BMT 2017

Photo by Einar Fredriksen

ORLANDO, FL—A 2-drug combination is “an exceptional candidate for clinical translation” as prophylaxis for graft-vs-host disease (GVHD), according to a presenter at the 2017 BMT Tandem Meetings.

The combination consists of sirolimus and KY1005, a monoclonal antibody that binds to OX40L and stops it from activating OX40, a protein that induces prolonged responses in T cells.

Experiments in rhesus macaques showed that KY1005 alone can have a modest effect on GVHD, but the combination of KY1005 and sirolimus can provide long-term, GVHD-free survival.

Victor Tkachev, PhD, of Seattle Children’s Research Institute in Washington, presented these results as one of the “Best Abstracts” at the recent BMT Tandem Meetings (abstract 3). This research was supported by Kymab, the company developing KY1005.

Dr Tkachev and his colleagues tested KY1005 alone and in combination with sirolimus in a previously described model of GVHD. In this model, rhesus macaques that do not receive prophylaxis develop severe GVHD after haploidentical hematopoietic stem cell transplant (HSCT).

For the current study, the animals received no prophylaxis, KY1005 alone, sirolimus alone, or KY1005 plus sirolimus.

When compared to no prophylaxis, KY1005 delayed the progression of acute GVHD and significantly prolonged the survival of HSCT recipients. However, all KY1005-treated animals eventually developed lethal GVHD.

Dr Tkachev noted that KY1005 provided partial control of T-cell activation, decreasing CD4 T-cell proliferation but having no significant effect on CD8 T-cell expansion.

As with KY1005 alone, sirolimus alone delayed GVHD progression and prolonged survival when compared to no GVHD prophylaxis.

However, all animals treated with sirolimus monotherapy eventually developed GVHD and died, and sirolimus alone wasn’t able to control T-cell proliferation.

On the other hand, the combination of KY1005 and sirolimus provided long-term, GVHD-free survival. All of the animals that received this combination survived, without developing GVHD, through day 100 after HSCT.

Dr Tkachev noted that, when given together, KY1005 and sirolimus synergistically controlled both CD4 and CD8 T-cell proliferation. However, this effect did not result in a lack of engraftment. In fact, animals that received the combination “displayed robust hematopoietic reconstitution” and maintained a high number of donor T cells.

Further investigation revealed that combination treatment with KY1005 and sirolimus preserves the reconstitution of regulatory T cells after HSCT and prevents both Th1- and Th17-driven alloimmunity.

Dr Tkachev and his colleagues also found that KY1005 plus sirolimus demonstrates an “unprecedented capacity” to protect against acute GVHD. Results with this combination were superior to those observed with tacrolimus and methotrexate in combination as well as abatacept and sirolimus in combination.

“Taken together, these data suggest that combined prophylaxis with KY1005 plus sirolimus represents an exceptional candidate for clinical translation,” Dr Tkachev concluded.

Kymab has said it will begin testing KY1005 in clinical trials this year.

Photo by Einar Fredriksen

ORLANDO, FL—A 2-drug combination is “an exceptional candidate for clinical translation” as prophylaxis for graft-vs-host disease (GVHD), according to a presenter at the 2017 BMT Tandem Meetings.

The combination consists of sirolimus and KY1005, a monoclonal antibody that binds to OX40L and stops it from activating OX40, a protein that induces prolonged responses in T cells.

Experiments in rhesus macaques showed that KY1005 alone can have a modest effect on GVHD, but the combination of KY1005 and sirolimus can provide long-term, GVHD-free survival.

Victor Tkachev, PhD, of Seattle Children’s Research Institute in Washington, presented these results as one of the “Best Abstracts” at the recent BMT Tandem Meetings (abstract 3). This research was supported by Kymab, the company developing KY1005.

Dr Tkachev and his colleagues tested KY1005 alone and in combination with sirolimus in a previously described model of GVHD. In this model, rhesus macaques that do not receive prophylaxis develop severe GVHD after haploidentical hematopoietic stem cell transplant (HSCT).

For the current study, the animals received no prophylaxis, KY1005 alone, sirolimus alone, or KY1005 plus sirolimus.

When compared to no prophylaxis, KY1005 delayed the progression of acute GVHD and significantly prolonged the survival of HSCT recipients. However, all KY1005-treated animals eventually developed lethal GVHD.

Dr Tkachev noted that KY1005 provided partial control of T-cell activation, decreasing CD4 T-cell proliferation but having no significant effect on CD8 T-cell expansion.

As with KY1005 alone, sirolimus alone delayed GVHD progression and prolonged survival when compared to no GVHD prophylaxis.

However, all animals treated with sirolimus monotherapy eventually developed GVHD and died, and sirolimus alone wasn’t able to control T-cell proliferation.

On the other hand, the combination of KY1005 and sirolimus provided long-term, GVHD-free survival. All of the animals that received this combination survived, without developing GVHD, through day 100 after HSCT.

Dr Tkachev noted that, when given together, KY1005 and sirolimus synergistically controlled both CD4 and CD8 T-cell proliferation. However, this effect did not result in a lack of engraftment. In fact, animals that received the combination “displayed robust hematopoietic reconstitution” and maintained a high number of donor T cells.

Further investigation revealed that combination treatment with KY1005 and sirolimus preserves the reconstitution of regulatory T cells after HSCT and prevents both Th1- and Th17-driven alloimmunity.

Dr Tkachev and his colleagues also found that KY1005 plus sirolimus demonstrates an “unprecedented capacity” to protect against acute GVHD. Results with this combination were superior to those observed with tacrolimus and methotrexate in combination as well as abatacept and sirolimus in combination.

“Taken together, these data suggest that combined prophylaxis with KY1005 plus sirolimus represents an exceptional candidate for clinical translation,” Dr Tkachev concluded.

Kymab has said it will begin testing KY1005 in clinical trials this year.

Photo by Einar Fredriksen

ORLANDO, FL—A 2-drug combination is “an exceptional candidate for clinical translation” as prophylaxis for graft-vs-host disease (GVHD), according to a presenter at the 2017 BMT Tandem Meetings.

The combination consists of sirolimus and KY1005, a monoclonal antibody that binds to OX40L and stops it from activating OX40, a protein that induces prolonged responses in T cells.

Experiments in rhesus macaques showed that KY1005 alone can have a modest effect on GVHD, but the combination of KY1005 and sirolimus can provide long-term, GVHD-free survival.

Victor Tkachev, PhD, of Seattle Children’s Research Institute in Washington, presented these results as one of the “Best Abstracts” at the recent BMT Tandem Meetings (abstract 3). This research was supported by Kymab, the company developing KY1005.

Dr Tkachev and his colleagues tested KY1005 alone and in combination with sirolimus in a previously described model of GVHD. In this model, rhesus macaques that do not receive prophylaxis develop severe GVHD after haploidentical hematopoietic stem cell transplant (HSCT).

For the current study, the animals received no prophylaxis, KY1005 alone, sirolimus alone, or KY1005 plus sirolimus.

When compared to no prophylaxis, KY1005 delayed the progression of acute GVHD and significantly prolonged the survival of HSCT recipients. However, all KY1005-treated animals eventually developed lethal GVHD.

Dr Tkachev noted that KY1005 provided partial control of T-cell activation, decreasing CD4 T-cell proliferation but having no significant effect on CD8 T-cell expansion.

As with KY1005 alone, sirolimus alone delayed GVHD progression and prolonged survival when compared to no GVHD prophylaxis.

However, all animals treated with sirolimus monotherapy eventually developed GVHD and died, and sirolimus alone wasn’t able to control T-cell proliferation.

On the other hand, the combination of KY1005 and sirolimus provided long-term, GVHD-free survival. All of the animals that received this combination survived, without developing GVHD, through day 100 after HSCT.

Dr Tkachev noted that, when given together, KY1005 and sirolimus synergistically controlled both CD4 and CD8 T-cell proliferation. However, this effect did not result in a lack of engraftment. In fact, animals that received the combination “displayed robust hematopoietic reconstitution” and maintained a high number of donor T cells.

Further investigation revealed that combination treatment with KY1005 and sirolimus preserves the reconstitution of regulatory T cells after HSCT and prevents both Th1- and Th17-driven alloimmunity.

Dr Tkachev and his colleagues also found that KY1005 plus sirolimus demonstrates an “unprecedented capacity” to protect against acute GVHD. Results with this combination were superior to those observed with tacrolimus and methotrexate in combination as well as abatacept and sirolimus in combination.

“Taken together, these data suggest that combined prophylaxis with KY1005 plus sirolimus represents an exceptional candidate for clinical translation,” Dr Tkachev concluded.

Kymab has said it will begin testing KY1005 in clinical trials this year.

Photo by Bill Branson

ORLANDO, FL—A pilot study to determine the burden of mucositis in pediatric patients undergoing hematopoietic stem cell transplant (HSCT) showed that more than 50% of patients required a change in their opioids either for toxicity or lack of efficacy.

Investigators also observed that patients’ genotypes were associated with time to optimal pain control, although this needs to be defined more clearly in larger prospective studies.

“Pain from mucositis is a major problem during the early post-transplant period in pediatric patients,” said M. Christa Krupski, DO, of Cincinnati Children’s Hospital Medical Center in Ohio.

The pain frequently requires intravenous (IV) pain medication, but adequate pain management is often delayed by the trial and error of finding the right agent or the right dose, Dr Krupski added.

She and her colleagues tried to find predictors of mucositis that would help optimize pain control and minimize adverse effects of pain medication.

Dr Krupski presented the group’s findings at the 2017 BMT Tandem Meetings as abstract 50*.

Based on the investigators’ previous experience using a pain chip, they hypothesized that host genetic polymorphisms would predict perception of mucositis pain, opioid efficacy, and opioid-induced adverse effects in pediatric patients undergoing HSCT.

The pain chip was comprised of a panel of 46 single-nucleotide polymorphisms (SNPs) in a set of candidate genes known to influence opioid effect.

Study design

In this single-institution, retrospective pilot study, investigators genotyped 100 consecutive HSCT patients using pre-transplant samples.

The team collected demographic and transplant data, information on the utilization of pain medication, and mucositis data according to the standard CTCAE guidelines.

“And it must be noted,” Dr Krupski said, “that many of our patients required total parenteral nutrition during the transplant process, which automatically made them a grade 3 for mucositis.”

The investigators assessed pain using 2 scales, the Face, Legs, Activity, Cry, Consolability (FLACC) Scale, which is an objective measurement, and the more subjective Numeric Rating Scores (NRS).

Demographics

Patients were a median age of 9.9 years (range, 0.5–32.8), 65% were male, 87% were Caucasian, and 13% non-Caucasian.

The main indications for transplant were malignancy (45%), immune deficiency/dysregulation (30%), and bone marrow failure syndrome (19%).

More than two-thirds (68%) of patients had received a myeloablative conditioning regimen.

Results—mucositis

Seventy-six patients experienced mucositis, three-quarters of whom (78%) had received a myeloablative conditioning regimen.

The majority of patients (57%) had severe mucositis, which developed a median of 3 days after transplant (range, -2 to 17).

Regarding treatment, 13 (17%) had medication as needed or no medication, 5 (7%) had scheduled IV opioid, and 58 (76%) had patient-controlled analgesia (PCA).

For analysis purposes, the investigators grouped together the scheduled IV opioid and PCA treatment groups.

Results—opioid efficacy

The opioid efficacy analysis was based on 63 patients.

Time to optimal pain control was a median of 7 days (range, 0–22), and the morphine dose at the time of optimal pain control was a median of 1.5 mg/kg (range, 0.2–15.7).

“You will note, though, the wide inter-patient variability,” Dr Krupski pointed out, “with some of our patients immediately achieving optimal pain control the day the medication was started and others taking over 3 weeks to reach optimal pain control.”

Investigators observed similar inter-patient variability in morphine equivalent use at the time of optimal pain control and total morphine equivalent use.

The total time patients were on PCA was a median of 16 days (range, 1–32), and the median total morphine equivalent use was 0.99 mg/kg/day (range, 0.10–8.07).

“Most interesting, though, was that 18 patients, or nearly one-third of the patients requiring IV opioids, required a change in this opioid due to poor efficacy,” Dr Krupski said.

Results—opioid toxicity

Thirty-two (51%) patients experienced at least 1 adverse effect from their pain medication.

Specific toxicities, based on 32 patients, included pruritus (53%), sedation (16%), and nausea/vomiting (9%). Six patients (19%) had more than one adverse event.

“Similar to what we observed with respect to opioid efficacy,” Dr Krupski said, “another one-third of our patients with mucositis required a change in opioid due to toxicity.”

Results—impact of race

Non-Caucasians patients (n=13) had a significantly higher incidence of mucositis (100%) than Caucasians (n=87, 72%, P=0.03).

Non-Caucasian patients also experienced significantly more pain with mucositis (P=0.03), even though the severity of mucositis did not differ between the 2 groups.

The total equivalent dose of morphine used also did not differ between the groups.

“This raises the question of whether there are factors other than race that may be contributing to this difference,” Dr Krupski said.

Genetic findings

The UGT2B7 gene encodes the main enzyme metabolizer of morphine, and SNPs of this gene (rs7668258 and rs7439366) vary by race.

Non-Caucasian patients had significantly more wild-type SNPs than Caucasian patients (P=0.001). And patients with the wild-type UGT2B7 genotype spent more total days on IV opioids than patients with variant alleles (P=0.03).

On examination of rs4633, a SNP of the COMT gene, which is a key regulator of pain perception, the investigators observed some different findings from what had previously been reported.

There was no difference in mucositis severity between patients with the wild-type and variant allele (P=0.3).

However, patients with the variant allele required more days to optimal pain control than patients with the wild-type allele (P=0.04). This finding confirmed increased pain sensitivity associated with the genotype, irrespective of race.

“[I]f this association holds true in future studies,” Dr Krupski explained, “one may be more aggressive in the initial opioid titration to optimize pain control.”

Despite limitations of sample size, especially with respect to non-Caucasian patients, the pilot study showed association, but not causation, with respect to genetic variants.

“Racial differences affect mucositis pain perception and opioid requirement,” Dr Krupski said. “If genotyping is not feasible, it is important to pay particular attention to this difference while managing patients’ pain from mucositis.”

“We have an opportunity here to improve our care. Therefore, our plan is to validate these findings in additional patients before we use them to achieve our ultimate goal: precision dosing of opioids to individual patients.” 

*Data in the abstract differ slightly from the presentation.

Photo by Bill Branson

ORLANDO, FL—A pilot study to determine the burden of mucositis in pediatric patients undergoing hematopoietic stem cell transplant (HSCT) showed that more than 50% of patients required a change in their opioids either for toxicity or lack of efficacy.

Investigators also observed that patients’ genotypes were associated with time to optimal pain control, although this needs to be defined more clearly in larger prospective studies.

“Pain from mucositis is a major problem during the early post-transplant period in pediatric patients,” said M. Christa Krupski, DO, of Cincinnati Children’s Hospital Medical Center in Ohio.

The pain frequently requires intravenous (IV) pain medication, but adequate pain management is often delayed by the trial and error of finding the right agent or the right dose, Dr Krupski added.

She and her colleagues tried to find predictors of mucositis that would help optimize pain control and minimize adverse effects of pain medication.

Dr Krupski presented the group’s findings at the 2017 BMT Tandem Meetings as abstract 50*.

Based on the investigators’ previous experience using a pain chip, they hypothesized that host genetic polymorphisms would predict perception of mucositis pain, opioid efficacy, and opioid-induced adverse effects in pediatric patients undergoing HSCT.

The pain chip was comprised of a panel of 46 single-nucleotide polymorphisms (SNPs) in a set of candidate genes known to influence opioid effect.

Study design

In this single-institution, retrospective pilot study, investigators genotyped 100 consecutive HSCT patients using pre-transplant samples.

The team collected demographic and transplant data, information on the utilization of pain medication, and mucositis data according to the standard CTCAE guidelines.

“And it must be noted,” Dr Krupski said, “that many of our patients required total parenteral nutrition during the transplant process, which automatically made them a grade 3 for mucositis.”

The investigators assessed pain using 2 scales, the Face, Legs, Activity, Cry, Consolability (FLACC) Scale, which is an objective measurement, and the more subjective Numeric Rating Scores (NRS).

Demographics

Patients were a median age of 9.9 years (range, 0.5–32.8), 65% were male, 87% were Caucasian, and 13% non-Caucasian.

The main indications for transplant were malignancy (45%), immune deficiency/dysregulation (30%), and bone marrow failure syndrome (19%).

More than two-thirds (68%) of patients had received a myeloablative conditioning regimen.

Results—mucositis

Seventy-six patients experienced mucositis, three-quarters of whom (78%) had received a myeloablative conditioning regimen.

The majority of patients (57%) had severe mucositis, which developed a median of 3 days after transplant (range, -2 to 17).

Regarding treatment, 13 (17%) had medication as needed or no medication, 5 (7%) had scheduled IV opioid, and 58 (76%) had patient-controlled analgesia (PCA).

For analysis purposes, the investigators grouped together the scheduled IV opioid and PCA treatment groups.

Results—opioid efficacy

The opioid efficacy analysis was based on 63 patients.

Time to optimal pain control was a median of 7 days (range, 0–22), and the morphine dose at the time of optimal pain control was a median of 1.5 mg/kg (range, 0.2–15.7).

“You will note, though, the wide inter-patient variability,” Dr Krupski pointed out, “with some of our patients immediately achieving optimal pain control the day the medication was started and others taking over 3 weeks to reach optimal pain control.”

Investigators observed similar inter-patient variability in morphine equivalent use at the time of optimal pain control and total morphine equivalent use.

The total time patients were on PCA was a median of 16 days (range, 1–32), and the median total morphine equivalent use was 0.99 mg/kg/day (range, 0.10–8.07).

“Most interesting, though, was that 18 patients, or nearly one-third of the patients requiring IV opioids, required a change in this opioid due to poor efficacy,” Dr Krupski said.

Results—opioid toxicity

Thirty-two (51%) patients experienced at least 1 adverse effect from their pain medication.

Specific toxicities, based on 32 patients, included pruritus (53%), sedation (16%), and nausea/vomiting (9%). Six patients (19%) had more than one adverse event.

“Similar to what we observed with respect to opioid efficacy,” Dr Krupski said, “another one-third of our patients with mucositis required a change in opioid due to toxicity.”

Results—impact of race

Non-Caucasians patients (n=13) had a significantly higher incidence of mucositis (100%) than Caucasians (n=87, 72%, P=0.03).

Non-Caucasian patients also experienced significantly more pain with mucositis (P=0.03), even though the severity of mucositis did not differ between the 2 groups.

The total equivalent dose of morphine used also did not differ between the groups.

“This raises the question of whether there are factors other than race that may be contributing to this difference,” Dr Krupski said.

Genetic findings

The UGT2B7 gene encodes the main enzyme metabolizer of morphine, and SNPs of this gene (rs7668258 and rs7439366) vary by race.

Non-Caucasian patients had significantly more wild-type SNPs than Caucasian patients (P=0.001). And patients with the wild-type UGT2B7 genotype spent more total days on IV opioids than patients with variant alleles (P=0.03).

On examination of rs4633, a SNP of the COMT gene, which is a key regulator of pain perception, the investigators observed some different findings from what had previously been reported.

There was no difference in mucositis severity between patients with the wild-type and variant allele (P=0.3).

However, patients with the variant allele required more days to optimal pain control than patients with the wild-type allele (P=0.04). This finding confirmed increased pain sensitivity associated with the genotype, irrespective of race.

“[I]f this association holds true in future studies,” Dr Krupski explained, “one may be more aggressive in the initial opioid titration to optimize pain control.”

Despite limitations of sample size, especially with respect to non-Caucasian patients, the pilot study showed association, but not causation, with respect to genetic variants.

“Racial differences affect mucositis pain perception and opioid requirement,” Dr Krupski said. “If genotyping is not feasible, it is important to pay particular attention to this difference while managing patients’ pain from mucositis.”

“We have an opportunity here to improve our care. Therefore, our plan is to validate these findings in additional patients before we use them to achieve our ultimate goal: precision dosing of opioids to individual patients.” 

*Data in the abstract differ slightly from the presentation.

Photo by Bill Branson

ORLANDO, FL—A pilot study to determine the burden of mucositis in pediatric patients undergoing hematopoietic stem cell transplant (HSCT) showed that more than 50% of patients required a change in their opioids either for toxicity or lack of efficacy.

Investigators also observed that patients’ genotypes were associated with time to optimal pain control, although this needs to be defined more clearly in larger prospective studies.

“Pain from mucositis is a major problem during the early post-transplant period in pediatric patients,” said M. Christa Krupski, DO, of Cincinnati Children’s Hospital Medical Center in Ohio.

The pain frequently requires intravenous (IV) pain medication, but adequate pain management is often delayed by the trial and error of finding the right agent or the right dose, Dr Krupski added.

She and her colleagues tried to find predictors of mucositis that would help optimize pain control and minimize adverse effects of pain medication.

Dr Krupski presented the group’s findings at the 2017 BMT Tandem Meetings as abstract 50*.

Based on the investigators’ previous experience using a pain chip, they hypothesized that host genetic polymorphisms would predict perception of mucositis pain, opioid efficacy, and opioid-induced adverse effects in pediatric patients undergoing HSCT.

The pain chip was comprised of a panel of 46 single-nucleotide polymorphisms (SNPs) in a set of candidate genes known to influence opioid effect.

Study design

In this single-institution, retrospective pilot study, investigators genotyped 100 consecutive HSCT patients using pre-transplant samples.

The team collected demographic and transplant data, information on the utilization of pain medication, and mucositis data according to the standard CTCAE guidelines.

“And it must be noted,” Dr Krupski said, “that many of our patients required total parenteral nutrition during the transplant process, which automatically made them a grade 3 for mucositis.”

The investigators assessed pain using 2 scales, the Face, Legs, Activity, Cry, Consolability (FLACC) Scale, which is an objective measurement, and the more subjective Numeric Rating Scores (NRS).

Demographics

Patients were a median age of 9.9 years (range, 0.5–32.8), 65% were male, 87% were Caucasian, and 13% non-Caucasian.

The main indications for transplant were malignancy (45%), immune deficiency/dysregulation (30%), and bone marrow failure syndrome (19%).

More than two-thirds (68%) of patients had received a myeloablative conditioning regimen.

Results—mucositis

Seventy-six patients experienced mucositis, three-quarters of whom (78%) had received a myeloablative conditioning regimen.

The majority of patients (57%) had severe mucositis, which developed a median of 3 days after transplant (range, -2 to 17).

Regarding treatment, 13 (17%) had medication as needed or no medication, 5 (7%) had scheduled IV opioid, and 58 (76%) had patient-controlled analgesia (PCA).

For analysis purposes, the investigators grouped together the scheduled IV opioid and PCA treatment groups.

Results—opioid efficacy

The opioid efficacy analysis was based on 63 patients.

Time to optimal pain control was a median of 7 days (range, 0–22), and the morphine dose at the time of optimal pain control was a median of 1.5 mg/kg (range, 0.2–15.7).

“You will note, though, the wide inter-patient variability,” Dr Krupski pointed out, “with some of our patients immediately achieving optimal pain control the day the medication was started and others taking over 3 weeks to reach optimal pain control.”

Investigators observed similar inter-patient variability in morphine equivalent use at the time of optimal pain control and total morphine equivalent use.

The total time patients were on PCA was a median of 16 days (range, 1–32), and the median total morphine equivalent use was 0.99 mg/kg/day (range, 0.10–8.07).

“Most interesting, though, was that 18 patients, or nearly one-third of the patients requiring IV opioids, required a change in this opioid due to poor efficacy,” Dr Krupski said.

Results—opioid toxicity

Thirty-two (51%) patients experienced at least 1 adverse effect from their pain medication.

Specific toxicities, based on 32 patients, included pruritus (53%), sedation (16%), and nausea/vomiting (9%). Six patients (19%) had more than one adverse event.

“Similar to what we observed with respect to opioid efficacy,” Dr Krupski said, “another one-third of our patients with mucositis required a change in opioid due to toxicity.”

Results—impact of race

Non-Caucasians patients (n=13) had a significantly higher incidence of mucositis (100%) than Caucasians (n=87, 72%, P=0.03).

Non-Caucasian patients also experienced significantly more pain with mucositis (P=0.03), even though the severity of mucositis did not differ between the 2 groups.

The total equivalent dose of morphine used also did not differ between the groups.

“This raises the question of whether there are factors other than race that may be contributing to this difference,” Dr Krupski said.

Genetic findings

The UGT2B7 gene encodes the main enzyme metabolizer of morphine, and SNPs of this gene (rs7668258 and rs7439366) vary by race.

Non-Caucasian patients had significantly more wild-type SNPs than Caucasian patients (P=0.001). And patients with the wild-type UGT2B7 genotype spent more total days on IV opioids than patients with variant alleles (P=0.03).

On examination of rs4633, a SNP of the COMT gene, which is a key regulator of pain perception, the investigators observed some different findings from what had previously been reported.

There was no difference in mucositis severity between patients with the wild-type and variant allele (P=0.3).

However, patients with the variant allele required more days to optimal pain control than patients with the wild-type allele (P=0.04). This finding confirmed increased pain sensitivity associated with the genotype, irrespective of race.

“[I]f this association holds true in future studies,” Dr Krupski explained, “one may be more aggressive in the initial opioid titration to optimize pain control.”

Despite limitations of sample size, especially with respect to non-Caucasian patients, the pilot study showed association, but not causation, with respect to genetic variants.

“Racial differences affect mucositis pain perception and opioid requirement,” Dr Krupski said. “If genotyping is not feasible, it is important to pay particular attention to this difference while managing patients’ pain from mucositis.”

“We have an opportunity here to improve our care. Therefore, our plan is to validate these findings in additional patients before we use them to achieve our ultimate goal: precision dosing of opioids to individual patients.” 

*Data in the abstract differ slightly from the presentation.

ORLANDO – Allogeneic hematopoietic stem cell transplantation using a matched donor is a valid treatment option – and potential cure – for leukemias with markers of both myeloid and lymphoid lineages, or mixed phenotype acute leukemias, according to findings from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (ALWP-EBMT) database.

Treatment outcomes at 3 years in 519 patients from the database who received an allogeneic transplant (allo-HCT) for mixed-phenotype acute leukemia (MPAL) between 2000 and 2014 and were transplanted in complete remission (CR1) included an overall survival of 56.3%, a leukemia-free survival of 46.5%, a relapse incidence of 31.4%, a nonrelapse mortality of 22.1%, and an incidence of chronic graft-versus-host disease (GVHD) of 37.5%, Reinhold Munker, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“The outcome in this large adult study is pretty favorable based upon 519 patients; 45%-65% can expect overall survival at 5 years,” he said.

The median age of the study subjects was 38.1 years (range, 18-75). Transplants were from a matched sibling donor in 54.5% of cases, and from a matched unrelated donor in 45.5% of cases. Myeloablative conditioning was used in 400 patients and included only chemotherapy in 140 patients and chemotherapy with total body irradiation in 260 patients. The remaining patients received nonmyeloablative conditioning, said Dr. Munker of Tulane University, New Orleans.

The source of stem cells was bone marrow in 26% of patients, and peripheral blood in 73%. Grade II-IV acute GVHD developed in 32.5% of patients. Median follow-up was 32 months, he noted.

In univariate analysis, age at transplant was strongly associated with leukemia-free survival, nonrelapse mortality, relapse incidence, and overall survival. The best outcomes were among those aged 18-35 years. The nonrelapse mortality rate and overall survival rate were lower for transplants done in 2005-2014 vs. 2000-2004 (20% vs 33.2% and 58.3 vs 44.7%, respectively). No differences in outcomes were found between related and unrelated donors, but chronic GVHD was more common with female donors and male recipients, with no in vivo T-cell depletion, and with use of peripheral blood stem cells – findings which are not unexpected, Dr. Munker noted.

Use of myeloablative conditioning with total-body irradiation correlated with a lower relapse incidence and with better leukemia-free survival vs. both myeloablative conditioning with only chemotherapy and reduced-intensity conditioning, he said.

In multivariate analysis, younger age and more recent year of transplant were associated with a better leukemia-free survival and overall survival, and use of myeloablative conditioning with total-body irradiation was associated with better leukemia-free survival and with a trend for higher overall survival.

MPALs are rare, accounting for only 2%-5% of all acute leukemias, Dr. Munker said, noting that prognosis is considered to be intermediate in children and unfavorable in adults.

The diagnostic criteria for MPAL were revised by the World Health Organization (WHO) in 2008 and accepted by most centers, but until recently data were lacking with respect to the recommended treatment strategy of induction regimens similar to those used in acute lymphoblastic leukemia, and consolidation by allogeneic transplant, he explained.

However, the Center for International Blood and Marrow Transplant Research last year published a series of 95 cases showing encouraging long-term survival with allo-HCT in MPAL patients with a median age of 20 years.

The current findings confirm and extend those prior findings, Dr. Munker said.

Dr. Munker reported having no disclosures.

sworcester@frontlinemedcom.com

ORLANDO – Allogeneic hematopoietic stem cell transplantation using a matched donor is a valid treatment option – and potential cure – for leukemias with markers of both myeloid and lymphoid lineages, or mixed phenotype acute leukemias, according to findings from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (ALWP-EBMT) database.

Treatment outcomes at 3 years in 519 patients from the database who received an allogeneic transplant (allo-HCT) for mixed-phenotype acute leukemia (MPAL) between 2000 and 2014 and were transplanted in complete remission (CR1) included an overall survival of 56.3%, a leukemia-free survival of 46.5%, a relapse incidence of 31.4%, a nonrelapse mortality of 22.1%, and an incidence of chronic graft-versus-host disease (GVHD) of 37.5%, Reinhold Munker, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“The outcome in this large adult study is pretty favorable based upon 519 patients; 45%-65% can expect overall survival at 5 years,” he said.

The median age of the study subjects was 38.1 years (range, 18-75). Transplants were from a matched sibling donor in 54.5% of cases, and from a matched unrelated donor in 45.5% of cases. Myeloablative conditioning was used in 400 patients and included only chemotherapy in 140 patients and chemotherapy with total body irradiation in 260 patients. The remaining patients received nonmyeloablative conditioning, said Dr. Munker of Tulane University, New Orleans.

The source of stem cells was bone marrow in 26% of patients, and peripheral blood in 73%. Grade II-IV acute GVHD developed in 32.5% of patients. Median follow-up was 32 months, he noted.

In univariate analysis, age at transplant was strongly associated with leukemia-free survival, nonrelapse mortality, relapse incidence, and overall survival. The best outcomes were among those aged 18-35 years. The nonrelapse mortality rate and overall survival rate were lower for transplants done in 2005-2014 vs. 2000-2004 (20% vs 33.2% and 58.3 vs 44.7%, respectively). No differences in outcomes were found between related and unrelated donors, but chronic GVHD was more common with female donors and male recipients, with no in vivo T-cell depletion, and with use of peripheral blood stem cells – findings which are not unexpected, Dr. Munker noted.

Use of myeloablative conditioning with total-body irradiation correlated with a lower relapse incidence and with better leukemia-free survival vs. both myeloablative conditioning with only chemotherapy and reduced-intensity conditioning, he said.

In multivariate analysis, younger age and more recent year of transplant were associated with a better leukemia-free survival and overall survival, and use of myeloablative conditioning with total-body irradiation was associated with better leukemia-free survival and with a trend for higher overall survival.

MPALs are rare, accounting for only 2%-5% of all acute leukemias, Dr. Munker said, noting that prognosis is considered to be intermediate in children and unfavorable in adults.

The diagnostic criteria for MPAL were revised by the World Health Organization (WHO) in 2008 and accepted by most centers, but until recently data were lacking with respect to the recommended treatment strategy of induction regimens similar to those used in acute lymphoblastic leukemia, and consolidation by allogeneic transplant, he explained.

However, the Center for International Blood and Marrow Transplant Research last year published a series of 95 cases showing encouraging long-term survival with allo-HCT in MPAL patients with a median age of 20 years.

The current findings confirm and extend those prior findings, Dr. Munker said.

Dr. Munker reported having no disclosures.

sworcester@frontlinemedcom.com

ORLANDO – Allogeneic hematopoietic stem cell transplantation using a matched donor is a valid treatment option – and potential cure – for leukemias with markers of both myeloid and lymphoid lineages, or mixed phenotype acute leukemias, according to findings from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (ALWP-EBMT) database.

Treatment outcomes at 3 years in 519 patients from the database who received an allogeneic transplant (allo-HCT) for mixed-phenotype acute leukemia (MPAL) between 2000 and 2014 and were transplanted in complete remission (CR1) included an overall survival of 56.3%, a leukemia-free survival of 46.5%, a relapse incidence of 31.4%, a nonrelapse mortality of 22.1%, and an incidence of chronic graft-versus-host disease (GVHD) of 37.5%, Reinhold Munker, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“The outcome in this large adult study is pretty favorable based upon 519 patients; 45%-65% can expect overall survival at 5 years,” he said.

The median age of the study subjects was 38.1 years (range, 18-75). Transplants were from a matched sibling donor in 54.5% of cases, and from a matched unrelated donor in 45.5% of cases. Myeloablative conditioning was used in 400 patients and included only chemotherapy in 140 patients and chemotherapy with total body irradiation in 260 patients. The remaining patients received nonmyeloablative conditioning, said Dr. Munker of Tulane University, New Orleans.

The source of stem cells was bone marrow in 26% of patients, and peripheral blood in 73%. Grade II-IV acute GVHD developed in 32.5% of patients. Median follow-up was 32 months, he noted.

In univariate analysis, age at transplant was strongly associated with leukemia-free survival, nonrelapse mortality, relapse incidence, and overall survival. The best outcomes were among those aged 18-35 years. The nonrelapse mortality rate and overall survival rate were lower for transplants done in 2005-2014 vs. 2000-2004 (20% vs 33.2% and 58.3 vs 44.7%, respectively). No differences in outcomes were found between related and unrelated donors, but chronic GVHD was more common with female donors and male recipients, with no in vivo T-cell depletion, and with use of peripheral blood stem cells – findings which are not unexpected, Dr. Munker noted.

Use of myeloablative conditioning with total-body irradiation correlated with a lower relapse incidence and with better leukemia-free survival vs. both myeloablative conditioning with only chemotherapy and reduced-intensity conditioning, he said.

In multivariate analysis, younger age and more recent year of transplant were associated with a better leukemia-free survival and overall survival, and use of myeloablative conditioning with total-body irradiation was associated with better leukemia-free survival and with a trend for higher overall survival.

MPALs are rare, accounting for only 2%-5% of all acute leukemias, Dr. Munker said, noting that prognosis is considered to be intermediate in children and unfavorable in adults.

The diagnostic criteria for MPAL were revised by the World Health Organization (WHO) in 2008 and accepted by most centers, but until recently data were lacking with respect to the recommended treatment strategy of induction regimens similar to those used in acute lymphoblastic leukemia, and consolidation by allogeneic transplant, he explained.

However, the Center for International Blood and Marrow Transplant Research last year published a series of 95 cases showing encouraging long-term survival with allo-HCT in MPAL patients with a median age of 20 years.

The current findings confirm and extend those prior findings, Dr. Munker said.

Dr. Munker reported having no disclosures.

sworcester@frontlinemedcom.com

ORLANDO – Minimal residual disease (MRD) measured before and after allogeneic hematopoietic stem cell transplantation (HCT) is a powerful predictor of survival in children with acute lymphoblastic leukemia (ALL), according to a review of hundreds of cases from around the world.

The findings could have implications for using minimal residual disease measures to guide posttransplant interventions, Michael A. Pulsipher, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“MRD pretransplant was a very powerful predictor of outcomes. MRD posttransplant highlights individual patients at risk,” Dr. Pulsipher said. Results comparing reverse transcriptase–polymerase chain reaction with flow cytometry require validation by direct comparison in the same patient cohort, but “the new risk scores ... very nicely predict outcomes both pre- and post-transplant and can guide study planning and patient counseling.”

A total of 2,960 bone marrow MRD measurements were performed in the 747 patients included in the study. MRD was assessed prior to HCT and on or near days 30, 60, 100, 180, and 365 and beyond after HCT.

Patients were grouped for analysis according to MRD level: Group 1 had no detectable MRD, group 2 had low detectable MRD levels (less than 10E-4, or 0.01% by flow cytometry), and group 3 had high detectable MRD levels (10E-4 or higher). A second analysis compared findings in those tested by flow cytometry and those tested by real-time quantitative PCR (RQ-PCR), said Dr. Pulsipher of Children’s Hospital Los Angeles.

In 648 patients with pre-HCT MRD measurements available, the 4-year probability of event-free survival was 62%, 67%, and 37% for groups 1, 2, and 3, respectively. Group 3 – the high MRD level group – had 2.47 times the increased hazard ratio for relapse and 1.67 times the increased risk of treatment-related mortality, Dr. Pulsipher said, adding that pre-HCT MRD and remission status both significantly influenced survival, while age, sex, relapse site, cytogenetics, donor type, and stem cell source did not influence outcome.

Post-HCT MRD values were analyzed as time-dependent covariates.

“As time went by more and more, any detectable level of MRD led to a very poor prognosis, whereas patients arriving at day 365 with no detectable MRD had exceptional prognosis with survival approaching 90%,” he said.

Specifically, the 4-year probability of event-free survival for groups 1, 2, and 3, respectively, were 59%, 65%, and 43% at day 30; 64%, 47%, and 36% at day 60; 65%, 69%, and 44% at day 90; 79%, 40%, and 12% at day 180; and 87%, 36%, and 25% at day 365.

Of note, a very significant interaction was seen between acute graft-versus-host disease (GVHD) and MRD, Dr. Pulsipher said, explaining that patients who were MRD positive and had developed GVHD had a significant decrease in the cumulative incidence of relapse, compared with those with no GVHD.

“This translated into improved event-free survival with patients post transplant, who were MRD-positive [and] developing GVHD, still having a reasonable chance of survival, whereas patients post transplant who had MRD measured who did not develop GVHD had a very poor chance of survival,” he added.

Additionally, based on detailed multivariate analysis including a number of clinical factors, risk predictive scores were developed for event-free survival risk at 18 months or cumulative incidence of relapse at 18 months. Multiple scores were developed for each, but, as an example of factors that had an important effect on outcomes, patients with very early pretransplant relapse (those who went into remission but relapsed within 18 months) or with greater than 2nd relapse had a high risk for poor event-free survival. Mismatched donors and unrelated cord-blood stem cell transplant recipients also had high risk, he said, noting that, “of course, MRD had a significant effect” and was the most important factor prior to transplant.

These patients, who had a 4-point or greater risk score, were the poorest risk group, with survival that was less than 50%, as opposed to better risk groups that exceeded 90%, he said.

“A score of greater than 5 could identify 80% of patients who were going to relapse after transplant, and of course, event-free and overall survival in those patients were very poor,” he added.

As time went by, the early risk of GVHD diminished somewhat, as did the risk of mismatched donors.

“Most of the risk was associated with any MRD detection,” he said.

Flow cytometry and RQ-PCR levels of at least 10-4 were highly predictive of relapse at all pre- and post-HCT time points; however, RQ-PCR values between 10-4 and 10-3, in cases where adequate numbers were available for comparison, better predicted relapse as compared with flow cytometry results.

For example, before HCT, hazard ratios were 1.26 and 2.41 with flow cytometry vs. RQ-PCR. At day 30, the hazard ratios were 1.33 and 2.53, and at day 365, they were 3.54 and 31.84, Dr. Pulsipher reported.

The findings provide important information for improving outcomes in children with high-risk ALL undergoing HCT, he said.

“Older prognostic models for relapsed and refractory high-risk ALL have focused on timing and location of relapse, as well as disease phenotype. But it is clear that, in order to treat children with very high risk ALL with transplantation, MRD has become the most important thing to look at in the pretreatment setting. The challenges that we face in assessing MRD, however, have been hampered by the fact that we have differing MRD measurements,” he said, noting that RQ-PCR is often used in Europe, while flow cytometry is more often used in the United States. As such, direct comparisons are lacking, as are T-cell and posttransplant data.

The current study represents a “tremendous effort” by international collaborators to address these shortcoming, he said.

“This is a great opportunity, as our goal, of course, is to avoid futility in transplantation, but, more importantly, to find opportunities to identify groups for which we can improve our outcomes,” he added.

Patients included in the study were treated in Europe, North America, and Australia and were transplanted during Sept. 1999-May 2016. Most were in first or second remission, and most (586) had pre-B ALL. A notable 145 had T-cell ALL – “more than ever has been analyzed previously” – and 16 had B-lineage or biphenotypic ALL. About half were under age 10 years, 62% were boys, and stem cell sources were typical, although 20% received a cord blood transplant.

Dr. Pulsipher reported serving as an advisor and/or consultant for Chimerix, Novartis, Jazz Pharmaceutical, and receiving housing support from Medac Pharma for an educational meeting.

sworcester@frontlinemedcom.com

ORLANDO – Minimal residual disease (MRD) measured before and after allogeneic hematopoietic stem cell transplantation (HCT) is a powerful predictor of survival in children with acute lymphoblastic leukemia (ALL), according to a review of hundreds of cases from around the world.

The findings could have implications for using minimal residual disease measures to guide posttransplant interventions, Michael A. Pulsipher, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“MRD pretransplant was a very powerful predictor of outcomes. MRD posttransplant highlights individual patients at risk,” Dr. Pulsipher said. Results comparing reverse transcriptase–polymerase chain reaction with flow cytometry require validation by direct comparison in the same patient cohort, but “the new risk scores ... very nicely predict outcomes both pre- and post-transplant and can guide study planning and patient counseling.”

A total of 2,960 bone marrow MRD measurements were performed in the 747 patients included in the study. MRD was assessed prior to HCT and on or near days 30, 60, 100, 180, and 365 and beyond after HCT.

Patients were grouped for analysis according to MRD level: Group 1 had no detectable MRD, group 2 had low detectable MRD levels (less than 10E-4, or 0.01% by flow cytometry), and group 3 had high detectable MRD levels (10E-4 or higher). A second analysis compared findings in those tested by flow cytometry and those tested by real-time quantitative PCR (RQ-PCR), said Dr. Pulsipher of Children’s Hospital Los Angeles.

In 648 patients with pre-HCT MRD measurements available, the 4-year probability of event-free survival was 62%, 67%, and 37% for groups 1, 2, and 3, respectively. Group 3 – the high MRD level group – had 2.47 times the increased hazard ratio for relapse and 1.67 times the increased risk of treatment-related mortality, Dr. Pulsipher said, adding that pre-HCT MRD and remission status both significantly influenced survival, while age, sex, relapse site, cytogenetics, donor type, and stem cell source did not influence outcome.

Post-HCT MRD values were analyzed as time-dependent covariates.

“As time went by more and more, any detectable level of MRD led to a very poor prognosis, whereas patients arriving at day 365 with no detectable MRD had exceptional prognosis with survival approaching 90%,” he said.

Specifically, the 4-year probability of event-free survival for groups 1, 2, and 3, respectively, were 59%, 65%, and 43% at day 30; 64%, 47%, and 36% at day 60; 65%, 69%, and 44% at day 90; 79%, 40%, and 12% at day 180; and 87%, 36%, and 25% at day 365.

Of note, a very significant interaction was seen between acute graft-versus-host disease (GVHD) and MRD, Dr. Pulsipher said, explaining that patients who were MRD positive and had developed GVHD had a significant decrease in the cumulative incidence of relapse, compared with those with no GVHD.

“This translated into improved event-free survival with patients post transplant, who were MRD-positive [and] developing GVHD, still having a reasonable chance of survival, whereas patients post transplant who had MRD measured who did not develop GVHD had a very poor chance of survival,” he added.

Additionally, based on detailed multivariate analysis including a number of clinical factors, risk predictive scores were developed for event-free survival risk at 18 months or cumulative incidence of relapse at 18 months. Multiple scores were developed for each, but, as an example of factors that had an important effect on outcomes, patients with very early pretransplant relapse (those who went into remission but relapsed within 18 months) or with greater than 2nd relapse had a high risk for poor event-free survival. Mismatched donors and unrelated cord-blood stem cell transplant recipients also had high risk, he said, noting that, “of course, MRD had a significant effect” and was the most important factor prior to transplant.

These patients, who had a 4-point or greater risk score, were the poorest risk group, with survival that was less than 50%, as opposed to better risk groups that exceeded 90%, he said.

“A score of greater than 5 could identify 80% of patients who were going to relapse after transplant, and of course, event-free and overall survival in those patients were very poor,” he added.

As time went by, the early risk of GVHD diminished somewhat, as did the risk of mismatched donors.

“Most of the risk was associated with any MRD detection,” he said.

Flow cytometry and RQ-PCR levels of at least 10-4 were highly predictive of relapse at all pre- and post-HCT time points; however, RQ-PCR values between 10-4 and 10-3, in cases where adequate numbers were available for comparison, better predicted relapse as compared with flow cytometry results.

For example, before HCT, hazard ratios were 1.26 and 2.41 with flow cytometry vs. RQ-PCR. At day 30, the hazard ratios were 1.33 and 2.53, and at day 365, they were 3.54 and 31.84, Dr. Pulsipher reported.

The findings provide important information for improving outcomes in children with high-risk ALL undergoing HCT, he said.

“Older prognostic models for relapsed and refractory high-risk ALL have focused on timing and location of relapse, as well as disease phenotype. But it is clear that, in order to treat children with very high risk ALL with transplantation, MRD has become the most important thing to look at in the pretreatment setting. The challenges that we face in assessing MRD, however, have been hampered by the fact that we have differing MRD measurements,” he said, noting that RQ-PCR is often used in Europe, while flow cytometry is more often used in the United States. As such, direct comparisons are lacking, as are T-cell and posttransplant data.

The current study represents a “tremendous effort” by international collaborators to address these shortcoming, he said.

“This is a great opportunity, as our goal, of course, is to avoid futility in transplantation, but, more importantly, to find opportunities to identify groups for which we can improve our outcomes,” he added.

Patients included in the study were treated in Europe, North America, and Australia and were transplanted during Sept. 1999-May 2016. Most were in first or second remission, and most (586) had pre-B ALL. A notable 145 had T-cell ALL – “more than ever has been analyzed previously” – and 16 had B-lineage or biphenotypic ALL. About half were under age 10 years, 62% were boys, and stem cell sources were typical, although 20% received a cord blood transplant.

Dr. Pulsipher reported serving as an advisor and/or consultant for Chimerix, Novartis, Jazz Pharmaceutical, and receiving housing support from Medac Pharma for an educational meeting.

sworcester@frontlinemedcom.com

ORLANDO – Minimal residual disease (MRD) measured before and after allogeneic hematopoietic stem cell transplantation (HCT) is a powerful predictor of survival in children with acute lymphoblastic leukemia (ALL), according to a review of hundreds of cases from around the world.

The findings could have implications for using minimal residual disease measures to guide posttransplant interventions, Michael A. Pulsipher, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“MRD pretransplant was a very powerful predictor of outcomes. MRD posttransplant highlights individual patients at risk,” Dr. Pulsipher said. Results comparing reverse transcriptase–polymerase chain reaction with flow cytometry require validation by direct comparison in the same patient cohort, but “the new risk scores ... very nicely predict outcomes both pre- and post-transplant and can guide study planning and patient counseling.”

A total of 2,960 bone marrow MRD measurements were performed in the 747 patients included in the study. MRD was assessed prior to HCT and on or near days 30, 60, 100, 180, and 365 and beyond after HCT.

Patients were grouped for analysis according to MRD level: Group 1 had no detectable MRD, group 2 had low detectable MRD levels (less than 10E-4, or 0.01% by flow cytometry), and group 3 had high detectable MRD levels (10E-4 or higher). A second analysis compared findings in those tested by flow cytometry and those tested by real-time quantitative PCR (RQ-PCR), said Dr. Pulsipher of Children’s Hospital Los Angeles.

In 648 patients with pre-HCT MRD measurements available, the 4-year probability of event-free survival was 62%, 67%, and 37% for groups 1, 2, and 3, respectively. Group 3 – the high MRD level group – had 2.47 times the increased hazard ratio for relapse and 1.67 times the increased risk of treatment-related mortality, Dr. Pulsipher said, adding that pre-HCT MRD and remission status both significantly influenced survival, while age, sex, relapse site, cytogenetics, donor type, and stem cell source did not influence outcome.

Post-HCT MRD values were analyzed as time-dependent covariates.

“As time went by more and more, any detectable level of MRD led to a very poor prognosis, whereas patients arriving at day 365 with no detectable MRD had exceptional prognosis with survival approaching 90%,” he said.

Specifically, the 4-year probability of event-free survival for groups 1, 2, and 3, respectively, were 59%, 65%, and 43% at day 30; 64%, 47%, and 36% at day 60; 65%, 69%, and 44% at day 90; 79%, 40%, and 12% at day 180; and 87%, 36%, and 25% at day 365.

Of note, a very significant interaction was seen between acute graft-versus-host disease (GVHD) and MRD, Dr. Pulsipher said, explaining that patients who were MRD positive and had developed GVHD had a significant decrease in the cumulative incidence of relapse, compared with those with no GVHD.

“This translated into improved event-free survival with patients post transplant, who were MRD-positive [and] developing GVHD, still having a reasonable chance of survival, whereas patients post transplant who had MRD measured who did not develop GVHD had a very poor chance of survival,” he added.

Additionally, based on detailed multivariate analysis including a number of clinical factors, risk predictive scores were developed for event-free survival risk at 18 months or cumulative incidence of relapse at 18 months. Multiple scores were developed for each, but, as an example of factors that had an important effect on outcomes, patients with very early pretransplant relapse (those who went into remission but relapsed within 18 months) or with greater than 2nd relapse had a high risk for poor event-free survival. Mismatched donors and unrelated cord-blood stem cell transplant recipients also had high risk, he said, noting that, “of course, MRD had a significant effect” and was the most important factor prior to transplant.

These patients, who had a 4-point or greater risk score, were the poorest risk group, with survival that was less than 50%, as opposed to better risk groups that exceeded 90%, he said.

“A score of greater than 5 could identify 80% of patients who were going to relapse after transplant, and of course, event-free and overall survival in those patients were very poor,” he added.

As time went by, the early risk of GVHD diminished somewhat, as did the risk of mismatched donors.

“Most of the risk was associated with any MRD detection,” he said.

Flow cytometry and RQ-PCR levels of at least 10-4 were highly predictive of relapse at all pre- and post-HCT time points; however, RQ-PCR values between 10-4 and 10-3, in cases where adequate numbers were available for comparison, better predicted relapse as compared with flow cytometry results.

For example, before HCT, hazard ratios were 1.26 and 2.41 with flow cytometry vs. RQ-PCR. At day 30, the hazard ratios were 1.33 and 2.53, and at day 365, they were 3.54 and 31.84, Dr. Pulsipher reported.

The findings provide important information for improving outcomes in children with high-risk ALL undergoing HCT, he said.

“Older prognostic models for relapsed and refractory high-risk ALL have focused on timing and location of relapse, as well as disease phenotype. But it is clear that, in order to treat children with very high risk ALL with transplantation, MRD has become the most important thing to look at in the pretreatment setting. The challenges that we face in assessing MRD, however, have been hampered by the fact that we have differing MRD measurements,” he said, noting that RQ-PCR is often used in Europe, while flow cytometry is more often used in the United States. As such, direct comparisons are lacking, as are T-cell and posttransplant data.

The current study represents a “tremendous effort” by international collaborators to address these shortcoming, he said.

“This is a great opportunity, as our goal, of course, is to avoid futility in transplantation, but, more importantly, to find opportunities to identify groups for which we can improve our outcomes,” he added.

Patients included in the study were treated in Europe, North America, and Australia and were transplanted during Sept. 1999-May 2016. Most were in first or second remission, and most (586) had pre-B ALL. A notable 145 had T-cell ALL – “more than ever has been analyzed previously” – and 16 had B-lineage or biphenotypic ALL. About half were under age 10 years, 62% were boys, and stem cell sources were typical, although 20% received a cord blood transplant.

Dr. Pulsipher reported serving as an advisor and/or consultant for Chimerix, Novartis, Jazz Pharmaceutical, and receiving housing support from Medac Pharma for an educational meeting.

sworcester@frontlinemedcom.com

ORLANDO – Rituximab conferred a significant progression-free survival benefit in reduced intensity conditioning regimens for patients with B-cell non-Hodgkin lymphoma who underwent allogeneic hematopoietic cell transplantation, based on data from the Center for International Blood & Marrow Transplant Research.

Further, higher cumulative rituximab doses appeared to confer a benefit in overall survival.

Rituximab is frequently a component of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic cell transplantation (HCT), but there has been a “paucity of comparative data” for rituximab-containing (R-RIC) versus non–R-RIC conditioning regimens for allogeneic transplant patients, Narendranath Epperla, MD, of the Medical College of Wisconsin, Milwaukee, said during the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.

Using data from the Center for International Blood & Marrow Transplant Research, Dr. Epperla and his colleagues identified 1,022 patients who received rituximab and 379 patients who did not with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. The patients received their first RIC or non-myeloablative allogeneic HCT between 2008 and 2014. The donors were matched, and either related or 8x8 allele-matched unrelated; the graft source could be bone marrow or peripheral blood. Graft versus host disease (GVHD) suppression was calcineurin inhibitor based.

Patients who had received myeloablative conditioning, or who had received radioimmunotherapy or alemtuzumab were excluded, as were those who received alternative donor allografts.

Dr. Epperla and his colleagues factored in patient and disease characteristics, as well as differences in transplant regimen, in determining the adjusted cumulative incidence of relapse or progression, as well as the incidence of nonrelapse mortality.

In the multivariable analysis, overall survival did not differ between the R-RIC and the non–R-RIC cohorts (relative risk [RR] of all-cause mortality, R-RIC = 0.83, 95% CI 0.67-1.03, P = .09).

Based on the cumulative dose of rituximab that patients had received, though, “we noted that patients who got higher doses of rituximab had lower risk of nonrelapse mortality,” Dr. Epperla said. “Higher cumulative doses of rituximab seem to confer overall survival benefit.” This was true even though the higher rituximab doses had no significant effect on the risk of therapy failure, nonrelapse mortality, or the risk of progression/relapse.

When the cumulative rituximab dose was 2,000 to 3,375 mg/m², the hazard ratio for all-cause mortality fell to 0.43 compared to a cumulative rituximab dose of less than 1,000 mg/m² (95% confidence interval [CI] 0.21-0.90, P = .02).

Among the R-RIC group, there was a nonsignificant trend toward reduced risk of progression or relapse (relative risk of progression/relapse, R-RIC = 0.79, 95% CI 0.63-1.01, P = .055). However, the R-RIC group fared significantly better in terms of progression-free survival (RR of PFS, R-RIC = 0.76, 95% CI 0.62-0.92, P = .006).

After transplant, patients in the R-RIC group were no more likely than those in the non–R-RIC group to experience chronic GVHD (RR of GVHD, R-RIC = 1.15, 95% CI 0.96-1.39, P = .13). There was no difference in the adjusted curves of nonrelapse mortality between the groups (RR of nonrelapse mortality, R-RIC = 0.90, 95% CI 0.67-1.22, P = .51).

Also, there were no fatal cytopenias in the R-RIC arm, although the literature warrants some concern for increased risk of infection with rituximab, Dr. Epperla said.

At baseline, there were no significant differences in demographic characteristics between the nonrituximab and rituximab arms of the study population. More than 90% of patients were white, and 65% were male; the median age was 57 years (range, 18-74).

Patients had been diagnosed about 3 years before receiving HCT; about 60% of patients had a baseline Karnofsky performance score greater than 90, and the HCT comorbidity index was 2. About 86% of patients were chemosensitive, and patients in both study arms had received a median of three prior lines of therapy.

There were some differences in conditioning regimens between the two groups. “There were a significantly higher number of patients in the nonrituximab group who received fludarabine/busulfan, while there were a significantly high number in the rituximab group who received a fludarabine/cyclophosphamide-based conditioning regimen,” Dr. Epperla said. Follicular lymphomas were more common in the R-RIC arm, while diffuse large B-cell lymphomas were seen more in the non–R-RIC arm.

Given the survival benefit and similar rates of chronic GVHD seen in the retrospective analysis, a prospective, randomized head-to-head trial of R-RIC versus non–R-RIC is warranted, Dr. Epperla concluded.

During the postpresentation discussion, Dr. Epperla acknowledged the variability of the lymphomas in the study, but that there was no significant statistical effect of specific histologies on the findings in a subgroup analysis. Dr. Epperla added that the chemosensitivity status at transplant was checked to account for patient exposure to rituximab before RIC, and that there was no effect of prior rituximab exposure on the outcomes examined.

Dr. Epperla reported no conflicts of interest.
 

koakes@frontlinemedcom.com

On Twitter @karioakes

ORLANDO – Rituximab conferred a significant progression-free survival benefit in reduced intensity conditioning regimens for patients with B-cell non-Hodgkin lymphoma who underwent allogeneic hematopoietic cell transplantation, based on data from the Center for International Blood & Marrow Transplant Research.

Further, higher cumulative rituximab doses appeared to confer a benefit in overall survival.

Rituximab is frequently a component of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic cell transplantation (HCT), but there has been a “paucity of comparative data” for rituximab-containing (R-RIC) versus non–R-RIC conditioning regimens for allogeneic transplant patients, Narendranath Epperla, MD, of the Medical College of Wisconsin, Milwaukee, said during the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.

Using data from the Center for International Blood & Marrow Transplant Research, Dr. Epperla and his colleagues identified 1,022 patients who received rituximab and 379 patients who did not with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. The patients received their first RIC or non-myeloablative allogeneic HCT between 2008 and 2014. The donors were matched, and either related or 8x8 allele-matched unrelated; the graft source could be bone marrow or peripheral blood. Graft versus host disease (GVHD) suppression was calcineurin inhibitor based.

Patients who had received myeloablative conditioning, or who had received radioimmunotherapy or alemtuzumab were excluded, as were those who received alternative donor allografts.

Dr. Epperla and his colleagues factored in patient and disease characteristics, as well as differences in transplant regimen, in determining the adjusted cumulative incidence of relapse or progression, as well as the incidence of nonrelapse mortality.

In the multivariable analysis, overall survival did not differ between the R-RIC and the non–R-RIC cohorts (relative risk [RR] of all-cause mortality, R-RIC = 0.83, 95% CI 0.67-1.03, P = .09).

Based on the cumulative dose of rituximab that patients had received, though, “we noted that patients who got higher doses of rituximab had lower risk of nonrelapse mortality,” Dr. Epperla said. “Higher cumulative doses of rituximab seem to confer overall survival benefit.” This was true even though the higher rituximab doses had no significant effect on the risk of therapy failure, nonrelapse mortality, or the risk of progression/relapse.

When the cumulative rituximab dose was 2,000 to 3,375 mg/m², the hazard ratio for all-cause mortality fell to 0.43 compared to a cumulative rituximab dose of less than 1,000 mg/m² (95% confidence interval [CI] 0.21-0.90, P = .02).

Among the R-RIC group, there was a nonsignificant trend toward reduced risk of progression or relapse (relative risk of progression/relapse, R-RIC = 0.79, 95% CI 0.63-1.01, P = .055). However, the R-RIC group fared significantly better in terms of progression-free survival (RR of PFS, R-RIC = 0.76, 95% CI 0.62-0.92, P = .006).

After transplant, patients in the R-RIC group were no more likely than those in the non–R-RIC group to experience chronic GVHD (RR of GVHD, R-RIC = 1.15, 95% CI 0.96-1.39, P = .13). There was no difference in the adjusted curves of nonrelapse mortality between the groups (RR of nonrelapse mortality, R-RIC = 0.90, 95% CI 0.67-1.22, P = .51).

Also, there were no fatal cytopenias in the R-RIC arm, although the literature warrants some concern for increased risk of infection with rituximab, Dr. Epperla said.

At baseline, there were no significant differences in demographic characteristics between the nonrituximab and rituximab arms of the study population. More than 90% of patients were white, and 65% were male; the median age was 57 years (range, 18-74).

Patients had been diagnosed about 3 years before receiving HCT; about 60% of patients had a baseline Karnofsky performance score greater than 90, and the HCT comorbidity index was 2. About 86% of patients were chemosensitive, and patients in both study arms had received a median of three prior lines of therapy.

There were some differences in conditioning regimens between the two groups. “There were a significantly higher number of patients in the nonrituximab group who received fludarabine/busulfan, while there were a significantly high number in the rituximab group who received a fludarabine/cyclophosphamide-based conditioning regimen,” Dr. Epperla said. Follicular lymphomas were more common in the R-RIC arm, while diffuse large B-cell lymphomas were seen more in the non–R-RIC arm.

Given the survival benefit and similar rates of chronic GVHD seen in the retrospective analysis, a prospective, randomized head-to-head trial of R-RIC versus non–R-RIC is warranted, Dr. Epperla concluded.

During the postpresentation discussion, Dr. Epperla acknowledged the variability of the lymphomas in the study, but that there was no significant statistical effect of specific histologies on the findings in a subgroup analysis. Dr. Epperla added that the chemosensitivity status at transplant was checked to account for patient exposure to rituximab before RIC, and that there was no effect of prior rituximab exposure on the outcomes examined.

Dr. Epperla reported no conflicts of interest.
 

koakes@frontlinemedcom.com

On Twitter @karioakes

ORLANDO – Rituximab conferred a significant progression-free survival benefit in reduced intensity conditioning regimens for patients with B-cell non-Hodgkin lymphoma who underwent allogeneic hematopoietic cell transplantation, based on data from the Center for International Blood & Marrow Transplant Research.

Further, higher cumulative rituximab doses appeared to confer a benefit in overall survival.

Rituximab is frequently a component of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic cell transplantation (HCT), but there has been a “paucity of comparative data” for rituximab-containing (R-RIC) versus non–R-RIC conditioning regimens for allogeneic transplant patients, Narendranath Epperla, MD, of the Medical College of Wisconsin, Milwaukee, said during the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.

Using data from the Center for International Blood & Marrow Transplant Research, Dr. Epperla and his colleagues identified 1,022 patients who received rituximab and 379 patients who did not with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. The patients received their first RIC or non-myeloablative allogeneic HCT between 2008 and 2014. The donors were matched, and either related or 8x8 allele-matched unrelated; the graft source could be bone marrow or peripheral blood. Graft versus host disease (GVHD) suppression was calcineurin inhibitor based.

Patients who had received myeloablative conditioning, or who had received radioimmunotherapy or alemtuzumab were excluded, as were those who received alternative donor allografts.

Dr. Epperla and his colleagues factored in patient and disease characteristics, as well as differences in transplant regimen, in determining the adjusted cumulative incidence of relapse or progression, as well as the incidence of nonrelapse mortality.

In the multivariable analysis, overall survival did not differ between the R-RIC and the non–R-RIC cohorts (relative risk [RR] of all-cause mortality, R-RIC = 0.83, 95% CI 0.67-1.03, P = .09).

Based on the cumulative dose of rituximab that patients had received, though, “we noted that patients who got higher doses of rituximab had lower risk of nonrelapse mortality,” Dr. Epperla said. “Higher cumulative doses of rituximab seem to confer overall survival benefit.” This was true even though the higher rituximab doses had no significant effect on the risk of therapy failure, nonrelapse mortality, or the risk of progression/relapse.

When the cumulative rituximab dose was 2,000 to 3,375 mg/m², the hazard ratio for all-cause mortality fell to 0.43 compared to a cumulative rituximab dose of less than 1,000 mg/m² (95% confidence interval [CI] 0.21-0.90, P = .02).

Among the R-RIC group, there was a nonsignificant trend toward reduced risk of progression or relapse (relative risk of progression/relapse, R-RIC = 0.79, 95% CI 0.63-1.01, P = .055). However, the R-RIC group fared significantly better in terms of progression-free survival (RR of PFS, R-RIC = 0.76, 95% CI 0.62-0.92, P = .006).

After transplant, patients in the R-RIC group were no more likely than those in the non–R-RIC group to experience chronic GVHD (RR of GVHD, R-RIC = 1.15, 95% CI 0.96-1.39, P = .13). There was no difference in the adjusted curves of nonrelapse mortality between the groups (RR of nonrelapse mortality, R-RIC = 0.90, 95% CI 0.67-1.22, P = .51).

Also, there were no fatal cytopenias in the R-RIC arm, although the literature warrants some concern for increased risk of infection with rituximab, Dr. Epperla said.

At baseline, there were no significant differences in demographic characteristics between the nonrituximab and rituximab arms of the study population. More than 90% of patients were white, and 65% were male; the median age was 57 years (range, 18-74).

Patients had been diagnosed about 3 years before receiving HCT; about 60% of patients had a baseline Karnofsky performance score greater than 90, and the HCT comorbidity index was 2. About 86% of patients were chemosensitive, and patients in both study arms had received a median of three prior lines of therapy.

There were some differences in conditioning regimens between the two groups. “There were a significantly higher number of patients in the nonrituximab group who received fludarabine/busulfan, while there were a significantly high number in the rituximab group who received a fludarabine/cyclophosphamide-based conditioning regimen,” Dr. Epperla said. Follicular lymphomas were more common in the R-RIC arm, while diffuse large B-cell lymphomas were seen more in the non–R-RIC arm.

Given the survival benefit and similar rates of chronic GVHD seen in the retrospective analysis, a prospective, randomized head-to-head trial of R-RIC versus non–R-RIC is warranted, Dr. Epperla concluded.

During the postpresentation discussion, Dr. Epperla acknowledged the variability of the lymphomas in the study, but that there was no significant statistical effect of specific histologies on the findings in a subgroup analysis. Dr. Epperla added that the chemosensitivity status at transplant was checked to account for patient exposure to rituximab before RIC, and that there was no effect of prior rituximab exposure on the outcomes examined.

Dr. Epperla reported no conflicts of interest.
 

koakes@frontlinemedcom.com

On Twitter @karioakes

ORLANDO – Ibrutinib was associated with clinically meaningful and durable responses in patients with chronic graft-versus-host disease that did not respond to frontline systemic therapy, based on the final results of a phase II study.

Preliminary findings from that study led in 2016 to a Food and Drug Administration Breakthrough Therapy Designation for ibrutinib for chronic graft-versus-host disease (cGVHD) after the failure of one or more lines of systemic therapy, and the responses seen in this pretreated, high-risk population support the study of ibrutinib for frontline treatment of cGVHD, said David Miklos, MD, of Stanford (Calif.) University.

Sharon Worcester/Frontline Medical news

ORLANDO – Ibrutinib was associated with clinically meaningful and durable responses in patients with chronic graft-versus-host disease that did not respond to frontline systemic therapy, based on the final results of a phase II study.

Preliminary findings from that study led in 2016 to a Food and Drug Administration Breakthrough Therapy Designation for ibrutinib for chronic graft-versus-host disease (cGVHD) after the failure of one or more lines of systemic therapy, and the responses seen in this pretreated, high-risk population support the study of ibrutinib for frontline treatment of cGVHD, said David Miklos, MD, of Stanford (Calif.) University.

Sharon Worcester/Frontline Medical news

ORLANDO – Ibrutinib was associated with clinically meaningful and durable responses in patients with chronic graft-versus-host disease that did not respond to frontline systemic therapy, based on the final results of a phase II study.

Preliminary findings from that study led in 2016 to a Food and Drug Administration Breakthrough Therapy Designation for ibrutinib for chronic graft-versus-host disease (cGVHD) after the failure of one or more lines of systemic therapy, and the responses seen in this pretreated, high-risk population support the study of ibrutinib for frontline treatment of cGVHD, said David Miklos, MD, of Stanford (Calif.) University.

Sharon Worcester/Frontline Medical news

Photo by Steven Fruitsmaak

ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.

The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.

However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.

Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.

“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.

And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.

So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.

Study design

The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.

All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.

Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.

Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks

The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.

The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.

Patient characteristics

Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.

“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”

Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.

Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.

Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.

Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.

“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”

Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.

Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.

At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.

Results

At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).

For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.

Sixty-five patients were available for the day 365 efficacy analysis.

Bone density did not change significantly between day 100 and 365 for the entire group.

“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”

But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).

Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).

When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100  (P=0.001) and day 365 (P<0.0001).

The researchers observed no serious adverse events with ZA.

Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”

Photo by Steven Fruitsmaak

ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.

The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.

However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.

Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.

“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.

And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.

So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.

Study design

The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.

All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.

Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.

Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks

The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.

The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.

Patient characteristics

Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.

“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”

Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.

Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.

Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.

Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.

“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”

Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.

Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.

At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.

Results

At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).

For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.

Sixty-five patients were available for the day 365 efficacy analysis.

Bone density did not change significantly between day 100 and 365 for the entire group.

“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”

But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).

Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).

When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100  (P=0.001) and day 365 (P<0.0001).

The researchers observed no serious adverse events with ZA.

Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”

Photo by Steven Fruitsmaak

ORLANDO, FL—A single, 4 mg-dose of the bisphosphonate zoledronic acid (ZA) prior to allogeneic hematopoietic stem cell transplant (HSCT) prevents femoral neck (FN) bone loss at day 100 in patients with lymphoid or myeloid malignancies, according to new research.

The study also suggests that patients who receive risk-adapted ZA therapy after transplant can experience significant reductions in bone loss between days 100 and 365.

However, patients with acute and chronic graft-versus-host disease (GVHD) continue to be at risk of bone loss.

Eric Wong, of the Royal Melbourne Hospital in Parkville, Australia, presented these findings at the 2017 BMT Tandem Meetings (abstract 53) on behalf of the Australasian Leukaemia and Lymphoma Group.

“Previous studies have demonstrated that efforts to prevent bone loss through calcium and vitamin D supplementation as well as hormone-replacement therapy alone have been ineffective in preventing bone loss,” Wong explained.

And monthly pamidronate begun prior to HSCT reduces, but does not prevent, FN bone density loss.

So Wong and his colleagues began a trial of ZA, which is approximately 100-fold more potent than pamidronate.

Study design

The researchers enrolled 82 patients into the phase 2 ALLG BM07 trial. All patients received a single shot of ZA prior to HSCT conditioning.

All patients also received vitamin D and calcium supplements, and pre-menopausal women received hormone replacement therapy.

Depending on their risk of bone loss, patients received individualized ZA therapy after transplant. Researchers assessed the patients’ bone density at days 100, 180, 270, and 365 post-HSCT. Patients at high risk of bone loss received additional doses of ZA.

Risks for bone loss included bone mineral density (BMD) reduction of 5% or greater compared to baseline, prednisolone exposure of 1 mg/kg/d or greater for 2 weeks, or prednisolone exposure of 10 mg/d or more for 6 weeks

The primary endpoint of the study was the change in FN BMD at days 100 and 365 after HSCT compared to baseline.

The researchers also compared patients’ FN BMD with 35 untreated historical controls assessed at the same time points.

Patient characteristics

Seventy patients were alive and had not relapsed at day 100. Most (87%) were 60 years or younger, 60% were male, 53% had myeloid disease, 43% lymphoid, and 4% other disease.

“The most common indications for transplant were acute myeloid leukemia and acute lymphoblastic leukemia,” Wong said, “which, together, formed over 50% of the entire cohort.”

Seventy percent of patients were ECOG status 0 or 1, and 30% were 2 or greater.

Most (59%) had received myeloablative conditioning, the predominant regimens being busulfan/cyclophosphamide or cyclophosphamide/total-body irradiation. And the most common reduced-intensity conditioning regimen was fludarabine/melphalan.

Fifty-six percent of patients had a sibling donor, and 43% had a matched unrelated donor.

Thirty-eight percent of patients developed acute GVHD—19% grade 1, and 19% grade 2 to 3.

“Of note,” Wong said, “no patient developed grade 4 acute GVHD.”

Patients received a median of 2 ZA doses (range, 1–4), including the pre-transplant dose.

Sixty patients received at least 1 dose of ZA between day 100 and day 365, including 33% who received multiple doses.

At day 100, 33 patients received additional ZA. At day 180, 27 patients received additional ZA, including 8 patients who did not have it at day 100. And at day 270, 18 patients had additional ZA, including 1 patient who had no additional ZA at earlier time points.

Results

At day 100, there was no statistically significant change in FN bone density compared with baseline. The mean change was -2.6% (range, -6.6% to 1.4%).

For patients with acute GVHD, however, the change in bone density was significant (P=0.03). Patients with grade 1-2 GVHD had a mean change of -1.6% ± 3.7%, and patients with grade 3-4 GVHD had a mean change of -8.5% ± 11.2%.

Sixty-five patients were available for the day 365 efficacy analysis.

Bone density did not change significantly between day 100 and 365 for the entire group.

“By day 365,” Wong noted, “there was a net loss of bone density of -2.9%.”

But by day 365, patients with extensive chronic GVHD had significantly more bone loss compared with patients who had no chronic GVHD (P=0.03).

Age, sex, duration of cyclosporine, and mean steroid dose were not associated with a change in bone density at day 100 or 365, although there was a trend for an association between high steroid exposure and increased bone loss (P=0.07).

When the researchers compared the patients to untreated historical controls, patients who received ZA had significantly less bone loss at day 100  (P=0.001) and day 365 (P<0.0001).

The researchers observed no serious adverse events with ZA.

Wong concluded that patients with extensive GVHD are a “high-risk cohort that needs augmented therapies.”

Photo by Bill Branson

ORLANDO, FL—Results of a phase 3 trial suggest an inactivated varicella zoster virus (VZV) vaccine known as V212 can reduce the risk of herpes zoster (HZ) in patients who have undergone autologous hematopoietic stem cell transplant (HSCT).

V212 reduced the hazard rate of HZ by an estimated 64% compared to placebo.

The vaccine also reduced the incidence of moderate-to-severe HZ pain and other HZ-related complications, such as hospitalization.

The overall incidence of adverse events (AEs) and the incidence of serious AEs were similar among vaccinated patients and those who received placebo.

Drew J. Winston, MD, of the University of California Los Angeles Medical Center, presented these results as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 6). The trial was sponsored by Merck, the company developing V212.

Treatment

This randomized, double-blind trial enrolled 1230 patients age 18 and older who were undergoing HSCT for any indication and had a history of varicella infection and/or were seropositive for VZV antibody.

The patients were randomized to receive:

• A 4-dose regimen of V212 (n=560) from a consistency lot (a lot having a targeted potency as required by regulators in order to demonstrate that the vaccine can be manufactured consistently)
• A 4-dose regimen of V212 (n=106) from a high-antigen lot (a lot having a higher antigen potency added to assess the safety profile of V212)
• Placebo (n=564).

Randomization was stratified by age (< 50 years vs ≥ 50 years) and by intended duration of post-transplant antiviral prophylaxis (≤3 months vs >3 to 6 months).

Dose 1 of V212 or placebo was given within approximately 30 days before HSCT, and doses 2, 3, and 4 were given approximately 30, 60, and 90 days after HSCT.

Patient characteristics

The median patient age was 57 (range, 19-76) for the consistency lot group, 56 (range, 21-75) for the high-antigen lot group, and 56 (range, 19-79) for the placebo group.

Underlying diseases were non-Hodgkin lymphoma (42%, 40%, and 44%, respectively), Hodgkin lymphoma (10%, 9%, and 9%, respectively), multiple myeloma (44%, 47% and 41%, respectively), acute leukemia (2%, 1%, and 2%, respectively), and “other” diseases (2%, 3% and 4%, respectively).

Roughly 30% of patients in each group received anti-viral agents for 3 months or less after HSCT. Twenty percent to 25% received antiviral therapy for more than 3 months to 6 months.

Thirty-seven percent to 40% received antiviral agents for more than 6 months. And 7% to 12% of patients did not receive any antiviral therapy.

HZ incidence

The average follow-up time for HZ surveillance was approximately 2.3 years (median: 2.6 years) post-vaccination.

Confirmed HZ occurred in 42 of the 538 patients who received V212 from a consistency lot and 113 of the 535 patients who received placebo. (Patients receiving V212 from a high-antigen lot were only included in the safety analysis.)

The estimated efficacy of V212 was 63.8% after adjustment for patient age and the duration of antiviral prophylaxis. Vaccine efficacy against HZ was defined as the relative reduction of hazard rate of HZ in vaccine recipients compared with placebo recipients.

The vaccine met the pre-specified criterion for success, as the lower bound of the 95% confidence interval (CI) was greater than 25%. The 95% CI was 48.4% to 74.6% (P<0.0001).

“The study demonstrates that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr Winston said.

Pain, PHN, and other complications

V212 also reduced the incidence of moderate-to-severe HZ pain—according to the Zoster Brief Pain Inventory (ZBPI) score—by an estimated 69.5% (95% CI, 0.490-0.818).

Nineteen patients in the V212 consistency lot group had moderate-to-severe pain, as did 61 placebo-treated patients.

V212 conferred an estimated 83.7% (95% CI, 0.446-0.952) reduction in the incidence of post-herpetic neuralgia (PHN). Three patients in the V212 consistency lot group and 18 patients in the placebo group had PHN.

PHN was defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0-10 scale) on the ZBPI that persists or appears 90 days or beyond after HZ rash onset following HSCT.

Patients who received V212 also saw an estimated 73.5% (95% CI, 0.498-0.860) reduction in “other” HZ complications. Twelve patients in the V212 consistency group and 44 in the placebo group had such complications.

“Other” complications included hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, and the administration of intravenous acyclovir therapy for the treatment of HZ post-HSCT.

Safety

All patients who received at least 1 dose of the vaccine or placebo and had follow-up data were included in the safety analysis. Patients were followed for AEs up to 28 days after the fourth vaccination dose.

AEs occurred in 97% of patients who received the vaccine (consistency and high-antigen groups assessed together) and 96.9% of placebo-treated patients. Vaccine-related AEs occurred in 32.6% and 12.6%, respectively.

“Of course, in this population of autologous stem cell transplant patients, adverse events of any type were very common in almost all patients,” Dr Winston said. “However, vaccine-related adverse events were greater in the vaccine recipients compared to the placebo patients, but this was primarily due to an increased incidence of injection-site adverse events in the vaccine recipients.”

Injection-site reactions occurred in 191 vaccinated patients and 36 placebo-treated patients.

The most common systemic AEs—in vaccinated and placebo-treated patients, respectively—were diarrhea (60.1% and 61.9%), nausea (56.5% and 57.8%), pyrexia (49.8% and 46.9%), mucosal inflammation (39.7% and 41.7%), thrombocytopenia (36.4% and 38.4%), febrile neutropenia (33.9% and 28.3%), vomiting (32.6% and 36.6%), anemia (26.6% and 24.4%), neutropenia (25.1% and 23.5%), decreased appetite (23.1% and 23.8%), fatigue (21.8% and 20.7%), hypokalemia (21.3% and 19.9%), and constipation (16.1% and 18.4%).

The incidence of serious AEs was 32.9% in vaccinated patients and 32.7% in the placebo group. The incidence of serious vaccine-related AEs was 0.8% and 0.9%, respectively.

The most common serious AEs—in vaccinated and placebo-treated patients, respectively—were infection (12.3% and 11.9%), relapsed malignancy (7.8% for both), febrile neutropenia (5.3% and 4.9%), pyrexia (3.2% and 4.0%), gastrointestinal disorders (3.2% and 3.6%), respiratory failure (2.7% and 2.2%), cardiac disorders (1.7% and 1.6%), and mucositis (1.2% and 0.9%).

Death occurred in 6.2% of vaccinated patients and 6.3% of placebo-treated patients. Three percent and 3.1%, respectively, discontinued the study due to AEs.

Photo by Bill Branson

ORLANDO, FL—Results of a phase 3 trial suggest an inactivated varicella zoster virus (VZV) vaccine known as V212 can reduce the risk of herpes zoster (HZ) in patients who have undergone autologous hematopoietic stem cell transplant (HSCT).

V212 reduced the hazard rate of HZ by an estimated 64% compared to placebo.

The vaccine also reduced the incidence of moderate-to-severe HZ pain and other HZ-related complications, such as hospitalization.

The overall incidence of adverse events (AEs) and the incidence of serious AEs were similar among vaccinated patients and those who received placebo.

Drew J. Winston, MD, of the University of California Los Angeles Medical Center, presented these results as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 6). The trial was sponsored by Merck, the company developing V212.

Treatment

This randomized, double-blind trial enrolled 1230 patients age 18 and older who were undergoing HSCT for any indication and had a history of varicella infection and/or were seropositive for VZV antibody.

The patients were randomized to receive:

• A 4-dose regimen of V212 (n=560) from a consistency lot (a lot having a targeted potency as required by regulators in order to demonstrate that the vaccine can be manufactured consistently)
• A 4-dose regimen of V212 (n=106) from a high-antigen lot (a lot having a higher antigen potency added to assess the safety profile of V212)
• Placebo (n=564).

Randomization was stratified by age (< 50 years vs ≥ 50 years) and by intended duration of post-transplant antiviral prophylaxis (≤3 months vs >3 to 6 months).

Dose 1 of V212 or placebo was given within approximately 30 days before HSCT, and doses 2, 3, and 4 were given approximately 30, 60, and 90 days after HSCT.

Patient characteristics

The median patient age was 57 (range, 19-76) for the consistency lot group, 56 (range, 21-75) for the high-antigen lot group, and 56 (range, 19-79) for the placebo group.

Underlying diseases were non-Hodgkin lymphoma (42%, 40%, and 44%, respectively), Hodgkin lymphoma (10%, 9%, and 9%, respectively), multiple myeloma (44%, 47% and 41%, respectively), acute leukemia (2%, 1%, and 2%, respectively), and “other” diseases (2%, 3% and 4%, respectively).

Roughly 30% of patients in each group received anti-viral agents for 3 months or less after HSCT. Twenty percent to 25% received antiviral therapy for more than 3 months to 6 months.

Thirty-seven percent to 40% received antiviral agents for more than 6 months. And 7% to 12% of patients did not receive any antiviral therapy.

HZ incidence

The average follow-up time for HZ surveillance was approximately 2.3 years (median: 2.6 years) post-vaccination.

Confirmed HZ occurred in 42 of the 538 patients who received V212 from a consistency lot and 113 of the 535 patients who received placebo. (Patients receiving V212 from a high-antigen lot were only included in the safety analysis.)

The estimated efficacy of V212 was 63.8% after adjustment for patient age and the duration of antiviral prophylaxis. Vaccine efficacy against HZ was defined as the relative reduction of hazard rate of HZ in vaccine recipients compared with placebo recipients.

The vaccine met the pre-specified criterion for success, as the lower bound of the 95% confidence interval (CI) was greater than 25%. The 95% CI was 48.4% to 74.6% (P<0.0001).

“The study demonstrates that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr Winston said.

Pain, PHN, and other complications

V212 also reduced the incidence of moderate-to-severe HZ pain—according to the Zoster Brief Pain Inventory (ZBPI) score—by an estimated 69.5% (95% CI, 0.490-0.818).

Nineteen patients in the V212 consistency lot group had moderate-to-severe pain, as did 61 placebo-treated patients.

V212 conferred an estimated 83.7% (95% CI, 0.446-0.952) reduction in the incidence of post-herpetic neuralgia (PHN). Three patients in the V212 consistency lot group and 18 patients in the placebo group had PHN.

PHN was defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0-10 scale) on the ZBPI that persists or appears 90 days or beyond after HZ rash onset following HSCT.

Patients who received V212 also saw an estimated 73.5% (95% CI, 0.498-0.860) reduction in “other” HZ complications. Twelve patients in the V212 consistency group and 44 in the placebo group had such complications.

“Other” complications included hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, and the administration of intravenous acyclovir therapy for the treatment of HZ post-HSCT.

Safety

All patients who received at least 1 dose of the vaccine or placebo and had follow-up data were included in the safety analysis. Patients were followed for AEs up to 28 days after the fourth vaccination dose.

AEs occurred in 97% of patients who received the vaccine (consistency and high-antigen groups assessed together) and 96.9% of placebo-treated patients. Vaccine-related AEs occurred in 32.6% and 12.6%, respectively.

“Of course, in this population of autologous stem cell transplant patients, adverse events of any type were very common in almost all patients,” Dr Winston said. “However, vaccine-related adverse events were greater in the vaccine recipients compared to the placebo patients, but this was primarily due to an increased incidence of injection-site adverse events in the vaccine recipients.”

Injection-site reactions occurred in 191 vaccinated patients and 36 placebo-treated patients.

The most common systemic AEs—in vaccinated and placebo-treated patients, respectively—were diarrhea (60.1% and 61.9%), nausea (56.5% and 57.8%), pyrexia (49.8% and 46.9%), mucosal inflammation (39.7% and 41.7%), thrombocytopenia (36.4% and 38.4%), febrile neutropenia (33.9% and 28.3%), vomiting (32.6% and 36.6%), anemia (26.6% and 24.4%), neutropenia (25.1% and 23.5%), decreased appetite (23.1% and 23.8%), fatigue (21.8% and 20.7%), hypokalemia (21.3% and 19.9%), and constipation (16.1% and 18.4%).

The incidence of serious AEs was 32.9% in vaccinated patients and 32.7% in the placebo group. The incidence of serious vaccine-related AEs was 0.8% and 0.9%, respectively.

The most common serious AEs—in vaccinated and placebo-treated patients, respectively—were infection (12.3% and 11.9%), relapsed malignancy (7.8% for both), febrile neutropenia (5.3% and 4.9%), pyrexia (3.2% and 4.0%), gastrointestinal disorders (3.2% and 3.6%), respiratory failure (2.7% and 2.2%), cardiac disorders (1.7% and 1.6%), and mucositis (1.2% and 0.9%).

Death occurred in 6.2% of vaccinated patients and 6.3% of placebo-treated patients. Three percent and 3.1%, respectively, discontinued the study due to AEs.

Photo by Bill Branson

ORLANDO, FL—Results of a phase 3 trial suggest an inactivated varicella zoster virus (VZV) vaccine known as V212 can reduce the risk of herpes zoster (HZ) in patients who have undergone autologous hematopoietic stem cell transplant (HSCT).

V212 reduced the hazard rate of HZ by an estimated 64% compared to placebo.

The vaccine also reduced the incidence of moderate-to-severe HZ pain and other HZ-related complications, such as hospitalization.

The overall incidence of adverse events (AEs) and the incidence of serious AEs were similar among vaccinated patients and those who received placebo.

Drew J. Winston, MD, of the University of California Los Angeles Medical Center, presented these results as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 6). The trial was sponsored by Merck, the company developing V212.

Treatment

This randomized, double-blind trial enrolled 1230 patients age 18 and older who were undergoing HSCT for any indication and had a history of varicella infection and/or were seropositive for VZV antibody.

The patients were randomized to receive:

• A 4-dose regimen of V212 (n=560) from a consistency lot (a lot having a targeted potency as required by regulators in order to demonstrate that the vaccine can be manufactured consistently)
• A 4-dose regimen of V212 (n=106) from a high-antigen lot (a lot having a higher antigen potency added to assess the safety profile of V212)
• Placebo (n=564).

Randomization was stratified by age (< 50 years vs ≥ 50 years) and by intended duration of post-transplant antiviral prophylaxis (≤3 months vs >3 to 6 months).

Dose 1 of V212 or placebo was given within approximately 30 days before HSCT, and doses 2, 3, and 4 were given approximately 30, 60, and 90 days after HSCT.

Patient characteristics

The median patient age was 57 (range, 19-76) for the consistency lot group, 56 (range, 21-75) for the high-antigen lot group, and 56 (range, 19-79) for the placebo group.

Underlying diseases were non-Hodgkin lymphoma (42%, 40%, and 44%, respectively), Hodgkin lymphoma (10%, 9%, and 9%, respectively), multiple myeloma (44%, 47% and 41%, respectively), acute leukemia (2%, 1%, and 2%, respectively), and “other” diseases (2%, 3% and 4%, respectively).

Roughly 30% of patients in each group received anti-viral agents for 3 months or less after HSCT. Twenty percent to 25% received antiviral therapy for more than 3 months to 6 months.

Thirty-seven percent to 40% received antiviral agents for more than 6 months. And 7% to 12% of patients did not receive any antiviral therapy.

HZ incidence

The average follow-up time for HZ surveillance was approximately 2.3 years (median: 2.6 years) post-vaccination.

Confirmed HZ occurred in 42 of the 538 patients who received V212 from a consistency lot and 113 of the 535 patients who received placebo. (Patients receiving V212 from a high-antigen lot were only included in the safety analysis.)

The estimated efficacy of V212 was 63.8% after adjustment for patient age and the duration of antiviral prophylaxis. Vaccine efficacy against HZ was defined as the relative reduction of hazard rate of HZ in vaccine recipients compared with placebo recipients.

The vaccine met the pre-specified criterion for success, as the lower bound of the 95% confidence interval (CI) was greater than 25%. The 95% CI was 48.4% to 74.6% (P<0.0001).

“The study demonstrates that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr Winston said.

Pain, PHN, and other complications

V212 also reduced the incidence of moderate-to-severe HZ pain—according to the Zoster Brief Pain Inventory (ZBPI) score—by an estimated 69.5% (95% CI, 0.490-0.818).

Nineteen patients in the V212 consistency lot group had moderate-to-severe pain, as did 61 placebo-treated patients.

V212 conferred an estimated 83.7% (95% CI, 0.446-0.952) reduction in the incidence of post-herpetic neuralgia (PHN). Three patients in the V212 consistency lot group and 18 patients in the placebo group had PHN.

PHN was defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0-10 scale) on the ZBPI that persists or appears 90 days or beyond after HZ rash onset following HSCT.

Patients who received V212 also saw an estimated 73.5% (95% CI, 0.498-0.860) reduction in “other” HZ complications. Twelve patients in the V212 consistency group and 44 in the placebo group had such complications.

“Other” complications included hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, and the administration of intravenous acyclovir therapy for the treatment of HZ post-HSCT.

Safety

All patients who received at least 1 dose of the vaccine or placebo and had follow-up data were included in the safety analysis. Patients were followed for AEs up to 28 days after the fourth vaccination dose.

AEs occurred in 97% of patients who received the vaccine (consistency and high-antigen groups assessed together) and 96.9% of placebo-treated patients. Vaccine-related AEs occurred in 32.6% and 12.6%, respectively.

“Of course, in this population of autologous stem cell transplant patients, adverse events of any type were very common in almost all patients,” Dr Winston said. “However, vaccine-related adverse events were greater in the vaccine recipients compared to the placebo patients, but this was primarily due to an increased incidence of injection-site adverse events in the vaccine recipients.”

Injection-site reactions occurred in 191 vaccinated patients and 36 placebo-treated patients.

The most common systemic AEs—in vaccinated and placebo-treated patients, respectively—were diarrhea (60.1% and 61.9%), nausea (56.5% and 57.8%), pyrexia (49.8% and 46.9%), mucosal inflammation (39.7% and 41.7%), thrombocytopenia (36.4% and 38.4%), febrile neutropenia (33.9% and 28.3%), vomiting (32.6% and 36.6%), anemia (26.6% and 24.4%), neutropenia (25.1% and 23.5%), decreased appetite (23.1% and 23.8%), fatigue (21.8% and 20.7%), hypokalemia (21.3% and 19.9%), and constipation (16.1% and 18.4%).

The incidence of serious AEs was 32.9% in vaccinated patients and 32.7% in the placebo group. The incidence of serious vaccine-related AEs was 0.8% and 0.9%, respectively.

The most common serious AEs—in vaccinated and placebo-treated patients, respectively—were infection (12.3% and 11.9%), relapsed malignancy (7.8% for both), febrile neutropenia (5.3% and 4.9%), pyrexia (3.2% and 4.0%), gastrointestinal disorders (3.2% and 3.6%), respiratory failure (2.7% and 2.2%), cardiac disorders (1.7% and 1.6%), and mucositis (1.2% and 0.9%).

Death occurred in 6.2% of vaccinated patients and 6.3% of placebo-treated patients. Three percent and 3.1%, respectively, discontinued the study due to AEs.

Photo courtesy of CDC

ORLANDO, FL—New research shows that patients who received inpatient palliative care while undergoing hematopoietic stem cell transplant (HSCT) experienced significant improvements in quality of life (QOL), decreases in depression, and reductions in symptom burden compared to patients who received transplant care alone.

Areej R. El-Jawahri, MD, of Harvard Medical School in Boston, Massachusetts, presented these results at the 2017 BMT Tandem Meetings (abstract 49).

She noted that palliative care is rarely used for patients with hematologic malignancies, “in part, because of misperceptions equating palliative care with just end-of-life care.”

So Dr El-Jawahri and her colleagues decided to evaluate palliative care in patients with hematologic malignancies who were scheduled to undergo HSCT.

The researchers enrolled 160 patients on the trial. Eighty-one were randomized to receive inpatient palliative care integrated with transplant care (intervention arm), and 79 were randomized to transplant care alone (control).

The latter group could request palliative care consultations, but only 2 patients did so, Dr El-Jawahri pointed out.

Patients receiving the intervention had at least twice-weekly visits with a palliative care clinician throughout their hospitalization.

“Importantly, palliative care only followed patients during their transplant hospitalization,” Dr El-Jawahri noted. “This was purely an inpatient palliative care intervention.”

Palliative care focused primarily on managing patients’ symptoms, establishing rapport with patients and families, and helping them cope with their illness. The predominant symptoms addressed included pain, nausea, diarrhea, constipation, insomnia, fatigue, depression, and anxiety.

Researchers assessed QOL, symptom burden, and mood at baseline, during hospitalization (Week 2), and at 3 and 6 months using well-validated scales.

They assessed QOL using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale, mood using the Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire (PHQ-9), and symptom burden using the Edmonton Symptom Assessment Scale (ESAS).

They also measured post-traumatic stress (PTSD) at baseline as well as 3 and 6 months after HSCT using the PTSD checklist.

The primary endpoint of the study was patient-reported QOL at Week 2 of hospitalization. Researchers chose Week 2 because studies have shown the highest symptom burden and QOL deterioration during that period.

Demographics

Patients were a mean age of 57, and a little more than half were female. Most were white, had a college degree or higher, and were married.

Their diagnoses included, for the control and intervention arms, respectively: acute lymphoblastic leukemia (9%, 5%), acute myeloid leukemia/myelodysplastic syndromes (30%, 30%), myelofibrosis/chronic myeloid leukemia (9%, 10%), lymphoma (33%, 23%), and multiple myeloma (19%, 33%).

Results

At baseline, patients in each group had comparable QOL and mood scores.

However, at Week 2, after ANCOVA adjustment for baseline scores, patients in the intervention arm had a clinically and statistically significant effect of the intervention in all areas measured except for the PHQ-9 depression score.

In particular, the HADS depression and anxiety scores were significantly improved, at P=0.008 and P<0.001, respectively, compared to control.

At 3 months, the FACT-BMT (P=0.048), HADS-Depression (P=0.002), PHQ-9-Depression (P=0.002), and  PTSD symptom (P=0.002) scores were significantly improved in the intervention group.

And at 6 months, the HADS-Depression assessment (P=0.024), the PHQ-9-Depression assessment (P=0.027), and the PTSD symptom assessment (P=0.013) remained significantly improved. However, there were no significant differences in anxiety between the 2 groups.

The researchers concluded that a relatively brief inpatient care intervention led to “remarkable sustained improvements” in depression and post-traumatic stress symptoms at 3 and 6 months after HSCT.

“This is the first study showing the benefits of palliative care for patients with hematologic malignancies undergoing stem cell transplant,” Dr El-Jawahri said.

“It’s also the first study showing the benefits of palliative care for patients with cancer pursuing curative therapy and extends the potential benefit of palliative care in a population of patients with serious illness. [T]he significant part of what palliative care does is helping patients and families cope with serious and potentially life-threatening illness.”

The researchers recommend future studies to evaluate the impact of early integration of palliative care for this patient population.

Photo courtesy of CDC

ORLANDO, FL—New research shows that patients who received inpatient palliative care while undergoing hematopoietic stem cell transplant (HSCT) experienced significant improvements in quality of life (QOL), decreases in depression, and reductions in symptom burden compared to patients who received transplant care alone.

Areej R. El-Jawahri, MD, of Harvard Medical School in Boston, Massachusetts, presented these results at the 2017 BMT Tandem Meetings (abstract 49).

She noted that palliative care is rarely used for patients with hematologic malignancies, “in part, because of misperceptions equating palliative care with just end-of-life care.”

So Dr El-Jawahri and her colleagues decided to evaluate palliative care in patients with hematologic malignancies who were scheduled to undergo HSCT.

The researchers enrolled 160 patients on the trial. Eighty-one were randomized to receive inpatient palliative care integrated with transplant care (intervention arm), and 79 were randomized to transplant care alone (control).

The latter group could request palliative care consultations, but only 2 patients did so, Dr El-Jawahri pointed out.

Patients receiving the intervention had at least twice-weekly visits with a palliative care clinician throughout their hospitalization.

“Importantly, palliative care only followed patients during their transplant hospitalization,” Dr El-Jawahri noted. “This was purely an inpatient palliative care intervention.”

Palliative care focused primarily on managing patients’ symptoms, establishing rapport with patients and families, and helping them cope with their illness. The predominant symptoms addressed included pain, nausea, diarrhea, constipation, insomnia, fatigue, depression, and anxiety.

Researchers assessed QOL, symptom burden, and mood at baseline, during hospitalization (Week 2), and at 3 and 6 months using well-validated scales.

They assessed QOL using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale, mood using the Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire (PHQ-9), and symptom burden using the Edmonton Symptom Assessment Scale (ESAS).

They also measured post-traumatic stress (PTSD) at baseline as well as 3 and 6 months after HSCT using the PTSD checklist.

The primary endpoint of the study was patient-reported QOL at Week 2 of hospitalization. Researchers chose Week 2 because studies have shown the highest symptom burden and QOL deterioration during that period.

Demographics

Patients were a mean age of 57, and a little more than half were female. Most were white, had a college degree or higher, and were married.

Their diagnoses included, for the control and intervention arms, respectively: acute lymphoblastic leukemia (9%, 5%), acute myeloid leukemia/myelodysplastic syndromes (30%, 30%), myelofibrosis/chronic myeloid leukemia (9%, 10%), lymphoma (33%, 23%), and multiple myeloma (19%, 33%).

Results

At baseline, patients in each group had comparable QOL and mood scores.

However, at Week 2, after ANCOVA adjustment for baseline scores, patients in the intervention arm had a clinically and statistically significant effect of the intervention in all areas measured except for the PHQ-9 depression score.

In particular, the HADS depression and anxiety scores were significantly improved, at P=0.008 and P<0.001, respectively, compared to control.

At 3 months, the FACT-BMT (P=0.048), HADS-Depression (P=0.002), PHQ-9-Depression (P=0.002), and  PTSD symptom (P=0.002) scores were significantly improved in the intervention group.

And at 6 months, the HADS-Depression assessment (P=0.024), the PHQ-9-Depression assessment (P=0.027), and the PTSD symptom assessment (P=0.013) remained significantly improved. However, there were no significant differences in anxiety between the 2 groups.

The researchers concluded that a relatively brief inpatient care intervention led to “remarkable sustained improvements” in depression and post-traumatic stress symptoms at 3 and 6 months after HSCT.

“This is the first study showing the benefits of palliative care for patients with hematologic malignancies undergoing stem cell transplant,” Dr El-Jawahri said.

“It’s also the first study showing the benefits of palliative care for patients with cancer pursuing curative therapy and extends the potential benefit of palliative care in a population of patients with serious illness. [T]he significant part of what palliative care does is helping patients and families cope with serious and potentially life-threatening illness.”

The researchers recommend future studies to evaluate the impact of early integration of palliative care for this patient population.

Photo courtesy of CDC

ORLANDO, FL—New research shows that patients who received inpatient palliative care while undergoing hematopoietic stem cell transplant (HSCT) experienced significant improvements in quality of life (QOL), decreases in depression, and reductions in symptom burden compared to patients who received transplant care alone.

Areej R. El-Jawahri, MD, of Harvard Medical School in Boston, Massachusetts, presented these results at the 2017 BMT Tandem Meetings (abstract 49).

She noted that palliative care is rarely used for patients with hematologic malignancies, “in part, because of misperceptions equating palliative care with just end-of-life care.”

So Dr El-Jawahri and her colleagues decided to evaluate palliative care in patients with hematologic malignancies who were scheduled to undergo HSCT.

The researchers enrolled 160 patients on the trial. Eighty-one were randomized to receive inpatient palliative care integrated with transplant care (intervention arm), and 79 were randomized to transplant care alone (control).

The latter group could request palliative care consultations, but only 2 patients did so, Dr El-Jawahri pointed out.

Patients receiving the intervention had at least twice-weekly visits with a palliative care clinician throughout their hospitalization.

“Importantly, palliative care only followed patients during their transplant hospitalization,” Dr El-Jawahri noted. “This was purely an inpatient palliative care intervention.”

Palliative care focused primarily on managing patients’ symptoms, establishing rapport with patients and families, and helping them cope with their illness. The predominant symptoms addressed included pain, nausea, diarrhea, constipation, insomnia, fatigue, depression, and anxiety.

Researchers assessed QOL, symptom burden, and mood at baseline, during hospitalization (Week 2), and at 3 and 6 months using well-validated scales.

They assessed QOL using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale, mood using the Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire (PHQ-9), and symptom burden using the Edmonton Symptom Assessment Scale (ESAS).

They also measured post-traumatic stress (PTSD) at baseline as well as 3 and 6 months after HSCT using the PTSD checklist.

The primary endpoint of the study was patient-reported QOL at Week 2 of hospitalization. Researchers chose Week 2 because studies have shown the highest symptom burden and QOL deterioration during that period.

Demographics

Patients were a mean age of 57, and a little more than half were female. Most were white, had a college degree or higher, and were married.

Their diagnoses included, for the control and intervention arms, respectively: acute lymphoblastic leukemia (9%, 5%), acute myeloid leukemia/myelodysplastic syndromes (30%, 30%), myelofibrosis/chronic myeloid leukemia (9%, 10%), lymphoma (33%, 23%), and multiple myeloma (19%, 33%).

Results

At baseline, patients in each group had comparable QOL and mood scores.

However, at Week 2, after ANCOVA adjustment for baseline scores, patients in the intervention arm had a clinically and statistically significant effect of the intervention in all areas measured except for the PHQ-9 depression score.

In particular, the HADS depression and anxiety scores were significantly improved, at P=0.008 and P<0.001, respectively, compared to control.

At 3 months, the FACT-BMT (P=0.048), HADS-Depression (P=0.002), PHQ-9-Depression (P=0.002), and  PTSD symptom (P=0.002) scores were significantly improved in the intervention group.

And at 6 months, the HADS-Depression assessment (P=0.024), the PHQ-9-Depression assessment (P=0.027), and the PTSD symptom assessment (P=0.013) remained significantly improved. However, there were no significant differences in anxiety between the 2 groups.

The researchers concluded that a relatively brief inpatient care intervention led to “remarkable sustained improvements” in depression and post-traumatic stress symptoms at 3 and 6 months after HSCT.

“This is the first study showing the benefits of palliative care for patients with hematologic malignancies undergoing stem cell transplant,” Dr El-Jawahri said.

“It’s also the first study showing the benefits of palliative care for patients with cancer pursuing curative therapy and extends the potential benefit of palliative care in a population of patients with serious illness. [T]he significant part of what palliative care does is helping patients and families cope with serious and potentially life-threatening illness.”

The researchers recommend future studies to evaluate the impact of early integration of palliative care for this patient population.

ORLANDO – A composite score based on day 28 plasma levels of the angiogenic factors follistatin and endoglin predicts 1-year nonrelapse mortality in patients who have undergone myeloablative allogeneic hematopoietic cell transplantation, based on findings from the randomized Blood and Marrow Transplant Clinical Trials Network acute graft-versus-host prophylaxis study 0402 (BMT CTN 0402).

Elevations in these factors at day 28 may reflect susceptibility to regimen-related and other toxicities that adversely affect tissue repair and survival, Shernan Holtan, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Sharon Worcester/Frontline Medical News

Of 221 patients from BMT CTN 0402 with pretreatment and day 28 plasma samples available for analysis, 25 had died at 1 year of causes unrelated to relapse. In a univariate analysis, nonrelapse mortality was associated with levels of follistatin, endoglin, and angiopoietin-2. When combined to assess for an overall pattern of damage, only follistatin and endoglin were significantly associated with nonrelapse mortality.

The relative risk of death unrelated to relapse was 4.5-fold higher in patients with the highest score (score of 3) on multivariate regression analysis of follistatin and endoglin levels. Grade II-IV acute GVHD was not significantly associated with 1-year nonrelapse mortality in multivariate analyses, but age over 50 years was.

“Notably, the composite score was a better predictor than any factor alone,” Dr. Holtan said.

The composite score was also predictive of the development of acute GVHD.

“We found that a moderate score of 2 was associated with a 2.3-fold increased risk of acute GVHD prior to day 100. Interestingly, the higher score [3] was not associated with acute GVHD. There was no association of the composite score with chronic GVHD,” she said.

The risk of nonrelapse mortality was less than 10% in patients with a composite score of 1.

Among patients in the study with a score of 3, more than half of the deaths were related to organ toxicity, including liver failure and respiratory failure, which were predominantly infection-related. Those with a low composite score had very few deaths associated with organ toxicity, she noted.

While there are many unanswered questions, these findings highlight possible opportunities to improve survival after allogeneic hematopoietic cell transplantation that warrant further study, she said.

“We need to learn how to constrain this angiogenic inflammatory response with the ultimate goal of hopefully identifying novel treatment strategies to mitigate nonrelapse mortality in our patients,” she concluded.

Dr. Holtan is an investigator for Alexion and is site principal investigator on the GI GVHD clinical trial.

sworcester@frontlinemedcom.com

ORLANDO – A composite score based on day 28 plasma levels of the angiogenic factors follistatin and endoglin predicts 1-year nonrelapse mortality in patients who have undergone myeloablative allogeneic hematopoietic cell transplantation, based on findings from the randomized Blood and Marrow Transplant Clinical Trials Network acute graft-versus-host prophylaxis study 0402 (BMT CTN 0402).

Elevations in these factors at day 28 may reflect susceptibility to regimen-related and other toxicities that adversely affect tissue repair and survival, Shernan Holtan, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Sharon Worcester/Frontline Medical News

Of 221 patients from BMT CTN 0402 with pretreatment and day 28 plasma samples available for analysis, 25 had died at 1 year of causes unrelated to relapse. In a univariate analysis, nonrelapse mortality was associated with levels of follistatin, endoglin, and angiopoietin-2. When combined to assess for an overall pattern of damage, only follistatin and endoglin were significantly associated with nonrelapse mortality.

The relative risk of death unrelated to relapse was 4.5-fold higher in patients with the highest score (score of 3) on multivariate regression analysis of follistatin and endoglin levels. Grade II-IV acute GVHD was not significantly associated with 1-year nonrelapse mortality in multivariate analyses, but age over 50 years was.

“Notably, the composite score was a better predictor than any factor alone,” Dr. Holtan said.

The composite score was also predictive of the development of acute GVHD.

“We found that a moderate score of 2 was associated with a 2.3-fold increased risk of acute GVHD prior to day 100. Interestingly, the higher score [3] was not associated with acute GVHD. There was no association of the composite score with chronic GVHD,” she said.

The risk of nonrelapse mortality was less than 10% in patients with a composite score of 1.

Among patients in the study with a score of 3, more than half of the deaths were related to organ toxicity, including liver failure and respiratory failure, which were predominantly infection-related. Those with a low composite score had very few deaths associated with organ toxicity, she noted.

While there are many unanswered questions, these findings highlight possible opportunities to improve survival after allogeneic hematopoietic cell transplantation that warrant further study, she said.

“We need to learn how to constrain this angiogenic inflammatory response with the ultimate goal of hopefully identifying novel treatment strategies to mitigate nonrelapse mortality in our patients,” she concluded.

Dr. Holtan is an investigator for Alexion and is site principal investigator on the GI GVHD clinical trial.

sworcester@frontlinemedcom.com

ORLANDO – A composite score based on day 28 plasma levels of the angiogenic factors follistatin and endoglin predicts 1-year nonrelapse mortality in patients who have undergone myeloablative allogeneic hematopoietic cell transplantation, based on findings from the randomized Blood and Marrow Transplant Clinical Trials Network acute graft-versus-host prophylaxis study 0402 (BMT CTN 0402).

Elevations in these factors at day 28 may reflect susceptibility to regimen-related and other toxicities that adversely affect tissue repair and survival, Shernan Holtan, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Sharon Worcester/Frontline Medical News

Of 221 patients from BMT CTN 0402 with pretreatment and day 28 plasma samples available for analysis, 25 had died at 1 year of causes unrelated to relapse. In a univariate analysis, nonrelapse mortality was associated with levels of follistatin, endoglin, and angiopoietin-2. When combined to assess for an overall pattern of damage, only follistatin and endoglin were significantly associated with nonrelapse mortality.

The relative risk of death unrelated to relapse was 4.5-fold higher in patients with the highest score (score of 3) on multivariate regression analysis of follistatin and endoglin levels. Grade II-IV acute GVHD was not significantly associated with 1-year nonrelapse mortality in multivariate analyses, but age over 50 years was.

“Notably, the composite score was a better predictor than any factor alone,” Dr. Holtan said.

The composite score was also predictive of the development of acute GVHD.

“We found that a moderate score of 2 was associated with a 2.3-fold increased risk of acute GVHD prior to day 100. Interestingly, the higher score [3] was not associated with acute GVHD. There was no association of the composite score with chronic GVHD,” she said.

The risk of nonrelapse mortality was less than 10% in patients with a composite score of 1.

Among patients in the study with a score of 3, more than half of the deaths were related to organ toxicity, including liver failure and respiratory failure, which were predominantly infection-related. Those with a low composite score had very few deaths associated with organ toxicity, she noted.

While there are many unanswered questions, these findings highlight possible opportunities to improve survival after allogeneic hematopoietic cell transplantation that warrant further study, she said.

“We need to learn how to constrain this angiogenic inflammatory response with the ultimate goal of hopefully identifying novel treatment strategies to mitigate nonrelapse mortality in our patients,” she concluded.

Dr. Holtan is an investigator for Alexion and is site principal investigator on the GI GVHD clinical trial.

sworcester@frontlinemedcom.com