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MRD predicts outcome of HSCT in ALL, study suggests
ORLANDO, FL—Minimal residual disease (MRD) measurements before and after hematopoietic stem cell transplant (HSCT) can help predict outcomes in patients with childhood acute lymphoblastic leukemia (ALL), according to researchers.
Their work also suggests several other factors can be used to predict event-free survival (EFS) in this patient population, and the team developed risk scores incorporating these factors.
Michael A. Pulsipher, MD, of Children’s Hospital Los Angeles in California, presented this work as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 4*).
“The new risk scores that we were able to develop very nicely predict outcomes post-transplant and can guide study planning,” Dr Pulsipher said.
“MRD pre-transplant was a very powerful predictor of outcome, and MRD post-transplant highlights individual patients at risk.”
For this study, Dr Pulsipher and his colleagues retrospectively analyzed 747 patients treated in Europe, North America, and Australia. The patients received transplants between September 1999 and May 2015.
Most patients had pre-B ALL (78%, n=586), 19% (n=145) had T-cell ALL, 2% had “other” ALLs (n=8) or no data on ALL type (n=8). Sixty-two percent (n=466) were male.
Nearly half of patients were between the ages of 2 and 10 (49%, n=365), 47% (n=351) were older than 10, and 4% (n=31) were younger than 2.
Transplant details
Patients received grafts from matched unrelated donors (42%, n=314), matched sibling donors (30%, n=227), mismatched donors (10%, n=75), and cord blood from unrelated donors (17%, n=128). There was no data on donor type for 3 patients.
Most patients received bone marrow transplants (61%, n=458), 20% (n=147) received cord blood, and 18% (n=131) received peripheral blood stem cells. Eight patients received “other” types of transplants, and 3 patients had no data on stem cell source.
More than half of the patients (55%, n=410) were in their second complete remission (CR) at transplant. Thirty-seven percent were in their first CR (n=275), 7% were in their third or greater CR (n=53), and 1% were not in remission (n=7). Two patients had no data on remission status.
MRD
MRD was assessed before HSCT as well as after—on or near days 30, 60, 90, 180, 365, and beyond.
There were 4 MRD categories:
- MRD negative: No signal
- MRD low: >0 to <10-4 (<0.01%)
- MRD high: ≥10-4 to <10-3 (0.01 to 0.1%)
- MRD very high: ≥10-3 to <10-2 (>0.1%).
Dr Pulsipher noted that, when analyzing MRD pre-HSCT or at 30 days after HSCT, the estimated 5-year EFS was similar for patients in the MRD-negative and MRD-low groups. However, as time went on (at days 90, 180, and 365), any detectable level of MRD was associated with a poor prognosis.
“And patients arriving at day 365 with no detectable MRD had an exceptional prognosis, with survival approaching 90%,” Dr Pulsipher said.
He also pointed out an interaction between acute graft-vs-host disease (aGVHD) and MRD post-HSCT. He and his colleagues observed better survival for MRD-positive patients with aGVHD (grade 1-2) than for MRD-positive patients without aGVHD.
Pre-HSCT risk score
Via an adjusted Cox regression analysis, the researchers identified several pre-transplant factors that predicted EFS at 18 months.
These included remission status, donor type, immunophenotype, and MRD. The researchers assigned points to each of these factors to create a risk score.
Compared to patients in first CR, the hazard ratio (HR) for patients in early second CR was 2.53, and the score was 3. For patients in third CR or greater, the HR was 1.95, and the score was 2.
Compared to patients with a matched sibling donor, the HR for patients with a mismatched donor was 1.41, and the score was 1. For patients who received cord blood from an unrelated donor, the HR was 1.48, and the score was 1.
Compared to patients with T-cell ALL, the HR for patients with pre-B ALL was 1.35, and the score was 1.
Compared to patients with MRD <10-4, the HR for patients with MRD ≥10-4 was 2.32, and the score was 2.
The probability of EFS at 18 months was 78% ± 2% for patients with 0 to 1 points, 54% ± 3% for those with 2 to 3 points, and 46% ± 5% for patients with 4 or more points.
Day 30 post-HSCT risk score
When considering patients at day 30 post-HSCT, factors that predicted 18-month EFS included remission status, donor type, immunophenotype, aGVHD status, and MRD.
The HR for patients in early second CR was 2.51, and the score was 3. For patients in third CR or greater, the HR was 2.09, and the score was 2.
The HR for patients with a mismatched donor was 1.75, and the score was 2. The HR for patients with pre-B ALL was 1.40, and the score was 1.
Compared to patients with grade 1-2 aGVHD, the HR was 2.02 for patients with grade 0 aGVHD, and the score was 2. For patients with grade 3 aGVHD, the HR was 1.44, and the score was 1. For patients with grade 4 aGVHD, the HR was 7.12, and the score was 7.
The researchers evaluated MRD prior to HSCT and MRD at day 30, using a reference of MRD <10-4 at both time points. For patients with MRD <10-4 pre-HSCT and ≥10-4 at day 30, the HR was 2.29, and the score was 2.
For patients with MRD ≥10-4 pre-HSCT and <10-4 at day 30, the HR was 3.17, and the score was 3. For patients with MRD ≥10-4 pre-HSCT and at day 30, the HR was 3.63, and the score was 4.
The probability of EFS at 18 months was 80% ± 2% for patients with 0 to 3 points, 54% ± 4% for those with 4 to 6 points, and 25% ± 6% for those with 7 or more points.
Day 90 post-HSCT risk score
When considering patients at day 90 post-HSCT, factors that predicted 18-month EFS included remission status, aGVHD status, and MRD.
For patients in early second CR, the HR was 2.81, and the score was 3. For those in third CR or greater, the HR was 1.85, and the score was 2.
Compared to patients with grade 1-2 aGVHD, the HR was 1.60 for patients with grade 0 aGVHD, and the score was 2. For patients with grade 4 aGVHD, the HR was 2.49, and the score was 2.
The researchers assessed MRD prior to HSCT and MRD at day 90, using a reference of MRD <10-4 at both time points. For patients with MRD <10-4 pre-HSCT and ≥10-4 at day 90, the HR was 6.03, and the score was 6.
For patients with MRD ≥10-4 pre-HSCT and <10-4 at day 90, the HR was 3.11, and the score was 3. For patients with MRD ≥10-4 pre-HSCT and at day 90, the HR was 4.59, and the score was 5.
The probability of EFS at 18 months was 83% ± 2% for patients with 0 to 2 points, 60% ± 4% for those with 3 to 5 points, and 17% ± 11 for those with 6 or more points. 
*Information in the abstract differs from the presentation.
ORLANDO, FL—Minimal residual disease (MRD) measurements before and after hematopoietic stem cell transplant (HSCT) can help predict outcomes in patients with childhood acute lymphoblastic leukemia (ALL), according to researchers.
Their work also suggests several other factors can be used to predict event-free survival (EFS) in this patient population, and the team developed risk scores incorporating these factors.
Michael A. Pulsipher, MD, of Children’s Hospital Los Angeles in California, presented this work as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 4*).
“The new risk scores that we were able to develop very nicely predict outcomes post-transplant and can guide study planning,” Dr Pulsipher said.
“MRD pre-transplant was a very powerful predictor of outcome, and MRD post-transplant highlights individual patients at risk.”
For this study, Dr Pulsipher and his colleagues retrospectively analyzed 747 patients treated in Europe, North America, and Australia. The patients received transplants between September 1999 and May 2015.
Most patients had pre-B ALL (78%, n=586), 19% (n=145) had T-cell ALL, 2% had “other” ALLs (n=8) or no data on ALL type (n=8). Sixty-two percent (n=466) were male.
Nearly half of patients were between the ages of 2 and 10 (49%, n=365), 47% (n=351) were older than 10, and 4% (n=31) were younger than 2.
Transplant details
Patients received grafts from matched unrelated donors (42%, n=314), matched sibling donors (30%, n=227), mismatched donors (10%, n=75), and cord blood from unrelated donors (17%, n=128). There was no data on donor type for 3 patients.
Most patients received bone marrow transplants (61%, n=458), 20% (n=147) received cord blood, and 18% (n=131) received peripheral blood stem cells. Eight patients received “other” types of transplants, and 3 patients had no data on stem cell source.
More than half of the patients (55%, n=410) were in their second complete remission (CR) at transplant. Thirty-seven percent were in their first CR (n=275), 7% were in their third or greater CR (n=53), and 1% were not in remission (n=7). Two patients had no data on remission status.
MRD
MRD was assessed before HSCT as well as after—on or near days 30, 60, 90, 180, 365, and beyond.
There were 4 MRD categories:
- MRD negative: No signal
- MRD low: >0 to <10-4 (<0.01%)
- MRD high: ≥10-4 to <10-3 (0.01 to 0.1%)
- MRD very high: ≥10-3 to <10-2 (>0.1%).
Dr Pulsipher noted that, when analyzing MRD pre-HSCT or at 30 days after HSCT, the estimated 5-year EFS was similar for patients in the MRD-negative and MRD-low groups. However, as time went on (at days 90, 180, and 365), any detectable level of MRD was associated with a poor prognosis.
“And patients arriving at day 365 with no detectable MRD had an exceptional prognosis, with survival approaching 90%,” Dr Pulsipher said.
He also pointed out an interaction between acute graft-vs-host disease (aGVHD) and MRD post-HSCT. He and his colleagues observed better survival for MRD-positive patients with aGVHD (grade 1-2) than for MRD-positive patients without aGVHD.
Pre-HSCT risk score
Via an adjusted Cox regression analysis, the researchers identified several pre-transplant factors that predicted EFS at 18 months.
These included remission status, donor type, immunophenotype, and MRD. The researchers assigned points to each of these factors to create a risk score.
Compared to patients in first CR, the hazard ratio (HR) for patients in early second CR was 2.53, and the score was 3. For patients in third CR or greater, the HR was 1.95, and the score was 2.
Compared to patients with a matched sibling donor, the HR for patients with a mismatched donor was 1.41, and the score was 1. For patients who received cord blood from an unrelated donor, the HR was 1.48, and the score was 1.
Compared to patients with T-cell ALL, the HR for patients with pre-B ALL was 1.35, and the score was 1.
Compared to patients with MRD <10-4, the HR for patients with MRD ≥10-4 was 2.32, and the score was 2.
The probability of EFS at 18 months was 78% ± 2% for patients with 0 to 1 points, 54% ± 3% for those with 2 to 3 points, and 46% ± 5% for patients with 4 or more points.
Day 30 post-HSCT risk score
When considering patients at day 30 post-HSCT, factors that predicted 18-month EFS included remission status, donor type, immunophenotype, aGVHD status, and MRD.
The HR for patients in early second CR was 2.51, and the score was 3. For patients in third CR or greater, the HR was 2.09, and the score was 2.
The HR for patients with a mismatched donor was 1.75, and the score was 2. The HR for patients with pre-B ALL was 1.40, and the score was 1.
Compared to patients with grade 1-2 aGVHD, the HR was 2.02 for patients with grade 0 aGVHD, and the score was 2. For patients with grade 3 aGVHD, the HR was 1.44, and the score was 1. For patients with grade 4 aGVHD, the HR was 7.12, and the score was 7.
The researchers evaluated MRD prior to HSCT and MRD at day 30, using a reference of MRD <10-4 at both time points. For patients with MRD <10-4 pre-HSCT and ≥10-4 at day 30, the HR was 2.29, and the score was 2.
For patients with MRD ≥10-4 pre-HSCT and <10-4 at day 30, the HR was 3.17, and the score was 3. For patients with MRD ≥10-4 pre-HSCT and at day 30, the HR was 3.63, and the score was 4.
The probability of EFS at 18 months was 80% ± 2% for patients with 0 to 3 points, 54% ± 4% for those with 4 to 6 points, and 25% ± 6% for those with 7 or more points.
Day 90 post-HSCT risk score
When considering patients at day 90 post-HSCT, factors that predicted 18-month EFS included remission status, aGVHD status, and MRD.
For patients in early second CR, the HR was 2.81, and the score was 3. For those in third CR or greater, the HR was 1.85, and the score was 2.
Compared to patients with grade 1-2 aGVHD, the HR was 1.60 for patients with grade 0 aGVHD, and the score was 2. For patients with grade 4 aGVHD, the HR was 2.49, and the score was 2.
The researchers assessed MRD prior to HSCT and MRD at day 90, using a reference of MRD <10-4 at both time points. For patients with MRD <10-4 pre-HSCT and ≥10-4 at day 90, the HR was 6.03, and the score was 6.
For patients with MRD ≥10-4 pre-HSCT and <10-4 at day 90, the HR was 3.11, and the score was 3. For patients with MRD ≥10-4 pre-HSCT and at day 90, the HR was 4.59, and the score was 5.
The probability of EFS at 18 months was 83% ± 2% for patients with 0 to 2 points, 60% ± 4% for those with 3 to 5 points, and 17% ± 11 for those with 6 or more points.
*Information in the abstract differs from the presentation.
ORLANDO, FL—Minimal residual disease (MRD) measurements before and after hematopoietic stem cell transplant (HSCT) can help predict outcomes in patients with childhood acute lymphoblastic leukemia (ALL), according to researchers.
Their work also suggests several other factors can be used to predict event-free survival (EFS) in this patient population, and the team developed risk scores incorporating these factors.
Michael A. Pulsipher, MD, of Children’s Hospital Los Angeles in California, presented this work as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 4*).
“The new risk scores that we were able to develop very nicely predict outcomes post-transplant and can guide study planning,” Dr Pulsipher said.
“MRD pre-transplant was a very powerful predictor of outcome, and MRD post-transplant highlights individual patients at risk.”
For this study, Dr Pulsipher and his colleagues retrospectively analyzed 747 patients treated in Europe, North America, and Australia. The patients received transplants between September 1999 and May 2015.
Most patients had pre-B ALL (78%, n=586), 19% (n=145) had T-cell ALL, 2% had “other” ALLs (n=8) or no data on ALL type (n=8). Sixty-two percent (n=466) were male.
Nearly half of patients were between the ages of 2 and 10 (49%, n=365), 47% (n=351) were older than 10, and 4% (n=31) were younger than 2.
Transplant details
Patients received grafts from matched unrelated donors (42%, n=314), matched sibling donors (30%, n=227), mismatched donors (10%, n=75), and cord blood from unrelated donors (17%, n=128). There was no data on donor type for 3 patients.
Most patients received bone marrow transplants (61%, n=458), 20% (n=147) received cord blood, and 18% (n=131) received peripheral blood stem cells. Eight patients received “other” types of transplants, and 3 patients had no data on stem cell source.
More than half of the patients (55%, n=410) were in their second complete remission (CR) at transplant. Thirty-seven percent were in their first CR (n=275), 7% were in their third or greater CR (n=53), and 1% were not in remission (n=7). Two patients had no data on remission status.
MRD
MRD was assessed before HSCT as well as after—on or near days 30, 60, 90, 180, 365, and beyond.
There were 4 MRD categories:
- MRD negative: No signal
- MRD low: >0 to <10-4 (<0.01%)
- MRD high: ≥10-4 to <10-3 (0.01 to 0.1%)
- MRD very high: ≥10-3 to <10-2 (>0.1%).
Dr Pulsipher noted that, when analyzing MRD pre-HSCT or at 30 days after HSCT, the estimated 5-year EFS was similar for patients in the MRD-negative and MRD-low groups. However, as time went on (at days 90, 180, and 365), any detectable level of MRD was associated with a poor prognosis.
“And patients arriving at day 365 with no detectable MRD had an exceptional prognosis, with survival approaching 90%,” Dr Pulsipher said.
He also pointed out an interaction between acute graft-vs-host disease (aGVHD) and MRD post-HSCT. He and his colleagues observed better survival for MRD-positive patients with aGVHD (grade 1-2) than for MRD-positive patients without aGVHD.
Pre-HSCT risk score
Via an adjusted Cox regression analysis, the researchers identified several pre-transplant factors that predicted EFS at 18 months.
These included remission status, donor type, immunophenotype, and MRD. The researchers assigned points to each of these factors to create a risk score.
Compared to patients in first CR, the hazard ratio (HR) for patients in early second CR was 2.53, and the score was 3. For patients in third CR or greater, the HR was 1.95, and the score was 2.
Compared to patients with a matched sibling donor, the HR for patients with a mismatched donor was 1.41, and the score was 1. For patients who received cord blood from an unrelated donor, the HR was 1.48, and the score was 1.
Compared to patients with T-cell ALL, the HR for patients with pre-B ALL was 1.35, and the score was 1.
Compared to patients with MRD <10-4, the HR for patients with MRD ≥10-4 was 2.32, and the score was 2.
The probability of EFS at 18 months was 78% ± 2% for patients with 0 to 1 points, 54% ± 3% for those with 2 to 3 points, and 46% ± 5% for patients with 4 or more points.
Day 30 post-HSCT risk score
When considering patients at day 30 post-HSCT, factors that predicted 18-month EFS included remission status, donor type, immunophenotype, aGVHD status, and MRD.
The HR for patients in early second CR was 2.51, and the score was 3. For patients in third CR or greater, the HR was 2.09, and the score was 2.
The HR for patients with a mismatched donor was 1.75, and the score was 2. The HR for patients with pre-B ALL was 1.40, and the score was 1.
Compared to patients with grade 1-2 aGVHD, the HR was 2.02 for patients with grade 0 aGVHD, and the score was 2. For patients with grade 3 aGVHD, the HR was 1.44, and the score was 1. For patients with grade 4 aGVHD, the HR was 7.12, and the score was 7.
The researchers evaluated MRD prior to HSCT and MRD at day 30, using a reference of MRD <10-4 at both time points. For patients with MRD <10-4 pre-HSCT and ≥10-4 at day 30, the HR was 2.29, and the score was 2.
For patients with MRD ≥10-4 pre-HSCT and <10-4 at day 30, the HR was 3.17, and the score was 3. For patients with MRD ≥10-4 pre-HSCT and at day 30, the HR was 3.63, and the score was 4.
The probability of EFS at 18 months was 80% ± 2% for patients with 0 to 3 points, 54% ± 4% for those with 4 to 6 points, and 25% ± 6% for those with 7 or more points.
Day 90 post-HSCT risk score
When considering patients at day 90 post-HSCT, factors that predicted 18-month EFS included remission status, aGVHD status, and MRD.
For patients in early second CR, the HR was 2.81, and the score was 3. For those in third CR or greater, the HR was 1.85, and the score was 2.
Compared to patients with grade 1-2 aGVHD, the HR was 1.60 for patients with grade 0 aGVHD, and the score was 2. For patients with grade 4 aGVHD, the HR was 2.49, and the score was 2.
The researchers assessed MRD prior to HSCT and MRD at day 90, using a reference of MRD <10-4 at both time points. For patients with MRD <10-4 pre-HSCT and ≥10-4 at day 90, the HR was 6.03, and the score was 6.
For patients with MRD ≥10-4 pre-HSCT and <10-4 at day 90, the HR was 3.11, and the score was 3. For patients with MRD ≥10-4 pre-HSCT and at day 90, the HR was 4.59, and the score was 5.
The probability of EFS at 18 months was 83% ± 2% for patients with 0 to 2 points, 60% ± 4% for those with 3 to 5 points, and 17% ± 11 for those with 6 or more points.
*Information in the abstract differs from the presentation.
Study confirms increased adiposity in HSCT survivors
ORLANDO, FL—A recently conducted study confirms that survivors of hematopoietic stem cell transplant (HSCT) have increased body fat mass and lower lean mass compared to normal controls. And this is despite having a comparable body mass index (BMI).
Researchers say the abnormalities in adipokine levels—leptin and adiponectin—could provide insight into the mechanisms that contribute to the metabolic syndrome and cardiovascular complications that often develop in HSCT survivors.
Leptin and adiponectin are associated with obesity, insulin secretion, insulin resistance, endothelial function, vascular homeostasis, and atherosclerosis.
“So knowing that there is a dynamic interplay between obesity and insulin resistance and cytokine and adipokine profiles and, ultimately, insulin-resistance syndrome, we sought to evaluate, as part of a larger study, how treatment effects, including high-dose chemotherapy and radiation, alter cytokine profiles as well as obesity and body composition,” said Tyler G. Ketterl, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Dr Ketterl presented the findings at the 2017 BMT Tandem Meetings as abstract 52.*
Study design
The research team compared 151 HSCT recipients who had survived more than 2 years after transplant with 92 sibling controls.
HSCT survivors were randomly recruited from 2 centers—Fred Hutchinson Cancer Research Center and University of Minnesota Masonic Children’s Hospital—and were younger than 21 years when diagnosed.
The researchers evaluated all participants for body composition, cardiovascular risk factors, and adipokines using anthropomorphic measurements, DXA scans for muscle and fat mass, and laboratory bloodwork.
The team stratified the HSCT survivors by the preparative regimen they had received—total body irradiation (TBI) alone, TBI plus cranial radiation (CRT), and chemotherapy alone.
Study population
Males comprised more than half the study population in each arm, 58% of HSCT survivors and 54% of siblings.
Nine percent and 8% in the HSCT and sibling arms, respectively, were non-white and/or Hispanic, and the mean current ages were 24.0 (range, 10-51) for HSCT survivors and 24.2 (range, 10-48) for siblings.
The survivors’ mean age at diagnosis was 9.1 years (range, 0.4–20.6), their mean age at transplant was 11.2 years (range, 0.6–32.6), and the mean time from transplant to study participation was 13.5 years (range, 2.6–32).
Most patients received a transplant for leukemia—54 (36%) for acute myeloid leukemia, 46 (31%) for acute lymphoblastic leukemia, and 15 (10%) for chronic myeloid leukemia. Thirteen (9%) received transplants for myelodysplastic syndromes, 12 (8%) for Hodgkin lymphoma, and 10 (6%) for non-Hodgkin lymphoma.
A little more than half had TBI (85, 56%) as the preparative regimen, 31 (21%) had TBI plus CRT, and 35 (23%) had chemotherapy only.
About three-quarters (116, 77%) had an allogeneic transplant, and 35 (23%) had an autologous transplant.
Results
Overall, HSCT survivors had significantly lower adiponectin levels than siblings (P<0.001).
Survivors who received TBI with or without CRT had significantly lower adiponectin levels than siblings (P<0.001), while survivors who received chemotherapy alone did not (P=0.42).
Adiponectin is involved in insulin sensitization, hepatoprotective action, antiatherogenic action, protection against the development of diabetes, and regulation of lipid metabolism.
Overall, survivors had significantly higher leptin levels than siblings (P<0.001).
This held true regardless of conditioning regimen, although levels for patients who received chemotherapy only were not as significantly high (P=0.02) as for survivors who received TBI (P<0.001).
Leptin helps increase energy expenditure, decrease appetite and food uptake, modify insulin sensitivity on muscles and liver, prevent ectopic lipid deposition, and regulate immune function.
BMI adjusted for age, sex, and Tanner stage was not significantly different between survivors and siblings, but percent fat mass was significantly higher across all conditioning regimens for survivors compared to siblings (P<0.001).
“And this goes along with previous data,” Dr Ketterl said, “that shows sarcopenic obesity is common amongst transplant survivors.”
The researchers believe these significant differences may provide insight into the underlying risk of developing metabolic syndrome and cardiovascular complications in transplant survivors.
*Some details in the abstract differ from the presentation.
ORLANDO, FL—A recently conducted study confirms that survivors of hematopoietic stem cell transplant (HSCT) have increased body fat mass and lower lean mass compared to normal controls. And this is despite having a comparable body mass index (BMI).
Researchers say the abnormalities in adipokine levels—leptin and adiponectin—could provide insight into the mechanisms that contribute to the metabolic syndrome and cardiovascular complications that often develop in HSCT survivors.
Leptin and adiponectin are associated with obesity, insulin secretion, insulin resistance, endothelial function, vascular homeostasis, and atherosclerosis.
“So knowing that there is a dynamic interplay between obesity and insulin resistance and cytokine and adipokine profiles and, ultimately, insulin-resistance syndrome, we sought to evaluate, as part of a larger study, how treatment effects, including high-dose chemotherapy and radiation, alter cytokine profiles as well as obesity and body composition,” said Tyler G. Ketterl, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Dr Ketterl presented the findings at the 2017 BMT Tandem Meetings as abstract 52.*
Study design
The research team compared 151 HSCT recipients who had survived more than 2 years after transplant with 92 sibling controls.
HSCT survivors were randomly recruited from 2 centers—Fred Hutchinson Cancer Research Center and University of Minnesota Masonic Children’s Hospital—and were younger than 21 years when diagnosed.
The researchers evaluated all participants for body composition, cardiovascular risk factors, and adipokines using anthropomorphic measurements, DXA scans for muscle and fat mass, and laboratory bloodwork.
The team stratified the HSCT survivors by the preparative regimen they had received—total body irradiation (TBI) alone, TBI plus cranial radiation (CRT), and chemotherapy alone.
Study population
Males comprised more than half the study population in each arm, 58% of HSCT survivors and 54% of siblings.
Nine percent and 8% in the HSCT and sibling arms, respectively, were non-white and/or Hispanic, and the mean current ages were 24.0 (range, 10-51) for HSCT survivors and 24.2 (range, 10-48) for siblings.
The survivors’ mean age at diagnosis was 9.1 years (range, 0.4–20.6), their mean age at transplant was 11.2 years (range, 0.6–32.6), and the mean time from transplant to study participation was 13.5 years (range, 2.6–32).
Most patients received a transplant for leukemia—54 (36%) for acute myeloid leukemia, 46 (31%) for acute lymphoblastic leukemia, and 15 (10%) for chronic myeloid leukemia. Thirteen (9%) received transplants for myelodysplastic syndromes, 12 (8%) for Hodgkin lymphoma, and 10 (6%) for non-Hodgkin lymphoma.
A little more than half had TBI (85, 56%) as the preparative regimen, 31 (21%) had TBI plus CRT, and 35 (23%) had chemotherapy only.
About three-quarters (116, 77%) had an allogeneic transplant, and 35 (23%) had an autologous transplant.
Results
Overall, HSCT survivors had significantly lower adiponectin levels than siblings (P<0.001).
Survivors who received TBI with or without CRT had significantly lower adiponectin levels than siblings (P<0.001), while survivors who received chemotherapy alone did not (P=0.42).
Adiponectin is involved in insulin sensitization, hepatoprotective action, antiatherogenic action, protection against the development of diabetes, and regulation of lipid metabolism.
Overall, survivors had significantly higher leptin levels than siblings (P<0.001).
This held true regardless of conditioning regimen, although levels for patients who received chemotherapy only were not as significantly high (P=0.02) as for survivors who received TBI (P<0.001).
Leptin helps increase energy expenditure, decrease appetite and food uptake, modify insulin sensitivity on muscles and liver, prevent ectopic lipid deposition, and regulate immune function.
BMI adjusted for age, sex, and Tanner stage was not significantly different between survivors and siblings, but percent fat mass was significantly higher across all conditioning regimens for survivors compared to siblings (P<0.001).
“And this goes along with previous data,” Dr Ketterl said, “that shows sarcopenic obesity is common amongst transplant survivors.”
The researchers believe these significant differences may provide insight into the underlying risk of developing metabolic syndrome and cardiovascular complications in transplant survivors.
*Some details in the abstract differ from the presentation.
ORLANDO, FL—A recently conducted study confirms that survivors of hematopoietic stem cell transplant (HSCT) have increased body fat mass and lower lean mass compared to normal controls. And this is despite having a comparable body mass index (BMI).
Researchers say the abnormalities in adipokine levels—leptin and adiponectin—could provide insight into the mechanisms that contribute to the metabolic syndrome and cardiovascular complications that often develop in HSCT survivors.
Leptin and adiponectin are associated with obesity, insulin secretion, insulin resistance, endothelial function, vascular homeostasis, and atherosclerosis.
“So knowing that there is a dynamic interplay between obesity and insulin resistance and cytokine and adipokine profiles and, ultimately, insulin-resistance syndrome, we sought to evaluate, as part of a larger study, how treatment effects, including high-dose chemotherapy and radiation, alter cytokine profiles as well as obesity and body composition,” said Tyler G. Ketterl, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Dr Ketterl presented the findings at the 2017 BMT Tandem Meetings as abstract 52.*
Study design
The research team compared 151 HSCT recipients who had survived more than 2 years after transplant with 92 sibling controls.
HSCT survivors were randomly recruited from 2 centers—Fred Hutchinson Cancer Research Center and University of Minnesota Masonic Children’s Hospital—and were younger than 21 years when diagnosed.
The researchers evaluated all participants for body composition, cardiovascular risk factors, and adipokines using anthropomorphic measurements, DXA scans for muscle and fat mass, and laboratory bloodwork.
The team stratified the HSCT survivors by the preparative regimen they had received—total body irradiation (TBI) alone, TBI plus cranial radiation (CRT), and chemotherapy alone.
Study population
Males comprised more than half the study population in each arm, 58% of HSCT survivors and 54% of siblings.
Nine percent and 8% in the HSCT and sibling arms, respectively, were non-white and/or Hispanic, and the mean current ages were 24.0 (range, 10-51) for HSCT survivors and 24.2 (range, 10-48) for siblings.
The survivors’ mean age at diagnosis was 9.1 years (range, 0.4–20.6), their mean age at transplant was 11.2 years (range, 0.6–32.6), and the mean time from transplant to study participation was 13.5 years (range, 2.6–32).
Most patients received a transplant for leukemia—54 (36%) for acute myeloid leukemia, 46 (31%) for acute lymphoblastic leukemia, and 15 (10%) for chronic myeloid leukemia. Thirteen (9%) received transplants for myelodysplastic syndromes, 12 (8%) for Hodgkin lymphoma, and 10 (6%) for non-Hodgkin lymphoma.
A little more than half had TBI (85, 56%) as the preparative regimen, 31 (21%) had TBI plus CRT, and 35 (23%) had chemotherapy only.
About three-quarters (116, 77%) had an allogeneic transplant, and 35 (23%) had an autologous transplant.
Results
Overall, HSCT survivors had significantly lower adiponectin levels than siblings (P<0.001).
Survivors who received TBI with or without CRT had significantly lower adiponectin levels than siblings (P<0.001), while survivors who received chemotherapy alone did not (P=0.42).
Adiponectin is involved in insulin sensitization, hepatoprotective action, antiatherogenic action, protection against the development of diabetes, and regulation of lipid metabolism.
Overall, survivors had significantly higher leptin levels than siblings (P<0.001).
This held true regardless of conditioning regimen, although levels for patients who received chemotherapy only were not as significantly high (P=0.02) as for survivors who received TBI (P<0.001).
Leptin helps increase energy expenditure, decrease appetite and food uptake, modify insulin sensitivity on muscles and liver, prevent ectopic lipid deposition, and regulate immune function.
BMI adjusted for age, sex, and Tanner stage was not significantly different between survivors and siblings, but percent fat mass was significantly higher across all conditioning regimens for survivors compared to siblings (P<0.001).
“And this goes along with previous data,” Dr Ketterl said, “that shows sarcopenic obesity is common amongst transplant survivors.”
The researchers believe these significant differences may provide insight into the underlying risk of developing metabolic syndrome and cardiovascular complications in transplant survivors.
*Some details in the abstract differ from the presentation.
MSC product granted fast track designation
The US Food and Drug Administration (FDA) has granted fast track designation to a mesenchymal stem cell (MSC) product, MSC-100-IV, as a treatment for children with steroid-refractory acute graft-vs-host disease (aGVHD).
MSC-100-IV consists of human MSCs derived from donor bone marrow and expanded in culture.
Fast track designation has the potential to shorten the time to FDA approval for MSC-100-IV through priority review, which reduces the FDA review process from 10 months to 6 months.
The designation also allows for a rolling review process, whereby completed sections of the Biologics License Application can be submitted for FDA review as they become available, instead of waiting for all sections to be completed.
In addition, fast track designation provides product developers with opportunities for more frequent meetings and written communications with the FDA.
MSC-100-IV is being developed by Mesoblast Limited in partnership with Mallinckrodt Pharmaceuticals.
Trial results
The application for fast track designation for MSC-100-IV was supported by a trial of 241 pediatric patients with steroid-refractory aGVHD. Results from this trial were presented at the 2016 BMT Tandem Meetings.
Patients initially received 2 million MSCs/kg twice a week for 4 weeks, at least 3 days apart. If they achieved a partial or mixed response (improvement in one organ with deterioration in another) at the day-28 assessment, patients then received 2 million MSCs/kg once a week for 4 weeks.
The patients received a total of 2434 infusions—a median of 11 (range, 1-24)—and had a median treatment duration of 46 days (range, 1-186).
Fifty-seven percent of patients (n=138) had at least 1 serious adverse event. About 5% (n=11) were considered treatment-related, and 1.7% (n=4) led to study discontinuation. There was 1 infusion reaction.
The overall response rate at day 28 was 65%, and the complete response rate was 14%. Responses were observed for all aGVHD grades and did not differ by baseline organ involvement.
Day 100 survival was significantly better in children who achieved a response at day 28—82%, compared to 39% for non-responders (P<0.0001).
In November 2016, Mesoblast reported success in an ongoing, phase 3 registration trial of MSC-100-IV in 60 children with steroid-refractory aGVHD.
The company said the trial was successful in a pre-specified interim futility analysis using the primary endpoint of day-28 overall response. Enrollment in this trial is expected to be complete in mid-2017.
The US Food and Drug Administration (FDA) has granted fast track designation to a mesenchymal stem cell (MSC) product, MSC-100-IV, as a treatment for children with steroid-refractory acute graft-vs-host disease (aGVHD).
MSC-100-IV consists of human MSCs derived from donor bone marrow and expanded in culture.
Fast track designation has the potential to shorten the time to FDA approval for MSC-100-IV through priority review, which reduces the FDA review process from 10 months to 6 months.
The designation also allows for a rolling review process, whereby completed sections of the Biologics License Application can be submitted for FDA review as they become available, instead of waiting for all sections to be completed.
In addition, fast track designation provides product developers with opportunities for more frequent meetings and written communications with the FDA.
MSC-100-IV is being developed by Mesoblast Limited in partnership with Mallinckrodt Pharmaceuticals.
Trial results
The application for fast track designation for MSC-100-IV was supported by a trial of 241 pediatric patients with steroid-refractory aGVHD. Results from this trial were presented at the 2016 BMT Tandem Meetings.
Patients initially received 2 million MSCs/kg twice a week for 4 weeks, at least 3 days apart. If they achieved a partial or mixed response (improvement in one organ with deterioration in another) at the day-28 assessment, patients then received 2 million MSCs/kg once a week for 4 weeks.
The patients received a total of 2434 infusions—a median of 11 (range, 1-24)—and had a median treatment duration of 46 days (range, 1-186).
Fifty-seven percent of patients (n=138) had at least 1 serious adverse event. About 5% (n=11) were considered treatment-related, and 1.7% (n=4) led to study discontinuation. There was 1 infusion reaction.
The overall response rate at day 28 was 65%, and the complete response rate was 14%. Responses were observed for all aGVHD grades and did not differ by baseline organ involvement.
Day 100 survival was significantly better in children who achieved a response at day 28—82%, compared to 39% for non-responders (P<0.0001).
In November 2016, Mesoblast reported success in an ongoing, phase 3 registration trial of MSC-100-IV in 60 children with steroid-refractory aGVHD.
The company said the trial was successful in a pre-specified interim futility analysis using the primary endpoint of day-28 overall response. Enrollment in this trial is expected to be complete in mid-2017.
The US Food and Drug Administration (FDA) has granted fast track designation to a mesenchymal stem cell (MSC) product, MSC-100-IV, as a treatment for children with steroid-refractory acute graft-vs-host disease (aGVHD).
MSC-100-IV consists of human MSCs derived from donor bone marrow and expanded in culture.
Fast track designation has the potential to shorten the time to FDA approval for MSC-100-IV through priority review, which reduces the FDA review process from 10 months to 6 months.
The designation also allows for a rolling review process, whereby completed sections of the Biologics License Application can be submitted for FDA review as they become available, instead of waiting for all sections to be completed.
In addition, fast track designation provides product developers with opportunities for more frequent meetings and written communications with the FDA.
MSC-100-IV is being developed by Mesoblast Limited in partnership with Mallinckrodt Pharmaceuticals.
Trial results
The application for fast track designation for MSC-100-IV was supported by a trial of 241 pediatric patients with steroid-refractory aGVHD. Results from this trial were presented at the 2016 BMT Tandem Meetings.
Patients initially received 2 million MSCs/kg twice a week for 4 weeks, at least 3 days apart. If they achieved a partial or mixed response (improvement in one organ with deterioration in another) at the day-28 assessment, patients then received 2 million MSCs/kg once a week for 4 weeks.
The patients received a total of 2434 infusions—a median of 11 (range, 1-24)—and had a median treatment duration of 46 days (range, 1-186).
Fifty-seven percent of patients (n=138) had at least 1 serious adverse event. About 5% (n=11) were considered treatment-related, and 1.7% (n=4) led to study discontinuation. There was 1 infusion reaction.
The overall response rate at day 28 was 65%, and the complete response rate was 14%. Responses were observed for all aGVHD grades and did not differ by baseline organ involvement.
Day 100 survival was significantly better in children who achieved a response at day 28—82%, compared to 39% for non-responders (P<0.0001).
In November 2016, Mesoblast reported success in an ongoing, phase 3 registration trial of MSC-100-IV in 60 children with steroid-refractory aGVHD.
The company said the trial was successful in a pre-specified interim futility analysis using the primary endpoint of day-28 overall response. Enrollment in this trial is expected to be complete in mid-2017.
Genetic variants linked to HSCT outcomes in ALL
ORLANDO, FL—Results of a genome-wide association study suggest that several genetic variants are associated with outcomes of allogeneic hematopoietic stem cell transplant (HSCT) in patients with acute lymphoblastic leukemia (ALL).
Investigators identified several single-nucleotide polymorphisms (SNPs) in ALL patients and their unrelated donors that were associated with disease-related death or progression-free survival (PFS) within 1 year of HSCT.
“We believe that these findings will lead to a better understanding of the biology of this disease,” said investigator Theresa Hahn, PhD, of Roswell Park Cancer Institute in Buffalo, New York.
“Additionally, we expect that this work will eventually help clinical teams to identify unrelated donors with genotypes that yield better survival in transplant patients and enhance the chances for successful blood and marrow transplants.”
Dr Hahn presented this work as a “Best Abstract” at the 2017 BMT Tandem Meetings (abstract 1).
For this study, she and her colleagues analyzed data on patients treated at more than 150 US transplant centers between 2000 and 2011. The investigators evaluated data on more than 3000 patients with acute leukemias or myelodysplastic syndromes, but Dr Hahn only presented findings in the ALL patients and their donors.
The patients and donors were divided into 2 cohorts. Cohort 1 included 483 ALL patients who underwent HSCT from 2000 to 2008 and 466 unrelated donors who were a 10/10 HLA match for the patients.
Cohort 2 included 94 ALL patients who received a transplant from a 10/10 HLA-matched donor between 2009 and 2011 or from an 8/8 HLA-matched donor between 2000 and 2011. There were 92 donors in this cohort.
The investigators sequenced blood samples from the recipients and donors to identify SNPs. The SNPs were then measured for association with disease-related death and PFS using Cox proportional hazards models adjusted for recipient age, disease status at HSCT (early, intermediate, or advanced), graft source (blood or marrow), and year of transplant.
SNPs in donors
The top 2 SNPs in donors that were associated with a significant increase in disease-related death were:
- rs79503405 in LRP2 on chromosome 2.
- rs77618918 in ASIC2 on chromosome 17.
Dr Hahn noted that rs79503405 is in complete linkage disequilibrium (r2=1.0) with a genotyped missense variant (rs17848149) and a synonymous coding variant (rs35114151) in LRP2.
She also pointed out that the other top SNP (rs77618918) associated with disease-related death is not in linkage disequilibrium with other SNPs of functional importance, so the significance of this SNP is unknown.
There were no SNPs in donors that were significantly associated with PFS.
SNPs in recipients
In HSCT recipients, there were 3 linked variants in NRG1 on chromosome 8 (rs79853417, rs6990973, and rs145488394) that were significantly associated with disease-related death.
Another SNP (rs60640657) on chromosome 2 (CTNNA3/LOC101928961/LRRTM3) was also significantly associated with ALL-related death.
In addition, Dr Hahn and her colleagues found that 1 region in recipient genomes contains multiple variants (rs113263921 and others) associated with PFS. The SNPs are located on chromosome 3 in MLH1 and TRANK1.
“The donor and recipient genetic variants contributed independently to death due to ALL,” Dr Hahn said in closing. “Genetic variants for PFS do not overlap with death due to ALL, and this is probably due to the inclusion of both non-fatal disease progression as well as transplant-related mortality in the definition of PFS.”
“Constitutional genetic variants in recipients and donors increase the risk of death due to ALL, and they warrant further study into the impact of these genes on disease and transplant-related biology.”
ORLANDO, FL—Results of a genome-wide association study suggest that several genetic variants are associated with outcomes of allogeneic hematopoietic stem cell transplant (HSCT) in patients with acute lymphoblastic leukemia (ALL).
Investigators identified several single-nucleotide polymorphisms (SNPs) in ALL patients and their unrelated donors that were associated with disease-related death or progression-free survival (PFS) within 1 year of HSCT.
“We believe that these findings will lead to a better understanding of the biology of this disease,” said investigator Theresa Hahn, PhD, of Roswell Park Cancer Institute in Buffalo, New York.
“Additionally, we expect that this work will eventually help clinical teams to identify unrelated donors with genotypes that yield better survival in transplant patients and enhance the chances for successful blood and marrow transplants.”
Dr Hahn presented this work as a “Best Abstract” at the 2017 BMT Tandem Meetings (abstract 1).
For this study, she and her colleagues analyzed data on patients treated at more than 150 US transplant centers between 2000 and 2011. The investigators evaluated data on more than 3000 patients with acute leukemias or myelodysplastic syndromes, but Dr Hahn only presented findings in the ALL patients and their donors.
The patients and donors were divided into 2 cohorts. Cohort 1 included 483 ALL patients who underwent HSCT from 2000 to 2008 and 466 unrelated donors who were a 10/10 HLA match for the patients.
Cohort 2 included 94 ALL patients who received a transplant from a 10/10 HLA-matched donor between 2009 and 2011 or from an 8/8 HLA-matched donor between 2000 and 2011. There were 92 donors in this cohort.
The investigators sequenced blood samples from the recipients and donors to identify SNPs. The SNPs were then measured for association with disease-related death and PFS using Cox proportional hazards models adjusted for recipient age, disease status at HSCT (early, intermediate, or advanced), graft source (blood or marrow), and year of transplant.
SNPs in donors
The top 2 SNPs in donors that were associated with a significant increase in disease-related death were:
- rs79503405 in LRP2 on chromosome 2.
- rs77618918 in ASIC2 on chromosome 17.
Dr Hahn noted that rs79503405 is in complete linkage disequilibrium (r2=1.0) with a genotyped missense variant (rs17848149) and a synonymous coding variant (rs35114151) in LRP2.
She also pointed out that the other top SNP (rs77618918) associated with disease-related death is not in linkage disequilibrium with other SNPs of functional importance, so the significance of this SNP is unknown.
There were no SNPs in donors that were significantly associated with PFS.
SNPs in recipients
In HSCT recipients, there were 3 linked variants in NRG1 on chromosome 8 (rs79853417, rs6990973, and rs145488394) that were significantly associated with disease-related death.
Another SNP (rs60640657) on chromosome 2 (CTNNA3/LOC101928961/LRRTM3) was also significantly associated with ALL-related death.
In addition, Dr Hahn and her colleagues found that 1 region in recipient genomes contains multiple variants (rs113263921 and others) associated with PFS. The SNPs are located on chromosome 3 in MLH1 and TRANK1.
“The donor and recipient genetic variants contributed independently to death due to ALL,” Dr Hahn said in closing. “Genetic variants for PFS do not overlap with death due to ALL, and this is probably due to the inclusion of both non-fatal disease progression as well as transplant-related mortality in the definition of PFS.”
“Constitutional genetic variants in recipients and donors increase the risk of death due to ALL, and they warrant further study into the impact of these genes on disease and transplant-related biology.”
ORLANDO, FL—Results of a genome-wide association study suggest that several genetic variants are associated with outcomes of allogeneic hematopoietic stem cell transplant (HSCT) in patients with acute lymphoblastic leukemia (ALL).
Investigators identified several single-nucleotide polymorphisms (SNPs) in ALL patients and their unrelated donors that were associated with disease-related death or progression-free survival (PFS) within 1 year of HSCT.
“We believe that these findings will lead to a better understanding of the biology of this disease,” said investigator Theresa Hahn, PhD, of Roswell Park Cancer Institute in Buffalo, New York.
“Additionally, we expect that this work will eventually help clinical teams to identify unrelated donors with genotypes that yield better survival in transplant patients and enhance the chances for successful blood and marrow transplants.”
Dr Hahn presented this work as a “Best Abstract” at the 2017 BMT Tandem Meetings (abstract 1).
For this study, she and her colleagues analyzed data on patients treated at more than 150 US transplant centers between 2000 and 2011. The investigators evaluated data on more than 3000 patients with acute leukemias or myelodysplastic syndromes, but Dr Hahn only presented findings in the ALL patients and their donors.
The patients and donors were divided into 2 cohorts. Cohort 1 included 483 ALL patients who underwent HSCT from 2000 to 2008 and 466 unrelated donors who were a 10/10 HLA match for the patients.
Cohort 2 included 94 ALL patients who received a transplant from a 10/10 HLA-matched donor between 2009 and 2011 or from an 8/8 HLA-matched donor between 2000 and 2011. There were 92 donors in this cohort.
The investigators sequenced blood samples from the recipients and donors to identify SNPs. The SNPs were then measured for association with disease-related death and PFS using Cox proportional hazards models adjusted for recipient age, disease status at HSCT (early, intermediate, or advanced), graft source (blood or marrow), and year of transplant.
SNPs in donors
The top 2 SNPs in donors that were associated with a significant increase in disease-related death were:
- rs79503405 in LRP2 on chromosome 2.
- rs77618918 in ASIC2 on chromosome 17.
Dr Hahn noted that rs79503405 is in complete linkage disequilibrium (r2=1.0) with a genotyped missense variant (rs17848149) and a synonymous coding variant (rs35114151) in LRP2.
She also pointed out that the other top SNP (rs77618918) associated with disease-related death is not in linkage disequilibrium with other SNPs of functional importance, so the significance of this SNP is unknown.
There were no SNPs in donors that were significantly associated with PFS.
SNPs in recipients
In HSCT recipients, there were 3 linked variants in NRG1 on chromosome 8 (rs79853417, rs6990973, and rs145488394) that were significantly associated with disease-related death.
Another SNP (rs60640657) on chromosome 2 (CTNNA3/LOC101928961/LRRTM3) was also significantly associated with ALL-related death.
In addition, Dr Hahn and her colleagues found that 1 region in recipient genomes contains multiple variants (rs113263921 and others) associated with PFS. The SNPs are located on chromosome 3 in MLH1 and TRANK1.
“The donor and recipient genetic variants contributed independently to death due to ALL,” Dr Hahn said in closing. “Genetic variants for PFS do not overlap with death due to ALL, and this is probably due to the inclusion of both non-fatal disease progression as well as transplant-related mortality in the definition of PFS.”
“Constitutional genetic variants in recipients and donors increase the risk of death due to ALL, and they warrant further study into the impact of these genes on disease and transplant-related biology.”
Gene therapy proves effective in SCD patient
Researchers have reported a favorable outcome in the first patient with severe sickle cell disease (SCD) to receive gene therapy in the HGB-205 study.
The subject, known as Patient 1204, was treated with LentiGlobin BB305, a product consisting of his own manipulated hematopoietic stem cells (HSCs).
A functional human β-globin gene was inserted into the patient’s HSCs ex vivo, and the cells were returned to him via transplant.
Fifteen months after receiving this treatment, Patient 1204 had high levels of anti-sickling hemoglobin (HbAT87Q), and there were no adverse events thought to be related to LentiGlobin BB305.
These results were published in NEJM. The research was supported by bluebird bio, the company developing LentiGlobin BB305.
Patient 1204 is a male with βS/βS genotype. In May 2014, at 13 years of age, the patient was enrolled in the HGB-205 study at Hôpital Necker-Enfants Malades in Paris, France.
The patient had received hydroxyurea from age 2 to 9 and had both a cholecystectomy and a splenectomy. He received regular transfusions (plus iron chelation with deferasirox) for 4 years prior to this study.
The patient had an average of 1.6 SCD-related events annually in the 9 years prior to starting transfusions. His complications from SCD included vaso-occlusive crises, acute-chest syndrome, bilateral hip osteonecrosis, and cerebral vasculopathy.
The patient underwent 2 bone marrow harvests to collect HSCs for gene transfer and back-up (6.2×108 and 5.4×108 total nucleated cells/kg harvested).
CD34+ cells were enriched from the harvested marrow and then transduced with LentiGlobin BB305 lentiviral vector.
The patient underwent myeloablation with intravenous busulfan (2.3 to 4.8 mg/kg per day for 4 days) with daily pharmacokinetic studies and dose adjustment. Total busulfan area under the curve was 19,363 μmol/min.
After a 2-day washout, the patient received LentiGlobin BB305 in October 2014 at a post-thaw total dose of 5.6×106 CD34+ cells/kg. Neutrophil and platelet engraftment were achieved on day 38 and day 91 post-transplant, respectively.
Red blood cell transfusions were to be continued after transplant until a sufficient proportion of HbAT87Q (25% to 30% of total hemoglobin) was detected. Transfusions were discontinued after day 88 post-transplant.
HbAT87Q reached 5.5 g/dL (46% of total hemoglobin) at month 9 and continued to increase to 5.7 g/dL at month 15 (48%). Hemoglobin S levels were 5.5 g/dL (46%) at month 9 and 5.8 g/dL (49%) at month 15.
Total hemoglobin levels were stable, between 10.6 and 12.0 g/dL, from months 6 to 15. Fetal hemoglobin levels remained below 1.0 g/dL.
No adverse events related to LentiGlobin BB305 were reported. There were, however, adverse events related to busulfan conditioning (grade 3 anemia, thrombocytopenia, and infection; grade 4 neutropenia).
During 15 months of follow-up, there were no SCD-related clinical events or hospitalizations. The patient was able to stop all medications, including pain medication.
The patient resumed regular school attendance and reported full participation in normal physical activities.
“We have managed this patient at Necker for more than 10 years, and standard treatments were not able to control his SCD symptoms,” said Marina Cavazzana, MD, PhD, of Hôpital Necker-Enfants Malades.
“He had to receive blood transfusions every month to prevent severe pain crises. Since receiving the autologous stem cell transplant with LentiGlobin, he has been free from severe symptoms and has resumed normal activities, without the need for further transfusions.”
Researchers have reported a favorable outcome in the first patient with severe sickle cell disease (SCD) to receive gene therapy in the HGB-205 study.
The subject, known as Patient 1204, was treated with LentiGlobin BB305, a product consisting of his own manipulated hematopoietic stem cells (HSCs).
A functional human β-globin gene was inserted into the patient’s HSCs ex vivo, and the cells were returned to him via transplant.
Fifteen months after receiving this treatment, Patient 1204 had high levels of anti-sickling hemoglobin (HbAT87Q), and there were no adverse events thought to be related to LentiGlobin BB305.
These results were published in NEJM. The research was supported by bluebird bio, the company developing LentiGlobin BB305.
Patient 1204 is a male with βS/βS genotype. In May 2014, at 13 years of age, the patient was enrolled in the HGB-205 study at Hôpital Necker-Enfants Malades in Paris, France.
The patient had received hydroxyurea from age 2 to 9 and had both a cholecystectomy and a splenectomy. He received regular transfusions (plus iron chelation with deferasirox) for 4 years prior to this study.
The patient had an average of 1.6 SCD-related events annually in the 9 years prior to starting transfusions. His complications from SCD included vaso-occlusive crises, acute-chest syndrome, bilateral hip osteonecrosis, and cerebral vasculopathy.
The patient underwent 2 bone marrow harvests to collect HSCs for gene transfer and back-up (6.2×108 and 5.4×108 total nucleated cells/kg harvested).
CD34+ cells were enriched from the harvested marrow and then transduced with LentiGlobin BB305 lentiviral vector.
The patient underwent myeloablation with intravenous busulfan (2.3 to 4.8 mg/kg per day for 4 days) with daily pharmacokinetic studies and dose adjustment. Total busulfan area under the curve was 19,363 μmol/min.
After a 2-day washout, the patient received LentiGlobin BB305 in October 2014 at a post-thaw total dose of 5.6×106 CD34+ cells/kg. Neutrophil and platelet engraftment were achieved on day 38 and day 91 post-transplant, respectively.
Red blood cell transfusions were to be continued after transplant until a sufficient proportion of HbAT87Q (25% to 30% of total hemoglobin) was detected. Transfusions were discontinued after day 88 post-transplant.
HbAT87Q reached 5.5 g/dL (46% of total hemoglobin) at month 9 and continued to increase to 5.7 g/dL at month 15 (48%). Hemoglobin S levels were 5.5 g/dL (46%) at month 9 and 5.8 g/dL (49%) at month 15.
Total hemoglobin levels were stable, between 10.6 and 12.0 g/dL, from months 6 to 15. Fetal hemoglobin levels remained below 1.0 g/dL.
No adverse events related to LentiGlobin BB305 were reported. There were, however, adverse events related to busulfan conditioning (grade 3 anemia, thrombocytopenia, and infection; grade 4 neutropenia).
During 15 months of follow-up, there were no SCD-related clinical events or hospitalizations. The patient was able to stop all medications, including pain medication.
The patient resumed regular school attendance and reported full participation in normal physical activities.
“We have managed this patient at Necker for more than 10 years, and standard treatments were not able to control his SCD symptoms,” said Marina Cavazzana, MD, PhD, of Hôpital Necker-Enfants Malades.
“He had to receive blood transfusions every month to prevent severe pain crises. Since receiving the autologous stem cell transplant with LentiGlobin, he has been free from severe symptoms and has resumed normal activities, without the need for further transfusions.”
Researchers have reported a favorable outcome in the first patient with severe sickle cell disease (SCD) to receive gene therapy in the HGB-205 study.
The subject, known as Patient 1204, was treated with LentiGlobin BB305, a product consisting of his own manipulated hematopoietic stem cells (HSCs).
A functional human β-globin gene was inserted into the patient’s HSCs ex vivo, and the cells were returned to him via transplant.
Fifteen months after receiving this treatment, Patient 1204 had high levels of anti-sickling hemoglobin (HbAT87Q), and there were no adverse events thought to be related to LentiGlobin BB305.
These results were published in NEJM. The research was supported by bluebird bio, the company developing LentiGlobin BB305.
Patient 1204 is a male with βS/βS genotype. In May 2014, at 13 years of age, the patient was enrolled in the HGB-205 study at Hôpital Necker-Enfants Malades in Paris, France.
The patient had received hydroxyurea from age 2 to 9 and had both a cholecystectomy and a splenectomy. He received regular transfusions (plus iron chelation with deferasirox) for 4 years prior to this study.
The patient had an average of 1.6 SCD-related events annually in the 9 years prior to starting transfusions. His complications from SCD included vaso-occlusive crises, acute-chest syndrome, bilateral hip osteonecrosis, and cerebral vasculopathy.
The patient underwent 2 bone marrow harvests to collect HSCs for gene transfer and back-up (6.2×108 and 5.4×108 total nucleated cells/kg harvested).
CD34+ cells were enriched from the harvested marrow and then transduced with LentiGlobin BB305 lentiviral vector.
The patient underwent myeloablation with intravenous busulfan (2.3 to 4.8 mg/kg per day for 4 days) with daily pharmacokinetic studies and dose adjustment. Total busulfan area under the curve was 19,363 μmol/min.
After a 2-day washout, the patient received LentiGlobin BB305 in October 2014 at a post-thaw total dose of 5.6×106 CD34+ cells/kg. Neutrophil and platelet engraftment were achieved on day 38 and day 91 post-transplant, respectively.
Red blood cell transfusions were to be continued after transplant until a sufficient proportion of HbAT87Q (25% to 30% of total hemoglobin) was detected. Transfusions were discontinued after day 88 post-transplant.
HbAT87Q reached 5.5 g/dL (46% of total hemoglobin) at month 9 and continued to increase to 5.7 g/dL at month 15 (48%). Hemoglobin S levels were 5.5 g/dL (46%) at month 9 and 5.8 g/dL (49%) at month 15.
Total hemoglobin levels were stable, between 10.6 and 12.0 g/dL, from months 6 to 15. Fetal hemoglobin levels remained below 1.0 g/dL.
No adverse events related to LentiGlobin BB305 were reported. There were, however, adverse events related to busulfan conditioning (grade 3 anemia, thrombocytopenia, and infection; grade 4 neutropenia).
During 15 months of follow-up, there were no SCD-related clinical events or hospitalizations. The patient was able to stop all medications, including pain medication.
The patient resumed regular school attendance and reported full participation in normal physical activities.
“We have managed this patient at Necker for more than 10 years, and standard treatments were not able to control his SCD symptoms,” said Marina Cavazzana, MD, PhD, of Hôpital Necker-Enfants Malades.
“He had to receive blood transfusions every month to prevent severe pain crises. Since receiving the autologous stem cell transplant with LentiGlobin, he has been free from severe symptoms and has resumed normal activities, without the need for further transfusions.”
Combo prevents GVHD, prolongs survival in monkeys
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.
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.
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.
Study advances precision opioid dosing for mucositis
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, 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, 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.
Single dose of ZA pre-transplant prevents bone loss
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.”
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.”
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.”
FDA expands approved indication for lenalidomide
The US Food and Drug Administration (FDA) has approved a new indication for lenalidomide (Revlimid).
The drug is now approved for use as maintenance therapy after autologous hematopoietic stem cell transplant (auto-HSCT) in patients with multiple myeloma (MM).
The expanded indication makes lenalidomide the first treatment to receive FDA approval for maintenance following auto-HSCT.
The drug was previously FDA-approved for use in combination with dexamethasone to treat patients with MM.
Lenalidomide is also FDA-approved to treat patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes associated with deletion 5q, with or without additional cytogenetic abnormalities.
And lenalidomide is FDA-approved to treat patients with mantle cell lymphoma who have relapsed or progressed after 2 prior therapies, one of which included bortezomib.
Lenalidomide is a product of Celgene.
Studies: Lenalidomide maintenance
The latest approval for lenalidomide was based on results of 2 cooperative group-led studies, CALGB 10010410 and IFM 2005-0211.
Results from both studies were published in NEJM in May 2012 (CALGB 100104, IFM 2005-02). The updated data reported here are included in the prescribing information for lenalidomide.
CALGB 100104 was a phase 3, double-blind study of 460 patients with newly diagnosed MM undergoing auto-HSCT. The patients received continuous daily treatment with lenalidomide or placebo until relapse.
IFM 2005-02 was a phase 3, double-blind study of 614 patients newly diagnosed with MM. The patients were randomized to receive a 2-month consolidation regimen after auto-HSCT, which consisted of lenalidomide monotherapy followed by continuous daily treatment with lenalidomide or placebo until relapse.
Survival
In both studies, the primary efficacy endpoint was progression-free survival (PFS). The PFS data for both studies were updated to reflect results as of March 2015.
In the CALGB study, the median PFS was 5.7 years in the lenalidomide arm and 1.9 years in the placebo arm (hazard ratio [HR]=0.38 [95% CI: 0.28-0.50]).
In the IFM study, the median PFS was 3.9 years in the lenalidomide arm and 2 years in the placebo arm (HR=0.53 [95% CI: 0.44-0.64]).
These studies were not powered for an overall survival (OS) endpoint. However, OS was recorded, and the OS data for both studies were updated to reflect results as of February 2016.
The median OS in the CALGB study was 9.3 years in the lenalidomide arm and 7 years in the placebo arm (HR=0.59 [95% CI: 0.44-0.78]).
In the IFM study, the median OS was 8.8 years in the lenalidomide arm and 7.3 years in the placebo arm (HR=0.90 [95% CI: 0.72-1.13]).
Adverse events
The most frequently reported adverse events in ≥20% of patients in the lenalidomide arm across both studies (CALGB and IFM, respectively) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%).
The most frequently reported grade 3/4 events (more than 20% in the lenalidomide arm) were neutropenia, thrombocytopenia, and leukopenia.
Hematologic second primary malignancies (SPM) occurred in 7.5% of patients receiving lenalidomide maintenance and 3.3% of controls.
The incidence of hematologic plus solid tumor SPM (excluding squamous cell carcinoma and basal cell carcinoma) was 14.9% in the lenalidomide group and 8.8% in the control group, with a median follow-up of 91.5 months.
Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving lenalidomide maintenance and 2.6% of controls.
The US Food and Drug Administration (FDA) has approved a new indication for lenalidomide (Revlimid).
The drug is now approved for use as maintenance therapy after autologous hematopoietic stem cell transplant (auto-HSCT) in patients with multiple myeloma (MM).
The expanded indication makes lenalidomide the first treatment to receive FDA approval for maintenance following auto-HSCT.
The drug was previously FDA-approved for use in combination with dexamethasone to treat patients with MM.
Lenalidomide is also FDA-approved to treat patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes associated with deletion 5q, with or without additional cytogenetic abnormalities.
And lenalidomide is FDA-approved to treat patients with mantle cell lymphoma who have relapsed or progressed after 2 prior therapies, one of which included bortezomib.
Lenalidomide is a product of Celgene.
Studies: Lenalidomide maintenance
The latest approval for lenalidomide was based on results of 2 cooperative group-led studies, CALGB 10010410 and IFM 2005-0211.
Results from both studies were published in NEJM in May 2012 (CALGB 100104, IFM 2005-02). The updated data reported here are included in the prescribing information for lenalidomide.
CALGB 100104 was a phase 3, double-blind study of 460 patients with newly diagnosed MM undergoing auto-HSCT. The patients received continuous daily treatment with lenalidomide or placebo until relapse.
IFM 2005-02 was a phase 3, double-blind study of 614 patients newly diagnosed with MM. The patients were randomized to receive a 2-month consolidation regimen after auto-HSCT, which consisted of lenalidomide monotherapy followed by continuous daily treatment with lenalidomide or placebo until relapse.
Survival
In both studies, the primary efficacy endpoint was progression-free survival (PFS). The PFS data for both studies were updated to reflect results as of March 2015.
In the CALGB study, the median PFS was 5.7 years in the lenalidomide arm and 1.9 years in the placebo arm (hazard ratio [HR]=0.38 [95% CI: 0.28-0.50]).
In the IFM study, the median PFS was 3.9 years in the lenalidomide arm and 2 years in the placebo arm (HR=0.53 [95% CI: 0.44-0.64]).
These studies were not powered for an overall survival (OS) endpoint. However, OS was recorded, and the OS data for both studies were updated to reflect results as of February 2016.
The median OS in the CALGB study was 9.3 years in the lenalidomide arm and 7 years in the placebo arm (HR=0.59 [95% CI: 0.44-0.78]).
In the IFM study, the median OS was 8.8 years in the lenalidomide arm and 7.3 years in the placebo arm (HR=0.90 [95% CI: 0.72-1.13]).
Adverse events
The most frequently reported adverse events in ≥20% of patients in the lenalidomide arm across both studies (CALGB and IFM, respectively) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%).
The most frequently reported grade 3/4 events (more than 20% in the lenalidomide arm) were neutropenia, thrombocytopenia, and leukopenia.
Hematologic second primary malignancies (SPM) occurred in 7.5% of patients receiving lenalidomide maintenance and 3.3% of controls.
The incidence of hematologic plus solid tumor SPM (excluding squamous cell carcinoma and basal cell carcinoma) was 14.9% in the lenalidomide group and 8.8% in the control group, with a median follow-up of 91.5 months.
Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving lenalidomide maintenance and 2.6% of controls.
The US Food and Drug Administration (FDA) has approved a new indication for lenalidomide (Revlimid).
The drug is now approved for use as maintenance therapy after autologous hematopoietic stem cell transplant (auto-HSCT) in patients with multiple myeloma (MM).
The expanded indication makes lenalidomide the first treatment to receive FDA approval for maintenance following auto-HSCT.
The drug was previously FDA-approved for use in combination with dexamethasone to treat patients with MM.
Lenalidomide is also FDA-approved to treat patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes associated with deletion 5q, with or without additional cytogenetic abnormalities.
And lenalidomide is FDA-approved to treat patients with mantle cell lymphoma who have relapsed or progressed after 2 prior therapies, one of which included bortezomib.
Lenalidomide is a product of Celgene.
Studies: Lenalidomide maintenance
The latest approval for lenalidomide was based on results of 2 cooperative group-led studies, CALGB 10010410 and IFM 2005-0211.
Results from both studies were published in NEJM in May 2012 (CALGB 100104, IFM 2005-02). The updated data reported here are included in the prescribing information for lenalidomide.
CALGB 100104 was a phase 3, double-blind study of 460 patients with newly diagnosed MM undergoing auto-HSCT. The patients received continuous daily treatment with lenalidomide or placebo until relapse.
IFM 2005-02 was a phase 3, double-blind study of 614 patients newly diagnosed with MM. The patients were randomized to receive a 2-month consolidation regimen after auto-HSCT, which consisted of lenalidomide monotherapy followed by continuous daily treatment with lenalidomide or placebo until relapse.
Survival
In both studies, the primary efficacy endpoint was progression-free survival (PFS). The PFS data for both studies were updated to reflect results as of March 2015.
In the CALGB study, the median PFS was 5.7 years in the lenalidomide arm and 1.9 years in the placebo arm (hazard ratio [HR]=0.38 [95% CI: 0.28-0.50]).
In the IFM study, the median PFS was 3.9 years in the lenalidomide arm and 2 years in the placebo arm (HR=0.53 [95% CI: 0.44-0.64]).
These studies were not powered for an overall survival (OS) endpoint. However, OS was recorded, and the OS data for both studies were updated to reflect results as of February 2016.
The median OS in the CALGB study was 9.3 years in the lenalidomide arm and 7 years in the placebo arm (HR=0.59 [95% CI: 0.44-0.78]).
In the IFM study, the median OS was 8.8 years in the lenalidomide arm and 7.3 years in the placebo arm (HR=0.90 [95% CI: 0.72-1.13]).
Adverse events
The most frequently reported adverse events in ≥20% of patients in the lenalidomide arm across both studies (CALGB and IFM, respectively) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%).
The most frequently reported grade 3/4 events (more than 20% in the lenalidomide arm) were neutropenia, thrombocytopenia, and leukopenia.
Hematologic second primary malignancies (SPM) occurred in 7.5% of patients receiving lenalidomide maintenance and 3.3% of controls.
The incidence of hematologic plus solid tumor SPM (excluding squamous cell carcinoma and basal cell carcinoma) was 14.9% in the lenalidomide group and 8.8% in the control group, with a median follow-up of 91.5 months.
Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving lenalidomide maintenance and 2.6% of controls.
VZV vaccine reduces HZ incidence after HSCT
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.
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.
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.