Transplant

AMSTERDAM – Patients with acute myeloid leukemia who were in morphological complete remission prior to allogeneic hematopoietic cell transplant but had genomic evidence of a lingering AML variant had worse posttransplant outcomes when they underwent reduced-intensity conditioning, rather than myeloablative conditioning, investigators reported.

Among adults with AML in remission after induction therapy who were randomized in a clinical trial to either reduced-intensity conditioning (RIC) or myeloablative conditioning prior to transplant, those with known AML variants detected with ultra-deep genomic sequencing who underwent RIC had significantly greater risk for relapse, decreased disease-free survival (DFS), and worse overall survival (OS), compared with similar patients who underwent myeloablative conditioning (MAC), reported Christopher S. Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, Md.

The findings suggest that those patients with pretransplant AML variants who can tolerate MAC should get it, and that investigators need to find new options for patients who can’t, he said in an interview at the annual congress of the European Hematology Association.

“If I wasn’t a lab investigator and was a clinical trialist, I would be very excited about doing some randomized trials now to try see about novel targeted agents. For example, we have FLT3 inhibitors, we have IDH1 and IDH2 inhibitors, and I would be looking to try to combine reduced-intensity conditioning with additional therapy to try to lower the relapse rate for that group at the highest risk,” he said.

Previous studies have shown that, regardless of the method used – flow cytometry, quantitative polymerase chain reaction, or next-generation sequencing – minimal residual disease (MRD) detected in patients with AML in complete remission prior to transplant is associated with both cumulative incidence of relapse and worse overall survival.
 

Measurable, not minimal

Dr. Hourigan contends that the word “minimal” – the “M” in “MRD” – is a misnomer and should be replaced by the word “measurable,” because MRD really reflects the limitations of disease-detection technology.

“If you tell patients ‘you have minimal residual disease, and you have a huge chance of dying over the next few years,’ there’s nothing minimal about that,” he said.

The fundamental question that Dr. Hourigan and colleagues asked is, “is MRD just useful for predicting prognosis? Is this fate, or can we as doctors do something about it?”

To get answers, they examined whole-blood samples from patients enrolled in the BMT CTN 0901 trial, which compared survival and other outcomes following allogeneic hematopoietic stem cell transplants (allo-HSCT) with either RIC or MAC for pretransplant conditioning in patients with AML or the myelodysplastic syndrome.

The trial was halted early after just 272 of a planned 356 patients were enrolled, following evidence of a significantly higher relapse rate among patients who had undergone RIC.

“Strikingly, over half the AML patients receiving RIC relapsed within 18 months after getting transplants,” Dr. Hourigan said.
 

Relapse, survival differences

For this substudy, the National Institutes of Health investigators developed a custom 13-gene panel that would detect at least one AML variant in approximately 80% of patients who were included in a previous study of genomic classification and prognosis in AML.

They used ultra-deep genomic sequencing to look for variants in blood samples from 188 patients in BMT CTN 0901. There were no variants detected in the blood of 31% of patients who had undergone MAC or in 33% of those who had undergone RIC.

Among patients who did have detectable variants, the average number of variants per patient was 2.5.

In this cohort, transplant-related mortality (TRM) was higher with MAC at 27% vs. 20% with RIC at 3 years, but there were no differences in TRM within conditioning arms for patients, with or without AML variants.

Relapse rates in the cohort studied by Dr. Hourigan and his colleagues were virtually identical to those seen in the full study set, with an 18-month relapse rate of 16% for patients treated with MAC vs. 51% for those treated with RIC.

Among patients randomized to RIC, 3-year relapse rates were 57% for patients with detectable pretransplant AML variants, compared with 32% for those without variants (P less than .001).

Although there were no significant differences in 3-year OS by variant status among patients assigned to MAC, variant-positive patients assigned to RIC had significantly worse 3-year OS than those without variants (P = .04).

Among patients with no detectable variants, there were no significant differences in OS between the MAC or RIC arms. However, among patients with variants, survival was significantly worse with RIC (P = .02).

In multivariate analysis controlling for disease risk and donor group among patients who tested positive for an AML variant pretransplant, RIC was significantly associated with an increased risk for relapse (hazard ratio, 5.98; P less than .001); decreased DFS (HR, 2.80; P less than .001), and worse OS (HR, 2.16; P = .003).

“This study provides evidence that intervention for AML patients with evidence of MRD can result in improved survival,” Dr. Hourigan said.

Questions that still need to be addressed include whether variants in different genes confer different degrees of relapse risk, whether next-generation sequencing positivity is equivalent to MRD positivity, and whether the 13-gene panel could be improved upon to lower the chance for false negatives, he said.

The study was supported by the NIH. Dr. Hourigan reported research funding from Merck and Sellas Life Sciences AG, research collaboration with Qiagen and Archer, advisory board participation as an NIH official duty for Janssen and Novartis, and part-time employment with the Johns Hopkins School of Medicine.

SOURCE: Hourigan CS et al. EHA Congress, Abstract LB2600.

AMSTERDAM – Patients with acute myeloid leukemia who were in morphological complete remission prior to allogeneic hematopoietic cell transplant but had genomic evidence of a lingering AML variant had worse posttransplant outcomes when they underwent reduced-intensity conditioning, rather than myeloablative conditioning, investigators reported.

Among adults with AML in remission after induction therapy who were randomized in a clinical trial to either reduced-intensity conditioning (RIC) or myeloablative conditioning prior to transplant, those with known AML variants detected with ultra-deep genomic sequencing who underwent RIC had significantly greater risk for relapse, decreased disease-free survival (DFS), and worse overall survival (OS), compared with similar patients who underwent myeloablative conditioning (MAC), reported Christopher S. Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, Md.

The findings suggest that those patients with pretransplant AML variants who can tolerate MAC should get it, and that investigators need to find new options for patients who can’t, he said in an interview at the annual congress of the European Hematology Association.

“If I wasn’t a lab investigator and was a clinical trialist, I would be very excited about doing some randomized trials now to try see about novel targeted agents. For example, we have FLT3 inhibitors, we have IDH1 and IDH2 inhibitors, and I would be looking to try to combine reduced-intensity conditioning with additional therapy to try to lower the relapse rate for that group at the highest risk,” he said.

Previous studies have shown that, regardless of the method used – flow cytometry, quantitative polymerase chain reaction, or next-generation sequencing – minimal residual disease (MRD) detected in patients with AML in complete remission prior to transplant is associated with both cumulative incidence of relapse and worse overall survival.
 

Measurable, not minimal

Dr. Hourigan contends that the word “minimal” – the “M” in “MRD” – is a misnomer and should be replaced by the word “measurable,” because MRD really reflects the limitations of disease-detection technology.

“If you tell patients ‘you have minimal residual disease, and you have a huge chance of dying over the next few years,’ there’s nothing minimal about that,” he said.

The fundamental question that Dr. Hourigan and colleagues asked is, “is MRD just useful for predicting prognosis? Is this fate, or can we as doctors do something about it?”

To get answers, they examined whole-blood samples from patients enrolled in the BMT CTN 0901 trial, which compared survival and other outcomes following allogeneic hematopoietic stem cell transplants (allo-HSCT) with either RIC or MAC for pretransplant conditioning in patients with AML or the myelodysplastic syndrome.

The trial was halted early after just 272 of a planned 356 patients were enrolled, following evidence of a significantly higher relapse rate among patients who had undergone RIC.

“Strikingly, over half the AML patients receiving RIC relapsed within 18 months after getting transplants,” Dr. Hourigan said.
 

Relapse, survival differences

For this substudy, the National Institutes of Health investigators developed a custom 13-gene panel that would detect at least one AML variant in approximately 80% of patients who were included in a previous study of genomic classification and prognosis in AML.

They used ultra-deep genomic sequencing to look for variants in blood samples from 188 patients in BMT CTN 0901. There were no variants detected in the blood of 31% of patients who had undergone MAC or in 33% of those who had undergone RIC.

Among patients who did have detectable variants, the average number of variants per patient was 2.5.

In this cohort, transplant-related mortality (TRM) was higher with MAC at 27% vs. 20% with RIC at 3 years, but there were no differences in TRM within conditioning arms for patients, with or without AML variants.

Relapse rates in the cohort studied by Dr. Hourigan and his colleagues were virtually identical to those seen in the full study set, with an 18-month relapse rate of 16% for patients treated with MAC vs. 51% for those treated with RIC.

Among patients randomized to RIC, 3-year relapse rates were 57% for patients with detectable pretransplant AML variants, compared with 32% for those without variants (P less than .001).

Although there were no significant differences in 3-year OS by variant status among patients assigned to MAC, variant-positive patients assigned to RIC had significantly worse 3-year OS than those without variants (P = .04).

Among patients with no detectable variants, there were no significant differences in OS between the MAC or RIC arms. However, among patients with variants, survival was significantly worse with RIC (P = .02).

In multivariate analysis controlling for disease risk and donor group among patients who tested positive for an AML variant pretransplant, RIC was significantly associated with an increased risk for relapse (hazard ratio, 5.98; P less than .001); decreased DFS (HR, 2.80; P less than .001), and worse OS (HR, 2.16; P = .003).

“This study provides evidence that intervention for AML patients with evidence of MRD can result in improved survival,” Dr. Hourigan said.

Questions that still need to be addressed include whether variants in different genes confer different degrees of relapse risk, whether next-generation sequencing positivity is equivalent to MRD positivity, and whether the 13-gene panel could be improved upon to lower the chance for false negatives, he said.

The study was supported by the NIH. Dr. Hourigan reported research funding from Merck and Sellas Life Sciences AG, research collaboration with Qiagen and Archer, advisory board participation as an NIH official duty for Janssen and Novartis, and part-time employment with the Johns Hopkins School of Medicine.

SOURCE: Hourigan CS et al. EHA Congress, Abstract LB2600.

AMSTERDAM – Patients with acute myeloid leukemia who were in morphological complete remission prior to allogeneic hematopoietic cell transplant but had genomic evidence of a lingering AML variant had worse posttransplant outcomes when they underwent reduced-intensity conditioning, rather than myeloablative conditioning, investigators reported.

Among adults with AML in remission after induction therapy who were randomized in a clinical trial to either reduced-intensity conditioning (RIC) or myeloablative conditioning prior to transplant, those with known AML variants detected with ultra-deep genomic sequencing who underwent RIC had significantly greater risk for relapse, decreased disease-free survival (DFS), and worse overall survival (OS), compared with similar patients who underwent myeloablative conditioning (MAC), reported Christopher S. Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute in Bethesda, Md.

The findings suggest that those patients with pretransplant AML variants who can tolerate MAC should get it, and that investigators need to find new options for patients who can’t, he said in an interview at the annual congress of the European Hematology Association.

“If I wasn’t a lab investigator and was a clinical trialist, I would be very excited about doing some randomized trials now to try see about novel targeted agents. For example, we have FLT3 inhibitors, we have IDH1 and IDH2 inhibitors, and I would be looking to try to combine reduced-intensity conditioning with additional therapy to try to lower the relapse rate for that group at the highest risk,” he said.

Previous studies have shown that, regardless of the method used – flow cytometry, quantitative polymerase chain reaction, or next-generation sequencing – minimal residual disease (MRD) detected in patients with AML in complete remission prior to transplant is associated with both cumulative incidence of relapse and worse overall survival.
 

Measurable, not minimal

Dr. Hourigan contends that the word “minimal” – the “M” in “MRD” – is a misnomer and should be replaced by the word “measurable,” because MRD really reflects the limitations of disease-detection technology.

“If you tell patients ‘you have minimal residual disease, and you have a huge chance of dying over the next few years,’ there’s nothing minimal about that,” he said.

The fundamental question that Dr. Hourigan and colleagues asked is, “is MRD just useful for predicting prognosis? Is this fate, or can we as doctors do something about it?”

To get answers, they examined whole-blood samples from patients enrolled in the BMT CTN 0901 trial, which compared survival and other outcomes following allogeneic hematopoietic stem cell transplants (allo-HSCT) with either RIC or MAC for pretransplant conditioning in patients with AML or the myelodysplastic syndrome.

The trial was halted early after just 272 of a planned 356 patients were enrolled, following evidence of a significantly higher relapse rate among patients who had undergone RIC.

“Strikingly, over half the AML patients receiving RIC relapsed within 18 months after getting transplants,” Dr. Hourigan said.
 

Relapse, survival differences

For this substudy, the National Institutes of Health investigators developed a custom 13-gene panel that would detect at least one AML variant in approximately 80% of patients who were included in a previous study of genomic classification and prognosis in AML.

They used ultra-deep genomic sequencing to look for variants in blood samples from 188 patients in BMT CTN 0901. There were no variants detected in the blood of 31% of patients who had undergone MAC or in 33% of those who had undergone RIC.

Among patients who did have detectable variants, the average number of variants per patient was 2.5.

In this cohort, transplant-related mortality (TRM) was higher with MAC at 27% vs. 20% with RIC at 3 years, but there were no differences in TRM within conditioning arms for patients, with or without AML variants.

Relapse rates in the cohort studied by Dr. Hourigan and his colleagues were virtually identical to those seen in the full study set, with an 18-month relapse rate of 16% for patients treated with MAC vs. 51% for those treated with RIC.

Among patients randomized to RIC, 3-year relapse rates were 57% for patients with detectable pretransplant AML variants, compared with 32% for those without variants (P less than .001).

Although there were no significant differences in 3-year OS by variant status among patients assigned to MAC, variant-positive patients assigned to RIC had significantly worse 3-year OS than those without variants (P = .04).

Among patients with no detectable variants, there were no significant differences in OS between the MAC or RIC arms. However, among patients with variants, survival was significantly worse with RIC (P = .02).

In multivariate analysis controlling for disease risk and donor group among patients who tested positive for an AML variant pretransplant, RIC was significantly associated with an increased risk for relapse (hazard ratio, 5.98; P less than .001); decreased DFS (HR, 2.80; P less than .001), and worse OS (HR, 2.16; P = .003).

“This study provides evidence that intervention for AML patients with evidence of MRD can result in improved survival,” Dr. Hourigan said.

Questions that still need to be addressed include whether variants in different genes confer different degrees of relapse risk, whether next-generation sequencing positivity is equivalent to MRD positivity, and whether the 13-gene panel could be improved upon to lower the chance for false negatives, he said.

The study was supported by the NIH. Dr. Hourigan reported research funding from Merck and Sellas Life Sciences AG, research collaboration with Qiagen and Archer, advisory board participation as an NIH official duty for Janssen and Novartis, and part-time employment with the Johns Hopkins School of Medicine.

SOURCE: Hourigan CS et al. EHA Congress, Abstract LB2600.

FORT LAUDERDALE, FLA. — A multicenter pilot study of a prophylactic regimen for both matched sibling donor and unrelated donor bone marrow transplantation in adults with severe sickle cell disease has found similar overall and event-free survival rates between the two approaches, exceeding 90% and 85%, respectively, at one year, according to preliminary results presented at the annual meeting of the Foundation for Sickle Cell Disease Research.

The results have led to a Phase 2 single-arm, multicenter trial, known as STRIDE , to evaluate a reduced toxicity preparative regimen consisting of busulfan (13.2 mg/kg), fludarabine (175   mg/m ² ) and antithymocyte globulin (ATG, 6 mg/kg) and cyclosporine or tacrolimus and methotrexate for graft-vs-host disease (GVHD) prophylaxis in adults with sickle cell disease (SCD), said Lakshmanan Krishnamurti, MD, of Children’s Healthcare of Atlanta/Emory University. “The data are similar with 91% overall survival and 86% event-free survival,” he said.

The pilot study, published recently ( Am J Hematol. 2019;94:446-54 ), indicated the effectiveness of non-myeloablative conditioning in SCD patients with matched-sibling bone marrow transplant (BMT), with a higher intensity regimen of busulfan/fludarabine/ATG effective in unrelated donor BMT for other conditions, Dr. Krishnamurti said.

The pilot study also found that three-year event-free survival (EFS) of 82%, and statistically significant improvements in pain and health-related quality of life.

STRIDE is the first comparative study of BMT vs. standard of care in severe SCD, Dr. Krishnamurti added. The primary endpoint is overall survival at two years after biologic assignment, with longer-term outcomes including survival at three to 10 years post-hematopoietic stem cell transplantation (HSCT), and impact of BMT on sickle-related events, organ function, health-related quality of life and chronic pain.  

The pilot study included 22 patients between the ages of 17 and 36 who had BMT at eight centers. Seventeen patients received marrow from a sibling-matched donor and five patients received marrow from an unrelated donor. 

Dr. Krishnamurti referenced a recent study out of France that showed chimerism levels after transplant may be a determining physiological factor for outcomes (Haematologica. doi:10.3324/haematol.2018.213207 ). “So if chimerism is stable, somewhere in the 25% to 50% or better range, and hemoglobin levels are improved, this decrease hemolysis,” he said. “This is very important in understanding how to manage these patients.”

That study showed that rates of chronic GVHD up to 10 years post-transplant have steadily improved over the past three decades in patients with SCD who’ve had BMT, Dr. Krishnamurti noted. “But chronic GVHD is higher in patients age 16 to 30 vs. patients 15 and younger,” he said, “so that’s the reason to consider transplantation sooner in patients who have a matched sibling donor.”

The French study shows that BMT with sibling-matched donors has excellent outcomes in young children, Dr. Krishnamurti said. “Outcomes for adults with transplantation is becoming similar to that in children,” he added. “Age is an important predictor of outcomes and the risk for progressive morbidity-impaired quality of life and risk of mortality still exists in adults with sickle cell disease.”

The bottom line, he said, is that patients and caregivers must be given the opportunity to consider transplantation as an option at younger ages.

Dr. Krishnamurti did not disclose any financial relationships.

SOURCE: Krishnamurti L et al. FSCDR 2019

FORT LAUDERDALE, FLA. — A multicenter pilot study of a prophylactic regimen for both matched sibling donor and unrelated donor bone marrow transplantation in adults with severe sickle cell disease has found similar overall and event-free survival rates between the two approaches, exceeding 90% and 85%, respectively, at one year, according to preliminary results presented at the annual meeting of the Foundation for Sickle Cell Disease Research.

The results have led to a Phase 2 single-arm, multicenter trial, known as STRIDE , to evaluate a reduced toxicity preparative regimen consisting of busulfan (13.2 mg/kg), fludarabine (175   mg/m ² ) and antithymocyte globulin (ATG, 6 mg/kg) and cyclosporine or tacrolimus and methotrexate for graft-vs-host disease (GVHD) prophylaxis in adults with sickle cell disease (SCD), said Lakshmanan Krishnamurti, MD, of Children’s Healthcare of Atlanta/Emory University. “The data are similar with 91% overall survival and 86% event-free survival,” he said.

The pilot study, published recently ( Am J Hematol. 2019;94:446-54 ), indicated the effectiveness of non-myeloablative conditioning in SCD patients with matched-sibling bone marrow transplant (BMT), with a higher intensity regimen of busulfan/fludarabine/ATG effective in unrelated donor BMT for other conditions, Dr. Krishnamurti said.

The pilot study also found that three-year event-free survival (EFS) of 82%, and statistically significant improvements in pain and health-related quality of life.

STRIDE is the first comparative study of BMT vs. standard of care in severe SCD, Dr. Krishnamurti added. The primary endpoint is overall survival at two years after biologic assignment, with longer-term outcomes including survival at three to 10 years post-hematopoietic stem cell transplantation (HSCT), and impact of BMT on sickle-related events, organ function, health-related quality of life and chronic pain.  

The pilot study included 22 patients between the ages of 17 and 36 who had BMT at eight centers. Seventeen patients received marrow from a sibling-matched donor and five patients received marrow from an unrelated donor. 

Dr. Krishnamurti referenced a recent study out of France that showed chimerism levels after transplant may be a determining physiological factor for outcomes (Haematologica. doi:10.3324/haematol.2018.213207 ). “So if chimerism is stable, somewhere in the 25% to 50% or better range, and hemoglobin levels are improved, this decrease hemolysis,” he said. “This is very important in understanding how to manage these patients.”

That study showed that rates of chronic GVHD up to 10 years post-transplant have steadily improved over the past three decades in patients with SCD who’ve had BMT, Dr. Krishnamurti noted. “But chronic GVHD is higher in patients age 16 to 30 vs. patients 15 and younger,” he said, “so that’s the reason to consider transplantation sooner in patients who have a matched sibling donor.”

The French study shows that BMT with sibling-matched donors has excellent outcomes in young children, Dr. Krishnamurti said. “Outcomes for adults with transplantation is becoming similar to that in children,” he added. “Age is an important predictor of outcomes and the risk for progressive morbidity-impaired quality of life and risk of mortality still exists in adults with sickle cell disease.”

The bottom line, he said, is that patients and caregivers must be given the opportunity to consider transplantation as an option at younger ages.

Dr. Krishnamurti did not disclose any financial relationships.

SOURCE: Krishnamurti L et al. FSCDR 2019

FORT LAUDERDALE, FLA. — A multicenter pilot study of a prophylactic regimen for both matched sibling donor and unrelated donor bone marrow transplantation in adults with severe sickle cell disease has found similar overall and event-free survival rates between the two approaches, exceeding 90% and 85%, respectively, at one year, according to preliminary results presented at the annual meeting of the Foundation for Sickle Cell Disease Research.

The results have led to a Phase 2 single-arm, multicenter trial, known as STRIDE , to evaluate a reduced toxicity preparative regimen consisting of busulfan (13.2 mg/kg), fludarabine (175   mg/m ² ) and antithymocyte globulin (ATG, 6 mg/kg) and cyclosporine or tacrolimus and methotrexate for graft-vs-host disease (GVHD) prophylaxis in adults with sickle cell disease (SCD), said Lakshmanan Krishnamurti, MD, of Children’s Healthcare of Atlanta/Emory University. “The data are similar with 91% overall survival and 86% event-free survival,” he said.

The pilot study, published recently ( Am J Hematol. 2019;94:446-54 ), indicated the effectiveness of non-myeloablative conditioning in SCD patients with matched-sibling bone marrow transplant (BMT), with a higher intensity regimen of busulfan/fludarabine/ATG effective in unrelated donor BMT for other conditions, Dr. Krishnamurti said.

The pilot study also found that three-year event-free survival (EFS) of 82%, and statistically significant improvements in pain and health-related quality of life.

STRIDE is the first comparative study of BMT vs. standard of care in severe SCD, Dr. Krishnamurti added. The primary endpoint is overall survival at two years after biologic assignment, with longer-term outcomes including survival at three to 10 years post-hematopoietic stem cell transplantation (HSCT), and impact of BMT on sickle-related events, organ function, health-related quality of life and chronic pain.  

The pilot study included 22 patients between the ages of 17 and 36 who had BMT at eight centers. Seventeen patients received marrow from a sibling-matched donor and five patients received marrow from an unrelated donor. 

Dr. Krishnamurti referenced a recent study out of France that showed chimerism levels after transplant may be a determining physiological factor for outcomes (Haematologica. doi:10.3324/haematol.2018.213207 ). “So if chimerism is stable, somewhere in the 25% to 50% or better range, and hemoglobin levels are improved, this decrease hemolysis,” he said. “This is very important in understanding how to manage these patients.”

That study showed that rates of chronic GVHD up to 10 years post-transplant have steadily improved over the past three decades in patients with SCD who’ve had BMT, Dr. Krishnamurti noted. “But chronic GVHD is higher in patients age 16 to 30 vs. patients 15 and younger,” he said, “so that’s the reason to consider transplantation sooner in patients who have a matched sibling donor.”

The French study shows that BMT with sibling-matched donors has excellent outcomes in young children, Dr. Krishnamurti said. “Outcomes for adults with transplantation is becoming similar to that in children,” he added. “Age is an important predictor of outcomes and the risk for progressive morbidity-impaired quality of life and risk of mortality still exists in adults with sickle cell disease.”

The bottom line, he said, is that patients and caregivers must be given the opportunity to consider transplantation as an option at younger ages.

Dr. Krishnamurti did not disclose any financial relationships.

SOURCE: Krishnamurti L et al. FSCDR 2019

The Food and Drug Administration has approved Jafaki (ruxolitinib) for treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older.

Ruxolitinib will be made available to appropriate patients immediately, according to a statement from Incyte, which markets the drug. The company noted that ruxolitinib is the first FDA-approved treatment for this indication.

The approval is based on data from the open-label, single-arm, multicenter REACH1 trial, which studied ruxolitinib in combination with corticosteroids. The 71 patients in the trial had grade 2-4 acute GVHD after allogeneic hematopoietic stem cell transplant; of these patients, 49 were refractory to steroids alone, 12 had received at least two prior therapies for GVHD, and 10 did not otherwise meet the FDA definition of steroid refractory.

The trial’s primary endpoints were day-28 overall response rate and response duration. Among the 49 patients with steroid only–refractory GVHD, the overall response rate was 100% for grade 2 GVHD, 40.7% for grade 3, and 44.4% for grade 4. Median response duration was 16 days. For all 49 of these patients, the overall response rate was 57%, and the complete response rate was 31%.

Among all 71 participants, the most frequently reported adverse reactions were infections (55%) and edema (51%); anemia (71%), thrombocytopenia (75%), and neutropenia (58%) were the most common laboratory abnormalities.

cpalmer@mdedge.com

The Food and Drug Administration has approved Jafaki (ruxolitinib) for treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older.

Ruxolitinib will be made available to appropriate patients immediately, according to a statement from Incyte, which markets the drug. The company noted that ruxolitinib is the first FDA-approved treatment for this indication.

The approval is based on data from the open-label, single-arm, multicenter REACH1 trial, which studied ruxolitinib in combination with corticosteroids. The 71 patients in the trial had grade 2-4 acute GVHD after allogeneic hematopoietic stem cell transplant; of these patients, 49 were refractory to steroids alone, 12 had received at least two prior therapies for GVHD, and 10 did not otherwise meet the FDA definition of steroid refractory.

The trial’s primary endpoints were day-28 overall response rate and response duration. Among the 49 patients with steroid only–refractory GVHD, the overall response rate was 100% for grade 2 GVHD, 40.7% for grade 3, and 44.4% for grade 4. Median response duration was 16 days. For all 49 of these patients, the overall response rate was 57%, and the complete response rate was 31%.

Among all 71 participants, the most frequently reported adverse reactions were infections (55%) and edema (51%); anemia (71%), thrombocytopenia (75%), and neutropenia (58%) were the most common laboratory abnormalities.

cpalmer@mdedge.com

The Food and Drug Administration has approved Jafaki (ruxolitinib) for treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older.

Ruxolitinib will be made available to appropriate patients immediately, according to a statement from Incyte, which markets the drug. The company noted that ruxolitinib is the first FDA-approved treatment for this indication.

The approval is based on data from the open-label, single-arm, multicenter REACH1 trial, which studied ruxolitinib in combination with corticosteroids. The 71 patients in the trial had grade 2-4 acute GVHD after allogeneic hematopoietic stem cell transplant; of these patients, 49 were refractory to steroids alone, 12 had received at least two prior therapies for GVHD, and 10 did not otherwise meet the FDA definition of steroid refractory.

The trial’s primary endpoints were day-28 overall response rate and response duration. Among the 49 patients with steroid only–refractory GVHD, the overall response rate was 100% for grade 2 GVHD, 40.7% for grade 3, and 44.4% for grade 4. Median response duration was 16 days. For all 49 of these patients, the overall response rate was 57%, and the complete response rate was 31%.

Among all 71 participants, the most frequently reported adverse reactions were infections (55%) and edema (51%); anemia (71%), thrombocytopenia (75%), and neutropenia (58%) were the most common laboratory abnormalities.

cpalmer@mdedge.com

CHICAGO – Compared with that of calcineurin inhibitors, belatacept appears to be associated with a lower risk of keratinocyte carcinomas in solid organ transplant patients, based on results from a single-center analysis presented at the annual meeting of the Society for Investigative Dermatology.

“Belatacept may offer a better risk-benefit profile in regards to skin cancer,” reported Michael Wang, a medical student who conducted this research in collaboration with the senior author, Oscar Colegio, MD, PhD, an associate professor of dermatology, pathology, and surgery at Yale University, New Haven, Conn.

Belatacept, a CTLA-4 fusion protein, has been compared with calcineurin inhibitors in two previous studies. The results were equivocal in one, and the other found no difference in risk and could not rule out the possibility that skin cancer risk was even higher on belatacept.

This single-center chart review included 110 kidney transplant patients, median age 58 years, who were switched from a calcineurin inhibitor, such as cyclosporine or tacrolimus, to belatacept. Ultimately, the study was limited to the 66 patients with at least 2 years of dermatologic follow-up both before and after the switch from a calcineurin inhibitor.

The primary outcome was the number of keratinocyte carcinomas overall and, specifically, the number of squamous cell carcinomas (SCCs) before and after the switch. Over the course of this study there were 128 cutaneous malignancies, 83 of which were SCCs.

When patients were on a calcineurin inhibitor, the risk of keratinocyte carcinomas increased incrementally by 2.6 events per 100 patients per year of follow-up, and the risk of SCCs increased by 1.7 events per 100 patients per year of follow-up. In the first 6 months after the switch to belatacept, there was no change in the rising trajectory of skin cancers, but rates declined thereafter.

Relative to rates prior to and 6 months after the switch, “the incidence of SCCs decreased at a rate of 5.9 events per 100 patients per year (P = .0068), and the incidence of keratinocyte carcinomas decreased by 7.1 events per 100 patients per year (P = .003),” Mr. Wang reported. He noted, however, that the incidence of basal cell carcinomas and melanomas following the switch remained unchanged.

When patients switched to belatacept were compared with another group of patients who remained on a calcineurin inhibitor after developing a SCC, the hazard ratio for a new SCC was 0.42, indicating a greater than 50% reduction in risk.

In patients on calcineurin inhibitors, the risk of keratinocyte carcinomas appears to be related to a direct effect of these agents on keratinocyte dedifferentiation. Belatacept is not believed to have any direct effects on keratinocytes, according to Mr. Wang.

As the chart review was retrospective and limited to a single center, “we hope [the findings] will encourage a prospective trial,” Mr. Wang said.

SOURCE: Wang M. SID 2019, Abstract 532.

CHICAGO – Compared with that of calcineurin inhibitors, belatacept appears to be associated with a lower risk of keratinocyte carcinomas in solid organ transplant patients, based on results from a single-center analysis presented at the annual meeting of the Society for Investigative Dermatology.

“Belatacept may offer a better risk-benefit profile in regards to skin cancer,” reported Michael Wang, a medical student who conducted this research in collaboration with the senior author, Oscar Colegio, MD, PhD, an associate professor of dermatology, pathology, and surgery at Yale University, New Haven, Conn.

Belatacept, a CTLA-4 fusion protein, has been compared with calcineurin inhibitors in two previous studies. The results were equivocal in one, and the other found no difference in risk and could not rule out the possibility that skin cancer risk was even higher on belatacept.

This single-center chart review included 110 kidney transplant patients, median age 58 years, who were switched from a calcineurin inhibitor, such as cyclosporine or tacrolimus, to belatacept. Ultimately, the study was limited to the 66 patients with at least 2 years of dermatologic follow-up both before and after the switch from a calcineurin inhibitor.

The primary outcome was the number of keratinocyte carcinomas overall and, specifically, the number of squamous cell carcinomas (SCCs) before and after the switch. Over the course of this study there were 128 cutaneous malignancies, 83 of which were SCCs.

When patients were on a calcineurin inhibitor, the risk of keratinocyte carcinomas increased incrementally by 2.6 events per 100 patients per year of follow-up, and the risk of SCCs increased by 1.7 events per 100 patients per year of follow-up. In the first 6 months after the switch to belatacept, there was no change in the rising trajectory of skin cancers, but rates declined thereafter.

Relative to rates prior to and 6 months after the switch, “the incidence of SCCs decreased at a rate of 5.9 events per 100 patients per year (P = .0068), and the incidence of keratinocyte carcinomas decreased by 7.1 events per 100 patients per year (P = .003),” Mr. Wang reported. He noted, however, that the incidence of basal cell carcinomas and melanomas following the switch remained unchanged.

When patients switched to belatacept were compared with another group of patients who remained on a calcineurin inhibitor after developing a SCC, the hazard ratio for a new SCC was 0.42, indicating a greater than 50% reduction in risk.

In patients on calcineurin inhibitors, the risk of keratinocyte carcinomas appears to be related to a direct effect of these agents on keratinocyte dedifferentiation. Belatacept is not believed to have any direct effects on keratinocytes, according to Mr. Wang.

As the chart review was retrospective and limited to a single center, “we hope [the findings] will encourage a prospective trial,” Mr. Wang said.

SOURCE: Wang M. SID 2019, Abstract 532.

CHICAGO – Compared with that of calcineurin inhibitors, belatacept appears to be associated with a lower risk of keratinocyte carcinomas in solid organ transplant patients, based on results from a single-center analysis presented at the annual meeting of the Society for Investigative Dermatology.

“Belatacept may offer a better risk-benefit profile in regards to skin cancer,” reported Michael Wang, a medical student who conducted this research in collaboration with the senior author, Oscar Colegio, MD, PhD, an associate professor of dermatology, pathology, and surgery at Yale University, New Haven, Conn.

Belatacept, a CTLA-4 fusion protein, has been compared with calcineurin inhibitors in two previous studies. The results were equivocal in one, and the other found no difference in risk and could not rule out the possibility that skin cancer risk was even higher on belatacept.

This single-center chart review included 110 kidney transplant patients, median age 58 years, who were switched from a calcineurin inhibitor, such as cyclosporine or tacrolimus, to belatacept. Ultimately, the study was limited to the 66 patients with at least 2 years of dermatologic follow-up both before and after the switch from a calcineurin inhibitor.

The primary outcome was the number of keratinocyte carcinomas overall and, specifically, the number of squamous cell carcinomas (SCCs) before and after the switch. Over the course of this study there were 128 cutaneous malignancies, 83 of which were SCCs.

When patients were on a calcineurin inhibitor, the risk of keratinocyte carcinomas increased incrementally by 2.6 events per 100 patients per year of follow-up, and the risk of SCCs increased by 1.7 events per 100 patients per year of follow-up. In the first 6 months after the switch to belatacept, there was no change in the rising trajectory of skin cancers, but rates declined thereafter.

Relative to rates prior to and 6 months after the switch, “the incidence of SCCs decreased at a rate of 5.9 events per 100 patients per year (P = .0068), and the incidence of keratinocyte carcinomas decreased by 7.1 events per 100 patients per year (P = .003),” Mr. Wang reported. He noted, however, that the incidence of basal cell carcinomas and melanomas following the switch remained unchanged.

When patients switched to belatacept were compared with another group of patients who remained on a calcineurin inhibitor after developing a SCC, the hazard ratio for a new SCC was 0.42, indicating a greater than 50% reduction in risk.

In patients on calcineurin inhibitors, the risk of keratinocyte carcinomas appears to be related to a direct effect of these agents on keratinocyte dedifferentiation. Belatacept is not believed to have any direct effects on keratinocytes, according to Mr. Wang.

As the chart review was retrospective and limited to a single center, “we hope [the findings] will encourage a prospective trial,” Mr. Wang said.

SOURCE: Wang M. SID 2019, Abstract 532.

NEWPORT BEACH, CALIF. – Researchers say they’ve found an association between the percentage of cytogenetically abnormal cells at allogeneic stem cell transplant (ASCT) and posttransplant outcomes in patients with myelodysplastic syndromes (MDS).

Patients who had more than 60% cytogenetically abnormal cells at ASCT had significantly inferior overall survival (OS) and relapse-free survival (RFS), compared to patients with fewer abnormal cells.

Dipenkumar Modi, MD, of Barbara Ann Karmanos Cancer Institute at Wayne State University in Detroit, and his colleagues conducted this research and presented the results at the Acute Leukemia Forum of Hemedicus.

The researchers studied 109 adult MDS patients who underwent ASCT from January 2000 through December 2016. The patients were divided into three groups based on the percentage of cytogenetically abnormal cells at ASCT:

• Group 1 had less than 30% (n = 22)
• Group 2 had 30%-60% (n = 23)
• Group 3 had greater than 60% (n = 64).

Baseline characteristics were largely similar between the groups. However, patients in group 3 were significantly more likely than those in groups 1 and 2 to have del(5q) and monosomy 5+7 (P = .048).

Patients in group 1 had a significantly higher percentage of bone marrow transplants (as opposed to peripheral blood stem cell transplants) than patients in groups 2 and 3 (P = .039). And patients in group 1 had significantly fewer blasts at ASCT than patients in groups 2 and 3 (P = .011).

The researchers found no significant between-group differences in relapse and nonrelapse mortality, but there were significant differences in OS and RFS.

Patients in group 3 had inferior RFS compared to patients in group 1, which was the reference group. The hazard ratio (HR) was 2.503 (P = .013) in a univariable analysis and 2.196 (P = .049) in a multivariable analysis.

Group 3 also had inferior OS compared to group 1. The hazard ratio was 2.589 (P = .021) in a univariable analysis and 2.478 (P = .040) in a multivariable analysis.

There was no significant difference in RFS or OS between groups 1 and 2. The HR for RFS in group 2 was 1.879 (P = .148) in a univariable analysis and 1.365 (P = .506) in a multivariable analysis. The HR for OS was 1.997 (P = .155) and 1.413 (P = .511), respectively.

Dr. Modi said these results suggest patients with greater than 60% cytogenetically abnormal cells at ASCT should be monitored more closely after transplant, and their immunosuppressive medication should be tapered as soon as possible.

Dr. Modi and his colleagues reported having no conflicts of interest relevant to this research.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

NEWPORT BEACH, CALIF. – Researchers say they’ve found an association between the percentage of cytogenetically abnormal cells at allogeneic stem cell transplant (ASCT) and posttransplant outcomes in patients with myelodysplastic syndromes (MDS).

Patients who had more than 60% cytogenetically abnormal cells at ASCT had significantly inferior overall survival (OS) and relapse-free survival (RFS), compared to patients with fewer abnormal cells.

Dipenkumar Modi, MD, of Barbara Ann Karmanos Cancer Institute at Wayne State University in Detroit, and his colleagues conducted this research and presented the results at the Acute Leukemia Forum of Hemedicus.

The researchers studied 109 adult MDS patients who underwent ASCT from January 2000 through December 2016. The patients were divided into three groups based on the percentage of cytogenetically abnormal cells at ASCT:

• Group 1 had less than 30% (n = 22)
• Group 2 had 30%-60% (n = 23)
• Group 3 had greater than 60% (n = 64).

Baseline characteristics were largely similar between the groups. However, patients in group 3 were significantly more likely than those in groups 1 and 2 to have del(5q) and monosomy 5+7 (P = .048).

Patients in group 1 had a significantly higher percentage of bone marrow transplants (as opposed to peripheral blood stem cell transplants) than patients in groups 2 and 3 (P = .039). And patients in group 1 had significantly fewer blasts at ASCT than patients in groups 2 and 3 (P = .011).

The researchers found no significant between-group differences in relapse and nonrelapse mortality, but there were significant differences in OS and RFS.

Patients in group 3 had inferior RFS compared to patients in group 1, which was the reference group. The hazard ratio (HR) was 2.503 (P = .013) in a univariable analysis and 2.196 (P = .049) in a multivariable analysis.

Group 3 also had inferior OS compared to group 1. The hazard ratio was 2.589 (P = .021) in a univariable analysis and 2.478 (P = .040) in a multivariable analysis.

There was no significant difference in RFS or OS between groups 1 and 2. The HR for RFS in group 2 was 1.879 (P = .148) in a univariable analysis and 1.365 (P = .506) in a multivariable analysis. The HR for OS was 1.997 (P = .155) and 1.413 (P = .511), respectively.

Dr. Modi said these results suggest patients with greater than 60% cytogenetically abnormal cells at ASCT should be monitored more closely after transplant, and their immunosuppressive medication should be tapered as soon as possible.

Dr. Modi and his colleagues reported having no conflicts of interest relevant to this research.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

NEWPORT BEACH, CALIF. – Researchers say they’ve found an association between the percentage of cytogenetically abnormal cells at allogeneic stem cell transplant (ASCT) and posttransplant outcomes in patients with myelodysplastic syndromes (MDS).

Patients who had more than 60% cytogenetically abnormal cells at ASCT had significantly inferior overall survival (OS) and relapse-free survival (RFS), compared to patients with fewer abnormal cells.

Dipenkumar Modi, MD, of Barbara Ann Karmanos Cancer Institute at Wayne State University in Detroit, and his colleagues conducted this research and presented the results at the Acute Leukemia Forum of Hemedicus.

The researchers studied 109 adult MDS patients who underwent ASCT from January 2000 through December 2016. The patients were divided into three groups based on the percentage of cytogenetically abnormal cells at ASCT:

• Group 1 had less than 30% (n = 22)
• Group 2 had 30%-60% (n = 23)
• Group 3 had greater than 60% (n = 64).

Baseline characteristics were largely similar between the groups. However, patients in group 3 were significantly more likely than those in groups 1 and 2 to have del(5q) and monosomy 5+7 (P = .048).

Patients in group 1 had a significantly higher percentage of bone marrow transplants (as opposed to peripheral blood stem cell transplants) than patients in groups 2 and 3 (P = .039). And patients in group 1 had significantly fewer blasts at ASCT than patients in groups 2 and 3 (P = .011).

The researchers found no significant between-group differences in relapse and nonrelapse mortality, but there were significant differences in OS and RFS.

Patients in group 3 had inferior RFS compared to patients in group 1, which was the reference group. The hazard ratio (HR) was 2.503 (P = .013) in a univariable analysis and 2.196 (P = .049) in a multivariable analysis.

Group 3 also had inferior OS compared to group 1. The hazard ratio was 2.589 (P = .021) in a univariable analysis and 2.478 (P = .040) in a multivariable analysis.

There was no significant difference in RFS or OS between groups 1 and 2. The HR for RFS in group 2 was 1.879 (P = .148) in a univariable analysis and 1.365 (P = .506) in a multivariable analysis. The HR for OS was 1.997 (P = .155) and 1.413 (P = .511), respectively.

Dr. Modi said these results suggest patients with greater than 60% cytogenetically abnormal cells at ASCT should be monitored more closely after transplant, and their immunosuppressive medication should be tapered as soon as possible.

Dr. Modi and his colleagues reported having no conflicts of interest relevant to this research.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

NEWPORT BEACH, CALIF. – Researchers say they have identified biomarkers that may help guide early treatment decisions in patients with acute graft-versus-host disease (GVHD).

The biomarkers, ST2 and REG3-alpha, were measured during the first month of GVHD treatment and proved more accurate than clinical response for predicting 6-month nonrelapse mortality (NRM). In fact, biomarker assessment revealed patients who responded to treatment but had a high risk of NRM and nonresponders who had a low risk of NRM.

The researchers also found that biomarkers changed over the first month of treatment but remained significant predictors of NRM. This suggests that modifying treatment according to biomarker findings at various time points could result in better outcomes for patients.

“We think this is going to transform the way we treat graft-versus-host disease,” said James L.M. Ferrara, MD, DSc, of the Icahn School of Medicine at Mount Sinai, New York.

Dr. Ferrara and Hrishikesh Srinagesh, along with their colleagues at Mount Sinai, have conducted extensive research with these biomarkers and presented some of their findings at the Acute Leukemia Forum of Hemedicus.

Comparing biomarkers and response

In one study, the researchers evaluated 355 patients who had undergone allogeneic hematopoietic stem cell transplant at 1 of 20 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between January 2016 and February 2018. All patients developed acute GVHD and received systemic steroids as treatment.

Patients provided blood samples weekly for the first month of treatment, and concentrations of ST2 and REG3-alpha were measured in each sample. Both biomarker concentrations were used to calculate the biomarker probability of NRM.

“The concentration of those two biomarkers are put into a computer, and we get … a single number, and that gives us the probability of mortality,” Dr. Ferrara said. “[W]e call this the MAGIC algorithm probability, or MAP. And when a MAP is low, the patient has a very low chance of dying from graft-versus-host disease, when it’s intermediate, they have an intermediate risk, and when it’s high, they have a high risk.”

The researchers then compared the MAP and clinical response for their ability to predict 6-month NRM throughout the first month of therapy for acute GVHD.

MAP bests response

After 1 month of therapy, the MAP was more accurate than clinical response for predicting 6-month NRM. The area under the curve was 0.84 and 0.65, respectively (P less than .001).

Likewise, the MAP after 1 week of therapy was more accurate than clinical response at 1 month for predicting 6-month NRM. The area under the curve was 0.80 and 0.65, respectively (P less than .001).

“[T]he clinical responses were good, but not great, at predicting long-term outcome, where the biomarker, the MAP, was significantly better,” Dr. Ferrara said. “[A]t every time point we tested, the biomarkers were better than the clinical responses.”

The researchers also identified subgroups of clinical responders and nonresponders for whom MAP more accurately predicted 6-month NRM.

The team found that 61% of clinical nonresponders were actually low risk according to MAP. And the incidence of 6-month NRM was significantly lower in the MAP-designated low-risk patients than in MAP-designated high-risk patients – 22% and 56%, respectively (P less than .001).

On the other hand, 10% of clinical responders were high risk according to MAP. The incidence of 6-month NRM was significantly higher in the high-risk patients than in the low-risk patients – 40% and 13%, respectively (P less than .001).

Assessing changes over time

The researchers found that patients who were initially high risk by MAP but had not experienced NRM by 6 months had significant decreases in their MAP after 4 weeks of treatment (P = .003). Patients who did experience NRM had a significant increase in their MAP whether their initial MAP was low (P = .007) or high (P = .024).

“What we found was that patients who lived tended to either have low biomarkers at the start of treatment and stay low or start out with high biomarkers and have reductions over the first month of therapy,” Mr. Srinagesh said. “Conversely, patients who tended to do worse were those who had either increases in their biomarkers or stayed high at all time points.”

The researchers identified a threshold – 0.290 – for separating patients by mortality risk.

“Patients who started out above the threshold and then went below it had a 5-fold reduction in mortality, whereas patients who started out below the threshold and rose above it had a 5-fold increase in mortality,” Mr. Srinagesh said.

MAP in clinical trials and practice

Based on these findings and results from related studies, the researchers theorize that MAP would be a better endpoint for clinical trials than clinical response.

At present, there are three trials in which researchers are using MAP as an endpoint to assess the efficacy of treatment for GVHD (NCT02133924, NCT03459040, and NCT03846479). Dr. Ferrara said a fourth trial is set to begin this summer.

Additionally, MAP is being used in clinical practice. A company called Viracor Eurofins Clinical Diagnostics licensed the MAGIC algorithm and provides three related tests for consumer use.

Viracor’s aGVHD Pre-Symptomatic Algorithm assigns patients to high- and low-risk groups based on results from samples collected 7 days after transplant. The aGVHD Symptomatic Onset Algorithm assigns patients to high-, intermediate-, and low-risk groups. The aGVHD Post-Treatment Algorithm, which can be used 7 days or more after GVHD treatment initiation, stratifies steroid-resistant patients into high- or low-risk groups for both NRM and overall survival.

“We are still in early days of figuring out how to use [the biomarker tests], but … what I’ve heard is that people are finding them to be useful in their clinical practice,” Dr. Ferrara said.

Dr. Ferrara has an ownership interest in and receives royalties from Viracor. Mr. Srinagesh reported having no relevant conflicts of interest. The research was supported by grants from the National Cancer Institute and the American Cancer Society.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

NEWPORT BEACH, CALIF. – Researchers say they have identified biomarkers that may help guide early treatment decisions in patients with acute graft-versus-host disease (GVHD).

The biomarkers, ST2 and REG3-alpha, were measured during the first month of GVHD treatment and proved more accurate than clinical response for predicting 6-month nonrelapse mortality (NRM). In fact, biomarker assessment revealed patients who responded to treatment but had a high risk of NRM and nonresponders who had a low risk of NRM.

The researchers also found that biomarkers changed over the first month of treatment but remained significant predictors of NRM. This suggests that modifying treatment according to biomarker findings at various time points could result in better outcomes for patients.

“We think this is going to transform the way we treat graft-versus-host disease,” said James L.M. Ferrara, MD, DSc, of the Icahn School of Medicine at Mount Sinai, New York.

Dr. Ferrara and Hrishikesh Srinagesh, along with their colleagues at Mount Sinai, have conducted extensive research with these biomarkers and presented some of their findings at the Acute Leukemia Forum of Hemedicus.

Comparing biomarkers and response

In one study, the researchers evaluated 355 patients who had undergone allogeneic hematopoietic stem cell transplant at 1 of 20 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between January 2016 and February 2018. All patients developed acute GVHD and received systemic steroids as treatment.

Patients provided blood samples weekly for the first month of treatment, and concentrations of ST2 and REG3-alpha were measured in each sample. Both biomarker concentrations were used to calculate the biomarker probability of NRM.

“The concentration of those two biomarkers are put into a computer, and we get … a single number, and that gives us the probability of mortality,” Dr. Ferrara said. “[W]e call this the MAGIC algorithm probability, or MAP. And when a MAP is low, the patient has a very low chance of dying from graft-versus-host disease, when it’s intermediate, they have an intermediate risk, and when it’s high, they have a high risk.”

The researchers then compared the MAP and clinical response for their ability to predict 6-month NRM throughout the first month of therapy for acute GVHD.

MAP bests response

After 1 month of therapy, the MAP was more accurate than clinical response for predicting 6-month NRM. The area under the curve was 0.84 and 0.65, respectively (P less than .001).

Likewise, the MAP after 1 week of therapy was more accurate than clinical response at 1 month for predicting 6-month NRM. The area under the curve was 0.80 and 0.65, respectively (P less than .001).

“[T]he clinical responses were good, but not great, at predicting long-term outcome, where the biomarker, the MAP, was significantly better,” Dr. Ferrara said. “[A]t every time point we tested, the biomarkers were better than the clinical responses.”

The researchers also identified subgroups of clinical responders and nonresponders for whom MAP more accurately predicted 6-month NRM.

The team found that 61% of clinical nonresponders were actually low risk according to MAP. And the incidence of 6-month NRM was significantly lower in the MAP-designated low-risk patients than in MAP-designated high-risk patients – 22% and 56%, respectively (P less than .001).

On the other hand, 10% of clinical responders were high risk according to MAP. The incidence of 6-month NRM was significantly higher in the high-risk patients than in the low-risk patients – 40% and 13%, respectively (P less than .001).

Assessing changes over time

The researchers found that patients who were initially high risk by MAP but had not experienced NRM by 6 months had significant decreases in their MAP after 4 weeks of treatment (P = .003). Patients who did experience NRM had a significant increase in their MAP whether their initial MAP was low (P = .007) or high (P = .024).

“What we found was that patients who lived tended to either have low biomarkers at the start of treatment and stay low or start out with high biomarkers and have reductions over the first month of therapy,” Mr. Srinagesh said. “Conversely, patients who tended to do worse were those who had either increases in their biomarkers or stayed high at all time points.”

The researchers identified a threshold – 0.290 – for separating patients by mortality risk.

“Patients who started out above the threshold and then went below it had a 5-fold reduction in mortality, whereas patients who started out below the threshold and rose above it had a 5-fold increase in mortality,” Mr. Srinagesh said.

MAP in clinical trials and practice

Based on these findings and results from related studies, the researchers theorize that MAP would be a better endpoint for clinical trials than clinical response.

At present, there are three trials in which researchers are using MAP as an endpoint to assess the efficacy of treatment for GVHD (NCT02133924, NCT03459040, and NCT03846479). Dr. Ferrara said a fourth trial is set to begin this summer.

Additionally, MAP is being used in clinical practice. A company called Viracor Eurofins Clinical Diagnostics licensed the MAGIC algorithm and provides three related tests for consumer use.

Viracor’s aGVHD Pre-Symptomatic Algorithm assigns patients to high- and low-risk groups based on results from samples collected 7 days after transplant. The aGVHD Symptomatic Onset Algorithm assigns patients to high-, intermediate-, and low-risk groups. The aGVHD Post-Treatment Algorithm, which can be used 7 days or more after GVHD treatment initiation, stratifies steroid-resistant patients into high- or low-risk groups for both NRM and overall survival.

“We are still in early days of figuring out how to use [the biomarker tests], but … what I’ve heard is that people are finding them to be useful in their clinical practice,” Dr. Ferrara said.

Dr. Ferrara has an ownership interest in and receives royalties from Viracor. Mr. Srinagesh reported having no relevant conflicts of interest. The research was supported by grants from the National Cancer Institute and the American Cancer Society.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

NEWPORT BEACH, CALIF. – Researchers say they have identified biomarkers that may help guide early treatment decisions in patients with acute graft-versus-host disease (GVHD).

The biomarkers, ST2 and REG3-alpha, were measured during the first month of GVHD treatment and proved more accurate than clinical response for predicting 6-month nonrelapse mortality (NRM). In fact, biomarker assessment revealed patients who responded to treatment but had a high risk of NRM and nonresponders who had a low risk of NRM.

The researchers also found that biomarkers changed over the first month of treatment but remained significant predictors of NRM. This suggests that modifying treatment according to biomarker findings at various time points could result in better outcomes for patients.

“We think this is going to transform the way we treat graft-versus-host disease,” said James L.M. Ferrara, MD, DSc, of the Icahn School of Medicine at Mount Sinai, New York.

Dr. Ferrara and Hrishikesh Srinagesh, along with their colleagues at Mount Sinai, have conducted extensive research with these biomarkers and presented some of their findings at the Acute Leukemia Forum of Hemedicus.

Comparing biomarkers and response

In one study, the researchers evaluated 355 patients who had undergone allogeneic hematopoietic stem cell transplant at 1 of 20 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between January 2016 and February 2018. All patients developed acute GVHD and received systemic steroids as treatment.

Patients provided blood samples weekly for the first month of treatment, and concentrations of ST2 and REG3-alpha were measured in each sample. Both biomarker concentrations were used to calculate the biomarker probability of NRM.

“The concentration of those two biomarkers are put into a computer, and we get … a single number, and that gives us the probability of mortality,” Dr. Ferrara said. “[W]e call this the MAGIC algorithm probability, or MAP. And when a MAP is low, the patient has a very low chance of dying from graft-versus-host disease, when it’s intermediate, they have an intermediate risk, and when it’s high, they have a high risk.”

The researchers then compared the MAP and clinical response for their ability to predict 6-month NRM throughout the first month of therapy for acute GVHD.

MAP bests response

After 1 month of therapy, the MAP was more accurate than clinical response for predicting 6-month NRM. The area under the curve was 0.84 and 0.65, respectively (P less than .001).

Likewise, the MAP after 1 week of therapy was more accurate than clinical response at 1 month for predicting 6-month NRM. The area under the curve was 0.80 and 0.65, respectively (P less than .001).

“[T]he clinical responses were good, but not great, at predicting long-term outcome, where the biomarker, the MAP, was significantly better,” Dr. Ferrara said. “[A]t every time point we tested, the biomarkers were better than the clinical responses.”

The researchers also identified subgroups of clinical responders and nonresponders for whom MAP more accurately predicted 6-month NRM.

The team found that 61% of clinical nonresponders were actually low risk according to MAP. And the incidence of 6-month NRM was significantly lower in the MAP-designated low-risk patients than in MAP-designated high-risk patients – 22% and 56%, respectively (P less than .001).

On the other hand, 10% of clinical responders were high risk according to MAP. The incidence of 6-month NRM was significantly higher in the high-risk patients than in the low-risk patients – 40% and 13%, respectively (P less than .001).

Assessing changes over time

The researchers found that patients who were initially high risk by MAP but had not experienced NRM by 6 months had significant decreases in their MAP after 4 weeks of treatment (P = .003). Patients who did experience NRM had a significant increase in their MAP whether their initial MAP was low (P = .007) or high (P = .024).

“What we found was that patients who lived tended to either have low biomarkers at the start of treatment and stay low or start out with high biomarkers and have reductions over the first month of therapy,” Mr. Srinagesh said. “Conversely, patients who tended to do worse were those who had either increases in their biomarkers or stayed high at all time points.”

The researchers identified a threshold – 0.290 – for separating patients by mortality risk.

“Patients who started out above the threshold and then went below it had a 5-fold reduction in mortality, whereas patients who started out below the threshold and rose above it had a 5-fold increase in mortality,” Mr. Srinagesh said.

MAP in clinical trials and practice

Based on these findings and results from related studies, the researchers theorize that MAP would be a better endpoint for clinical trials than clinical response.

At present, there are three trials in which researchers are using MAP as an endpoint to assess the efficacy of treatment for GVHD (NCT02133924, NCT03459040, and NCT03846479). Dr. Ferrara said a fourth trial is set to begin this summer.

Additionally, MAP is being used in clinical practice. A company called Viracor Eurofins Clinical Diagnostics licensed the MAGIC algorithm and provides three related tests for consumer use.

Viracor’s aGVHD Pre-Symptomatic Algorithm assigns patients to high- and low-risk groups based on results from samples collected 7 days after transplant. The aGVHD Symptomatic Onset Algorithm assigns patients to high-, intermediate-, and low-risk groups. The aGVHD Post-Treatment Algorithm, which can be used 7 days or more after GVHD treatment initiation, stratifies steroid-resistant patients into high- or low-risk groups for both NRM and overall survival.

“We are still in early days of figuring out how to use [the biomarker tests], but … what I’ve heard is that people are finding them to be useful in their clinical practice,” Dr. Ferrara said.

Dr. Ferrara has an ownership interest in and receives royalties from Viracor. Mr. Srinagesh reported having no relevant conflicts of interest. The research was supported by grants from the National Cancer Institute and the American Cancer Society.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

For patients with multiple myeloma in relapse after an autologous stem cell transplant (ASCT), salvage ASCT is associated with reduced quality of life and greater pain in the near term, compared with nontransplantation consolidation (NTC) therapy, a secondary analysis from the United Kingdom’s Myeloma X trial suggested.

Courtesy Wikimedia Commons/KGH/Creative Commons License

But global health status scores for salvage ASCT (sASCT) lagged only in the first 100 days after randomization, whereas pain scores were worse with salvage transplantation in the first 2 years but slightly better thereafter, reported Sam H. Ahmedzai, MBChB, from the University of Sheffield, England, and his colleagues.

“The small and diminishing differences in global health status and side effects of treatment need to be considered alongside the results of Myeloma X, which showed a significant benefit of sASCT on [overall survival]. The benefits of sASCT should be considered alongside the relatively short-term negative effects on [quality of life] and pain when making patient treatment decisions and further support the use of sASCT,” they wrote in the Journal of Clinical Oncology.

The BSBMT/UKMF Myeloma X trial was a multicenter, randomized, phase 3 trial comparing sASCT with weekly oral cyclophosphamide in patients with multiple myeloma who had relapsed after a prior ASCT. In the final overall survival analysis, median overall survival was superior for the sASCT, at 67 months vs. 52 months for nontransplantation consolidation (P = .022; hazard ratio, 0.56; P = .0169).

In the current study, the investigators reported on secondary patient-reported pain and quality of life outcomes assessed using the validated European Organization for Research and Treatment of Cancer Questionnaire (QLQ-C30) and its myeloma-specific module, QLQ-MY20; the Brief Pain Inventory (Short Form), and the Leeds Assessment of Neuropathic Symptoms and Signs (Self-Assessment) scale.

Of the 297 patients enrolled, 288 had consented to the quality of life portion of the study, and of this group, 171 (88 assigned to sASCT and 83 assigned to NTC) were included.

After a median follow-up of 52 months, the QLQ-C30 global health status scores were 9.2 points higher (indicating better) for patients in the nontransplantation group (P = .0496) at 100 days after transplantation, but there were no significant differences between the groups for this measure at any later time point.

“This deterioration in global health status for patients receiving sASCT, compared with NTC, dissipated to a trivial difference at 6 months and a smaller trivial difference at 1 year,” Dr. Ahmedzai and his colleagues wrote.

At 2 years, the pendulum had swung to favor sASCT, but also by a “trivial” amount.

The side effects of treatment subscale was slightly higher (worse) with sASCT at 100 days and 6 months after treatment, but this difference dwindled thereafter.

Pain interference scores adjusted for baseline score and baseline neuropathic pain level were not significantly different 100 days after randomization, but there were significant differences at both 6 months and up to 2 years. At all the time points considered, pain interference scores were approximately 1 point lower in the NTC group, which the authors noted is a clinically relevant difference.

Patients who had undergone sASCT and reported below-median scores on a side-effect subscale had significantly longer time to progression, compared with patients who received NTC (HR, 0.24; P = .003), a difference that held up on multivariable regression analysis (HR, 0.20; P = .0499).

Pain scores were not significantly predictive of either time to progression or overall survival, however.

The study was supported by Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK. Dr. Ahmedzai reported honoraria, consulting, research funding, and travel fees from various companies, not including the study sponsors.

SOURCE: Ahmedzai SH et al. J Clin Oncol. 2019 Apr 10. doi: 10.1200/JCO.18.01006.

For patients with multiple myeloma in relapse after an autologous stem cell transplant (ASCT), salvage ASCT is associated with reduced quality of life and greater pain in the near term, compared with nontransplantation consolidation (NTC) therapy, a secondary analysis from the United Kingdom’s Myeloma X trial suggested.

Courtesy Wikimedia Commons/KGH/Creative Commons License

But global health status scores for salvage ASCT (sASCT) lagged only in the first 100 days after randomization, whereas pain scores were worse with salvage transplantation in the first 2 years but slightly better thereafter, reported Sam H. Ahmedzai, MBChB, from the University of Sheffield, England, and his colleagues.

“The small and diminishing differences in global health status and side effects of treatment need to be considered alongside the results of Myeloma X, which showed a significant benefit of sASCT on [overall survival]. The benefits of sASCT should be considered alongside the relatively short-term negative effects on [quality of life] and pain when making patient treatment decisions and further support the use of sASCT,” they wrote in the Journal of Clinical Oncology.

The BSBMT/UKMF Myeloma X trial was a multicenter, randomized, phase 3 trial comparing sASCT with weekly oral cyclophosphamide in patients with multiple myeloma who had relapsed after a prior ASCT. In the final overall survival analysis, median overall survival was superior for the sASCT, at 67 months vs. 52 months for nontransplantation consolidation (P = .022; hazard ratio, 0.56; P = .0169).

In the current study, the investigators reported on secondary patient-reported pain and quality of life outcomes assessed using the validated European Organization for Research and Treatment of Cancer Questionnaire (QLQ-C30) and its myeloma-specific module, QLQ-MY20; the Brief Pain Inventory (Short Form), and the Leeds Assessment of Neuropathic Symptoms and Signs (Self-Assessment) scale.

Of the 297 patients enrolled, 288 had consented to the quality of life portion of the study, and of this group, 171 (88 assigned to sASCT and 83 assigned to NTC) were included.

After a median follow-up of 52 months, the QLQ-C30 global health status scores were 9.2 points higher (indicating better) for patients in the nontransplantation group (P = .0496) at 100 days after transplantation, but there were no significant differences between the groups for this measure at any later time point.

“This deterioration in global health status for patients receiving sASCT, compared with NTC, dissipated to a trivial difference at 6 months and a smaller trivial difference at 1 year,” Dr. Ahmedzai and his colleagues wrote.

At 2 years, the pendulum had swung to favor sASCT, but also by a “trivial” amount.

The side effects of treatment subscale was slightly higher (worse) with sASCT at 100 days and 6 months after treatment, but this difference dwindled thereafter.

Pain interference scores adjusted for baseline score and baseline neuropathic pain level were not significantly different 100 days after randomization, but there were significant differences at both 6 months and up to 2 years. At all the time points considered, pain interference scores were approximately 1 point lower in the NTC group, which the authors noted is a clinically relevant difference.

Patients who had undergone sASCT and reported below-median scores on a side-effect subscale had significantly longer time to progression, compared with patients who received NTC (HR, 0.24; P = .003), a difference that held up on multivariable regression analysis (HR, 0.20; P = .0499).

Pain scores were not significantly predictive of either time to progression or overall survival, however.

The study was supported by Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK. Dr. Ahmedzai reported honoraria, consulting, research funding, and travel fees from various companies, not including the study sponsors.

SOURCE: Ahmedzai SH et al. J Clin Oncol. 2019 Apr 10. doi: 10.1200/JCO.18.01006.

For patients with multiple myeloma in relapse after an autologous stem cell transplant (ASCT), salvage ASCT is associated with reduced quality of life and greater pain in the near term, compared with nontransplantation consolidation (NTC) therapy, a secondary analysis from the United Kingdom’s Myeloma X trial suggested.

Courtesy Wikimedia Commons/KGH/Creative Commons License

But global health status scores for salvage ASCT (sASCT) lagged only in the first 100 days after randomization, whereas pain scores were worse with salvage transplantation in the first 2 years but slightly better thereafter, reported Sam H. Ahmedzai, MBChB, from the University of Sheffield, England, and his colleagues.

“The small and diminishing differences in global health status and side effects of treatment need to be considered alongside the results of Myeloma X, which showed a significant benefit of sASCT on [overall survival]. The benefits of sASCT should be considered alongside the relatively short-term negative effects on [quality of life] and pain when making patient treatment decisions and further support the use of sASCT,” they wrote in the Journal of Clinical Oncology.

The BSBMT/UKMF Myeloma X trial was a multicenter, randomized, phase 3 trial comparing sASCT with weekly oral cyclophosphamide in patients with multiple myeloma who had relapsed after a prior ASCT. In the final overall survival analysis, median overall survival was superior for the sASCT, at 67 months vs. 52 months for nontransplantation consolidation (P = .022; hazard ratio, 0.56; P = .0169).

In the current study, the investigators reported on secondary patient-reported pain and quality of life outcomes assessed using the validated European Organization for Research and Treatment of Cancer Questionnaire (QLQ-C30) and its myeloma-specific module, QLQ-MY20; the Brief Pain Inventory (Short Form), and the Leeds Assessment of Neuropathic Symptoms and Signs (Self-Assessment) scale.

Of the 297 patients enrolled, 288 had consented to the quality of life portion of the study, and of this group, 171 (88 assigned to sASCT and 83 assigned to NTC) were included.

After a median follow-up of 52 months, the QLQ-C30 global health status scores were 9.2 points higher (indicating better) for patients in the nontransplantation group (P = .0496) at 100 days after transplantation, but there were no significant differences between the groups for this measure at any later time point.

“This deterioration in global health status for patients receiving sASCT, compared with NTC, dissipated to a trivial difference at 6 months and a smaller trivial difference at 1 year,” Dr. Ahmedzai and his colleagues wrote.

At 2 years, the pendulum had swung to favor sASCT, but also by a “trivial” amount.

The side effects of treatment subscale was slightly higher (worse) with sASCT at 100 days and 6 months after treatment, but this difference dwindled thereafter.

Pain interference scores adjusted for baseline score and baseline neuropathic pain level were not significantly different 100 days after randomization, but there were significant differences at both 6 months and up to 2 years. At all the time points considered, pain interference scores were approximately 1 point lower in the NTC group, which the authors noted is a clinically relevant difference.

Patients who had undergone sASCT and reported below-median scores on a side-effect subscale had significantly longer time to progression, compared with patients who received NTC (HR, 0.24; P = .003), a difference that held up on multivariable regression analysis (HR, 0.20; P = .0499).

Pain scores were not significantly predictive of either time to progression or overall survival, however.

The study was supported by Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK. Dr. Ahmedzai reported honoraria, consulting, research funding, and travel fees from various companies, not including the study sponsors.

SOURCE: Ahmedzai SH et al. J Clin Oncol. 2019 Apr 10. doi: 10.1200/JCO.18.01006.

NEWPORT BEACH, CALIF. – The evolving treatment of acute myeloid leukemia (AML) was highlighted at the Acute Leukemia Forum of Hemedicus.

In a video interview, Martin Tallman, MD, of Memorial Sloan Kettering Cancer Center in New York, discussed several meeting presentations on the treatment of AML.

In his presentation, Craig Jordan, PhD, of the University of Colorado at Denver, Aurora, explained how the combination of venetoclax and azacitidine appears to target leukemic stem cells in AML.

Courtney DiNardo, MD, of the University of Texas MD Anderson Cancer Center, Houston, presented information on novel agents for AML, including antibody-drug conjugates; bispecific therapies; checkpoint inhibitors; and inhibitors of IDH1/2, MCL1, and MDM2.

Richard Larson, MD, of the University of Chicago, explored the possibility of an individualized approach to postremission therapy in AML.

Frederick Appelbaum, MD, of Fred Hutchinson Cancer Research Center in Seattle, showed that various maintenance therapies given after allogeneic hematopoietic stem cell transplant (HSCT) have not proven beneficial for AML patients.

Richard Jones, MD, of Johns Hopkins Medicine in Baltimore, presented data showing that post-HSCT cyclophosphamide has made haploidentical transplants safer and more effective for AML patients.

And James Ferrara, MD, of the Icahn School of Medicine at Mount Sinai, New York, detailed research showing that biomarkers of graft-versus-host disease can predict nonrelapse mortality after HSCT.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

NEWPORT BEACH, CALIF. – The evolving treatment of acute myeloid leukemia (AML) was highlighted at the Acute Leukemia Forum of Hemedicus.

In a video interview, Martin Tallman, MD, of Memorial Sloan Kettering Cancer Center in New York, discussed several meeting presentations on the treatment of AML.

In his presentation, Craig Jordan, PhD, of the University of Colorado at Denver, Aurora, explained how the combination of venetoclax and azacitidine appears to target leukemic stem cells in AML.

Courtney DiNardo, MD, of the University of Texas MD Anderson Cancer Center, Houston, presented information on novel agents for AML, including antibody-drug conjugates; bispecific therapies; checkpoint inhibitors; and inhibitors of IDH1/2, MCL1, and MDM2.

Richard Larson, MD, of the University of Chicago, explored the possibility of an individualized approach to postremission therapy in AML.

Frederick Appelbaum, MD, of Fred Hutchinson Cancer Research Center in Seattle, showed that various maintenance therapies given after allogeneic hematopoietic stem cell transplant (HSCT) have not proven beneficial for AML patients.

Richard Jones, MD, of Johns Hopkins Medicine in Baltimore, presented data showing that post-HSCT cyclophosphamide has made haploidentical transplants safer and more effective for AML patients.

And James Ferrara, MD, of the Icahn School of Medicine at Mount Sinai, New York, detailed research showing that biomarkers of graft-versus-host disease can predict nonrelapse mortality after HSCT.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

NEWPORT BEACH, CALIF. – The evolving treatment of acute myeloid leukemia (AML) was highlighted at the Acute Leukemia Forum of Hemedicus.

In a video interview, Martin Tallman, MD, of Memorial Sloan Kettering Cancer Center in New York, discussed several meeting presentations on the treatment of AML.

In his presentation, Craig Jordan, PhD, of the University of Colorado at Denver, Aurora, explained how the combination of venetoclax and azacitidine appears to target leukemic stem cells in AML.

Courtney DiNardo, MD, of the University of Texas MD Anderson Cancer Center, Houston, presented information on novel agents for AML, including antibody-drug conjugates; bispecific therapies; checkpoint inhibitors; and inhibitors of IDH1/2, MCL1, and MDM2.

Richard Larson, MD, of the University of Chicago, explored the possibility of an individualized approach to postremission therapy in AML.

Frederick Appelbaum, MD, of Fred Hutchinson Cancer Research Center in Seattle, showed that various maintenance therapies given after allogeneic hematopoietic stem cell transplant (HSCT) have not proven beneficial for AML patients.

Richard Jones, MD, of Johns Hopkins Medicine in Baltimore, presented data showing that post-HSCT cyclophosphamide has made haploidentical transplants safer and more effective for AML patients.

And James Ferrara, MD, of the Icahn School of Medicine at Mount Sinai, New York, detailed research showing that biomarkers of graft-versus-host disease can predict nonrelapse mortality after HSCT.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

Hemodynamic complications of arteriovenous (AV) access are uncommon but can be potentially life threatening. Fistulas and grafts can cause a decrease in systemic vascular resistance and secondary increase in cardiac output in patients who may already have myocardial dysfunction secondary to their end-stage renal disease.¹ This increased cardiac output is usually insignificant but in rare cases can result in clinically significant cardiac failure. Patients with high-output fistulas with volume flow greater than 2 L/min may be at increased risk of heart failure but volume flow less than 2 L/min does not preclude this complication.²

In patients with AV access–related heart failure, optimal medical management and reduction of fistula flow or ligation of the dialysis access should be considered. If continued hemodialysis is necessary, loss of a functioning dialysis access is problematic and difficult management decisions must be made. Following successful renal transplantation, ligation of vascular access in the presence of symptomatic heart failure may represent a straightforward decision. Nonetheless, there is no clear consensus of how to manage patent fistulas or grafts in patients following renal transplantation in the absence of significant cardiac symptoms with particular concern to the important issues of transplant survival and long-term cardiac prognosis. Yaffe and Greenstein³ recommend preservation of almost all fistulas after transplantation in the absence of significant complications such as venous hypertension, pseudoaneurysm, significant high-output cardiac failure or hand ischemia. They recommend taking into account the 10-year adjusted renal transplantation graft survival rates and the relative paucity of donors, recognizing the possibility that the patient may have to return to dialysis at some point in the future. They also reference the lack of information regarding the beneficial impact of fistula ligation on cardiac morphology and function as a rationale for access preservation.

A recent presentation at the American Heart Association Scientific Sessions by Michael B. Stokes, MD,⁴ from the department of cardiology at Royal Adelaide Hospital in Australia, suggests that cardiovascular disease is responsible for 40% of deaths among kidney transplant recipients and that left ventricular (LV) mass is strongly associated with cardiovascular mortality.

He states that, although there is no guideline consensus on the management of an AV fistula following successful renal transplantation, the fistula continues to contribute adversely to cardiac remodeling and function. The lack of previous randomized controlled trials in this area led Dr. Stokes and his colleagues to randomly assign 64 patients at least 1 year following successful kidney transplantation with stable renal function and a functioning AV fistula to either fistula ligation or no intervention. All patients underwent cardiac MRI at baseline and 6 months.

The primary endpoint of decrease in LV mass at 6 months was significant in the ligation group but not in the control group. The ligation group also had significant decrease in LV end diastolic volume, LV end systolic volume, and multiple other parameters. In addition, NT-proBNP levels and left atrial volume were significantly reduced in the ligation group when compared with the control group. Complications in the ligation group included six patients with thrombosis of their fistula vein and two infections, all of which resolved with outpatient anti-inflammatory or antimicrobial therapy.

Dr. Stokes believes that control patients in his study face “persisting and substantial deleterious cardiac remodeling” and that “further investigation would clarify the impact of AV fistula ligation on clinical outcomes following kidney transplantation.”

I believe this is important information and represents the first randomized controlled data regarding the long-term adverse cardiac effects of a patent fistula after renal transplantation. Unfortunately, information regarding baseline fistula volume flow is not provided in this abstract. As discussed earlier, patients with high-flow fistulas may be at increased risk of heart failure and hemodynamic data can be critical in establishing an algorithm for managing these challenging patients.

Ligation of a functioning and asymptomatic access in a patient with a successful renal transplant should be recommended only after informed discussion with the patient weighing the ongoing potential negative effects on cardiac function of continued access patency versus the potential need for future hemodialysis. Dr. Stokes presents interesting data that must be considered in this controversy. I believe that, in the absence of a universally applicable algorithm, the clinical decision to recommend AV fistula ligation after successful kidney transplantation should be individualized and based on ongoing assessment of cardiac and renal function and fistula complications and hemodynamics.

References

1. Eur Heart J 2017;38:1913-23.

2. Nephrol Dial Transplant 2008;23:282-7.

3. J Vasc Access 2012;13:405-8.

4. Stokes MB, et al. LBS.05 – Late Breaking Clinical Trial: Hot News in HF. Presented at American Heart Association Scientific Sessions. 2018 Nov 10-12. Chicago.
 

Larry A. Scher, MD, is a vascular surgeon at the Montefiore Greene Medical Arts Pavilion, New York, and an associate medical editor for Vascular Specialist.

Hemodynamic complications of arteriovenous (AV) access are uncommon but can be potentially life threatening. Fistulas and grafts can cause a decrease in systemic vascular resistance and secondary increase in cardiac output in patients who may already have myocardial dysfunction secondary to their end-stage renal disease.¹ This increased cardiac output is usually insignificant but in rare cases can result in clinically significant cardiac failure. Patients with high-output fistulas with volume flow greater than 2 L/min may be at increased risk of heart failure but volume flow less than 2 L/min does not preclude this complication.²

In patients with AV access–related heart failure, optimal medical management and reduction of fistula flow or ligation of the dialysis access should be considered. If continued hemodialysis is necessary, loss of a functioning dialysis access is problematic and difficult management decisions must be made. Following successful renal transplantation, ligation of vascular access in the presence of symptomatic heart failure may represent a straightforward decision. Nonetheless, there is no clear consensus of how to manage patent fistulas or grafts in patients following renal transplantation in the absence of significant cardiac symptoms with particular concern to the important issues of transplant survival and long-term cardiac prognosis. Yaffe and Greenstein³ recommend preservation of almost all fistulas after transplantation in the absence of significant complications such as venous hypertension, pseudoaneurysm, significant high-output cardiac failure or hand ischemia. They recommend taking into account the 10-year adjusted renal transplantation graft survival rates and the relative paucity of donors, recognizing the possibility that the patient may have to return to dialysis at some point in the future. They also reference the lack of information regarding the beneficial impact of fistula ligation on cardiac morphology and function as a rationale for access preservation.

A recent presentation at the American Heart Association Scientific Sessions by Michael B. Stokes, MD,⁴ from the department of cardiology at Royal Adelaide Hospital in Australia, suggests that cardiovascular disease is responsible for 40% of deaths among kidney transplant recipients and that left ventricular (LV) mass is strongly associated with cardiovascular mortality.

He states that, although there is no guideline consensus on the management of an AV fistula following successful renal transplantation, the fistula continues to contribute adversely to cardiac remodeling and function. The lack of previous randomized controlled trials in this area led Dr. Stokes and his colleagues to randomly assign 64 patients at least 1 year following successful kidney transplantation with stable renal function and a functioning AV fistula to either fistula ligation or no intervention. All patients underwent cardiac MRI at baseline and 6 months.

The primary endpoint of decrease in LV mass at 6 months was significant in the ligation group but not in the control group. The ligation group also had significant decrease in LV end diastolic volume, LV end systolic volume, and multiple other parameters. In addition, NT-proBNP levels and left atrial volume were significantly reduced in the ligation group when compared with the control group. Complications in the ligation group included six patients with thrombosis of their fistula vein and two infections, all of which resolved with outpatient anti-inflammatory or antimicrobial therapy.

Dr. Stokes believes that control patients in his study face “persisting and substantial deleterious cardiac remodeling” and that “further investigation would clarify the impact of AV fistula ligation on clinical outcomes following kidney transplantation.”

I believe this is important information and represents the first randomized controlled data regarding the long-term adverse cardiac effects of a patent fistula after renal transplantation. Unfortunately, information regarding baseline fistula volume flow is not provided in this abstract. As discussed earlier, patients with high-flow fistulas may be at increased risk of heart failure and hemodynamic data can be critical in establishing an algorithm for managing these challenging patients.

Ligation of a functioning and asymptomatic access in a patient with a successful renal transplant should be recommended only after informed discussion with the patient weighing the ongoing potential negative effects on cardiac function of continued access patency versus the potential need for future hemodialysis. Dr. Stokes presents interesting data that must be considered in this controversy. I believe that, in the absence of a universally applicable algorithm, the clinical decision to recommend AV fistula ligation after successful kidney transplantation should be individualized and based on ongoing assessment of cardiac and renal function and fistula complications and hemodynamics.

References

1. Eur Heart J 2017;38:1913-23.

2. Nephrol Dial Transplant 2008;23:282-7.

3. J Vasc Access 2012;13:405-8.

4. Stokes MB, et al. LBS.05 – Late Breaking Clinical Trial: Hot News in HF. Presented at American Heart Association Scientific Sessions. 2018 Nov 10-12. Chicago.
 

Larry A. Scher, MD, is a vascular surgeon at the Montefiore Greene Medical Arts Pavilion, New York, and an associate medical editor for Vascular Specialist.

Hemodynamic complications of arteriovenous (AV) access are uncommon but can be potentially life threatening. Fistulas and grafts can cause a decrease in systemic vascular resistance and secondary increase in cardiac output in patients who may already have myocardial dysfunction secondary to their end-stage renal disease.¹ This increased cardiac output is usually insignificant but in rare cases can result in clinically significant cardiac failure. Patients with high-output fistulas with volume flow greater than 2 L/min may be at increased risk of heart failure but volume flow less than 2 L/min does not preclude this complication.²

In patients with AV access–related heart failure, optimal medical management and reduction of fistula flow or ligation of the dialysis access should be considered. If continued hemodialysis is necessary, loss of a functioning dialysis access is problematic and difficult management decisions must be made. Following successful renal transplantation, ligation of vascular access in the presence of symptomatic heart failure may represent a straightforward decision. Nonetheless, there is no clear consensus of how to manage patent fistulas or grafts in patients following renal transplantation in the absence of significant cardiac symptoms with particular concern to the important issues of transplant survival and long-term cardiac prognosis. Yaffe and Greenstein³ recommend preservation of almost all fistulas after transplantation in the absence of significant complications such as venous hypertension, pseudoaneurysm, significant high-output cardiac failure or hand ischemia. They recommend taking into account the 10-year adjusted renal transplantation graft survival rates and the relative paucity of donors, recognizing the possibility that the patient may have to return to dialysis at some point in the future. They also reference the lack of information regarding the beneficial impact of fistula ligation on cardiac morphology and function as a rationale for access preservation.

A recent presentation at the American Heart Association Scientific Sessions by Michael B. Stokes, MD,⁴ from the department of cardiology at Royal Adelaide Hospital in Australia, suggests that cardiovascular disease is responsible for 40% of deaths among kidney transplant recipients and that left ventricular (LV) mass is strongly associated with cardiovascular mortality.

He states that, although there is no guideline consensus on the management of an AV fistula following successful renal transplantation, the fistula continues to contribute adversely to cardiac remodeling and function. The lack of previous randomized controlled trials in this area led Dr. Stokes and his colleagues to randomly assign 64 patients at least 1 year following successful kidney transplantation with stable renal function and a functioning AV fistula to either fistula ligation or no intervention. All patients underwent cardiac MRI at baseline and 6 months.

The primary endpoint of decrease in LV mass at 6 months was significant in the ligation group but not in the control group. The ligation group also had significant decrease in LV end diastolic volume, LV end systolic volume, and multiple other parameters. In addition, NT-proBNP levels and left atrial volume were significantly reduced in the ligation group when compared with the control group. Complications in the ligation group included six patients with thrombosis of their fistula vein and two infections, all of which resolved with outpatient anti-inflammatory or antimicrobial therapy.

Dr. Stokes believes that control patients in his study face “persisting and substantial deleterious cardiac remodeling” and that “further investigation would clarify the impact of AV fistula ligation on clinical outcomes following kidney transplantation.”

I believe this is important information and represents the first randomized controlled data regarding the long-term adverse cardiac effects of a patent fistula after renal transplantation. Unfortunately, information regarding baseline fistula volume flow is not provided in this abstract. As discussed earlier, patients with high-flow fistulas may be at increased risk of heart failure and hemodynamic data can be critical in establishing an algorithm for managing these challenging patients.

Ligation of a functioning and asymptomatic access in a patient with a successful renal transplant should be recommended only after informed discussion with the patient weighing the ongoing potential negative effects on cardiac function of continued access patency versus the potential need for future hemodialysis. Dr. Stokes presents interesting data that must be considered in this controversy. I believe that, in the absence of a universally applicable algorithm, the clinical decision to recommend AV fistula ligation after successful kidney transplantation should be individualized and based on ongoing assessment of cardiac and renal function and fistula complications and hemodynamics.

References

1. Eur Heart J 2017;38:1913-23.

2. Nephrol Dial Transplant 2008;23:282-7.

3. J Vasc Access 2012;13:405-8.

4. Stokes MB, et al. LBS.05 – Late Breaking Clinical Trial: Hot News in HF. Presented at American Heart Association Scientific Sessions. 2018 Nov 10-12. Chicago.
 

Larry A. Scher, MD, is a vascular surgeon at the Montefiore Greene Medical Arts Pavilion, New York, and an associate medical editor for Vascular Specialist.

In recent years, the proportion of patients undergoing liver transplantation for alcohol-associated liver disease (ALD) has doubled, suggesting a major shift in attitudes related to transplant indication, according to an analysis of registry data.

VILevi/Thinkstock

“The findings suggest that early liver transplant for alcoholic hepatitis may be leading to broader acceptance of ALD for liver transplant,” Brian P. Lee, MD, of the University of California, San Francisco, and his colleagues wrote in JAMA Internal Medicine.

The researchers conducted a prospective cohort study of 9,438 patients with ALD who received a liver transplant from 2002 to 2016. Data were obtained from the United Network for Organ Sharing national database.

Study participants were evaluated for patterns, both nationally and regionally, related to liver transplant for the treatment of ALD. In addition, Dr. Lee and his colleagues completed a sensitivity analysis, which evaluated specific clinical parameters, including patient and graft survival, hepatocellular carcinoma (HCC), and hepatitis C viral (HCV) infection.

“Because there is no national policy regarding early liver transplant, we hypothesized that changes may vary regionally as liver transplant programs shifted their attitudes toward increased acceptance of early liver transplant for alcoholic hepatitis and ALD,” the researchers wrote.

After analysis, the researchers found that liver transplantation for patients with ALD increased proportionally from 24.2% to 36.7% from 2002 to 2016, respectively. With HCV-infected recipients included, the proportion of liver transplants rose from 15.3% to 30.6% over the same period, representing a twofold increase of transplants received for this indication.

The degree of increase was reported to vary based on geographic region and was linked with differences in patient-specific factors.

“There may be regional disparities in access to liver transplant for ALD; whether this is related to different attitudes toward ALD and requirements for sobriety is unknown,” they added.

The researchers acknowledged that a key limitation of the study was the use of registry data. As a result, Dr. Lee and his colleagues reported that all conclusions are not causal, but rather only by association.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases UCSF Liver Center. The authors reported no conflicts of interests.
 

SOURCE: Lee BP et al. JAMA Intern Med. 2019 Jan 22. doi: 10.1001/jamainternmed.2018.6536.

In recent years, the proportion of patients undergoing liver transplantation for alcohol-associated liver disease (ALD) has doubled, suggesting a major shift in attitudes related to transplant indication, according to an analysis of registry data.

VILevi/Thinkstock

“The findings suggest that early liver transplant for alcoholic hepatitis may be leading to broader acceptance of ALD for liver transplant,” Brian P. Lee, MD, of the University of California, San Francisco, and his colleagues wrote in JAMA Internal Medicine.

The researchers conducted a prospective cohort study of 9,438 patients with ALD who received a liver transplant from 2002 to 2016. Data were obtained from the United Network for Organ Sharing national database.

Study participants were evaluated for patterns, both nationally and regionally, related to liver transplant for the treatment of ALD. In addition, Dr. Lee and his colleagues completed a sensitivity analysis, which evaluated specific clinical parameters, including patient and graft survival, hepatocellular carcinoma (HCC), and hepatitis C viral (HCV) infection.

“Because there is no national policy regarding early liver transplant, we hypothesized that changes may vary regionally as liver transplant programs shifted their attitudes toward increased acceptance of early liver transplant for alcoholic hepatitis and ALD,” the researchers wrote.

After analysis, the researchers found that liver transplantation for patients with ALD increased proportionally from 24.2% to 36.7% from 2002 to 2016, respectively. With HCV-infected recipients included, the proportion of liver transplants rose from 15.3% to 30.6% over the same period, representing a twofold increase of transplants received for this indication.

The degree of increase was reported to vary based on geographic region and was linked with differences in patient-specific factors.

“There may be regional disparities in access to liver transplant for ALD; whether this is related to different attitudes toward ALD and requirements for sobriety is unknown,” they added.

The researchers acknowledged that a key limitation of the study was the use of registry data. As a result, Dr. Lee and his colleagues reported that all conclusions are not causal, but rather only by association.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases UCSF Liver Center. The authors reported no conflicts of interests.
 

SOURCE: Lee BP et al. JAMA Intern Med. 2019 Jan 22. doi: 10.1001/jamainternmed.2018.6536.

In recent years, the proportion of patients undergoing liver transplantation for alcohol-associated liver disease (ALD) has doubled, suggesting a major shift in attitudes related to transplant indication, according to an analysis of registry data.

VILevi/Thinkstock

“The findings suggest that early liver transplant for alcoholic hepatitis may be leading to broader acceptance of ALD for liver transplant,” Brian P. Lee, MD, of the University of California, San Francisco, and his colleagues wrote in JAMA Internal Medicine.

The researchers conducted a prospective cohort study of 9,438 patients with ALD who received a liver transplant from 2002 to 2016. Data were obtained from the United Network for Organ Sharing national database.

Study participants were evaluated for patterns, both nationally and regionally, related to liver transplant for the treatment of ALD. In addition, Dr. Lee and his colleagues completed a sensitivity analysis, which evaluated specific clinical parameters, including patient and graft survival, hepatocellular carcinoma (HCC), and hepatitis C viral (HCV) infection.

“Because there is no national policy regarding early liver transplant, we hypothesized that changes may vary regionally as liver transplant programs shifted their attitudes toward increased acceptance of early liver transplant for alcoholic hepatitis and ALD,” the researchers wrote.

After analysis, the researchers found that liver transplantation for patients with ALD increased proportionally from 24.2% to 36.7% from 2002 to 2016, respectively. With HCV-infected recipients included, the proportion of liver transplants rose from 15.3% to 30.6% over the same period, representing a twofold increase of transplants received for this indication.

The degree of increase was reported to vary based on geographic region and was linked with differences in patient-specific factors.

“There may be regional disparities in access to liver transplant for ALD; whether this is related to different attitudes toward ALD and requirements for sobriety is unknown,” they added.

The researchers acknowledged that a key limitation of the study was the use of registry data. As a result, Dr. Lee and his colleagues reported that all conclusions are not causal, but rather only by association.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases UCSF Liver Center. The authors reported no conflicts of interests.
 

SOURCE: Lee BP et al. JAMA Intern Med. 2019 Jan 22. doi: 10.1001/jamainternmed.2018.6536.