Transplant

Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.

The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.

Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.

“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.

The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.

“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.

While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.

There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).

A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.

Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.

Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.

The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.

That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.

However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.

“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.

The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.

SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.

Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.

The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.

Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.

“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.

The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.

“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.

While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.

There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).

A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.

Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.

Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.

The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.

That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.

However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.

“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.

The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.

SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.

Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.

The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.

Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.

“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.

The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.

“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.

While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.

There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).

A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.

Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.

Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.

The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.

That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.

However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.

“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.

The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.

SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.

FORT LAUDERDALE, FLA. – Hip joint pain and deterioration can be a painful and disabling outcome for patients with sickle cell disease, but femoral head core decompression with the addition of bone marrow aspirate concentrate decreases their pain and may help avoid or delay hip replacement, according to results of a pilot study presented at the annual meeting of the Foundation for Sickle Cell Disease Research.

Eric Fornari, MD, of the Children’s Hospital at Montefiore in Bronx, N.Y., reported on results of core decompression (CD) in 35 hips of 26 sickle cell patients; 17 underwent CD only and 18 had CD with injection of bone marrow aspirate concentrate (CD+BMAC). The average patient age was 24.3 years, with a range from 9.7-50.7 years.

“Compared to patients treated with CD alone, patients treated with CD+BMAC complained of significantly less pain and had significant improvement in their functional scores and patient-related outcomes at short-term follow-up,” Dr. Fornari said.

Among the CD+BMAC patients, pain scores declined two points on average, from 6 preoperatively to 4 postoperatively, he said. This was clinically significant, compared with the CD-only group, Dr. Fornari said.

Patients in the CD+BMAC group also reported consistently superior hip outcome and modified Harris hip scores. With either treatment, more than 90% of patients were pain-free and walked independently at their most recent follow-up, he said.

The objective of CD is to relieve pressure within the head of the femur, stimulate vascularity and target the avascular necrosis (AVN) lesion within the head that is visible on imaging. To get the bone marrow aspirate concentrate, Dr. Fornari extracts 120 cc of bone marrow from the iliac crest, then concentrates it to 12 cc. The same instrument is used to tap into the femoral head and inject the bone marrow aspirate concentrate. The study looked at clinical and radiographic outcomes of treated patients.

Average follow-up for the entire study population was 3.6 years, but that varied widely between the two groups (CD-only at almost 6 years, CD+BMAC at 1.4 years) because CD+BMAC has only been done for the last 3 years, Dr. Fornari said.

Progression to total hip arthroplasty (THA) was similar between both groups: 5 of 17 patients (29%) for CD-only vs. 4 of 18 patients (22%) for CD+BMAC (P = .711).

“When you look at progression, there were a number of hips that got CD or CD+BMAC and were better postoperatively; they went from a Ficat score of stage II to a stage I, or stage III to stage II,” he said.

X-rays were not always a reliable marker of outcome after either CD procedure, Dr. Fornari noted. “I’ve seen patients who’ve had terrible looking X-rays who have no pain, and patients who have totally normal X-rays that are completely debilitated,” he said. “We have to start asking ourselves, ‘What is the marker of success?’ because when we do this patients are feeling better.”

Multivariate analysis was used to identify factors predictive of progression to THA after the procedure, Dr. Fornari said. “Age of diagnosis, age of surgery, female gender, and lower hydroxyurea dose at surgery were predictive of advancing disease, whereas a higher dose of hydroxyurea was predictive against advancement,” he said.

The average age of patients who had no THA after either procedure was 21 years, compared with 33.9 years for those who had THA (P = .003). Average hydroxyurea dose at surgery was 24.7 mg/kg in the no-THA group vs. 12.5 mg/kg in those who had THA (P = .005).

Notably, there were no readmissions, fractures, deep vein thromboses, pulmonary embolisms or infarctions after CD, Dr. Fornari said. Transfusions were required in two CD-only and three CD+BMAC patients. Hospitalization rates for vaso-occlusive crisis were similar between groups (P = .103).

Dr. Fornari said the challenge is to identify suitable patients for these procedures. “These are complicated patients and you don’t want to put them through the process of having surgery, putting them on crutches and restricted weight bearing, if they’re not going to get better,” he said. “This procedure done minimally invasively is not the end all and be all, but we have to figure out who are the right patients for it. Patient selection is key.”

Finding those patients starts with a rigorous history and physical exam, he said. Physicians should have a “low threshold” for MRI in these patients because that will reveal findings, such as pre-collapse disease and characteristic of AVN lesions, that may appear normal on X-ray. Patient education is also important. “To think that an injection into the top of the hip is going to solve all their problems is a little naive, so you have to have an honest conversation with the patient,” he said.

Dr. Fornari reported having no financial disclosures.

SOURCE: Fornari ED et al. FSCDR 2019, Abstract JSCDH-D-19-00004.

FORT LAUDERDALE, FLA. – Hip joint pain and deterioration can be a painful and disabling outcome for patients with sickle cell disease, but femoral head core decompression with the addition of bone marrow aspirate concentrate decreases their pain and may help avoid or delay hip replacement, according to results of a pilot study presented at the annual meeting of the Foundation for Sickle Cell Disease Research.

Eric Fornari, MD, of the Children’s Hospital at Montefiore in Bronx, N.Y., reported on results of core decompression (CD) in 35 hips of 26 sickle cell patients; 17 underwent CD only and 18 had CD with injection of bone marrow aspirate concentrate (CD+BMAC). The average patient age was 24.3 years, with a range from 9.7-50.7 years.

“Compared to patients treated with CD alone, patients treated with CD+BMAC complained of significantly less pain and had significant improvement in their functional scores and patient-related outcomes at short-term follow-up,” Dr. Fornari said.

Among the CD+BMAC patients, pain scores declined two points on average, from 6 preoperatively to 4 postoperatively, he said. This was clinically significant, compared with the CD-only group, Dr. Fornari said.

Patients in the CD+BMAC group also reported consistently superior hip outcome and modified Harris hip scores. With either treatment, more than 90% of patients were pain-free and walked independently at their most recent follow-up, he said.

The objective of CD is to relieve pressure within the head of the femur, stimulate vascularity and target the avascular necrosis (AVN) lesion within the head that is visible on imaging. To get the bone marrow aspirate concentrate, Dr. Fornari extracts 120 cc of bone marrow from the iliac crest, then concentrates it to 12 cc. The same instrument is used to tap into the femoral head and inject the bone marrow aspirate concentrate. The study looked at clinical and radiographic outcomes of treated patients.

Average follow-up for the entire study population was 3.6 years, but that varied widely between the two groups (CD-only at almost 6 years, CD+BMAC at 1.4 years) because CD+BMAC has only been done for the last 3 years, Dr. Fornari said.

Progression to total hip arthroplasty (THA) was similar between both groups: 5 of 17 patients (29%) for CD-only vs. 4 of 18 patients (22%) for CD+BMAC (P = .711).

“When you look at progression, there were a number of hips that got CD or CD+BMAC and were better postoperatively; they went from a Ficat score of stage II to a stage I, or stage III to stage II,” he said.

X-rays were not always a reliable marker of outcome after either CD procedure, Dr. Fornari noted. “I’ve seen patients who’ve had terrible looking X-rays who have no pain, and patients who have totally normal X-rays that are completely debilitated,” he said. “We have to start asking ourselves, ‘What is the marker of success?’ because when we do this patients are feeling better.”

Multivariate analysis was used to identify factors predictive of progression to THA after the procedure, Dr. Fornari said. “Age of diagnosis, age of surgery, female gender, and lower hydroxyurea dose at surgery were predictive of advancing disease, whereas a higher dose of hydroxyurea was predictive against advancement,” he said.

The average age of patients who had no THA after either procedure was 21 years, compared with 33.9 years for those who had THA (P = .003). Average hydroxyurea dose at surgery was 24.7 mg/kg in the no-THA group vs. 12.5 mg/kg in those who had THA (P = .005).

Notably, there were no readmissions, fractures, deep vein thromboses, pulmonary embolisms or infarctions after CD, Dr. Fornari said. Transfusions were required in two CD-only and three CD+BMAC patients. Hospitalization rates for vaso-occlusive crisis were similar between groups (P = .103).

Dr. Fornari said the challenge is to identify suitable patients for these procedures. “These are complicated patients and you don’t want to put them through the process of having surgery, putting them on crutches and restricted weight bearing, if they’re not going to get better,” he said. “This procedure done minimally invasively is not the end all and be all, but we have to figure out who are the right patients for it. Patient selection is key.”

Finding those patients starts with a rigorous history and physical exam, he said. Physicians should have a “low threshold” for MRI in these patients because that will reveal findings, such as pre-collapse disease and characteristic of AVN lesions, that may appear normal on X-ray. Patient education is also important. “To think that an injection into the top of the hip is going to solve all their problems is a little naive, so you have to have an honest conversation with the patient,” he said.

Dr. Fornari reported having no financial disclosures.

SOURCE: Fornari ED et al. FSCDR 2019, Abstract JSCDH-D-19-00004.

FORT LAUDERDALE, FLA. – Hip joint pain and deterioration can be a painful and disabling outcome for patients with sickle cell disease, but femoral head core decompression with the addition of bone marrow aspirate concentrate decreases their pain and may help avoid or delay hip replacement, according to results of a pilot study presented at the annual meeting of the Foundation for Sickle Cell Disease Research.

Eric Fornari, MD, of the Children’s Hospital at Montefiore in Bronx, N.Y., reported on results of core decompression (CD) in 35 hips of 26 sickle cell patients; 17 underwent CD only and 18 had CD with injection of bone marrow aspirate concentrate (CD+BMAC). The average patient age was 24.3 years, with a range from 9.7-50.7 years.

“Compared to patients treated with CD alone, patients treated with CD+BMAC complained of significantly less pain and had significant improvement in their functional scores and patient-related outcomes at short-term follow-up,” Dr. Fornari said.

Among the CD+BMAC patients, pain scores declined two points on average, from 6 preoperatively to 4 postoperatively, he said. This was clinically significant, compared with the CD-only group, Dr. Fornari said.

Patients in the CD+BMAC group also reported consistently superior hip outcome and modified Harris hip scores. With either treatment, more than 90% of patients were pain-free and walked independently at their most recent follow-up, he said.

The objective of CD is to relieve pressure within the head of the femur, stimulate vascularity and target the avascular necrosis (AVN) lesion within the head that is visible on imaging. To get the bone marrow aspirate concentrate, Dr. Fornari extracts 120 cc of bone marrow from the iliac crest, then concentrates it to 12 cc. The same instrument is used to tap into the femoral head and inject the bone marrow aspirate concentrate. The study looked at clinical and radiographic outcomes of treated patients.

Average follow-up for the entire study population was 3.6 years, but that varied widely between the two groups (CD-only at almost 6 years, CD+BMAC at 1.4 years) because CD+BMAC has only been done for the last 3 years, Dr. Fornari said.

Progression to total hip arthroplasty (THA) was similar between both groups: 5 of 17 patients (29%) for CD-only vs. 4 of 18 patients (22%) for CD+BMAC (P = .711).

“When you look at progression, there were a number of hips that got CD or CD+BMAC and were better postoperatively; they went from a Ficat score of stage II to a stage I, or stage III to stage II,” he said.

X-rays were not always a reliable marker of outcome after either CD procedure, Dr. Fornari noted. “I’ve seen patients who’ve had terrible looking X-rays who have no pain, and patients who have totally normal X-rays that are completely debilitated,” he said. “We have to start asking ourselves, ‘What is the marker of success?’ because when we do this patients are feeling better.”

Multivariate analysis was used to identify factors predictive of progression to THA after the procedure, Dr. Fornari said. “Age of diagnosis, age of surgery, female gender, and lower hydroxyurea dose at surgery were predictive of advancing disease, whereas a higher dose of hydroxyurea was predictive against advancement,” he said.

The average age of patients who had no THA after either procedure was 21 years, compared with 33.9 years for those who had THA (P = .003). Average hydroxyurea dose at surgery was 24.7 mg/kg in the no-THA group vs. 12.5 mg/kg in those who had THA (P = .005).

Notably, there were no readmissions, fractures, deep vein thromboses, pulmonary embolisms or infarctions after CD, Dr. Fornari said. Transfusions were required in two CD-only and three CD+BMAC patients. Hospitalization rates for vaso-occlusive crisis were similar between groups (P = .103).

Dr. Fornari said the challenge is to identify suitable patients for these procedures. “These are complicated patients and you don’t want to put them through the process of having surgery, putting them on crutches and restricted weight bearing, if they’re not going to get better,” he said. “This procedure done minimally invasively is not the end all and be all, but we have to figure out who are the right patients for it. Patient selection is key.”

Finding those patients starts with a rigorous history and physical exam, he said. Physicians should have a “low threshold” for MRI in these patients because that will reveal findings, such as pre-collapse disease and characteristic of AVN lesions, that may appear normal on X-ray. Patient education is also important. “To think that an injection into the top of the hip is going to solve all their problems is a little naive, so you have to have an honest conversation with the patient,” he said.

Dr. Fornari reported having no financial disclosures.

SOURCE: Fornari ED et al. FSCDR 2019, Abstract JSCDH-D-19-00004.

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