Transplantation

GRAPEVINE, TEXAS—Results of a large, retrospective study suggest that allogeneic stem cell transplant (allo-SCT) can overcome the poor prognosis associated with central nervous system (CNS) involvement in acute myeloid leukemia (AML).

By analyzing transplant outcomes in more than 5000 patients, researchers found that subjects with CNS AML had rates of relapse and survival that were similar to those of patients without CNS involvement.

The team also identified factors that can predict for survival in CNS AML, including cytogenetic risk group, the presence of chronic GVHD, and whether a patient was in complete response at transplant.

Jun Aoki, MD, of Tokyo Metropolitan Komagome Hospital in Japan, presented these findings at the 2014 BMT Tandem Meetings as abstract 68.

Dr Aoki pointed out that CNS involvement is rare in adult AML, occurring in about 5% of patients. However, these patients generally have poor prognosis. And although allo-SCT is one of the options used to treat CNS AML, exactly how CNS involvement impacts transplant outcomes remains unclear.

So Dr Aoki and his colleagues conducted a nationwide, retrospective study to gain some insight.  They collected data from the registry database of the Japan Society for Hematopoietic Cell Transplantation.

Patients had to be older than 15 years of age, have their first allo-SCT between 2006 and 2011, and not have acute promyelocytic leukemia.

The researchers identified 5068 patients who met these criteria, and 157 of them had CNS AML. CNS involvement was defined as infiltration of leukemia cells into CNS or myeloid sarcoma in CNS that were identified at any time from diagnosis to transplant.

No difference in relapse, survival

There were no significant differences between CNS patients and controls with regard to the estimated overall survival (OS), leukemia-free survival, cumulative incidence of relapse, or non-relapse mortality at 5 years.

OS was 39.9% among controls and 38.5% among CNS patients (P=0.847). Leukemia-free survival was 41.2% and 41.5%, respectively (P=0.82).

The cumulative incidence of relapse was 29.8% among controls and 31.8% among CNS patients (P=0.418). And non-relapse mortality was 22.5% and 26.5%, respectively (P=0.142).

Factors predicting OS

To determine the impact of patient and treatment characteristics on OS, the researchers conducted a multivariate analysis. This confirmed that CNS involvement was not a risk factor for OS.

But it revealed a number of other factors that adversely affect OS, including age of 50 or older (P<0.001), lack of a complete response at allo-SCT (P<0.001), a donor source of unrelated cord blood (P=0.005), having a prognostic score of 2-4 (P<0.001), unfavorable cytogenetics (P<0.001), and the absence of acute or chronic GVHD (P<0.001 for both).

When the researchers analyzed only CNS patients, they discovered that not all of these factors retained significance. Only the absence of chronic GVHD (P=0.002), lack of complete response at transplant (P<0.001), and having either intermediate (P=0.003) or unfavorable cytogenetics (P=0.011) were adversely associated with OS in these patients.

GRAPEVINE, TEXAS—Results of a large, retrospective study suggest that allogeneic stem cell transplant (allo-SCT) can overcome the poor prognosis associated with central nervous system (CNS) involvement in acute myeloid leukemia (AML).

By analyzing transplant outcomes in more than 5000 patients, researchers found that subjects with CNS AML had rates of relapse and survival that were similar to those of patients without CNS involvement.

The team also identified factors that can predict for survival in CNS AML, including cytogenetic risk group, the presence of chronic GVHD, and whether a patient was in complete response at transplant.

Jun Aoki, MD, of Tokyo Metropolitan Komagome Hospital in Japan, presented these findings at the 2014 BMT Tandem Meetings as abstract 68.

Dr Aoki pointed out that CNS involvement is rare in adult AML, occurring in about 5% of patients. However, these patients generally have poor prognosis. And although allo-SCT is one of the options used to treat CNS AML, exactly how CNS involvement impacts transplant outcomes remains unclear.

So Dr Aoki and his colleagues conducted a nationwide, retrospective study to gain some insight.  They collected data from the registry database of the Japan Society for Hematopoietic Cell Transplantation.

Patients had to be older than 15 years of age, have their first allo-SCT between 2006 and 2011, and not have acute promyelocytic leukemia.

The researchers identified 5068 patients who met these criteria, and 157 of them had CNS AML. CNS involvement was defined as infiltration of leukemia cells into CNS or myeloid sarcoma in CNS that were identified at any time from diagnosis to transplant.

No difference in relapse, survival

There were no significant differences between CNS patients and controls with regard to the estimated overall survival (OS), leukemia-free survival, cumulative incidence of relapse, or non-relapse mortality at 5 years.

OS was 39.9% among controls and 38.5% among CNS patients (P=0.847). Leukemia-free survival was 41.2% and 41.5%, respectively (P=0.82).

The cumulative incidence of relapse was 29.8% among controls and 31.8% among CNS patients (P=0.418). And non-relapse mortality was 22.5% and 26.5%, respectively (P=0.142).

Factors predicting OS

To determine the impact of patient and treatment characteristics on OS, the researchers conducted a multivariate analysis. This confirmed that CNS involvement was not a risk factor for OS.

But it revealed a number of other factors that adversely affect OS, including age of 50 or older (P<0.001), lack of a complete response at allo-SCT (P<0.001), a donor source of unrelated cord blood (P=0.005), having a prognostic score of 2-4 (P<0.001), unfavorable cytogenetics (P<0.001), and the absence of acute or chronic GVHD (P<0.001 for both).

When the researchers analyzed only CNS patients, they discovered that not all of these factors retained significance. Only the absence of chronic GVHD (P=0.002), lack of complete response at transplant (P<0.001), and having either intermediate (P=0.003) or unfavorable cytogenetics (P=0.011) were adversely associated with OS in these patients.

GRAPEVINE, TEXAS—Results of a large, retrospective study suggest that allogeneic stem cell transplant (allo-SCT) can overcome the poor prognosis associated with central nervous system (CNS) involvement in acute myeloid leukemia (AML).

By analyzing transplant outcomes in more than 5000 patients, researchers found that subjects with CNS AML had rates of relapse and survival that were similar to those of patients without CNS involvement.

The team also identified factors that can predict for survival in CNS AML, including cytogenetic risk group, the presence of chronic GVHD, and whether a patient was in complete response at transplant.

Jun Aoki, MD, of Tokyo Metropolitan Komagome Hospital in Japan, presented these findings at the 2014 BMT Tandem Meetings as abstract 68.

Dr Aoki pointed out that CNS involvement is rare in adult AML, occurring in about 5% of patients. However, these patients generally have poor prognosis. And although allo-SCT is one of the options used to treat CNS AML, exactly how CNS involvement impacts transplant outcomes remains unclear.

So Dr Aoki and his colleagues conducted a nationwide, retrospective study to gain some insight.  They collected data from the registry database of the Japan Society for Hematopoietic Cell Transplantation.

Patients had to be older than 15 years of age, have their first allo-SCT between 2006 and 2011, and not have acute promyelocytic leukemia.

The researchers identified 5068 patients who met these criteria, and 157 of them had CNS AML. CNS involvement was defined as infiltration of leukemia cells into CNS or myeloid sarcoma in CNS that were identified at any time from diagnosis to transplant.

No difference in relapse, survival

There were no significant differences between CNS patients and controls with regard to the estimated overall survival (OS), leukemia-free survival, cumulative incidence of relapse, or non-relapse mortality at 5 years.

OS was 39.9% among controls and 38.5% among CNS patients (P=0.847). Leukemia-free survival was 41.2% and 41.5%, respectively (P=0.82).

The cumulative incidence of relapse was 29.8% among controls and 31.8% among CNS patients (P=0.418). And non-relapse mortality was 22.5% and 26.5%, respectively (P=0.142).

Factors predicting OS

To determine the impact of patient and treatment characteristics on OS, the researchers conducted a multivariate analysis. This confirmed that CNS involvement was not a risk factor for OS.

But it revealed a number of other factors that adversely affect OS, including age of 50 or older (P<0.001), lack of a complete response at allo-SCT (P<0.001), a donor source of unrelated cord blood (P=0.005), having a prognostic score of 2-4 (P<0.001), unfavorable cytogenetics (P<0.001), and the absence of acute or chronic GVHD (P<0.001 for both).

When the researchers analyzed only CNS patients, they discovered that not all of these factors retained significance. Only the absence of chronic GVHD (P=0.002), lack of complete response at transplant (P<0.001), and having either intermediate (P=0.003) or unfavorable cytogenetics (P=0.011) were adversely associated with OS in these patients.

GRAPEVINE, TEXAS—Intestinal bacteria can offer protection from death related to graft-vs-host disease (GVHD), according to research presented at the 2014 BMT Tandem Meetings.

Experiments showed that Blautia, commensal bacteria found in the intestinal tract, can protect against GVHD-related mortality in mice and in humans.

So efforts to support Blautia survival—such as restricting the use of antibiotics and promoting better nutrition—may

prevent GVHD-related death, according to researchers.

Robert Jenq, MD, of Memorial Sloan-Kettering Cancer Center in New York, discussed this possibility when presenting this research, which was designated one of the “Best Abstracts” at the meeting (abstract 1*).

Dr Jenq noted that researchers have been trying for decades to determine whether the intestinal flora impact GVHD. Clinical studies have suggested that prophylaxis against anaerobes and gram-positive bacteria can reduce GVHD.

And murine studies have indicated that prophylaxis against gram-negative bacteria can reduce GVHD, that Lactobacillus can reduce GVHD, and that donor microbiota do not impact GVHD.

“If you’re confused, so are we,” Dr Jenq said. “It seems like it’s a mixed picture.”

So he and his colleagues conducted a series of experiments in an attempt to determine if any bacterial subgroups impact the risk of gut GVHD in mice and humans.

Bacteria seem to impact GVHD

The researchers first studied 76 adult transplant patients, analyzing stool samples taken at roughly 10 days after transplant (+/- 4 days). The team performed 16S gene sequencing using the Roche 454 platform.

This revealed the presence of several types of bacteria, including 6 gram-positive Firmicutes, 2 gram-negative Proteobacteria, and 2 gram-negative Bacteroidetes.

The researchers then used a computational assay to determine which of these bacteria might be associated with protection from GVHD. And they identified 2 possibilities—Lactobacillus and Blautia.

Additional analyses revealed that Blautia and Lactobacillus were significantly associated with GVHD-related mortality at 1500 days after transplant (P=0.03 and 0.01, respectively). But there was no significant association with Bacteroides (P=0.6), Enterobacteriales (P=0.2), or Enterococcus (P=0.3).

Blautia appears to affect GVHD-related mortality

To confirm their initial findings, Dr Jenq and his colleagues analyzed a second cohort of 50 adult transplant patients. The team analyzed stool samples for the abundance of bacterial subgroups using a different sequencing platform, Illumina miseq.

This time, they found that Blautia abundance predicted GVHD-related mortality at more than 500 days after transplant, but the abundance of Lactobacillus did not (P=0.01 and 1, respectively).

“Not enough Blautia in your gut seems to lead to an increase in GVHD-related mortality,” Dr Jenq said. “So what does this do to overall survival? In the first cohort, there’s a big difference in overall survival between the ‘haves’ and ‘have nots’ with Blautia [P=0.0008]. And this also holds up in the second cohort [P=0.04].”

Further analyses of data from both cohorts suggested that Blautia abundance was associated with GVHD-related mortality (P=0.004) and relapse-related mortality (P=0.01) but not non-relapse- and non-GVHD-related mortality (P=0.4).

“I don’t have a good explanation for [the relationship between Blautia and relapse-related death],” Dr Jenq said. “This was a surprise finding.”

The researchers also looked at Blautia’s ability to predict GVHD-related mortality. They found that, around day 10 after transplant, Blautia abundance predicts “very strongly” for GVHD-related death.

Another question was whether known GVHD risk factors—such as donor type, race, gender, and performance status—impact Blautia abundance. But an analysis revealed that Blautia is an independent risk factor for GVHD-related mortality.

A possible mechanism

To gain more insight into the association between Blautia and GVHD-related death, Dr Jenq and his colleagues decided to study it in mice.

The team killed off Blautia in mice using vancomycin and ampicillin, then introduced either murine Blautia or murine Enterococcus, transplanted the mice with MHC-disparate T cells, and monitored them for GVHD.

Mice that received Blautia had significantly better overall survival (at more than 80 days after transplant) than mice that received Enterococcus (P<0.001).

“So how is this happening?” Dr Jenq asked. “We think, potentially, it might be due to short-chain fatty acids . . . butyric acid, propionic acid, and acetic acid. These are metabolites that bacteria produce when they ferment glucose and other sugars.”

To test this theory, the researchers treated mice with antibiotics and introduced Blautia or Enterococcus.

Blautia increased the level of short-chain fatty acids (butyrate and propionate) when compared to Enterococcus, although levels were not as high as those observed in mice that did not receive antibiotics. Nevertheless, these results point to a possible mechanism, according to Dr Jenq.

Explaining Blautia reduction

Dr Jenq also noted that antibiotics may contribute to the decrease in Blautia observed in transplant patients. When patients come in for transplant, they often have more than 25% Blautia in their stool. But the bacteria decrease to negligible levels by day 2 after transplant.

To determine the role of antibiotics, the researchers treated mice with 4 different antibiotics and looked at the levels of different bacteria.

They found that aztreonam and cefepime increased the levels of Bacteroidales and Clostridiales (the family to which Blautia belongs), but imipenem and metronidazole decreased bacteria levels.

So antibiotics do affect Blautia levels, Dr Jenq said, but they’re only part of the problem. He noted that patients’ Blautia levels start to decrease before antibiotics are administered. So he and his colleagues believe nutrition might also play a part.

The team found a significant difference in Blautia abundance between patients who received total parenteral nutrition and those who did not (P<0.001).

The researchers also discovered that reduced caloric intake led to a loss of Blautia and other Clostridiales. They analyzed 50 samples from 5 patients and found that patients who consumed fewer than 500 calories had a marked reduction in Blautia (P<0.0001).

And experiments in mice confirmed this association. A week of calorie restriction significantly reduced the abundance of Blautia and other Clostridiales (P=0.0002).

“In GVHD, as we all know, patients and mice eat less because of the nausea,” Dr Jenq said. “And we found that GVHD itself can also lead to a reduction in Clostridiales, both in humans [P=0.02] and in mice [P=0.01].”

Protecting Blautia to prevent GVHD

Having confirmed the role of nutrition in Blautia reduction, the researchers set out to identify a nutrition-based intervention to support Blautia in transplant recipients.

They settled on a sugar called raffinose, which is found in beans, cruciferous vegetables, and whole grains. It passes undigested through the upper intestine but is fermented in the lower intestine and metabolized to produce short-chain fatty acids.

The team tested raffinose in mice by introducing it into their drinking water. At 100 days after transplant, mice that received raffinose had significantly better overall survival than controls (P<0.001).

Based on these results, Dr Jenq and his colleagues believe nutritional intervention can protect Blautia and, therefore, may prevent GVHD and related death. The team thinks encouraging eating, gastric nutritional supplementation, and flora-targeted nutritional supplements might all prove effective.

But other interventions might work as well, such as reintroducing endogenous flora (via autologous fecal microbiota transplant), reintroducing select bacteria with beneficial potential, selecting antibiotics that spare bacteria with beneficial potential, and identifying and introducing bacterial metabolites that mediate anti-inflammatory effects.

*Data in the abstract differ from data presented.

GRAPEVINE, TEXAS—Intestinal bacteria can offer protection from death related to graft-vs-host disease (GVHD), according to research presented at the 2014 BMT Tandem Meetings.

Experiments showed that Blautia, commensal bacteria found in the intestinal tract, can protect against GVHD-related mortality in mice and in humans.

So efforts to support Blautia survival—such as restricting the use of antibiotics and promoting better nutrition—may

prevent GVHD-related death, according to researchers.

Robert Jenq, MD, of Memorial Sloan-Kettering Cancer Center in New York, discussed this possibility when presenting this research, which was designated one of the “Best Abstracts” at the meeting (abstract 1*).

Dr Jenq noted that researchers have been trying for decades to determine whether the intestinal flora impact GVHD. Clinical studies have suggested that prophylaxis against anaerobes and gram-positive bacteria can reduce GVHD.

And murine studies have indicated that prophylaxis against gram-negative bacteria can reduce GVHD, that Lactobacillus can reduce GVHD, and that donor microbiota do not impact GVHD.

“If you’re confused, so are we,” Dr Jenq said. “It seems like it’s a mixed picture.”

So he and his colleagues conducted a series of experiments in an attempt to determine if any bacterial subgroups impact the risk of gut GVHD in mice and humans.

Bacteria seem to impact GVHD

The researchers first studied 76 adult transplant patients, analyzing stool samples taken at roughly 10 days after transplant (+/- 4 days). The team performed 16S gene sequencing using the Roche 454 platform.

This revealed the presence of several types of bacteria, including 6 gram-positive Firmicutes, 2 gram-negative Proteobacteria, and 2 gram-negative Bacteroidetes.

The researchers then used a computational assay to determine which of these bacteria might be associated with protection from GVHD. And they identified 2 possibilities—Lactobacillus and Blautia.

Additional analyses revealed that Blautia and Lactobacillus were significantly associated with GVHD-related mortality at 1500 days after transplant (P=0.03 and 0.01, respectively). But there was no significant association with Bacteroides (P=0.6), Enterobacteriales (P=0.2), or Enterococcus (P=0.3).

Blautia appears to affect GVHD-related mortality

To confirm their initial findings, Dr Jenq and his colleagues analyzed a second cohort of 50 adult transplant patients. The team analyzed stool samples for the abundance of bacterial subgroups using a different sequencing platform, Illumina miseq.

This time, they found that Blautia abundance predicted GVHD-related mortality at more than 500 days after transplant, but the abundance of Lactobacillus did not (P=0.01 and 1, respectively).

“Not enough Blautia in your gut seems to lead to an increase in GVHD-related mortality,” Dr Jenq said. “So what does this do to overall survival? In the first cohort, there’s a big difference in overall survival between the ‘haves’ and ‘have nots’ with Blautia [P=0.0008]. And this also holds up in the second cohort [P=0.04].”

Further analyses of data from both cohorts suggested that Blautia abundance was associated with GVHD-related mortality (P=0.004) and relapse-related mortality (P=0.01) but not non-relapse- and non-GVHD-related mortality (P=0.4).

“I don’t have a good explanation for [the relationship between Blautia and relapse-related death],” Dr Jenq said. “This was a surprise finding.”

The researchers also looked at Blautia’s ability to predict GVHD-related mortality. They found that, around day 10 after transplant, Blautia abundance predicts “very strongly” for GVHD-related death.

Another question was whether known GVHD risk factors—such as donor type, race, gender, and performance status—impact Blautia abundance. But an analysis revealed that Blautia is an independent risk factor for GVHD-related mortality.

A possible mechanism

To gain more insight into the association between Blautia and GVHD-related death, Dr Jenq and his colleagues decided to study it in mice.

The team killed off Blautia in mice using vancomycin and ampicillin, then introduced either murine Blautia or murine Enterococcus, transplanted the mice with MHC-disparate T cells, and monitored them for GVHD.

Mice that received Blautia had significantly better overall survival (at more than 80 days after transplant) than mice that received Enterococcus (P<0.001).

“So how is this happening?” Dr Jenq asked. “We think, potentially, it might be due to short-chain fatty acids . . . butyric acid, propionic acid, and acetic acid. These are metabolites that bacteria produce when they ferment glucose and other sugars.”

To test this theory, the researchers treated mice with antibiotics and introduced Blautia or Enterococcus.

Blautia increased the level of short-chain fatty acids (butyrate and propionate) when compared to Enterococcus, although levels were not as high as those observed in mice that did not receive antibiotics. Nevertheless, these results point to a possible mechanism, according to Dr Jenq.

Explaining Blautia reduction

Dr Jenq also noted that antibiotics may contribute to the decrease in Blautia observed in transplant patients. When patients come in for transplant, they often have more than 25% Blautia in their stool. But the bacteria decrease to negligible levels by day 2 after transplant.

To determine the role of antibiotics, the researchers treated mice with 4 different antibiotics and looked at the levels of different bacteria.

They found that aztreonam and cefepime increased the levels of Bacteroidales and Clostridiales (the family to which Blautia belongs), but imipenem and metronidazole decreased bacteria levels.

So antibiotics do affect Blautia levels, Dr Jenq said, but they’re only part of the problem. He noted that patients’ Blautia levels start to decrease before antibiotics are administered. So he and his colleagues believe nutrition might also play a part.

The team found a significant difference in Blautia abundance between patients who received total parenteral nutrition and those who did not (P<0.001).

The researchers also discovered that reduced caloric intake led to a loss of Blautia and other Clostridiales. They analyzed 50 samples from 5 patients and found that patients who consumed fewer than 500 calories had a marked reduction in Blautia (P<0.0001).

And experiments in mice confirmed this association. A week of calorie restriction significantly reduced the abundance of Blautia and other Clostridiales (P=0.0002).

“In GVHD, as we all know, patients and mice eat less because of the nausea,” Dr Jenq said. “And we found that GVHD itself can also lead to a reduction in Clostridiales, both in humans [P=0.02] and in mice [P=0.01].”

Protecting Blautia to prevent GVHD

Having confirmed the role of nutrition in Blautia reduction, the researchers set out to identify a nutrition-based intervention to support Blautia in transplant recipients.

They settled on a sugar called raffinose, which is found in beans, cruciferous vegetables, and whole grains. It passes undigested through the upper intestine but is fermented in the lower intestine and metabolized to produce short-chain fatty acids.

The team tested raffinose in mice by introducing it into their drinking water. At 100 days after transplant, mice that received raffinose had significantly better overall survival than controls (P<0.001).

Based on these results, Dr Jenq and his colleagues believe nutritional intervention can protect Blautia and, therefore, may prevent GVHD and related death. The team thinks encouraging eating, gastric nutritional supplementation, and flora-targeted nutritional supplements might all prove effective.

But other interventions might work as well, such as reintroducing endogenous flora (via autologous fecal microbiota transplant), reintroducing select bacteria with beneficial potential, selecting antibiotics that spare bacteria with beneficial potential, and identifying and introducing bacterial metabolites that mediate anti-inflammatory effects.

*Data in the abstract differ from data presented.

GRAPEVINE, TEXAS—Intestinal bacteria can offer protection from death related to graft-vs-host disease (GVHD), according to research presented at the 2014 BMT Tandem Meetings.

Experiments showed that Blautia, commensal bacteria found in the intestinal tract, can protect against GVHD-related mortality in mice and in humans.

So efforts to support Blautia survival—such as restricting the use of antibiotics and promoting better nutrition—may

prevent GVHD-related death, according to researchers.

Robert Jenq, MD, of Memorial Sloan-Kettering Cancer Center in New York, discussed this possibility when presenting this research, which was designated one of the “Best Abstracts” at the meeting (abstract 1*).

Dr Jenq noted that researchers have been trying for decades to determine whether the intestinal flora impact GVHD. Clinical studies have suggested that prophylaxis against anaerobes and gram-positive bacteria can reduce GVHD.

And murine studies have indicated that prophylaxis against gram-negative bacteria can reduce GVHD, that Lactobacillus can reduce GVHD, and that donor microbiota do not impact GVHD.

“If you’re confused, so are we,” Dr Jenq said. “It seems like it’s a mixed picture.”

So he and his colleagues conducted a series of experiments in an attempt to determine if any bacterial subgroups impact the risk of gut GVHD in mice and humans.

Bacteria seem to impact GVHD

The researchers first studied 76 adult transplant patients, analyzing stool samples taken at roughly 10 days after transplant (+/- 4 days). The team performed 16S gene sequencing using the Roche 454 platform.

This revealed the presence of several types of bacteria, including 6 gram-positive Firmicutes, 2 gram-negative Proteobacteria, and 2 gram-negative Bacteroidetes.

The researchers then used a computational assay to determine which of these bacteria might be associated with protection from GVHD. And they identified 2 possibilities—Lactobacillus and Blautia.

Additional analyses revealed that Blautia and Lactobacillus were significantly associated with GVHD-related mortality at 1500 days after transplant (P=0.03 and 0.01, respectively). But there was no significant association with Bacteroides (P=0.6), Enterobacteriales (P=0.2), or Enterococcus (P=0.3).

Blautia appears to affect GVHD-related mortality

To confirm their initial findings, Dr Jenq and his colleagues analyzed a second cohort of 50 adult transplant patients. The team analyzed stool samples for the abundance of bacterial subgroups using a different sequencing platform, Illumina miseq.

This time, they found that Blautia abundance predicted GVHD-related mortality at more than 500 days after transplant, but the abundance of Lactobacillus did not (P=0.01 and 1, respectively).

“Not enough Blautia in your gut seems to lead to an increase in GVHD-related mortality,” Dr Jenq said. “So what does this do to overall survival? In the first cohort, there’s a big difference in overall survival between the ‘haves’ and ‘have nots’ with Blautia [P=0.0008]. And this also holds up in the second cohort [P=0.04].”

Further analyses of data from both cohorts suggested that Blautia abundance was associated with GVHD-related mortality (P=0.004) and relapse-related mortality (P=0.01) but not non-relapse- and non-GVHD-related mortality (P=0.4).

“I don’t have a good explanation for [the relationship between Blautia and relapse-related death],” Dr Jenq said. “This was a surprise finding.”

The researchers also looked at Blautia’s ability to predict GVHD-related mortality. They found that, around day 10 after transplant, Blautia abundance predicts “very strongly” for GVHD-related death.

Another question was whether known GVHD risk factors—such as donor type, race, gender, and performance status—impact Blautia abundance. But an analysis revealed that Blautia is an independent risk factor for GVHD-related mortality.

A possible mechanism

To gain more insight into the association between Blautia and GVHD-related death, Dr Jenq and his colleagues decided to study it in mice.

The team killed off Blautia in mice using vancomycin and ampicillin, then introduced either murine Blautia or murine Enterococcus, transplanted the mice with MHC-disparate T cells, and monitored them for GVHD.

Mice that received Blautia had significantly better overall survival (at more than 80 days after transplant) than mice that received Enterococcus (P<0.001).

“So how is this happening?” Dr Jenq asked. “We think, potentially, it might be due to short-chain fatty acids . . . butyric acid, propionic acid, and acetic acid. These are metabolites that bacteria produce when they ferment glucose and other sugars.”

To test this theory, the researchers treated mice with antibiotics and introduced Blautia or Enterococcus.

Blautia increased the level of short-chain fatty acids (butyrate and propionate) when compared to Enterococcus, although levels were not as high as those observed in mice that did not receive antibiotics. Nevertheless, these results point to a possible mechanism, according to Dr Jenq.

Explaining Blautia reduction

Dr Jenq also noted that antibiotics may contribute to the decrease in Blautia observed in transplant patients. When patients come in for transplant, they often have more than 25% Blautia in their stool. But the bacteria decrease to negligible levels by day 2 after transplant.

To determine the role of antibiotics, the researchers treated mice with 4 different antibiotics and looked at the levels of different bacteria.

They found that aztreonam and cefepime increased the levels of Bacteroidales and Clostridiales (the family to which Blautia belongs), but imipenem and metronidazole decreased bacteria levels.

So antibiotics do affect Blautia levels, Dr Jenq said, but they’re only part of the problem. He noted that patients’ Blautia levels start to decrease before antibiotics are administered. So he and his colleagues believe nutrition might also play a part.

The team found a significant difference in Blautia abundance between patients who received total parenteral nutrition and those who did not (P<0.001).

The researchers also discovered that reduced caloric intake led to a loss of Blautia and other Clostridiales. They analyzed 50 samples from 5 patients and found that patients who consumed fewer than 500 calories had a marked reduction in Blautia (P<0.0001).

And experiments in mice confirmed this association. A week of calorie restriction significantly reduced the abundance of Blautia and other Clostridiales (P=0.0002).

“In GVHD, as we all know, patients and mice eat less because of the nausea,” Dr Jenq said. “And we found that GVHD itself can also lead to a reduction in Clostridiales, both in humans [P=0.02] and in mice [P=0.01].”

Protecting Blautia to prevent GVHD

Having confirmed the role of nutrition in Blautia reduction, the researchers set out to identify a nutrition-based intervention to support Blautia in transplant recipients.

They settled on a sugar called raffinose, which is found in beans, cruciferous vegetables, and whole grains. It passes undigested through the upper intestine but is fermented in the lower intestine and metabolized to produce short-chain fatty acids.

The team tested raffinose in mice by introducing it into their drinking water. At 100 days after transplant, mice that received raffinose had significantly better overall survival than controls (P<0.001).

Based on these results, Dr Jenq and his colleagues believe nutritional intervention can protect Blautia and, therefore, may prevent GVHD and related death. The team thinks encouraging eating, gastric nutritional supplementation, and flora-targeted nutritional supplements might all prove effective.

But other interventions might work as well, such as reintroducing endogenous flora (via autologous fecal microbiota transplant), reintroducing select bacteria with beneficial potential, selecting antibiotics that spare bacteria with beneficial potential, and identifying and introducing bacterial metabolites that mediate anti-inflammatory effects.

*Data in the abstract differ from data presented.

GRAPEVINE, TEXAS—The total nucleated cell (TNC) dose delivered in an allogeneic peripheral blood stem cell transplant (allo-PBSCT) can affect outcomes in certain patients, according to a study presented at the 2014 BMT Tandem Meetings.

Researchers found that a higher TNC dose was associated with better progression-free survival (PFS) and overall survival (OS) among patients who received allo-PBSCT with reduced-intensity conditioning (RIC) and total-body irradiation (TBI).

On the other hand, the dose of CD3+, CD4+, CD8+, or CD34+ cells did not have a significant impact on survival rates in these patients.

And none of the cell doses studied had a significant impact in patients who did not receive TBI or in those who received TBI with myeloablative conditioning.

Michael Burns, of Roswell Park Cancer Institute in Buffalo, New York, presented these findings at the meeting as abstract 12.*

Burns noted that studies have produced conflicting results regarding the correlation between patient outcomes and the dose of CD34+, CD3+, CD4+, or CD8+ cells given in allo-PBSCT. In addition, TNC dose has not been analyzed much in the context of PBSCTs.

Therefore, he and his colleagues retrospectively analyzed graft cell composition in 254 patients who received their first allo-PBSCT from January 2001 to September 2012.

Fifty-eight percent of the patients were male, and the median age was 50 (range, 19-73 years). Forty-four percent of patients had acute myeloid leukemia, 18% had myelodysplastic syndromes or myeloproliferative neoplasms, 13% had acute lymphoblastic leukemia, 13% had non-Hodgkin lymphoma, and 12% had other diseases.

Of the 254 patients studied, 93 had received TBI. Among these, 53 received myeloablative conditioning (91% cyclophosphamide, 120 cGy), and 40 received RIC (100% fludarabine and melphalan, 400 cGy).

Of the 161 patients who did not receive TBI, 41 received myeloablative conditioning (88% busulfan and cyclophosphamide), and 120 received RIC (87% fludarabine and melphalan).

Patients received T-cell-replete, G-CSF mobilized, PB allografts. Fifty-six percent had a 6/6 HLA matched related donor, and 44% had an 8/8 HLA matched unrelated donor. Forty-nine percent of patients were in complete remission at the time of transplant.

The researchers analyzed cell doses according to the median dose (above vs below). But they also analyzed CD34+ dose as < 4 x 10⁶ cells/kg vs ≥ 4 x 10⁶ cells/kg and as < 4 x 10⁶ cells/kg vs 4 to 8 x 10⁶ cells/kg vs > 8 x 10⁶ cells/kg. They analyzed TNC as < 8 x 10⁸ cells/kg vs ≥ to 8 x 10⁸ cells/kg.

The team found that a CD34+ cell dose greater than 4 x 10⁶ cells/kg was significantly associated with time to platelet engraftment in all patients. It was also associated with time to neutrophil engraftment in the TBI group, but this was predominantly among patients who received RIC.

On the other hand, CD3+, CD4+, CD8+, and TNC doses were not significantly associated with platelet or neutrophil engraftment in any patients.

CD34+, CD3+, CD4+, and CD8+ cell dose were not associated with OS, PFS, or acute graft-vs-host disease (GVHD). And TNC had no significant effect on acute GVHD.

“However, we did find that the TNC dose did show some pretty interesting survival outcomes,” Burns said.

A higher TNC dose (≥ 8 x10⁸ cells/kg) was associated with significantly better PFS (P=0.027) and OS (P=0.018) in the TBI patients but not in patients who did not receive TBI (P>0.1 for PFS and OS).

When they analyzed patients according to conditioning regimen, the researchers found the association retained significance among patients who received RIC (P=0.01 for PFS and P=0.007 for OS) but not among patients who received myeloablative conditioning (P>0.1 for PFS and OS).

Burns and his colleagues also conducted a multivariate analysis to see if any other factors affected the relationship between TNC and survival. They controlled for patient age, Karnofsky performance status, and body mass index. And they stratified patients into 4 groups according to TBI and conditioning regimen.

The results showed that patients who received TBI and RIC, as well as a TNC dose less than 8 x 10⁸ cells/kg, had a relative risk of 3.3 for PFS (P=0.026) and a relative risk of 3.4 for OS (P=0.021).

“The association of higher TNC dose with better progression-free and overall survival implies there is a population of nucleated cells which mitigate GVHD but enhance the [graft-vs-leukemia] effect after reduced-intensity TBI conditioning,” Burns said.

“Myeloablative conditioning regimens result in more direct tumor killing. Thus, they rely less on the graft-vs-leukemia effect than the RIC regimens.”

He also noted that the lack of an association between TNC dose and survival rates with non-TBI-based regimens implies there are different mechanisms of tumor kill with TBI and non-TBI-containing regimens.

And a more detailed analysis of cell population subsets in apheresis product may allow researchers to identify cell populations that could improve patient outcomes.

*Some data in the abstract differ from data presented at the meeting.

GRAPEVINE, TEXAS—The total nucleated cell (TNC) dose delivered in an allogeneic peripheral blood stem cell transplant (allo-PBSCT) can affect outcomes in certain patients, according to a study presented at the 2014 BMT Tandem Meetings.

Researchers found that a higher TNC dose was associated with better progression-free survival (PFS) and overall survival (OS) among patients who received allo-PBSCT with reduced-intensity conditioning (RIC) and total-body irradiation (TBI).

On the other hand, the dose of CD3+, CD4+, CD8+, or CD34+ cells did not have a significant impact on survival rates in these patients.

And none of the cell doses studied had a significant impact in patients who did not receive TBI or in those who received TBI with myeloablative conditioning.

Michael Burns, of Roswell Park Cancer Institute in Buffalo, New York, presented these findings at the meeting as abstract 12.*

Burns noted that studies have produced conflicting results regarding the correlation between patient outcomes and the dose of CD34+, CD3+, CD4+, or CD8+ cells given in allo-PBSCT. In addition, TNC dose has not been analyzed much in the context of PBSCTs.

Therefore, he and his colleagues retrospectively analyzed graft cell composition in 254 patients who received their first allo-PBSCT from January 2001 to September 2012.

Fifty-eight percent of the patients were male, and the median age was 50 (range, 19-73 years). Forty-four percent of patients had acute myeloid leukemia, 18% had myelodysplastic syndromes or myeloproliferative neoplasms, 13% had acute lymphoblastic leukemia, 13% had non-Hodgkin lymphoma, and 12% had other diseases.

Of the 254 patients studied, 93 had received TBI. Among these, 53 received myeloablative conditioning (91% cyclophosphamide, 120 cGy), and 40 received RIC (100% fludarabine and melphalan, 400 cGy).

Of the 161 patients who did not receive TBI, 41 received myeloablative conditioning (88% busulfan and cyclophosphamide), and 120 received RIC (87% fludarabine and melphalan).

Patients received T-cell-replete, G-CSF mobilized, PB allografts. Fifty-six percent had a 6/6 HLA matched related donor, and 44% had an 8/8 HLA matched unrelated donor. Forty-nine percent of patients were in complete remission at the time of transplant.

The researchers analyzed cell doses according to the median dose (above vs below). But they also analyzed CD34+ dose as < 4 x 10⁶ cells/kg vs ≥ 4 x 10⁶ cells/kg and as < 4 x 10⁶ cells/kg vs 4 to 8 x 10⁶ cells/kg vs > 8 x 10⁶ cells/kg. They analyzed TNC as < 8 x 10⁸ cells/kg vs ≥ to 8 x 10⁸ cells/kg.

The team found that a CD34+ cell dose greater than 4 x 10⁶ cells/kg was significantly associated with time to platelet engraftment in all patients. It was also associated with time to neutrophil engraftment in the TBI group, but this was predominantly among patients who received RIC.

On the other hand, CD3+, CD4+, CD8+, and TNC doses were not significantly associated with platelet or neutrophil engraftment in any patients.

CD34+, CD3+, CD4+, and CD8+ cell dose were not associated with OS, PFS, or acute graft-vs-host disease (GVHD). And TNC had no significant effect on acute GVHD.

“However, we did find that the TNC dose did show some pretty interesting survival outcomes,” Burns said.

A higher TNC dose (≥ 8 x10⁸ cells/kg) was associated with significantly better PFS (P=0.027) and OS (P=0.018) in the TBI patients but not in patients who did not receive TBI (P>0.1 for PFS and OS).

When they analyzed patients according to conditioning regimen, the researchers found the association retained significance among patients who received RIC (P=0.01 for PFS and P=0.007 for OS) but not among patients who received myeloablative conditioning (P>0.1 for PFS and OS).

Burns and his colleagues also conducted a multivariate analysis to see if any other factors affected the relationship between TNC and survival. They controlled for patient age, Karnofsky performance status, and body mass index. And they stratified patients into 4 groups according to TBI and conditioning regimen.

The results showed that patients who received TBI and RIC, as well as a TNC dose less than 8 x 10⁸ cells/kg, had a relative risk of 3.3 for PFS (P=0.026) and a relative risk of 3.4 for OS (P=0.021).

“The association of higher TNC dose with better progression-free and overall survival implies there is a population of nucleated cells which mitigate GVHD but enhance the [graft-vs-leukemia] effect after reduced-intensity TBI conditioning,” Burns said.

“Myeloablative conditioning regimens result in more direct tumor killing. Thus, they rely less on the graft-vs-leukemia effect than the RIC regimens.”

He also noted that the lack of an association between TNC dose and survival rates with non-TBI-based regimens implies there are different mechanisms of tumor kill with TBI and non-TBI-containing regimens.

And a more detailed analysis of cell population subsets in apheresis product may allow researchers to identify cell populations that could improve patient outcomes.

*Some data in the abstract differ from data presented at the meeting.

GRAPEVINE, TEXAS—The total nucleated cell (TNC) dose delivered in an allogeneic peripheral blood stem cell transplant (allo-PBSCT) can affect outcomes in certain patients, according to a study presented at the 2014 BMT Tandem Meetings.

Researchers found that a higher TNC dose was associated with better progression-free survival (PFS) and overall survival (OS) among patients who received allo-PBSCT with reduced-intensity conditioning (RIC) and total-body irradiation (TBI).

On the other hand, the dose of CD3+, CD4+, CD8+, or CD34+ cells did not have a significant impact on survival rates in these patients.

And none of the cell doses studied had a significant impact in patients who did not receive TBI or in those who received TBI with myeloablative conditioning.

Michael Burns, of Roswell Park Cancer Institute in Buffalo, New York, presented these findings at the meeting as abstract 12.*

Burns noted that studies have produced conflicting results regarding the correlation between patient outcomes and the dose of CD34+, CD3+, CD4+, or CD8+ cells given in allo-PBSCT. In addition, TNC dose has not been analyzed much in the context of PBSCTs.

Therefore, he and his colleagues retrospectively analyzed graft cell composition in 254 patients who received their first allo-PBSCT from January 2001 to September 2012.

Fifty-eight percent of the patients were male, and the median age was 50 (range, 19-73 years). Forty-four percent of patients had acute myeloid leukemia, 18% had myelodysplastic syndromes or myeloproliferative neoplasms, 13% had acute lymphoblastic leukemia, 13% had non-Hodgkin lymphoma, and 12% had other diseases.

Of the 254 patients studied, 93 had received TBI. Among these, 53 received myeloablative conditioning (91% cyclophosphamide, 120 cGy), and 40 received RIC (100% fludarabine and melphalan, 400 cGy).

Of the 161 patients who did not receive TBI, 41 received myeloablative conditioning (88% busulfan and cyclophosphamide), and 120 received RIC (87% fludarabine and melphalan).

Patients received T-cell-replete, G-CSF mobilized, PB allografts. Fifty-six percent had a 6/6 HLA matched related donor, and 44% had an 8/8 HLA matched unrelated donor. Forty-nine percent of patients were in complete remission at the time of transplant.

The researchers analyzed cell doses according to the median dose (above vs below). But they also analyzed CD34+ dose as < 4 x 10⁶ cells/kg vs ≥ 4 x 10⁶ cells/kg and as < 4 x 10⁶ cells/kg vs 4 to 8 x 10⁶ cells/kg vs > 8 x 10⁶ cells/kg. They analyzed TNC as < 8 x 10⁸ cells/kg vs ≥ to 8 x 10⁸ cells/kg.

The team found that a CD34+ cell dose greater than 4 x 10⁶ cells/kg was significantly associated with time to platelet engraftment in all patients. It was also associated with time to neutrophil engraftment in the TBI group, but this was predominantly among patients who received RIC.

On the other hand, CD3+, CD4+, CD8+, and TNC doses were not significantly associated with platelet or neutrophil engraftment in any patients.

CD34+, CD3+, CD4+, and CD8+ cell dose were not associated with OS, PFS, or acute graft-vs-host disease (GVHD). And TNC had no significant effect on acute GVHD.

“However, we did find that the TNC dose did show some pretty interesting survival outcomes,” Burns said.

A higher TNC dose (≥ 8 x10⁸ cells/kg) was associated with significantly better PFS (P=0.027) and OS (P=0.018) in the TBI patients but not in patients who did not receive TBI (P>0.1 for PFS and OS).

When they analyzed patients according to conditioning regimen, the researchers found the association retained significance among patients who received RIC (P=0.01 for PFS and P=0.007 for OS) but not among patients who received myeloablative conditioning (P>0.1 for PFS and OS).

Burns and his colleagues also conducted a multivariate analysis to see if any other factors affected the relationship between TNC and survival. They controlled for patient age, Karnofsky performance status, and body mass index. And they stratified patients into 4 groups according to TBI and conditioning regimen.

The results showed that patients who received TBI and RIC, as well as a TNC dose less than 8 x 10⁸ cells/kg, had a relative risk of 3.3 for PFS (P=0.026) and a relative risk of 3.4 for OS (P=0.021).

“The association of higher TNC dose with better progression-free and overall survival implies there is a population of nucleated cells which mitigate GVHD but enhance the [graft-vs-leukemia] effect after reduced-intensity TBI conditioning,” Burns said.

“Myeloablative conditioning regimens result in more direct tumor killing. Thus, they rely less on the graft-vs-leukemia effect than the RIC regimens.”

He also noted that the lack of an association between TNC dose and survival rates with non-TBI-based regimens implies there are different mechanisms of tumor kill with TBI and non-TBI-containing regimens.

And a more detailed analysis of cell population subsets in apheresis product may allow researchers to identify cell populations that could improve patient outcomes.

*Some data in the abstract differ from data presented at the meeting.

Lab mouse

Results of preclinical research point to a possible way of preventing mucositis, graft-vs-host disease, and other disorders associated with epithelial permeability.

Investigators created a mouse model of mucositis and discovered that interleukin-1 (IL-1) beta, a protein secreted by the stressed mucosa, played an important role in the condition.

But inhibiting IL-1 beta alleviated mucositis. So the researchers speculated that targeting IL-1 beta might prevent mucositis in humans.

Naama Kanarek, a doctoral student at Hebrew University Hadassah Medical School in Jerusalem, and her colleagues described this research in PNAS.

The investigators began by generating a mouse model deficient in a gene encoding the enzyme beta-TrCP. They chose this enzyme because it’s a major regulator of inflammatory cascades.

The team found that beta-TrCP deletion in the gut caused mucosal DNA damage in the mice, mimicking the effects of chemotherapy and irradiation. Similar to human patients, a severe mucositis reaction occurred in mice that were genetically engineered to be beta-TrCP-deficient.

Tracing the pathological basis of the mouse mucositis revealed that the source of the problem was IL-1 beta. IL-1 beta opened the gut lining, allowing gut bacteria to penetrate and destroy the gut interior.

To confirm this finding, the researchers treated mice with an antibody neutralizing IL-1 beta prior to deleting beta-TrCP. They found this prevented the onset of mucositis.

Therefore, the team has proposed that IL-1 receptor agonists should be tested as mucositis prophylaxis in humans. An example is anakinra (Kineret), which is used to treat chronic inflammatory conditions, such as rheumatoid arthritis and Crohn’s disease.

The investigators believe such treatments might also be used to prevent graft-vs-host disease, burn injuries, head and neck trauma, and other disorders associated with

epithelial permeability.

Lab mouse

Results of preclinical research point to a possible way of preventing mucositis, graft-vs-host disease, and other disorders associated with epithelial permeability.

Investigators created a mouse model of mucositis and discovered that interleukin-1 (IL-1) beta, a protein secreted by the stressed mucosa, played an important role in the condition.

But inhibiting IL-1 beta alleviated mucositis. So the researchers speculated that targeting IL-1 beta might prevent mucositis in humans.

Naama Kanarek, a doctoral student at Hebrew University Hadassah Medical School in Jerusalem, and her colleagues described this research in PNAS.

The investigators began by generating a mouse model deficient in a gene encoding the enzyme beta-TrCP. They chose this enzyme because it’s a major regulator of inflammatory cascades.

The team found that beta-TrCP deletion in the gut caused mucosal DNA damage in the mice, mimicking the effects of chemotherapy and irradiation. Similar to human patients, a severe mucositis reaction occurred in mice that were genetically engineered to be beta-TrCP-deficient.

Tracing the pathological basis of the mouse mucositis revealed that the source of the problem was IL-1 beta. IL-1 beta opened the gut lining, allowing gut bacteria to penetrate and destroy the gut interior.

To confirm this finding, the researchers treated mice with an antibody neutralizing IL-1 beta prior to deleting beta-TrCP. They found this prevented the onset of mucositis.

Therefore, the team has proposed that IL-1 receptor agonists should be tested as mucositis prophylaxis in humans. An example is anakinra (Kineret), which is used to treat chronic inflammatory conditions, such as rheumatoid arthritis and Crohn’s disease.

The investigators believe such treatments might also be used to prevent graft-vs-host disease, burn injuries, head and neck trauma, and other disorders associated with

epithelial permeability.

Lab mouse

Results of preclinical research point to a possible way of preventing mucositis, graft-vs-host disease, and other disorders associated with epithelial permeability.

Investigators created a mouse model of mucositis and discovered that interleukin-1 (IL-1) beta, a protein secreted by the stressed mucosa, played an important role in the condition.

But inhibiting IL-1 beta alleviated mucositis. So the researchers speculated that targeting IL-1 beta might prevent mucositis in humans.

Naama Kanarek, a doctoral student at Hebrew University Hadassah Medical School in Jerusalem, and her colleagues described this research in PNAS.

The investigators began by generating a mouse model deficient in a gene encoding the enzyme beta-TrCP. They chose this enzyme because it’s a major regulator of inflammatory cascades.

The team found that beta-TrCP deletion in the gut caused mucosal DNA damage in the mice, mimicking the effects of chemotherapy and irradiation. Similar to human patients, a severe mucositis reaction occurred in mice that were genetically engineered to be beta-TrCP-deficient.

Tracing the pathological basis of the mouse mucositis revealed that the source of the problem was IL-1 beta. IL-1 beta opened the gut lining, allowing gut bacteria to penetrate and destroy the gut interior.

To confirm this finding, the researchers treated mice with an antibody neutralizing IL-1 beta prior to deleting beta-TrCP. They found this prevented the onset of mucositis.

Therefore, the team has proposed that IL-1 receptor agonists should be tested as mucositis prophylaxis in humans. An example is anakinra (Kineret), which is used to treat chronic inflammatory conditions, such as rheumatoid arthritis and Crohn’s disease.

The investigators believe such treatments might also be used to prevent graft-vs-host disease, burn injuries, head and neck trauma, and other disorders associated with

epithelial permeability.

Michel Sadelain, MD, PhD

Credit: MSKCC

Several studies have shown that infusions of T cells modified with chimeric antigen receptors (CARs) can elicit complete responses in leukemia patients who have run out of treatment options.

However, the therapy also puts patients at risk of developing cytokine release syndrome (CRS).

With updated research, investigators have again shown that CAR T cells can produce complete responses in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), thereby allowing them to receive allogeneic stem cell transplant (allo-SCT).

But the researchers have also used this group of patients to define diagnostic criteria for severe CRS. And the team has discovered that measuring C-reactive protein levels can help predict the severity of CRS.

Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues described these findings in Science Translational Medicine.

Response, bridge to allo-SCT

Dr Sadelain and his colleagues previously reported results in 5 patients with relapsed/refractory B-ALL who received autologous T cells expressing a CD19-specific, CD28/CD3z CAR called 19-28z.

After receiving salvage chemotherapy and CAR T cells, all 5 patients were negative for minimal residual disease. And 4 of the patients went on to receive allo-SCT.

Now, the investigators have expanded upon these findings, reporting results in a total of 16 patients with relapsed/refractory B-ALL who received the 19-28z CAR T cells.

Forty-four percent of patients (n=7) had a complete response to the salvage chemotherapy, and 88% (n=14) had a complete response after CAR T-cell therapy (alghough some had incomplete count recovery). Sixty-three percent of patients (n=10) achieved a complete remission.

Of the 10 patients who were eligible for allo-SCT, 7 underwent the procedure, and all 7 remain free of relapse.

“These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies,” Dr Sadelain said. “Our initial findings have held up in a larger cohort of patients, and we are already looking at new clinical studies to advance this novel therapeutic approach in fighting cancer.”

CRS diagnosis, stratification

In their analysis of 5 B-ALL patients, Dr Sadelain and his colleagues observed a correlation between cytokine elevation and tumor burden at the time of CAR T-cell administration. The team confirmed this correlation in the larger cohort of 16 patients and identified 7 cytokines whose elevation was correlated with pretreatment tumor burden and severe CRS.

Patients with CRS that required intensive medical intervention had a 75-fold increase over baseline levels in 2 of the 7 cytokines, which included IFN-γ, IL-5, IL-6, IL-10, Flt-3L, Fracktalkine, and GM-CSF. These patients also had at least 1 of the following: hypoxia, hypotension, and neurologic changes (such as delirium and seizure-like activity).

Taking these findings together, the researchers concluded that patients had severe CRS if they had persistent fevers (38°C) for more than 3 days, selected cytokine elevations, and additional clinical evidence of toxicity.

The investigators stressed that these patients should be closely monitored. Patients with severe CRS are more likely to need medical intervention than patients with mild CRS, which is characterized by low-grade fever and mild cytokine increases, or absent CRS, which is defined as no fevers and/or no significant cytokine elevations.

Finally, the researchers found that measuring C-reactive protein in serum samples could predict the severity of CRS. Only those patients who met the criteria for severe CRS had a C-reactive protein level of 20 mg/dL or higher.

Patients who had received high-dose steroids were excluded from this analysis, due to the inverse correlation between high-dose steroid treatment and serum C-reactive protein.

Incidentally, the investigators confirmed prior findings that the monoclonal antibody tocilizumab can ameliorate severe CRS as effectively as steroid treatment, without inhibiting the expansion of CAR T cells.

Michel Sadelain, MD, PhD

Credit: MSKCC

Several studies have shown that infusions of T cells modified with chimeric antigen receptors (CARs) can elicit complete responses in leukemia patients who have run out of treatment options.

However, the therapy also puts patients at risk of developing cytokine release syndrome (CRS).

With updated research, investigators have again shown that CAR T cells can produce complete responses in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), thereby allowing them to receive allogeneic stem cell transplant (allo-SCT).

But the researchers have also used this group of patients to define diagnostic criteria for severe CRS. And the team has discovered that measuring C-reactive protein levels can help predict the severity of CRS.

Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues described these findings in Science Translational Medicine.

Response, bridge to allo-SCT

Dr Sadelain and his colleagues previously reported results in 5 patients with relapsed/refractory B-ALL who received autologous T cells expressing a CD19-specific, CD28/CD3z CAR called 19-28z.

After receiving salvage chemotherapy and CAR T cells, all 5 patients were negative for minimal residual disease. And 4 of the patients went on to receive allo-SCT.

Now, the investigators have expanded upon these findings, reporting results in a total of 16 patients with relapsed/refractory B-ALL who received the 19-28z CAR T cells.

Forty-four percent of patients (n=7) had a complete response to the salvage chemotherapy, and 88% (n=14) had a complete response after CAR T-cell therapy (alghough some had incomplete count recovery). Sixty-three percent of patients (n=10) achieved a complete remission.

Of the 10 patients who were eligible for allo-SCT, 7 underwent the procedure, and all 7 remain free of relapse.

“These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies,” Dr Sadelain said. “Our initial findings have held up in a larger cohort of patients, and we are already looking at new clinical studies to advance this novel therapeutic approach in fighting cancer.”

CRS diagnosis, stratification

In their analysis of 5 B-ALL patients, Dr Sadelain and his colleagues observed a correlation between cytokine elevation and tumor burden at the time of CAR T-cell administration. The team confirmed this correlation in the larger cohort of 16 patients and identified 7 cytokines whose elevation was correlated with pretreatment tumor burden and severe CRS.

Patients with CRS that required intensive medical intervention had a 75-fold increase over baseline levels in 2 of the 7 cytokines, which included IFN-γ, IL-5, IL-6, IL-10, Flt-3L, Fracktalkine, and GM-CSF. These patients also had at least 1 of the following: hypoxia, hypotension, and neurologic changes (such as delirium and seizure-like activity).

Taking these findings together, the researchers concluded that patients had severe CRS if they had persistent fevers (38°C) for more than 3 days, selected cytokine elevations, and additional clinical evidence of toxicity.

The investigators stressed that these patients should be closely monitored. Patients with severe CRS are more likely to need medical intervention than patients with mild CRS, which is characterized by low-grade fever and mild cytokine increases, or absent CRS, which is defined as no fevers and/or no significant cytokine elevations.

Finally, the researchers found that measuring C-reactive protein in serum samples could predict the severity of CRS. Only those patients who met the criteria for severe CRS had a C-reactive protein level of 20 mg/dL or higher.

Patients who had received high-dose steroids were excluded from this analysis, due to the inverse correlation between high-dose steroid treatment and serum C-reactive protein.

Incidentally, the investigators confirmed prior findings that the monoclonal antibody tocilizumab can ameliorate severe CRS as effectively as steroid treatment, without inhibiting the expansion of CAR T cells.

Michel Sadelain, MD, PhD

Credit: MSKCC

Several studies have shown that infusions of T cells modified with chimeric antigen receptors (CARs) can elicit complete responses in leukemia patients who have run out of treatment options.

However, the therapy also puts patients at risk of developing cytokine release syndrome (CRS).

With updated research, investigators have again shown that CAR T cells can produce complete responses in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), thereby allowing them to receive allogeneic stem cell transplant (allo-SCT).

But the researchers have also used this group of patients to define diagnostic criteria for severe CRS. And the team has discovered that measuring C-reactive protein levels can help predict the severity of CRS.

Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues described these findings in Science Translational Medicine.

Response, bridge to allo-SCT

Dr Sadelain and his colleagues previously reported results in 5 patients with relapsed/refractory B-ALL who received autologous T cells expressing a CD19-specific, CD28/CD3z CAR called 19-28z.

After receiving salvage chemotherapy and CAR T cells, all 5 patients were negative for minimal residual disease. And 4 of the patients went on to receive allo-SCT.

Now, the investigators have expanded upon these findings, reporting results in a total of 16 patients with relapsed/refractory B-ALL who received the 19-28z CAR T cells.

Forty-four percent of patients (n=7) had a complete response to the salvage chemotherapy, and 88% (n=14) had a complete response after CAR T-cell therapy (alghough some had incomplete count recovery). Sixty-three percent of patients (n=10) achieved a complete remission.

Of the 10 patients who were eligible for allo-SCT, 7 underwent the procedure, and all 7 remain free of relapse.

“These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies,” Dr Sadelain said. “Our initial findings have held up in a larger cohort of patients, and we are already looking at new clinical studies to advance this novel therapeutic approach in fighting cancer.”

CRS diagnosis, stratification

In their analysis of 5 B-ALL patients, Dr Sadelain and his colleagues observed a correlation between cytokine elevation and tumor burden at the time of CAR T-cell administration. The team confirmed this correlation in the larger cohort of 16 patients and identified 7 cytokines whose elevation was correlated with pretreatment tumor burden and severe CRS.

Patients with CRS that required intensive medical intervention had a 75-fold increase over baseline levels in 2 of the 7 cytokines, which included IFN-γ, IL-5, IL-6, IL-10, Flt-3L, Fracktalkine, and GM-CSF. These patients also had at least 1 of the following: hypoxia, hypotension, and neurologic changes (such as delirium and seizure-like activity).

Taking these findings together, the researchers concluded that patients had severe CRS if they had persistent fevers (38°C) for more than 3 days, selected cytokine elevations, and additional clinical evidence of toxicity.

The investigators stressed that these patients should be closely monitored. Patients with severe CRS are more likely to need medical intervention than patients with mild CRS, which is characterized by low-grade fever and mild cytokine increases, or absent CRS, which is defined as no fevers and/or no significant cytokine elevations.

Finally, the researchers found that measuring C-reactive protein in serum samples could predict the severity of CRS. Only those patients who met the criteria for severe CRS had a C-reactive protein level of 20 mg/dL or higher.

Patients who had received high-dose steroids were excluded from this analysis, due to the inverse correlation between high-dose steroid treatment and serum C-reactive protein.

Incidentally, the investigators confirmed prior findings that the monoclonal antibody tocilizumab can ameliorate severe CRS as effectively as steroid treatment, without inhibiting the expansion of CAR T cells.

Mother and son

Credit: George Hodan

Although they initially show signs of psychological distress, parents of children undergoing stem cell transplant (SCT) are as resilient as the children themselves, new research suggests.

Investigators evaluated psychological adjustment in 171 children undergoing SCT and their parents.

Results in the children, which were previously reported in Pediatrics, suggested they were well-adjusted after SCT, whether or not they had received therapy to promote psychological well-being.

Results in the parents, which are now available in Biology of Blood and Marrow Transplantation, are similar.

“The aim of the study was to examine an intervention to promote positive adjustment of patients and their parents,” said study author Jennifer Lindwall, PhD, of St Jude Children’s Research Hospital and Children’s Hospital of Colorado.

The 171 parent/child pairs were randomized to receive a child-targeted intervention, a child and parent intervention, or standard care. The child intervention consisted of massage and humor therapy, and the parent intervention included massage and relaxation/imagery training.

The investigators measured psychological distress and positive affect from the time of admission for a child’s SCT until 6 weeks after the procedure.

The team also measured depression, post-traumatic stress disorder (PTSD), and benefit-finding (potential positive outcomes that result from enduring a difficult experience) at the time of admission and 24 weeks after.

There were no significant differences among the 3 groups with regard to measures of parental distress. And distress decreased significantly from baseline to week 6.

Improvements also occurred over time with regard to positive affect. However, parents in the child/parent-intervention group and child-only-intervention group experienced significant benefits over the standard-care group.

On the other hand, there were no significant differences among the 3 groups with regard to depression, PTSD, and benefit-finding.

Parents from all groups experienced significant decreases in depression and PTSD from baseline to the 24-week mark. And they showed significant increases in benefit-finding.

“In many respects, a parent’s distress parallels the child’s distress,” Dr Lindwall said. “As things get better for the child, they get better for the parent as well.”

Dr Lindwall noted that, although this study suggests resiliency is the norm, there are parents who remain distressed as a result of their child’s illness.

“Our challenge now is to predict which parents are at the highest risk for difficulties,” she said, “and to design interventions that can help these parents cope during their child’s medical challenges.”

Mother and son

Credit: George Hodan

Although they initially show signs of psychological distress, parents of children undergoing stem cell transplant (SCT) are as resilient as the children themselves, new research suggests.

Investigators evaluated psychological adjustment in 171 children undergoing SCT and their parents.

Results in the children, which were previously reported in Pediatrics, suggested they were well-adjusted after SCT, whether or not they had received therapy to promote psychological well-being.

Results in the parents, which are now available in Biology of Blood and Marrow Transplantation, are similar.

“The aim of the study was to examine an intervention to promote positive adjustment of patients and their parents,” said study author Jennifer Lindwall, PhD, of St Jude Children’s Research Hospital and Children’s Hospital of Colorado.

The 171 parent/child pairs were randomized to receive a child-targeted intervention, a child and parent intervention, or standard care. The child intervention consisted of massage and humor therapy, and the parent intervention included massage and relaxation/imagery training.

The investigators measured psychological distress and positive affect from the time of admission for a child’s SCT until 6 weeks after the procedure.

The team also measured depression, post-traumatic stress disorder (PTSD), and benefit-finding (potential positive outcomes that result from enduring a difficult experience) at the time of admission and 24 weeks after.

There were no significant differences among the 3 groups with regard to measures of parental distress. And distress decreased significantly from baseline to week 6.

Improvements also occurred over time with regard to positive affect. However, parents in the child/parent-intervention group and child-only-intervention group experienced significant benefits over the standard-care group.

On the other hand, there were no significant differences among the 3 groups with regard to depression, PTSD, and benefit-finding.

Parents from all groups experienced significant decreases in depression and PTSD from baseline to the 24-week mark. And they showed significant increases in benefit-finding.

“In many respects, a parent’s distress parallels the child’s distress,” Dr Lindwall said. “As things get better for the child, they get better for the parent as well.”

Dr Lindwall noted that, although this study suggests resiliency is the norm, there are parents who remain distressed as a result of their child’s illness.

“Our challenge now is to predict which parents are at the highest risk for difficulties,” she said, “and to design interventions that can help these parents cope during their child’s medical challenges.”

Mother and son

Credit: George Hodan

Although they initially show signs of psychological distress, parents of children undergoing stem cell transplant (SCT) are as resilient as the children themselves, new research suggests.

Investigators evaluated psychological adjustment in 171 children undergoing SCT and their parents.

Results in the children, which were previously reported in Pediatrics, suggested they were well-adjusted after SCT, whether or not they had received therapy to promote psychological well-being.

Results in the parents, which are now available in Biology of Blood and Marrow Transplantation, are similar.

“The aim of the study was to examine an intervention to promote positive adjustment of patients and their parents,” said study author Jennifer Lindwall, PhD, of St Jude Children’s Research Hospital and Children’s Hospital of Colorado.

The 171 parent/child pairs were randomized to receive a child-targeted intervention, a child and parent intervention, or standard care. The child intervention consisted of massage and humor therapy, and the parent intervention included massage and relaxation/imagery training.

The investigators measured psychological distress and positive affect from the time of admission for a child’s SCT until 6 weeks after the procedure.

The team also measured depression, post-traumatic stress disorder (PTSD), and benefit-finding (potential positive outcomes that result from enduring a difficult experience) at the time of admission and 24 weeks after.

There were no significant differences among the 3 groups with regard to measures of parental distress. And distress decreased significantly from baseline to week 6.

Improvements also occurred over time with regard to positive affect. However, parents in the child/parent-intervention group and child-only-intervention group experienced significant benefits over the standard-care group.

On the other hand, there were no significant differences among the 3 groups with regard to depression, PTSD, and benefit-finding.

Parents from all groups experienced significant decreases in depression and PTSD from baseline to the 24-week mark. And they showed significant increases in benefit-finding.

“In many respects, a parent’s distress parallels the child’s distress,” Dr Lindwall said. “As things get better for the child, they get better for the parent as well.”

Dr Lindwall noted that, although this study suggests resiliency is the norm, there are parents who remain distressed as a result of their child’s illness.

“Our challenge now is to predict which parents are at the highest risk for difficulties,” she said, “and to design interventions that can help these parents cope during their child’s medical challenges.”

SAN FRANCISCO—A single-center study suggests that transplant can induce remissions and improve survival in certain patients with advanced cutaneous T-cell lymphomas.

Allogeneic stem cell transplant (SCT) proved particularly effective in patients with Sézary syndrome (SS).

It also conferred benefits to mycosis fungoides (MF) patients with large-cell transformation (LCT), but patients with SS and LCT did not fare as well.

Madeleine Duvic, MD, of the MD Anderson Cancer Center in Houston, presented these results at the 6th Annual T-cell Lymphoma Forum. The data were updated from a previously published report (Duvic et al, JCO 2010).

Patient characteristics

Dr Duvic and her colleagues evaluated 48 patients who had biopsy-proven MF or SS. They underwent SCT at MD Anderson between July 2001 and September 2013.

The patients were in good health but had advanced disease. They had received a median of 6 prior therapies (range, 2-11).

The median age was 51.5 years (range, 19-72 years), and 54% of patients were female. Sixty-nine percent were Caucasian, 23% were African American, and 8% were Hispanic.

Fourteen patients had SS only, 16 had MF with LCT, 9 had SS and LCT, 5 had stage IVA or IIB disease (4 nodal, 1 tumor), and 4 had folliculotropic MF.

Transplant and other treatment

Patients had to have a 9/10 or 10/10 HLA-matched donor (related or unrelated). Most of the stem cells were collected via apheresis, but bone marrow aspiration was used for patients receiving mismatched transplants.

Forty-three of the patients underwent tumor and skin debulking with total skin electron beam (TBSEB) radiation (35 Gy) 1 or 2 months prior to SCT.

Most patients received a conditioning regimen of fludarabine and melphalan, but a few received fludarabine and cyclophosphamide. Patients received tacrolimus and methotrexate as graft-vs-host disease (GVHD) prophylaxis, as well as extracorporeal photopheresis if they developed GVHD.

All of the SS patients received vancomycin, fluconazole, and valacyclovir to ward off infections.

Response and GVHD

The overall complete response rate was 58% (28/48). Eight percent of patients did not engraft—3 MF patients with LCT and 1 SS patient.

“The response rate was much higher in Sézary patients [than in the rest of the cohort],” Dr Duvic said. “The worst prognosis was for patients who had both Sézary and large-cell transformation, who relapsed early and were generally refractory to prior therapies.”

Complete responses occurred in 79% of SS patients, 56% of MF patients with LCT, 44% of patients with SS and LCT, 40% of patients with stage IVA/IIB disease, and 50% of those with folliculotropic MF.

Among patients who received TBSEB, 58% (25/43) achieved a complete response. Of the 5 patients who did not receive TBSEB, 3 had a complete response (60%).

Sixty percent of patients developed GVHD (29/48). Eighteen patients had acute skin GVHD, 9 had acute gastrointestinal GVHD, 13 had chronic skin GVHD, and 6 had chronic gastrointestinal GVHD.

Relapse and survival

Overall, the relapse rate was 33% (16/48). Twenty-one percent of SS patients relapsed, as did 25% of MF patients with LCT and 56% of patients with SS and LCT.

The mortality rate was 44% (21/48). Patients died of relapsed MF, sepsis, infection, second malignancy, and other causes.

The overall survival (OS) was 10.2 years from diagnosis and 5.7 years from SCT. The progression-free survival (PFS) was 6 years from diagnosis and 1.8 years from SCT.

“We also looked at whether large-cell transformation had an effect on survival and therapy,” Dr Duvic said. “Large-cell transformation in MF has been reported to have a more aggressive course and a shorter overall survival than untransformed MF.”

“In our cohort of patients, we found an overall survival of 4.79 years in patients with large-cell transformation, which is a little bit higher than [survival rates in] the literature.”

Among MF patients with LCT, OS was 84% at 1 year from SCT and 38% at both 5 years and 10 years. PFS was 55% at 1 year, 16% at 5 years, and 0% at 10 years.

In comparison, among SS patients without LCT, OS was 88% at 1 year from SCT and 70% at both 5 years and 10 years. PFS was 63% at 1 year and 49% at 5 years and 10 years.

SAN FRANCISCO—A single-center study suggests that transplant can induce remissions and improve survival in certain patients with advanced cutaneous T-cell lymphomas.

Allogeneic stem cell transplant (SCT) proved particularly effective in patients with Sézary syndrome (SS).

It also conferred benefits to mycosis fungoides (MF) patients with large-cell transformation (LCT), but patients with SS and LCT did not fare as well.

Madeleine Duvic, MD, of the MD Anderson Cancer Center in Houston, presented these results at the 6th Annual T-cell Lymphoma Forum. The data were updated from a previously published report (Duvic et al, JCO 2010).

Patient characteristics

Dr Duvic and her colleagues evaluated 48 patients who had biopsy-proven MF or SS. They underwent SCT at MD Anderson between July 2001 and September 2013.

The patients were in good health but had advanced disease. They had received a median of 6 prior therapies (range, 2-11).

The median age was 51.5 years (range, 19-72 years), and 54% of patients were female. Sixty-nine percent were Caucasian, 23% were African American, and 8% were Hispanic.

Fourteen patients had SS only, 16 had MF with LCT, 9 had SS and LCT, 5 had stage IVA or IIB disease (4 nodal, 1 tumor), and 4 had folliculotropic MF.

Transplant and other treatment

Patients had to have a 9/10 or 10/10 HLA-matched donor (related or unrelated). Most of the stem cells were collected via apheresis, but bone marrow aspiration was used for patients receiving mismatched transplants.

Forty-three of the patients underwent tumor and skin debulking with total skin electron beam (TBSEB) radiation (35 Gy) 1 or 2 months prior to SCT.

Most patients received a conditioning regimen of fludarabine and melphalan, but a few received fludarabine and cyclophosphamide. Patients received tacrolimus and methotrexate as graft-vs-host disease (GVHD) prophylaxis, as well as extracorporeal photopheresis if they developed GVHD.

All of the SS patients received vancomycin, fluconazole, and valacyclovir to ward off infections.

Response and GVHD

The overall complete response rate was 58% (28/48). Eight percent of patients did not engraft—3 MF patients with LCT and 1 SS patient.

“The response rate was much higher in Sézary patients [than in the rest of the cohort],” Dr Duvic said. “The worst prognosis was for patients who had both Sézary and large-cell transformation, who relapsed early and were generally refractory to prior therapies.”

Complete responses occurred in 79% of SS patients, 56% of MF patients with LCT, 44% of patients with SS and LCT, 40% of patients with stage IVA/IIB disease, and 50% of those with folliculotropic MF.

Among patients who received TBSEB, 58% (25/43) achieved a complete response. Of the 5 patients who did not receive TBSEB, 3 had a complete response (60%).

Sixty percent of patients developed GVHD (29/48). Eighteen patients had acute skin GVHD, 9 had acute gastrointestinal GVHD, 13 had chronic skin GVHD, and 6 had chronic gastrointestinal GVHD.

Relapse and survival

Overall, the relapse rate was 33% (16/48). Twenty-one percent of SS patients relapsed, as did 25% of MF patients with LCT and 56% of patients with SS and LCT.

The mortality rate was 44% (21/48). Patients died of relapsed MF, sepsis, infection, second malignancy, and other causes.

The overall survival (OS) was 10.2 years from diagnosis and 5.7 years from SCT. The progression-free survival (PFS) was 6 years from diagnosis and 1.8 years from SCT.

“We also looked at whether large-cell transformation had an effect on survival and therapy,” Dr Duvic said. “Large-cell transformation in MF has been reported to have a more aggressive course and a shorter overall survival than untransformed MF.”

“In our cohort of patients, we found an overall survival of 4.79 years in patients with large-cell transformation, which is a little bit higher than [survival rates in] the literature.”

Among MF patients with LCT, OS was 84% at 1 year from SCT and 38% at both 5 years and 10 years. PFS was 55% at 1 year, 16% at 5 years, and 0% at 10 years.

In comparison, among SS patients without LCT, OS was 88% at 1 year from SCT and 70% at both 5 years and 10 years. PFS was 63% at 1 year and 49% at 5 years and 10 years.

SAN FRANCISCO—A single-center study suggests that transplant can induce remissions and improve survival in certain patients with advanced cutaneous T-cell lymphomas.

Allogeneic stem cell transplant (SCT) proved particularly effective in patients with Sézary syndrome (SS).

It also conferred benefits to mycosis fungoides (MF) patients with large-cell transformation (LCT), but patients with SS and LCT did not fare as well.

Madeleine Duvic, MD, of the MD Anderson Cancer Center in Houston, presented these results at the 6th Annual T-cell Lymphoma Forum. The data were updated from a previously published report (Duvic et al, JCO 2010).

Patient characteristics

Dr Duvic and her colleagues evaluated 48 patients who had biopsy-proven MF or SS. They underwent SCT at MD Anderson between July 2001 and September 2013.

The patients were in good health but had advanced disease. They had received a median of 6 prior therapies (range, 2-11).

The median age was 51.5 years (range, 19-72 years), and 54% of patients were female. Sixty-nine percent were Caucasian, 23% were African American, and 8% were Hispanic.

Fourteen patients had SS only, 16 had MF with LCT, 9 had SS and LCT, 5 had stage IVA or IIB disease (4 nodal, 1 tumor), and 4 had folliculotropic MF.

Transplant and other treatment

Patients had to have a 9/10 or 10/10 HLA-matched donor (related or unrelated). Most of the stem cells were collected via apheresis, but bone marrow aspiration was used for patients receiving mismatched transplants.

Forty-three of the patients underwent tumor and skin debulking with total skin electron beam (TBSEB) radiation (35 Gy) 1 or 2 months prior to SCT.

Most patients received a conditioning regimen of fludarabine and melphalan, but a few received fludarabine and cyclophosphamide. Patients received tacrolimus and methotrexate as graft-vs-host disease (GVHD) prophylaxis, as well as extracorporeal photopheresis if they developed GVHD.

All of the SS patients received vancomycin, fluconazole, and valacyclovir to ward off infections.

Response and GVHD

The overall complete response rate was 58% (28/48). Eight percent of patients did not engraft—3 MF patients with LCT and 1 SS patient.

“The response rate was much higher in Sézary patients [than in the rest of the cohort],” Dr Duvic said. “The worst prognosis was for patients who had both Sézary and large-cell transformation, who relapsed early and were generally refractory to prior therapies.”

Complete responses occurred in 79% of SS patients, 56% of MF patients with LCT, 44% of patients with SS and LCT, 40% of patients with stage IVA/IIB disease, and 50% of those with folliculotropic MF.

Among patients who received TBSEB, 58% (25/43) achieved a complete response. Of the 5 patients who did not receive TBSEB, 3 had a complete response (60%).

Sixty percent of patients developed GVHD (29/48). Eighteen patients had acute skin GVHD, 9 had acute gastrointestinal GVHD, 13 had chronic skin GVHD, and 6 had chronic gastrointestinal GVHD.

Relapse and survival

Overall, the relapse rate was 33% (16/48). Twenty-one percent of SS patients relapsed, as did 25% of MF patients with LCT and 56% of patients with SS and LCT.

The mortality rate was 44% (21/48). Patients died of relapsed MF, sepsis, infection, second malignancy, and other causes.

The overall survival (OS) was 10.2 years from diagnosis and 5.7 years from SCT. The progression-free survival (PFS) was 6 years from diagnosis and 1.8 years from SCT.

“We also looked at whether large-cell transformation had an effect on survival and therapy,” Dr Duvic said. “Large-cell transformation in MF has been reported to have a more aggressive course and a shorter overall survival than untransformed MF.”

“In our cohort of patients, we found an overall survival of 4.79 years in patients with large-cell transformation, which is a little bit higher than [survival rates in] the literature.”

Among MF patients with LCT, OS was 84% at 1 year from SCT and 38% at both 5 years and 10 years. PFS was 55% at 1 year, 16% at 5 years, and 0% at 10 years.

In comparison, among SS patients without LCT, OS was 88% at 1 year from SCT and 70% at both 5 years and 10 years. PFS was 63% at 1 year and 49% at 5 years and 10 years.

CliniMACS system

Credit: Miltenyi Biotec

The US Food and Drug Administration (FDA) has granted approval for a device system that can prevent graft-vs-host disease (GVHD).

The CliniMACS CD34 Reagent System is intended for use in patients with acute myeloid leukemia who are in first complete remission and undergoing stem cell transplant (SCT) from a matched, related donor.

This in vitro system enriches CD34+ hematopoietic stem cells from a donated apheresis product, while depleting other cells that can cause GVHD.

The system employs a reagent consisting of a CD34 antibody conjugated to an iron-containing nanoparticle. It enriches CD34+ cells by passing the antibody/nanoparticle-labeled cell suspension through a magnetic separation column, which is provided as part of a single-use, disposable tubing set.

Magnetically labeled CD34+ target cells are retained within the separation column, while the unlabeled cells flow through. The CD34+ cells can be recovered by removing the magnetic field and eluting the targeted CD34+ cells into a collection bag.

The FDA’s approval of this system was based on data from a phase 2 study (BMT CTN 0303) conducted by the Blood and Marrow Transplant Clinical Trials Network (Pasquini et al, JCO 2012).

The trial included 128 patients undergoing SCT from a matched, sibling donor. Forty-four patients received grafts that were T-cell depleted (TCD) using the CliniMACS system as the sole form of immune suppression. The other 84 patients received T-cell-replete grafts and pharmacologic immune suppression therapy (IST).

The 2 groups were largely similar, although more patients in the TCD arm received treatment regimens that included radiation—100% vs 50%.

Neutrophil engraftment was similar between the 2 groups. At 28 days, 96% of patients in the IST arm and 100% in the TCD arm had achieved engraftment.

Patients in the TCD arm had a significantly lower rate of chronic GVHD than those in the IST arm. The TCD patients also had a lower rate of acute GVHD, but the difference was not significant.

At 100 days, the rates of grade 2-4, acute GVHD were 39% with IST and 23% with TCD grafts (P=0.07). At 2 years, the rates of chronic GVHD were 19% with TCD grafts and 50% with IST (P<0.001).

There were no significant differences between the 2 groups with regard to graft rejection, leukemia relapse, treatment-related mortality, disease-free survival, or overall survival. However, patients in the TCD arm had a higher rate of GVHD-free survival at 2 years—41% vs 19% (P=0.006).

The CliniMACS CD34 Reagent System is manufactured by Miltenyi Biotec. For more information on the system, see the company’s website.

CliniMACS system

Credit: Miltenyi Biotec

The US Food and Drug Administration (FDA) has granted approval for a device system that can prevent graft-vs-host disease (GVHD).

The CliniMACS CD34 Reagent System is intended for use in patients with acute myeloid leukemia who are in first complete remission and undergoing stem cell transplant (SCT) from a matched, related donor.

This in vitro system enriches CD34+ hematopoietic stem cells from a donated apheresis product, while depleting other cells that can cause GVHD.

The system employs a reagent consisting of a CD34 antibody conjugated to an iron-containing nanoparticle. It enriches CD34+ cells by passing the antibody/nanoparticle-labeled cell suspension through a magnetic separation column, which is provided as part of a single-use, disposable tubing set.

Magnetically labeled CD34+ target cells are retained within the separation column, while the unlabeled cells flow through. The CD34+ cells can be recovered by removing the magnetic field and eluting the targeted CD34+ cells into a collection bag.

The FDA’s approval of this system was based on data from a phase 2 study (BMT CTN 0303) conducted by the Blood and Marrow Transplant Clinical Trials Network (Pasquini et al, JCO 2012).

The trial included 128 patients undergoing SCT from a matched, sibling donor. Forty-four patients received grafts that were T-cell depleted (TCD) using the CliniMACS system as the sole form of immune suppression. The other 84 patients received T-cell-replete grafts and pharmacologic immune suppression therapy (IST).

The 2 groups were largely similar, although more patients in the TCD arm received treatment regimens that included radiation—100% vs 50%.

Neutrophil engraftment was similar between the 2 groups. At 28 days, 96% of patients in the IST arm and 100% in the TCD arm had achieved engraftment.

Patients in the TCD arm had a significantly lower rate of chronic GVHD than those in the IST arm. The TCD patients also had a lower rate of acute GVHD, but the difference was not significant.

At 100 days, the rates of grade 2-4, acute GVHD were 39% with IST and 23% with TCD grafts (P=0.07). At 2 years, the rates of chronic GVHD were 19% with TCD grafts and 50% with IST (P<0.001).

There were no significant differences between the 2 groups with regard to graft rejection, leukemia relapse, treatment-related mortality, disease-free survival, or overall survival. However, patients in the TCD arm had a higher rate of GVHD-free survival at 2 years—41% vs 19% (P=0.006).

The CliniMACS CD34 Reagent System is manufactured by Miltenyi Biotec. For more information on the system, see the company’s website.

CliniMACS system

Credit: Miltenyi Biotec

The US Food and Drug Administration (FDA) has granted approval for a device system that can prevent graft-vs-host disease (GVHD).

The CliniMACS CD34 Reagent System is intended for use in patients with acute myeloid leukemia who are in first complete remission and undergoing stem cell transplant (SCT) from a matched, related donor.

This in vitro system enriches CD34+ hematopoietic stem cells from a donated apheresis product, while depleting other cells that can cause GVHD.

The system employs a reagent consisting of a CD34 antibody conjugated to an iron-containing nanoparticle. It enriches CD34+ cells by passing the antibody/nanoparticle-labeled cell suspension through a magnetic separation column, which is provided as part of a single-use, disposable tubing set.

Magnetically labeled CD34+ target cells are retained within the separation column, while the unlabeled cells flow through. The CD34+ cells can be recovered by removing the magnetic field and eluting the targeted CD34+ cells into a collection bag.

The FDA’s approval of this system was based on data from a phase 2 study (BMT CTN 0303) conducted by the Blood and Marrow Transplant Clinical Trials Network (Pasquini et al, JCO 2012).

The trial included 128 patients undergoing SCT from a matched, sibling donor. Forty-four patients received grafts that were T-cell depleted (TCD) using the CliniMACS system as the sole form of immune suppression. The other 84 patients received T-cell-replete grafts and pharmacologic immune suppression therapy (IST).

The 2 groups were largely similar, although more patients in the TCD arm received treatment regimens that included radiation—100% vs 50%.

Neutrophil engraftment was similar between the 2 groups. At 28 days, 96% of patients in the IST arm and 100% in the TCD arm had achieved engraftment.

Patients in the TCD arm had a significantly lower rate of chronic GVHD than those in the IST arm. The TCD patients also had a lower rate of acute GVHD, but the difference was not significant.

At 100 days, the rates of grade 2-4, acute GVHD were 39% with IST and 23% with TCD grafts (P=0.07). At 2 years, the rates of chronic GVHD were 19% with TCD grafts and 50% with IST (P<0.001).

There were no significant differences between the 2 groups with regard to graft rejection, leukemia relapse, treatment-related mortality, disease-free survival, or overall survival. However, patients in the TCD arm had a higher rate of GVHD-free survival at 2 years—41% vs 19% (P=0.006).

The CliniMACS CD34 Reagent System is manufactured by Miltenyi Biotec. For more information on the system, see the company’s website.

Cell undergoing mitosis

(endoplasmic reticulum in

green, mitochondria in red,

and chromosomes in blue)

Wellcome Images

The dynein-binding protein Lis1 is critical for hematopoietic stem cell (HSC) function and blood formation, according to a paper published in Nature Genetics.

Investigators found that Lis1 regulates asymmetric division of HSCs, ensuring the cells correctly differentiate to provide an adequate supply of new blood cells.

The research also indicated that Lis1 plays a key role in leukemias, as leukemic stem cells rely on the protein to regulate and sustain their growth.

“[Asymmetric division] is very important for the proper generation of all the cells needed for the development and function of many normal tissues,” said study author Tannishtha Reya, PhD, of the University of California, San Diego School of Medicine.

When cells divide, Lis1 controls orientation of the mitotic spindle, an apparatus of subcellular fibers that segregates chromosomes during cell division.

“During division, the spindle is attached to a particular point on the cell membrane, which also determines the axis along which the cell will divide,” Dr Reya said. “Because proteins are not evenly distributed throughout the cell, the axis of division, in turn, determines the types and amounts of proteins that get distributed to each daughter cell.”

When the investigators deleted Lis1 from mouse HSCs, differentiation was radically altered. Asymmetric division increased and accelerated differentiation.

This led to an oversupply of specialized cells and an ever-diminishing reserve of undifferentiated stem cells, which eventually resulted in a bloodless mouse.

“What we found was that a large part of the defect in blood formation was due to a failure of stem cells to expand,” Dr Reya said.

“Instead of undergoing symmetric divisions to generate 2 stem cell daughters, they predominantly underwent asymmetric division to generate more specialized cells. As a result, the mice were unable to generate enough stem cells to sustain blood cell production.”

The investigators next looked at how leukemic stem cells in mice behaved when the Lis1 signaling pathway was blocked. And the team discovered that these cells also lost the ability to renew and propagate.

“In this sense, the effect Lis1 has on leukemic self-renewal parallels its role in normal stem cell self-renewal,” Dr Reya said.

She added that these findings shed new light on the fundamental regulators of cell growth, both in normal development and in cancer.

“Our work shows that elimination of Lis1 potently inhibits cancer growth and identifies Lis1 and other regulators of protein inheritance as a new class of molecules that could be targeted in cancer therapy,” she said.

However, it remains to be seen whether inhibiting Lis1 in cancer cells would produce unacceptable consequences in normal cells as well.

“Agents that target Lis1 might be more specific and less toxic [than chemotherapy],” Dr Reya said, “which would give them significant clinical value.”

Cell undergoing mitosis

(endoplasmic reticulum in

green, mitochondria in red,

and chromosomes in blue)

Wellcome Images

The dynein-binding protein Lis1 is critical for hematopoietic stem cell (HSC) function and blood formation, according to a paper published in Nature Genetics.

Investigators found that Lis1 regulates asymmetric division of HSCs, ensuring the cells correctly differentiate to provide an adequate supply of new blood cells.

The research also indicated that Lis1 plays a key role in leukemias, as leukemic stem cells rely on the protein to regulate and sustain their growth.

“[Asymmetric division] is very important for the proper generation of all the cells needed for the development and function of many normal tissues,” said study author Tannishtha Reya, PhD, of the University of California, San Diego School of Medicine.

When cells divide, Lis1 controls orientation of the mitotic spindle, an apparatus of subcellular fibers that segregates chromosomes during cell division.

“During division, the spindle is attached to a particular point on the cell membrane, which also determines the axis along which the cell will divide,” Dr Reya said. “Because proteins are not evenly distributed throughout the cell, the axis of division, in turn, determines the types and amounts of proteins that get distributed to each daughter cell.”

When the investigators deleted Lis1 from mouse HSCs, differentiation was radically altered. Asymmetric division increased and accelerated differentiation.

This led to an oversupply of specialized cells and an ever-diminishing reserve of undifferentiated stem cells, which eventually resulted in a bloodless mouse.

“What we found was that a large part of the defect in blood formation was due to a failure of stem cells to expand,” Dr Reya said.

“Instead of undergoing symmetric divisions to generate 2 stem cell daughters, they predominantly underwent asymmetric division to generate more specialized cells. As a result, the mice were unable to generate enough stem cells to sustain blood cell production.”

The investigators next looked at how leukemic stem cells in mice behaved when the Lis1 signaling pathway was blocked. And the team discovered that these cells also lost the ability to renew and propagate.

“In this sense, the effect Lis1 has on leukemic self-renewal parallels its role in normal stem cell self-renewal,” Dr Reya said.

She added that these findings shed new light on the fundamental regulators of cell growth, both in normal development and in cancer.

“Our work shows that elimination of Lis1 potently inhibits cancer growth and identifies Lis1 and other regulators of protein inheritance as a new class of molecules that could be targeted in cancer therapy,” she said.

However, it remains to be seen whether inhibiting Lis1 in cancer cells would produce unacceptable consequences in normal cells as well.

“Agents that target Lis1 might be more specific and less toxic [than chemotherapy],” Dr Reya said, “which would give them significant clinical value.”

Cell undergoing mitosis

(endoplasmic reticulum in

green, mitochondria in red,

and chromosomes in blue)

Wellcome Images

The dynein-binding protein Lis1 is critical for hematopoietic stem cell (HSC) function and blood formation, according to a paper published in Nature Genetics.

Investigators found that Lis1 regulates asymmetric division of HSCs, ensuring the cells correctly differentiate to provide an adequate supply of new blood cells.

The research also indicated that Lis1 plays a key role in leukemias, as leukemic stem cells rely on the protein to regulate and sustain their growth.

“[Asymmetric division] is very important for the proper generation of all the cells needed for the development and function of many normal tissues,” said study author Tannishtha Reya, PhD, of the University of California, San Diego School of Medicine.

When cells divide, Lis1 controls orientation of the mitotic spindle, an apparatus of subcellular fibers that segregates chromosomes during cell division.

“During division, the spindle is attached to a particular point on the cell membrane, which also determines the axis along which the cell will divide,” Dr Reya said. “Because proteins are not evenly distributed throughout the cell, the axis of division, in turn, determines the types and amounts of proteins that get distributed to each daughter cell.”

When the investigators deleted Lis1 from mouse HSCs, differentiation was radically altered. Asymmetric division increased and accelerated differentiation.

This led to an oversupply of specialized cells and an ever-diminishing reserve of undifferentiated stem cells, which eventually resulted in a bloodless mouse.

“What we found was that a large part of the defect in blood formation was due to a failure of stem cells to expand,” Dr Reya said.

“Instead of undergoing symmetric divisions to generate 2 stem cell daughters, they predominantly underwent asymmetric division to generate more specialized cells. As a result, the mice were unable to generate enough stem cells to sustain blood cell production.”

The investigators next looked at how leukemic stem cells in mice behaved when the Lis1 signaling pathway was blocked. And the team discovered that these cells also lost the ability to renew and propagate.

“In this sense, the effect Lis1 has on leukemic self-renewal parallels its role in normal stem cell self-renewal,” Dr Reya said.

She added that these findings shed new light on the fundamental regulators of cell growth, both in normal development and in cancer.

“Our work shows that elimination of Lis1 potently inhibits cancer growth and identifies Lis1 and other regulators of protein inheritance as a new class of molecules that could be targeted in cancer therapy,” she said.

However, it remains to be seen whether inhibiting Lis1 in cancer cells would produce unacceptable consequences in normal cells as well.

“Agents that target Lis1 might be more specific and less toxic [than chemotherapy],” Dr Reya said, “which would give them significant clinical value.”

Stem cells for transplant

Credit: Chad McNeeley

A music therapy intervention can help adolescents and young adults (AYAs) cope with cancer and its treatment, according to research published in the journal Cancer.

The intervention consisted of writing song lyrics and producing music videos.

It helped AYA cancer patients communicate their feelings about their disease and its treatment, hematopoietic stem cell transplant (HSCT).

The program also had positive effects on patients’ social integration and family environment.

About the intervention

The therapeutic music video (TMV) intervention was designed to improve resilience in AYA cancer patients undergoing HSCT. Resilience is the process of positively adjusting to stressors.

“Adolescents and young adults who are resilient have the ability to rise above their illness, gain a sense of mastery and confidence in how they have dealt with their cancer, and demonstrate a desire to reach out and help others,” said study author Joan Haase, PhD, RN, of the Indiana University School of Nursing.

Dr Haase and her colleagues wanted to use the TMV intervention to help AYAs explore and express thoughts and emotions about their disease and treatment that might otherwise go unspoken.

The patients did this by writing song lyrics and producing videos with the help of a board-certified music therapist. As they moved through phases of the intervention—making sound recordings, collecting video images, and storyboarding—patients had opportunities to involve family, friends, and healthcare providers in their project.

Results of the study

To test the intervention, Dr Haase and her colleagues enrolled 113 cancer patients (aged 11 to 24 years) who were undergoing HSCT.

The patients were randomized to the TMV intervention group or a control group that received audiobooks. All patients completed 6 sessions over 3 weeks.

After the intervention, the TMV group reported significantly better courageous coping. And at 100 days after HSCT, the TMV group reported significantly better social integration and family environments.

Parents reported that the videos gave them insight into their children’s cancer experiences. However, parents needed help to initiate and sustain conversations about messages shared through their children’s videos.

The investigators said these findings provide evidence supporting the use of a music-based intervention delivered by a music therapist to help AYAs cope with high-risk, high-intensity cancer treatments.

“The availability of music therapy services from a board-certified music therapist in the United States has become more widespread, and, through studies like this one, we hope to see increased availability and access to this important allied health service,” said study author Sheri L. Robb, PhD, also of the Indiana University School of Nursing.

“One of our team’s next steps is to disseminate findings, train professional music therapists on this intervention, and then conduct an implementation study to examine how the intervention may change as it moves into the standard care setting and whether, in the presence of these changes, patient benefits are maintained.”

Stem cells for transplant

Credit: Chad McNeeley

A music therapy intervention can help adolescents and young adults (AYAs) cope with cancer and its treatment, according to research published in the journal Cancer.

The intervention consisted of writing song lyrics and producing music videos.

It helped AYA cancer patients communicate their feelings about their disease and its treatment, hematopoietic stem cell transplant (HSCT).

The program also had positive effects on patients’ social integration and family environment.

About the intervention

The therapeutic music video (TMV) intervention was designed to improve resilience in AYA cancer patients undergoing HSCT. Resilience is the process of positively adjusting to stressors.

“Adolescents and young adults who are resilient have the ability to rise above their illness, gain a sense of mastery and confidence in how they have dealt with their cancer, and demonstrate a desire to reach out and help others,” said study author Joan Haase, PhD, RN, of the Indiana University School of Nursing.

Dr Haase and her colleagues wanted to use the TMV intervention to help AYAs explore and express thoughts and emotions about their disease and treatment that might otherwise go unspoken.

The patients did this by writing song lyrics and producing videos with the help of a board-certified music therapist. As they moved through phases of the intervention—making sound recordings, collecting video images, and storyboarding—patients had opportunities to involve family, friends, and healthcare providers in their project.

Results of the study

To test the intervention, Dr Haase and her colleagues enrolled 113 cancer patients (aged 11 to 24 years) who were undergoing HSCT.

The patients were randomized to the TMV intervention group or a control group that received audiobooks. All patients completed 6 sessions over 3 weeks.

After the intervention, the TMV group reported significantly better courageous coping. And at 100 days after HSCT, the TMV group reported significantly better social integration and family environments.

Parents reported that the videos gave them insight into their children’s cancer experiences. However, parents needed help to initiate and sustain conversations about messages shared through their children’s videos.

The investigators said these findings provide evidence supporting the use of a music-based intervention delivered by a music therapist to help AYAs cope with high-risk, high-intensity cancer treatments.

“The availability of music therapy services from a board-certified music therapist in the United States has become more widespread, and, through studies like this one, we hope to see increased availability and access to this important allied health service,” said study author Sheri L. Robb, PhD, also of the Indiana University School of Nursing.

“One of our team’s next steps is to disseminate findings, train professional music therapists on this intervention, and then conduct an implementation study to examine how the intervention may change as it moves into the standard care setting and whether, in the presence of these changes, patient benefits are maintained.”

Stem cells for transplant

Credit: Chad McNeeley

A music therapy intervention can help adolescents and young adults (AYAs) cope with cancer and its treatment, according to research published in the journal Cancer.

The intervention consisted of writing song lyrics and producing music videos.

It helped AYA cancer patients communicate their feelings about their disease and its treatment, hematopoietic stem cell transplant (HSCT).

The program also had positive effects on patients’ social integration and family environment.

About the intervention

The therapeutic music video (TMV) intervention was designed to improve resilience in AYA cancer patients undergoing HSCT. Resilience is the process of positively adjusting to stressors.

“Adolescents and young adults who are resilient have the ability to rise above their illness, gain a sense of mastery and confidence in how they have dealt with their cancer, and demonstrate a desire to reach out and help others,” said study author Joan Haase, PhD, RN, of the Indiana University School of Nursing.

Dr Haase and her colleagues wanted to use the TMV intervention to help AYAs explore and express thoughts and emotions about their disease and treatment that might otherwise go unspoken.

The patients did this by writing song lyrics and producing videos with the help of a board-certified music therapist. As they moved through phases of the intervention—making sound recordings, collecting video images, and storyboarding—patients had opportunities to involve family, friends, and healthcare providers in their project.

Results of the study

To test the intervention, Dr Haase and her colleagues enrolled 113 cancer patients (aged 11 to 24 years) who were undergoing HSCT.

The patients were randomized to the TMV intervention group or a control group that received audiobooks. All patients completed 6 sessions over 3 weeks.

After the intervention, the TMV group reported significantly better courageous coping. And at 100 days after HSCT, the TMV group reported significantly better social integration and family environments.

Parents reported that the videos gave them insight into their children’s cancer experiences. However, parents needed help to initiate and sustain conversations about messages shared through their children’s videos.

The investigators said these findings provide evidence supporting the use of a music-based intervention delivered by a music therapist to help AYAs cope with high-risk, high-intensity cancer treatments.

“The availability of music therapy services from a board-certified music therapist in the United States has become more widespread, and, through studies like this one, we hope to see increased availability and access to this important allied health service,” said study author Sheri L. Robb, PhD, also of the Indiana University School of Nursing.

“One of our team’s next steps is to disseminate findings, train professional music therapists on this intervention, and then conduct an implementation study to examine how the intervention may change as it moves into the standard care setting and whether, in the presence of these changes, patient benefits are maintained.”