Jen Smith

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.

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.

SAN FRANCISCO—A group’s effort to identify optimal front-line treatment for peripheral T-cell lymphomas (PTCLs) was not as successful as researchers anticipated.

The North American PTCL Consortium set out to find a treatment that could best CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), as studies have suggested this regimen is inadequate for patients with PTCL.

So the group organized a trial testing

a potentially more promising regimen: cyclophosphamide, etoposide, vincristine, and prednisone, alternating with pralatrexate (CEOP-P).

However, CEOP-P elicited a complete response (CR) rate comparable to rates historically seen with CHOP, and progression-free survival rates with the new regimen were “not particularly encouraging.”

Ranjana Advani, MD, of Stanford University Medical Center in California, discussed this trial’s inception, execution, and results at the 6th Annual T-cell Lymphoma Forum.

Trial inception

It all began with the first meeting of the North American PTCL Consortium, which took place at the 2006 ASH Annual Meeting. Physicians from 17 centers gathered to discuss the state of PTCL research in North America.

The group realized there were too many open studies for such a rare disease, and efforts should be more focused. However, they could not agree publicly as to which studies should get priority, so they used an anonymous survey to obtain a consensus.

Survey responses were “all over the map,” Dr Advani said. But ultimately, the consensus was that ongoing trials were not sufficient, and a new trial was necessary.

The group decided to first lend their support to ongoing trials and then launch a new study. At the fourth and fifth meetings of the North American PTCL Consortium (both in 2009), they drafted the concept of a front-line trial testing CEOP-P.

“We decided to use [CEOP] as a backbone because there were reservations about anthracyclines having a role in PTCL, and there was data . . . in patients [with B-cell lymphomas] who were not anthracycline-eligible and did reasonably well when etoposide was substituted [for hydroxydaunorubicin],” Dr Advani said.

As for for the second “P” in CEOP-P, pralatrexate was the first drug approved for patients with relapsed PTCL, which provided the rationale for evaluating it in the front-line setting.

Execution and results

The primary aim of this study was to improve the CR rate from 40% to 60% with CEOP-P followed by optional transplant. A literature review had revealed that CRs with CHOP have been in the range of 40% to 50%.

The researchers enrolled a total of 34 patients, but 1 withdrew consent. Twenty-seven patients received at least 2 cycles of CEOP-P. Of the 6 patients who received a single cycle, 4 discontinued treatment due to early disease progression, and 2 discontinued because of adverse events.

Grade 3-4 adverse events associated with CEOP-P included anemia, thrombocytopenia, febrile neutropenia, mucositis, sepsis, increased creatinine, and liver transaminases.

The researchers had used a 2-stage Simon design (alpha=0.10, 90% power) to test the null hypothesis that the CR rate would be 40% or greater.

For the first stage of 20 evaluable patients, the trial would be terminated if 8 or fewer patients experienced a CR after course 2B of chemotherapy. For the second stage, 34 patients were required, and at least 17 had to achieve a CR at the end of therapy for the regimen to be considered useful.

At the end of stage 1, 50% of the patients (10/20) had achieved a CR. Ultimately, 52% of all patients (n=17) achieved a CR.

This suggests CEOP-P is a useful regimen, according to the study design. But the primary aim of improving CR from 40% to 60% was not met.

Furthermore, the estimated 1-year and 2-year progression-free survival rates were “not particularly encouraging,” according to Dr Advani. The rates were 50% and 34%, respectively. And the estimated 1-year and 2-year overall survival rate was 64%.

“So this was a lesson in working together and getting a trial from ground zero, to up and running, to a presentation, and publication underway,” Dr Advani said.

“And even though it took in all the ingredients of what everybody thought was important . . . , it’s not a regimen which has that much promise to move to a randomized setting. And so defining the optimal front-line therapy in PTCL continues to be a challenge and an unmet need.”

Now, the North American PTCL Consortium is working on a second front-line trial testing cyclophosphamide, hydroxydaunorubicin, vincristine, etoposide, and prednisone (CHOEP) plus lenalidomide in stage II, III, and IV PTCL. The final protocol has been circulated, and the group anticipates the first patient will be enrolled by June or July of this year.

Dr Advani and her colleagues also presented results of the CEOP-P trial at the 2013 ASH Annual Meeting as abstract 3044. (Information in the abstract differs from that presented at the T-cell Lymphoma Forum.)

SAN FRANCISCO—A group’s effort to identify optimal front-line treatment for peripheral T-cell lymphomas (PTCLs) was not as successful as researchers anticipated.

The North American PTCL Consortium set out to find a treatment that could best CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), as studies have suggested this regimen is inadequate for patients with PTCL.

So the group organized a trial testing

a potentially more promising regimen: cyclophosphamide, etoposide, vincristine, and prednisone, alternating with pralatrexate (CEOP-P).

However, CEOP-P elicited a complete response (CR) rate comparable to rates historically seen with CHOP, and progression-free survival rates with the new regimen were “not particularly encouraging.”

Ranjana Advani, MD, of Stanford University Medical Center in California, discussed this trial’s inception, execution, and results at the 6th Annual T-cell Lymphoma Forum.

Trial inception

It all began with the first meeting of the North American PTCL Consortium, which took place at the 2006 ASH Annual Meeting. Physicians from 17 centers gathered to discuss the state of PTCL research in North America.

The group realized there were too many open studies for such a rare disease, and efforts should be more focused. However, they could not agree publicly as to which studies should get priority, so they used an anonymous survey to obtain a consensus.

Survey responses were “all over the map,” Dr Advani said. But ultimately, the consensus was that ongoing trials were not sufficient, and a new trial was necessary.

The group decided to first lend their support to ongoing trials and then launch a new study. At the fourth and fifth meetings of the North American PTCL Consortium (both in 2009), they drafted the concept of a front-line trial testing CEOP-P.

“We decided to use [CEOP] as a backbone because there were reservations about anthracyclines having a role in PTCL, and there was data . . . in patients [with B-cell lymphomas] who were not anthracycline-eligible and did reasonably well when etoposide was substituted [for hydroxydaunorubicin],” Dr Advani said.

As for for the second “P” in CEOP-P, pralatrexate was the first drug approved for patients with relapsed PTCL, which provided the rationale for evaluating it in the front-line setting.

Execution and results

The primary aim of this study was to improve the CR rate from 40% to 60% with CEOP-P followed by optional transplant. A literature review had revealed that CRs with CHOP have been in the range of 40% to 50%.

The researchers enrolled a total of 34 patients, but 1 withdrew consent. Twenty-seven patients received at least 2 cycles of CEOP-P. Of the 6 patients who received a single cycle, 4 discontinued treatment due to early disease progression, and 2 discontinued because of adverse events.

Grade 3-4 adverse events associated with CEOP-P included anemia, thrombocytopenia, febrile neutropenia, mucositis, sepsis, increased creatinine, and liver transaminases.

The researchers had used a 2-stage Simon design (alpha=0.10, 90% power) to test the null hypothesis that the CR rate would be 40% or greater.

For the first stage of 20 evaluable patients, the trial would be terminated if 8 or fewer patients experienced a CR after course 2B of chemotherapy. For the second stage, 34 patients were required, and at least 17 had to achieve a CR at the end of therapy for the regimen to be considered useful.

At the end of stage 1, 50% of the patients (10/20) had achieved a CR. Ultimately, 52% of all patients (n=17) achieved a CR.

This suggests CEOP-P is a useful regimen, according to the study design. But the primary aim of improving CR from 40% to 60% was not met.

Furthermore, the estimated 1-year and 2-year progression-free survival rates were “not particularly encouraging,” according to Dr Advani. The rates were 50% and 34%, respectively. And the estimated 1-year and 2-year overall survival rate was 64%.

“So this was a lesson in working together and getting a trial from ground zero, to up and running, to a presentation, and publication underway,” Dr Advani said.

“And even though it took in all the ingredients of what everybody thought was important . . . , it’s not a regimen which has that much promise to move to a randomized setting. And so defining the optimal front-line therapy in PTCL continues to be a challenge and an unmet need.”

Now, the North American PTCL Consortium is working on a second front-line trial testing cyclophosphamide, hydroxydaunorubicin, vincristine, etoposide, and prednisone (CHOEP) plus lenalidomide in stage II, III, and IV PTCL. The final protocol has been circulated, and the group anticipates the first patient will be enrolled by June or July of this year.

Dr Advani and her colleagues also presented results of the CEOP-P trial at the 2013 ASH Annual Meeting as abstract 3044. (Information in the abstract differs from that presented at the T-cell Lymphoma Forum.)

SAN FRANCISCO—A group’s effort to identify optimal front-line treatment for peripheral T-cell lymphomas (PTCLs) was not as successful as researchers anticipated.

The North American PTCL Consortium set out to find a treatment that could best CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), as studies have suggested this regimen is inadequate for patients with PTCL.

So the group organized a trial testing

a potentially more promising regimen: cyclophosphamide, etoposide, vincristine, and prednisone, alternating with pralatrexate (CEOP-P).

However, CEOP-P elicited a complete response (CR) rate comparable to rates historically seen with CHOP, and progression-free survival rates with the new regimen were “not particularly encouraging.”

Ranjana Advani, MD, of Stanford University Medical Center in California, discussed this trial’s inception, execution, and results at the 6th Annual T-cell Lymphoma Forum.

Trial inception

It all began with the first meeting of the North American PTCL Consortium, which took place at the 2006 ASH Annual Meeting. Physicians from 17 centers gathered to discuss the state of PTCL research in North America.

The group realized there were too many open studies for such a rare disease, and efforts should be more focused. However, they could not agree publicly as to which studies should get priority, so they used an anonymous survey to obtain a consensus.

Survey responses were “all over the map,” Dr Advani said. But ultimately, the consensus was that ongoing trials were not sufficient, and a new trial was necessary.

The group decided to first lend their support to ongoing trials and then launch a new study. At the fourth and fifth meetings of the North American PTCL Consortium (both in 2009), they drafted the concept of a front-line trial testing CEOP-P.

“We decided to use [CEOP] as a backbone because there were reservations about anthracyclines having a role in PTCL, and there was data . . . in patients [with B-cell lymphomas] who were not anthracycline-eligible and did reasonably well when etoposide was substituted [for hydroxydaunorubicin],” Dr Advani said.

As for for the second “P” in CEOP-P, pralatrexate was the first drug approved for patients with relapsed PTCL, which provided the rationale for evaluating it in the front-line setting.

Execution and results

The primary aim of this study was to improve the CR rate from 40% to 60% with CEOP-P followed by optional transplant. A literature review had revealed that CRs with CHOP have been in the range of 40% to 50%.

The researchers enrolled a total of 34 patients, but 1 withdrew consent. Twenty-seven patients received at least 2 cycles of CEOP-P. Of the 6 patients who received a single cycle, 4 discontinued treatment due to early disease progression, and 2 discontinued because of adverse events.

Grade 3-4 adverse events associated with CEOP-P included anemia, thrombocytopenia, febrile neutropenia, mucositis, sepsis, increased creatinine, and liver transaminases.

The researchers had used a 2-stage Simon design (alpha=0.10, 90% power) to test the null hypothesis that the CR rate would be 40% or greater.

For the first stage of 20 evaluable patients, the trial would be terminated if 8 or fewer patients experienced a CR after course 2B of chemotherapy. For the second stage, 34 patients were required, and at least 17 had to achieve a CR at the end of therapy for the regimen to be considered useful.

At the end of stage 1, 50% of the patients (10/20) had achieved a CR. Ultimately, 52% of all patients (n=17) achieved a CR.

This suggests CEOP-P is a useful regimen, according to the study design. But the primary aim of improving CR from 40% to 60% was not met.

Furthermore, the estimated 1-year and 2-year progression-free survival rates were “not particularly encouraging,” according to Dr Advani. The rates were 50% and 34%, respectively. And the estimated 1-year and 2-year overall survival rate was 64%.

“So this was a lesson in working together and getting a trial from ground zero, to up and running, to a presentation, and publication underway,” Dr Advani said.

“And even though it took in all the ingredients of what everybody thought was important . . . , it’s not a regimen which has that much promise to move to a randomized setting. And so defining the optimal front-line therapy in PTCL continues to be a challenge and an unmet need.”

Now, the North American PTCL Consortium is working on a second front-line trial testing cyclophosphamide, hydroxydaunorubicin, vincristine, etoposide, and prednisone (CHOEP) plus lenalidomide in stage II, III, and IV PTCL. The final protocol has been circulated, and the group anticipates the first patient will be enrolled by June or July of this year.

Dr Advani and her colleagues also presented results of the CEOP-P trial at the 2013 ASH Annual Meeting as abstract 3044. (Information in the abstract differs from that presented at the T-cell Lymphoma Forum.)

SAN FRANCISCO—Results of a single-center study suggest that a 3-drug regimen may be a safe and effective treatment option for patients with newly diagnosed or relapsed/refractory extranodal natural killer/T-cell lymphoma (ENKTL).

The combination of pegaspargase, gemcitabine, and oxaliplatin (P-Gemox) elicited a high rate of response in this cohort of 60 Chinese patients.

P-Gemox also produced higher survival rates than those previously observed with the EPOCH regimen.

Grade 1/2 myelosuppression occurred in more than half of patients in this study, and nearly three-quarters of patients experienced grade 1/2 nausea. But grade 3/4 adverse events were minimal.

Hui-qiang Huang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented these results at the 6th Annual T-cell Lymphoma Forum.

Dr Huang noted that advanced ENKTL is relatively resistant to anthracycline-based chemotherapy. And although the SMILE and AspaMetDex regimens are effective, they confer relatively severe toxicities and are inconvenient to administer.

“So chemotherapeutic combinations with high efficacy and low toxicities are urgently needed,” he said.

With this in mind, he and his colleagues assessed P-Gemox in 61 patients with ENKTL. Thirty-six patients were newly diagnosed, and 25 had relapsed/refractory disease. Roughly 69% of patients were male, and about 86% were older than 60 years of age.

Overall, 36.1% of patients had stage IE disease, 31.1% had stage IIE, 4.9% had stage IIIE, and 27.9% had stage IVE.

The relapsed/refractory patients had received a range of prior treatment regimens, including CHOP/L-ASP+CHOP, EPOCH, V-EPOCH, ICE, IMVP-16, and SMILE. And 13 patients had received radiotherapy.

For this study, all 61 patients received intravenous gemcitabine at 1000 mg/m² on days 1 and 8, intravenous oxaliplatin at 130 mg/m² on day 1, and intramuscular pegaspargase at 2500 U/m² on day 1. This regimen was repeated every 3 weeks.

Patients with stage IE/IIE disease received 3 cycles followed by radiotherapy (50-56 Gy). Relapsed/refractory patients received 2 to 6 cycles, and those who responded well were recommended for autologous transplant.

Response and subsequent treatment

Sixty patients were evaluable for response. (One patient in the newly diagnosed group was not evaluable).

The overall response rate (ORR) was 90%, with 63.3% of patients achieving a complete response (CR), 26.7% achieving a partial response (PR), and 8.3% maintaining stable disease (SD).

Among newly diagnosed patients, the ORR was 94.3%. CRs occurred in 74.3% of patients, PRs in in 20%, and SD in 5.7%.

And among the relapsed/refractory patients, the ORR was 84%. CRs were seen in 48% of patients, PRs in 36%, and SD in 12%.

“For patients with early stage disease, we found P-Gemox can further improve the outcomes of radiotherapy,” Dr Huang noted.

The treatment also provided a good bridge to transplant. Eight patients underwent transplant after achieving CR. One of these patients died 9 months after the procedure, but the other 7 patients were still in CR at a median of 14.6 months (range, 4.8-19.7 months).

‘Encouraging’ survival

The median follow-up was 29.5 months. The researchers confirmed progressive disease in 18 of the 61 patients—7 in the newly diagnosed group and 11 in the relapsed/refractory group.

Nine patients died of disease progression—1 in the newly diagnosed group and 8 in the relapsed/refractory group.

The 2-year overall survival was 86%, and the 2-year progression-free survival was 75.6%. Both overall and progression-free survival were superior in the newly diagnosed patients (P=0.054 and P=0.004, respectively).

“For the relapsed/refractory cases, considering they had already received a lot of previous treatments, we thought this outcome with P-Gemox is still quite encouraging,” Dr Huang said.

When the researchers compared overall survival with P-Gemox to previous results observed with EPOCH in newly diagnosed ENKTL patients (Huang et al, Leuk & Lymph 2011), they found P-Gemox was superior.

‘Tolerable’ toxicity

Toxicity with P-Gemox was tolerable and manageable, according to Dr Huang. The main adverse events were nausea and myelosuppression. But the rate of grade 3/4 events was low, and there were no treatment-related deaths.

Specifically, the grade 1/2 adverse events included nausea (73.8%), neutropenia (58%), thrombocytopenia (52.4%), hypoprotinemia (52.4%), anemia (52.4%), vomiting (49.2%), prolonged APTT (44.2%), elevated transaminase (34.1%), elevated bilirubin (27.9%), mucositis (24.5%), decreased fibrinogen (23%), elevated BUN (4.9%), intracranial bleeding (1.6%), stomach bleeding (1.6%), pancreatitis (1.6%), and herpes (1.6%).

Grade 3/4 adverse events included neutropenia (19.7%), thrombocytopenia (16.4%), hypoprotinemia (1.6%), anemia (1.6%), vomiting (3.2%), elevated transaminase (1.6%), and decreased fibrinogen (1.6%).

“We found that P-Gemox is an effective, safe, and convenient regimen in Chinese patients with ENKTL, both treatment-naïve and relapsed/refractory,” Dr Huang concluded. “These results provide a basis for subsequent studies.”

Dr Huang and his colleagues also presented the results of this research at the ASH Annual Meeting in December as abstract 642. (Information presented at the T-cell Lymphoma Forum differs from that in the ASH abstract).

SAN FRANCISCO—Results of a single-center study suggest that a 3-drug regimen may be a safe and effective treatment option for patients with newly diagnosed or relapsed/refractory extranodal natural killer/T-cell lymphoma (ENKTL).

The combination of pegaspargase, gemcitabine, and oxaliplatin (P-Gemox) elicited a high rate of response in this cohort of 60 Chinese patients.

P-Gemox also produced higher survival rates than those previously observed with the EPOCH regimen.

Grade 1/2 myelosuppression occurred in more than half of patients in this study, and nearly three-quarters of patients experienced grade 1/2 nausea. But grade 3/4 adverse events were minimal.

Hui-qiang Huang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented these results at the 6th Annual T-cell Lymphoma Forum.

Dr Huang noted that advanced ENKTL is relatively resistant to anthracycline-based chemotherapy. And although the SMILE and AspaMetDex regimens are effective, they confer relatively severe toxicities and are inconvenient to administer.

“So chemotherapeutic combinations with high efficacy and low toxicities are urgently needed,” he said.

With this in mind, he and his colleagues assessed P-Gemox in 61 patients with ENKTL. Thirty-six patients were newly diagnosed, and 25 had relapsed/refractory disease. Roughly 69% of patients were male, and about 86% were older than 60 years of age.

Overall, 36.1% of patients had stage IE disease, 31.1% had stage IIE, 4.9% had stage IIIE, and 27.9% had stage IVE.

The relapsed/refractory patients had received a range of prior treatment regimens, including CHOP/L-ASP+CHOP, EPOCH, V-EPOCH, ICE, IMVP-16, and SMILE. And 13 patients had received radiotherapy.

For this study, all 61 patients received intravenous gemcitabine at 1000 mg/m² on days 1 and 8, intravenous oxaliplatin at 130 mg/m² on day 1, and intramuscular pegaspargase at 2500 U/m² on day 1. This regimen was repeated every 3 weeks.

Patients with stage IE/IIE disease received 3 cycles followed by radiotherapy (50-56 Gy). Relapsed/refractory patients received 2 to 6 cycles, and those who responded well were recommended for autologous transplant.

Response and subsequent treatment

Sixty patients were evaluable for response. (One patient in the newly diagnosed group was not evaluable).

The overall response rate (ORR) was 90%, with 63.3% of patients achieving a complete response (CR), 26.7% achieving a partial response (PR), and 8.3% maintaining stable disease (SD).

Among newly diagnosed patients, the ORR was 94.3%. CRs occurred in 74.3% of patients, PRs in in 20%, and SD in 5.7%.

And among the relapsed/refractory patients, the ORR was 84%. CRs were seen in 48% of patients, PRs in 36%, and SD in 12%.

“For patients with early stage disease, we found P-Gemox can further improve the outcomes of radiotherapy,” Dr Huang noted.

The treatment also provided a good bridge to transplant. Eight patients underwent transplant after achieving CR. One of these patients died 9 months after the procedure, but the other 7 patients were still in CR at a median of 14.6 months (range, 4.8-19.7 months).

‘Encouraging’ survival

The median follow-up was 29.5 months. The researchers confirmed progressive disease in 18 of the 61 patients—7 in the newly diagnosed group and 11 in the relapsed/refractory group.

Nine patients died of disease progression—1 in the newly diagnosed group and 8 in the relapsed/refractory group.

The 2-year overall survival was 86%, and the 2-year progression-free survival was 75.6%. Both overall and progression-free survival were superior in the newly diagnosed patients (P=0.054 and P=0.004, respectively).

“For the relapsed/refractory cases, considering they had already received a lot of previous treatments, we thought this outcome with P-Gemox is still quite encouraging,” Dr Huang said.

When the researchers compared overall survival with P-Gemox to previous results observed with EPOCH in newly diagnosed ENKTL patients (Huang et al, Leuk & Lymph 2011), they found P-Gemox was superior.

‘Tolerable’ toxicity

Toxicity with P-Gemox was tolerable and manageable, according to Dr Huang. The main adverse events were nausea and myelosuppression. But the rate of grade 3/4 events was low, and there were no treatment-related deaths.

Specifically, the grade 1/2 adverse events included nausea (73.8%), neutropenia (58%), thrombocytopenia (52.4%), hypoprotinemia (52.4%), anemia (52.4%), vomiting (49.2%), prolonged APTT (44.2%), elevated transaminase (34.1%), elevated bilirubin (27.9%), mucositis (24.5%), decreased fibrinogen (23%), elevated BUN (4.9%), intracranial bleeding (1.6%), stomach bleeding (1.6%), pancreatitis (1.6%), and herpes (1.6%).

Grade 3/4 adverse events included neutropenia (19.7%), thrombocytopenia (16.4%), hypoprotinemia (1.6%), anemia (1.6%), vomiting (3.2%), elevated transaminase (1.6%), and decreased fibrinogen (1.6%).

“We found that P-Gemox is an effective, safe, and convenient regimen in Chinese patients with ENKTL, both treatment-naïve and relapsed/refractory,” Dr Huang concluded. “These results provide a basis for subsequent studies.”

Dr Huang and his colleagues also presented the results of this research at the ASH Annual Meeting in December as abstract 642. (Information presented at the T-cell Lymphoma Forum differs from that in the ASH abstract).

SAN FRANCISCO—Results of a single-center study suggest that a 3-drug regimen may be a safe and effective treatment option for patients with newly diagnosed or relapsed/refractory extranodal natural killer/T-cell lymphoma (ENKTL).

The combination of pegaspargase, gemcitabine, and oxaliplatin (P-Gemox) elicited a high rate of response in this cohort of 60 Chinese patients.

P-Gemox also produced higher survival rates than those previously observed with the EPOCH regimen.

Grade 1/2 myelosuppression occurred in more than half of patients in this study, and nearly three-quarters of patients experienced grade 1/2 nausea. But grade 3/4 adverse events were minimal.

Hui-qiang Huang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented these results at the 6th Annual T-cell Lymphoma Forum.

Dr Huang noted that advanced ENKTL is relatively resistant to anthracycline-based chemotherapy. And although the SMILE and AspaMetDex regimens are effective, they confer relatively severe toxicities and are inconvenient to administer.

“So chemotherapeutic combinations with high efficacy and low toxicities are urgently needed,” he said.

With this in mind, he and his colleagues assessed P-Gemox in 61 patients with ENKTL. Thirty-six patients were newly diagnosed, and 25 had relapsed/refractory disease. Roughly 69% of patients were male, and about 86% were older than 60 years of age.

Overall, 36.1% of patients had stage IE disease, 31.1% had stage IIE, 4.9% had stage IIIE, and 27.9% had stage IVE.

The relapsed/refractory patients had received a range of prior treatment regimens, including CHOP/L-ASP+CHOP, EPOCH, V-EPOCH, ICE, IMVP-16, and SMILE. And 13 patients had received radiotherapy.

For this study, all 61 patients received intravenous gemcitabine at 1000 mg/m² on days 1 and 8, intravenous oxaliplatin at 130 mg/m² on day 1, and intramuscular pegaspargase at 2500 U/m² on day 1. This regimen was repeated every 3 weeks.

Patients with stage IE/IIE disease received 3 cycles followed by radiotherapy (50-56 Gy). Relapsed/refractory patients received 2 to 6 cycles, and those who responded well were recommended for autologous transplant.

Response and subsequent treatment

Sixty patients were evaluable for response. (One patient in the newly diagnosed group was not evaluable).

The overall response rate (ORR) was 90%, with 63.3% of patients achieving a complete response (CR), 26.7% achieving a partial response (PR), and 8.3% maintaining stable disease (SD).

Among newly diagnosed patients, the ORR was 94.3%. CRs occurred in 74.3% of patients, PRs in in 20%, and SD in 5.7%.

And among the relapsed/refractory patients, the ORR was 84%. CRs were seen in 48% of patients, PRs in 36%, and SD in 12%.

“For patients with early stage disease, we found P-Gemox can further improve the outcomes of radiotherapy,” Dr Huang noted.

The treatment also provided a good bridge to transplant. Eight patients underwent transplant after achieving CR. One of these patients died 9 months after the procedure, but the other 7 patients were still in CR at a median of 14.6 months (range, 4.8-19.7 months).

‘Encouraging’ survival

The median follow-up was 29.5 months. The researchers confirmed progressive disease in 18 of the 61 patients—7 in the newly diagnosed group and 11 in the relapsed/refractory group.

Nine patients died of disease progression—1 in the newly diagnosed group and 8 in the relapsed/refractory group.

The 2-year overall survival was 86%, and the 2-year progression-free survival was 75.6%. Both overall and progression-free survival were superior in the newly diagnosed patients (P=0.054 and P=0.004, respectively).

“For the relapsed/refractory cases, considering they had already received a lot of previous treatments, we thought this outcome with P-Gemox is still quite encouraging,” Dr Huang said.

When the researchers compared overall survival with P-Gemox to previous results observed with EPOCH in newly diagnosed ENKTL patients (Huang et al, Leuk & Lymph 2011), they found P-Gemox was superior.

‘Tolerable’ toxicity

Toxicity with P-Gemox was tolerable and manageable, according to Dr Huang. The main adverse events were nausea and myelosuppression. But the rate of grade 3/4 events was low, and there were no treatment-related deaths.

Specifically, the grade 1/2 adverse events included nausea (73.8%), neutropenia (58%), thrombocytopenia (52.4%), hypoprotinemia (52.4%), anemia (52.4%), vomiting (49.2%), prolonged APTT (44.2%), elevated transaminase (34.1%), elevated bilirubin (27.9%), mucositis (24.5%), decreased fibrinogen (23%), elevated BUN (4.9%), intracranial bleeding (1.6%), stomach bleeding (1.6%), pancreatitis (1.6%), and herpes (1.6%).

Grade 3/4 adverse events included neutropenia (19.7%), thrombocytopenia (16.4%), hypoprotinemia (1.6%), anemia (1.6%), vomiting (3.2%), elevated transaminase (1.6%), and decreased fibrinogen (1.6%).

“We found that P-Gemox is an effective, safe, and convenient regimen in Chinese patients with ENKTL, both treatment-naïve and relapsed/refractory,” Dr Huang concluded. “These results provide a basis for subsequent studies.”

Dr Huang and his colleagues also presented the results of this research at the ASH Annual Meeting in December as abstract 642. (Information presented at the T-cell Lymphoma Forum differs from that in the ASH abstract).

SAN FRANCISCO—Researchers have found evidence to suggest that tumor necrosis factor receptor II (TNFRII) may be an important driver of cutaneous T-cell lymphomas (CTCLs).

The team discovered that a mutation in this receptor—TNFRII T377I—is present in patients with mycosis fungoides (MF) and those with Sézary syndrome (SS).

And previous research showed that the region encoding TNFRII on chromosome 1 is sometimes amplified in MF and SS patients.

So if, as these factors suggest, TNFRII does play a key role in CTCL, a number of currently available drugs—including proteasome inhibitors and MEK inhibitors—may be effective treatment options.

Alexander Ungewickell, MD, PhD, of Stanford University in California, discussed this possibility and the research supporting it at the 6th Annual T-cell Lymphoma Forum.

A novel mutation

Dr Ungewickell and his colleagues began this research by conducting transcriptome sequencing on samples from 3 patients with SS (Lee et al, Blood 2012). This revealed about 500 genes that were upregulated and about 500 that were downregulated in SS cells.

And pathway enrichment analysis showed that molecular mechanisms of cancer were the most significantly altered pathways. But the researchers also observed PI3 kinase signaling, T-cell receptor signaling, regulation of IL-2, and CD8 signaling.

To better understand the basis for these transcriptional changes, the team performed whole-exome sequencing in 11 CTCL-normal pairs. They uncovered an average of 46 mutations per exome, as well as pathways similar to those observed in the transcriptional analysis.

The researchers then used this information to generate a 245-gene capture reagent. And they used that to perform ultra-deep targeted resequencing on 83 samples from CTCL patients.

“Two things that stood out right away were that TNFRSF1B and KRAS had recurrent point mutations that suggested an activating phenotype,” Dr Ungewickell said. “It’s already known that KRAS is mutated in many human cancers, including CTCL. TNFRSF1B encodes TNFRII and was not previously associated with any malignancies.”

“We also found a smattering of other genes that were mutated, [but] we were most interested in the TNFRII mutation because of the novelty of the finding and also the potential for therapeutic intervention.”

Driving disease

Dr Ungewickell noted that TNFRII is expressed in CD4 and CD8 T lymphocytes but relatively few other cell types. TNFRII is activated by membrane-bound TNFα, which mediates the signal through TRAF proteins and CIAP proteins to activate the NF-κB-inducing kinase (NIK).

This activates the I kappa B kinase (IKK) complex to phosphorylate p100. When phosphorylated, it is processed in the proteasome and translocates to the nucleus. There, it interacts with RelB to mediate transcription that tends to cause T-cell activation and proliferation.

TNFRII also binds to TRAF2 and induces its degradation. The recurrent mutation the researchers identified in TNFRII (T377I) is in the TRAF2 regulatory domain in an evolutionarily conserved residue.

The ultra-deep targeted resequencing of 83 CTCL samples showed 4 mutations at that locus, all of which were acquired in the lymphoma.

This suggests TNFRII is important in CTCL. And the researchers hypothesized that, if that’s the case, TNFRII might be overexpressed in SS cells. So they looked at their transcriptome data and found TNFRII to be overexpressed in all 3 patients.

“Interestingly, the region that encodes TNFRII on chromosome 1 is also amplified in 1 of the 4 commonly used CTCL cell lines, suggesting that amplification may be another way of activating this pathway,” Dr Ungewickell said.

“And we were very interested by a study published by van Doorn et al a few years ago [Blood 2009], which showed that that region of chromosome 1 p36 is, in fact, amplified in 45% of cases of MF and 15% of cases of Sézary syndrome.”

“So we are currently doing FISH studies to confirm that this receptor is actually amplified in as many as half of cases of MF, suggesting that maybe, between mutation and amplification, this is an important driver of CTCL.”

Therapeutic possibilities

The researchers also thought that, if TNFRII is an important driver of CTCL, there would be some kind of transcriptional mark on the lymphoma cells. So they performed gene set enrichment analyses on 24 CTCL samples that had undergone 3-seq.

By comparing tumors expressing high levels of TNFRII and those expressing low levels of TNFRII, the team identified an expression signature that corresponds to the receptor’s known effects on RNA levels in T cells.

When they searched publicly available datasets, the researchers found this signature in 63 cases of MF (Shin et al, Blood 2007). And results of control experiments suggested the signature is specific to CTCL.

“If TNFRII is more active [in CTCL] and the mutation that we found is a hyperactivating mutation, we would expect this pathway to show increased activity downstream; namely, you would expect more processing of p100 to p52,” Dr Ungewickell said.

To investigate this possibility, the researchers generated Jurkat cells expressing empty vector, wild-type TNFRII, or mutant TNFRII and looked at NF-κB processing. They did see an increase in processing with the mutant receptor, compared to the wild-type receptor or empty vector.

“We also found, somewhat surprisingly, increases in phospho-ERK with the mutant receptor, as well as phospho-MEK,” Dr Ungewickell said.

“And to our knowledge, the RAS/MAP kinase pathway has not previously been linked to TNFRII signaling, suggesting that there is some kind of direct or indirect cross-talk between these pathways. We think it’s very interesting, since there are KRAS mutations that activate the RAS/MAP kinase pathway in a subset of these cases, suggesting some kind of synergy.”

Introducing the mutant receptor into primary CD4+ T cells had an effect similar to that observed in the Jurkat cells. The researchers did western blotting for NF-kB processing, and they saw an increase in p100 to p52 processing.

“This is a preliminary experiment, but we’re actually quite excited about this, since Jurkat cells have many abnormalities, due to the fact that they’re a leukemia line, and primary T cells will have the rest of the genome intact,” Dr Ungewickell said.

Now, he and his colleagues are conducting several studies to identify the changes that occur in primary T cells when mutant TNFRII is expressed. They also want to see if they can recapitulate CTCL and identify the transcriptional signature they previously found in patient biopsies and cells.

Lastly, the researchers are performing functional assays to evaluate proliferation, apoptosis, and pharmacological information, with the goal of identifying therapies that might be effective in patients with TNFRII mutation or amplification.

“Patients who have increased TNFRII signaling might respond to proteasome inhibitors, since p100 and p52 processing requires the proteasome,” Dr Ungewickell said. “And given that cross-talk with the RAS/MAP kinase signaling, as well as the KRAS mutations, we also think . . . that MEK inhibitors might be effective in the treatment of CTCL.”

SAN FRANCISCO—Researchers have found evidence to suggest that tumor necrosis factor receptor II (TNFRII) may be an important driver of cutaneous T-cell lymphomas (CTCLs).

The team discovered that a mutation in this receptor—TNFRII T377I—is present in patients with mycosis fungoides (MF) and those with Sézary syndrome (SS).

And previous research showed that the region encoding TNFRII on chromosome 1 is sometimes amplified in MF and SS patients.

So if, as these factors suggest, TNFRII does play a key role in CTCL, a number of currently available drugs—including proteasome inhibitors and MEK inhibitors—may be effective treatment options.

Alexander Ungewickell, MD, PhD, of Stanford University in California, discussed this possibility and the research supporting it at the 6th Annual T-cell Lymphoma Forum.

A novel mutation

Dr Ungewickell and his colleagues began this research by conducting transcriptome sequencing on samples from 3 patients with SS (Lee et al, Blood 2012). This revealed about 500 genes that were upregulated and about 500 that were downregulated in SS cells.

And pathway enrichment analysis showed that molecular mechanisms of cancer were the most significantly altered pathways. But the researchers also observed PI3 kinase signaling, T-cell receptor signaling, regulation of IL-2, and CD8 signaling.

To better understand the basis for these transcriptional changes, the team performed whole-exome sequencing in 11 CTCL-normal pairs. They uncovered an average of 46 mutations per exome, as well as pathways similar to those observed in the transcriptional analysis.

The researchers then used this information to generate a 245-gene capture reagent. And they used that to perform ultra-deep targeted resequencing on 83 samples from CTCL patients.

“Two things that stood out right away were that TNFRSF1B and KRAS had recurrent point mutations that suggested an activating phenotype,” Dr Ungewickell said. “It’s already known that KRAS is mutated in many human cancers, including CTCL. TNFRSF1B encodes TNFRII and was not previously associated with any malignancies.”

“We also found a smattering of other genes that were mutated, [but] we were most interested in the TNFRII mutation because of the novelty of the finding and also the potential for therapeutic intervention.”

Driving disease

Dr Ungewickell noted that TNFRII is expressed in CD4 and CD8 T lymphocytes but relatively few other cell types. TNFRII is activated by membrane-bound TNFα, which mediates the signal through TRAF proteins and CIAP proteins to activate the NF-κB-inducing kinase (NIK).

This activates the I kappa B kinase (IKK) complex to phosphorylate p100. When phosphorylated, it is processed in the proteasome and translocates to the nucleus. There, it interacts with RelB to mediate transcription that tends to cause T-cell activation and proliferation.

TNFRII also binds to TRAF2 and induces its degradation. The recurrent mutation the researchers identified in TNFRII (T377I) is in the TRAF2 regulatory domain in an evolutionarily conserved residue.

The ultra-deep targeted resequencing of 83 CTCL samples showed 4 mutations at that locus, all of which were acquired in the lymphoma.

This suggests TNFRII is important in CTCL. And the researchers hypothesized that, if that’s the case, TNFRII might be overexpressed in SS cells. So they looked at their transcriptome data and found TNFRII to be overexpressed in all 3 patients.

“Interestingly, the region that encodes TNFRII on chromosome 1 is also amplified in 1 of the 4 commonly used CTCL cell lines, suggesting that amplification may be another way of activating this pathway,” Dr Ungewickell said.

“And we were very interested by a study published by van Doorn et al a few years ago [Blood 2009], which showed that that region of chromosome 1 p36 is, in fact, amplified in 45% of cases of MF and 15% of cases of Sézary syndrome.”

“So we are currently doing FISH studies to confirm that this receptor is actually amplified in as many as half of cases of MF, suggesting that maybe, between mutation and amplification, this is an important driver of CTCL.”

Therapeutic possibilities

The researchers also thought that, if TNFRII is an important driver of CTCL, there would be some kind of transcriptional mark on the lymphoma cells. So they performed gene set enrichment analyses on 24 CTCL samples that had undergone 3-seq.

By comparing tumors expressing high levels of TNFRII and those expressing low levels of TNFRII, the team identified an expression signature that corresponds to the receptor’s known effects on RNA levels in T cells.

When they searched publicly available datasets, the researchers found this signature in 63 cases of MF (Shin et al, Blood 2007). And results of control experiments suggested the signature is specific to CTCL.

“If TNFRII is more active [in CTCL] and the mutation that we found is a hyperactivating mutation, we would expect this pathway to show increased activity downstream; namely, you would expect more processing of p100 to p52,” Dr Ungewickell said.

To investigate this possibility, the researchers generated Jurkat cells expressing empty vector, wild-type TNFRII, or mutant TNFRII and looked at NF-κB processing. They did see an increase in processing with the mutant receptor, compared to the wild-type receptor or empty vector.

“We also found, somewhat surprisingly, increases in phospho-ERK with the mutant receptor, as well as phospho-MEK,” Dr Ungewickell said.

“And to our knowledge, the RAS/MAP kinase pathway has not previously been linked to TNFRII signaling, suggesting that there is some kind of direct or indirect cross-talk between these pathways. We think it’s very interesting, since there are KRAS mutations that activate the RAS/MAP kinase pathway in a subset of these cases, suggesting some kind of synergy.”

Introducing the mutant receptor into primary CD4+ T cells had an effect similar to that observed in the Jurkat cells. The researchers did western blotting for NF-kB processing, and they saw an increase in p100 to p52 processing.

“This is a preliminary experiment, but we’re actually quite excited about this, since Jurkat cells have many abnormalities, due to the fact that they’re a leukemia line, and primary T cells will have the rest of the genome intact,” Dr Ungewickell said.

Now, he and his colleagues are conducting several studies to identify the changes that occur in primary T cells when mutant TNFRII is expressed. They also want to see if they can recapitulate CTCL and identify the transcriptional signature they previously found in patient biopsies and cells.

Lastly, the researchers are performing functional assays to evaluate proliferation, apoptosis, and pharmacological information, with the goal of identifying therapies that might be effective in patients with TNFRII mutation or amplification.

“Patients who have increased TNFRII signaling might respond to proteasome inhibitors, since p100 and p52 processing requires the proteasome,” Dr Ungewickell said. “And given that cross-talk with the RAS/MAP kinase signaling, as well as the KRAS mutations, we also think . . . that MEK inhibitors might be effective in the treatment of CTCL.”

SAN FRANCISCO—Researchers have found evidence to suggest that tumor necrosis factor receptor II (TNFRII) may be an important driver of cutaneous T-cell lymphomas (CTCLs).

The team discovered that a mutation in this receptor—TNFRII T377I—is present in patients with mycosis fungoides (MF) and those with Sézary syndrome (SS).

And previous research showed that the region encoding TNFRII on chromosome 1 is sometimes amplified in MF and SS patients.

So if, as these factors suggest, TNFRII does play a key role in CTCL, a number of currently available drugs—including proteasome inhibitors and MEK inhibitors—may be effective treatment options.

Alexander Ungewickell, MD, PhD, of Stanford University in California, discussed this possibility and the research supporting it at the 6th Annual T-cell Lymphoma Forum.

A novel mutation

Dr Ungewickell and his colleagues began this research by conducting transcriptome sequencing on samples from 3 patients with SS (Lee et al, Blood 2012). This revealed about 500 genes that were upregulated and about 500 that were downregulated in SS cells.

And pathway enrichment analysis showed that molecular mechanisms of cancer were the most significantly altered pathways. But the researchers also observed PI3 kinase signaling, T-cell receptor signaling, regulation of IL-2, and CD8 signaling.

To better understand the basis for these transcriptional changes, the team performed whole-exome sequencing in 11 CTCL-normal pairs. They uncovered an average of 46 mutations per exome, as well as pathways similar to those observed in the transcriptional analysis.

The researchers then used this information to generate a 245-gene capture reagent. And they used that to perform ultra-deep targeted resequencing on 83 samples from CTCL patients.

“Two things that stood out right away were that TNFRSF1B and KRAS had recurrent point mutations that suggested an activating phenotype,” Dr Ungewickell said. “It’s already known that KRAS is mutated in many human cancers, including CTCL. TNFRSF1B encodes TNFRII and was not previously associated with any malignancies.”

“We also found a smattering of other genes that were mutated, [but] we were most interested in the TNFRII mutation because of the novelty of the finding and also the potential for therapeutic intervention.”

Driving disease

Dr Ungewickell noted that TNFRII is expressed in CD4 and CD8 T lymphocytes but relatively few other cell types. TNFRII is activated by membrane-bound TNFα, which mediates the signal through TRAF proteins and CIAP proteins to activate the NF-κB-inducing kinase (NIK).

This activates the I kappa B kinase (IKK) complex to phosphorylate p100. When phosphorylated, it is processed in the proteasome and translocates to the nucleus. There, it interacts with RelB to mediate transcription that tends to cause T-cell activation and proliferation.

TNFRII also binds to TRAF2 and induces its degradation. The recurrent mutation the researchers identified in TNFRII (T377I) is in the TRAF2 regulatory domain in an evolutionarily conserved residue.

The ultra-deep targeted resequencing of 83 CTCL samples showed 4 mutations at that locus, all of which were acquired in the lymphoma.

This suggests TNFRII is important in CTCL. And the researchers hypothesized that, if that’s the case, TNFRII might be overexpressed in SS cells. So they looked at their transcriptome data and found TNFRII to be overexpressed in all 3 patients.

“Interestingly, the region that encodes TNFRII on chromosome 1 is also amplified in 1 of the 4 commonly used CTCL cell lines, suggesting that amplification may be another way of activating this pathway,” Dr Ungewickell said.

“And we were very interested by a study published by van Doorn et al a few years ago [Blood 2009], which showed that that region of chromosome 1 p36 is, in fact, amplified in 45% of cases of MF and 15% of cases of Sézary syndrome.”

“So we are currently doing FISH studies to confirm that this receptor is actually amplified in as many as half of cases of MF, suggesting that maybe, between mutation and amplification, this is an important driver of CTCL.”

Therapeutic possibilities

The researchers also thought that, if TNFRII is an important driver of CTCL, there would be some kind of transcriptional mark on the lymphoma cells. So they performed gene set enrichment analyses on 24 CTCL samples that had undergone 3-seq.

By comparing tumors expressing high levels of TNFRII and those expressing low levels of TNFRII, the team identified an expression signature that corresponds to the receptor’s known effects on RNA levels in T cells.

When they searched publicly available datasets, the researchers found this signature in 63 cases of MF (Shin et al, Blood 2007). And results of control experiments suggested the signature is specific to CTCL.

“If TNFRII is more active [in CTCL] and the mutation that we found is a hyperactivating mutation, we would expect this pathway to show increased activity downstream; namely, you would expect more processing of p100 to p52,” Dr Ungewickell said.

To investigate this possibility, the researchers generated Jurkat cells expressing empty vector, wild-type TNFRII, or mutant TNFRII and looked at NF-κB processing. They did see an increase in processing with the mutant receptor, compared to the wild-type receptor or empty vector.

“We also found, somewhat surprisingly, increases in phospho-ERK with the mutant receptor, as well as phospho-MEK,” Dr Ungewickell said.

“And to our knowledge, the RAS/MAP kinase pathway has not previously been linked to TNFRII signaling, suggesting that there is some kind of direct or indirect cross-talk between these pathways. We think it’s very interesting, since there are KRAS mutations that activate the RAS/MAP kinase pathway in a subset of these cases, suggesting some kind of synergy.”

Introducing the mutant receptor into primary CD4+ T cells had an effect similar to that observed in the Jurkat cells. The researchers did western blotting for NF-kB processing, and they saw an increase in p100 to p52 processing.

“This is a preliminary experiment, but we’re actually quite excited about this, since Jurkat cells have many abnormalities, due to the fact that they’re a leukemia line, and primary T cells will have the rest of the genome intact,” Dr Ungewickell said.

Now, he and his colleagues are conducting several studies to identify the changes that occur in primary T cells when mutant TNFRII is expressed. They also want to see if they can recapitulate CTCL and identify the transcriptional signature they previously found in patient biopsies and cells.

Lastly, the researchers are performing functional assays to evaluate proliferation, apoptosis, and pharmacological information, with the goal of identifying therapies that might be effective in patients with TNFRII mutation or amplification.

“Patients who have increased TNFRII signaling might respond to proteasome inhibitors, since p100 and p52 processing requires the proteasome,” Dr Ungewickell said. “And given that cross-talk with the RAS/MAP kinase signaling, as well as the KRAS mutations, we also think . . . that MEK inhibitors might be effective in the treatment of CTCL.”

SAN FRANCISCO—Preliminary results of a phase 1 trial suggest the PI3K-delta/gamma inhibitor IPI-145 is active in patients with relapsed or refractory T-cell lymphomas.

Among 26 evaluable patients, 9 experienced partial responses to treatment with IPI-145, and 1 achieved a complete response, for an overall response rate (ORR) of 38%.

The drug also appeared to be well-tolerated, although 30% of patients did experience treatment-related severe adverse events.

Steven Horwitz, MD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues presented these results in a poster at the 6th Annual T-cell Lymphoma Forum, which took place January 23-25.

The study was sponsored by Infinity Pharmaceuticals, Inc., the company developing IPI-145.

Patient and treatment characteristics

The trial included 30 patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Of the 17 CTCL patients, 16 had mycosis fungoides or Sezary syndrome, and 1 had primary cutaneous anaplastic large-cell lymphoma (ALCL).

Of the 13 patients with PTCL, 3 had angioimmunoblastic T-cell lymphoma (AITL), 3 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL), 3 had PTCL-not otherwise specified, 2 had ALCL, 1 had enteropathy-associated T-cell lymphoma (EATL), and 1 had NK T-cell lymphoma (NKTL).

The patients had advanced disease, with a median of 5 prior systemic therapies (range, 1-11) and a median of 1 month from their last therapy to the first dose on study (range, 0.2-12).

Patients received IPI-145 in escalating doses, from 25 mg to 100 mg twice daily (n=10) and in an expansion cohort at 75 mg twice daily (n=20). All 30 patients were evaluable for the safety analysis, but only 26 were evaluable for clinical activity.

Response by disease type

The ORR for all 26 patients was 38% (1 complete and 9 partial responses).

Among the 11 evaluable PTCL patients, the ORR was 55%. One patient had a complete response, and 5 had partial responses.

Of the 15 evaluable CTCL patients, 4 had partial responses, for an ORR of 27%. In addition, 7 CTCL patients had stable disease.

The median time to response was 1.9 months (range, 1.5-2.7) for patients with PTCL and 2.4 months (range, 1.7-3.8) for patients with CTCL.

Four patients with PTCL and 3 patients with CTCL remain on treatment.

Adverse events 

IPI-145 was generally well-tolerated, according to the researchers.

The most common adverse events of any grade were an increases in ALT/AST (47%), fatigue (37%), pyrexia (33%), diarrhea (30%), cough (27%), headache (27%), nausea (27%), rash (23%), increases in alkaline phosphatase (20%), increases in blood creatinine (17%), and weight loss (17%).

Grade 3 side effects included increased ALT/AST (33%), rash (13%), and fatigue (10%). One patient (3%) had grade 4 ALT/AST increases.

Forty percent of patients had severe adverse events, and 30% were treatment-related. Among CTCL patients, the severe events included ALT/AST increases (n=1), pneumonitis (n=1), HSV pneumonitis (n=1), lung infection (n=1), pyrexia (n=1), and staphylococcal sepsis (n=1).

Among PTCL patients, severe events included diarrhea (n=2), pneumonia (n=2), vomiting (n=2), cellulitis (n=1), colitis (n=1), dehydration (n=1), hypotension (n=1), pneumonia cytomegaloviral (n=1), pyrexia (n=1), and rash (macular papular; n=1).

Six CTCL patients and 3 PTCL patients discontinued treatment due to adverse events.

Pharmacodynamics

The data showed that treatment with IPI-145 led to decreases in serum levels of cytokines and chemokines known to play important roles in lymphocyte trafficking and function.

The researchers said this further supports the rationale that inhibiting PI3K-delta and PI3K-gamma has the potential to provide a therapeutic benefit for T-cell lymphomas and other hematologic malignancies.

For more details on this research, see the poster on Infinity’s website: http://www.infi.com/product-candidates-publications.asp.

SAN FRANCISCO—Preliminary results of a phase 1 trial suggest the PI3K-delta/gamma inhibitor IPI-145 is active in patients with relapsed or refractory T-cell lymphomas.

Among 26 evaluable patients, 9 experienced partial responses to treatment with IPI-145, and 1 achieved a complete response, for an overall response rate (ORR) of 38%.

The drug also appeared to be well-tolerated, although 30% of patients did experience treatment-related severe adverse events.

Steven Horwitz, MD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues presented these results in a poster at the 6th Annual T-cell Lymphoma Forum, which took place January 23-25.

The study was sponsored by Infinity Pharmaceuticals, Inc., the company developing IPI-145.

Patient and treatment characteristics

The trial included 30 patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Of the 17 CTCL patients, 16 had mycosis fungoides or Sezary syndrome, and 1 had primary cutaneous anaplastic large-cell lymphoma (ALCL).

Of the 13 patients with PTCL, 3 had angioimmunoblastic T-cell lymphoma (AITL), 3 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL), 3 had PTCL-not otherwise specified, 2 had ALCL, 1 had enteropathy-associated T-cell lymphoma (EATL), and 1 had NK T-cell lymphoma (NKTL).

The patients had advanced disease, with a median of 5 prior systemic therapies (range, 1-11) and a median of 1 month from their last therapy to the first dose on study (range, 0.2-12).

Patients received IPI-145 in escalating doses, from 25 mg to 100 mg twice daily (n=10) and in an expansion cohort at 75 mg twice daily (n=20). All 30 patients were evaluable for the safety analysis, but only 26 were evaluable for clinical activity.

Response by disease type

The ORR for all 26 patients was 38% (1 complete and 9 partial responses).

Among the 11 evaluable PTCL patients, the ORR was 55%. One patient had a complete response, and 5 had partial responses.

Of the 15 evaluable CTCL patients, 4 had partial responses, for an ORR of 27%. In addition, 7 CTCL patients had stable disease.

The median time to response was 1.9 months (range, 1.5-2.7) for patients with PTCL and 2.4 months (range, 1.7-3.8) for patients with CTCL.

Four patients with PTCL and 3 patients with CTCL remain on treatment.

Adverse events 

IPI-145 was generally well-tolerated, according to the researchers.

The most common adverse events of any grade were an increases in ALT/AST (47%), fatigue (37%), pyrexia (33%), diarrhea (30%), cough (27%), headache (27%), nausea (27%), rash (23%), increases in alkaline phosphatase (20%), increases in blood creatinine (17%), and weight loss (17%).

Grade 3 side effects included increased ALT/AST (33%), rash (13%), and fatigue (10%). One patient (3%) had grade 4 ALT/AST increases.

Forty percent of patients had severe adverse events, and 30% were treatment-related. Among CTCL patients, the severe events included ALT/AST increases (n=1), pneumonitis (n=1), HSV pneumonitis (n=1), lung infection (n=1), pyrexia (n=1), and staphylococcal sepsis (n=1).

Among PTCL patients, severe events included diarrhea (n=2), pneumonia (n=2), vomiting (n=2), cellulitis (n=1), colitis (n=1), dehydration (n=1), hypotension (n=1), pneumonia cytomegaloviral (n=1), pyrexia (n=1), and rash (macular papular; n=1).

Six CTCL patients and 3 PTCL patients discontinued treatment due to adverse events.

Pharmacodynamics

The data showed that treatment with IPI-145 led to decreases in serum levels of cytokines and chemokines known to play important roles in lymphocyte trafficking and function.

The researchers said this further supports the rationale that inhibiting PI3K-delta and PI3K-gamma has the potential to provide a therapeutic benefit for T-cell lymphomas and other hematologic malignancies.

For more details on this research, see the poster on Infinity’s website: http://www.infi.com/product-candidates-publications.asp.

SAN FRANCISCO—Preliminary results of a phase 1 trial suggest the PI3K-delta/gamma inhibitor IPI-145 is active in patients with relapsed or refractory T-cell lymphomas.

Among 26 evaluable patients, 9 experienced partial responses to treatment with IPI-145, and 1 achieved a complete response, for an overall response rate (ORR) of 38%.

The drug also appeared to be well-tolerated, although 30% of patients did experience treatment-related severe adverse events.

Steven Horwitz, MD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues presented these results in a poster at the 6th Annual T-cell Lymphoma Forum, which took place January 23-25.

The study was sponsored by Infinity Pharmaceuticals, Inc., the company developing IPI-145.

Patient and treatment characteristics

The trial included 30 patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Of the 17 CTCL patients, 16 had mycosis fungoides or Sezary syndrome, and 1 had primary cutaneous anaplastic large-cell lymphoma (ALCL).

Of the 13 patients with PTCL, 3 had angioimmunoblastic T-cell lymphoma (AITL), 3 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL), 3 had PTCL-not otherwise specified, 2 had ALCL, 1 had enteropathy-associated T-cell lymphoma (EATL), and 1 had NK T-cell lymphoma (NKTL).

The patients had advanced disease, with a median of 5 prior systemic therapies (range, 1-11) and a median of 1 month from their last therapy to the first dose on study (range, 0.2-12).

Patients received IPI-145 in escalating doses, from 25 mg to 100 mg twice daily (n=10) and in an expansion cohort at 75 mg twice daily (n=20). All 30 patients were evaluable for the safety analysis, but only 26 were evaluable for clinical activity.

Response by disease type

The ORR for all 26 patients was 38% (1 complete and 9 partial responses).

Among the 11 evaluable PTCL patients, the ORR was 55%. One patient had a complete response, and 5 had partial responses.

Of the 15 evaluable CTCL patients, 4 had partial responses, for an ORR of 27%. In addition, 7 CTCL patients had stable disease.

The median time to response was 1.9 months (range, 1.5-2.7) for patients with PTCL and 2.4 months (range, 1.7-3.8) for patients with CTCL.

Four patients with PTCL and 3 patients with CTCL remain on treatment.

Adverse events 

IPI-145 was generally well-tolerated, according to the researchers.

The most common adverse events of any grade were an increases in ALT/AST (47%), fatigue (37%), pyrexia (33%), diarrhea (30%), cough (27%), headache (27%), nausea (27%), rash (23%), increases in alkaline phosphatase (20%), increases in blood creatinine (17%), and weight loss (17%).

Grade 3 side effects included increased ALT/AST (33%), rash (13%), and fatigue (10%). One patient (3%) had grade 4 ALT/AST increases.

Forty percent of patients had severe adverse events, and 30% were treatment-related. Among CTCL patients, the severe events included ALT/AST increases (n=1), pneumonitis (n=1), HSV pneumonitis (n=1), lung infection (n=1), pyrexia (n=1), and staphylococcal sepsis (n=1).

Among PTCL patients, severe events included diarrhea (n=2), pneumonia (n=2), vomiting (n=2), cellulitis (n=1), colitis (n=1), dehydration (n=1), hypotension (n=1), pneumonia cytomegaloviral (n=1), pyrexia (n=1), and rash (macular papular; n=1).

Six CTCL patients and 3 PTCL patients discontinued treatment due to adverse events.

Pharmacodynamics

The data showed that treatment with IPI-145 led to decreases in serum levels of cytokines and chemokines known to play important roles in lymphocyte trafficking and function.

The researchers said this further supports the rationale that inhibiting PI3K-delta and PI3K-gamma has the potential to provide a therapeutic benefit for T-cell lymphomas and other hematologic malignancies.

For more details on this research, see the poster on Infinity’s website: http://www.infi.com/product-candidates-publications.asp.

SAN FRANCISCO—Unlike its predecessors, a new prognostic model suggests race and histology are important predictors of outcome in patients with peripheral T-cell lymphoma (PTCL).

Researchers analyzed nearly 9000 patients diagnosed with PTCL in the US and found evidence to suggest that patient age and race, as well as histology and disease stage can be used to predict overall survival (OS).

The group’s findings also suggested the use of radiation is associated with improved OS. And later diagnosis may be associated with favorable outcome.

Adam M. Petrich, MD, of Northwestern University in Chicago, presented this research at the 6th Annual T-cell Lymphoma Forum, which took place January 23-25. Dr Petrich was 1 of 2 speakers to receive a Young Investigator Award for his presentation.

Dr Petrich noted that at least 5 models have been used to predict outcomes in patients with newly diagnosed PTCL—the International Prognostic Index (IPI), the Prognostic Index for PTCL (PIT), the International PTCL Project model (IPTCLP), the modified Prognostic Index for T-cell Lymphoma (mPIT), and the Extranodal Natural Killer/T Cell Lymphoma (ENKTL) model.

But these models have limitations, including small patient numbers and issues with applicability. So Dr Petrich and his colleagues wanted to take a closer look at prognostic factors in PTCL, to determine which factors from previously published models remain relevant.

Patient characteristics

The researchers used data from the SEER database, which included 20 state and local registries and captured 28% of the US population. There were 8802 cases of PTCL diagnosed between 2000 and 2010.

Patients ranged in age from 20 to 85 years, and 59% were male. With regard to race, 77% of patients were white, 13% were black, 9% were classified as “other,” and 1% were of unknown race.

Forty-eight percent of patients had stage I-II disease, 31% had stage III-IV, and the stage was unknown for 21% of patients. Extranodal disease was absent in 60% of patients, present in 26%, and unknown in 14%.

Histologies were as follows:

• 38.1% of patients had PTCL-not otherwise specified (PTCL-NOS)
• 24.2% had anaplastic large-cell lymphoma (ALCL)
• 12.7% had angioimmunoblastic T-cell lymphoma (AITL)
• 9.3% had adult T-cell leukemia/lymphoma (ATLL)
• 6.9% had extranodal NK/T-cell lymphoma (ENKTL)
• 3.2% had T-cell-prolymphocytic leukemia(T-PLL)
• 2.5% had T-cell large granular lymphocytic leukemia (T-LGL)
• 1.2% had subcutaneous panniculitis-like T-cell lymphoma (SCPTCL)
• 1.1% had enteropathy-associated T-cell lymphoma (EATL)
• 0.6% had hepatosplenic T-cell lymphoma (HSTL).

Prognostic factors revealed

The researchers performed univariate and multivariate analyses to determine the importance of the aforementioned factors on OS.

“We decided, since we have a large number of patients, to use a very stringent P value,” Dr Petrich said. “Only those that are less than 0.0001 were considered significant.”

In univariate analysis, age, race, disease stage, extranodal disease, use of radiation, and histology all significantly impacted OS. But in multivariate analysis, only race, age, histology, and disease stage retained significance.

“Extranodal disease is associated with protection from overall survival, but that P value did not reach significance (P=0.009),” Dr Petrich said.

Likewise, patients diagnosed from 2009 to 2010 had better OS than patients diagnosed from 2000 to 2008, but this did not meet the significance criterion (P=0.0002).

On the other hand, OS was significantly worse for black patients compared to white patients. And compared to patients aged 20-24, those 55 years of age and older had a significantly increased risk of death.

Compared to patients with PTCL-NOS, those with EATL, ENKTL, and T-LGL all had significantly worse OS. And patients with advanced-stage disease had significantly worse OS.

The researchers also looked at the use of radiation and found that it had a significant impact on survival.

“Of course, this isn’t a pre-treatment variable, but we did add it as sort of an exploratory analysis,” Dr Petrich said. “And regardless of disease stage, [radiation] seems to be associated with improved survival. But when we include it in a multivariate analysis, it’s also highly associated with protection from 5-year mortality (P<0.0001).”

Creating, validating the prognostic model

Dr Petrich and his colleagues created a prognostic model based on some of the aforementioned factors. They assigned points according to hazard ratios (HRs).

Patients received 1 point for each of the following factors: age 55 or older (HR 1.51), black race (HR 1.43), distant-stage disease (HR 1.79), PTCL-NOS (reference), AITL (HR 1.19), ALCL (HR 0.88), and ATLL (HR 1.34).

Patients received 2 points for each of the following histologies: HSTL (HR 1.76), EATL (HR 2.32), ENKTL (HR 1.50), and T-PLL (HR couldn’t be calculated). And they received 0 points for SCPTL (HR 0.71) and T-LGL (HR 0.43).

The researchers then applied the model to the population of 8802 patients and evaluated survival. The median OS was more than 120 months for patients with a score of 0-1, 36 months for those with a score of 2, 14 months for those with a score of 3, and 9 months for those with score of 4 or 5.

“We have good discrimination of outcome based on this scoring system, with patients with the most favorable prognosis having median survival that’s out over 10 years,” Dr Petrich said.

The researchers also obtained good discrimination when they tested the model in a validation cohort of 112 patients, Dr Petrich said. He noted, however, that validating the model with a larger patient population would provide better results.

He also pointed out that this study had its limitations, such as missing data and a lack of uniformity with regard to treatment. But the research does reveal factors that are likely important prognostic indicators in PTCL.

SAN FRANCISCO—Unlike its predecessors, a new prognostic model suggests race and histology are important predictors of outcome in patients with peripheral T-cell lymphoma (PTCL).

Researchers analyzed nearly 9000 patients diagnosed with PTCL in the US and found evidence to suggest that patient age and race, as well as histology and disease stage can be used to predict overall survival (OS).

The group’s findings also suggested the use of radiation is associated with improved OS. And later diagnosis may be associated with favorable outcome.

Adam M. Petrich, MD, of Northwestern University in Chicago, presented this research at the 6th Annual T-cell Lymphoma Forum, which took place January 23-25. Dr Petrich was 1 of 2 speakers to receive a Young Investigator Award for his presentation.

Dr Petrich noted that at least 5 models have been used to predict outcomes in patients with newly diagnosed PTCL—the International Prognostic Index (IPI), the Prognostic Index for PTCL (PIT), the International PTCL Project model (IPTCLP), the modified Prognostic Index for T-cell Lymphoma (mPIT), and the Extranodal Natural Killer/T Cell Lymphoma (ENKTL) model.

But these models have limitations, including small patient numbers and issues with applicability. So Dr Petrich and his colleagues wanted to take a closer look at prognostic factors in PTCL, to determine which factors from previously published models remain relevant.

Patient characteristics

The researchers used data from the SEER database, which included 20 state and local registries and captured 28% of the US population. There were 8802 cases of PTCL diagnosed between 2000 and 2010.

Patients ranged in age from 20 to 85 years, and 59% were male. With regard to race, 77% of patients were white, 13% were black, 9% were classified as “other,” and 1% were of unknown race.

Forty-eight percent of patients had stage I-II disease, 31% had stage III-IV, and the stage was unknown for 21% of patients. Extranodal disease was absent in 60% of patients, present in 26%, and unknown in 14%.

Histologies were as follows:

• 38.1% of patients had PTCL-not otherwise specified (PTCL-NOS)
• 24.2% had anaplastic large-cell lymphoma (ALCL)
• 12.7% had angioimmunoblastic T-cell lymphoma (AITL)
• 9.3% had adult T-cell leukemia/lymphoma (ATLL)
• 6.9% had extranodal NK/T-cell lymphoma (ENKTL)
• 3.2% had T-cell-prolymphocytic leukemia(T-PLL)
• 2.5% had T-cell large granular lymphocytic leukemia (T-LGL)
• 1.2% had subcutaneous panniculitis-like T-cell lymphoma (SCPTCL)
• 1.1% had enteropathy-associated T-cell lymphoma (EATL)
• 0.6% had hepatosplenic T-cell lymphoma (HSTL).

Prognostic factors revealed

The researchers performed univariate and multivariate analyses to determine the importance of the aforementioned factors on OS.

“We decided, since we have a large number of patients, to use a very stringent P value,” Dr Petrich said. “Only those that are less than 0.0001 were considered significant.”

In univariate analysis, age, race, disease stage, extranodal disease, use of radiation, and histology all significantly impacted OS. But in multivariate analysis, only race, age, histology, and disease stage retained significance.

“Extranodal disease is associated with protection from overall survival, but that P value did not reach significance (P=0.009),” Dr Petrich said.

Likewise, patients diagnosed from 2009 to 2010 had better OS than patients diagnosed from 2000 to 2008, but this did not meet the significance criterion (P=0.0002).

On the other hand, OS was significantly worse for black patients compared to white patients. And compared to patients aged 20-24, those 55 years of age and older had a significantly increased risk of death.

Compared to patients with PTCL-NOS, those with EATL, ENKTL, and T-LGL all had significantly worse OS. And patients with advanced-stage disease had significantly worse OS.

The researchers also looked at the use of radiation and found that it had a significant impact on survival.

“Of course, this isn’t a pre-treatment variable, but we did add it as sort of an exploratory analysis,” Dr Petrich said. “And regardless of disease stage, [radiation] seems to be associated with improved survival. But when we include it in a multivariate analysis, it’s also highly associated with protection from 5-year mortality (P<0.0001).”

Creating, validating the prognostic model

Dr Petrich and his colleagues created a prognostic model based on some of the aforementioned factors. They assigned points according to hazard ratios (HRs).

Patients received 1 point for each of the following factors: age 55 or older (HR 1.51), black race (HR 1.43), distant-stage disease (HR 1.79), PTCL-NOS (reference), AITL (HR 1.19), ALCL (HR 0.88), and ATLL (HR 1.34).

Patients received 2 points for each of the following histologies: HSTL (HR 1.76), EATL (HR 2.32), ENKTL (HR 1.50), and T-PLL (HR couldn’t be calculated). And they received 0 points for SCPTL (HR 0.71) and T-LGL (HR 0.43).

The researchers then applied the model to the population of 8802 patients and evaluated survival. The median OS was more than 120 months for patients with a score of 0-1, 36 months for those with a score of 2, 14 months for those with a score of 3, and 9 months for those with score of 4 or 5.

“We have good discrimination of outcome based on this scoring system, with patients with the most favorable prognosis having median survival that’s out over 10 years,” Dr Petrich said.

The researchers also obtained good discrimination when they tested the model in a validation cohort of 112 patients, Dr Petrich said. He noted, however, that validating the model with a larger patient population would provide better results.

He also pointed out that this study had its limitations, such as missing data and a lack of uniformity with regard to treatment. But the research does reveal factors that are likely important prognostic indicators in PTCL.

SAN FRANCISCO—Unlike its predecessors, a new prognostic model suggests race and histology are important predictors of outcome in patients with peripheral T-cell lymphoma (PTCL).

Researchers analyzed nearly 9000 patients diagnosed with PTCL in the US and found evidence to suggest that patient age and race, as well as histology and disease stage can be used to predict overall survival (OS).

The group’s findings also suggested the use of radiation is associated with improved OS. And later diagnosis may be associated with favorable outcome.

Adam M. Petrich, MD, of Northwestern University in Chicago, presented this research at the 6th Annual T-cell Lymphoma Forum, which took place January 23-25. Dr Petrich was 1 of 2 speakers to receive a Young Investigator Award for his presentation.

Dr Petrich noted that at least 5 models have been used to predict outcomes in patients with newly diagnosed PTCL—the International Prognostic Index (IPI), the Prognostic Index for PTCL (PIT), the International PTCL Project model (IPTCLP), the modified Prognostic Index for T-cell Lymphoma (mPIT), and the Extranodal Natural Killer/T Cell Lymphoma (ENKTL) model.

But these models have limitations, including small patient numbers and issues with applicability. So Dr Petrich and his colleagues wanted to take a closer look at prognostic factors in PTCL, to determine which factors from previously published models remain relevant.

Patient characteristics

The researchers used data from the SEER database, which included 20 state and local registries and captured 28% of the US population. There were 8802 cases of PTCL diagnosed between 2000 and 2010.

Patients ranged in age from 20 to 85 years, and 59% were male. With regard to race, 77% of patients were white, 13% were black, 9% were classified as “other,” and 1% were of unknown race.

Forty-eight percent of patients had stage I-II disease, 31% had stage III-IV, and the stage was unknown for 21% of patients. Extranodal disease was absent in 60% of patients, present in 26%, and unknown in 14%.

Histologies were as follows:

• 38.1% of patients had PTCL-not otherwise specified (PTCL-NOS)
• 24.2% had anaplastic large-cell lymphoma (ALCL)
• 12.7% had angioimmunoblastic T-cell lymphoma (AITL)
• 9.3% had adult T-cell leukemia/lymphoma (ATLL)
• 6.9% had extranodal NK/T-cell lymphoma (ENKTL)
• 3.2% had T-cell-prolymphocytic leukemia(T-PLL)
• 2.5% had T-cell large granular lymphocytic leukemia (T-LGL)
• 1.2% had subcutaneous panniculitis-like T-cell lymphoma (SCPTCL)
• 1.1% had enteropathy-associated T-cell lymphoma (EATL)
• 0.6% had hepatosplenic T-cell lymphoma (HSTL).

Prognostic factors revealed

The researchers performed univariate and multivariate analyses to determine the importance of the aforementioned factors on OS.

“We decided, since we have a large number of patients, to use a very stringent P value,” Dr Petrich said. “Only those that are less than 0.0001 were considered significant.”

In univariate analysis, age, race, disease stage, extranodal disease, use of radiation, and histology all significantly impacted OS. But in multivariate analysis, only race, age, histology, and disease stage retained significance.

“Extranodal disease is associated with protection from overall survival, but that P value did not reach significance (P=0.009),” Dr Petrich said.

Likewise, patients diagnosed from 2009 to 2010 had better OS than patients diagnosed from 2000 to 2008, but this did not meet the significance criterion (P=0.0002).

On the other hand, OS was significantly worse for black patients compared to white patients. And compared to patients aged 20-24, those 55 years of age and older had a significantly increased risk of death.

Compared to patients with PTCL-NOS, those with EATL, ENKTL, and T-LGL all had significantly worse OS. And patients with advanced-stage disease had significantly worse OS.

The researchers also looked at the use of radiation and found that it had a significant impact on survival.

“Of course, this isn’t a pre-treatment variable, but we did add it as sort of an exploratory analysis,” Dr Petrich said. “And regardless of disease stage, [radiation] seems to be associated with improved survival. But when we include it in a multivariate analysis, it’s also highly associated with protection from 5-year mortality (P<0.0001).”

Creating, validating the prognostic model

Dr Petrich and his colleagues created a prognostic model based on some of the aforementioned factors. They assigned points according to hazard ratios (HRs).

Patients received 1 point for each of the following factors: age 55 or older (HR 1.51), black race (HR 1.43), distant-stage disease (HR 1.79), PTCL-NOS (reference), AITL (HR 1.19), ALCL (HR 0.88), and ATLL (HR 1.34).

Patients received 2 points for each of the following histologies: HSTL (HR 1.76), EATL (HR 2.32), ENKTL (HR 1.50), and T-PLL (HR couldn’t be calculated). And they received 0 points for SCPTL (HR 0.71) and T-LGL (HR 0.43).

The researchers then applied the model to the population of 8802 patients and evaluated survival. The median OS was more than 120 months for patients with a score of 0-1, 36 months for those with a score of 2, 14 months for those with a score of 3, and 9 months for those with score of 4 or 5.

“We have good discrimination of outcome based on this scoring system, with patients with the most favorable prognosis having median survival that’s out over 10 years,” Dr Petrich said.

The researchers also obtained good discrimination when they tested the model in a validation cohort of 112 patients, Dr Petrich said. He noted, however, that validating the model with a larger patient population would provide better results.

He also pointed out that this study had its limitations, such as missing data and a lack of uniformity with regard to treatment. But the research does reveal factors that are likely important prognostic indicators in PTCL.

 

Anas Younes, MD

 

SAN FRANCISCO—The US currently has 284 open clinical trials enrolling patients with T-cell lymphomas, a fact that is actually detrimental to this patient population, according to an expert in the field.  

Anas Younes, MD, of MD Anderson Cancer Center in Houston, presented this perspective at the 4th Annual T-cell Lymphoma Forum, which took place January 26-28.

Dr Younes noted that there are 361 clinical trials worldwide that are currently accruing patients with T-cell lymphomas. Of those, 284 are taking place in the US. Less than half of the US trials are new; 124 of them have been submitted since January 2010.

The new trials are divided pretty evenly between phase 1 and phase 2—66 and 61 trials, respectively. But only 1 of the studies is a phase 3, which suggests that having such a large number of trials may be hindering drug development as well as patient treatment.

“[W]e have too many clinical trials available for a small pool of patients,” Dr Younes said. “I think it’s not a good idea to have that. We’re diluting our efforts, major trials are not able to enroll in a timely manner, and most of them will close before they even enroll [an] adequate [number of] patients.”

As an example, Dr Younes cited lymphoma trials developed at MD Anderson that were open between 2004 and 2011. The center’s accrual of follicular lymphoma patients during this period ranged from roughly 40 to 160 patients. The number of Hodgkin lymphoma patients enrolled ranged from about 25 to 110, and the number of mantle cell lymphoma patients ranged from about 30 to 70.

But the largest number of T-cell lymphoma patients enrolled was about 50 in 2007. And on the whole, the center has not enrolled more than 10 to 15 patients per year.

“And the reason is there are so many competing trials in the United States,” Dr Younes said. “By the time [patients are] referred to us, they’re either not eligible or too sick to be treated . . . . So I think it’s becoming unhealthy competition with such a large number of protocols available for these patients.”

As of right now, MD Anderson is running 5 trials for T-cell lymphoma patients (and planning to open 3 more trials soon), but patient accrual has been slow.

For instance, a trial of vorinostat plus CHOP for untreated T-cell lymphoma has been open since 2008. It has accrued 12 patients but still has 40 slots open.

And a trial of MK-2206 in relapsed or refractory T-cell lymphoma has been open since 2010. It has accrued 1 patient and has 15 slots still open.

“We’re really unable to enroll enough patients in a timely manner anymore,” Dr Younes said. “So we need to prioritize [our trials]. We need to collaborate more.”

 

Anas Younes, MD

 

SAN FRANCISCO—The US currently has 284 open clinical trials enrolling patients with T-cell lymphomas, a fact that is actually detrimental to this patient population, according to an expert in the field.  

Anas Younes, MD, of MD Anderson Cancer Center in Houston, presented this perspective at the 4th Annual T-cell Lymphoma Forum, which took place January 26-28.

Dr Younes noted that there are 361 clinical trials worldwide that are currently accruing patients with T-cell lymphomas. Of those, 284 are taking place in the US. Less than half of the US trials are new; 124 of them have been submitted since January 2010.

The new trials are divided pretty evenly between phase 1 and phase 2—66 and 61 trials, respectively. But only 1 of the studies is a phase 3, which suggests that having such a large number of trials may be hindering drug development as well as patient treatment.

“[W]e have too many clinical trials available for a small pool of patients,” Dr Younes said. “I think it’s not a good idea to have that. We’re diluting our efforts, major trials are not able to enroll in a timely manner, and most of them will close before they even enroll [an] adequate [number of] patients.”

As an example, Dr Younes cited lymphoma trials developed at MD Anderson that were open between 2004 and 2011. The center’s accrual of follicular lymphoma patients during this period ranged from roughly 40 to 160 patients. The number of Hodgkin lymphoma patients enrolled ranged from about 25 to 110, and the number of mantle cell lymphoma patients ranged from about 30 to 70.

But the largest number of T-cell lymphoma patients enrolled was about 50 in 2007. And on the whole, the center has not enrolled more than 10 to 15 patients per year.

“And the reason is there are so many competing trials in the United States,” Dr Younes said. “By the time [patients are] referred to us, they’re either not eligible or too sick to be treated . . . . So I think it’s becoming unhealthy competition with such a large number of protocols available for these patients.”

As of right now, MD Anderson is running 5 trials for T-cell lymphoma patients (and planning to open 3 more trials soon), but patient accrual has been slow.

For instance, a trial of vorinostat plus CHOP for untreated T-cell lymphoma has been open since 2008. It has accrued 12 patients but still has 40 slots open.

And a trial of MK-2206 in relapsed or refractory T-cell lymphoma has been open since 2010. It has accrued 1 patient and has 15 slots still open.

“We’re really unable to enroll enough patients in a timely manner anymore,” Dr Younes said. “So we need to prioritize [our trials]. We need to collaborate more.”

 

Anas Younes, MD

 

SAN FRANCISCO—The US currently has 284 open clinical trials enrolling patients with T-cell lymphomas, a fact that is actually detrimental to this patient population, according to an expert in the field.  

Anas Younes, MD, of MD Anderson Cancer Center in Houston, presented this perspective at the 4th Annual T-cell Lymphoma Forum, which took place January 26-28.

Dr Younes noted that there are 361 clinical trials worldwide that are currently accruing patients with T-cell lymphomas. Of those, 284 are taking place in the US. Less than half of the US trials are new; 124 of them have been submitted since January 2010.

The new trials are divided pretty evenly between phase 1 and phase 2—66 and 61 trials, respectively. But only 1 of the studies is a phase 3, which suggests that having such a large number of trials may be hindering drug development as well as patient treatment.

“[W]e have too many clinical trials available for a small pool of patients,” Dr Younes said. “I think it’s not a good idea to have that. We’re diluting our efforts, major trials are not able to enroll in a timely manner, and most of them will close before they even enroll [an] adequate [number of] patients.”

As an example, Dr Younes cited lymphoma trials developed at MD Anderson that were open between 2004 and 2011. The center’s accrual of follicular lymphoma patients during this period ranged from roughly 40 to 160 patients. The number of Hodgkin lymphoma patients enrolled ranged from about 25 to 110, and the number of mantle cell lymphoma patients ranged from about 30 to 70.

But the largest number of T-cell lymphoma patients enrolled was about 50 in 2007. And on the whole, the center has not enrolled more than 10 to 15 patients per year.

“And the reason is there are so many competing trials in the United States,” Dr Younes said. “By the time [patients are] referred to us, they’re either not eligible or too sick to be treated . . . . So I think it’s becoming unhealthy competition with such a large number of protocols available for these patients.”

As of right now, MD Anderson is running 5 trials for T-cell lymphoma patients (and planning to open 3 more trials soon), but patient accrual has been slow.

For instance, a trial of vorinostat plus CHOP for untreated T-cell lymphoma has been open since 2008. It has accrued 12 patients but still has 40 slots open.

And a trial of MK-2206 in relapsed or refractory T-cell lymphoma has been open since 2010. It has accrued 1 patient and has 15 slots still open.

“We’re really unable to enroll enough patients in a timely manner anymore,” Dr Younes said. “So we need to prioritize [our trials]. We need to collaborate more.”