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Cognitive impairment in HSCT recipients
New research suggests the risk of cognitive impairment after hematopoietic stem cell transplant (HSCT) is greatest among recipients of myeloablative allogeneic (allo) HSCTs.
Compared to healthy controls, patients who received myeloablative allo-HSCT had a significantly higher risk of global cognitive deficit at a few time points after transplant.
There was a trend toward increased global cognitive deficit in recipients of allo-HSCT who had reduced-intensity conditioning (RIC), but there was no increased risk of global cognitive deficit in recipients of autologous (auto) HSCT.
Researchers reported these findings in the Journal of Clinical Oncology.
“With this research from our longitudinal prospective assessment, we are able to deduce that a significant population of allogeneic [HSCT] survivors will experience cognitive impairment that can and will impact different aspects of their lives moving forward,” said study author Noha Sharafeldin, MD, PhD, of the University of Alabama at Birmingham.
“And it’s critical that we as clinicians develop interventions for these patients. This research is just the beginning of our figuring out how we can best care for [HSCT] survivors and enable them to live healthy lives.”
This study included 477 patients who underwent HSCT between 2004 and 2014. There were 236 auto-HSCTs, 128 RIC allo-HSCTs, and 113 myeloablative allo-HSCTs.
Patients underwent standardized neuropsychological testing before HSCT as well as at 6 months, 1 year, 2 years, and 3 years after transplant.
There were 429 patients who completed pre-HSCT testing (89.9%), 341 (81.6%) who underwent testing at 6 months after HSCT, 308 (81.5%) at 1 year, 247 (80.7%) at 2 years, and 227 (81.4%) at 3 years.
Testing was conducted on 8 cognitive domains—executive function, verbal fluency and speed, processing speed, working memory, visual and auditory memory, and fine motor dexterity.
The researchers conducted this testing in 99 healthy control subjects as well.
Before and after HSCT
Prior to HSCT, there were no significant differences in the cognitive domains tested between auto-HSCT recipients and controls or between RIC allo-HSCT recipients and controls.
Recipients of myeloablative allo-HSCT had significantly lower pre-HSCT scores for processing speed (P=0.001), as compared to controls.
After HSCT, there were no significant differences in overall scores between auto-HSCT recipients and controls or between RIC allo-HSCT recipients and controls.
However, recipients of myeloablative allo-HSCT had significantly lower scores than controls for executive function, verbal speed, processing speed, auditory memory, and fine motor dexterity (P≤0.003 for all).
Outcomes over time
For auto-HSCT recipients, there was a significant improvement from pre-HSCT to 6 months post-HSCT in verbal fluency (P<0.001). Meanwhile, there was a significant decrease in verbal processing and fine motor dexterity (P<0.001 for both).
At 3 years, auto-HSCT recipients had a significant increase in verbal fluency (P<0.001) but a significant decrease in visual memory (P=0.001) and fine motor dexterity (P<0.001).
For RIC allo-HSCT recipients, there was a significant decrease from pre-HSCT to 3 years post-HSCT in executive functioning (P=0.003), verbal fluency (P<0.001), and working memory (P<0.001). There were no significant differences between pre-HSCT and 6-month scores.
For patients who received myeloablative allo-HSCT, the only significant difference from pre-HSCT to 6 months or 3 years was a decrease in fine motor dexterity (P<0.001 for both time points).
Global cognitive deficit
There was no significant difference in the prevalence of global cognitive deficit between auto-HSCT recipients and controls before HSCT (22.5% vs 17.2%; P=0.28) or at any time point after—6 months (26.1% vs 16.5%; P=0.07), 1 year (21.4% vs 19.5%; P=0.73), 2 years (21.1% vs 16.4%; P=0.43), and 3 years (18.7% vs 8.7%, P=0.11).
There was no significant difference in the prevalence of global cognitive deficit between RIC allo-HSCT recipients and controls before HSCT (17.2% for both; P=1.0), at 6 months (22.0% vs 16.5%; P=0.35), 1 year (24.1% vs 19.5%; P=0.46), or 2 years (30.6% vs 16.4%; P=0.05) after HSCT.
However, the prevalence was significantly higher for RIC allo-HSCT recipients 3 years after HSCT (35.4% vs 8.7%; P=0.0012).
There was no significant difference in the prevalence of global cognitive deficit between myeloablative allo-HSCT recipients and controls before HSCT (22.3% vs 17.2%; P=0.37) or at 1 year after (28.4% vs 19.5%; P=0.20).
However, the prevalence was significantly higher for myeloablative allo-HSCT recipients at 6 months (31.1% vs 16.5%; P=0.03), 2 years (34.6% vs 16.4%; P=0.02), and 3 years after HSCT (36.0% vs 8.7%; P=0.0015).
“From this data, it’s clear that we have to make strides in supporting allogeneic [HSCT] recipients in their recovery to ensure that we are educating patients and their families on signs of cognitive impairment,” Dr Sharafeldin said. “This data will help us identify patients at highest risk of cognitive impairment and inform the development of interventions that facilitate a patient’s recovery and return to normal life.”
New research suggests the risk of cognitive impairment after hematopoietic stem cell transplant (HSCT) is greatest among recipients of myeloablative allogeneic (allo) HSCTs.
Compared to healthy controls, patients who received myeloablative allo-HSCT had a significantly higher risk of global cognitive deficit at a few time points after transplant.
There was a trend toward increased global cognitive deficit in recipients of allo-HSCT who had reduced-intensity conditioning (RIC), but there was no increased risk of global cognitive deficit in recipients of autologous (auto) HSCT.
Researchers reported these findings in the Journal of Clinical Oncology.
“With this research from our longitudinal prospective assessment, we are able to deduce that a significant population of allogeneic [HSCT] survivors will experience cognitive impairment that can and will impact different aspects of their lives moving forward,” said study author Noha Sharafeldin, MD, PhD, of the University of Alabama at Birmingham.
“And it’s critical that we as clinicians develop interventions for these patients. This research is just the beginning of our figuring out how we can best care for [HSCT] survivors and enable them to live healthy lives.”
This study included 477 patients who underwent HSCT between 2004 and 2014. There were 236 auto-HSCTs, 128 RIC allo-HSCTs, and 113 myeloablative allo-HSCTs.
Patients underwent standardized neuropsychological testing before HSCT as well as at 6 months, 1 year, 2 years, and 3 years after transplant.
There were 429 patients who completed pre-HSCT testing (89.9%), 341 (81.6%) who underwent testing at 6 months after HSCT, 308 (81.5%) at 1 year, 247 (80.7%) at 2 years, and 227 (81.4%) at 3 years.
Testing was conducted on 8 cognitive domains—executive function, verbal fluency and speed, processing speed, working memory, visual and auditory memory, and fine motor dexterity.
The researchers conducted this testing in 99 healthy control subjects as well.
Before and after HSCT
Prior to HSCT, there were no significant differences in the cognitive domains tested between auto-HSCT recipients and controls or between RIC allo-HSCT recipients and controls.
Recipients of myeloablative allo-HSCT had significantly lower pre-HSCT scores for processing speed (P=0.001), as compared to controls.
After HSCT, there were no significant differences in overall scores between auto-HSCT recipients and controls or between RIC allo-HSCT recipients and controls.
However, recipients of myeloablative allo-HSCT had significantly lower scores than controls for executive function, verbal speed, processing speed, auditory memory, and fine motor dexterity (P≤0.003 for all).
Outcomes over time
For auto-HSCT recipients, there was a significant improvement from pre-HSCT to 6 months post-HSCT in verbal fluency (P<0.001). Meanwhile, there was a significant decrease in verbal processing and fine motor dexterity (P<0.001 for both).
At 3 years, auto-HSCT recipients had a significant increase in verbal fluency (P<0.001) but a significant decrease in visual memory (P=0.001) and fine motor dexterity (P<0.001).
For RIC allo-HSCT recipients, there was a significant decrease from pre-HSCT to 3 years post-HSCT in executive functioning (P=0.003), verbal fluency (P<0.001), and working memory (P<0.001). There were no significant differences between pre-HSCT and 6-month scores.
For patients who received myeloablative allo-HSCT, the only significant difference from pre-HSCT to 6 months or 3 years was a decrease in fine motor dexterity (P<0.001 for both time points).
Global cognitive deficit
There was no significant difference in the prevalence of global cognitive deficit between auto-HSCT recipients and controls before HSCT (22.5% vs 17.2%; P=0.28) or at any time point after—6 months (26.1% vs 16.5%; P=0.07), 1 year (21.4% vs 19.5%; P=0.73), 2 years (21.1% vs 16.4%; P=0.43), and 3 years (18.7% vs 8.7%, P=0.11).
There was no significant difference in the prevalence of global cognitive deficit between RIC allo-HSCT recipients and controls before HSCT (17.2% for both; P=1.0), at 6 months (22.0% vs 16.5%; P=0.35), 1 year (24.1% vs 19.5%; P=0.46), or 2 years (30.6% vs 16.4%; P=0.05) after HSCT.
However, the prevalence was significantly higher for RIC allo-HSCT recipients 3 years after HSCT (35.4% vs 8.7%; P=0.0012).
There was no significant difference in the prevalence of global cognitive deficit between myeloablative allo-HSCT recipients and controls before HSCT (22.3% vs 17.2%; P=0.37) or at 1 year after (28.4% vs 19.5%; P=0.20).
However, the prevalence was significantly higher for myeloablative allo-HSCT recipients at 6 months (31.1% vs 16.5%; P=0.03), 2 years (34.6% vs 16.4%; P=0.02), and 3 years after HSCT (36.0% vs 8.7%; P=0.0015).
“From this data, it’s clear that we have to make strides in supporting allogeneic [HSCT] recipients in their recovery to ensure that we are educating patients and their families on signs of cognitive impairment,” Dr Sharafeldin said. “This data will help us identify patients at highest risk of cognitive impairment and inform the development of interventions that facilitate a patient’s recovery and return to normal life.”
New research suggests the risk of cognitive impairment after hematopoietic stem cell transplant (HSCT) is greatest among recipients of myeloablative allogeneic (allo) HSCTs.
Compared to healthy controls, patients who received myeloablative allo-HSCT had a significantly higher risk of global cognitive deficit at a few time points after transplant.
There was a trend toward increased global cognitive deficit in recipients of allo-HSCT who had reduced-intensity conditioning (RIC), but there was no increased risk of global cognitive deficit in recipients of autologous (auto) HSCT.
Researchers reported these findings in the Journal of Clinical Oncology.
“With this research from our longitudinal prospective assessment, we are able to deduce that a significant population of allogeneic [HSCT] survivors will experience cognitive impairment that can and will impact different aspects of their lives moving forward,” said study author Noha Sharafeldin, MD, PhD, of the University of Alabama at Birmingham.
“And it’s critical that we as clinicians develop interventions for these patients. This research is just the beginning of our figuring out how we can best care for [HSCT] survivors and enable them to live healthy lives.”
This study included 477 patients who underwent HSCT between 2004 and 2014. There were 236 auto-HSCTs, 128 RIC allo-HSCTs, and 113 myeloablative allo-HSCTs.
Patients underwent standardized neuropsychological testing before HSCT as well as at 6 months, 1 year, 2 years, and 3 years after transplant.
There were 429 patients who completed pre-HSCT testing (89.9%), 341 (81.6%) who underwent testing at 6 months after HSCT, 308 (81.5%) at 1 year, 247 (80.7%) at 2 years, and 227 (81.4%) at 3 years.
Testing was conducted on 8 cognitive domains—executive function, verbal fluency and speed, processing speed, working memory, visual and auditory memory, and fine motor dexterity.
The researchers conducted this testing in 99 healthy control subjects as well.
Before and after HSCT
Prior to HSCT, there were no significant differences in the cognitive domains tested between auto-HSCT recipients and controls or between RIC allo-HSCT recipients and controls.
Recipients of myeloablative allo-HSCT had significantly lower pre-HSCT scores for processing speed (P=0.001), as compared to controls.
After HSCT, there were no significant differences in overall scores between auto-HSCT recipients and controls or between RIC allo-HSCT recipients and controls.
However, recipients of myeloablative allo-HSCT had significantly lower scores than controls for executive function, verbal speed, processing speed, auditory memory, and fine motor dexterity (P≤0.003 for all).
Outcomes over time
For auto-HSCT recipients, there was a significant improvement from pre-HSCT to 6 months post-HSCT in verbal fluency (P<0.001). Meanwhile, there was a significant decrease in verbal processing and fine motor dexterity (P<0.001 for both).
At 3 years, auto-HSCT recipients had a significant increase in verbal fluency (P<0.001) but a significant decrease in visual memory (P=0.001) and fine motor dexterity (P<0.001).
For RIC allo-HSCT recipients, there was a significant decrease from pre-HSCT to 3 years post-HSCT in executive functioning (P=0.003), verbal fluency (P<0.001), and working memory (P<0.001). There were no significant differences between pre-HSCT and 6-month scores.
For patients who received myeloablative allo-HSCT, the only significant difference from pre-HSCT to 6 months or 3 years was a decrease in fine motor dexterity (P<0.001 for both time points).
Global cognitive deficit
There was no significant difference in the prevalence of global cognitive deficit between auto-HSCT recipients and controls before HSCT (22.5% vs 17.2%; P=0.28) or at any time point after—6 months (26.1% vs 16.5%; P=0.07), 1 year (21.4% vs 19.5%; P=0.73), 2 years (21.1% vs 16.4%; P=0.43), and 3 years (18.7% vs 8.7%, P=0.11).
There was no significant difference in the prevalence of global cognitive deficit between RIC allo-HSCT recipients and controls before HSCT (17.2% for both; P=1.0), at 6 months (22.0% vs 16.5%; P=0.35), 1 year (24.1% vs 19.5%; P=0.46), or 2 years (30.6% vs 16.4%; P=0.05) after HSCT.
However, the prevalence was significantly higher for RIC allo-HSCT recipients 3 years after HSCT (35.4% vs 8.7%; P=0.0012).
There was no significant difference in the prevalence of global cognitive deficit between myeloablative allo-HSCT recipients and controls before HSCT (22.3% vs 17.2%; P=0.37) or at 1 year after (28.4% vs 19.5%; P=0.20).
However, the prevalence was significantly higher for myeloablative allo-HSCT recipients at 6 months (31.1% vs 16.5%; P=0.03), 2 years (34.6% vs 16.4%; P=0.02), and 3 years after HSCT (36.0% vs 8.7%; P=0.0015).
“From this data, it’s clear that we have to make strides in supporting allogeneic [HSCT] recipients in their recovery to ensure that we are educating patients and their families on signs of cognitive impairment,” Dr Sharafeldin said. “This data will help us identify patients at highest risk of cognitive impairment and inform the development of interventions that facilitate a patient’s recovery and return to normal life.”
JAK2 inhibition could reduce risk of GVHD
Preclinical research suggests that targeting JAK2 can reduce the risk of graft-versus-host disease (GVHD) in transplant recipients.
Researchers found that genetic ablation of JAK2 on donor T cells or inhibition of JAK2 via treatment with pacritinib reduced GVHD in mice without compromising graft-versus-leukemia (GVL) activity.
“An effort to identify selective immune suppression whereby GVHD is reduced and the antitumor activity of the graft is preserved is key to improving the success of blood and marrow transplantation,” said Brian C. Betts, MD, of Moffitt Cancer Center in Tampa, Florida.
Dr Betts and his colleagues conducted this research and recounted their findings in PNAS.
In experiments with mice, the researchers found that donor T cells with JAK2 deletion were less likely than wild-type donor T cells to induce GVHD. However, JAK2 deletion did not impair the GVL effect.
Mice that received JAK2−/− T cells had longer survival, higher body weights, and less GVHD than control mice.
The researchers said targeting JAK2 may reduce GVHD, in part, by limiting Th1 differentiation and the migratory capacity of alloreactive T cells. However, targeting JAK2 promotes beneficial regulatory-T-cell and Th2 differentiation as well.
The researchers also tested the effects of JAK2 inhibition with pacritinib. Mice received allografts and were treated with pacritinib or vehicle control for 3 weeks.
As before, JAK2 inhibition reduced acute GVHD mortality while preserving the GVL effect.
The team also discovered that pacritinib could protect mice from tissue graft rejection, suggesting the drug could be used to prevent kidney or liver transplant rejection.
Now, the researchers are working on a phase 1/2 trial designed to determine if pacritinib and standard immune suppression can prevent acute GVHD after hematopoietic stem cell transplant (NCT02891603). 
Preclinical research suggests that targeting JAK2 can reduce the risk of graft-versus-host disease (GVHD) in transplant recipients.
Researchers found that genetic ablation of JAK2 on donor T cells or inhibition of JAK2 via treatment with pacritinib reduced GVHD in mice without compromising graft-versus-leukemia (GVL) activity.
“An effort to identify selective immune suppression whereby GVHD is reduced and the antitumor activity of the graft is preserved is key to improving the success of blood and marrow transplantation,” said Brian C. Betts, MD, of Moffitt Cancer Center in Tampa, Florida.
Dr Betts and his colleagues conducted this research and recounted their findings in PNAS.
In experiments with mice, the researchers found that donor T cells with JAK2 deletion were less likely than wild-type donor T cells to induce GVHD. However, JAK2 deletion did not impair the GVL effect.
Mice that received JAK2−/− T cells had longer survival, higher body weights, and less GVHD than control mice.
The researchers said targeting JAK2 may reduce GVHD, in part, by limiting Th1 differentiation and the migratory capacity of alloreactive T cells. However, targeting JAK2 promotes beneficial regulatory-T-cell and Th2 differentiation as well.
The researchers also tested the effects of JAK2 inhibition with pacritinib. Mice received allografts and were treated with pacritinib or vehicle control for 3 weeks.
As before, JAK2 inhibition reduced acute GVHD mortality while preserving the GVL effect.
The team also discovered that pacritinib could protect mice from tissue graft rejection, suggesting the drug could be used to prevent kidney or liver transplant rejection.
Now, the researchers are working on a phase 1/2 trial designed to determine if pacritinib and standard immune suppression can prevent acute GVHD after hematopoietic stem cell transplant (NCT02891603).
Preclinical research suggests that targeting JAK2 can reduce the risk of graft-versus-host disease (GVHD) in transplant recipients.
Researchers found that genetic ablation of JAK2 on donor T cells or inhibition of JAK2 via treatment with pacritinib reduced GVHD in mice without compromising graft-versus-leukemia (GVL) activity.
“An effort to identify selective immune suppression whereby GVHD is reduced and the antitumor activity of the graft is preserved is key to improving the success of blood and marrow transplantation,” said Brian C. Betts, MD, of Moffitt Cancer Center in Tampa, Florida.
Dr Betts and his colleagues conducted this research and recounted their findings in PNAS.
In experiments with mice, the researchers found that donor T cells with JAK2 deletion were less likely than wild-type donor T cells to induce GVHD. However, JAK2 deletion did not impair the GVL effect.
Mice that received JAK2−/− T cells had longer survival, higher body weights, and less GVHD than control mice.
The researchers said targeting JAK2 may reduce GVHD, in part, by limiting Th1 differentiation and the migratory capacity of alloreactive T cells. However, targeting JAK2 promotes beneficial regulatory-T-cell and Th2 differentiation as well.
The researchers also tested the effects of JAK2 inhibition with pacritinib. Mice received allografts and were treated with pacritinib or vehicle control for 3 weeks.
As before, JAK2 inhibition reduced acute GVHD mortality while preserving the GVL effect.
The team also discovered that pacritinib could protect mice from tissue graft rejection, suggesting the drug could be used to prevent kidney or liver transplant rejection.
Now, the researchers are working on a phase 1/2 trial designed to determine if pacritinib and standard immune suppression can prevent acute GVHD after hematopoietic stem cell transplant (NCT02891603).
Agent can decrease GI toxicity in MM patients
Results of a case-control study suggest a cytoprotective agent can reduce treatment-related gastrointestinal (GI) toxicity in patients with multiple myeloma (MM).
Use of this agent, amifostine, was associated with significantly lower rates of grade 2 or higher oral mucositis, nausea, vomiting, and diarrhea.
Additionally, amifostine did not appear to compromise the anti-myeloma activity of treatment, which consisted of high-dose melphalan (HDM) and autologous hematopoietic stem cell transplant (auto-HSCT).
Ehsan Malek, MD, of Case Western Reserve University in Cleveland, Ohio, and his colleagues reported these findings in Leukemia & Lymphoma.
The researchers compared HDM plus auto-HSCT, with or without pre-treatment amifostine, in previously treated MM patients.
There were 107 patients who received amifostine and 114 who did not. The 107 patients received amifostine at 740 mg/m2, given as a bolus infusion at 24 hours and 15 minutes before HDM.
Baseline characteristics were largely similar in the amifostine and control groups. However, more patients in the amifostine group received a tandem HSCT (17 vs 0), and more patients in the control group had an ECOG performance status of 0 (64.3% vs 43%).
Patients in the amifostine group had a longer median time from diagnosis to first HSCT—10 months (range, 4-39) vs 7 months (range, 1-95).
A majority of patients in both groups were in partial response or better at baseline. However, more patients in the control group had stable disease (6.2% vs 1%) or progressive disease (8% vs 0%).
Results
For all-grade GI toxicities, there was largely no significant difference between the amifostine and control groups. However, patients in the amifostine group had significantly lower rates of grade 2 or higher GI toxicities.
Rates of all-grade GI toxicities in the amifostine and control groups, respectively, were:
- Oral mucositis—53.3% vs 64.0%, P=0.104
- Nausea—90.7% vs 95.6%, P=0.143
- Vomiting—65.4% vs 75.4%, P=0.102
- Diarrhea—93.5% vs 84.2%,P=0.030.
Rates of grade 2 or higher GI toxicities in the amifostine and control groups, respectively, were:
- Oral mucositis—27.1% vs 47.4%, P=0.002
- Nausea—31.8% vs 86.0%, P<0.0001
- Vomiting—18.7% vs 52.6%, P<0.0001
- Diarrhea—56.1% vs 73.7%, P=0.006.
The researchers said amifostine was well tolerated and produced no significant adverse effects.
They also said amifostine had “no discernable effect” on engraftment, progression-free survival, or overall survival.
The median time to neutrophil engraftment was 11 days (range, 9-16) in the control group and 10 days (range, 6-21) in the amifostine group (P=0.011). The median time to platelet engraftment was 18 days (range, 0-26) and 19 days (range, 8-71), respectively (P<0.21).
The median progression-free survival was 40 months in the amifostine group and 32 months in the control group (P=0.012). The median overall survival was 70 months and 67 months, respectively (P=0.84).
Results of a case-control study suggest a cytoprotective agent can reduce treatment-related gastrointestinal (GI) toxicity in patients with multiple myeloma (MM).
Use of this agent, amifostine, was associated with significantly lower rates of grade 2 or higher oral mucositis, nausea, vomiting, and diarrhea.
Additionally, amifostine did not appear to compromise the anti-myeloma activity of treatment, which consisted of high-dose melphalan (HDM) and autologous hematopoietic stem cell transplant (auto-HSCT).
Ehsan Malek, MD, of Case Western Reserve University in Cleveland, Ohio, and his colleagues reported these findings in Leukemia & Lymphoma.
The researchers compared HDM plus auto-HSCT, with or without pre-treatment amifostine, in previously treated MM patients.
There were 107 patients who received amifostine and 114 who did not. The 107 patients received amifostine at 740 mg/m2, given as a bolus infusion at 24 hours and 15 minutes before HDM.
Baseline characteristics were largely similar in the amifostine and control groups. However, more patients in the amifostine group received a tandem HSCT (17 vs 0), and more patients in the control group had an ECOG performance status of 0 (64.3% vs 43%).
Patients in the amifostine group had a longer median time from diagnosis to first HSCT—10 months (range, 4-39) vs 7 months (range, 1-95).
A majority of patients in both groups were in partial response or better at baseline. However, more patients in the control group had stable disease (6.2% vs 1%) or progressive disease (8% vs 0%).
Results
For all-grade GI toxicities, there was largely no significant difference between the amifostine and control groups. However, patients in the amifostine group had significantly lower rates of grade 2 or higher GI toxicities.
Rates of all-grade GI toxicities in the amifostine and control groups, respectively, were:
- Oral mucositis—53.3% vs 64.0%, P=0.104
- Nausea—90.7% vs 95.6%, P=0.143
- Vomiting—65.4% vs 75.4%, P=0.102
- Diarrhea—93.5% vs 84.2%,P=0.030.
Rates of grade 2 or higher GI toxicities in the amifostine and control groups, respectively, were:
- Oral mucositis—27.1% vs 47.4%, P=0.002
- Nausea—31.8% vs 86.0%, P<0.0001
- Vomiting—18.7% vs 52.6%, P<0.0001
- Diarrhea—56.1% vs 73.7%, P=0.006.
The researchers said amifostine was well tolerated and produced no significant adverse effects.
They also said amifostine had “no discernable effect” on engraftment, progression-free survival, or overall survival.
The median time to neutrophil engraftment was 11 days (range, 9-16) in the control group and 10 days (range, 6-21) in the amifostine group (P=0.011). The median time to platelet engraftment was 18 days (range, 0-26) and 19 days (range, 8-71), respectively (P<0.21).
The median progression-free survival was 40 months in the amifostine group and 32 months in the control group (P=0.012). The median overall survival was 70 months and 67 months, respectively (P=0.84).
Results of a case-control study suggest a cytoprotective agent can reduce treatment-related gastrointestinal (GI) toxicity in patients with multiple myeloma (MM).
Use of this agent, amifostine, was associated with significantly lower rates of grade 2 or higher oral mucositis, nausea, vomiting, and diarrhea.
Additionally, amifostine did not appear to compromise the anti-myeloma activity of treatment, which consisted of high-dose melphalan (HDM) and autologous hematopoietic stem cell transplant (auto-HSCT).
Ehsan Malek, MD, of Case Western Reserve University in Cleveland, Ohio, and his colleagues reported these findings in Leukemia & Lymphoma.
The researchers compared HDM plus auto-HSCT, with or without pre-treatment amifostine, in previously treated MM patients.
There were 107 patients who received amifostine and 114 who did not. The 107 patients received amifostine at 740 mg/m2, given as a bolus infusion at 24 hours and 15 minutes before HDM.
Baseline characteristics were largely similar in the amifostine and control groups. However, more patients in the amifostine group received a tandem HSCT (17 vs 0), and more patients in the control group had an ECOG performance status of 0 (64.3% vs 43%).
Patients in the amifostine group had a longer median time from diagnosis to first HSCT—10 months (range, 4-39) vs 7 months (range, 1-95).
A majority of patients in both groups were in partial response or better at baseline. However, more patients in the control group had stable disease (6.2% vs 1%) or progressive disease (8% vs 0%).
Results
For all-grade GI toxicities, there was largely no significant difference between the amifostine and control groups. However, patients in the amifostine group had significantly lower rates of grade 2 or higher GI toxicities.
Rates of all-grade GI toxicities in the amifostine and control groups, respectively, were:
- Oral mucositis—53.3% vs 64.0%, P=0.104
- Nausea—90.7% vs 95.6%, P=0.143
- Vomiting—65.4% vs 75.4%, P=0.102
- Diarrhea—93.5% vs 84.2%,P=0.030.
Rates of grade 2 or higher GI toxicities in the amifostine and control groups, respectively, were:
- Oral mucositis—27.1% vs 47.4%, P=0.002
- Nausea—31.8% vs 86.0%, P<0.0001
- Vomiting—18.7% vs 52.6%, P<0.0001
- Diarrhea—56.1% vs 73.7%, P=0.006.
The researchers said amifostine was well tolerated and produced no significant adverse effects.
They also said amifostine had “no discernable effect” on engraftment, progression-free survival, or overall survival.
The median time to neutrophil engraftment was 11 days (range, 9-16) in the control group and 10 days (range, 6-21) in the amifostine group (P=0.011). The median time to platelet engraftment was 18 days (range, 0-26) and 19 days (range, 8-71), respectively (P<0.21).
The median progression-free survival was 40 months in the amifostine group and 32 months in the control group (P=0.012). The median overall survival was 70 months and 67 months, respectively (P=0.84).
FDA investigating VTEs related to ECP
The US Food and Drug Administration (FDA) says it is evaluating reports of venous thromboembolism (VTE) in patients treated with the CELLEX Photopheresis System by Therakos, Inc.
This extracorporeal photopheresis (ECP) device system is FDA-approved for use in patients with cutaneous T-cell lymphoma (CTCL).
The system is used to perform ultraviolet-A irradiation of a patient’s own leukocyte-enriched blood that is then used as palliative treatment for skin manifestations of CTCL that are unresponsive to other forms of treatment.
The CELLEX Photopheresis System is also used to treat graft-vs-host disease (GVHD) that is resistant to standard immunosuppressive therapy and acute cardiac allograft rejection that is resistant to standard immunosuppressive therapy.
The CELLEX Photopheresis System uses methoxsalen as a photosensitizing agent and heparin as an anticoagulant.
Since 2012, the FDA has received 7 reports of pulmonary embolism (PE) and 2 reports of deep vein thrombosis (DVT) occurring during or soon after treatment with the CELLEX Photopheresis System.
Two of the patients who developed a PE died, although it’s not clear whether PE was the cause of death.
Four of the 7 PEs occurred in patients undergoing treatment for GVHD, including the 2 patients who died. Both DVTs occurred in patients undergoing treatment for GVHD as well.
The FDA is recommending that healthcare providers inform patients, clinical staff, and technicians that PE and DVT can occur during or after an ECP procedure.
The agency also recommends that healthcare providers consult device labeling regarding anticoagulation and use clinical judgment in adjusting a patient’s heparin dosage.
Finally, providers should report VTEs related to ECP procedures to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
If possible, reports should include the following:
- The indication for ECP therapy
- Comorbidities that may predispose a patient to increased coagulation and history of DVT or PE
- The anticoagulation regimen used
- The number of ECP sessions the patient underwent prior to VTE onset, including the date of the first treatment session, frequency of treatment sessions, and timing of the final treatment
- Timing of the VTE in relation to the most recent treatment session
- Interventions required to manage the VTE.
The US Food and Drug Administration (FDA) says it is evaluating reports of venous thromboembolism (VTE) in patients treated with the CELLEX Photopheresis System by Therakos, Inc.
This extracorporeal photopheresis (ECP) device system is FDA-approved for use in patients with cutaneous T-cell lymphoma (CTCL).
The system is used to perform ultraviolet-A irradiation of a patient’s own leukocyte-enriched blood that is then used as palliative treatment for skin manifestations of CTCL that are unresponsive to other forms of treatment.
The CELLEX Photopheresis System is also used to treat graft-vs-host disease (GVHD) that is resistant to standard immunosuppressive therapy and acute cardiac allograft rejection that is resistant to standard immunosuppressive therapy.
The CELLEX Photopheresis System uses methoxsalen as a photosensitizing agent and heparin as an anticoagulant.
Since 2012, the FDA has received 7 reports of pulmonary embolism (PE) and 2 reports of deep vein thrombosis (DVT) occurring during or soon after treatment with the CELLEX Photopheresis System.
Two of the patients who developed a PE died, although it’s not clear whether PE was the cause of death.
Four of the 7 PEs occurred in patients undergoing treatment for GVHD, including the 2 patients who died. Both DVTs occurred in patients undergoing treatment for GVHD as well.
The FDA is recommending that healthcare providers inform patients, clinical staff, and technicians that PE and DVT can occur during or after an ECP procedure.
The agency also recommends that healthcare providers consult device labeling regarding anticoagulation and use clinical judgment in adjusting a patient’s heparin dosage.
Finally, providers should report VTEs related to ECP procedures to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
If possible, reports should include the following:
- The indication for ECP therapy
- Comorbidities that may predispose a patient to increased coagulation and history of DVT or PE
- The anticoagulation regimen used
- The number of ECP sessions the patient underwent prior to VTE onset, including the date of the first treatment session, frequency of treatment sessions, and timing of the final treatment
- Timing of the VTE in relation to the most recent treatment session
- Interventions required to manage the VTE.
The US Food and Drug Administration (FDA) says it is evaluating reports of venous thromboembolism (VTE) in patients treated with the CELLEX Photopheresis System by Therakos, Inc.
This extracorporeal photopheresis (ECP) device system is FDA-approved for use in patients with cutaneous T-cell lymphoma (CTCL).
The system is used to perform ultraviolet-A irradiation of a patient’s own leukocyte-enriched blood that is then used as palliative treatment for skin manifestations of CTCL that are unresponsive to other forms of treatment.
The CELLEX Photopheresis System is also used to treat graft-vs-host disease (GVHD) that is resistant to standard immunosuppressive therapy and acute cardiac allograft rejection that is resistant to standard immunosuppressive therapy.
The CELLEX Photopheresis System uses methoxsalen as a photosensitizing agent and heparin as an anticoagulant.
Since 2012, the FDA has received 7 reports of pulmonary embolism (PE) and 2 reports of deep vein thrombosis (DVT) occurring during or soon after treatment with the CELLEX Photopheresis System.
Two of the patients who developed a PE died, although it’s not clear whether PE was the cause of death.
Four of the 7 PEs occurred in patients undergoing treatment for GVHD, including the 2 patients who died. Both DVTs occurred in patients undergoing treatment for GVHD as well.
The FDA is recommending that healthcare providers inform patients, clinical staff, and technicians that PE and DVT can occur during or after an ECP procedure.
The agency also recommends that healthcare providers consult device labeling regarding anticoagulation and use clinical judgment in adjusting a patient’s heparin dosage.
Finally, providers should report VTEs related to ECP procedures to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.
If possible, reports should include the following:
- The indication for ECP therapy
- Comorbidities that may predispose a patient to increased coagulation and history of DVT or PE
- The anticoagulation regimen used
- The number of ECP sessions the patient underwent prior to VTE onset, including the date of the first treatment session, frequency of treatment sessions, and timing of the final treatment
- Timing of the VTE in relation to the most recent treatment session
- Interventions required to manage the VTE.
FDA places T-cell therapy on clinical hold
The US Food and Drug Administration (FDA) has placed BPX-501, a T-cell therapy being evaluated in patients who undergo haploidentical hematopoietic stem cell transplants (HSCTs), on clinical hold.
Three cases of encephalopathy possibly related to BPX-501 prompted the agency to impose the hold.
Bellicum Pharmaceuticals is the developer of BPX-501, and the company was conducting 4 trials in the US in children and adults with hematologic disorders.
The BPX-501 registration trial in Europe is not affected by the clinical hold.
BPX-501 is designed to fight infection, support engraftment, prevent disease relapse, and potentially stop graft-versus-host disease (GVHD) should it occur.
BPX-501 contains a safety switch, CaspaCIDe®, that can be activated with the administration of rimiducid to kill the toxic T cells in the event of GVHD.
The 3 cases of encephalopathy are complex, according to a company press release, and have confounding factors. These include prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications.
Encephalopathy had not emerged as an adverse event in 240 patients treated with the cell therapy, until now.
BPX-501 had produced encouraging results, according to trial data presented at EHA 2017 and ASH 2017 (abstract 211*).
In this trial, 112 pediatric patients were transfused with BPX-501 cells about 2 weeks after transplant. Patients had acute leukemia (n=53), primary immune deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9).
Investigators reported that infused cells expanded and persisted, with peak expansion reached at 9 months after infusion. Investigators continued to detect BPX-501 cells after 2 years.
The European Commission granted BPX-501 orphan drug designation for the agent for treatment in HSCT, and for the activator agent rimiducid for the treatment of GVHD.
And the FDA had granted the agents orphan drug status as a combination replacement T-cell therapy for the treatment of immunodeficiency and GVHD after HSCT.
Bellicum says it is working with the FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.
* Data in the abstract were updated in the oral presentation and reported on the company’s website.
The US Food and Drug Administration (FDA) has placed BPX-501, a T-cell therapy being evaluated in patients who undergo haploidentical hematopoietic stem cell transplants (HSCTs), on clinical hold.
Three cases of encephalopathy possibly related to BPX-501 prompted the agency to impose the hold.
Bellicum Pharmaceuticals is the developer of BPX-501, and the company was conducting 4 trials in the US in children and adults with hematologic disorders.
The BPX-501 registration trial in Europe is not affected by the clinical hold.
BPX-501 is designed to fight infection, support engraftment, prevent disease relapse, and potentially stop graft-versus-host disease (GVHD) should it occur.
BPX-501 contains a safety switch, CaspaCIDe®, that can be activated with the administration of rimiducid to kill the toxic T cells in the event of GVHD.
The 3 cases of encephalopathy are complex, according to a company press release, and have confounding factors. These include prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications.
Encephalopathy had not emerged as an adverse event in 240 patients treated with the cell therapy, until now.
BPX-501 had produced encouraging results, according to trial data presented at EHA 2017 and ASH 2017 (abstract 211*).
In this trial, 112 pediatric patients were transfused with BPX-501 cells about 2 weeks after transplant. Patients had acute leukemia (n=53), primary immune deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9).
Investigators reported that infused cells expanded and persisted, with peak expansion reached at 9 months after infusion. Investigators continued to detect BPX-501 cells after 2 years.
The European Commission granted BPX-501 orphan drug designation for the agent for treatment in HSCT, and for the activator agent rimiducid for the treatment of GVHD.
And the FDA had granted the agents orphan drug status as a combination replacement T-cell therapy for the treatment of immunodeficiency and GVHD after HSCT.
Bellicum says it is working with the FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.
* Data in the abstract were updated in the oral presentation and reported on the company’s website.
The US Food and Drug Administration (FDA) has placed BPX-501, a T-cell therapy being evaluated in patients who undergo haploidentical hematopoietic stem cell transplants (HSCTs), on clinical hold.
Three cases of encephalopathy possibly related to BPX-501 prompted the agency to impose the hold.
Bellicum Pharmaceuticals is the developer of BPX-501, and the company was conducting 4 trials in the US in children and adults with hematologic disorders.
The BPX-501 registration trial in Europe is not affected by the clinical hold.
BPX-501 is designed to fight infection, support engraftment, prevent disease relapse, and potentially stop graft-versus-host disease (GVHD) should it occur.
BPX-501 contains a safety switch, CaspaCIDe®, that can be activated with the administration of rimiducid to kill the toxic T cells in the event of GVHD.
The 3 cases of encephalopathy are complex, according to a company press release, and have confounding factors. These include prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications.
Encephalopathy had not emerged as an adverse event in 240 patients treated with the cell therapy, until now.
BPX-501 had produced encouraging results, according to trial data presented at EHA 2017 and ASH 2017 (abstract 211*).
In this trial, 112 pediatric patients were transfused with BPX-501 cells about 2 weeks after transplant. Patients had acute leukemia (n=53), primary immune deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9).
Investigators reported that infused cells expanded and persisted, with peak expansion reached at 9 months after infusion. Investigators continued to detect BPX-501 cells after 2 years.
The European Commission granted BPX-501 orphan drug designation for the agent for treatment in HSCT, and for the activator agent rimiducid for the treatment of GVHD.
And the FDA had granted the agents orphan drug status as a combination replacement T-cell therapy for the treatment of immunodeficiency and GVHD after HSCT.
Bellicum says it is working with the FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.
* Data in the abstract were updated in the oral presentation and reported on the company’s website.
Adjunct to HSCT receives orphan designation
The European Commission (EC) has granted orphan designation to NLA101 as an adjunct to hematopoietic stem cell transplant (HSCT).
NLA101 is a universal, off-the-shelf, stem and progenitor cell therapy intended to provide a short-term bridge for hematopoietic recovery while also providing long-term immunologic and clinical benefits in HSCT recipients.
NLA101 is a product of Nohla Therapeutics Inc.
The company says more than 125 infusions of NLA101 have been administered since 2009. The therapy is under investigation in patients receiving intensive chemotherapy as well as in HSCT recipients.
Results from a pilot study of NLA101 in HSCT recipients were presented at the 2014 ASH Annual Meeting.
In this study, 15 patients with hematologic malignancies underwent myeloablative cord blood transplant, with or without NLA101.
Patients who received NLA101 had a significantly reduced median time to platelet and neutrophil recovery, compared to controls. At 5 years, disease-free survival was 86% in the NLA101 group and 67% in the control group.
The rate of grade 3-4 acute graft-versus-host disease was 0% in the NLA101 group and 29% in the control group. The rate of transplant-related mortality was 0% and 22%, respectively.
Phase 2 studies of NLA101 in chemotherapy and HSCT recipients are ongoing.
About orphan designation
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.
The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
The European Commission (EC) has granted orphan designation to NLA101 as an adjunct to hematopoietic stem cell transplant (HSCT).
NLA101 is a universal, off-the-shelf, stem and progenitor cell therapy intended to provide a short-term bridge for hematopoietic recovery while also providing long-term immunologic and clinical benefits in HSCT recipients.
NLA101 is a product of Nohla Therapeutics Inc.
The company says more than 125 infusions of NLA101 have been administered since 2009. The therapy is under investigation in patients receiving intensive chemotherapy as well as in HSCT recipients.
Results from a pilot study of NLA101 in HSCT recipients were presented at the 2014 ASH Annual Meeting.
In this study, 15 patients with hematologic malignancies underwent myeloablative cord blood transplant, with or without NLA101.
Patients who received NLA101 had a significantly reduced median time to platelet and neutrophil recovery, compared to controls. At 5 years, disease-free survival was 86% in the NLA101 group and 67% in the control group.
The rate of grade 3-4 acute graft-versus-host disease was 0% in the NLA101 group and 29% in the control group. The rate of transplant-related mortality was 0% and 22%, respectively.
Phase 2 studies of NLA101 in chemotherapy and HSCT recipients are ongoing.
About orphan designation
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.
The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
The European Commission (EC) has granted orphan designation to NLA101 as an adjunct to hematopoietic stem cell transplant (HSCT).
NLA101 is a universal, off-the-shelf, stem and progenitor cell therapy intended to provide a short-term bridge for hematopoietic recovery while also providing long-term immunologic and clinical benefits in HSCT recipients.
NLA101 is a product of Nohla Therapeutics Inc.
The company says more than 125 infusions of NLA101 have been administered since 2009. The therapy is under investigation in patients receiving intensive chemotherapy as well as in HSCT recipients.
Results from a pilot study of NLA101 in HSCT recipients were presented at the 2014 ASH Annual Meeting.
In this study, 15 patients with hematologic malignancies underwent myeloablative cord blood transplant, with or without NLA101.
Patients who received NLA101 had a significantly reduced median time to platelet and neutrophil recovery, compared to controls. At 5 years, disease-free survival was 86% in the NLA101 group and 67% in the control group.
The rate of grade 3-4 acute graft-versus-host disease was 0% in the NLA101 group and 29% in the control group. The rate of transplant-related mortality was 0% and 22%, respectively.
Phase 2 studies of NLA101 in chemotherapy and HSCT recipients are ongoing.
About orphan designation
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval.
The designation also provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
HLF proves ‘critical’ for HSC quiescence
Preclinical research suggests hepatic leukemia factor (HLF) protects hematopoietic stem cells (HSCs) by helping them maintain quiescence.
Researchers found that HLF-deficient HSCs were more sensitive than wild-type HSCs to chemotherapy and irradiation.
After transplantation in mice, HLF-deficient HSCs were less able than wild-type HSCs to reconstitute hematopoiesis.
These findings were published in Cell Reports.
“The study confirms several previous studies that show the HLF gene’s significance in blood formation,” said study author Mattias Magnusson, PhD, of Lund University in Sweden.
“Identifying the factors that control blood stem cells provides knowledge needed to be able to propagate the stem cells outside the body. This has long been one of the major goals in the blood stem cell field, as it would increase possibilities for blood stem cell transplantation when, for example, there is a shortage of stem cells or donors. In addition, we will increase our understanding of how leukemia arises.”
Previous research by Dr Magnusson and his colleagues suggested that HLF may regulate HSCs in both normal and malignant hematopoiesis.
With the current study, the researchers found that HLF was “dispensable for steady-state hematopoiesis.” In fact, HLF-knockout mice had “essentially normal hematopoietic parameters” in steady-state conditions.
However, when HLF-deficient HSCs were serially transplanted in mice, the cells showed a reduction in regenerative potential, when compared to wild-type HSCs.
Additionally, mice with HLF-deficient HSCs exhibited increased sensitivity to the myeloablative agent 5-fluorouracil and reduced survival after sublethal irradiation, as compared to control mice.
“It’s surprising that the mice [initially] lived a normal life without the HLF gene, but when they had an acute need for new blood after an external damage such as cytostatic treatment, the mice did not survive,” Dr Magnusson said.
“All the blood stem cells were eliminated by the treatment, as they were active rather than in a resting state. Without the HLF gene, the blood stem cells were no longer protected against cytostatic treatment or other types of stress such as transplantation.”
Taking their findings together, Dr Magnusson and his colleagues concluded that HLF is a “critical” regulator of HSC quiescence and “essential” for maintaining HSCs’ ability to produce new blood.
Preclinical research suggests hepatic leukemia factor (HLF) protects hematopoietic stem cells (HSCs) by helping them maintain quiescence.
Researchers found that HLF-deficient HSCs were more sensitive than wild-type HSCs to chemotherapy and irradiation.
After transplantation in mice, HLF-deficient HSCs were less able than wild-type HSCs to reconstitute hematopoiesis.
These findings were published in Cell Reports.
“The study confirms several previous studies that show the HLF gene’s significance in blood formation,” said study author Mattias Magnusson, PhD, of Lund University in Sweden.
“Identifying the factors that control blood stem cells provides knowledge needed to be able to propagate the stem cells outside the body. This has long been one of the major goals in the blood stem cell field, as it would increase possibilities for blood stem cell transplantation when, for example, there is a shortage of stem cells or donors. In addition, we will increase our understanding of how leukemia arises.”
Previous research by Dr Magnusson and his colleagues suggested that HLF may regulate HSCs in both normal and malignant hematopoiesis.
With the current study, the researchers found that HLF was “dispensable for steady-state hematopoiesis.” In fact, HLF-knockout mice had “essentially normal hematopoietic parameters” in steady-state conditions.
However, when HLF-deficient HSCs were serially transplanted in mice, the cells showed a reduction in regenerative potential, when compared to wild-type HSCs.
Additionally, mice with HLF-deficient HSCs exhibited increased sensitivity to the myeloablative agent 5-fluorouracil and reduced survival after sublethal irradiation, as compared to control mice.
“It’s surprising that the mice [initially] lived a normal life without the HLF gene, but when they had an acute need for new blood after an external damage such as cytostatic treatment, the mice did not survive,” Dr Magnusson said.
“All the blood stem cells were eliminated by the treatment, as they were active rather than in a resting state. Without the HLF gene, the blood stem cells were no longer protected against cytostatic treatment or other types of stress such as transplantation.”
Taking their findings together, Dr Magnusson and his colleagues concluded that HLF is a “critical” regulator of HSC quiescence and “essential” for maintaining HSCs’ ability to produce new blood.
Preclinical research suggests hepatic leukemia factor (HLF) protects hematopoietic stem cells (HSCs) by helping them maintain quiescence.
Researchers found that HLF-deficient HSCs were more sensitive than wild-type HSCs to chemotherapy and irradiation.
After transplantation in mice, HLF-deficient HSCs were less able than wild-type HSCs to reconstitute hematopoiesis.
These findings were published in Cell Reports.
“The study confirms several previous studies that show the HLF gene’s significance in blood formation,” said study author Mattias Magnusson, PhD, of Lund University in Sweden.
“Identifying the factors that control blood stem cells provides knowledge needed to be able to propagate the stem cells outside the body. This has long been one of the major goals in the blood stem cell field, as it would increase possibilities for blood stem cell transplantation when, for example, there is a shortage of stem cells or donors. In addition, we will increase our understanding of how leukemia arises.”
Previous research by Dr Magnusson and his colleagues suggested that HLF may regulate HSCs in both normal and malignant hematopoiesis.
With the current study, the researchers found that HLF was “dispensable for steady-state hematopoiesis.” In fact, HLF-knockout mice had “essentially normal hematopoietic parameters” in steady-state conditions.
However, when HLF-deficient HSCs were serially transplanted in mice, the cells showed a reduction in regenerative potential, when compared to wild-type HSCs.
Additionally, mice with HLF-deficient HSCs exhibited increased sensitivity to the myeloablative agent 5-fluorouracil and reduced survival after sublethal irradiation, as compared to control mice.
“It’s surprising that the mice [initially] lived a normal life without the HLF gene, but when they had an acute need for new blood after an external damage such as cytostatic treatment, the mice did not survive,” Dr Magnusson said.
“All the blood stem cells were eliminated by the treatment, as they were active rather than in a resting state. Without the HLF gene, the blood stem cells were no longer protected against cytostatic treatment or other types of stress such as transplantation.”
Taking their findings together, Dr Magnusson and his colleagues concluded that HLF is a “critical” regulator of HSC quiescence and “essential” for maintaining HSCs’ ability to produce new blood.
Interventions can increase cord blood donations
Simple interventions can increase cord blood donations, according to research published in Scientific Reports.
Researchers saw a significant increase in cord blood donation when expectant mothers received information about the procedure and were asked to indicate their interest in donating at both early and late stages of their pregnancies.
“We more than doubled the number of cord blood units that were collected,” said study author Nicola Lacetera, PhD, of the University of Toronto Mississauga in Ontario, Canada.
“We learned a lot, and we did a little bit of good too, so that feels nice.”
Dr Lacetera and his colleagues conducted this study in Milan, Italy, where private cord blood banking is banned.
The team set out to determine if providing expectant mothers with information about cord blood donation and prompting them to consider the procedure would increase donations to a public cord blood bank.
Interventions
The researchers enrolled 850 expectant mothers and divided them into 6 treatment cohorts.
The T0 cohort included 217 control subjects who did not receive any information on cord blood donation.
The T1 cohort included 64 subjects who received information on cord blood donation during their first trimester.
The T2 cohort included 88 subjects who were given information on cord blood donation and asked about their intentions to donate in their first trimester.
The T3 cohort included 197 subjects who received information on cord blood donation in their third trimester.
The T4 cohort included 249 subjects who were given information on cord blood donation and asked about their intentions to donate during their third trimester.
The T5 cohort included 35 subjects who were given information on cord blood donation and asked about their intentions to donate during the first trimester and the third trimester.
Results
The researchers found that T5 subjects had the highest donation rate.
In the entire study sample, the donation rate was 2.3% (5/217) in controls, 6.3% (4/64) in T1 subjects, 1.1% (1/88) in T2, 8.1% (16/197) in T3, 10.0% (25/249) in T4, and 17.1% in T5 (6/35).
These results may not be entirely accurate, however, because the researchers could only confirm patients’ donation status if mothers delivered their babies at the study hospital, Ospedale dei Bambini Vittore Buzzi (also known as Buzzi Hospital, BH).
Among women who delivered at BH, donation rates were 2.7% (5/183) in controls, 11.7% (4/34) in T1, 2.2% (1/45) in T2, 8.9% (16/179) in T3, 11.4% (25/42) in T4, and 21.4% (6/28) in T5.
Though these data suggest the various interventions tested can increase cord blood donations, donation rates in this study could have been even higher, according to the researchers.
There were 197 women who submitted consent forms to donate cord blood, were medically eligible to donate, and delivered their babies at BH. However, only 57 of these women successfully donated cord blood.
There were 62 women (56.9%) who could not donate because of medical complications during delivery.
Thirty-three women (30.3%) failed to donate because of organizational reasons, including overcrowding of the delivery room and the absence of obstetric nurses certified to collect and process cord blood at the time of delivery.
There were 14 women (7.1%) who did not donate for institution-related reasons. For example, the women gave birth when the Milan Cord Blood Bank was closed.
There were no details on the remaining 31 women who failed to donate.
Simple interventions can increase cord blood donations, according to research published in Scientific Reports.
Researchers saw a significant increase in cord blood donation when expectant mothers received information about the procedure and were asked to indicate their interest in donating at both early and late stages of their pregnancies.
“We more than doubled the number of cord blood units that were collected,” said study author Nicola Lacetera, PhD, of the University of Toronto Mississauga in Ontario, Canada.
“We learned a lot, and we did a little bit of good too, so that feels nice.”
Dr Lacetera and his colleagues conducted this study in Milan, Italy, where private cord blood banking is banned.
The team set out to determine if providing expectant mothers with information about cord blood donation and prompting them to consider the procedure would increase donations to a public cord blood bank.
Interventions
The researchers enrolled 850 expectant mothers and divided them into 6 treatment cohorts.
The T0 cohort included 217 control subjects who did not receive any information on cord blood donation.
The T1 cohort included 64 subjects who received information on cord blood donation during their first trimester.
The T2 cohort included 88 subjects who were given information on cord blood donation and asked about their intentions to donate in their first trimester.
The T3 cohort included 197 subjects who received information on cord blood donation in their third trimester.
The T4 cohort included 249 subjects who were given information on cord blood donation and asked about their intentions to donate during their third trimester.
The T5 cohort included 35 subjects who were given information on cord blood donation and asked about their intentions to donate during the first trimester and the third trimester.
Results
The researchers found that T5 subjects had the highest donation rate.
In the entire study sample, the donation rate was 2.3% (5/217) in controls, 6.3% (4/64) in T1 subjects, 1.1% (1/88) in T2, 8.1% (16/197) in T3, 10.0% (25/249) in T4, and 17.1% in T5 (6/35).
These results may not be entirely accurate, however, because the researchers could only confirm patients’ donation status if mothers delivered their babies at the study hospital, Ospedale dei Bambini Vittore Buzzi (also known as Buzzi Hospital, BH).
Among women who delivered at BH, donation rates were 2.7% (5/183) in controls, 11.7% (4/34) in T1, 2.2% (1/45) in T2, 8.9% (16/179) in T3, 11.4% (25/42) in T4, and 21.4% (6/28) in T5.
Though these data suggest the various interventions tested can increase cord blood donations, donation rates in this study could have been even higher, according to the researchers.
There were 197 women who submitted consent forms to donate cord blood, were medically eligible to donate, and delivered their babies at BH. However, only 57 of these women successfully donated cord blood.
There were 62 women (56.9%) who could not donate because of medical complications during delivery.
Thirty-three women (30.3%) failed to donate because of organizational reasons, including overcrowding of the delivery room and the absence of obstetric nurses certified to collect and process cord blood at the time of delivery.
There were 14 women (7.1%) who did not donate for institution-related reasons. For example, the women gave birth when the Milan Cord Blood Bank was closed.
There were no details on the remaining 31 women who failed to donate.
Simple interventions can increase cord blood donations, according to research published in Scientific Reports.
Researchers saw a significant increase in cord blood donation when expectant mothers received information about the procedure and were asked to indicate their interest in donating at both early and late stages of their pregnancies.
“We more than doubled the number of cord blood units that were collected,” said study author Nicola Lacetera, PhD, of the University of Toronto Mississauga in Ontario, Canada.
“We learned a lot, and we did a little bit of good too, so that feels nice.”
Dr Lacetera and his colleagues conducted this study in Milan, Italy, where private cord blood banking is banned.
The team set out to determine if providing expectant mothers with information about cord blood donation and prompting them to consider the procedure would increase donations to a public cord blood bank.
Interventions
The researchers enrolled 850 expectant mothers and divided them into 6 treatment cohorts.
The T0 cohort included 217 control subjects who did not receive any information on cord blood donation.
The T1 cohort included 64 subjects who received information on cord blood donation during their first trimester.
The T2 cohort included 88 subjects who were given information on cord blood donation and asked about their intentions to donate in their first trimester.
The T3 cohort included 197 subjects who received information on cord blood donation in their third trimester.
The T4 cohort included 249 subjects who were given information on cord blood donation and asked about their intentions to donate during their third trimester.
The T5 cohort included 35 subjects who were given information on cord blood donation and asked about their intentions to donate during the first trimester and the third trimester.
Results
The researchers found that T5 subjects had the highest donation rate.
In the entire study sample, the donation rate was 2.3% (5/217) in controls, 6.3% (4/64) in T1 subjects, 1.1% (1/88) in T2, 8.1% (16/197) in T3, 10.0% (25/249) in T4, and 17.1% in T5 (6/35).
These results may not be entirely accurate, however, because the researchers could only confirm patients’ donation status if mothers delivered their babies at the study hospital, Ospedale dei Bambini Vittore Buzzi (also known as Buzzi Hospital, BH).
Among women who delivered at BH, donation rates were 2.7% (5/183) in controls, 11.7% (4/34) in T1, 2.2% (1/45) in T2, 8.9% (16/179) in T3, 11.4% (25/42) in T4, and 21.4% (6/28) in T5.
Though these data suggest the various interventions tested can increase cord blood donations, donation rates in this study could have been even higher, according to the researchers.
There were 197 women who submitted consent forms to donate cord blood, were medically eligible to donate, and delivered their babies at BH. However, only 57 of these women successfully donated cord blood.
There were 62 women (56.9%) who could not donate because of medical complications during delivery.
Thirty-three women (30.3%) failed to donate because of organizational reasons, including overcrowding of the delivery room and the absence of obstetric nurses certified to collect and process cord blood at the time of delivery.
There were 14 women (7.1%) who did not donate for institution-related reasons. For example, the women gave birth when the Milan Cord Blood Bank was closed.
There were no details on the remaining 31 women who failed to donate.
Antiviral receives breakthrough designation for CMV
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to maribavir (SHP620) as a treatment for cytomegalovirus (CMV) infection and disease in transplant recipients who are resistant or refractory to prior therapy.
Maribavir, an antiviral therapy that belongs to a class of drugs called benzimidazole ribosides, is being evaluated in patients who have CMV infection after undergoing hematopoietic stem cell transplant or solid organ transplant.
The drug inhibits the CMV UL97 protein kinase and is thought to affect several critical processes in CMV replication, including viral DNA synthesis, viral gene expression, encapsidation, and egress of mature capsids from the nucleus.
The FDA granted maribavir breakthrough designation based on data from two phase 2 studies. For one of these studies (NCT00223925), data are not yet available.
The other study (NCT01611974) was presented at IDWeek 2016. This study included 120 patients ages 12 and older with CMV infection (≥1000 DNA copies/mL of blood plasma) that was resistant or refractory to (val)ganciclovir or foscarnet.
Forty-seven of the patients had received a hematopoietic stem cell transplant, and 73 had a solid organ transplant.
The patients were randomized to 1 of 3 twice-daily oral doses of maribavir—400 mg, 800 mg, or 1200 mg—for up to 24 weeks of treatment.
The study’s primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Sixty-seven percent (80/120) of patients met this endpoint. This included 70% (n=28) of patients in the 400 mg group, 63% (n=25) in the 800 mg group, and 67% (n=27) in the 1200 mg group.
CMV infection recurred in 30 patients, including 7 in the 400 mg group, 11 in the 800 mg group, and 12 in the 1200 mg group.
The incidence of treatment-emergent adverse events (AEs) was 78% (n=93) overall, 78% (n=31) in the 400 mg group, 80% (n=32) in the 800 mg group, and 75% (n=30) in the 1200 mg group.
Twenty-seven percent of patients died due to any AE, 1 of which (multi-organ failure) was considered possibly related to maribavir.
Forty-one patients (34%) discontinued treatment with maribavir due to an AE, including 17 patients who discontinued due to CMV infection.
Dysgeusia was the most common treatment-emergent AE and led to treatment discontinuation in 1 patient. Dysgeusia occurred in 65% (n=78) of all patients, including 60% (n=24) in the 400 mg group, 63% (n=25) in the 800 mg group, and 73% (n=29) in the 1200 mg group.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to maribavir (SHP620) as a treatment for cytomegalovirus (CMV) infection and disease in transplant recipients who are resistant or refractory to prior therapy.
Maribavir, an antiviral therapy that belongs to a class of drugs called benzimidazole ribosides, is being evaluated in patients who have CMV infection after undergoing hematopoietic stem cell transplant or solid organ transplant.
The drug inhibits the CMV UL97 protein kinase and is thought to affect several critical processes in CMV replication, including viral DNA synthesis, viral gene expression, encapsidation, and egress of mature capsids from the nucleus.
The FDA granted maribavir breakthrough designation based on data from two phase 2 studies. For one of these studies (NCT00223925), data are not yet available.
The other study (NCT01611974) was presented at IDWeek 2016. This study included 120 patients ages 12 and older with CMV infection (≥1000 DNA copies/mL of blood plasma) that was resistant or refractory to (val)ganciclovir or foscarnet.
Forty-seven of the patients had received a hematopoietic stem cell transplant, and 73 had a solid organ transplant.
The patients were randomized to 1 of 3 twice-daily oral doses of maribavir—400 mg, 800 mg, or 1200 mg—for up to 24 weeks of treatment.
The study’s primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Sixty-seven percent (80/120) of patients met this endpoint. This included 70% (n=28) of patients in the 400 mg group, 63% (n=25) in the 800 mg group, and 67% (n=27) in the 1200 mg group.
CMV infection recurred in 30 patients, including 7 in the 400 mg group, 11 in the 800 mg group, and 12 in the 1200 mg group.
The incidence of treatment-emergent adverse events (AEs) was 78% (n=93) overall, 78% (n=31) in the 400 mg group, 80% (n=32) in the 800 mg group, and 75% (n=30) in the 1200 mg group.
Twenty-seven percent of patients died due to any AE, 1 of which (multi-organ failure) was considered possibly related to maribavir.
Forty-one patients (34%) discontinued treatment with maribavir due to an AE, including 17 patients who discontinued due to CMV infection.
Dysgeusia was the most common treatment-emergent AE and led to treatment discontinuation in 1 patient. Dysgeusia occurred in 65% (n=78) of all patients, including 60% (n=24) in the 400 mg group, 63% (n=25) in the 800 mg group, and 73% (n=29) in the 1200 mg group.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to maribavir (SHP620) as a treatment for cytomegalovirus (CMV) infection and disease in transplant recipients who are resistant or refractory to prior therapy.
Maribavir, an antiviral therapy that belongs to a class of drugs called benzimidazole ribosides, is being evaluated in patients who have CMV infection after undergoing hematopoietic stem cell transplant or solid organ transplant.
The drug inhibits the CMV UL97 protein kinase and is thought to affect several critical processes in CMV replication, including viral DNA synthesis, viral gene expression, encapsidation, and egress of mature capsids from the nucleus.
The FDA granted maribavir breakthrough designation based on data from two phase 2 studies. For one of these studies (NCT00223925), data are not yet available.
The other study (NCT01611974) was presented at IDWeek 2016. This study included 120 patients ages 12 and older with CMV infection (≥1000 DNA copies/mL of blood plasma) that was resistant or refractory to (val)ganciclovir or foscarnet.
Forty-seven of the patients had received a hematopoietic stem cell transplant, and 73 had a solid organ transplant.
The patients were randomized to 1 of 3 twice-daily oral doses of maribavir—400 mg, 800 mg, or 1200 mg—for up to 24 weeks of treatment.
The study’s primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Sixty-seven percent (80/120) of patients met this endpoint. This included 70% (n=28) of patients in the 400 mg group, 63% (n=25) in the 800 mg group, and 67% (n=27) in the 1200 mg group.
CMV infection recurred in 30 patients, including 7 in the 400 mg group, 11 in the 800 mg group, and 12 in the 1200 mg group.
The incidence of treatment-emergent adverse events (AEs) was 78% (n=93) overall, 78% (n=31) in the 400 mg group, 80% (n=32) in the 800 mg group, and 75% (n=30) in the 1200 mg group.
Twenty-seven percent of patients died due to any AE, 1 of which (multi-organ failure) was considered possibly related to maribavir.
Forty-one patients (34%) discontinued treatment with maribavir due to an AE, including 17 patients who discontinued due to CMV infection.
Dysgeusia was the most common treatment-emergent AE and led to treatment discontinuation in 1 patient. Dysgeusia occurred in 65% (n=78) of all patients, including 60% (n=24) in the 400 mg group, 63% (n=25) in the 800 mg group, and 73% (n=29) in the 1200 mg group.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
Obesity has negative impact on HSC compartment
Obesity can affect the long-term health of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.
Conducted largely in models of obese mice, the research showed that obesity causes durable and harmful changes to the HSC compartment.
“Keeping this compartment healthy is essential to human health,” said study author Damien Reynaud, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“This includes maintaining the diverse pool of [HSCs] needed to produce blood cells the body needs to function properly.”
Although still poorly understood, research is showing that age and environmental stresses can lessen the healthy diversity of cells in the hematopoietic system.
This can include skewing blood cell formation toward myeloid cells and possibly promoting pre-leukemic fates, according to Dr Reynaud and his colleagues.
With the current study, the team found that obesity-related stresses alter the cellular architecture of the HSC compartment and reduce its long-term functional fitness.
Tests in obese mice showed these effects were progressive. And some of the harmful manifestations persisted even after the researchers normalized the animals’ weight through dietary controls.
These alterations of the hematopoietic system appear to be linked to overexpression of the transcription factor Gfi1.
The researchers found that oxidative stresses in the body caused by obesity drive overexpression of Gfi1. When this happens, it produces a lasting alteration of the HSC compartment.
The researchers said their study provides groundwork to investigate how lifestyle choices, such as diet, can durably impact blood formation and may contribute to the development of blood cancers.
The study also raises questions about the use of HSCs isolated from obese transplant donors.
“Little is known about how obesity in marrow donors could affect the quality of the hematopoietic stem cell compartment,” Dr Reynaud explained.
“We want to better understand the molecular alterations in obesity to predict potential risks associated with the therapeutic use of stem cells isolated from obese donors.”
Obesity can affect the long-term health of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.
Conducted largely in models of obese mice, the research showed that obesity causes durable and harmful changes to the HSC compartment.
“Keeping this compartment healthy is essential to human health,” said study author Damien Reynaud, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“This includes maintaining the diverse pool of [HSCs] needed to produce blood cells the body needs to function properly.”
Although still poorly understood, research is showing that age and environmental stresses can lessen the healthy diversity of cells in the hematopoietic system.
This can include skewing blood cell formation toward myeloid cells and possibly promoting pre-leukemic fates, according to Dr Reynaud and his colleagues.
With the current study, the team found that obesity-related stresses alter the cellular architecture of the HSC compartment and reduce its long-term functional fitness.
Tests in obese mice showed these effects were progressive. And some of the harmful manifestations persisted even after the researchers normalized the animals’ weight through dietary controls.
These alterations of the hematopoietic system appear to be linked to overexpression of the transcription factor Gfi1.
The researchers found that oxidative stresses in the body caused by obesity drive overexpression of Gfi1. When this happens, it produces a lasting alteration of the HSC compartment.
The researchers said their study provides groundwork to investigate how lifestyle choices, such as diet, can durably impact blood formation and may contribute to the development of blood cancers.
The study also raises questions about the use of HSCs isolated from obese transplant donors.
“Little is known about how obesity in marrow donors could affect the quality of the hematopoietic stem cell compartment,” Dr Reynaud explained.
“We want to better understand the molecular alterations in obesity to predict potential risks associated with the therapeutic use of stem cells isolated from obese donors.”
Obesity can affect the long-term health of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.
Conducted largely in models of obese mice, the research showed that obesity causes durable and harmful changes to the HSC compartment.
“Keeping this compartment healthy is essential to human health,” said study author Damien Reynaud, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“This includes maintaining the diverse pool of [HSCs] needed to produce blood cells the body needs to function properly.”
Although still poorly understood, research is showing that age and environmental stresses can lessen the healthy diversity of cells in the hematopoietic system.
This can include skewing blood cell formation toward myeloid cells and possibly promoting pre-leukemic fates, according to Dr Reynaud and his colleagues.
With the current study, the team found that obesity-related stresses alter the cellular architecture of the HSC compartment and reduce its long-term functional fitness.
Tests in obese mice showed these effects were progressive. And some of the harmful manifestations persisted even after the researchers normalized the animals’ weight through dietary controls.
These alterations of the hematopoietic system appear to be linked to overexpression of the transcription factor Gfi1.
The researchers found that oxidative stresses in the body caused by obesity drive overexpression of Gfi1. When this happens, it produces a lasting alteration of the HSC compartment.
The researchers said their study provides groundwork to investigate how lifestyle choices, such as diet, can durably impact blood formation and may contribute to the development of blood cancers.
The study also raises questions about the use of HSCs isolated from obese transplant donors.
“Little is known about how obesity in marrow donors could affect the quality of the hematopoietic stem cell compartment,” Dr Reynaud explained.
“We want to better understand the molecular alterations in obesity to predict potential risks associated with the therapeutic use of stem cells isolated from obese donors.”