Leukemia, Myelodysplasia, Transplantation

Photo by Chad McNeeley

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.

Photo by Chad McNeeley

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.

Photo by Chad McNeeley

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.

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted orphan drug designation for BI 836858, an anti-CD33 monoclonal antibody (mAb), in the treatment of myelodysplastic syndromes (MDS).

BI 836858 previously received orphan designation for the treatment of acute myeloid leukemia (AML).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.

Orphan designation provides companies with certain incentives to develop products for rare diseases.

This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

About BI 836858

BI 836858 is a fully human, immunoglobulin G1 anti-CD33 mAb. It has been engineered for improved binding to FcgRIIIa to mediate natural killer cell antibody-dependent cellular cytotoxicity against CD33-expressing tumor cells.

BI 836858 is being developed by Boehringer Ingelheim.

A phase 1/2 trial (NCT02240706) of BI 836858 in patients with MDS is ongoing. The phase 1 portion was designed to evaluate various doses of the mAb in patients with low or intermediate-1 risk MDS with symptomatic anemia.

The phase 2 portion was designed to compare BI 836858 plus best supportive care to best supportive care alone in patients with low- or intermediate-1-risk MDS who have symptomatic anemia but do not have a 5q deletion.

BI 836858 is also being tested in combination with decitabine in a phase 1/2 study (NCT02632721) of patients with AML.

The goals of the phase 1 portion and the phase 1 extension are to determine the maximum-tolerated dose/recommended dose, safety, pharmacokinetics, and efficacy of BI 836858 in combination with decitabine.

The goals of the phase 2 portion of the study are to investigate the efficacy, safety, and pharmacokinetics of BI 836858 in combination with decitabine compared to decitabine monotherapy.

BI 836858 was previously evaluated in combination with decitabine in a preclinical study. The combination exhibited activity against AML in vitro. The research was published in Blood last year.

BI 836858 is also being evaluated as part of the Leukemia & Lymphoma Society’s Beat AML Master Trial program to advance treatment for patients with AML.

In this trial, investigators are using genomic technology to identify AML mutations in newly diagnosed patients over the age of 60 and match the patients with an investigational drug or drugs best suited to attack the mutations found.

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted orphan drug designation for BI 836858, an anti-CD33 monoclonal antibody (mAb), in the treatment of myelodysplastic syndromes (MDS).

BI 836858 previously received orphan designation for the treatment of acute myeloid leukemia (AML).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.

Orphan designation provides companies with certain incentives to develop products for rare diseases.

This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

About BI 836858

BI 836858 is a fully human, immunoglobulin G1 anti-CD33 mAb. It has been engineered for improved binding to FcgRIIIa to mediate natural killer cell antibody-dependent cellular cytotoxicity against CD33-expressing tumor cells.

BI 836858 is being developed by Boehringer Ingelheim.

A phase 1/2 trial (NCT02240706) of BI 836858 in patients with MDS is ongoing. The phase 1 portion was designed to evaluate various doses of the mAb in patients with low or intermediate-1 risk MDS with symptomatic anemia.

The phase 2 portion was designed to compare BI 836858 plus best supportive care to best supportive care alone in patients with low- or intermediate-1-risk MDS who have symptomatic anemia but do not have a 5q deletion.

BI 836858 is also being tested in combination with decitabine in a phase 1/2 study (NCT02632721) of patients with AML.

The goals of the phase 1 portion and the phase 1 extension are to determine the maximum-tolerated dose/recommended dose, safety, pharmacokinetics, and efficacy of BI 836858 in combination with decitabine.

The goals of the phase 2 portion of the study are to investigate the efficacy, safety, and pharmacokinetics of BI 836858 in combination with decitabine compared to decitabine monotherapy.

BI 836858 was previously evaluated in combination with decitabine in a preclinical study. The combination exhibited activity against AML in vitro. The research was published in Blood last year.

BI 836858 is also being evaluated as part of the Leukemia & Lymphoma Society’s Beat AML Master Trial program to advance treatment for patients with AML.

In this trial, investigators are using genomic technology to identify AML mutations in newly diagnosed patients over the age of 60 and match the patients with an investigational drug or drugs best suited to attack the mutations found.

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted orphan drug designation for BI 836858, an anti-CD33 monoclonal antibody (mAb), in the treatment of myelodysplastic syndromes (MDS).

BI 836858 previously received orphan designation for the treatment of acute myeloid leukemia (AML).

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.

Orphan designation provides companies with certain incentives to develop products for rare diseases.

This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

About BI 836858

BI 836858 is a fully human, immunoglobulin G1 anti-CD33 mAb. It has been engineered for improved binding to FcgRIIIa to mediate natural killer cell antibody-dependent cellular cytotoxicity against CD33-expressing tumor cells.

BI 836858 is being developed by Boehringer Ingelheim.

A phase 1/2 trial (NCT02240706) of BI 836858 in patients with MDS is ongoing. The phase 1 portion was designed to evaluate various doses of the mAb in patients with low or intermediate-1 risk MDS with symptomatic anemia.

The phase 2 portion was designed to compare BI 836858 plus best supportive care to best supportive care alone in patients with low- or intermediate-1-risk MDS who have symptomatic anemia but do not have a 5q deletion.

BI 836858 is also being tested in combination with decitabine in a phase 1/2 study (NCT02632721) of patients with AML.

The goals of the phase 1 portion and the phase 1 extension are to determine the maximum-tolerated dose/recommended dose, safety, pharmacokinetics, and efficacy of BI 836858 in combination with decitabine.

The goals of the phase 2 portion of the study are to investigate the efficacy, safety, and pharmacokinetics of BI 836858 in combination with decitabine compared to decitabine monotherapy.

BI 836858 was previously evaluated in combination with decitabine in a preclinical study. The combination exhibited activity against AML in vitro. The research was published in Blood last year.

BI 836858 is also being evaluated as part of the Leukemia & Lymphoma Society’s Beat AML Master Trial program to advance treatment for patients with AML.

In this trial, investigators are using genomic technology to identify AML mutations in newly diagnosed patients over the age of 60 and match the patients with an investigational drug or drugs best suited to attack the mutations found.

Adipose tissue

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.

Adipose tissue

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.

Adipose tissue

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.

Photo by Patrick Pelletier

Long-term follow-up of patients treated with imatinib suggests the drug can remain effective beyond 10 years and does not confer “unacceptable” cumulative toxicity, according to researchers.

The group evaluated data on patients who had newly diagnosed, chronic-phase chronic myeloid leukemia (CML) when they began treatment with imatinib.

The median treatment duration was 8.9 years, and the estimated 10-year survival rate ranged from 64.4% to 84.4%.

The researchers said serious adverse events (AEs) thought to be related to imatinib were uncommon and typically occurred early, within the first year of treatment.

These results were reported in NEJM. The research was funded by Novartis Pharmaceuticals, which markets imatinib as Gleevec.

“The long-term success of this treatment confirms the remarkable success we’ve seen since the very first Gleevec trials,” said study author Brian Druker, MD, a physician-scientist at Oregon Health & Science University in Portland, Oregon, who led the original clinical development of Gleevec.

“This study reinforces the notion that we can create effective and non-toxic therapies.”

The study enrolled 1106 newly diagnosed, chronic-phase CML patients at 177 cancer centers in more than 16 countries. Half were assigned to treatment with imatinib (n=533) and the other half to interferon alfa plus cytarabine.

This study allowed for cross-over between the treatment arms, and 65.6% of patients in the cytarabine/interferon alfa arm ultimately crossed over to the imatinib arm.

However, when assessing the effects of imatinib, the researchers focused only on the patients who were first randomized to receive imatinib.

The median follow-up was 10.9 years (range, 0 to 11.7, which included follow-up after patients discontinued study treatment).

Of the patients randomized to imatinib, 48.3% (n=267) completed treatment with the drug. The median duration of first-line imatinib was 8.9 years (range, <0.1 to 11.7).

For patients who did not complete imatinib treatment, reasons for discontinuation included a lack of efficacy (15.9%), withdrawn consent (10.3%), AEs (6.9%), because they proceeded to transplant (3.8%), death (3.4%), protocol violation (3.1%), loss to follow-up (2.7%), cross over to the interferon arm (2.5%), administrative problems (2.2%), abnormal laboratory values (0.5%), or abnormal procedure (0.4%).

Safety

The incidence of serious AEs considered related to imatinib was 9.3% (51/551).

Drug-related serious AEs occurring in at least 2 patients included abdominal pain (n=4), anemia (n=3), congestive cardiac failure (n=3), gastrointestinal hemorrhage (n=3), vomiting (n=3), alanine aminotransferase increase (n=2), cardiac arrest (n=2), conjunctival hemorrhage (n=2), and melana (n=2).

Six patients had a second neoplasm (benign, malignant, or unspecified).

Response

The cumulative rate of complete cytogenetic response (CCR) at the end of the trial was 82.8%.

In the intent-to-treat population, the rate of CCR went from 52.8% in the first year to 22.2% at year 10.

Among evaluable patients, the rate of CCR went from 70.9% (292/412) in the first year to 91.8% (123/134) in year 10.

In the intent-to-treat population, the rate of major molecular response went from 27.7% in the first year to 34.4% at year 10.

Among evaluable patients, the rate of major molecular response went from 50.2% (153/305) in the first year to 93.1% (190/204) in year 10.

Progression and survival

The rate of progression was 6.9% (38/553) in the intent-to-treat population. Most of these patients (n=34) progressed during the first 4 years.

There were 260 patients who were still alive and receiving imatinib at 10 years and 96 patients who were alive but not receiving imatinib.

The researchers did not know the survival status of 111 patients, and there were 86 known deaths at 10 years (89 by the end of the study).

The estimated 10-year survival rate ranged from 64.4% (assuming all 111 patients with unknown status had died) to 84.4% (assuming all 111 were alive).

The cause of death was CML in 50 patients, a secondary malignant condition in 11, a cardiac disorder/cardiovascular disease in 7, infectious disease in 5, and “other” causes in 16 patients.

Photo by Patrick Pelletier

Long-term follow-up of patients treated with imatinib suggests the drug can remain effective beyond 10 years and does not confer “unacceptable” cumulative toxicity, according to researchers.

The group evaluated data on patients who had newly diagnosed, chronic-phase chronic myeloid leukemia (CML) when they began treatment with imatinib.

The median treatment duration was 8.9 years, and the estimated 10-year survival rate ranged from 64.4% to 84.4%.

The researchers said serious adverse events (AEs) thought to be related to imatinib were uncommon and typically occurred early, within the first year of treatment.

These results were reported in NEJM. The research was funded by Novartis Pharmaceuticals, which markets imatinib as Gleevec.

“The long-term success of this treatment confirms the remarkable success we’ve seen since the very first Gleevec trials,” said study author Brian Druker, MD, a physician-scientist at Oregon Health & Science University in Portland, Oregon, who led the original clinical development of Gleevec.

“This study reinforces the notion that we can create effective and non-toxic therapies.”

The study enrolled 1106 newly diagnosed, chronic-phase CML patients at 177 cancer centers in more than 16 countries. Half were assigned to treatment with imatinib (n=533) and the other half to interferon alfa plus cytarabine.

This study allowed for cross-over between the treatment arms, and 65.6% of patients in the cytarabine/interferon alfa arm ultimately crossed over to the imatinib arm.

However, when assessing the effects of imatinib, the researchers focused only on the patients who were first randomized to receive imatinib.

The median follow-up was 10.9 years (range, 0 to 11.7, which included follow-up after patients discontinued study treatment).

Of the patients randomized to imatinib, 48.3% (n=267) completed treatment with the drug. The median duration of first-line imatinib was 8.9 years (range, <0.1 to 11.7).

For patients who did not complete imatinib treatment, reasons for discontinuation included a lack of efficacy (15.9%), withdrawn consent (10.3%), AEs (6.9%), because they proceeded to transplant (3.8%), death (3.4%), protocol violation (3.1%), loss to follow-up (2.7%), cross over to the interferon arm (2.5%), administrative problems (2.2%), abnormal laboratory values (0.5%), or abnormal procedure (0.4%).

Safety

The incidence of serious AEs considered related to imatinib was 9.3% (51/551).

Drug-related serious AEs occurring in at least 2 patients included abdominal pain (n=4), anemia (n=3), congestive cardiac failure (n=3), gastrointestinal hemorrhage (n=3), vomiting (n=3), alanine aminotransferase increase (n=2), cardiac arrest (n=2), conjunctival hemorrhage (n=2), and melana (n=2).

Six patients had a second neoplasm (benign, malignant, or unspecified).

Response

The cumulative rate of complete cytogenetic response (CCR) at the end of the trial was 82.8%.

In the intent-to-treat population, the rate of CCR went from 52.8% in the first year to 22.2% at year 10.

Among evaluable patients, the rate of CCR went from 70.9% (292/412) in the first year to 91.8% (123/134) in year 10.

In the intent-to-treat population, the rate of major molecular response went from 27.7% in the first year to 34.4% at year 10.

Among evaluable patients, the rate of major molecular response went from 50.2% (153/305) in the first year to 93.1% (190/204) in year 10.

Progression and survival

The rate of progression was 6.9% (38/553) in the intent-to-treat population. Most of these patients (n=34) progressed during the first 4 years.

There were 260 patients who were still alive and receiving imatinib at 10 years and 96 patients who were alive but not receiving imatinib.

The researchers did not know the survival status of 111 patients, and there were 86 known deaths at 10 years (89 by the end of the study).

The estimated 10-year survival rate ranged from 64.4% (assuming all 111 patients with unknown status had died) to 84.4% (assuming all 111 were alive).

The cause of death was CML in 50 patients, a secondary malignant condition in 11, a cardiac disorder/cardiovascular disease in 7, infectious disease in 5, and “other” causes in 16 patients.

Photo by Patrick Pelletier

Long-term follow-up of patients treated with imatinib suggests the drug can remain effective beyond 10 years and does not confer “unacceptable” cumulative toxicity, according to researchers.

The group evaluated data on patients who had newly diagnosed, chronic-phase chronic myeloid leukemia (CML) when they began treatment with imatinib.

The median treatment duration was 8.9 years, and the estimated 10-year survival rate ranged from 64.4% to 84.4%.

The researchers said serious adverse events (AEs) thought to be related to imatinib were uncommon and typically occurred early, within the first year of treatment.

These results were reported in NEJM. The research was funded by Novartis Pharmaceuticals, which markets imatinib as Gleevec.

“The long-term success of this treatment confirms the remarkable success we’ve seen since the very first Gleevec trials,” said study author Brian Druker, MD, a physician-scientist at Oregon Health & Science University in Portland, Oregon, who led the original clinical development of Gleevec.

“This study reinforces the notion that we can create effective and non-toxic therapies.”

The study enrolled 1106 newly diagnosed, chronic-phase CML patients at 177 cancer centers in more than 16 countries. Half were assigned to treatment with imatinib (n=533) and the other half to interferon alfa plus cytarabine.

This study allowed for cross-over between the treatment arms, and 65.6% of patients in the cytarabine/interferon alfa arm ultimately crossed over to the imatinib arm.

However, when assessing the effects of imatinib, the researchers focused only on the patients who were first randomized to receive imatinib.

The median follow-up was 10.9 years (range, 0 to 11.7, which included follow-up after patients discontinued study treatment).

Of the patients randomized to imatinib, 48.3% (n=267) completed treatment with the drug. The median duration of first-line imatinib was 8.9 years (range, <0.1 to 11.7).

For patients who did not complete imatinib treatment, reasons for discontinuation included a lack of efficacy (15.9%), withdrawn consent (10.3%), AEs (6.9%), because they proceeded to transplant (3.8%), death (3.4%), protocol violation (3.1%), loss to follow-up (2.7%), cross over to the interferon arm (2.5%), administrative problems (2.2%), abnormal laboratory values (0.5%), or abnormal procedure (0.4%).

Safety

The incidence of serious AEs considered related to imatinib was 9.3% (51/551).

Drug-related serious AEs occurring in at least 2 patients included abdominal pain (n=4), anemia (n=3), congestive cardiac failure (n=3), gastrointestinal hemorrhage (n=3), vomiting (n=3), alanine aminotransferase increase (n=2), cardiac arrest (n=2), conjunctival hemorrhage (n=2), and melana (n=2).

Six patients had a second neoplasm (benign, malignant, or unspecified).

Response

The cumulative rate of complete cytogenetic response (CCR) at the end of the trial was 82.8%.

In the intent-to-treat population, the rate of CCR went from 52.8% in the first year to 22.2% at year 10.

Among evaluable patients, the rate of CCR went from 70.9% (292/412) in the first year to 91.8% (123/134) in year 10.

In the intent-to-treat population, the rate of major molecular response went from 27.7% in the first year to 34.4% at year 10.

Among evaluable patients, the rate of major molecular response went from 50.2% (153/305) in the first year to 93.1% (190/204) in year 10.

Progression and survival

The rate of progression was 6.9% (38/553) in the intent-to-treat population. Most of these patients (n=34) progressed during the first 4 years.

There were 260 patients who were still alive and receiving imatinib at 10 years and 96 patients who were alive but not receiving imatinib.

The researchers did not know the survival status of 111 patients, and there were 86 known deaths at 10 years (89 by the end of the study).

The estimated 10-year survival rate ranged from 64.4% (assuming all 111 patients with unknown status had died) to 84.4% (assuming all 111 were alive).

The cause of death was CML in 50 patients, a secondary malignant condition in 11, a cardiac disorder/cardiovascular disease in 7, infectious disease in 5, and “other” causes in 16 patients.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has lifted the clinical hold placed on 3 trials of vadastuximab talirine (SGN-CD33A), an antibody-drug conjugate targeting CD33, in acute myeloid leukemia (AML).

Last December, 1 trial was placed on full clinical hold (enrollment was halted and no further dosing of subjects was allowed), and 2 were placed on partial hold (enrollment was halted, but existing patients could continue treatment with re-consent).

All 3 of the holds were due to the potential risk of hepatotoxicity in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) before or after treatment with vadastuximab talirine.

In particular, the holds were in response to 6 cases of hepatotoxicity, including several cases of veno-occlusive disease (VOD), with 4 fatal events.

At the time the holds were announced, Seattle Genetics, Inc., the company developing vadastuximab talirine, said it was working with the FDA to determine whether there is an association between hepatotoxicity and treatment with the drug.

The company analyzed data from more than 350 patients treated with vadastuximab talirine and found no such association.

The rate of VOD they observed was “within the background rate of VOD in AML patients receiving allo-transplant,” according to Clay B. Siegall, PhD, president, chief executive officer, and chairman of the board at Seattle Genetics.

Dr Siegall said the company would not disclose the exact rate of VOD in these trials.

Resuming trials

As Seattle Genetics found no evidence to suggest that vadastuximab talirine increased the risk of hepatotoxicity, the FDA lifted the clinical holds on all 3 trials. The 2 trials placed on partial hold will continue, but the trial placed on full hold will not.

One of the trials that will continue is a phase 1 study of vadastuximab talirine alone and in combination with hypomethylating agents in both newly diagnosed and relapsed AML patients.

The other trial is a phase 1 study of vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients. (Results from this trial were presented at the 2016 ASH Annual Meeting.)

Cancelled trial

The trial that will not resume is a phase 1/2 study of vadastuximab talirine monotherapy pre- and post-allogeneic HSCT in patients with relapsed, chemo-resistant AML.

Seattle Genetics said it will not continue with this trial because of the challenges of developing therapies in this specific setting.

“It’s a very small group of patients, and we’re going to focus on the 3 biggest groups of patients [older and younger patients newly diagnosed with AML and patients with myelodysplastic syndromes] so we can really impact AML in the biggest way,” Dr Siegall said.

He noted that this decision does not prevent patients from undergoing HSCT after receiving vadastuximab talirine.

In the phase 1/2 trial, patients received vadastuximab talirine directly before HSCT, a practice that will not continue. However, patients can undergo HSCT as long as the transplant doesn’t occur immediately after treatment with vadastuximab talirine.

Moving forward

Two other trials of vadastuximab talirine were not affected by the clinical holds and have continued to enroll patients.

One is CASCADE, a randomized, phase 3 trial of vadastuximab talirine as front-line therapy in older AML patients. The other is a phase 1/2 trial of vadastuximab talirine as front-line therapy in patients with myelodysplastic syndromes.

Seattle Genetics is also planning to begin a randomized, phase 2 trial comparing 7+3 chemotherapy alone to 7+3 in combination with vadastuximab talirine in younger patients with previously untreated AML. The company plans to start the trial later this year.

Going forward, additional risk mitigation measures will be implemented in all vadastuximab talirine studies, including revised eligibility criteria and stopping rules for VOD.

Specifically, trials will not be stopped if the incidence of VOD is considered within the normal range, and an adjudication committee consisting of 2 experts will be tasked with verifying reports of VOD.

In addition, patients with liver cirrhosis due to alcohol abuse are no longer eligible for trials of vadastuximab talirine.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has lifted the clinical hold placed on 3 trials of vadastuximab talirine (SGN-CD33A), an antibody-drug conjugate targeting CD33, in acute myeloid leukemia (AML).

Last December, 1 trial was placed on full clinical hold (enrollment was halted and no further dosing of subjects was allowed), and 2 were placed on partial hold (enrollment was halted, but existing patients could continue treatment with re-consent).

All 3 of the holds were due to the potential risk of hepatotoxicity in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) before or after treatment with vadastuximab talirine.

In particular, the holds were in response to 6 cases of hepatotoxicity, including several cases of veno-occlusive disease (VOD), with 4 fatal events.

At the time the holds were announced, Seattle Genetics, Inc., the company developing vadastuximab talirine, said it was working with the FDA to determine whether there is an association between hepatotoxicity and treatment with the drug.

The company analyzed data from more than 350 patients treated with vadastuximab talirine and found no such association.

The rate of VOD they observed was “within the background rate of VOD in AML patients receiving allo-transplant,” according to Clay B. Siegall, PhD, president, chief executive officer, and chairman of the board at Seattle Genetics.

Dr Siegall said the company would not disclose the exact rate of VOD in these trials.

Resuming trials

As Seattle Genetics found no evidence to suggest that vadastuximab talirine increased the risk of hepatotoxicity, the FDA lifted the clinical holds on all 3 trials. The 2 trials placed on partial hold will continue, but the trial placed on full hold will not.

One of the trials that will continue is a phase 1 study of vadastuximab talirine alone and in combination with hypomethylating agents in both newly diagnosed and relapsed AML patients.

The other trial is a phase 1 study of vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients. (Results from this trial were presented at the 2016 ASH Annual Meeting.)

Cancelled trial

The trial that will not resume is a phase 1/2 study of vadastuximab talirine monotherapy pre- and post-allogeneic HSCT in patients with relapsed, chemo-resistant AML.

Seattle Genetics said it will not continue with this trial because of the challenges of developing therapies in this specific setting.

“It’s a very small group of patients, and we’re going to focus on the 3 biggest groups of patients [older and younger patients newly diagnosed with AML and patients with myelodysplastic syndromes] so we can really impact AML in the biggest way,” Dr Siegall said.

He noted that this decision does not prevent patients from undergoing HSCT after receiving vadastuximab talirine.

In the phase 1/2 trial, patients received vadastuximab talirine directly before HSCT, a practice that will not continue. However, patients can undergo HSCT as long as the transplant doesn’t occur immediately after treatment with vadastuximab talirine.

Moving forward

Two other trials of vadastuximab talirine were not affected by the clinical holds and have continued to enroll patients.

One is CASCADE, a randomized, phase 3 trial of vadastuximab talirine as front-line therapy in older AML patients. The other is a phase 1/2 trial of vadastuximab talirine as front-line therapy in patients with myelodysplastic syndromes.

Seattle Genetics is also planning to begin a randomized, phase 2 trial comparing 7+3 chemotherapy alone to 7+3 in combination with vadastuximab talirine in younger patients with previously untreated AML. The company plans to start the trial later this year.

Going forward, additional risk mitigation measures will be implemented in all vadastuximab talirine studies, including revised eligibility criteria and stopping rules for VOD.

Specifically, trials will not be stopped if the incidence of VOD is considered within the normal range, and an adjudication committee consisting of 2 experts will be tasked with verifying reports of VOD.

In addition, patients with liver cirrhosis due to alcohol abuse are no longer eligible for trials of vadastuximab talirine.

Image by Lance Liotta

The US Food and Drug Administration (FDA) has lifted the clinical hold placed on 3 trials of vadastuximab talirine (SGN-CD33A), an antibody-drug conjugate targeting CD33, in acute myeloid leukemia (AML).

Last December, 1 trial was placed on full clinical hold (enrollment was halted and no further dosing of subjects was allowed), and 2 were placed on partial hold (enrollment was halted, but existing patients could continue treatment with re-consent).

All 3 of the holds were due to the potential risk of hepatotoxicity in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) before or after treatment with vadastuximab talirine.

In particular, the holds were in response to 6 cases of hepatotoxicity, including several cases of veno-occlusive disease (VOD), with 4 fatal events.

At the time the holds were announced, Seattle Genetics, Inc., the company developing vadastuximab talirine, said it was working with the FDA to determine whether there is an association between hepatotoxicity and treatment with the drug.

The company analyzed data from more than 350 patients treated with vadastuximab talirine and found no such association.

The rate of VOD they observed was “within the background rate of VOD in AML patients receiving allo-transplant,” according to Clay B. Siegall, PhD, president, chief executive officer, and chairman of the board at Seattle Genetics.

Dr Siegall said the company would not disclose the exact rate of VOD in these trials.

Resuming trials

As Seattle Genetics found no evidence to suggest that vadastuximab talirine increased the risk of hepatotoxicity, the FDA lifted the clinical holds on all 3 trials. The 2 trials placed on partial hold will continue, but the trial placed on full hold will not.

One of the trials that will continue is a phase 1 study of vadastuximab talirine alone and in combination with hypomethylating agents in both newly diagnosed and relapsed AML patients.

The other trial is a phase 1 study of vadastuximab talirine in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients. (Results from this trial were presented at the 2016 ASH Annual Meeting.)

Cancelled trial

The trial that will not resume is a phase 1/2 study of vadastuximab talirine monotherapy pre- and post-allogeneic HSCT in patients with relapsed, chemo-resistant AML.

Seattle Genetics said it will not continue with this trial because of the challenges of developing therapies in this specific setting.

“It’s a very small group of patients, and we’re going to focus on the 3 biggest groups of patients [older and younger patients newly diagnosed with AML and patients with myelodysplastic syndromes] so we can really impact AML in the biggest way,” Dr Siegall said.

He noted that this decision does not prevent patients from undergoing HSCT after receiving vadastuximab talirine.

In the phase 1/2 trial, patients received vadastuximab talirine directly before HSCT, a practice that will not continue. However, patients can undergo HSCT as long as the transplant doesn’t occur immediately after treatment with vadastuximab talirine.

Moving forward

Two other trials of vadastuximab talirine were not affected by the clinical holds and have continued to enroll patients.

One is CASCADE, a randomized, phase 3 trial of vadastuximab talirine as front-line therapy in older AML patients. The other is a phase 1/2 trial of vadastuximab talirine as front-line therapy in patients with myelodysplastic syndromes.

Seattle Genetics is also planning to begin a randomized, phase 2 trial comparing 7+3 chemotherapy alone to 7+3 in combination with vadastuximab talirine in younger patients with previously untreated AML. The company plans to start the trial later this year.

Going forward, additional risk mitigation measures will be implemented in all vadastuximab talirine studies, including revised eligibility criteria and stopping rules for VOD.

Specifically, trials will not be stopped if the incidence of VOD is considered within the normal range, and an adjudication committee consisting of 2 experts will be tasked with verifying reports of VOD.

In addition, patients with liver cirrhosis due to alcohol abuse are no longer eligible for trials of vadastuximab talirine.

ORLANDO – Azacitadine and valproic acid can be safely coadministered as maintenance therapy after allogeneic stem cell transplantation in patients with high-risk acute myelogenous leukemia (AML), according to interim findings from an investigator-initiated phase II study.

One-year relapse-free and overall survival rates were about 80%, and no significant toxicities were reported in 28 such patients who began the treatment at least 40 days after transplant and were treated for 4 months, Patrick A. Hagen, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The Armed Forces Institute of Pathology/Public Domain

[email protected]

ORLANDO – Azacitadine and valproic acid can be safely coadministered as maintenance therapy after allogeneic stem cell transplantation in patients with high-risk acute myelogenous leukemia (AML), according to interim findings from an investigator-initiated phase II study.

One-year relapse-free and overall survival rates were about 80%, and no significant toxicities were reported in 28 such patients who began the treatment at least 40 days after transplant and were treated for 4 months, Patrick A. Hagen, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The Armed Forces Institute of Pathology/Public Domain

[email protected]

ORLANDO – Azacitadine and valproic acid can be safely coadministered as maintenance therapy after allogeneic stem cell transplantation in patients with high-risk acute myelogenous leukemia (AML), according to interim findings from an investigator-initiated phase II study.

One-year relapse-free and overall survival rates were about 80%, and no significant toxicities were reported in 28 such patients who began the treatment at least 40 days after transplant and were treated for 4 months, Patrick A. Hagen, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The Armed Forces Institute of Pathology/Public Domain

[email protected]

Add-on idelalisib boosted the progression-free survival (PFS) of patients with relapsed and refractory chronic lymphocytic leukemia by over 9 months in a double-blind, placebo-controlled trial of 416 participants. But that improvement came at the price of a 4% absolute increase in treatment-emergent adverse events leading to death.

At a median follow-up of 14 months, the median PFS was 20.8 months in the 207 patients in the idelalisib group and 11.1 months in the 209 patients in the placebo group. However, 11% of patients in the idelalisib group and 7% of those in the placebo group had treatment-related adverse events that resulted in death.

©Ed Uthman/Flickr

[email protected]

On Twitter @maryjodales

Add-on idelalisib boosted the progression-free survival (PFS) of patients with relapsed and refractory chronic lymphocytic leukemia by over 9 months in a double-blind, placebo-controlled trial of 416 participants. But that improvement came at the price of a 4% absolute increase in treatment-emergent adverse events leading to death.

At a median follow-up of 14 months, the median PFS was 20.8 months in the 207 patients in the idelalisib group and 11.1 months in the 209 patients in the placebo group. However, 11% of patients in the idelalisib group and 7% of those in the placebo group had treatment-related adverse events that resulted in death.

©Ed Uthman/Flickr

[email protected]

On Twitter @maryjodales

Add-on idelalisib boosted the progression-free survival (PFS) of patients with relapsed and refractory chronic lymphocytic leukemia by over 9 months in a double-blind, placebo-controlled trial of 416 participants. But that improvement came at the price of a 4% absolute increase in treatment-emergent adverse events leading to death.

At a median follow-up of 14 months, the median PFS was 20.8 months in the 207 patients in the idelalisib group and 11.1 months in the 209 patients in the placebo group. However, 11% of patients in the idelalisib group and 7% of those in the placebo group had treatment-related adverse events that resulted in death.

©Ed Uthman/Flickr

[email protected]

On Twitter @maryjodales

In patients with chronic myeloid leukemia (CML), the safety and benefits of imatinib persisted over the course of 10 years in a follow-up study reported online March 9 in the New England Journal of Medicine.

The initial results of the phase III International Randomized Study of Interferon and ST1571 (IRIS) trial “fundamentally changed CML treatment and led to marked improvements in prognosis for patients” when imatinib was shown more effective than interferon plus cytarabine among newly diagnosed patients in the chronic phase of the disease, said Andreas Hochhaus, MD, of the Klinik für Innere Medizin II, Universitätsklinikum Jena (Germany), and his associates. The researchers are now reporting the final follow-up results after a median of 10.9 years for the 553 patients who had been randomly assigned to receive daily oral imatinib in the IRIS trial.

Courtesy Wikimedia Commons/Difu Wu/Creative Commons License

In patients with chronic myeloid leukemia (CML), the safety and benefits of imatinib persisted over the course of 10 years in a follow-up study reported online March 9 in the New England Journal of Medicine.

The initial results of the phase III International Randomized Study of Interferon and ST1571 (IRIS) trial “fundamentally changed CML treatment and led to marked improvements in prognosis for patients” when imatinib was shown more effective than interferon plus cytarabine among newly diagnosed patients in the chronic phase of the disease, said Andreas Hochhaus, MD, of the Klinik für Innere Medizin II, Universitätsklinikum Jena (Germany), and his associates. The researchers are now reporting the final follow-up results after a median of 10.9 years for the 553 patients who had been randomly assigned to receive daily oral imatinib in the IRIS trial.

Courtesy Wikimedia Commons/Difu Wu/Creative Commons License

In patients with chronic myeloid leukemia (CML), the safety and benefits of imatinib persisted over the course of 10 years in a follow-up study reported online March 9 in the New England Journal of Medicine.

The initial results of the phase III International Randomized Study of Interferon and ST1571 (IRIS) trial “fundamentally changed CML treatment and led to marked improvements in prognosis for patients” when imatinib was shown more effective than interferon plus cytarabine among newly diagnosed patients in the chronic phase of the disease, said Andreas Hochhaus, MD, of the Klinik für Innere Medizin II, Universitätsklinikum Jena (Germany), and his associates. The researchers are now reporting the final follow-up results after a median of 10.9 years for the 553 patients who had been randomly assigned to receive daily oral imatinib in the IRIS trial.

Courtesy Wikimedia Commons/Difu Wu/Creative Commons License

Image courtesy of the National Institute of General Medical Sciences

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.”

Image courtesy of the National Institute of General Medical Sciences

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.”

Image courtesy of the National Institute of General Medical Sciences

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.”

Researchers from the University of Toronto had found in earlier studies that low-density lipoprotein (LDL) levels are elevated in up to 75% of patients with chronic lymphocytic leukemia (CLL). They also found that statins delayed the need for chemotherapy in those patients by nearly 3 years. They furthered their research using data on 2,124 patients with CLL and 7,935 controls in a population-based, case-control study. The researchers found a significantly higher incidence of hypercholesterolemia before CLL was diagnosed and a survival benefit of 3.7 years for patients taking statins.

In a new study to understand why hypercholesterolemia is apparently a tumor promoter for CLL, researchers first used an in vitro model of the “microenvironments” called pseudofollicles, where CLL cells proliferate. The researchers purified CLL cells from patients and activated them in lipid-poor conditions with interleukin-2 and resiquimod to represent stimulatory signals in pseudofollicles.

Related: New Treatments for Chronic Lymphocytic Leukemia

Adding LDLs increased viable cell numbers and signal transduction in molecules that mediate growth and proliferation of CLL cells.

To determine whether the effects were unique to CLL, the researchers conducted a similar experiment using peripheral blood mononuclear cells from donors without CLL. Their results suggested that normal blood cells handled cholesterol from LDLs in a different way than did CLL cells.

In another experiment, the researchers used circulating CLL cells from an additional cohort of 30 patients, including 11 who had been taking statins for at least 6 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels, suggesting that LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Statin use was associated with lower cholesterol in CLL cells, fewer circulating leukemia cells, and longer doubling times in vivo.

Related: Pneumatic Tube-Induced Reverse Pseudohyperkalemia in a Patient With Chronic Lymphocytic Leukemia

Researchers from the University of Toronto had found in earlier studies that low-density lipoprotein (LDL) levels are elevated in up to 75% of patients with chronic lymphocytic leukemia (CLL). They also found that statins delayed the need for chemotherapy in those patients by nearly 3 years. They furthered their research using data on 2,124 patients with CLL and 7,935 controls in a population-based, case-control study. The researchers found a significantly higher incidence of hypercholesterolemia before CLL was diagnosed and a survival benefit of 3.7 years for patients taking statins.

In a new study to understand why hypercholesterolemia is apparently a tumor promoter for CLL, researchers first used an in vitro model of the “microenvironments” called pseudofollicles, where CLL cells proliferate. The researchers purified CLL cells from patients and activated them in lipid-poor conditions with interleukin-2 and resiquimod to represent stimulatory signals in pseudofollicles.

Related: New Treatments for Chronic Lymphocytic Leukemia

Adding LDLs increased viable cell numbers and signal transduction in molecules that mediate growth and proliferation of CLL cells.

To determine whether the effects were unique to CLL, the researchers conducted a similar experiment using peripheral blood mononuclear cells from donors without CLL. Their results suggested that normal blood cells handled cholesterol from LDLs in a different way than did CLL cells.

In another experiment, the researchers used circulating CLL cells from an additional cohort of 30 patients, including 11 who had been taking statins for at least 6 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels, suggesting that LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Statin use was associated with lower cholesterol in CLL cells, fewer circulating leukemia cells, and longer doubling times in vivo.

Related: Pneumatic Tube-Induced Reverse Pseudohyperkalemia in a Patient With Chronic Lymphocytic Leukemia

Researchers from the University of Toronto had found in earlier studies that low-density lipoprotein (LDL) levels are elevated in up to 75% of patients with chronic lymphocytic leukemia (CLL). They also found that statins delayed the need for chemotherapy in those patients by nearly 3 years. They furthered their research using data on 2,124 patients with CLL and 7,935 controls in a population-based, case-control study. The researchers found a significantly higher incidence of hypercholesterolemia before CLL was diagnosed and a survival benefit of 3.7 years for patients taking statins.

In a new study to understand why hypercholesterolemia is apparently a tumor promoter for CLL, researchers first used an in vitro model of the “microenvironments” called pseudofollicles, where CLL cells proliferate. The researchers purified CLL cells from patients and activated them in lipid-poor conditions with interleukin-2 and resiquimod to represent stimulatory signals in pseudofollicles.

Related: New Treatments for Chronic Lymphocytic Leukemia

Adding LDLs increased viable cell numbers and signal transduction in molecules that mediate growth and proliferation of CLL cells.

To determine whether the effects were unique to CLL, the researchers conducted a similar experiment using peripheral blood mononuclear cells from donors without CLL. Their results suggested that normal blood cells handled cholesterol from LDLs in a different way than did CLL cells.

In another experiment, the researchers used circulating CLL cells from an additional cohort of 30 patients, including 11 who had been taking statins for at least 6 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels, suggesting that LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Statin use was associated with lower cholesterol in CLL cells, fewer circulating leukemia cells, and longer doubling times in vivo.

Related: Pneumatic Tube-Induced Reverse Pseudohyperkalemia in a Patient With Chronic Lymphocytic Leukemia