and 43% received PBSCs.

For related HSCTs in the Americas, 75% of patients received bone marrow and 25% received PBSCs. In Europe, 63% received bone marrow and 37% received PBSCs. In the Eastern Mediterranean and Africa, 47% received bone marrow and 53% received PBSCs. And in the Asia-Pacific region, 37% received bone marrow and 63% received PBSCs.

Among patients who had unrelated donors, 57% received bone marrow and 43% received PBSCs.

For unrelated HSCTs in the Americas, 74% of patients received bone marrow and 26% received PBSCs. In Europe, 56% received bone marrow and 44% received PBSCs. In the Asia-Pacific region, 47% received bone marrow and 53% received PBSCs. And in the Eastern Mediterranean and Africa, 100% received PBSCs.

The use of bone marrow increased from 20% in countries with low and low-middle incomes to 50% in countries with high-middle incomes and 64% in countries with high incomes (P<0.001). There was a significant association between gross national income per capita and stem cell source (P=0.002).

The researchers speculated that PBSCs are still used in BMF patients, despite the disadvantages, because transplant centers routinely obtain PBSCs for other indications, cell separators are available at any transplant center, and PBSC transplants can be performed at a lower cost than bone marrow transplants.

The team said the association between graft source and income supports the idea that short-term financial considerations are important.

So transplant organizations and authorities should help foster regional-accredited bone marrow harvest centers for patients with nonmalignant disorders. And unrelated donor registries should provide information on the necessity of bone marrow donation for patients with BMF.

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ATG can reduce risk, severity of chronic GVHD

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ATG can reduce risk, severity of chronic GVHD

Skin biopsy showing GVHD

Image courtesy of PLOS ONE

Results of a phase 3 study suggest that administering antihuman T-lymphocyte immune globulin (ATG) prior to hematopoietic stem cell transplant (HSCT) can decrease the risk and severity of chronic graft-versus-host disease (GVHD).

Study investigators included ATG in the conditioning regimens of leukemia patients receiving peripheral blood stem cells from an HLA-identical sibling donor.

Two years after HSCT, these patients had less than half the rate of chronic GVHD of patients who did not receive ATG.

In addition, patients who received ATG were less likely to have severe chronic GVHD.

Nicolaus Kroger, MD, of the University Medical Center Hamburg-Eppendorf in Hamburg, Germany, and his colleagues reported these results in NEJM.

The investigators enrolled 168 patients undergoing HSCT at 27 centers. They were randomized in a 1:1 ratio to receive ATG or not.

One hundred and fifty-five patients were randomized and evaluable—83 in the ATG group and 72 in the non-ATG group.

The only significant difference in baseline characteristics was age. The median age was 39 (range, 18-64) in the ATG group and 43.5 (range, 21-61) in the non-ATG group (P=0.04).

Most patients in both groups were male (63.9% and 55.6%, respectively), and most had acute myeloid leukemia (66.3% and 76.4%, respectively) rather than acute lymphoblastic leukemia (33.8% and 23.6%, respectively).

Most patients had intermediate-risk disease (75.9% and 82.1%, respectively), and a minority had high-risk cytogenetics (37.3% and 30.6%, respectively).

The median time between diagnosis and HSCT was about 5 months in both groups. Both groups had a median of 2 courses of chemotherapy before transplant (overall range, 1-8).

Most patients in both groups received busulfan plus cyclophosphamide as conditioning—67.5% of the ATG group and 70.8% of the non-ATG group. Some received total-body irradiation plus cyclophosphamide (27.7% and 25.0%, respectively), and a few received total-body irradiation plus etoposide (4.8% and 4.2%, respectively).

Results

After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was significantly lower in the ATG group than the non-ATG group—32.2% and 68.7%, respectively (P<0.001).

In addition, patients in the ATG group were significantly less likely to have severe or extensive chronic GVHD.

According to revised Seattle criteria, the rate of limited chronic GVHD was 20.5% in the ATG group and 30.6% in the non-ATG group. And the rates of extensive chronic GVHD were 6% and 33.3%, respectively (P<0.001).

According to revised NIH criteria, the rate of mild chronic GVHD was 15.7% in the ATG group and 16.7% in the non-ATG group. The rates of moderate chronic GVHD were 8.4% and 25%, respectively. And the rates of severe chronic GVHD were 2.4% and 22.2%, respectively (P<0.001).

However, all other outcomes, when assessed alone, were similar between the treatment groups.

The rate of 2-year relapse-free survival was 59.4% in the ATG group and 64.6% in the non-ATG group (P=0.21). The overall survival rates were 74.1% and 77.9%, respectively (P=0.46).

The incidence of relapse was 32.2% and 35.5%, respectively (P=0.17). Infectious complications occurred in 57.8% and 54.2%, respectively (P=0.65). And the rates of acute GVHD were 10.8% and 18.1%, respectively (P=0.13).

However, the rate of a composite endpoint of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than the non-ATG group—36.6% and 16.8%, respectively (P=0.005).

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Skin biopsy showing GVHD

Image courtesy of PLOS ONE

Results of a phase 3 study suggest that administering antihuman T-lymphocyte immune globulin (ATG) prior to hematopoietic stem cell transplant (HSCT) can decrease the risk and severity of chronic graft-versus-host disease (GVHD).

Study investigators included ATG in the conditioning regimens of leukemia patients receiving peripheral blood stem cells from an HLA-identical sibling donor.

Two years after HSCT, these patients had less than half the rate of chronic GVHD of patients who did not receive ATG.

In addition, patients who received ATG were less likely to have severe chronic GVHD.

Nicolaus Kroger, MD, of the University Medical Center Hamburg-Eppendorf in Hamburg, Germany, and his colleagues reported these results in NEJM.

The investigators enrolled 168 patients undergoing HSCT at 27 centers. They were randomized in a 1:1 ratio to receive ATG or not.

One hundred and fifty-five patients were randomized and evaluable—83 in the ATG group and 72 in the non-ATG group.

The only significant difference in baseline characteristics was age. The median age was 39 (range, 18-64) in the ATG group and 43.5 (range, 21-61) in the non-ATG group (P=0.04).

Most patients in both groups were male (63.9% and 55.6%, respectively), and most had acute myeloid leukemia (66.3% and 76.4%, respectively) rather than acute lymphoblastic leukemia (33.8% and 23.6%, respectively).

Most patients had intermediate-risk disease (75.9% and 82.1%, respectively), and a minority had high-risk cytogenetics (37.3% and 30.6%, respectively).

The median time between diagnosis and HSCT was about 5 months in both groups. Both groups had a median of 2 courses of chemotherapy before transplant (overall range, 1-8).

Most patients in both groups received busulfan plus cyclophosphamide as conditioning—67.5% of the ATG group and 70.8% of the non-ATG group. Some received total-body irradiation plus cyclophosphamide (27.7% and 25.0%, respectively), and a few received total-body irradiation plus etoposide (4.8% and 4.2%, respectively).

Results

After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was significantly lower in the ATG group than the non-ATG group—32.2% and 68.7%, respectively (P<0.001).

In addition, patients in the ATG group were significantly less likely to have severe or extensive chronic GVHD.

According to revised Seattle criteria, the rate of limited chronic GVHD was 20.5% in the ATG group and 30.6% in the non-ATG group. And the rates of extensive chronic GVHD were 6% and 33.3%, respectively (P<0.001).

According to revised NIH criteria, the rate of mild chronic GVHD was 15.7% in the ATG group and 16.7% in the non-ATG group. The rates of moderate chronic GVHD were 8.4% and 25%, respectively. And the rates of severe chronic GVHD were 2.4% and 22.2%, respectively (P<0.001).

However, all other outcomes, when assessed alone, were similar between the treatment groups.

The rate of 2-year relapse-free survival was 59.4% in the ATG group and 64.6% in the non-ATG group (P=0.21). The overall survival rates were 74.1% and 77.9%, respectively (P=0.46).

The incidence of relapse was 32.2% and 35.5%, respectively (P=0.17). Infectious complications occurred in 57.8% and 54.2%, respectively (P=0.65). And the rates of acute GVHD were 10.8% and 18.1%, respectively (P=0.13).

However, the rate of a composite endpoint of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than the non-ATG group—36.6% and 16.8%, respectively (P=0.005).

Skin biopsy showing GVHD

Image courtesy of PLOS ONE

Results of a phase 3 study suggest that administering antihuman T-lymphocyte immune globulin (ATG) prior to hematopoietic stem cell transplant (HSCT) can decrease the risk and severity of chronic graft-versus-host disease (GVHD).

Study investigators included ATG in the conditioning regimens of leukemia patients receiving peripheral blood stem cells from an HLA-identical sibling donor.

Two years after HSCT, these patients had less than half the rate of chronic GVHD of patients who did not receive ATG.

In addition, patients who received ATG were less likely to have severe chronic GVHD.

Nicolaus Kroger, MD, of the University Medical Center Hamburg-Eppendorf in Hamburg, Germany, and his colleagues reported these results in NEJM.

The investigators enrolled 168 patients undergoing HSCT at 27 centers. They were randomized in a 1:1 ratio to receive ATG or not.

One hundred and fifty-five patients were randomized and evaluable—83 in the ATG group and 72 in the non-ATG group.

The only significant difference in baseline characteristics was age. The median age was 39 (range, 18-64) in the ATG group and 43.5 (range, 21-61) in the non-ATG group (P=0.04).

Most patients in both groups were male (63.9% and 55.6%, respectively), and most had acute myeloid leukemia (66.3% and 76.4%, respectively) rather than acute lymphoblastic leukemia (33.8% and 23.6%, respectively).

Most patients had intermediate-risk disease (75.9% and 82.1%, respectively), and a minority had high-risk cytogenetics (37.3% and 30.6%, respectively).

The median time between diagnosis and HSCT was about 5 months in both groups. Both groups had a median of 2 courses of chemotherapy before transplant (overall range, 1-8).

Most patients in both groups received busulfan plus cyclophosphamide as conditioning—67.5% of the ATG group and 70.8% of the non-ATG group. Some received total-body irradiation plus cyclophosphamide (27.7% and 25.0%, respectively), and a few received total-body irradiation plus etoposide (4.8% and 4.2%, respectively).

Results

After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was significantly lower in the ATG group than the non-ATG group—32.2% and 68.7%, respectively (P<0.001).

In addition, patients in the ATG group were significantly less likely to have severe or extensive chronic GVHD.

According to revised Seattle criteria, the rate of limited chronic GVHD was 20.5% in the ATG group and 30.6% in the non-ATG group. And the rates of extensive chronic GVHD were 6% and 33.3%, respectively (P<0.001).

According to revised NIH criteria, the rate of mild chronic GVHD was 15.7% in the ATG group and 16.7% in the non-ATG group. The rates of moderate chronic GVHD were 8.4% and 25%, respectively. And the rates of severe chronic GVHD were 2.4% and 22.2%, respectively (P<0.001).

However, all other outcomes, when assessed alone, were similar between the treatment groups.

The rate of 2-year relapse-free survival was 59.4% in the ATG group and 64.6% in the non-ATG group (P=0.21). The overall survival rates were 74.1% and 77.9%, respectively (P=0.46).

The incidence of relapse was 32.2% and 35.5%, respectively (P=0.17). Infectious complications occurred in 57.8% and 54.2%, respectively (P=0.65). And the rates of acute GVHD were 10.8% and 18.1%, respectively (P=0.13).

However, the rate of a composite endpoint of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than the non-ATG group—36.6% and 16.8%, respectively (P=0.005).

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HSPCs shape their own environment, team says

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HSPCs shape their own environment, team says

Hematopoietic stem cells

in the bone marrow

New research has revealed a mechanism through which hematopoietic stem and progenitor cells (HSPCs) control both their own proliferation and the characteristics of the niche that houses them.

Researchers detected high expression of the protein E-selectin ligand-1 (ESL-1) in HSPCs and also found that ESL-1 controls HSPCs’ production of the cytokine TGF-β.

The team said this is important because TGF-β has antiproliferative properties and is essential for impeding the loss of HSPCs in some diseases, such as some types of anemia.

The researchers also showed that HSPCs lacking ESL-1 are resistant to chemotherapeutic and cytotoxic agents.

These results suggest ESL-1 is a potential target for therapies aimed at improving bone marrow regeneration after chemotherapy or for expanding the HSPC population in preparation for donation.

Magdalena Leiva, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues reported these findings in Nature Communications.

The researchers first found that ESL-1 deficiency causes HSPC quiescence and expansion, and elevated TGF-β causes quiescence in the absence of ESL-1. In addition, ESL-1 controls HSPC proliferation independently of E-selectin, and HSPCs are a relevant source of TGF-β.

The team also discovered that ESL-1 exerts local effects on distinct cell populations in the stromal niche. They found that hematopoietic-borne ESL-1 can control HSPC proliferation directly through cytokine secretion, and/or indirectly through repressive effects on supportive niche cells.

According to Dr Leiva, this finding opens the path to new therapies “that use genetically modified stem cells to treat hematological diseases, such as certain types of leukemia, in which the hematopoietic niche and HSPCs are very affected.”

The researchers made these discoveries by analyzing the bone marrow of mice deficient in ESL-1. In the absence of ESL-1, HSPCs proliferated less and were therefore of superior quality and more suitable for potential therapeutic applications, the team found.

“We see that these cells are resistant to processes associated with bone marrow damage, such as cell death triggered by cytotoxic agents,” Dr Leiva said.

She and her colleagues found that stem cells lacking ESL-1 were resistant to the deleterious effects of 5-fluorouracil and hydroxyurea. They said this suggests ESL-1 is a possible therapeutic target for improved regeneration of the bone marrow during chemotherapy.

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Hematopoietic stem cells

in the bone marrow

New research has revealed a mechanism through which hematopoietic stem and progenitor cells (HSPCs) control both their own proliferation and the characteristics of the niche that houses them.

Researchers detected high expression of the protein E-selectin ligand-1 (ESL-1) in HSPCs and also found that ESL-1 controls HSPCs’ production of the cytokine TGF-β.

The team said this is important because TGF-β has antiproliferative properties and is essential for impeding the loss of HSPCs in some diseases, such as some types of anemia.

The researchers also showed that HSPCs lacking ESL-1 are resistant to chemotherapeutic and cytotoxic agents.

These results suggest ESL-1 is a potential target for therapies aimed at improving bone marrow regeneration after chemotherapy or for expanding the HSPC population in preparation for donation.

Magdalena Leiva, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues reported these findings in Nature Communications.

The researchers first found that ESL-1 deficiency causes HSPC quiescence and expansion, and elevated TGF-β causes quiescence in the absence of ESL-1. In addition, ESL-1 controls HSPC proliferation independently of E-selectin, and HSPCs are a relevant source of TGF-β.

The team also discovered that ESL-1 exerts local effects on distinct cell populations in the stromal niche. They found that hematopoietic-borne ESL-1 can control HSPC proliferation directly through cytokine secretion, and/or indirectly through repressive effects on supportive niche cells.

According to Dr Leiva, this finding opens the path to new therapies “that use genetically modified stem cells to treat hematological diseases, such as certain types of leukemia, in which the hematopoietic niche and HSPCs are very affected.”

The researchers made these discoveries by analyzing the bone marrow of mice deficient in ESL-1. In the absence of ESL-1, HSPCs proliferated less and were therefore of superior quality and more suitable for potential therapeutic applications, the team found.

“We see that these cells are resistant to processes associated with bone marrow damage, such as cell death triggered by cytotoxic agents,” Dr Leiva said.

She and her colleagues found that stem cells lacking ESL-1 were resistant to the deleterious effects of 5-fluorouracil and hydroxyurea. They said this suggests ESL-1 is a possible therapeutic target for improved regeneration of the bone marrow during chemotherapy.

Hematopoietic stem cells

in the bone marrow

New research has revealed a mechanism through which hematopoietic stem and progenitor cells (HSPCs) control both their own proliferation and the characteristics of the niche that houses them.

Researchers detected high expression of the protein E-selectin ligand-1 (ESL-1) in HSPCs and also found that ESL-1 controls HSPCs’ production of the cytokine TGF-β.

The team said this is important because TGF-β has antiproliferative properties and is essential for impeding the loss of HSPCs in some diseases, such as some types of anemia.

The researchers also showed that HSPCs lacking ESL-1 are resistant to chemotherapeutic and cytotoxic agents.

These results suggest ESL-1 is a potential target for therapies aimed at improving bone marrow regeneration after chemotherapy or for expanding the HSPC population in preparation for donation.

Magdalena Leiva, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues reported these findings in Nature Communications.

The researchers first found that ESL-1 deficiency causes HSPC quiescence and expansion, and elevated TGF-β causes quiescence in the absence of ESL-1. In addition, ESL-1 controls HSPC proliferation independently of E-selectin, and HSPCs are a relevant source of TGF-β.

The team also discovered that ESL-1 exerts local effects on distinct cell populations in the stromal niche. They found that hematopoietic-borne ESL-1 can control HSPC proliferation directly through cytokine secretion, and/or indirectly through repressive effects on supportive niche cells.

According to Dr Leiva, this finding opens the path to new therapies “that use genetically modified stem cells to treat hematological diseases, such as certain types of leukemia, in which the hematopoietic niche and HSPCs are very affected.”

The researchers made these discoveries by analyzing the bone marrow of mice deficient in ESL-1. In the absence of ESL-1, HSPCs proliferated less and were therefore of superior quality and more suitable for potential therapeutic applications, the team found.

“We see that these cells are resistant to processes associated with bone marrow damage, such as cell death triggered by cytotoxic agents,” Dr Leiva said.

She and her colleagues found that stem cells lacking ESL-1 were resistant to the deleterious effects of 5-fluorouracil and hydroxyurea. They said this suggests ESL-1 is a possible therapeutic target for improved regeneration of the bone marrow during chemotherapy.

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