Transplantation

Woman exercising in a park

Photo by Peter Griffin

ORLANDO, FL—Frailty after hematopoietic stem cell transplant (HSCT), while associated with higher mortality, is not necessarily a function of age, according to investigators studying the impact of frailty on transplant outcomes.

Instead, other factors, such as increasing time from transplant, employment status, medical leave or disability, and limitations of social activities, were significantly associated with higher odds of frailty.

The investigators prospectively studied 96 HSCT recipients, age 40 and older, to determine the prevalence of frailty in HSCT populations and its impact on outcomes, including early post-transplant non-relapse mortality (NRM).

Mukta Arora, MD, of the University of Minnesota in Minneapolis, reported the findings at the 2015 ASH Annual Meeting (abstract 388*).

The investigators defined frailty as the presence of 3 or more of the following criteria: low grip strength, exhaustion, slowed walking speed, low physical activity, and unintentional weight loss. They defined pre-frailty as having 1 or 2 of these characteristics.

The investigators conducted multi-domain geriatric assessments of patients prior to HSCT and after transplant at 100 days, 6 months, and 1 year. The assessment included function, comorbidity, cognition, psychological state, social activity/support, nutritional status, and demographic, transplant, and disease-related information.

Forty-eight patients were in the younger age group (40–59), and 48 were in the older age group (60–74). All had undergone HSCT between February 2014 and April 2015.

Patient demographics

Patients in the younger group were a median age of 54 (range, 40–59) at transplant. Sixty-five percent were male, 58% had an autologous transplant, and 79% received myeloablative conditioning.

Patients in the older group were a median age of 65 (range, 60–73) at transplant. Fifty-four percent were male, 46% had an autologous transplant, and 46% had myeloablative conditioning.

The difference between the older and younger groups in their conditioning regimen was significant (P<0.01).

The groups were comparable in terms of the HSCT comorbidity index but were significantly different in employment status (P<0.01).

“As expected,” Dr Arora said, “there were more patients who were retired in the older group.”

In the younger group, 31% were employed, 3% retired, 56% on medical leave or disabled, and 10% unemployed.

In the older group, 6% were employed, 62% retired, 28% on medical leave or disabled, and 4% unemployed.

“There was no difference in the social activity and social support scores between the 2 groups,” Dr Arora observed.

Frailty assessments

In the younger group, at baseline, the prevalence of pre-frailty was 47%, and the prevalence of frailty was 11%. At 6 months after HSCT, the prevalence of pre-frailty was 45%, and the prevalence of frailty was 41% (P<0.01).

In the older group, at baseline, the prevalence of pre-frailty was 42%, and the prevalence of frailty was 6%. At 6 months, the prevalence of pre-frailty was 44%, and the prevalence of frailty was 38% (P<0.01).

The investigators then estimated the predictors of frailty.

Significant predictors of frailty included time since HSCT (odds ratio [OR]=3.7, 95% CI: 1.9-7.2, P<0.01), employment status (retired: OR=7.3, 95% CI 1.2 – 46.2, P=0.03), on medical leave or disabled (OR=11.2, 95% CI: 1.8 – 67.7, P=0.01), limitations in social activities (OR=1.04, 95% CI: 1.01 – 1.08, P=0.01), and baseline pre-frailty (OR=3.1, 95% CI: 2.3 – 45.5, P<0.01).

Allogeneic transplant was associated with higher odds of frailty than autologous (OR=3.1, 95% CI: 0.9 – 10.2), although it did not reach significance (P=0.06).

Investigators next estimated the impact of frailty or pre-frailty on NRM and identified a trend toward increased NRM in frail patients.

The 46 patients classified as not frail at baseline had a 7% cumulative incidence of NRM (P=0.07). The 42 patients classified as pre-frail had a 23% cumulative incidence of NRM, while the 8 patients classified as frail at baseline had a 28% cumulative incidence of NRM.

“So, to conclude, in this early study, frailty was noted in 8% and pre-frailty in 44% of the transplant population prior to transplant, and was not dependent on age,” Dr Arora said. “Frailty is a transitional state and appears to reflect a dynamic progression from robustness to functional decline with time since [HSCT].”

Because frailty is associated with higher mortality, the investigators believe vulnerable populations should be identified and their need for specific interventions defined.

This research was funded by the Leukemia & Lymphoma Society.

*Data in the abstract differ from the presentation.

Woman exercising in a park

Photo by Peter Griffin

ORLANDO, FL—Frailty after hematopoietic stem cell transplant (HSCT), while associated with higher mortality, is not necessarily a function of age, according to investigators studying the impact of frailty on transplant outcomes.

Instead, other factors, such as increasing time from transplant, employment status, medical leave or disability, and limitations of social activities, were significantly associated with higher odds of frailty.

The investigators prospectively studied 96 HSCT recipients, age 40 and older, to determine the prevalence of frailty in HSCT populations and its impact on outcomes, including early post-transplant non-relapse mortality (NRM).

Mukta Arora, MD, of the University of Minnesota in Minneapolis, reported the findings at the 2015 ASH Annual Meeting (abstract 388*).

The investigators defined frailty as the presence of 3 or more of the following criteria: low grip strength, exhaustion, slowed walking speed, low physical activity, and unintentional weight loss. They defined pre-frailty as having 1 or 2 of these characteristics.

The investigators conducted multi-domain geriatric assessments of patients prior to HSCT and after transplant at 100 days, 6 months, and 1 year. The assessment included function, comorbidity, cognition, psychological state, social activity/support, nutritional status, and demographic, transplant, and disease-related information.

Forty-eight patients were in the younger age group (40–59), and 48 were in the older age group (60–74). All had undergone HSCT between February 2014 and April 2015.

Patient demographics

Patients in the younger group were a median age of 54 (range, 40–59) at transplant. Sixty-five percent were male, 58% had an autologous transplant, and 79% received myeloablative conditioning.

Patients in the older group were a median age of 65 (range, 60–73) at transplant. Fifty-four percent were male, 46% had an autologous transplant, and 46% had myeloablative conditioning.

The difference between the older and younger groups in their conditioning regimen was significant (P<0.01).

The groups were comparable in terms of the HSCT comorbidity index but were significantly different in employment status (P<0.01).

“As expected,” Dr Arora said, “there were more patients who were retired in the older group.”

In the younger group, 31% were employed, 3% retired, 56% on medical leave or disabled, and 10% unemployed.

In the older group, 6% were employed, 62% retired, 28% on medical leave or disabled, and 4% unemployed.

“There was no difference in the social activity and social support scores between the 2 groups,” Dr Arora observed.

Frailty assessments

In the younger group, at baseline, the prevalence of pre-frailty was 47%, and the prevalence of frailty was 11%. At 6 months after HSCT, the prevalence of pre-frailty was 45%, and the prevalence of frailty was 41% (P<0.01).

In the older group, at baseline, the prevalence of pre-frailty was 42%, and the prevalence of frailty was 6%. At 6 months, the prevalence of pre-frailty was 44%, and the prevalence of frailty was 38% (P<0.01).

The investigators then estimated the predictors of frailty.

Significant predictors of frailty included time since HSCT (odds ratio [OR]=3.7, 95% CI: 1.9-7.2, P<0.01), employment status (retired: OR=7.3, 95% CI 1.2 – 46.2, P=0.03), on medical leave or disabled (OR=11.2, 95% CI: 1.8 – 67.7, P=0.01), limitations in social activities (OR=1.04, 95% CI: 1.01 – 1.08, P=0.01), and baseline pre-frailty (OR=3.1, 95% CI: 2.3 – 45.5, P<0.01).

Allogeneic transplant was associated with higher odds of frailty than autologous (OR=3.1, 95% CI: 0.9 – 10.2), although it did not reach significance (P=0.06).

Investigators next estimated the impact of frailty or pre-frailty on NRM and identified a trend toward increased NRM in frail patients.

The 46 patients classified as not frail at baseline had a 7% cumulative incidence of NRM (P=0.07). The 42 patients classified as pre-frail had a 23% cumulative incidence of NRM, while the 8 patients classified as frail at baseline had a 28% cumulative incidence of NRM.

“So, to conclude, in this early study, frailty was noted in 8% and pre-frailty in 44% of the transplant population prior to transplant, and was not dependent on age,” Dr Arora said. “Frailty is a transitional state and appears to reflect a dynamic progression from robustness to functional decline with time since [HSCT].”

Because frailty is associated with higher mortality, the investigators believe vulnerable populations should be identified and their need for specific interventions defined.

This research was funded by the Leukemia & Lymphoma Society.

*Data in the abstract differ from the presentation.

Woman exercising in a park

Photo by Peter Griffin

ORLANDO, FL—Frailty after hematopoietic stem cell transplant (HSCT), while associated with higher mortality, is not necessarily a function of age, according to investigators studying the impact of frailty on transplant outcomes.

Instead, other factors, such as increasing time from transplant, employment status, medical leave or disability, and limitations of social activities, were significantly associated with higher odds of frailty.

The investigators prospectively studied 96 HSCT recipients, age 40 and older, to determine the prevalence of frailty in HSCT populations and its impact on outcomes, including early post-transplant non-relapse mortality (NRM).

Mukta Arora, MD, of the University of Minnesota in Minneapolis, reported the findings at the 2015 ASH Annual Meeting (abstract 388*).

The investigators defined frailty as the presence of 3 or more of the following criteria: low grip strength, exhaustion, slowed walking speed, low physical activity, and unintentional weight loss. They defined pre-frailty as having 1 or 2 of these characteristics.

The investigators conducted multi-domain geriatric assessments of patients prior to HSCT and after transplant at 100 days, 6 months, and 1 year. The assessment included function, comorbidity, cognition, psychological state, social activity/support, nutritional status, and demographic, transplant, and disease-related information.

Forty-eight patients were in the younger age group (40–59), and 48 were in the older age group (60–74). All had undergone HSCT between February 2014 and April 2015.

Patient demographics

Patients in the younger group were a median age of 54 (range, 40–59) at transplant. Sixty-five percent were male, 58% had an autologous transplant, and 79% received myeloablative conditioning.

Patients in the older group were a median age of 65 (range, 60–73) at transplant. Fifty-four percent were male, 46% had an autologous transplant, and 46% had myeloablative conditioning.

The difference between the older and younger groups in their conditioning regimen was significant (P<0.01).

The groups were comparable in terms of the HSCT comorbidity index but were significantly different in employment status (P<0.01).

“As expected,” Dr Arora said, “there were more patients who were retired in the older group.”

In the younger group, 31% were employed, 3% retired, 56% on medical leave or disabled, and 10% unemployed.

In the older group, 6% were employed, 62% retired, 28% on medical leave or disabled, and 4% unemployed.

“There was no difference in the social activity and social support scores between the 2 groups,” Dr Arora observed.

Frailty assessments

In the younger group, at baseline, the prevalence of pre-frailty was 47%, and the prevalence of frailty was 11%. At 6 months after HSCT, the prevalence of pre-frailty was 45%, and the prevalence of frailty was 41% (P<0.01).

In the older group, at baseline, the prevalence of pre-frailty was 42%, and the prevalence of frailty was 6%. At 6 months, the prevalence of pre-frailty was 44%, and the prevalence of frailty was 38% (P<0.01).

The investigators then estimated the predictors of frailty.

Significant predictors of frailty included time since HSCT (odds ratio [OR]=3.7, 95% CI: 1.9-7.2, P<0.01), employment status (retired: OR=7.3, 95% CI 1.2 – 46.2, P=0.03), on medical leave or disabled (OR=11.2, 95% CI: 1.8 – 67.7, P=0.01), limitations in social activities (OR=1.04, 95% CI: 1.01 – 1.08, P=0.01), and baseline pre-frailty (OR=3.1, 95% CI: 2.3 – 45.5, P<0.01).

Allogeneic transplant was associated with higher odds of frailty than autologous (OR=3.1, 95% CI: 0.9 – 10.2), although it did not reach significance (P=0.06).

Investigators next estimated the impact of frailty or pre-frailty on NRM and identified a trend toward increased NRM in frail patients.

The 46 patients classified as not frail at baseline had a 7% cumulative incidence of NRM (P=0.07). The 42 patients classified as pre-frail had a 23% cumulative incidence of NRM, while the 8 patients classified as frail at baseline had a 28% cumulative incidence of NRM.

“So, to conclude, in this early study, frailty was noted in 8% and pre-frailty in 44% of the transplant population prior to transplant, and was not dependent on age,” Dr Arora said. “Frailty is a transitional state and appears to reflect a dynamic progression from robustness to functional decline with time since [HSCT].”

Because frailty is associated with higher mortality, the investigators believe vulnerable populations should be identified and their need for specific interventions defined.

This research was funded by the Leukemia & Lymphoma Society.

*Data in the abstract differ from the presentation.

The antiviral drug brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, according to the drug’s developer, Chimerix.

Brincidofovir did not prevent clinically significant cytomegalovirus (CMV) infection through week 24 after hematopoietic stem cell transplant (HSCT).

However, the president and CEO of Chimerix said the company still believes there is a “viable path forward” for the drug.

Brincidofovir is an oral nucleotide analog that has shown in vitro antiviral activity against all 5 families of DNA viruses that affect humans, including herpes viruses and adenovirus.

The SUPPRESS trial, which was initiated in August 2013 and fully enrolled in June 2015, was informed by a successful phase 2 trial conducted in HSCT recipients.

The SUPPRESS trial enrolled and treated 452 adults who received allogeneic HSCTs from more than 40 transplant centers in the US, Canada, and Europe.

Subjects received twice-weekly brincidofovir or placebo (2:1 ratio) from the early post-transplant period through week 14 post-transplant, the period of highest risk for viral infections.

All patients in the trial were CMV-seropositive, placing them at high risk of CMV infection. The most common indications leading to HSCT were acute myelogenous leukemia (43% of patients), myelodysplasia (17%), non-Hodgkin lymphoma (10%), and acute lymphocytic leukemia (9%).

During the on-treatment period through week 14 after HSCT, fewer patients in the brincidofovir arm had a CMV infection, which was consistent with results from the phase 2 study of the drug.

However, during the 10 weeks off treatment from week 14 to week 24, there was an increase in CMV infections in the brincidofovir arm compared to the control arm. And there was a non-statistically significant increase in mortality in the brincidofovir arm compared to the control arm.

Preliminary analysis suggests the failure in preventing CMV infections and the increased mortality in the brincidofovir arm were driven by confirmed cases of graft-versus-host-disease (GVHD), which resulted in a significantly higher use of corticosteroids than in the control arm.

Both GVHD and the use of corticosteroids are risk factors for “late” CMV infection that occurs after the discontinuation of the antiviral in HSCT recipients.

The rate of study drug discontinuation for gastrointestinal events was less than 10% in this study, which is comparable to that observed in the phase 2 trial of brincidofovir in a similar HSCT population.

“While we are clearly disappointed in the top-line results from SUPPRESS, we remain committed to better understanding the full data set as we consider potential paths forward for brincidofovir,” said M. Michelle Berrey, MD, president and CEO of Chimerix.

“We will be evaluating the subgroups of patients within SUPPRESS, such as T-cell-depleted transplant recipients who have a lower risk of GVHD, to better understand these results and inform our next steps,” said W. Garrett Nichols, MD, Chimerix’s chief medical officer.

“We are reaching out to investigators and other experts to help us assess the complete data set to understand what may have caused the results of the SUPPRESS trial to differ substantially from those seen in the phase 2 study. Additionally, we are in communication with the US Food and Drug Administration and other regulatory bodies and will share any updates on the brincidofovir clinical program when we can.”

“With data currently in hand, we believe that brincidofovir may ultimately demonstrate a positive risk-benefit profile for the treatment of adenovirus and smallpox, as well as use in other populations in need of a novel compound for DNA viral infections.”

Chimerix plans to continue the programs testing brincidofovir in serious adenovirus infections and in smallpox. Pending the availability of complete data from SUPPRESS, including secondary endpoints in other dsDNA viral infections, Chimerix has elected to pause further enrollment in the phase 3 SUSTAIN and SURPASS trials in kidney transplant recipients.

A full analysis of the SUPPRESS trial results is ongoing. The data are scheduled to be presented at the BMT Tandem Meetings in Honolulu, Hawaii, in February.

The antiviral drug brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, according to the drug’s developer, Chimerix.

Brincidofovir did not prevent clinically significant cytomegalovirus (CMV) infection through week 24 after hematopoietic stem cell transplant (HSCT).

However, the president and CEO of Chimerix said the company still believes there is a “viable path forward” for the drug.

Brincidofovir is an oral nucleotide analog that has shown in vitro antiviral activity against all 5 families of DNA viruses that affect humans, including herpes viruses and adenovirus.

The SUPPRESS trial, which was initiated in August 2013 and fully enrolled in June 2015, was informed by a successful phase 2 trial conducted in HSCT recipients.

The SUPPRESS trial enrolled and treated 452 adults who received allogeneic HSCTs from more than 40 transplant centers in the US, Canada, and Europe.

Subjects received twice-weekly brincidofovir or placebo (2:1 ratio) from the early post-transplant period through week 14 post-transplant, the period of highest risk for viral infections.

All patients in the trial were CMV-seropositive, placing them at high risk of CMV infection. The most common indications leading to HSCT were acute myelogenous leukemia (43% of patients), myelodysplasia (17%), non-Hodgkin lymphoma (10%), and acute lymphocytic leukemia (9%).

During the on-treatment period through week 14 after HSCT, fewer patients in the brincidofovir arm had a CMV infection, which was consistent with results from the phase 2 study of the drug.

However, during the 10 weeks off treatment from week 14 to week 24, there was an increase in CMV infections in the brincidofovir arm compared to the control arm. And there was a non-statistically significant increase in mortality in the brincidofovir arm compared to the control arm.

Preliminary analysis suggests the failure in preventing CMV infections and the increased mortality in the brincidofovir arm were driven by confirmed cases of graft-versus-host-disease (GVHD), which resulted in a significantly higher use of corticosteroids than in the control arm.

Both GVHD and the use of corticosteroids are risk factors for “late” CMV infection that occurs after the discontinuation of the antiviral in HSCT recipients.

The rate of study drug discontinuation for gastrointestinal events was less than 10% in this study, which is comparable to that observed in the phase 2 trial of brincidofovir in a similar HSCT population.

“While we are clearly disappointed in the top-line results from SUPPRESS, we remain committed to better understanding the full data set as we consider potential paths forward for brincidofovir,” said M. Michelle Berrey, MD, president and CEO of Chimerix.

“We will be evaluating the subgroups of patients within SUPPRESS, such as T-cell-depleted transplant recipients who have a lower risk of GVHD, to better understand these results and inform our next steps,” said W. Garrett Nichols, MD, Chimerix’s chief medical officer.

“We are reaching out to investigators and other experts to help us assess the complete data set to understand what may have caused the results of the SUPPRESS trial to differ substantially from those seen in the phase 2 study. Additionally, we are in communication with the US Food and Drug Administration and other regulatory bodies and will share any updates on the brincidofovir clinical program when we can.”

“With data currently in hand, we believe that brincidofovir may ultimately demonstrate a positive risk-benefit profile for the treatment of adenovirus and smallpox, as well as use in other populations in need of a novel compound for DNA viral infections.”

Chimerix plans to continue the programs testing brincidofovir in serious adenovirus infections and in smallpox. Pending the availability of complete data from SUPPRESS, including secondary endpoints in other dsDNA viral infections, Chimerix has elected to pause further enrollment in the phase 3 SUSTAIN and SURPASS trials in kidney transplant recipients.

A full analysis of the SUPPRESS trial results is ongoing. The data are scheduled to be presented at the BMT Tandem Meetings in Honolulu, Hawaii, in February.

The antiviral drug brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, according to the drug’s developer, Chimerix.

Brincidofovir did not prevent clinically significant cytomegalovirus (CMV) infection through week 24 after hematopoietic stem cell transplant (HSCT).

However, the president and CEO of Chimerix said the company still believes there is a “viable path forward” for the drug.

Brincidofovir is an oral nucleotide analog that has shown in vitro antiviral activity against all 5 families of DNA viruses that affect humans, including herpes viruses and adenovirus.

The SUPPRESS trial, which was initiated in August 2013 and fully enrolled in June 2015, was informed by a successful phase 2 trial conducted in HSCT recipients.

The SUPPRESS trial enrolled and treated 452 adults who received allogeneic HSCTs from more than 40 transplant centers in the US, Canada, and Europe.

Subjects received twice-weekly brincidofovir or placebo (2:1 ratio) from the early post-transplant period through week 14 post-transplant, the period of highest risk for viral infections.

All patients in the trial were CMV-seropositive, placing them at high risk of CMV infection. The most common indications leading to HSCT were acute myelogenous leukemia (43% of patients), myelodysplasia (17%), non-Hodgkin lymphoma (10%), and acute lymphocytic leukemia (9%).

During the on-treatment period through week 14 after HSCT, fewer patients in the brincidofovir arm had a CMV infection, which was consistent with results from the phase 2 study of the drug.

However, during the 10 weeks off treatment from week 14 to week 24, there was an increase in CMV infections in the brincidofovir arm compared to the control arm. And there was a non-statistically significant increase in mortality in the brincidofovir arm compared to the control arm.

Preliminary analysis suggests the failure in preventing CMV infections and the increased mortality in the brincidofovir arm were driven by confirmed cases of graft-versus-host-disease (GVHD), which resulted in a significantly higher use of corticosteroids than in the control arm.

Both GVHD and the use of corticosteroids are risk factors for “late” CMV infection that occurs after the discontinuation of the antiviral in HSCT recipients.

The rate of study drug discontinuation for gastrointestinal events was less than 10% in this study, which is comparable to that observed in the phase 2 trial of brincidofovir in a similar HSCT population.

“While we are clearly disappointed in the top-line results from SUPPRESS, we remain committed to better understanding the full data set as we consider potential paths forward for brincidofovir,” said M. Michelle Berrey, MD, president and CEO of Chimerix.

“We will be evaluating the subgroups of patients within SUPPRESS, such as T-cell-depleted transplant recipients who have a lower risk of GVHD, to better understand these results and inform our next steps,” said W. Garrett Nichols, MD, Chimerix’s chief medical officer.

“We are reaching out to investigators and other experts to help us assess the complete data set to understand what may have caused the results of the SUPPRESS trial to differ substantially from those seen in the phase 2 study. Additionally, we are in communication with the US Food and Drug Administration and other regulatory bodies and will share any updates on the brincidofovir clinical program when we can.”

“With data currently in hand, we believe that brincidofovir may ultimately demonstrate a positive risk-benefit profile for the treatment of adenovirus and smallpox, as well as use in other populations in need of a novel compound for DNA viral infections.”

Chimerix plans to continue the programs testing brincidofovir in serious adenovirus infections and in smallpox. Pending the availability of complete data from SUPPRESS, including secondary endpoints in other dsDNA viral infections, Chimerix has elected to pause further enrollment in the phase 3 SUSTAIN and SURPASS trials in kidney transplant recipients.

A full analysis of the SUPPRESS trial results is ongoing. The data are scheduled to be presented at the BMT Tandem Meetings in Honolulu, Hawaii, in February.

Bone marrow harvest

Photo by Chad McNeeley

ORLANDO, FL—In a large, registry-based study, transplants from human leukocyte antigen (HLA)-identical sibling donors proved successful in more than 90% of children and adults with severe sickle cell disease (SCD).

However, younger patients and those who received bone marrow (BM) or cord blood (CB) transplants fared the best.

Patient age and stem cell source were both independently associated with event-free and overall survival.

These results suggest SCD patients should be referred for transplant early but should not receive peripheral blood stem cell (PBSC) transplants, said Barbara Cappelli, MD, of the Eurocord International Registry in Paris, France.

Dr Cappelli presented the results of this study at the 2015 ASH Annual Meeting (abstract 541*).

The study included 1000 SCD patients who received HLA-identical sibling transplants from 1986 through 2013. The transplants took place at 88 centers in 23 countries and were reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

The patients’ median age was 9 (range, 1-54), and most (85%) were younger than 16. Most patients (94%) were homozygotes for hemoglobin S. Most had received red blood cell transfusions (94%), and a little more than half had received hydroxyurea (56%).

About half of HSCTs (53%) were performed after 2007, 29% from 2000 to 2006, 16% from 1991 to 1999, and 2% before 1999.

The most common indication for HSCT was recurrent vaso-occlusive crisis (77%), followed by stroke or central nervous system event (48%), and recurrent chest syndrome (32%), among other indications.

Most patients received BM transplants (84%), although a minority received CB (9%) or PBSC (7%) transplants.

A majority of patients received myeloablative conditioning regimens (n=873, 87%), largely based on the combination of busulfan and cyclophosphamide (n=719). Among the patients who received reduced-intensity conditioning (n=127, 13%), fludarabine with cyclophosphamide was the predominant regimen (n=48).

Most regimens included in vivo T-cell depletion (70%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The most common regimen for graft-vs-host disease (GVHD) prophylaxis was cyclosporine plus methotrexate (56%).

Results

The median follow-up was 45 months (range, 1-325).

At 60 days, the cumulative incidence of neutrophil engraftment was 98%, and the median time to neutrophil engraftment was 19 days. The cumulative incidence of platelet engraftment was 96%, and the median time to platelet engraftment was 25 days.

Acute GVHD occurred in 14.4% of patients, and chronic GVHD occurred 13.3%.

Multivariate analysis showed that the risk of acute GVHD was significantly higher in older patients, but none of the variables the researchers tested (T-cell depletion, conditioning regimen, etc.) were associated with chronic GVHD.

Younger age at HSCT and receiving a BM or CB transplant were independently associated with better event-free survival and overall survival. Undergoing HSCT after the year 2000 was associated with better overall survival.

The 3-year event-free survival was 90% overall, 90% for patients who received BM transplants, 78% for those who received PBSCs, and 97% for those who received CB transplants.

The 3-year overall survival was 94% overall, 94% for patients who received BM transplants, 80% for those who received PBSCs, and 99% for those who received CB transplants.

Seventy-one patients (7%) had autologous reconstitution (45 with late graft failure), 31 (3%) underwent a second HSCT, and 67 (7%) died—6% in the BM group, 21% in the PBSC group, and 1% in the CB group.

Death was related to transplant in 59 cases—14 due to infection, 12 due to toxicity, 9 due to GVHD, and 24 were of an unknown (but presumably HSCT-related) cause.

Three patients died from disease recurrence or persistence, 2 died from secondary malignancies, and 3 had unknown causes of death.

“This study shows excellent 3-year overall and event-free survival, with limited toxicity, despite the use of myeloablative conditioning regimens,” Dr Cappelli noted. “This should increase the early referral to transplant for patients with severe sickle cell disease, as age is an independent predictor for event-free survival and overall survival.”

She added that PBSC transplants “are not recommended,” as they were associated with higher mortality. And novel strategies are needed for lowing rates of graft failure and GVHD in SCD patients.

*Data in the abstract differ from the presentation.

Bone marrow harvest

Photo by Chad McNeeley

ORLANDO, FL—In a large, registry-based study, transplants from human leukocyte antigen (HLA)-identical sibling donors proved successful in more than 90% of children and adults with severe sickle cell disease (SCD).

However, younger patients and those who received bone marrow (BM) or cord blood (CB) transplants fared the best.

Patient age and stem cell source were both independently associated with event-free and overall survival.

These results suggest SCD patients should be referred for transplant early but should not receive peripheral blood stem cell (PBSC) transplants, said Barbara Cappelli, MD, of the Eurocord International Registry in Paris, France.

Dr Cappelli presented the results of this study at the 2015 ASH Annual Meeting (abstract 541*).

The study included 1000 SCD patients who received HLA-identical sibling transplants from 1986 through 2013. The transplants took place at 88 centers in 23 countries and were reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

The patients’ median age was 9 (range, 1-54), and most (85%) were younger than 16. Most patients (94%) were homozygotes for hemoglobin S. Most had received red blood cell transfusions (94%), and a little more than half had received hydroxyurea (56%).

About half of HSCTs (53%) were performed after 2007, 29% from 2000 to 2006, 16% from 1991 to 1999, and 2% before 1999.

The most common indication for HSCT was recurrent vaso-occlusive crisis (77%), followed by stroke or central nervous system event (48%), and recurrent chest syndrome (32%), among other indications.

Most patients received BM transplants (84%), although a minority received CB (9%) or PBSC (7%) transplants.

A majority of patients received myeloablative conditioning regimens (n=873, 87%), largely based on the combination of busulfan and cyclophosphamide (n=719). Among the patients who received reduced-intensity conditioning (n=127, 13%), fludarabine with cyclophosphamide was the predominant regimen (n=48).

Most regimens included in vivo T-cell depletion (70%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The most common regimen for graft-vs-host disease (GVHD) prophylaxis was cyclosporine plus methotrexate (56%).

Results

The median follow-up was 45 months (range, 1-325).

At 60 days, the cumulative incidence of neutrophil engraftment was 98%, and the median time to neutrophil engraftment was 19 days. The cumulative incidence of platelet engraftment was 96%, and the median time to platelet engraftment was 25 days.

Acute GVHD occurred in 14.4% of patients, and chronic GVHD occurred 13.3%.

Multivariate analysis showed that the risk of acute GVHD was significantly higher in older patients, but none of the variables the researchers tested (T-cell depletion, conditioning regimen, etc.) were associated with chronic GVHD.

Younger age at HSCT and receiving a BM or CB transplant were independently associated with better event-free survival and overall survival. Undergoing HSCT after the year 2000 was associated with better overall survival.

The 3-year event-free survival was 90% overall, 90% for patients who received BM transplants, 78% for those who received PBSCs, and 97% for those who received CB transplants.

The 3-year overall survival was 94% overall, 94% for patients who received BM transplants, 80% for those who received PBSCs, and 99% for those who received CB transplants.

Seventy-one patients (7%) had autologous reconstitution (45 with late graft failure), 31 (3%) underwent a second HSCT, and 67 (7%) died—6% in the BM group, 21% in the PBSC group, and 1% in the CB group.

Death was related to transplant in 59 cases—14 due to infection, 12 due to toxicity, 9 due to GVHD, and 24 were of an unknown (but presumably HSCT-related) cause.

Three patients died from disease recurrence or persistence, 2 died from secondary malignancies, and 3 had unknown causes of death.

“This study shows excellent 3-year overall and event-free survival, with limited toxicity, despite the use of myeloablative conditioning regimens,” Dr Cappelli noted. “This should increase the early referral to transplant for patients with severe sickle cell disease, as age is an independent predictor for event-free survival and overall survival.”

She added that PBSC transplants “are not recommended,” as they were associated with higher mortality. And novel strategies are needed for lowing rates of graft failure and GVHD in SCD patients.

*Data in the abstract differ from the presentation.

Bone marrow harvest

Photo by Chad McNeeley

ORLANDO, FL—In a large, registry-based study, transplants from human leukocyte antigen (HLA)-identical sibling donors proved successful in more than 90% of children and adults with severe sickle cell disease (SCD).

However, younger patients and those who received bone marrow (BM) or cord blood (CB) transplants fared the best.

Patient age and stem cell source were both independently associated with event-free and overall survival.

These results suggest SCD patients should be referred for transplant early but should not receive peripheral blood stem cell (PBSC) transplants, said Barbara Cappelli, MD, of the Eurocord International Registry in Paris, France.

Dr Cappelli presented the results of this study at the 2015 ASH Annual Meeting (abstract 541*).

The study included 1000 SCD patients who received HLA-identical sibling transplants from 1986 through 2013. The transplants took place at 88 centers in 23 countries and were reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

The patients’ median age was 9 (range, 1-54), and most (85%) were younger than 16. Most patients (94%) were homozygotes for hemoglobin S. Most had received red blood cell transfusions (94%), and a little more than half had received hydroxyurea (56%).

About half of HSCTs (53%) were performed after 2007, 29% from 2000 to 2006, 16% from 1991 to 1999, and 2% before 1999.

The most common indication for HSCT was recurrent vaso-occlusive crisis (77%), followed by stroke or central nervous system event (48%), and recurrent chest syndrome (32%), among other indications.

Most patients received BM transplants (84%), although a minority received CB (9%) or PBSC (7%) transplants.

A majority of patients received myeloablative conditioning regimens (n=873, 87%), largely based on the combination of busulfan and cyclophosphamide (n=719). Among the patients who received reduced-intensity conditioning (n=127, 13%), fludarabine with cyclophosphamide was the predominant regimen (n=48).

Most regimens included in vivo T-cell depletion (70%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The most common regimen for graft-vs-host disease (GVHD) prophylaxis was cyclosporine plus methotrexate (56%).

Results

The median follow-up was 45 months (range, 1-325).

At 60 days, the cumulative incidence of neutrophil engraftment was 98%, and the median time to neutrophil engraftment was 19 days. The cumulative incidence of platelet engraftment was 96%, and the median time to platelet engraftment was 25 days.

Acute GVHD occurred in 14.4% of patients, and chronic GVHD occurred 13.3%.

Multivariate analysis showed that the risk of acute GVHD was significantly higher in older patients, but none of the variables the researchers tested (T-cell depletion, conditioning regimen, etc.) were associated with chronic GVHD.

Younger age at HSCT and receiving a BM or CB transplant were independently associated with better event-free survival and overall survival. Undergoing HSCT after the year 2000 was associated with better overall survival.

The 3-year event-free survival was 90% overall, 90% for patients who received BM transplants, 78% for those who received PBSCs, and 97% for those who received CB transplants.

The 3-year overall survival was 94% overall, 94% for patients who received BM transplants, 80% for those who received PBSCs, and 99% for those who received CB transplants.

Seventy-one patients (7%) had autologous reconstitution (45 with late graft failure), 31 (3%) underwent a second HSCT, and 67 (7%) died—6% in the BM group, 21% in the PBSC group, and 1% in the CB group.

Death was related to transplant in 59 cases—14 due to infection, 12 due to toxicity, 9 due to GVHD, and 24 were of an unknown (but presumably HSCT-related) cause.

Three patients died from disease recurrence or persistence, 2 died from secondary malignancies, and 3 had unknown causes of death.

“This study shows excellent 3-year overall and event-free survival, with limited toxicity, despite the use of myeloablative conditioning regimens,” Dr Cappelli noted. “This should increase the early referral to transplant for patients with severe sickle cell disease, as age is an independent predictor for event-free survival and overall survival.”

She added that PBSC transplants “are not recommended,” as they were associated with higher mortality. And novel strategies are needed for lowing rates of graft failure and GVHD in SCD patients.

*Data in the abstract differ from the presentation.

Reef stonefish

Photo by Richard Ling

Research involving the stonefish—an animal that protects itself using razor-sharp, venom-filled spines—has provided unexpected insight into the human immune response that causes hematopoietic stem cell transplants (HSCTs) to fail.

The insight is now being used to develop immunosuppressants that could potentially improve the success rate of HSCTs.

Researchers explained this surprising connection in PNAS.

Their study indicated that the lethal component of stonefish venom, a protein called stonustoxin, is an ancient relative of the human immune protein perforin.

The body unleashes perforin to destroy virally infected and cancerous cells. Unwanted or excessive perforin activity is responsible for a range of medical problems, including the rejection of HSCTs.

Perforin proteins attach themselves to a cell and assemble to form giant pores on the cell surface. Each pore contains around 20 perforin proteins that stick together in a symmetrical fashion. The pores are big enough to allow toxins to enter the cell, killing it from within.

How these pores form is a mystery, but the current study has revealed a key part of the pore-assembly mechanism.

To make this discovery, the researchers used synchrotron radiation to visualize the atomic structure of stonustoxin. They found the toxin contains 2 perforin-like proteins stuck together.

Seeing how these 2 proteins interact has helped the researchers on their way to understanding how the full assembly of 20 perforin molecules forms a complete pore.

The team is also using their new insight to develop perforin inhibitors.

“Already, the structure of stonustoxin is starting to inform our drug development program, and we now understand the very first stages of perforin pore formation,” said James Whisstock, PhD, of Monash University in Melbourne, Victoria, Australia.

“This type of mechanistic information is extremely useful in developing new strategies to inhibit perforin itself.”

Reef stonefish

Photo by Richard Ling

Research involving the stonefish—an animal that protects itself using razor-sharp, venom-filled spines—has provided unexpected insight into the human immune response that causes hematopoietic stem cell transplants (HSCTs) to fail.

The insight is now being used to develop immunosuppressants that could potentially improve the success rate of HSCTs.

Researchers explained this surprising connection in PNAS.

Their study indicated that the lethal component of stonefish venom, a protein called stonustoxin, is an ancient relative of the human immune protein perforin.

The body unleashes perforin to destroy virally infected and cancerous cells. Unwanted or excessive perforin activity is responsible for a range of medical problems, including the rejection of HSCTs.

Perforin proteins attach themselves to a cell and assemble to form giant pores on the cell surface. Each pore contains around 20 perforin proteins that stick together in a symmetrical fashion. The pores are big enough to allow toxins to enter the cell, killing it from within.

How these pores form is a mystery, but the current study has revealed a key part of the pore-assembly mechanism.

To make this discovery, the researchers used synchrotron radiation to visualize the atomic structure of stonustoxin. They found the toxin contains 2 perforin-like proteins stuck together.

Seeing how these 2 proteins interact has helped the researchers on their way to understanding how the full assembly of 20 perforin molecules forms a complete pore.

The team is also using their new insight to develop perforin inhibitors.

“Already, the structure of stonustoxin is starting to inform our drug development program, and we now understand the very first stages of perforin pore formation,” said James Whisstock, PhD, of Monash University in Melbourne, Victoria, Australia.

“This type of mechanistic information is extremely useful in developing new strategies to inhibit perforin itself.”

Reef stonefish

Photo by Richard Ling

Research involving the stonefish—an animal that protects itself using razor-sharp, venom-filled spines—has provided unexpected insight into the human immune response that causes hematopoietic stem cell transplants (HSCTs) to fail.

The insight is now being used to develop immunosuppressants that could potentially improve the success rate of HSCTs.

Researchers explained this surprising connection in PNAS.

Their study indicated that the lethal component of stonefish venom, a protein called stonustoxin, is an ancient relative of the human immune protein perforin.

The body unleashes perforin to destroy virally infected and cancerous cells. Unwanted or excessive perforin activity is responsible for a range of medical problems, including the rejection of HSCTs.

Perforin proteins attach themselves to a cell and assemble to form giant pores on the cell surface. Each pore contains around 20 perforin proteins that stick together in a symmetrical fashion. The pores are big enough to allow toxins to enter the cell, killing it from within.

How these pores form is a mystery, but the current study has revealed a key part of the pore-assembly mechanism.

To make this discovery, the researchers used synchrotron radiation to visualize the atomic structure of stonustoxin. They found the toxin contains 2 perforin-like proteins stuck together.

Seeing how these 2 proteins interact has helped the researchers on their way to understanding how the full assembly of 20 perforin molecules forms a complete pore.

The team is also using their new insight to develop perforin inhibitors.

“Already, the structure of stonustoxin is starting to inform our drug development program, and we now understand the very first stages of perforin pore formation,” said James Whisstock, PhD, of Monash University in Melbourne, Victoria, Australia.

“This type of mechanistic information is extremely useful in developing new strategies to inhibit perforin itself.”

Fitbit Flex

Activity trackers like the Fitbit can count steps and measure sleep, but a new study suggests they can also be used to gauge patients’ symptoms and overall functional status after hematopoietic stem cell transplant (HSCT).

Researchers used Fitbits to track the physical activity of 32 HSCT recipients and found that decreases in average daily steps were associated with increases in pain, fatigue, and other symptoms, as well as a reduction in self-reported activities.

The researchers say the findings, published in Quality of Life Research, indicate that activity trackers could be a useful tool for tracking symptoms and physical function systematically, especially for patients who may not be able to self-report their symptoms using questionnaires because of language barriers, literacy, or cognitive or health status.

“We found that changes in daily steps are highly correlated with pain and fatigue,” said Antonia Bennett, PhD, of the University of North Carolina at Chapel Hill.

“These wearables provide a way to monitor how patients are doing, and they provide continuous data with very little patient burden.”

For this study, Dr Bennett and her colleagues evaluated daily steps, as measured by Fitbit Flex activity trackers, and symptoms in 32 adults who underwent autologous or allogeneic HSCT to treat leukemia, lymphoma, myeloma, myelodysplastic syndromes, aplastic anemia, or solid tumor malignancy.

The patients wore the activity trackers and completed assessments about their symptoms and quality of life for 4 weeks during transplant hospitalization and 4 weeks after discharge.

Each week, the patients reported symptomatic treatment toxicities using single items from PROCTCAE and symptoms, physical health, mental health, and quality of life using PROMIS_ Global-10. The researchers compared these answers with pedometry data, summarized as average daily steps per week, using linear mixed models.

These analyses showed that decreases in a patient’s average daily steps were associated with increases in the following:

• Pain (852 fewer steps per unit increase in pain score, P<0.001)
• Fatigue (886 fewer steps, P<0.001)
• Vomiting (518 fewer steps, P<0.01)
• Shaking/chills (587 fewer steps, P<0.01)
• Diarrhea (719 fewer steps, P<0.001)
• Shortness of breath (1018 fewer steps, P<0.05)
• Reduction in carrying out social activities (705 fewer steps, P<0.01)
• Reduction in carrying out physical activities (618 fewer steps, P<0.01)
• Global physical health (101 fewer steps, P<0.001).

However, decreases in daily steps were not linked to global mental health or quality of life.

“Studies like this demonstrate that wearable devices can measure an aspect of physical function that is directly related to symptomatic toxicities following treatment,” said William Wood, MD, of the University of North Carolina at Chapel Hill.

“As clinicians, we often want to know–overall, how well are our patients doing with treatment? Are they better, worse, or about the same? Data from wearable devices may allow us to answer these questions with much more precision than we’ve had in the past.”

Fitbit Flex

Activity trackers like the Fitbit can count steps and measure sleep, but a new study suggests they can also be used to gauge patients’ symptoms and overall functional status after hematopoietic stem cell transplant (HSCT).

Researchers used Fitbits to track the physical activity of 32 HSCT recipients and found that decreases in average daily steps were associated with increases in pain, fatigue, and other symptoms, as well as a reduction in self-reported activities.

The researchers say the findings, published in Quality of Life Research, indicate that activity trackers could be a useful tool for tracking symptoms and physical function systematically, especially for patients who may not be able to self-report their symptoms using questionnaires because of language barriers, literacy, or cognitive or health status.

“We found that changes in daily steps are highly correlated with pain and fatigue,” said Antonia Bennett, PhD, of the University of North Carolina at Chapel Hill.

“These wearables provide a way to monitor how patients are doing, and they provide continuous data with very little patient burden.”

For this study, Dr Bennett and her colleagues evaluated daily steps, as measured by Fitbit Flex activity trackers, and symptoms in 32 adults who underwent autologous or allogeneic HSCT to treat leukemia, lymphoma, myeloma, myelodysplastic syndromes, aplastic anemia, or solid tumor malignancy.

The patients wore the activity trackers and completed assessments about their symptoms and quality of life for 4 weeks during transplant hospitalization and 4 weeks after discharge.

Each week, the patients reported symptomatic treatment toxicities using single items from PROCTCAE and symptoms, physical health, mental health, and quality of life using PROMIS_ Global-10. The researchers compared these answers with pedometry data, summarized as average daily steps per week, using linear mixed models.

These analyses showed that decreases in a patient’s average daily steps were associated with increases in the following:

• Pain (852 fewer steps per unit increase in pain score, P<0.001)
• Fatigue (886 fewer steps, P<0.001)
• Vomiting (518 fewer steps, P<0.01)
• Shaking/chills (587 fewer steps, P<0.01)
• Diarrhea (719 fewer steps, P<0.001)
• Shortness of breath (1018 fewer steps, P<0.05)
• Reduction in carrying out social activities (705 fewer steps, P<0.01)
• Reduction in carrying out physical activities (618 fewer steps, P<0.01)
• Global physical health (101 fewer steps, P<0.001).

However, decreases in daily steps were not linked to global mental health or quality of life.

“Studies like this demonstrate that wearable devices can measure an aspect of physical function that is directly related to symptomatic toxicities following treatment,” said William Wood, MD, of the University of North Carolina at Chapel Hill.

“As clinicians, we often want to know–overall, how well are our patients doing with treatment? Are they better, worse, or about the same? Data from wearable devices may allow us to answer these questions with much more precision than we’ve had in the past.”

Fitbit Flex

Activity trackers like the Fitbit can count steps and measure sleep, but a new study suggests they can also be used to gauge patients’ symptoms and overall functional status after hematopoietic stem cell transplant (HSCT).

Researchers used Fitbits to track the physical activity of 32 HSCT recipients and found that decreases in average daily steps were associated with increases in pain, fatigue, and other symptoms, as well as a reduction in self-reported activities.

The researchers say the findings, published in Quality of Life Research, indicate that activity trackers could be a useful tool for tracking symptoms and physical function systematically, especially for patients who may not be able to self-report their symptoms using questionnaires because of language barriers, literacy, or cognitive or health status.

“We found that changes in daily steps are highly correlated with pain and fatigue,” said Antonia Bennett, PhD, of the University of North Carolina at Chapel Hill.

“These wearables provide a way to monitor how patients are doing, and they provide continuous data with very little patient burden.”

For this study, Dr Bennett and her colleagues evaluated daily steps, as measured by Fitbit Flex activity trackers, and symptoms in 32 adults who underwent autologous or allogeneic HSCT to treat leukemia, lymphoma, myeloma, myelodysplastic syndromes, aplastic anemia, or solid tumor malignancy.

The patients wore the activity trackers and completed assessments about their symptoms and quality of life for 4 weeks during transplant hospitalization and 4 weeks after discharge.

Each week, the patients reported symptomatic treatment toxicities using single items from PROCTCAE and symptoms, physical health, mental health, and quality of life using PROMIS_ Global-10. The researchers compared these answers with pedometry data, summarized as average daily steps per week, using linear mixed models.

These analyses showed that decreases in a patient’s average daily steps were associated with increases in the following:

• Pain (852 fewer steps per unit increase in pain score, P<0.001)
• Fatigue (886 fewer steps, P<0.001)
• Vomiting (518 fewer steps, P<0.01)
• Shaking/chills (587 fewer steps, P<0.01)
• Diarrhea (719 fewer steps, P<0.001)
• Shortness of breath (1018 fewer steps, P<0.05)
• Reduction in carrying out social activities (705 fewer steps, P<0.01)
• Reduction in carrying out physical activities (618 fewer steps, P<0.01)
• Global physical health (101 fewer steps, P<0.001).

However, decreases in daily steps were not linked to global mental health or quality of life.

“Studies like this demonstrate that wearable devices can measure an aspect of physical function that is directly related to symptomatic toxicities following treatment,” said William Wood, MD, of the University of North Carolina at Chapel Hill.

“As clinicians, we often want to know–overall, how well are our patients doing with treatment? Are they better, worse, or about the same? Data from wearable devices may allow us to answer these questions with much more precision than we’ve had in the past.”

Rhesus macaque

Photo by Einar Fredriksen

A gene expression profiling study has suggested the aurora kinase A (AURKA) pathway may drive graft-vs-host disease (GVHD).

This indicates that AURKA inhibitors, which are readily available in the clinic, might prove useful as GVHD prophylaxis.

Scott Furlan, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues conducted this research and reported the results in Science Translational Medicine.

The researchers compared the transcriptome of T cells from monkeys with acute GVHD, both treated and untreated for the complication, to healthy controls.

Specifically, the team measured the expression profiles of CD3+ T cells from 5 cohorts of rhesus macaques:

1. Allogeneic transplant recipients receiving no GHVD prophylaxis
2. Allogeneic transplant recipients receiving sirolimus monotherapy
3. Allogeneic transplant recipients receiving tacrolimus-methotrexate
4. Autologous transplant recipients
5. Healthy controls.

This comparison revealed pathways that were abnormally activated during GVHD in allogeneic transplant recipients receiving no prophylaxis. This included pathways involved in immune signaling, T-cell proliferation, and cell-cycle progression.

Within these pathways were potentially druggable targets that had never before been linked to GVHD.

The researchers said the most notable pathway was AURKA, which controls cell-cycle progression as well cell growth, differentiation, and survival.

When they analyzed tissue samples from transplant patients, the team found that T cells highly expressed AURKA during GVHD.

And in a mouse model of GVHD, a drug targeting AURKA (MLN8237) reduced the severity of GVHD and improved survival. The median survival time was 22.5 days in vehicle-treated controls and 40.5 days in mice that received MLN8237 (P<0.0001).

The researchers said these results suggest that AURKA inhibitors, many of which are commercially available or currently being tested in clinical trials, might help prevent GVHD.

Rhesus macaque

Photo by Einar Fredriksen

A gene expression profiling study has suggested the aurora kinase A (AURKA) pathway may drive graft-vs-host disease (GVHD).

This indicates that AURKA inhibitors, which are readily available in the clinic, might prove useful as GVHD prophylaxis.

Scott Furlan, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues conducted this research and reported the results in Science Translational Medicine.

The researchers compared the transcriptome of T cells from monkeys with acute GVHD, both treated and untreated for the complication, to healthy controls.

Specifically, the team measured the expression profiles of CD3+ T cells from 5 cohorts of rhesus macaques:

1. Allogeneic transplant recipients receiving no GHVD prophylaxis
2. Allogeneic transplant recipients receiving sirolimus monotherapy
3. Allogeneic transplant recipients receiving tacrolimus-methotrexate
4. Autologous transplant recipients
5. Healthy controls.

This comparison revealed pathways that were abnormally activated during GVHD in allogeneic transplant recipients receiving no prophylaxis. This included pathways involved in immune signaling, T-cell proliferation, and cell-cycle progression.

Within these pathways were potentially druggable targets that had never before been linked to GVHD.

The researchers said the most notable pathway was AURKA, which controls cell-cycle progression as well cell growth, differentiation, and survival.

When they analyzed tissue samples from transplant patients, the team found that T cells highly expressed AURKA during GVHD.

And in a mouse model of GVHD, a drug targeting AURKA (MLN8237) reduced the severity of GVHD and improved survival. The median survival time was 22.5 days in vehicle-treated controls and 40.5 days in mice that received MLN8237 (P<0.0001).

The researchers said these results suggest that AURKA inhibitors, many of which are commercially available or currently being tested in clinical trials, might help prevent GVHD.

Rhesus macaque

Photo by Einar Fredriksen

A gene expression profiling study has suggested the aurora kinase A (AURKA) pathway may drive graft-vs-host disease (GVHD).

This indicates that AURKA inhibitors, which are readily available in the clinic, might prove useful as GVHD prophylaxis.

Scott Furlan, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues conducted this research and reported the results in Science Translational Medicine.

The researchers compared the transcriptome of T cells from monkeys with acute GVHD, both treated and untreated for the complication, to healthy controls.

Specifically, the team measured the expression profiles of CD3+ T cells from 5 cohorts of rhesus macaques:

1. Allogeneic transplant recipients receiving no GHVD prophylaxis
2. Allogeneic transplant recipients receiving sirolimus monotherapy
3. Allogeneic transplant recipients receiving tacrolimus-methotrexate
4. Autologous transplant recipients
5. Healthy controls.

This comparison revealed pathways that were abnormally activated during GVHD in allogeneic transplant recipients receiving no prophylaxis. This included pathways involved in immune signaling, T-cell proliferation, and cell-cycle progression.

Within these pathways were potentially druggable targets that had never before been linked to GVHD.

The researchers said the most notable pathway was AURKA, which controls cell-cycle progression as well cell growth, differentiation, and survival.

When they analyzed tissue samples from transplant patients, the team found that T cells highly expressed AURKA during GVHD.

And in a mouse model of GVHD, a drug targeting AURKA (MLN8237) reduced the severity of GVHD and improved survival. The median survival time was 22.5 days in vehicle-treated controls and 40.5 days in mice that received MLN8237 (P<0.0001).

The researchers said these results suggest that AURKA inhibitors, many of which are commercially available or currently being tested in clinical trials, might help prevent GVHD.

Proliferating HSCs

Image by John Perry

Previous studies have shown that hematopoietic stresses—such as myelofibrosis, anemia, and myeloablation—can induce extramedullary hematopoiesis (EMH), in which hematopoietic stem cells (HSCs) are mobilized to sites outside the bone marrow.

The splenic red pulp is known to be a prominent site of EMH in both mice and humans, but not much is known about the EMH niche.

Now, investigators say they have characterized this niche.

They detailed their findings in Nature.

The team used mouse models to examine the expression patterns of 2 known niche cell factors, SCF and CXCL12.

They discovered that the hematopoietic microenvironment in the spleen is found near sinusoidal blood vessels and is created by endothelial cells and perivascular stromal cells, just like the microenvironment in the bone marrow.

“Under emergency conditions, the endothelial cells and perivascular stromal cells that reside in the spleen are induced to proliferate so they can sustain all the new blood-forming stem cells that migrate into the spleen,” explained study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center, Dallas.

“We determined that this process in the spleen is physiologically important for responding to hematopoietic stress. Without it, the mice we studied could not maintain normal blood cell counts during pregnancy or quickly regenerate blood cell counts after bleeding or chemotherapy.”

The investigators believe these findings could aid the development of therapeutic interventions to enhance blood formation following chemotherapy or HSC transplant and thus accelerate the recovery of blood cell counts.

Proliferating HSCs

Image by John Perry

Previous studies have shown that hematopoietic stresses—such as myelofibrosis, anemia, and myeloablation—can induce extramedullary hematopoiesis (EMH), in which hematopoietic stem cells (HSCs) are mobilized to sites outside the bone marrow.

The splenic red pulp is known to be a prominent site of EMH in both mice and humans, but not much is known about the EMH niche.

Now, investigators say they have characterized this niche.

They detailed their findings in Nature.

The team used mouse models to examine the expression patterns of 2 known niche cell factors, SCF and CXCL12.

They discovered that the hematopoietic microenvironment in the spleen is found near sinusoidal blood vessels and is created by endothelial cells and perivascular stromal cells, just like the microenvironment in the bone marrow.

“Under emergency conditions, the endothelial cells and perivascular stromal cells that reside in the spleen are induced to proliferate so they can sustain all the new blood-forming stem cells that migrate into the spleen,” explained study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center, Dallas.

“We determined that this process in the spleen is physiologically important for responding to hematopoietic stress. Without it, the mice we studied could not maintain normal blood cell counts during pregnancy or quickly regenerate blood cell counts after bleeding or chemotherapy.”

The investigators believe these findings could aid the development of therapeutic interventions to enhance blood formation following chemotherapy or HSC transplant and thus accelerate the recovery of blood cell counts.

Proliferating HSCs

Image by John Perry

Previous studies have shown that hematopoietic stresses—such as myelofibrosis, anemia, and myeloablation—can induce extramedullary hematopoiesis (EMH), in which hematopoietic stem cells (HSCs) are mobilized to sites outside the bone marrow.

The splenic red pulp is known to be a prominent site of EMH in both mice and humans, but not much is known about the EMH niche.

Now, investigators say they have characterized this niche.

They detailed their findings in Nature.

The team used mouse models to examine the expression patterns of 2 known niche cell factors, SCF and CXCL12.

They discovered that the hematopoietic microenvironment in the spleen is found near sinusoidal blood vessels and is created by endothelial cells and perivascular stromal cells, just like the microenvironment in the bone marrow.

“Under emergency conditions, the endothelial cells and perivascular stromal cells that reside in the spleen are induced to proliferate so they can sustain all the new blood-forming stem cells that migrate into the spleen,” explained study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center, Dallas.

“We determined that this process in the spleen is physiologically important for responding to hematopoietic stress. Without it, the mice we studied could not maintain normal blood cell counts during pregnancy or quickly regenerate blood cell counts after bleeding or chemotherapy.”

The investigators believe these findings could aid the development of therapeutic interventions to enhance blood formation following chemotherapy or HSC transplant and thus accelerate the recovery of blood cell counts.

Apheresis donation

Photo by ec-jpr

ANAHEIM, CA—A newer, more streamlined apheresis system yields more CD34+ cells from stem cell transplant donors than a previous system, according to a new study.

Researchers used both tools—the COBE Spectra Apheresis System and the Spectra Optia Apheresis System—to collect mononuclear cells (MNCs) from healthy donors and found the collection efficiency and yield was superior with the Spectra Optia.

There were no unanticipated or serious adverse events with either system, and the frequency of treatment-emergent adverse events did not differ according to the system used.

Jose A. Cancelas, MD, PhD, of Hoxworth Blood Center in Cincinnati, Ohio, presented the results of this research at the 2015 AABB Annual Meeting (abstract S21-020A). The study was supported by Terumo BCT, the company that makes both systems.

The COBE Spectra Apheresis System collects MNCs via single-step processing and separation. It has been the gold standard for hematopoietic stem and progenitor cell collection since 1987, Dr Cancelas noted.

The newer Spectra Optia Apheresis System uses optical sensors for tracking the separation process and real-time electronic adjustment of plasma pump velocity (automatic interface management). A single-step, continuous MNC collection (CMNC) protocol, which was recently approved for use with this system in the US, is intended to increase automation and MNC collection reproducibility.

To compare the 2 systems, Dr Cancelas and his colleagues conducted a prospective, randomized, crossover study of 22 healthy donors. They had a mean age of 35 and a mean body mass index of 34.2 kg/m².

The donors underwent 2 MNC collections, first with one apheresis system and then the other. Both times, the donors underwent apheresis on Days 5 and 6 after standard MNC mobilization with granulocyte colony-stimulating factor (G-CSF at 10 mg/kg/day) through Day 5. After the first collection, there was a 2-week washout period.

The study’s primary endpoint was CD34+ cell collection efficiency, which was the percentage of cells collected using the averaged pre/post-collection cell counts as the denominator (CE1). The secondary endpoint was also CD34+ cell collection efficiency, but this was the percentage of cells collected using only the pre-collection cell count as a denominator (CE2).

The researchers also assessed the CD34+ cell yield (CD34+ cells/kg), MNC product contamination/purity, procedure time, product volume, the need for operator involvement, and safety.

Results

All collections processed 1.5 times the total blood volume, and the procedures took nearly 2.5 hours, with no real time difference between the 2 systems.

The average flow rates were 66 mL/minute with the Spectra Optia and 68 mL/minute with COBE Spectra. Product volumes were 143 mL and 139 mL, respectively.

The Optia proved significantly superior to the COBE system with regard to CE1, CE2, and the CD34+ yield.

The mean CD34+ CE1 was 85% with Optia and 66.2% with COBE (P<0.001). The mean CD34+ CE2 was 62% and 48.4%, respectively (P<0.001). And the mean CD34+ yield (cells/kg) was 4.5 and 3.58, respectively (P=0.001).

In addition, granulocyte contamination was lower with the Optia system than the COBE system. The mean granulocyte yield was 7.7 x10⁹ and 10.6 x10⁹ granulocytes per unit, respectively (P=0.022).

However, red blood cell and platelet contaminations were similar between the systems. The mean red blood cell volume was 7.4 mL with Optia and 7.0 mL with COBE (P=0.660). And the mean platelet yield was 4.3 x10¹¹ and 4.6 x10¹¹, respectively (P=0.081).

Overall, there was no significant difference between the Optia and COBE systems in the need for operator adjustments, although there was a trend toward fewer adjustments with the Optia system. It required a median of 5.5 adjustments (range, 0-12), and the COBE system required a median of 6.5 adjustments (range, 1-14).

Dr Cancelas said the frequency of treatment-emergent adverse events did not differ according to the system used. And there were no unanticipated or serious adverse events.

The most frequently reported pre-collection treatment-emergent adverse events were back pain (n=10, 44%), bone pain (n=9, 39%), and fatigue (n=5, 22%).

“These results demonstrate that the Optia CMNC procedure is a safe and efficient means of collecting CD34+ cells in G-CSF mobilized donors,” Dr Cancelas said.

“The Optia collection efficiencies for CD34+ cells were significantly superior to the COBE . . . . And the Optia with automatic interface management system represents a technological advance in our ability to collect CD34+ cells.”

Apheresis donation

Photo by ec-jpr

ANAHEIM, CA—A newer, more streamlined apheresis system yields more CD34+ cells from stem cell transplant donors than a previous system, according to a new study.

Researchers used both tools—the COBE Spectra Apheresis System and the Spectra Optia Apheresis System—to collect mononuclear cells (MNCs) from healthy donors and found the collection efficiency and yield was superior with the Spectra Optia.

There were no unanticipated or serious adverse events with either system, and the frequency of treatment-emergent adverse events did not differ according to the system used.

Jose A. Cancelas, MD, PhD, of Hoxworth Blood Center in Cincinnati, Ohio, presented the results of this research at the 2015 AABB Annual Meeting (abstract S21-020A). The study was supported by Terumo BCT, the company that makes both systems.

The COBE Spectra Apheresis System collects MNCs via single-step processing and separation. It has been the gold standard for hematopoietic stem and progenitor cell collection since 1987, Dr Cancelas noted.

The newer Spectra Optia Apheresis System uses optical sensors for tracking the separation process and real-time electronic adjustment of plasma pump velocity (automatic interface management). A single-step, continuous MNC collection (CMNC) protocol, which was recently approved for use with this system in the US, is intended to increase automation and MNC collection reproducibility.

To compare the 2 systems, Dr Cancelas and his colleagues conducted a prospective, randomized, crossover study of 22 healthy donors. They had a mean age of 35 and a mean body mass index of 34.2 kg/m².

The donors underwent 2 MNC collections, first with one apheresis system and then the other. Both times, the donors underwent apheresis on Days 5 and 6 after standard MNC mobilization with granulocyte colony-stimulating factor (G-CSF at 10 mg/kg/day) through Day 5. After the first collection, there was a 2-week washout period.

The study’s primary endpoint was CD34+ cell collection efficiency, which was the percentage of cells collected using the averaged pre/post-collection cell counts as the denominator (CE1). The secondary endpoint was also CD34+ cell collection efficiency, but this was the percentage of cells collected using only the pre-collection cell count as a denominator (CE2).

The researchers also assessed the CD34+ cell yield (CD34+ cells/kg), MNC product contamination/purity, procedure time, product volume, the need for operator involvement, and safety.

Results

All collections processed 1.5 times the total blood volume, and the procedures took nearly 2.5 hours, with no real time difference between the 2 systems.

The average flow rates were 66 mL/minute with the Spectra Optia and 68 mL/minute with COBE Spectra. Product volumes were 143 mL and 139 mL, respectively.

The Optia proved significantly superior to the COBE system with regard to CE1, CE2, and the CD34+ yield.

The mean CD34+ CE1 was 85% with Optia and 66.2% with COBE (P<0.001). The mean CD34+ CE2 was 62% and 48.4%, respectively (P<0.001). And the mean CD34+ yield (cells/kg) was 4.5 and 3.58, respectively (P=0.001).

In addition, granulocyte contamination was lower with the Optia system than the COBE system. The mean granulocyte yield was 7.7 x10⁹ and 10.6 x10⁹ granulocytes per unit, respectively (P=0.022).

However, red blood cell and platelet contaminations were similar between the systems. The mean red blood cell volume was 7.4 mL with Optia and 7.0 mL with COBE (P=0.660). And the mean platelet yield was 4.3 x10¹¹ and 4.6 x10¹¹, respectively (P=0.081).

Overall, there was no significant difference between the Optia and COBE systems in the need for operator adjustments, although there was a trend toward fewer adjustments with the Optia system. It required a median of 5.5 adjustments (range, 0-12), and the COBE system required a median of 6.5 adjustments (range, 1-14).

Dr Cancelas said the frequency of treatment-emergent adverse events did not differ according to the system used. And there were no unanticipated or serious adverse events.

The most frequently reported pre-collection treatment-emergent adverse events were back pain (n=10, 44%), bone pain (n=9, 39%), and fatigue (n=5, 22%).

“These results demonstrate that the Optia CMNC procedure is a safe and efficient means of collecting CD34+ cells in G-CSF mobilized donors,” Dr Cancelas said.

“The Optia collection efficiencies for CD34+ cells were significantly superior to the COBE . . . . And the Optia with automatic interface management system represents a technological advance in our ability to collect CD34+ cells.”

Apheresis donation

Photo by ec-jpr

ANAHEIM, CA—A newer, more streamlined apheresis system yields more CD34+ cells from stem cell transplant donors than a previous system, according to a new study.

Researchers used both tools—the COBE Spectra Apheresis System and the Spectra Optia Apheresis System—to collect mononuclear cells (MNCs) from healthy donors and found the collection efficiency and yield was superior with the Spectra Optia.

There were no unanticipated or serious adverse events with either system, and the frequency of treatment-emergent adverse events did not differ according to the system used.

Jose A. Cancelas, MD, PhD, of Hoxworth Blood Center in Cincinnati, Ohio, presented the results of this research at the 2015 AABB Annual Meeting (abstract S21-020A). The study was supported by Terumo BCT, the company that makes both systems.

The COBE Spectra Apheresis System collects MNCs via single-step processing and separation. It has been the gold standard for hematopoietic stem and progenitor cell collection since 1987, Dr Cancelas noted.

The newer Spectra Optia Apheresis System uses optical sensors for tracking the separation process and real-time electronic adjustment of plasma pump velocity (automatic interface management). A single-step, continuous MNC collection (CMNC) protocol, which was recently approved for use with this system in the US, is intended to increase automation and MNC collection reproducibility.

To compare the 2 systems, Dr Cancelas and his colleagues conducted a prospective, randomized, crossover study of 22 healthy donors. They had a mean age of 35 and a mean body mass index of 34.2 kg/m².

The donors underwent 2 MNC collections, first with one apheresis system and then the other. Both times, the donors underwent apheresis on Days 5 and 6 after standard MNC mobilization with granulocyte colony-stimulating factor (G-CSF at 10 mg/kg/day) through Day 5. After the first collection, there was a 2-week washout period.

The study’s primary endpoint was CD34+ cell collection efficiency, which was the percentage of cells collected using the averaged pre/post-collection cell counts as the denominator (CE1). The secondary endpoint was also CD34+ cell collection efficiency, but this was the percentage of cells collected using only the pre-collection cell count as a denominator (CE2).

The researchers also assessed the CD34+ cell yield (CD34+ cells/kg), MNC product contamination/purity, procedure time, product volume, the need for operator involvement, and safety.

Results

All collections processed 1.5 times the total blood volume, and the procedures took nearly 2.5 hours, with no real time difference between the 2 systems.

The average flow rates were 66 mL/minute with the Spectra Optia and 68 mL/minute with COBE Spectra. Product volumes were 143 mL and 139 mL, respectively.

The Optia proved significantly superior to the COBE system with regard to CE1, CE2, and the CD34+ yield.

The mean CD34+ CE1 was 85% with Optia and 66.2% with COBE (P<0.001). The mean CD34+ CE2 was 62% and 48.4%, respectively (P<0.001). And the mean CD34+ yield (cells/kg) was 4.5 and 3.58, respectively (P=0.001).

In addition, granulocyte contamination was lower with the Optia system than the COBE system. The mean granulocyte yield was 7.7 x10⁹ and 10.6 x10⁹ granulocytes per unit, respectively (P=0.022).

However, red blood cell and platelet contaminations were similar between the systems. The mean red blood cell volume was 7.4 mL with Optia and 7.0 mL with COBE (P=0.660). And the mean platelet yield was 4.3 x10¹¹ and 4.6 x10¹¹, respectively (P=0.081).

Overall, there was no significant difference between the Optia and COBE systems in the need for operator adjustments, although there was a trend toward fewer adjustments with the Optia system. It required a median of 5.5 adjustments (range, 0-12), and the COBE system required a median of 6.5 adjustments (range, 1-14).

Dr Cancelas said the frequency of treatment-emergent adverse events did not differ according to the system used. And there were no unanticipated or serious adverse events.

The most frequently reported pre-collection treatment-emergent adverse events were back pain (n=10, 44%), bone pain (n=9, 39%), and fatigue (n=5, 22%).

“These results demonstrate that the Optia CMNC procedure is a safe and efficient means of collecting CD34+ cells in G-CSF mobilized donors,” Dr Cancelas said.

“The Optia collection efficiencies for CD34+ cells were significantly superior to the COBE . . . . And the Optia with automatic interface management system represents a technological advance in our ability to collect CD34+ cells.”

HSCT preparation

Photo by Chad McNeeley

Results of a phase 2 study suggest that reduced-intensity conditioning (RIC) may allow older patients with acute myeloid leukemia (AML) to remain in long-term remission after allogeneic hematopoietic stem cell transplant (HSCT).

The study included patients age 60 and older who were in their first complete remission (CR1) at transplant.

Two years later, the probability of overall survival was 48%, and the probability of disease-free survival was 42%.

“This new data offers strong support against using biological age as a limiting factor for stem cell transplantation in AML patients who are otherwise well positioned to tolerate and achieve long-term remission with this approach,” said Steven Devine, MD, of The Ohio State University in Columbus.

He and his colleagues shared the data in the Journal of Clinical Oncology.

The researchers wanted to determine whether RIC could improve long-term remission rates after HSCT for older patients with AML.

So the team studied 114 patients with a median age of 65 (range, 60-74) who were treated at 21 US hospitals between November 2004 and November 2011. Most patients were male (62%), and most had intermediate cytogenetics (70%).

All of the patients were in CR1 according to International Working Group criteria. The CR had to be achieved after no more than 2 cycles of induction chemotherapy, and patients were required to undergo HSCT within 6 months of the initial documentation of morphologic CR.

The median time from CR1 documentation to HSCT was 85 days (range, 9-184), and the median time from AML diagnosis to HSCT was 138 days (range, 61-265).

All patients received RIC (fludarabine followed by busulfan) prior to HSCT, which essentially cut treatment strength by half compared to traditional high-dose conditioning. The patients received tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis.

Forty-eight percent of patients underwent HSCT from a matched, related donor, and 52% had a matched, unrelated donor.

At 2 years, disease-free survival was 42%, and overall survival was 48%. Among patients with unrelated donors, disease-free survival was 40%, and overall survival was 50%.

The cumulative incidence of relapse was 44%, and non-relapse mortality was 15%. Twenty-eight percent of patients had chronic GVHD, and 9.6% had grade 2-4 acute GVHD.

“Close to half of the patients treated in this study achieved long-term, cancer-free survival after 2 years,” Dr Devine noted. “These outcomes are similar to what we would expect to see in younger patients and appear to be better results than those that can be achieved with conventional chemotherapy-based approaches typically used in AML patients over 60.”

HSCT preparation

Photo by Chad McNeeley

Results of a phase 2 study suggest that reduced-intensity conditioning (RIC) may allow older patients with acute myeloid leukemia (AML) to remain in long-term remission after allogeneic hematopoietic stem cell transplant (HSCT).

The study included patients age 60 and older who were in their first complete remission (CR1) at transplant.

Two years later, the probability of overall survival was 48%, and the probability of disease-free survival was 42%.

“This new data offers strong support against using biological age as a limiting factor for stem cell transplantation in AML patients who are otherwise well positioned to tolerate and achieve long-term remission with this approach,” said Steven Devine, MD, of The Ohio State University in Columbus.

He and his colleagues shared the data in the Journal of Clinical Oncology.

The researchers wanted to determine whether RIC could improve long-term remission rates after HSCT for older patients with AML.

So the team studied 114 patients with a median age of 65 (range, 60-74) who were treated at 21 US hospitals between November 2004 and November 2011. Most patients were male (62%), and most had intermediate cytogenetics (70%).

All of the patients were in CR1 according to International Working Group criteria. The CR had to be achieved after no more than 2 cycles of induction chemotherapy, and patients were required to undergo HSCT within 6 months of the initial documentation of morphologic CR.

The median time from CR1 documentation to HSCT was 85 days (range, 9-184), and the median time from AML diagnosis to HSCT was 138 days (range, 61-265).

All patients received RIC (fludarabine followed by busulfan) prior to HSCT, which essentially cut treatment strength by half compared to traditional high-dose conditioning. The patients received tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis.

Forty-eight percent of patients underwent HSCT from a matched, related donor, and 52% had a matched, unrelated donor.

At 2 years, disease-free survival was 42%, and overall survival was 48%. Among patients with unrelated donors, disease-free survival was 40%, and overall survival was 50%.

The cumulative incidence of relapse was 44%, and non-relapse mortality was 15%. Twenty-eight percent of patients had chronic GVHD, and 9.6% had grade 2-4 acute GVHD.

“Close to half of the patients treated in this study achieved long-term, cancer-free survival after 2 years,” Dr Devine noted. “These outcomes are similar to what we would expect to see in younger patients and appear to be better results than those that can be achieved with conventional chemotherapy-based approaches typically used in AML patients over 60.”

HSCT preparation

Photo by Chad McNeeley

Results of a phase 2 study suggest that reduced-intensity conditioning (RIC) may allow older patients with acute myeloid leukemia (AML) to remain in long-term remission after allogeneic hematopoietic stem cell transplant (HSCT).

The study included patients age 60 and older who were in their first complete remission (CR1) at transplant.

Two years later, the probability of overall survival was 48%, and the probability of disease-free survival was 42%.

“This new data offers strong support against using biological age as a limiting factor for stem cell transplantation in AML patients who are otherwise well positioned to tolerate and achieve long-term remission with this approach,” said Steven Devine, MD, of The Ohio State University in Columbus.

He and his colleagues shared the data in the Journal of Clinical Oncology.

The researchers wanted to determine whether RIC could improve long-term remission rates after HSCT for older patients with AML.

So the team studied 114 patients with a median age of 65 (range, 60-74) who were treated at 21 US hospitals between November 2004 and November 2011. Most patients were male (62%), and most had intermediate cytogenetics (70%).

All of the patients were in CR1 according to International Working Group criteria. The CR had to be achieved after no more than 2 cycles of induction chemotherapy, and patients were required to undergo HSCT within 6 months of the initial documentation of morphologic CR.

The median time from CR1 documentation to HSCT was 85 days (range, 9-184), and the median time from AML diagnosis to HSCT was 138 days (range, 61-265).

All patients received RIC (fludarabine followed by busulfan) prior to HSCT, which essentially cut treatment strength by half compared to traditional high-dose conditioning. The patients received tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis.

Forty-eight percent of patients underwent HSCT from a matched, related donor, and 52% had a matched, unrelated donor.

At 2 years, disease-free survival was 42%, and overall survival was 48%. Among patients with unrelated donors, disease-free survival was 40%, and overall survival was 50%.

The cumulative incidence of relapse was 44%, and non-relapse mortality was 15%. Twenty-eight percent of patients had chronic GVHD, and 9.6% had grade 2-4 acute GVHD.

“Close to half of the patients treated in this study achieved long-term, cancer-free survival after 2 years,” Dr Devine noted. “These outcomes are similar to what we would expect to see in younger patients and appear to be better results than those that can be achieved with conventional chemotherapy-based approaches typically used in AML patients over 60.”

HSCT preparation

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) has said that, at present, it cannot approve a propylene glycol-free melphalan formulation (Evomela) for use in patients with multiple myeloma (MM).

Spectrum Pharmaceuticals is seeking approval for Evomela as a high-dose conditioning treatment for MM patients undergoing hematopoietic stem cell transplant (HSCT) and for palliative treatment in MM patients for whom oral therapy is not appropriate.

The FDA issued a Complete Response Letter stating that the new drug application (NDA) for Evomela cannot be approved in its present form.

However, the FDA did not identify any clinical deficiency in the NDA package.

“We will work swiftly with the FDA to address the Complete Response Letter,” said Rajesh C. Shrotriya, MD, chairman and chief executive officer of Spectrum Pharmaceuticals. “We remain committed to bringing Evomela to the market for patients and plan to work closely with the FDA.”

About Evomela

Evomela is a Captisol-enabled, propylene glycol-free melphalan formulation. This formulation eliminates the need to use a propylene glycol-containing custom diluent, which is required with other intravenous melphalan formulations and has been reported to cause renal and cardiac side effects.

The use of Captisol technology to reformulate melphalan is reported to improve the drug’s stability, extending its use time to 5 hours. This is anticipated to simplify preparation and administration logistics and allow for slower infusion rates and longer administration durations for pre-transplant chemotherapy.

Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs.

Spectrum Pharmaceuticals gained global development and commercialization rights to Evomela from Ligand Pharmaceuticals Incorporated in March 2013. Spectrum assumed responsibility for completing the pivotal phase 2 clinical trial and was responsible for filing the NDA. Spectrum filed the NDA in December 2014, and the FDA accepted the application the following March.

The FDA has granted Evomela orphan drug designation for use as a high-dose conditioning regimen for MM patients undergoing HSCT.

Phase 2 study

Researchers have evaluated Evomela in a phase 2, multicenter trial. Initial results from this trial (phase 2a) were published in Bone Marrow Transplantation in June 2014. Phase 2b results were published in Biology of Blood and Marrow Transplantation last month.

The latest publication includes data on 61 patients. Fifty-six had newly diagnosed MM, and 5 had relapsed MM following prior HSCT. The patients received Evomela at 200 mg/m² given as 2 doses on Day -3 and Day -2 prior to HSCT (Day 0).

Efficacy was assessed by clinical response at Day +100. According to investigator assessment, the overall response rate was 95%, and the complete response (CR) rate was 31%.

According to independent pathology review, the overall response rate was 100%, and the CR rate was 21%. The lower rate of confirmed CRs in the independent review was due to missing data.

All 5 patients who had previously relapsed from a prior HSCT responded to Evomela.

All patients in the study achieved myeloablation with a median of 5 days post-HSCT. All patients had successful neutrophil and platelet engraftment at a median of 12 days and 13 days post-HSCT, respectively.

Treatment-related mortality was 0%, and non-hematologic adverse events were mostly grade 1 and 2 in severity. The incidence of grade 3 mucositis and grade 3 stomatitis were 10% and 5%, respectively, with no grade 4 mucositis or stomatitis reported.

Twenty percent of patients experienced treatment-emergent serious adverse events, most of which were grade 3 and consisted of events commonly reported in patients undergoing myeloablative chemotherapy. No new safety signals were identified.

HSCT preparation

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) has said that, at present, it cannot approve a propylene glycol-free melphalan formulation (Evomela) for use in patients with multiple myeloma (MM).

Spectrum Pharmaceuticals is seeking approval for Evomela as a high-dose conditioning treatment for MM patients undergoing hematopoietic stem cell transplant (HSCT) and for palliative treatment in MM patients for whom oral therapy is not appropriate.

The FDA issued a Complete Response Letter stating that the new drug application (NDA) for Evomela cannot be approved in its present form.

However, the FDA did not identify any clinical deficiency in the NDA package.

“We will work swiftly with the FDA to address the Complete Response Letter,” said Rajesh C. Shrotriya, MD, chairman and chief executive officer of Spectrum Pharmaceuticals. “We remain committed to bringing Evomela to the market for patients and plan to work closely with the FDA.”

About Evomela

Evomela is a Captisol-enabled, propylene glycol-free melphalan formulation. This formulation eliminates the need to use a propylene glycol-containing custom diluent, which is required with other intravenous melphalan formulations and has been reported to cause renal and cardiac side effects.

The use of Captisol technology to reformulate melphalan is reported to improve the drug’s stability, extending its use time to 5 hours. This is anticipated to simplify preparation and administration logistics and allow for slower infusion rates and longer administration durations for pre-transplant chemotherapy.

Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs.

Spectrum Pharmaceuticals gained global development and commercialization rights to Evomela from Ligand Pharmaceuticals Incorporated in March 2013. Spectrum assumed responsibility for completing the pivotal phase 2 clinical trial and was responsible for filing the NDA. Spectrum filed the NDA in December 2014, and the FDA accepted the application the following March.

The FDA has granted Evomela orphan drug designation for use as a high-dose conditioning regimen for MM patients undergoing HSCT.

Phase 2 study

Researchers have evaluated Evomela in a phase 2, multicenter trial. Initial results from this trial (phase 2a) were published in Bone Marrow Transplantation in June 2014. Phase 2b results were published in Biology of Blood and Marrow Transplantation last month.

The latest publication includes data on 61 patients. Fifty-six had newly diagnosed MM, and 5 had relapsed MM following prior HSCT. The patients received Evomela at 200 mg/m² given as 2 doses on Day -3 and Day -2 prior to HSCT (Day 0).

Efficacy was assessed by clinical response at Day +100. According to investigator assessment, the overall response rate was 95%, and the complete response (CR) rate was 31%.

According to independent pathology review, the overall response rate was 100%, and the CR rate was 21%. The lower rate of confirmed CRs in the independent review was due to missing data.

All 5 patients who had previously relapsed from a prior HSCT responded to Evomela.

All patients in the study achieved myeloablation with a median of 5 days post-HSCT. All patients had successful neutrophil and platelet engraftment at a median of 12 days and 13 days post-HSCT, respectively.

Treatment-related mortality was 0%, and non-hematologic adverse events were mostly grade 1 and 2 in severity. The incidence of grade 3 mucositis and grade 3 stomatitis were 10% and 5%, respectively, with no grade 4 mucositis or stomatitis reported.

Twenty percent of patients experienced treatment-emergent serious adverse events, most of which were grade 3 and consisted of events commonly reported in patients undergoing myeloablative chemotherapy. No new safety signals were identified.

HSCT preparation

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) has said that, at present, it cannot approve a propylene glycol-free melphalan formulation (Evomela) for use in patients with multiple myeloma (MM).

Spectrum Pharmaceuticals is seeking approval for Evomela as a high-dose conditioning treatment for MM patients undergoing hematopoietic stem cell transplant (HSCT) and for palliative treatment in MM patients for whom oral therapy is not appropriate.

The FDA issued a Complete Response Letter stating that the new drug application (NDA) for Evomela cannot be approved in its present form.

However, the FDA did not identify any clinical deficiency in the NDA package.

“We will work swiftly with the FDA to address the Complete Response Letter,” said Rajesh C. Shrotriya, MD, chairman and chief executive officer of Spectrum Pharmaceuticals. “We remain committed to bringing Evomela to the market for patients and plan to work closely with the FDA.”

About Evomela

Evomela is a Captisol-enabled, propylene glycol-free melphalan formulation. This formulation eliminates the need to use a propylene glycol-containing custom diluent, which is required with other intravenous melphalan formulations and has been reported to cause renal and cardiac side effects.

The use of Captisol technology to reformulate melphalan is reported to improve the drug’s stability, extending its use time to 5 hours. This is anticipated to simplify preparation and administration logistics and allow for slower infusion rates and longer administration durations for pre-transplant chemotherapy.

Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs.

Spectrum Pharmaceuticals gained global development and commercialization rights to Evomela from Ligand Pharmaceuticals Incorporated in March 2013. Spectrum assumed responsibility for completing the pivotal phase 2 clinical trial and was responsible for filing the NDA. Spectrum filed the NDA in December 2014, and the FDA accepted the application the following March.

The FDA has granted Evomela orphan drug designation for use as a high-dose conditioning regimen for MM patients undergoing HSCT.

Phase 2 study

Researchers have evaluated Evomela in a phase 2, multicenter trial. Initial results from this trial (phase 2a) were published in Bone Marrow Transplantation in June 2014. Phase 2b results were published in Biology of Blood and Marrow Transplantation last month.

The latest publication includes data on 61 patients. Fifty-six had newly diagnosed MM, and 5 had relapsed MM following prior HSCT. The patients received Evomela at 200 mg/m² given as 2 doses on Day -3 and Day -2 prior to HSCT (Day 0).

Efficacy was assessed by clinical response at Day +100. According to investigator assessment, the overall response rate was 95%, and the complete response (CR) rate was 31%.

According to independent pathology review, the overall response rate was 100%, and the CR rate was 21%. The lower rate of confirmed CRs in the independent review was due to missing data.

All 5 patients who had previously relapsed from a prior HSCT responded to Evomela.

All patients in the study achieved myeloablation with a median of 5 days post-HSCT. All patients had successful neutrophil and platelet engraftment at a median of 12 days and 13 days post-HSCT, respectively.

Treatment-related mortality was 0%, and non-hematologic adverse events were mostly grade 1 and 2 in severity. The incidence of grade 3 mucositis and grade 3 stomatitis were 10% and 5%, respectively, with no grade 4 mucositis or stomatitis reported.

Twenty percent of patients experienced treatment-emergent serious adverse events, most of which were grade 3 and consisted of events commonly reported in patients undergoing myeloablative chemotherapy. No new safety signals were identified.