Transplant

Prognoses remain extremely poor after hypomethylating agents (HMAs) fail in patients with higher-risk myelodysplastic syndromes (HR-MDS). But a hematologist-oncologist told colleagues that novel therapies are in the works, and some show promise.

Still, “the clinical development for drugs in this setting has been quite challenging, and we have had a lot of drugs that have died in this space over the years,” cautioned Amer Zeidan, MBBS, MHS, an associate professor at Yale University, New Haven, Conn., in a presentation at the virtual Acute Leukemia Forum of Hemedicus. For now, “the best way to manage HMA failure in MDS patients is by preventing HMA failure.”

Dr. Zeidan highlighted a 2016 study – which he led – that found the median overall survival from diagnosis was just a median of 17.0 months (95% confidence interval, 15.8-18.4) in 632 patients with HR-MDS. Another 2016 study, which he also led, reported median overall survival of 11 months (95% CI, 10-14) and 12 months (95% CI, 11-16; P = .26) for patients aged 66 or older who had HR-MDS and took azacitidine and decitabine, respectively. Median survival is even shorter after HMA failure, he said.

The most important obstacle to effective therapy is “the biologic and molecular heterogeneity of the disease,” he said. “Only a certain number of genes are altered in a significant number of patients. And then you have a very long tail, with so many alterations, but most of them are rare. That makes targeting all patients with the same mechanism quite challenging. Also, we poorly understand how hypomethylating agents work and the mechanism of primary and secondary failure. And many MDS patients are older with multiple conditions, multiple comorbidities. By the time of failure, they are generally beaten up and very difficult to enroll in clinical trials.”

Even so, he said, “the understanding of the molecular pathogenesis of MDS is starting to open the door for new drug development opportunities. What’s been changing over the last 5 years is an increased understanding of targeting some of the alterations that are specific to the patient – individualized targeting or precision medicine.”
 

Novel therapies

Dr. Zeidan said the novel therapies for HR-MDS after HMA failure fall into these categories: molecularly targeted agents, genetically agnostic small-molecule inhibitors, immunotherapies, and chemotherapy/epigenetic agents.

Multiple trials, for example, are examining a chemotherapy treatment CPX-351 (liposomal cytarabine-daunorubicin) in HR-MDS, and a 2018 study showed improvement in median survival in older patients with newly diagnosed secondary acute myeloid leukemia. “However, this remains an investigational treatment,” Dr. Zeidan cautioned.

Venetoclax is also being studied. Animal and cell culture data suggest there may be helpful synergistic activity between venetoclax and azacitidine in both the frontline and relapse settings. Dr. Zeidan highlighted his own 2019 report on a phase 1b study of venetoclax versus venetoclax and azacitidine in the HMA failure/HR-MDS setting. The results are “quite exciting,” he said.

The report noted that, “although the study is still ongoing, the 6-month OS [overall survival] estimate of 57% in monotherapy [patients] compares favorably to historical controls.”

Glasdegib is “another drug of interest,” although it’s mostly been studied in the frontline setting, he said, and “we don’t have much data with this drug in the refractory setting for MDS patients.” APR-246 is also intriguing, he said, but again lacks data in the refractory setting.

Dr. Zeidan noted research into other treatments – rigosertib (recent findings have been disappointing), ivosidenib for IDH1-mutated MDS, AG221-001 and enasidenib (targeting IDH2 mutations), trametinib (targeting RAS pathway mutations), and others. For now, “clinical trial participation should be the best way to manage these patients.”

Dr. Zeidan disclosed multiple disclosures, including relationships with Pfizer, Novartis, Abbvie, Pfizer, Medimmune/AstraZeneca and Boehringer Ingelheim, among others.

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

Prognoses remain extremely poor after hypomethylating agents (HMAs) fail in patients with higher-risk myelodysplastic syndromes (HR-MDS). But a hematologist-oncologist told colleagues that novel therapies are in the works, and some show promise.

Still, “the clinical development for drugs in this setting has been quite challenging, and we have had a lot of drugs that have died in this space over the years,” cautioned Amer Zeidan, MBBS, MHS, an associate professor at Yale University, New Haven, Conn., in a presentation at the virtual Acute Leukemia Forum of Hemedicus. For now, “the best way to manage HMA failure in MDS patients is by preventing HMA failure.”

Dr. Zeidan highlighted a 2016 study – which he led – that found the median overall survival from diagnosis was just a median of 17.0 months (95% confidence interval, 15.8-18.4) in 632 patients with HR-MDS. Another 2016 study, which he also led, reported median overall survival of 11 months (95% CI, 10-14) and 12 months (95% CI, 11-16; P = .26) for patients aged 66 or older who had HR-MDS and took azacitidine and decitabine, respectively. Median survival is even shorter after HMA failure, he said.

The most important obstacle to effective therapy is “the biologic and molecular heterogeneity of the disease,” he said. “Only a certain number of genes are altered in a significant number of patients. And then you have a very long tail, with so many alterations, but most of them are rare. That makes targeting all patients with the same mechanism quite challenging. Also, we poorly understand how hypomethylating agents work and the mechanism of primary and secondary failure. And many MDS patients are older with multiple conditions, multiple comorbidities. By the time of failure, they are generally beaten up and very difficult to enroll in clinical trials.”

Even so, he said, “the understanding of the molecular pathogenesis of MDS is starting to open the door for new drug development opportunities. What’s been changing over the last 5 years is an increased understanding of targeting some of the alterations that are specific to the patient – individualized targeting or precision medicine.”
 

Novel therapies

Dr. Zeidan said the novel therapies for HR-MDS after HMA failure fall into these categories: molecularly targeted agents, genetically agnostic small-molecule inhibitors, immunotherapies, and chemotherapy/epigenetic agents.

Multiple trials, for example, are examining a chemotherapy treatment CPX-351 (liposomal cytarabine-daunorubicin) in HR-MDS, and a 2018 study showed improvement in median survival in older patients with newly diagnosed secondary acute myeloid leukemia. “However, this remains an investigational treatment,” Dr. Zeidan cautioned.

Venetoclax is also being studied. Animal and cell culture data suggest there may be helpful synergistic activity between venetoclax and azacitidine in both the frontline and relapse settings. Dr. Zeidan highlighted his own 2019 report on a phase 1b study of venetoclax versus venetoclax and azacitidine in the HMA failure/HR-MDS setting. The results are “quite exciting,” he said.

The report noted that, “although the study is still ongoing, the 6-month OS [overall survival] estimate of 57% in monotherapy [patients] compares favorably to historical controls.”

Glasdegib is “another drug of interest,” although it’s mostly been studied in the frontline setting, he said, and “we don’t have much data with this drug in the refractory setting for MDS patients.” APR-246 is also intriguing, he said, but again lacks data in the refractory setting.

Dr. Zeidan noted research into other treatments – rigosertib (recent findings have been disappointing), ivosidenib for IDH1-mutated MDS, AG221-001 and enasidenib (targeting IDH2 mutations), trametinib (targeting RAS pathway mutations), and others. For now, “clinical trial participation should be the best way to manage these patients.”

Dr. Zeidan disclosed multiple disclosures, including relationships with Pfizer, Novartis, Abbvie, Pfizer, Medimmune/AstraZeneca and Boehringer Ingelheim, among others.

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

Prognoses remain extremely poor after hypomethylating agents (HMAs) fail in patients with higher-risk myelodysplastic syndromes (HR-MDS). But a hematologist-oncologist told colleagues that novel therapies are in the works, and some show promise.

Still, “the clinical development for drugs in this setting has been quite challenging, and we have had a lot of drugs that have died in this space over the years,” cautioned Amer Zeidan, MBBS, MHS, an associate professor at Yale University, New Haven, Conn., in a presentation at the virtual Acute Leukemia Forum of Hemedicus. For now, “the best way to manage HMA failure in MDS patients is by preventing HMA failure.”

Dr. Zeidan highlighted a 2016 study – which he led – that found the median overall survival from diagnosis was just a median of 17.0 months (95% confidence interval, 15.8-18.4) in 632 patients with HR-MDS. Another 2016 study, which he also led, reported median overall survival of 11 months (95% CI, 10-14) and 12 months (95% CI, 11-16; P = .26) for patients aged 66 or older who had HR-MDS and took azacitidine and decitabine, respectively. Median survival is even shorter after HMA failure, he said.

The most important obstacle to effective therapy is “the biologic and molecular heterogeneity of the disease,” he said. “Only a certain number of genes are altered in a significant number of patients. And then you have a very long tail, with so many alterations, but most of them are rare. That makes targeting all patients with the same mechanism quite challenging. Also, we poorly understand how hypomethylating agents work and the mechanism of primary and secondary failure. And many MDS patients are older with multiple conditions, multiple comorbidities. By the time of failure, they are generally beaten up and very difficult to enroll in clinical trials.”

Even so, he said, “the understanding of the molecular pathogenesis of MDS is starting to open the door for new drug development opportunities. What’s been changing over the last 5 years is an increased understanding of targeting some of the alterations that are specific to the patient – individualized targeting or precision medicine.”
 

Novel therapies

Dr. Zeidan said the novel therapies for HR-MDS after HMA failure fall into these categories: molecularly targeted agents, genetically agnostic small-molecule inhibitors, immunotherapies, and chemotherapy/epigenetic agents.

Multiple trials, for example, are examining a chemotherapy treatment CPX-351 (liposomal cytarabine-daunorubicin) in HR-MDS, and a 2018 study showed improvement in median survival in older patients with newly diagnosed secondary acute myeloid leukemia. “However, this remains an investigational treatment,” Dr. Zeidan cautioned.

Venetoclax is also being studied. Animal and cell culture data suggest there may be helpful synergistic activity between venetoclax and azacitidine in both the frontline and relapse settings. Dr. Zeidan highlighted his own 2019 report on a phase 1b study of venetoclax versus venetoclax and azacitidine in the HMA failure/HR-MDS setting. The results are “quite exciting,” he said.

The report noted that, “although the study is still ongoing, the 6-month OS [overall survival] estimate of 57% in monotherapy [patients] compares favorably to historical controls.”

Glasdegib is “another drug of interest,” although it’s mostly been studied in the frontline setting, he said, and “we don’t have much data with this drug in the refractory setting for MDS patients.” APR-246 is also intriguing, he said, but again lacks data in the refractory setting.

Dr. Zeidan noted research into other treatments – rigosertib (recent findings have been disappointing), ivosidenib for IDH1-mutated MDS, AG221-001 and enasidenib (targeting IDH2 mutations), trametinib (targeting RAS pathway mutations), and others. For now, “clinical trial participation should be the best way to manage these patients.”

Dr. Zeidan disclosed multiple disclosures, including relationships with Pfizer, Novartis, Abbvie, Pfizer, Medimmune/AstraZeneca and Boehringer Ingelheim, among others.

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

Hematopoietic stem cell transplantation (HCT) is one of the most important treatment options for acute leukemias. However, posttransplant cancer recurrence remains a continuing issue. And while there are reasons to think that hypomethylating agents (HMAS) could be helpful as maintenance tools to prevent cancer recurrence after HCT in leukemia, a hematologist/oncologist told colleagues that the treatment isn’t yet ready for prime time.

“I don’t think you can prefer hypomethylating agents over anything right now. Unfortunately, there’s no data that we can hang our hat on that says they are of benefit in the posttransplant setting,” said Frederick Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

However, there’s still plenty of room for improvement for patients following HCT, he said, pointing to the findings of a 2020 study. The report, which he cowrote, found that 200-day mortality after HCT fell by a third from 2003-2007 to 2013-20017, but also noted that “relapse of cancer remains the largest obstacle to better survival outcomes.”

Dr. Appelbaum described the findings this way: “Without a doubt, the major limitation to transplants for hematologic malignancies today is disease recurrence,” he said. “In fact, if you look at patients after day 100, over 60% of the reason for failure is tumor regrowth. Thus, people are very anxious to look at any method that we can to prevent posttransplant relapse, including the use of hypomethylating agents.”

In regard to strategy, “we don’t have to get rid of every last leukemic cell. Just delaying recurrence might be enough,” he said. “If you can keep the patient from relapsing for the first 3 months, and then take the brakes off the immune suppression and allow immunity to regrow, that may be enough to allow increased numbers of patients to be cured of their disease.”
 

A potential role

Why might HMAS be a possible option after transplant? They do appear to play a role after chemotherapy, he said, pointing to four 2019 studies: One that examined decitabine and three that examined azacytidine: Here, here, and here.

“These four studies provide convincing evidence that hypomethylating-agent therapy after conventional chemotherapy may either prevent or delay relapse when given as maintenance,” Dr. Appelbaum said.

If HMAS work after standard chemotherapy, why might they fail to work after transplantation? “For one, by the time the disease has been able to go through chemotherapy and transplant, you’re left with highly resistant cells,” he said. “Therefore, hypomethylating agents may not be enough to get rid of the disease. Secondly, any of you who have tried to give a maintenance therapy after transplantation know how difficult it can be with CMV [cytomegalovirus] reactivation, count suppression with ganciclovir, graft-versus-host disease [GVHD] causing nausea and vomiting, diarrhea and renal dysfunction caused by calcineurin inhibitors. These are daily events during the first 3 months after transplantation, making drug administration difficult.”

In addition, he said, “even if you can give the drug, the clinical and disease variability may make it very difficult to detect an effect.”

In another study, researchers “did make a valiant attempt to study azacitidine in the posttransplant setting by randomizing 181 patients to either azacitidine or observation,” Dr. Appelbaum said. “Unfortunately, as they reported in 2018, they could not detect a difference in either disease-free or overall survival.”

The researchers reported that nearly 75% of patients in the azacitidine arm failed to complete the planned 12 cycles of treatment, he said. “The reasons for stopping the drug were pretty profound. Half of the patients stopped because they relapsed. Others had stopped because of grades three or four toxicity, death, or severe GVHD or significant infections. It is very difficult to give the drug.”

In the future, “if we truly want to optimize the benefit of using hypomethylating agents after transplantation, it’s going to be very important for us to understand how they work,” he said. “Understanding that would then help us to select which drug we should use, what the dosing and schedule might be, and also to select patients that might benefit from it. Unfortunately, right now, it’s pretty much of a black box. We don’t really understand the effects of hypomethylating agents in the posttransplant period.”

Still, he added, “without question, the results that we have seen with the use of hypomethylating agents after conventional chemotherapy – prolonging disease-free and, probably, overall survival – are going to provide a very, very strong stimulus to study hypomethylating agents after transplantation as well.”

Dr. Appelbaum reports no disclosures.

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

Hematopoietic stem cell transplantation (HCT) is one of the most important treatment options for acute leukemias. However, posttransplant cancer recurrence remains a continuing issue. And while there are reasons to think that hypomethylating agents (HMAS) could be helpful as maintenance tools to prevent cancer recurrence after HCT in leukemia, a hematologist/oncologist told colleagues that the treatment isn’t yet ready for prime time.

“I don’t think you can prefer hypomethylating agents over anything right now. Unfortunately, there’s no data that we can hang our hat on that says they are of benefit in the posttransplant setting,” said Frederick Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

However, there’s still plenty of room for improvement for patients following HCT, he said, pointing to the findings of a 2020 study. The report, which he cowrote, found that 200-day mortality after HCT fell by a third from 2003-2007 to 2013-20017, but also noted that “relapse of cancer remains the largest obstacle to better survival outcomes.”

Dr. Appelbaum described the findings this way: “Without a doubt, the major limitation to transplants for hematologic malignancies today is disease recurrence,” he said. “In fact, if you look at patients after day 100, over 60% of the reason for failure is tumor regrowth. Thus, people are very anxious to look at any method that we can to prevent posttransplant relapse, including the use of hypomethylating agents.”

In regard to strategy, “we don’t have to get rid of every last leukemic cell. Just delaying recurrence might be enough,” he said. “If you can keep the patient from relapsing for the first 3 months, and then take the brakes off the immune suppression and allow immunity to regrow, that may be enough to allow increased numbers of patients to be cured of their disease.”
 

A potential role

Why might HMAS be a possible option after transplant? They do appear to play a role after chemotherapy, he said, pointing to four 2019 studies: One that examined decitabine and three that examined azacytidine: Here, here, and here.

“These four studies provide convincing evidence that hypomethylating-agent therapy after conventional chemotherapy may either prevent or delay relapse when given as maintenance,” Dr. Appelbaum said.

If HMAS work after standard chemotherapy, why might they fail to work after transplantation? “For one, by the time the disease has been able to go through chemotherapy and transplant, you’re left with highly resistant cells,” he said. “Therefore, hypomethylating agents may not be enough to get rid of the disease. Secondly, any of you who have tried to give a maintenance therapy after transplantation know how difficult it can be with CMV [cytomegalovirus] reactivation, count suppression with ganciclovir, graft-versus-host disease [GVHD] causing nausea and vomiting, diarrhea and renal dysfunction caused by calcineurin inhibitors. These are daily events during the first 3 months after transplantation, making drug administration difficult.”

In addition, he said, “even if you can give the drug, the clinical and disease variability may make it very difficult to detect an effect.”

In another study, researchers “did make a valiant attempt to study azacitidine in the posttransplant setting by randomizing 181 patients to either azacitidine or observation,” Dr. Appelbaum said. “Unfortunately, as they reported in 2018, they could not detect a difference in either disease-free or overall survival.”

The researchers reported that nearly 75% of patients in the azacitidine arm failed to complete the planned 12 cycles of treatment, he said. “The reasons for stopping the drug were pretty profound. Half of the patients stopped because they relapsed. Others had stopped because of grades three or four toxicity, death, or severe GVHD or significant infections. It is very difficult to give the drug.”

In the future, “if we truly want to optimize the benefit of using hypomethylating agents after transplantation, it’s going to be very important for us to understand how they work,” he said. “Understanding that would then help us to select which drug we should use, what the dosing and schedule might be, and also to select patients that might benefit from it. Unfortunately, right now, it’s pretty much of a black box. We don’t really understand the effects of hypomethylating agents in the posttransplant period.”

Still, he added, “without question, the results that we have seen with the use of hypomethylating agents after conventional chemotherapy – prolonging disease-free and, probably, overall survival – are going to provide a very, very strong stimulus to study hypomethylating agents after transplantation as well.”

Dr. Appelbaum reports no disclosures.

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

Hematopoietic stem cell transplantation (HCT) is one of the most important treatment options for acute leukemias. However, posttransplant cancer recurrence remains a continuing issue. And while there are reasons to think that hypomethylating agents (HMAS) could be helpful as maintenance tools to prevent cancer recurrence after HCT in leukemia, a hematologist/oncologist told colleagues that the treatment isn’t yet ready for prime time.

“I don’t think you can prefer hypomethylating agents over anything right now. Unfortunately, there’s no data that we can hang our hat on that says they are of benefit in the posttransplant setting,” said Frederick Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

However, there’s still plenty of room for improvement for patients following HCT, he said, pointing to the findings of a 2020 study. The report, which he cowrote, found that 200-day mortality after HCT fell by a third from 2003-2007 to 2013-20017, but also noted that “relapse of cancer remains the largest obstacle to better survival outcomes.”

Dr. Appelbaum described the findings this way: “Without a doubt, the major limitation to transplants for hematologic malignancies today is disease recurrence,” he said. “In fact, if you look at patients after day 100, over 60% of the reason for failure is tumor regrowth. Thus, people are very anxious to look at any method that we can to prevent posttransplant relapse, including the use of hypomethylating agents.”

In regard to strategy, “we don’t have to get rid of every last leukemic cell. Just delaying recurrence might be enough,” he said. “If you can keep the patient from relapsing for the first 3 months, and then take the brakes off the immune suppression and allow immunity to regrow, that may be enough to allow increased numbers of patients to be cured of their disease.”
 

A potential role

Why might HMAS be a possible option after transplant? They do appear to play a role after chemotherapy, he said, pointing to four 2019 studies: One that examined decitabine and three that examined azacytidine: Here, here, and here.

“These four studies provide convincing evidence that hypomethylating-agent therapy after conventional chemotherapy may either prevent or delay relapse when given as maintenance,” Dr. Appelbaum said.

If HMAS work after standard chemotherapy, why might they fail to work after transplantation? “For one, by the time the disease has been able to go through chemotherapy and transplant, you’re left with highly resistant cells,” he said. “Therefore, hypomethylating agents may not be enough to get rid of the disease. Secondly, any of you who have tried to give a maintenance therapy after transplantation know how difficult it can be with CMV [cytomegalovirus] reactivation, count suppression with ganciclovir, graft-versus-host disease [GVHD] causing nausea and vomiting, diarrhea and renal dysfunction caused by calcineurin inhibitors. These are daily events during the first 3 months after transplantation, making drug administration difficult.”

In addition, he said, “even if you can give the drug, the clinical and disease variability may make it very difficult to detect an effect.”

In another study, researchers “did make a valiant attempt to study azacitidine in the posttransplant setting by randomizing 181 patients to either azacitidine or observation,” Dr. Appelbaum said. “Unfortunately, as they reported in 2018, they could not detect a difference in either disease-free or overall survival.”

The researchers reported that nearly 75% of patients in the azacitidine arm failed to complete the planned 12 cycles of treatment, he said. “The reasons for stopping the drug were pretty profound. Half of the patients stopped because they relapsed. Others had stopped because of grades three or four toxicity, death, or severe GVHD or significant infections. It is very difficult to give the drug.”

In the future, “if we truly want to optimize the benefit of using hypomethylating agents after transplantation, it’s going to be very important for us to understand how they work,” he said. “Understanding that would then help us to select which drug we should use, what the dosing and schedule might be, and also to select patients that might benefit from it. Unfortunately, right now, it’s pretty much of a black box. We don’t really understand the effects of hypomethylating agents in the posttransplant period.”

Still, he added, “without question, the results that we have seen with the use of hypomethylating agents after conventional chemotherapy – prolonging disease-free and, probably, overall survival – are going to provide a very, very strong stimulus to study hypomethylating agents after transplantation as well.”

Dr. Appelbaum reports no disclosures.

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

Physicians are gaining a greater understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) in allo-hematopoietic cell transplantation (allo-HCT), a hematologist/oncologist told colleagues, and novel treatments are being tested.

However, options remain limited. There’s only one Food and Drug Administration–approved therapy for cGVHD that’s failed one or more treatments, and clinical trials remain a crucial option in some cases, said Mary E.D. Flowers, MD, professor of medicine at the University of Washington’s Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

According to Dr. Flowers, cGVHD – a product of a graft’s “immunological assault” against the person receiving a transplant – occurs in 40% of patients within a year after allo-HCT. The disorder “is associated with a poor quality of life, disability, and increased mortality after allo-transplantation,” she said. “It’s a syndrome that can be inflammatory and fibrotic. It involves several organs – the skin, the mouth, the eyes, the lungs, the GI tract.”

The median length of treatment after peripheral blood stem cell transplant is 3.5 years, Dr. Flowers said. Seven years after treatment, 10% of those who are alive – and have avoided relapse – will still need treatment. “Corticosteroids remain the first-line [treatment], at 0.5-1.0 [mg/kg], but they do not control at least 40% of the patients with cGVHD.”

In regard to pathophysiology, she highlighted a 2017 report that presented findings about the pathophysiology of cGVHD. The findings, the report authors wrote, “have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition.”

For now, no agents other than corticosteroids have shown benefit in cGVHD as initial therapy, Dr. Flowers said. In fact, several trials closed early from lack of benefit. But trials continue, she said: Results are pending for a completed phase 3 trial of ibrutinib, a Bruton tyrosine kinase inhibitor, plus steroids for initial treatment of cGVHD. Nearly 500 patients were enrolled, she said. And there’s an ongoing phase 2/3 trial of itacitinib, a Janus kinase 1 inhibitor plus steroids as initial treatment.

Dr. Flowers highlighted the case of a patient with moderate cGVHD. The patient was treated with infection prophylaxis, supportive care for oral and eyes manifestations, and prednisone 0.5 mg/kg (at a lower dose because of diabetes) plus a substitution of tacrolimus with sirolimus, a calcineurin inhibitor.

Why sirolimus? At this early point in progression, she said, the patient didn’t necessarily need systemwide chemo-suppression, and calcineurin inhibitors can be “quite effective” in management of inflammation in the liver. “It would be a completely different story once the patient develops severe cGVHR.” In that case, she said, calcineurin inhibitors wouldn’t be appropriate.

The patient’s status deteriorated to severe cGVHD, and sirolimus was replaced with ibrutinib. Other drugs were added to prevent infection and treat bronchiolitis obliterans syndrome.

In general, “the goal of the treatment is get adequate control of clinical manifestations and prevent more severe disease from developing,” Dr. Flowers said.

In response to a question about polypharmacy in patient with advanced disease – “we tend not to peel those drugs off” – Dr. Flowers said she does see new patients who appear to be taking too many medications. “They are on five drugs, and I say, ‘What are we doing?’ ”

Quite often, Dr. Flowers said, she doesn’t add therapies to existing ones but instead looks for substitutes. “A clinical lesson that I feel that I learned over time is: Ask your questions first. What would you like to see in 3 months? Or 6 months? Before you just add another therapy, do you really know what the trajectory of a disease might be?”

Dr. Flowers discloses research support (Pharmacyclics, Incyte), speaker honorarium (Janssen, Johnson & Johnson, Astellas, Mallinckrodt), and consulting relationships (Pharmacyclics, CSL Behring, Fresenius Kabi).

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

Physicians are gaining a greater understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) in allo-hematopoietic cell transplantation (allo-HCT), a hematologist/oncologist told colleagues, and novel treatments are being tested.

However, options remain limited. There’s only one Food and Drug Administration–approved therapy for cGVHD that’s failed one or more treatments, and clinical trials remain a crucial option in some cases, said Mary E.D. Flowers, MD, professor of medicine at the University of Washington’s Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

According to Dr. Flowers, cGVHD – a product of a graft’s “immunological assault” against the person receiving a transplant – occurs in 40% of patients within a year after allo-HCT. The disorder “is associated with a poor quality of life, disability, and increased mortality after allo-transplantation,” she said. “It’s a syndrome that can be inflammatory and fibrotic. It involves several organs – the skin, the mouth, the eyes, the lungs, the GI tract.”

The median length of treatment after peripheral blood stem cell transplant is 3.5 years, Dr. Flowers said. Seven years after treatment, 10% of those who are alive – and have avoided relapse – will still need treatment. “Corticosteroids remain the first-line [treatment], at 0.5-1.0 [mg/kg], but they do not control at least 40% of the patients with cGVHD.”

In regard to pathophysiology, she highlighted a 2017 report that presented findings about the pathophysiology of cGVHD. The findings, the report authors wrote, “have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition.”

For now, no agents other than corticosteroids have shown benefit in cGVHD as initial therapy, Dr. Flowers said. In fact, several trials closed early from lack of benefit. But trials continue, she said: Results are pending for a completed phase 3 trial of ibrutinib, a Bruton tyrosine kinase inhibitor, plus steroids for initial treatment of cGVHD. Nearly 500 patients were enrolled, she said. And there’s an ongoing phase 2/3 trial of itacitinib, a Janus kinase 1 inhibitor plus steroids as initial treatment.

Dr. Flowers highlighted the case of a patient with moderate cGVHD. The patient was treated with infection prophylaxis, supportive care for oral and eyes manifestations, and prednisone 0.5 mg/kg (at a lower dose because of diabetes) plus a substitution of tacrolimus with sirolimus, a calcineurin inhibitor.

Why sirolimus? At this early point in progression, she said, the patient didn’t necessarily need systemwide chemo-suppression, and calcineurin inhibitors can be “quite effective” in management of inflammation in the liver. “It would be a completely different story once the patient develops severe cGVHR.” In that case, she said, calcineurin inhibitors wouldn’t be appropriate.

The patient’s status deteriorated to severe cGVHD, and sirolimus was replaced with ibrutinib. Other drugs were added to prevent infection and treat bronchiolitis obliterans syndrome.

In general, “the goal of the treatment is get adequate control of clinical manifestations and prevent more severe disease from developing,” Dr. Flowers said.

In response to a question about polypharmacy in patient with advanced disease – “we tend not to peel those drugs off” – Dr. Flowers said she does see new patients who appear to be taking too many medications. “They are on five drugs, and I say, ‘What are we doing?’ ”

Quite often, Dr. Flowers said, she doesn’t add therapies to existing ones but instead looks for substitutes. “A clinical lesson that I feel that I learned over time is: Ask your questions first. What would you like to see in 3 months? Or 6 months? Before you just add another therapy, do you really know what the trajectory of a disease might be?”

Dr. Flowers discloses research support (Pharmacyclics, Incyte), speaker honorarium (Janssen, Johnson & Johnson, Astellas, Mallinckrodt), and consulting relationships (Pharmacyclics, CSL Behring, Fresenius Kabi).

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

Physicians are gaining a greater understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) in allo-hematopoietic cell transplantation (allo-HCT), a hematologist/oncologist told colleagues, and novel treatments are being tested.

However, options remain limited. There’s only one Food and Drug Administration–approved therapy for cGVHD that’s failed one or more treatments, and clinical trials remain a crucial option in some cases, said Mary E.D. Flowers, MD, professor of medicine at the University of Washington’s Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

According to Dr. Flowers, cGVHD – a product of a graft’s “immunological assault” against the person receiving a transplant – occurs in 40% of patients within a year after allo-HCT. The disorder “is associated with a poor quality of life, disability, and increased mortality after allo-transplantation,” she said. “It’s a syndrome that can be inflammatory and fibrotic. It involves several organs – the skin, the mouth, the eyes, the lungs, the GI tract.”

The median length of treatment after peripheral blood stem cell transplant is 3.5 years, Dr. Flowers said. Seven years after treatment, 10% of those who are alive – and have avoided relapse – will still need treatment. “Corticosteroids remain the first-line [treatment], at 0.5-1.0 [mg/kg], but they do not control at least 40% of the patients with cGVHD.”

In regard to pathophysiology, she highlighted a 2017 report that presented findings about the pathophysiology of cGVHD. The findings, the report authors wrote, “have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition.”

For now, no agents other than corticosteroids have shown benefit in cGVHD as initial therapy, Dr. Flowers said. In fact, several trials closed early from lack of benefit. But trials continue, she said: Results are pending for a completed phase 3 trial of ibrutinib, a Bruton tyrosine kinase inhibitor, plus steroids for initial treatment of cGVHD. Nearly 500 patients were enrolled, she said. And there’s an ongoing phase 2/3 trial of itacitinib, a Janus kinase 1 inhibitor plus steroids as initial treatment.

Dr. Flowers highlighted the case of a patient with moderate cGVHD. The patient was treated with infection prophylaxis, supportive care for oral and eyes manifestations, and prednisone 0.5 mg/kg (at a lower dose because of diabetes) plus a substitution of tacrolimus with sirolimus, a calcineurin inhibitor.

Why sirolimus? At this early point in progression, she said, the patient didn’t necessarily need systemwide chemo-suppression, and calcineurin inhibitors can be “quite effective” in management of inflammation in the liver. “It would be a completely different story once the patient develops severe cGVHR.” In that case, she said, calcineurin inhibitors wouldn’t be appropriate.

The patient’s status deteriorated to severe cGVHD, and sirolimus was replaced with ibrutinib. Other drugs were added to prevent infection and treat bronchiolitis obliterans syndrome.

In general, “the goal of the treatment is get adequate control of clinical manifestations and prevent more severe disease from developing,” Dr. Flowers said.

In response to a question about polypharmacy in patient with advanced disease – “we tend not to peel those drugs off” – Dr. Flowers said she does see new patients who appear to be taking too many medications. “They are on five drugs, and I say, ‘What are we doing?’ ”

Quite often, Dr. Flowers said, she doesn’t add therapies to existing ones but instead looks for substitutes. “A clinical lesson that I feel that I learned over time is: Ask your questions first. What would you like to see in 3 months? Or 6 months? Before you just add another therapy, do you really know what the trajectory of a disease might be?”

Dr. Flowers discloses research support (Pharmacyclics, Incyte), speaker honorarium (Janssen, Johnson & Johnson, Astellas, Mallinckrodt), and consulting relationships (Pharmacyclics, CSL Behring, Fresenius Kabi).

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

How old is too old for a patient to undergo hematopoietic cell transplantation (HCT)? That’s the wrong question to ask, a hematologist/oncologist told colleagues at the virtual Acute Leukemia Forum of Hemedicus. Instead, he said, look at other factors such as disease status and genetics.

“Transplantation for older patients, even beyond the age of 70, is acceptable, as long as it’s done with caution, care, and wisdom. So we’re all not too old for transplantation, at least not today,” said Daniel Weisdorf, MD, professor of medicine and deputy director of the University of Minnesota Clinical and Translational Science Institute.

As he noted, acute myeloid leukemia (AML) is often fatal. Among the general population, “the expected survival life expectancy at age 75 is 98% at 1 year, and most people living at 75 go on to live more than 10 years,” he said. “But if you have AML, at age 75, you have 20% survival at 1 year, 4% at 3 years. And since the median age of AML diagnosis is 68, and 75% of patients are diagnosed beyond the age of 55, this becomes relevant.”

Risk factors that affect survival after transplantation “certainly include age, but that interacts directly with the comorbidities people accumulate with age, their assessments of frailty, and their Karnofsky performance status, as well as the disease phenotype and molecular genetic markers,” Dr. Weisdorf said. “Perhaps most importantly, though not addressed very much, is patients’ willingness to undertake intensive therapy and their life outlook related to patient-reported outcomes when they get older.”

Despite the lack of indications that higher age by itself is an influential factor in survival after transplant, “we are generally reluctant to push the age of eligibility,” Dr. Weisdorf said. He noted that recently published American Society of Hematology guidelines for treatment of AML over the age of 55 “don’t discuss anything about transplantation fitness because they didn’t want to tackle that.”

Overall survival (OS) at 1 year after allogenic transplants only dipped slightly from ages 51-60 to 71 and above, according to Dr. Weisdorf’s analysis of U.S. data collected by the Center for International Blood and Marrow Transplant Research for the time period 2005-2019.

OS was 67.6% (66.8%-68.3%) for the 41-50 age group (n = 9,287) and 57.9% (56.1%-59.8%) for the 71 and older group, Dr. Weisdorf found. Overall, OS dropped by about 4 percentage points per decade of age, he said, revealing a “modest influence” of advancing years.

His analysis of autologous transplant data from the same source, also for 2005-2019, revealed “essentially no age influence.” OS was 90.8% (90.3%-91.2%) for the 41-50 age group (n = 15,075) and 86.6% (85.9%-87.3%) for the 71 and older group (n = 7,247).

Dr. Weisdorf also highlighted unpublished research that suggests that cord-blood transplant recipients older than 70 face a significantly higher risk of death than that of younger patients in the same category. Cord blood “may be option of last resort” because of a lack of other options, he explained. “And it may be part of the learning curve of cord blood transplantation, which grew a little bit in the early 2000s, and maybe past 2010, and then fell off as everybody got enamored with the haploidentical transplant option.”

How can physicians make decisions about transplants in older patients? “The transplant comorbidity index, the specific comorbidities themselves, performance score, and frailty are all measures of somebody’s fitness to be a good candidate for transplant, really at any age,” Dr. Weisdorf said. “But we also have to recognize that disease status, genetics, and the risk phenotype remain critical and should influence decision making.”

However, even as transplant survival improves overall, “very few people are incorporating any very specific biological markers” in decision-making, he said. “We’ve gotten to measures of frailty, but we haven’t gotten to any biologic measures of cytokines or other things that would predict poor chances for doing well. So I’m afraid we’re still standing at the foot of the bed saying: ‘You look okay.’ Or we’re measuring their comorbidity index. But it is disappointing that we’re using mostly very simple clinical measures to decide if somebody is sturdy enough to proceed, and we perhaps need something better. But I don’t have a great suggestion what it should be.”

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

Dr. Weisdorf disclosed consulting fees from Fate Therapeutics and Incyte Corp.

SOURCE: “The Ever-Increasing Upper Age for Transplant: Is This Evidence-Based?” Acute Leukemia Forum of Hemedicus, Oct. 15, 2020.

How old is too old for a patient to undergo hematopoietic cell transplantation (HCT)? That’s the wrong question to ask, a hematologist/oncologist told colleagues at the virtual Acute Leukemia Forum of Hemedicus. Instead, he said, look at other factors such as disease status and genetics.

“Transplantation for older patients, even beyond the age of 70, is acceptable, as long as it’s done with caution, care, and wisdom. So we’re all not too old for transplantation, at least not today,” said Daniel Weisdorf, MD, professor of medicine and deputy director of the University of Minnesota Clinical and Translational Science Institute.

As he noted, acute myeloid leukemia (AML) is often fatal. Among the general population, “the expected survival life expectancy at age 75 is 98% at 1 year, and most people living at 75 go on to live more than 10 years,” he said. “But if you have AML, at age 75, you have 20% survival at 1 year, 4% at 3 years. And since the median age of AML diagnosis is 68, and 75% of patients are diagnosed beyond the age of 55, this becomes relevant.”

Risk factors that affect survival after transplantation “certainly include age, but that interacts directly with the comorbidities people accumulate with age, their assessments of frailty, and their Karnofsky performance status, as well as the disease phenotype and molecular genetic markers,” Dr. Weisdorf said. “Perhaps most importantly, though not addressed very much, is patients’ willingness to undertake intensive therapy and their life outlook related to patient-reported outcomes when they get older.”

Despite the lack of indications that higher age by itself is an influential factor in survival after transplant, “we are generally reluctant to push the age of eligibility,” Dr. Weisdorf said. He noted that recently published American Society of Hematology guidelines for treatment of AML over the age of 55 “don’t discuss anything about transplantation fitness because they didn’t want to tackle that.”

Overall survival (OS) at 1 year after allogenic transplants only dipped slightly from ages 51-60 to 71 and above, according to Dr. Weisdorf’s analysis of U.S. data collected by the Center for International Blood and Marrow Transplant Research for the time period 2005-2019.

OS was 67.6% (66.8%-68.3%) for the 41-50 age group (n = 9,287) and 57.9% (56.1%-59.8%) for the 71 and older group, Dr. Weisdorf found. Overall, OS dropped by about 4 percentage points per decade of age, he said, revealing a “modest influence” of advancing years.

His analysis of autologous transplant data from the same source, also for 2005-2019, revealed “essentially no age influence.” OS was 90.8% (90.3%-91.2%) for the 41-50 age group (n = 15,075) and 86.6% (85.9%-87.3%) for the 71 and older group (n = 7,247).

Dr. Weisdorf also highlighted unpublished research that suggests that cord-blood transplant recipients older than 70 face a significantly higher risk of death than that of younger patients in the same category. Cord blood “may be option of last resort” because of a lack of other options, he explained. “And it may be part of the learning curve of cord blood transplantation, which grew a little bit in the early 2000s, and maybe past 2010, and then fell off as everybody got enamored with the haploidentical transplant option.”

How can physicians make decisions about transplants in older patients? “The transplant comorbidity index, the specific comorbidities themselves, performance score, and frailty are all measures of somebody’s fitness to be a good candidate for transplant, really at any age,” Dr. Weisdorf said. “But we also have to recognize that disease status, genetics, and the risk phenotype remain critical and should influence decision making.”

However, even as transplant survival improves overall, “very few people are incorporating any very specific biological markers” in decision-making, he said. “We’ve gotten to measures of frailty, but we haven’t gotten to any biologic measures of cytokines or other things that would predict poor chances for doing well. So I’m afraid we’re still standing at the foot of the bed saying: ‘You look okay.’ Or we’re measuring their comorbidity index. But it is disappointing that we’re using mostly very simple clinical measures to decide if somebody is sturdy enough to proceed, and we perhaps need something better. But I don’t have a great suggestion what it should be.”

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

Dr. Weisdorf disclosed consulting fees from Fate Therapeutics and Incyte Corp.

SOURCE: “The Ever-Increasing Upper Age for Transplant: Is This Evidence-Based?” Acute Leukemia Forum of Hemedicus, Oct. 15, 2020.

How old is too old for a patient to undergo hematopoietic cell transplantation (HCT)? That’s the wrong question to ask, a hematologist/oncologist told colleagues at the virtual Acute Leukemia Forum of Hemedicus. Instead, he said, look at other factors such as disease status and genetics.

“Transplantation for older patients, even beyond the age of 70, is acceptable, as long as it’s done with caution, care, and wisdom. So we’re all not too old for transplantation, at least not today,” said Daniel Weisdorf, MD, professor of medicine and deputy director of the University of Minnesota Clinical and Translational Science Institute.

As he noted, acute myeloid leukemia (AML) is often fatal. Among the general population, “the expected survival life expectancy at age 75 is 98% at 1 year, and most people living at 75 go on to live more than 10 years,” he said. “But if you have AML, at age 75, you have 20% survival at 1 year, 4% at 3 years. And since the median age of AML diagnosis is 68, and 75% of patients are diagnosed beyond the age of 55, this becomes relevant.”

Risk factors that affect survival after transplantation “certainly include age, but that interacts directly with the comorbidities people accumulate with age, their assessments of frailty, and their Karnofsky performance status, as well as the disease phenotype and molecular genetic markers,” Dr. Weisdorf said. “Perhaps most importantly, though not addressed very much, is patients’ willingness to undertake intensive therapy and their life outlook related to patient-reported outcomes when they get older.”

Despite the lack of indications that higher age by itself is an influential factor in survival after transplant, “we are generally reluctant to push the age of eligibility,” Dr. Weisdorf said. He noted that recently published American Society of Hematology guidelines for treatment of AML over the age of 55 “don’t discuss anything about transplantation fitness because they didn’t want to tackle that.”

Overall survival (OS) at 1 year after allogenic transplants only dipped slightly from ages 51-60 to 71 and above, according to Dr. Weisdorf’s analysis of U.S. data collected by the Center for International Blood and Marrow Transplant Research for the time period 2005-2019.

OS was 67.6% (66.8%-68.3%) for the 41-50 age group (n = 9,287) and 57.9% (56.1%-59.8%) for the 71 and older group, Dr. Weisdorf found. Overall, OS dropped by about 4 percentage points per decade of age, he said, revealing a “modest influence” of advancing years.

His analysis of autologous transplant data from the same source, also for 2005-2019, revealed “essentially no age influence.” OS was 90.8% (90.3%-91.2%) for the 41-50 age group (n = 15,075) and 86.6% (85.9%-87.3%) for the 71 and older group (n = 7,247).

Dr. Weisdorf also highlighted unpublished research that suggests that cord-blood transplant recipients older than 70 face a significantly higher risk of death than that of younger patients in the same category. Cord blood “may be option of last resort” because of a lack of other options, he explained. “And it may be part of the learning curve of cord blood transplantation, which grew a little bit in the early 2000s, and maybe past 2010, and then fell off as everybody got enamored with the haploidentical transplant option.”

How can physicians make decisions about transplants in older patients? “The transplant comorbidity index, the specific comorbidities themselves, performance score, and frailty are all measures of somebody’s fitness to be a good candidate for transplant, really at any age,” Dr. Weisdorf said. “But we also have to recognize that disease status, genetics, and the risk phenotype remain critical and should influence decision making.”

However, even as transplant survival improves overall, “very few people are incorporating any very specific biological markers” in decision-making, he said. “We’ve gotten to measures of frailty, but we haven’t gotten to any biologic measures of cytokines or other things that would predict poor chances for doing well. So I’m afraid we’re still standing at the foot of the bed saying: ‘You look okay.’ Or we’re measuring their comorbidity index. But it is disappointing that we’re using mostly very simple clinical measures to decide if somebody is sturdy enough to proceed, and we perhaps need something better. But I don’t have a great suggestion what it should be.”

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

Dr. Weisdorf disclosed consulting fees from Fate Therapeutics and Incyte Corp.

SOURCE: “The Ever-Increasing Upper Age for Transplant: Is This Evidence-Based?” Acute Leukemia Forum of Hemedicus, Oct. 15, 2020.

Six of eight relapsed/refractory acute myeloid leukemia patients, and one patient with accelerated phase chronic myelogenous leukemia, had no sign of residual disease 4 weeks after receiving compound CAR T therapy targeting both CD33 and CLL1.

Six patients moved on to subsequent hematopoietic stem cell transplantation (HSCT); the seventh responder withdrew from the study for personal reasons, according to a report at the virtual annual congress of the European Hematology Association.

Much work remains, but the initial results suggest that “CLL1-CD33 compound CAR T cell therapy could be developed as a bridge to transplant, a supplement to chemotherapy, or a standalone therapy for patients with acute myeloid leukemia” and other myeloid malignancies. The approach might also allow for reduced intensity conditioning or nonmyeloablative conditioning for HSCT, said lead investigator Fang Liu, MD, PhD, of the department of hematology at the Chengdu Military General Hospital, in Sichuan province, China.

It’s “a topic that will interest a lot of us.” For the first time, “a compound CAR with two independent CAR units induced remissions in AML,” said Pieter Sonneveld, MD, PhD, of the Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands, who introduced Dr. Liu’s presentation.

Chimeric antigen receptor (CAR) T cell therapy works well for B-cell malignancies, but translation to AML is “yet to be accomplished.” Meanwhile, despite progress against AML, about one-third of patients still relapse, “and prognosis for relapsed or refractory AML is dismal,” Dr. Liu and her team said.

CAR T is generally aimed against a single target, but AML bears heterogeneous cells that offset killing by single target therapies, resulting in disease relapse.

That problem suggested targeting multiple antigens simultaneously. CLL1 is an “ideal target,” Dr. Liu said, because the myeloid lineage antigen is highly expressed in AML, but absent in normal hematopoietic stem cells. CD33, meanwhile, is expressed on bulk AML cells in the majority of patients.

The CAR T cells were manufactured from autologous cells in eight of the subjects, and from a human leukocyte antigen-matched sibling donor cells for the ninth. The patients were lymphodepleted with fludarabine and cyclophosphamide, then infused with the therapeutic cells by a dose escalation at approximately 1-3 x 10⁶/kg in a single or split dose.

On disease reevaluation within 4 weeks, seven of nine patients – all with relapsed or refractory disease after multiple conventional treatments – were minimal residual disease negative by flow cytometry. The other two had no response, one of whom was CD33 positive but CLL1 negative, “indicating the importance of [the] CLL1 target in CAR T treatment,” the investigators said.

All nine patients developed grade 4 pancytopenia; eight had cytokine release syndrome (CRS), which was grade 3 in two; and four subjects developed neurotoxicity, which was grade 3 in three.

Five subjects had mild liver enzyme elevations; four had a coagulation disorder; four developed diarrhea; three developed sepsis; two fungal infections; and three pneumonia. One subject had a skin rash and one developed renal insufficiency.

The adverse events resolved after treatment. “Early intervention with steroids had a positive effect on the reduction of CRS and neurotoxicity,” the team noted.

Of the six patients who went on to HCST, one had standard myeloablative conditioning, but the rest had reduced intensity conditioning. Five subjects successfully engrafted with persistent full chimerism, but one died of sepsis before engraftment.

The median age was 32 years. The median bone marrow blast count before treatment was 47%. Seven subjects had de novo AML; one – a 6-year-old girl – had juvenile myelomonocytic leukemia that transformed into AML; and one had accelerated phase chronic myelogenous leukemia.

A phase 1 trial is underway (NCT03795779).

The work was funded by iCell Gene Therapeutics. Several investigators were employees. Dr. Liu didn’t report any disclosures.

aotto@mdedge.com

SOURCE: Liu F et al. EHA Congress. Abstract S149.

Six of eight relapsed/refractory acute myeloid leukemia patients, and one patient with accelerated phase chronic myelogenous leukemia, had no sign of residual disease 4 weeks after receiving compound CAR T therapy targeting both CD33 and CLL1.

Six patients moved on to subsequent hematopoietic stem cell transplantation (HSCT); the seventh responder withdrew from the study for personal reasons, according to a report at the virtual annual congress of the European Hematology Association.

Much work remains, but the initial results suggest that “CLL1-CD33 compound CAR T cell therapy could be developed as a bridge to transplant, a supplement to chemotherapy, or a standalone therapy for patients with acute myeloid leukemia” and other myeloid malignancies. The approach might also allow for reduced intensity conditioning or nonmyeloablative conditioning for HSCT, said lead investigator Fang Liu, MD, PhD, of the department of hematology at the Chengdu Military General Hospital, in Sichuan province, China.

It’s “a topic that will interest a lot of us.” For the first time, “a compound CAR with two independent CAR units induced remissions in AML,” said Pieter Sonneveld, MD, PhD, of the Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands, who introduced Dr. Liu’s presentation.

Chimeric antigen receptor (CAR) T cell therapy works well for B-cell malignancies, but translation to AML is “yet to be accomplished.” Meanwhile, despite progress against AML, about one-third of patients still relapse, “and prognosis for relapsed or refractory AML is dismal,” Dr. Liu and her team said.

CAR T is generally aimed against a single target, but AML bears heterogeneous cells that offset killing by single target therapies, resulting in disease relapse.

That problem suggested targeting multiple antigens simultaneously. CLL1 is an “ideal target,” Dr. Liu said, because the myeloid lineage antigen is highly expressed in AML, but absent in normal hematopoietic stem cells. CD33, meanwhile, is expressed on bulk AML cells in the majority of patients.

The CAR T cells were manufactured from autologous cells in eight of the subjects, and from a human leukocyte antigen-matched sibling donor cells for the ninth. The patients were lymphodepleted with fludarabine and cyclophosphamide, then infused with the therapeutic cells by a dose escalation at approximately 1-3 x 10⁶/kg in a single or split dose.

On disease reevaluation within 4 weeks, seven of nine patients – all with relapsed or refractory disease after multiple conventional treatments – were minimal residual disease negative by flow cytometry. The other two had no response, one of whom was CD33 positive but CLL1 negative, “indicating the importance of [the] CLL1 target in CAR T treatment,” the investigators said.

All nine patients developed grade 4 pancytopenia; eight had cytokine release syndrome (CRS), which was grade 3 in two; and four subjects developed neurotoxicity, which was grade 3 in three.

Five subjects had mild liver enzyme elevations; four had a coagulation disorder; four developed diarrhea; three developed sepsis; two fungal infections; and three pneumonia. One subject had a skin rash and one developed renal insufficiency.

The adverse events resolved after treatment. “Early intervention with steroids had a positive effect on the reduction of CRS and neurotoxicity,” the team noted.

Of the six patients who went on to HCST, one had standard myeloablative conditioning, but the rest had reduced intensity conditioning. Five subjects successfully engrafted with persistent full chimerism, but one died of sepsis before engraftment.

The median age was 32 years. The median bone marrow blast count before treatment was 47%. Seven subjects had de novo AML; one – a 6-year-old girl – had juvenile myelomonocytic leukemia that transformed into AML; and one had accelerated phase chronic myelogenous leukemia.

A phase 1 trial is underway (NCT03795779).

The work was funded by iCell Gene Therapeutics. Several investigators were employees. Dr. Liu didn’t report any disclosures.

aotto@mdedge.com

SOURCE: Liu F et al. EHA Congress. Abstract S149.

Six of eight relapsed/refractory acute myeloid leukemia patients, and one patient with accelerated phase chronic myelogenous leukemia, had no sign of residual disease 4 weeks after receiving compound CAR T therapy targeting both CD33 and CLL1.

Six patients moved on to subsequent hematopoietic stem cell transplantation (HSCT); the seventh responder withdrew from the study for personal reasons, according to a report at the virtual annual congress of the European Hematology Association.

Much work remains, but the initial results suggest that “CLL1-CD33 compound CAR T cell therapy could be developed as a bridge to transplant, a supplement to chemotherapy, or a standalone therapy for patients with acute myeloid leukemia” and other myeloid malignancies. The approach might also allow for reduced intensity conditioning or nonmyeloablative conditioning for HSCT, said lead investigator Fang Liu, MD, PhD, of the department of hematology at the Chengdu Military General Hospital, in Sichuan province, China.

It’s “a topic that will interest a lot of us.” For the first time, “a compound CAR with two independent CAR units induced remissions in AML,” said Pieter Sonneveld, MD, PhD, of the Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands, who introduced Dr. Liu’s presentation.

Chimeric antigen receptor (CAR) T cell therapy works well for B-cell malignancies, but translation to AML is “yet to be accomplished.” Meanwhile, despite progress against AML, about one-third of patients still relapse, “and prognosis for relapsed or refractory AML is dismal,” Dr. Liu and her team said.

CAR T is generally aimed against a single target, but AML bears heterogeneous cells that offset killing by single target therapies, resulting in disease relapse.

That problem suggested targeting multiple antigens simultaneously. CLL1 is an “ideal target,” Dr. Liu said, because the myeloid lineage antigen is highly expressed in AML, but absent in normal hematopoietic stem cells. CD33, meanwhile, is expressed on bulk AML cells in the majority of patients.

The CAR T cells were manufactured from autologous cells in eight of the subjects, and from a human leukocyte antigen-matched sibling donor cells for the ninth. The patients were lymphodepleted with fludarabine and cyclophosphamide, then infused with the therapeutic cells by a dose escalation at approximately 1-3 x 10⁶/kg in a single or split dose.

On disease reevaluation within 4 weeks, seven of nine patients – all with relapsed or refractory disease after multiple conventional treatments – were minimal residual disease negative by flow cytometry. The other two had no response, one of whom was CD33 positive but CLL1 negative, “indicating the importance of [the] CLL1 target in CAR T treatment,” the investigators said.

All nine patients developed grade 4 pancytopenia; eight had cytokine release syndrome (CRS), which was grade 3 in two; and four subjects developed neurotoxicity, which was grade 3 in three.

Five subjects had mild liver enzyme elevations; four had a coagulation disorder; four developed diarrhea; three developed sepsis; two fungal infections; and three pneumonia. One subject had a skin rash and one developed renal insufficiency.

The adverse events resolved after treatment. “Early intervention with steroids had a positive effect on the reduction of CRS and neurotoxicity,” the team noted.

Of the six patients who went on to HCST, one had standard myeloablative conditioning, but the rest had reduced intensity conditioning. Five subjects successfully engrafted with persistent full chimerism, but one died of sepsis before engraftment.

The median age was 32 years. The median bone marrow blast count before treatment was 47%. Seven subjects had de novo AML; one – a 6-year-old girl – had juvenile myelomonocytic leukemia that transformed into AML; and one had accelerated phase chronic myelogenous leukemia.

A phase 1 trial is underway (NCT03795779).

The work was funded by iCell Gene Therapeutics. Several investigators were employees. Dr. Liu didn’t report any disclosures.

aotto@mdedge.com

SOURCE: Liu F et al. EHA Congress. Abstract S149.

Tandem autologous hematopoietic stem cell transplantation (HSCT) could extend progression-free survival (PFS) for some patients with newly diagnosed multiple myeloma, based on long-term data from the phase 3 STaMINA trial.

While the intent-to-treat analysis showed no difference in 6-year PFS rate between single versus tandem HSCT, the as-treated analysis showed that patients who received two transplants had a 6-year PFS rate that was approximately 10% higher than those who received just one transplant, reported lead author Parameswaran Hari, MD, of the Medical College of Wisconsin, Milwaukee, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.

The STaMINA trial, also known as BMT CTN 0702, involved 758 patients who were randomized to receive one of three treatment regimens followed by 3 years of maintenance lenalidomide: tandem HSCT (auto/auto), single HSCT plus consolidation with lenalidomide/bortezomib/dexamethasone (auto/RVD), and single HSCT (auto/len).

“At the time, we intended the study to stop approximately 38 months from randomization, allowing for the time for transplant, and then 3 years of maintenance,” Dr. Hari said. However, as the results of lenalidomide maintenance in CALGB 00104 study were reported, they allowed for a follow-on protocol, which provided patients who are progression-free at the completion of the original STaMINA trial to go on to a second follow-on trial, which allowed lenalidomide maintenance on an indefinite basis, he added.

The present analysis looked at the long-term results of this follow-on trial, including the impact of discontinuing lenalidomide.

Aligning with the original study, the present intent-to-treat analysis showed no significant difference between treatment arms for 6-year PFS rate or overall survival. Respectively, PFS rates for auto/auto, auto/RVD, and auto/len were 43.9%, 39.7%, and 40.9% (P = .6).

But 32% of patients in the tandem group never underwent second HSCT, Dr. Hari noted, prompting the as-treated analysis. Although overall survival remained similar between groups, the 6-year PFS was significantly higher for patients who underwent tandem HSCT, at 49.4%, compared with 39.7% for auto/RVD and 38.6% for auto/len (P = .03).

Subgroup analysis showed the statistical benefit of tandem HSCT was driven by high-risk patients, who had a significantly better PFS after tandem transplant, compared with standard-risk patients, who showed no significant benefit.

Dr. Hari called the findings “provocative.”

“The tandem auto approach may still be relevant in high-risk multiple myeloma patients,” he said.

Dr. Hari and his colleagues also found that patients who stayed on maintenance lenalidomide after 38 months had a better 5-year PFS rate than those who discontinued maintenance therapy (79.5% vs. 61%; P = .0004). Subgroup analysis showed this benefit was statistically significant among patients with standard-risk disease (86.3% vs. 66%; P less than .001) but not among those in the high-risk subgroup (86.7% vs. 67.8%; P = .2).

However, Dr. Hari suggested that, based on the similarity of proportions between subgroups, the lack of significance in the high-risk subgroup was likely because of small sample size, suggesting the benefit of maintenance was actually shared across risk strata.

“Lenalidomide maintenance becomes a significant factor for preventing patients from progression,” Dr. Hari said, noting that the tandem transplant approach requires further study, and that he and his colleagues would soon publish minimal residual disease data.

He finished his presentation with a clear clinical recommendation. “Preplanned lenalidomide discontinuation at 3 years is not recommended based on inferior progression-free survival among those who stopped such therapy,” he said.

Invited discussant Joshua R. Richter, MD, of the Icahn School of Medicine at Mount Sinai, New York, said the findings encourage high-dose maintenance therapy, and for some, tandem HSCT.

“The STaMINA study presented today supports the notion that some patients with high-risk disease still may benefit and have further tumor burden reduction with the second transplant that leads to deeper remissions and hopefully abrogates diminished outcomes,” Dr. Richter said during a virtual presentation.

But improvements are needed to better identify such patients, Dr. Richter added. He highlighted a lack of standardization in risk modeling, with various factors currently employed, such as patient characteristics and genomic markers, among several others.

“Better definitions will allow us to cross compare and make true analyses about how to manage these patients,” Dr. Richter said. “Despite the improvements across the board that we’ve seen in myeloma patients, high-risk disease continues to represent a more complicated arena. And patients continue to suffer from worse outcomes, despite all of the other advances.”

The study was funded by the National Institutes of Health. The investigators disclosed additional relationships with Amgen, Celgene, Novartis, and others. Dr. Richter disclosed affiliations with Takeda, Sanofi, Janssen, and others.
 

SOURCE: Hari et al. ASCO 2020. Abstract 8506.

Tandem autologous hematopoietic stem cell transplantation (HSCT) could extend progression-free survival (PFS) for some patients with newly diagnosed multiple myeloma, based on long-term data from the phase 3 STaMINA trial.

While the intent-to-treat analysis showed no difference in 6-year PFS rate between single versus tandem HSCT, the as-treated analysis showed that patients who received two transplants had a 6-year PFS rate that was approximately 10% higher than those who received just one transplant, reported lead author Parameswaran Hari, MD, of the Medical College of Wisconsin, Milwaukee, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.

The STaMINA trial, also known as BMT CTN 0702, involved 758 patients who were randomized to receive one of three treatment regimens followed by 3 years of maintenance lenalidomide: tandem HSCT (auto/auto), single HSCT plus consolidation with lenalidomide/bortezomib/dexamethasone (auto/RVD), and single HSCT (auto/len).

“At the time, we intended the study to stop approximately 38 months from randomization, allowing for the time for transplant, and then 3 years of maintenance,” Dr. Hari said. However, as the results of lenalidomide maintenance in CALGB 00104 study were reported, they allowed for a follow-on protocol, which provided patients who are progression-free at the completion of the original STaMINA trial to go on to a second follow-on trial, which allowed lenalidomide maintenance on an indefinite basis, he added.

The present analysis looked at the long-term results of this follow-on trial, including the impact of discontinuing lenalidomide.

Aligning with the original study, the present intent-to-treat analysis showed no significant difference between treatment arms for 6-year PFS rate or overall survival. Respectively, PFS rates for auto/auto, auto/RVD, and auto/len were 43.9%, 39.7%, and 40.9% (P = .6).

But 32% of patients in the tandem group never underwent second HSCT, Dr. Hari noted, prompting the as-treated analysis. Although overall survival remained similar between groups, the 6-year PFS was significantly higher for patients who underwent tandem HSCT, at 49.4%, compared with 39.7% for auto/RVD and 38.6% for auto/len (P = .03).

Subgroup analysis showed the statistical benefit of tandem HSCT was driven by high-risk patients, who had a significantly better PFS after tandem transplant, compared with standard-risk patients, who showed no significant benefit.

Dr. Hari called the findings “provocative.”

“The tandem auto approach may still be relevant in high-risk multiple myeloma patients,” he said.

Dr. Hari and his colleagues also found that patients who stayed on maintenance lenalidomide after 38 months had a better 5-year PFS rate than those who discontinued maintenance therapy (79.5% vs. 61%; P = .0004). Subgroup analysis showed this benefit was statistically significant among patients with standard-risk disease (86.3% vs. 66%; P less than .001) but not among those in the high-risk subgroup (86.7% vs. 67.8%; P = .2).

However, Dr. Hari suggested that, based on the similarity of proportions between subgroups, the lack of significance in the high-risk subgroup was likely because of small sample size, suggesting the benefit of maintenance was actually shared across risk strata.

“Lenalidomide maintenance becomes a significant factor for preventing patients from progression,” Dr. Hari said, noting that the tandem transplant approach requires further study, and that he and his colleagues would soon publish minimal residual disease data.

He finished his presentation with a clear clinical recommendation. “Preplanned lenalidomide discontinuation at 3 years is not recommended based on inferior progression-free survival among those who stopped such therapy,” he said.

Invited discussant Joshua R. Richter, MD, of the Icahn School of Medicine at Mount Sinai, New York, said the findings encourage high-dose maintenance therapy, and for some, tandem HSCT.

“The STaMINA study presented today supports the notion that some patients with high-risk disease still may benefit and have further tumor burden reduction with the second transplant that leads to deeper remissions and hopefully abrogates diminished outcomes,” Dr. Richter said during a virtual presentation.

But improvements are needed to better identify such patients, Dr. Richter added. He highlighted a lack of standardization in risk modeling, with various factors currently employed, such as patient characteristics and genomic markers, among several others.

“Better definitions will allow us to cross compare and make true analyses about how to manage these patients,” Dr. Richter said. “Despite the improvements across the board that we’ve seen in myeloma patients, high-risk disease continues to represent a more complicated arena. And patients continue to suffer from worse outcomes, despite all of the other advances.”

The study was funded by the National Institutes of Health. The investigators disclosed additional relationships with Amgen, Celgene, Novartis, and others. Dr. Richter disclosed affiliations with Takeda, Sanofi, Janssen, and others.
 

SOURCE: Hari et al. ASCO 2020. Abstract 8506.

Tandem autologous hematopoietic stem cell transplantation (HSCT) could extend progression-free survival (PFS) for some patients with newly diagnosed multiple myeloma, based on long-term data from the phase 3 STaMINA trial.

While the intent-to-treat analysis showed no difference in 6-year PFS rate between single versus tandem HSCT, the as-treated analysis showed that patients who received two transplants had a 6-year PFS rate that was approximately 10% higher than those who received just one transplant, reported lead author Parameswaran Hari, MD, of the Medical College of Wisconsin, Milwaukee, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.

The STaMINA trial, also known as BMT CTN 0702, involved 758 patients who were randomized to receive one of three treatment regimens followed by 3 years of maintenance lenalidomide: tandem HSCT (auto/auto), single HSCT plus consolidation with lenalidomide/bortezomib/dexamethasone (auto/RVD), and single HSCT (auto/len).

“At the time, we intended the study to stop approximately 38 months from randomization, allowing for the time for transplant, and then 3 years of maintenance,” Dr. Hari said. However, as the results of lenalidomide maintenance in CALGB 00104 study were reported, they allowed for a follow-on protocol, which provided patients who are progression-free at the completion of the original STaMINA trial to go on to a second follow-on trial, which allowed lenalidomide maintenance on an indefinite basis, he added.

The present analysis looked at the long-term results of this follow-on trial, including the impact of discontinuing lenalidomide.

Aligning with the original study, the present intent-to-treat analysis showed no significant difference between treatment arms for 6-year PFS rate or overall survival. Respectively, PFS rates for auto/auto, auto/RVD, and auto/len were 43.9%, 39.7%, and 40.9% (P = .6).

But 32% of patients in the tandem group never underwent second HSCT, Dr. Hari noted, prompting the as-treated analysis. Although overall survival remained similar between groups, the 6-year PFS was significantly higher for patients who underwent tandem HSCT, at 49.4%, compared with 39.7% for auto/RVD and 38.6% for auto/len (P = .03).

Subgroup analysis showed the statistical benefit of tandem HSCT was driven by high-risk patients, who had a significantly better PFS after tandem transplant, compared with standard-risk patients, who showed no significant benefit.

Dr. Hari called the findings “provocative.”

“The tandem auto approach may still be relevant in high-risk multiple myeloma patients,” he said.

Dr. Hari and his colleagues also found that patients who stayed on maintenance lenalidomide after 38 months had a better 5-year PFS rate than those who discontinued maintenance therapy (79.5% vs. 61%; P = .0004). Subgroup analysis showed this benefit was statistically significant among patients with standard-risk disease (86.3% vs. 66%; P less than .001) but not among those in the high-risk subgroup (86.7% vs. 67.8%; P = .2).

However, Dr. Hari suggested that, based on the similarity of proportions between subgroups, the lack of significance in the high-risk subgroup was likely because of small sample size, suggesting the benefit of maintenance was actually shared across risk strata.

“Lenalidomide maintenance becomes a significant factor for preventing patients from progression,” Dr. Hari said, noting that the tandem transplant approach requires further study, and that he and his colleagues would soon publish minimal residual disease data.

He finished his presentation with a clear clinical recommendation. “Preplanned lenalidomide discontinuation at 3 years is not recommended based on inferior progression-free survival among those who stopped such therapy,” he said.

Invited discussant Joshua R. Richter, MD, of the Icahn School of Medicine at Mount Sinai, New York, said the findings encourage high-dose maintenance therapy, and for some, tandem HSCT.

“The STaMINA study presented today supports the notion that some patients with high-risk disease still may benefit and have further tumor burden reduction with the second transplant that leads to deeper remissions and hopefully abrogates diminished outcomes,” Dr. Richter said during a virtual presentation.

But improvements are needed to better identify such patients, Dr. Richter added. He highlighted a lack of standardization in risk modeling, with various factors currently employed, such as patient characteristics and genomic markers, among several others.

“Better definitions will allow us to cross compare and make true analyses about how to manage these patients,” Dr. Richter said. “Despite the improvements across the board that we’ve seen in myeloma patients, high-risk disease continues to represent a more complicated arena. And patients continue to suffer from worse outcomes, despite all of the other advances.”

The study was funded by the National Institutes of Health. The investigators disclosed additional relationships with Amgen, Celgene, Novartis, and others. Dr. Richter disclosed affiliations with Takeda, Sanofi, Janssen, and others.
 

SOURCE: Hari et al. ASCO 2020. Abstract 8506.

Approximately one-fifth of patients undergoing hematopoietic stem cell transplantation (HSCT) develop posttraumatic stress disorder (PTSD), based on a retrospective analysis.

Patient factors at time of transplantation, such as low quality of life and high anxiety, predicted PTSD 6 months later, reported lead author Sarah Griffith, MD, of Massachusetts General Hospital, Boston, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“We know that patients admitted for HSCT are often isolated in the hospital for a prolonged period of time, usually about 3-4 weeks, and that they endure substantial toxicities that impact both their physical and psychological well-being,” Dr. Griffith said. “We also know from the literature that HSCT can be considered a traumatic event and that it may lead to clinically significant PTSD symptoms.” But studies evaluating the prevalence and characteristics of PTSD in this patient population have been lacking, she noted.

Dr. Griffith and her colleagues therefore conducted a retrospective analysis involving 250 adults with hematologic malignancies who underwent autologous or allogeneic HSCT during clinical trials conducted from 2014 to 2016. Median patient age was 56 years.

The first objective of the study was to measure the prevalence of PTSD. The second was to characterize features of PTSD such as intrusion, which entails reliving experiences in the form of nightmares or flashbacks, and hypervigilance, which encompasses insomnia, irritability, and hyperarousal for threat. The third objective was to determine risk factors at baseline.

At time of admission for HSCT, after 2 weeks of hospitalization, and again 6 months after transplantation, patients were evaluated using the Functional Assessment of Cancer Therapy–Bone Marrow Transplant (FACT-BMT), and the Hospital Anxiety and Depression Scale (HADS), which measured of quality of life, anxiety, and depression. Six months after HSCT, patients also underwent screening for PTSD with the Post-Traumatic Stress Checklist (PTSD-CL). Multivariate regression models were used to determine predictive risk factors.

Six months after HSCT, 18.9% of patients had clinically significant PTSD symptoms; most common were symptoms of avoidance (92.3%), hypervigilance (92.3%), and intrusion (76.9%). Among those who did not have clinically significant PTSD, almost one-quarter (24.5%) demonstrated significant hypervigilance, while 13.7% showed symptoms of avoidance.

“Clinically significant PTSD symptoms are common in the transplant population,” Dr. Griffith said.

Baseline predictors of PTSD included single status and lower quality of life. More severe PTSD was predicted by single status, younger age, higher baseline scores for anxiety or depression, and increased anxiety during hospitalization.

Concluding her presentation, Dr. Griffith said that the findings, while correlative and not causative, should prompt concern and intervention.

“It is very important to be aware of and to manage PTSD symptoms in these patients,” she said. “There are several baseline factors that can be identified prior to HSCT that may illuminate patients at risk for developing worse PTSD symptoms down the road, and these patients may benefit from tailored supportive care interventions.”

Specifically, Dr. Griffith recommended integrating palliative care into hospitalization, as this has been shown to reduce anxiety.

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., highlighted the importance of the findings, while also noting that the impact of palliative care on risk of PTSD has yet to be demonstrated.

Dr. Shah suggested that future research may be improved through use of a formal diagnosis for PTSD, instead of a PTSD checklist, as was used in the present study.

“And certainly long-term follow-up would be important to evaluate the utility of this tool looking at symptoms beyond 6 months,” she said.

Dr. Shah went on to discuss the relevance of the findings for pediatric populations, as children may face unique risk factors and consequences related to PTSD.

“[PTSD in children] may be impacted by family dynamics and structure,” Dr. Shah said. “Children may also have significant neurocognitive implications as a result of their underlying disease or prior therapy. They may experience chronic pain as they go out into adulthood and long-term survivorship, and may also struggle with symptoms of anxiety and depression.”

According to Dr. Shah, one previous study involving more than 6,000 adult survivors of childhood cancer found that PTSD was relatively common, with prevalence rate of 9%, suggesting that interventional work is necessary.

“Applying the data in the study from Griffith et al. suggests that evaluation in the more proximal posttransplant period for children is needed to specifically evaluate PTSD and symptoms thereof, and to try to use this to identify an opportunity for intervention,” Dr. Shah said.

“Pediatric-specific assessments are essential to optimally capture disease and/or age-specific considerations,” she added.

The study was funded by the Lymphoma and Leukemia Society. The investigators disclosed additional relationships with Vector Oncology, Pfizer, AstraZeneca, and Gaido Health/BCG Digital Ventures.

SOURCE: Griffith et al. ASCO 2020. Abstract # 7505.

Approximately one-fifth of patients undergoing hematopoietic stem cell transplantation (HSCT) develop posttraumatic stress disorder (PTSD), based on a retrospective analysis.

Patient factors at time of transplantation, such as low quality of life and high anxiety, predicted PTSD 6 months later, reported lead author Sarah Griffith, MD, of Massachusetts General Hospital, Boston, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“We know that patients admitted for HSCT are often isolated in the hospital for a prolonged period of time, usually about 3-4 weeks, and that they endure substantial toxicities that impact both their physical and psychological well-being,” Dr. Griffith said. “We also know from the literature that HSCT can be considered a traumatic event and that it may lead to clinically significant PTSD symptoms.” But studies evaluating the prevalence and characteristics of PTSD in this patient population have been lacking, she noted.

Dr. Griffith and her colleagues therefore conducted a retrospective analysis involving 250 adults with hematologic malignancies who underwent autologous or allogeneic HSCT during clinical trials conducted from 2014 to 2016. Median patient age was 56 years.

The first objective of the study was to measure the prevalence of PTSD. The second was to characterize features of PTSD such as intrusion, which entails reliving experiences in the form of nightmares or flashbacks, and hypervigilance, which encompasses insomnia, irritability, and hyperarousal for threat. The third objective was to determine risk factors at baseline.

At time of admission for HSCT, after 2 weeks of hospitalization, and again 6 months after transplantation, patients were evaluated using the Functional Assessment of Cancer Therapy–Bone Marrow Transplant (FACT-BMT), and the Hospital Anxiety and Depression Scale (HADS), which measured of quality of life, anxiety, and depression. Six months after HSCT, patients also underwent screening for PTSD with the Post-Traumatic Stress Checklist (PTSD-CL). Multivariate regression models were used to determine predictive risk factors.

Six months after HSCT, 18.9% of patients had clinically significant PTSD symptoms; most common were symptoms of avoidance (92.3%), hypervigilance (92.3%), and intrusion (76.9%). Among those who did not have clinically significant PTSD, almost one-quarter (24.5%) demonstrated significant hypervigilance, while 13.7% showed symptoms of avoidance.

“Clinically significant PTSD symptoms are common in the transplant population,” Dr. Griffith said.

Baseline predictors of PTSD included single status and lower quality of life. More severe PTSD was predicted by single status, younger age, higher baseline scores for anxiety or depression, and increased anxiety during hospitalization.

Concluding her presentation, Dr. Griffith said that the findings, while correlative and not causative, should prompt concern and intervention.

“It is very important to be aware of and to manage PTSD symptoms in these patients,” she said. “There are several baseline factors that can be identified prior to HSCT that may illuminate patients at risk for developing worse PTSD symptoms down the road, and these patients may benefit from tailored supportive care interventions.”

Specifically, Dr. Griffith recommended integrating palliative care into hospitalization, as this has been shown to reduce anxiety.

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., highlighted the importance of the findings, while also noting that the impact of palliative care on risk of PTSD has yet to be demonstrated.

Dr. Shah suggested that future research may be improved through use of a formal diagnosis for PTSD, instead of a PTSD checklist, as was used in the present study.

“And certainly long-term follow-up would be important to evaluate the utility of this tool looking at symptoms beyond 6 months,” she said.

Dr. Shah went on to discuss the relevance of the findings for pediatric populations, as children may face unique risk factors and consequences related to PTSD.

“[PTSD in children] may be impacted by family dynamics and structure,” Dr. Shah said. “Children may also have significant neurocognitive implications as a result of their underlying disease or prior therapy. They may experience chronic pain as they go out into adulthood and long-term survivorship, and may also struggle with symptoms of anxiety and depression.”

According to Dr. Shah, one previous study involving more than 6,000 adult survivors of childhood cancer found that PTSD was relatively common, with prevalence rate of 9%, suggesting that interventional work is necessary.

“Applying the data in the study from Griffith et al. suggests that evaluation in the more proximal posttransplant period for children is needed to specifically evaluate PTSD and symptoms thereof, and to try to use this to identify an opportunity for intervention,” Dr. Shah said.

“Pediatric-specific assessments are essential to optimally capture disease and/or age-specific considerations,” she added.

The study was funded by the Lymphoma and Leukemia Society. The investigators disclosed additional relationships with Vector Oncology, Pfizer, AstraZeneca, and Gaido Health/BCG Digital Ventures.

SOURCE: Griffith et al. ASCO 2020. Abstract # 7505.

Approximately one-fifth of patients undergoing hematopoietic stem cell transplantation (HSCT) develop posttraumatic stress disorder (PTSD), based on a retrospective analysis.

Patient factors at time of transplantation, such as low quality of life and high anxiety, predicted PTSD 6 months later, reported lead author Sarah Griffith, MD, of Massachusetts General Hospital, Boston, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“We know that patients admitted for HSCT are often isolated in the hospital for a prolonged period of time, usually about 3-4 weeks, and that they endure substantial toxicities that impact both their physical and psychological well-being,” Dr. Griffith said. “We also know from the literature that HSCT can be considered a traumatic event and that it may lead to clinically significant PTSD symptoms.” But studies evaluating the prevalence and characteristics of PTSD in this patient population have been lacking, she noted.

Dr. Griffith and her colleagues therefore conducted a retrospective analysis involving 250 adults with hematologic malignancies who underwent autologous or allogeneic HSCT during clinical trials conducted from 2014 to 2016. Median patient age was 56 years.

The first objective of the study was to measure the prevalence of PTSD. The second was to characterize features of PTSD such as intrusion, which entails reliving experiences in the form of nightmares or flashbacks, and hypervigilance, which encompasses insomnia, irritability, and hyperarousal for threat. The third objective was to determine risk factors at baseline.

At time of admission for HSCT, after 2 weeks of hospitalization, and again 6 months after transplantation, patients were evaluated using the Functional Assessment of Cancer Therapy–Bone Marrow Transplant (FACT-BMT), and the Hospital Anxiety and Depression Scale (HADS), which measured of quality of life, anxiety, and depression. Six months after HSCT, patients also underwent screening for PTSD with the Post-Traumatic Stress Checklist (PTSD-CL). Multivariate regression models were used to determine predictive risk factors.

Six months after HSCT, 18.9% of patients had clinically significant PTSD symptoms; most common were symptoms of avoidance (92.3%), hypervigilance (92.3%), and intrusion (76.9%). Among those who did not have clinically significant PTSD, almost one-quarter (24.5%) demonstrated significant hypervigilance, while 13.7% showed symptoms of avoidance.

“Clinically significant PTSD symptoms are common in the transplant population,” Dr. Griffith said.

Baseline predictors of PTSD included single status and lower quality of life. More severe PTSD was predicted by single status, younger age, higher baseline scores for anxiety or depression, and increased anxiety during hospitalization.

Concluding her presentation, Dr. Griffith said that the findings, while correlative and not causative, should prompt concern and intervention.

“It is very important to be aware of and to manage PTSD symptoms in these patients,” she said. “There are several baseline factors that can be identified prior to HSCT that may illuminate patients at risk for developing worse PTSD symptoms down the road, and these patients may benefit from tailored supportive care interventions.”

Specifically, Dr. Griffith recommended integrating palliative care into hospitalization, as this has been shown to reduce anxiety.

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., highlighted the importance of the findings, while also noting that the impact of palliative care on risk of PTSD has yet to be demonstrated.

Dr. Shah suggested that future research may be improved through use of a formal diagnosis for PTSD, instead of a PTSD checklist, as was used in the present study.

“And certainly long-term follow-up would be important to evaluate the utility of this tool looking at symptoms beyond 6 months,” she said.

Dr. Shah went on to discuss the relevance of the findings for pediatric populations, as children may face unique risk factors and consequences related to PTSD.

“[PTSD in children] may be impacted by family dynamics and structure,” Dr. Shah said. “Children may also have significant neurocognitive implications as a result of their underlying disease or prior therapy. They may experience chronic pain as they go out into adulthood and long-term survivorship, and may also struggle with symptoms of anxiety and depression.”

According to Dr. Shah, one previous study involving more than 6,000 adult survivors of childhood cancer found that PTSD was relatively common, with prevalence rate of 9%, suggesting that interventional work is necessary.

“Applying the data in the study from Griffith et al. suggests that evaluation in the more proximal posttransplant period for children is needed to specifically evaluate PTSD and symptoms thereof, and to try to use this to identify an opportunity for intervention,” Dr. Shah said.

“Pediatric-specific assessments are essential to optimally capture disease and/or age-specific considerations,” she added.

The study was funded by the Lymphoma and Leukemia Society. The investigators disclosed additional relationships with Vector Oncology, Pfizer, AstraZeneca, and Gaido Health/BCG Digital Ventures.

SOURCE: Griffith et al. ASCO 2020. Abstract # 7505.

A disease risk index is now available for pediatric patients with acute myeloid leukemia or acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation.

The model, which was developed and validated using data from more than 2,000 patients, stratifies probabilities of leukemia-free survival (LFS) into four risk groups for acute myeloid leukemia (AML) and three risk groups for acute lymphoblastic leukemia (ALL), reported lead author Muna Qayed, MD, of Emory University, Atlanta, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“The outcome of stem cell transplantation for hematologic malignancy is influenced by disease type, cytogenetics, and disease status at transplantation,” Dr. Qayed said. “In adults, these attributes were used to develop the disease risk index, or DRI, that can stratify patients for overall survival for purposes such as prognostication or clinical trial entry.”

But no such model exists for pediatric patients, Dr. Qayed said, noting that the adult DRI was found to be inaccurate when applied to children.

“[T]he [adult] DRI did not differentiate [pediatric] patients by overall survival,” Dr. Qayed said. “Therefore, knowing that pediatric AML and ALL differ biologically from adult leukemia, and further, treatment strategies differ between adults and children, we aimed to develop a pediatric-specific DRI.”

This involved analysis of data from 1,135 children with AML and 1,228 children with ALL who underwent transplantation between 2008 and 2017. All patients had myeloablative conditioning, and 75% received an unrelated donor graft. Haploidentical transplants were excluded because of small sample size.

Analyses were conducted in AML and ALL cohorts, with patients in each population randomized to training and validation subgroups in a 1:1 ratio. The primary outcome was LFS. Cox regression models were used to identify significant characteristics, which were then integrated into a prognostic scoring system for the training groups. These scoring systems were then tested in the validation subgroups. Maximum likelihood was used to identify age cutoffs, which were 3 years for AML and 2 years for ALL.

In both cohorts, disease status at transplantation was characterized by complete remission and minimal residual disease status.

In the AML cohort, approximately one-third of patients were in first complete remission with negative minimal residual disease. Risk was stratified into four groups, including good, intermediate, high, and very high risk, with respective 5-year LFS probabilities of 81%, 56%, 44%, and 21%. Independent predictors of poorer outcome included unfavorable cytogenetics, first or second complete remission with minimal residual disease positivity, relapse at transplantation, and age less than 3 years.

In the ALL cohort, risk was stratified into three risk tiers: good, intermediate, and high, with 5-year LFS probabilities of 68%, 50%, and 15%, respectively. Independent predictors of poorer outcome included age less than 2 years, relapse at transplantation, and second complete remission regardless of minimal residual disease status.

The models for each disease also predicted overall survival.

For AML, hazard ratios, ascending from good to very-high-risk tiers, were 1.00, 3.52, 4.67, and 8.62. For ALL risk tiers, ascending hazard ratios were 1.00, 2.16, and 3.86.

“In summary, the pediatric disease risk index validated for leukemia-free survival and overall survival successfully stratifies children with acute leukemia at the time of transplantation,” Dr. Qayed said.

She concluded her presentation by highlighting the practicality and relevance of the new scoring system.

“The components included in the scoring system used information that is readily available pretransplantation, lending support to the deliverability of the prognostic scoring system,” Dr. Qayed said. “It can further be used for improved interpretation of multicenter data and in clinical trials for risk stratification.”

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., first emphasized the clinical importance of an accurate disease risk index for pediatric patients.

“When going into transplant, the No. 1 question that all parents will ask is: ‘Will my child be cured?’ ” she said.

According to Dr. Shah, the risk model developed by Dr. Qayed and colleagues is built on a strong foundation, including adequate sample size, comprehensive disease characterization, exclusion of patients that did not undergo myeloablative conditioning, and use of minimal residual disease status.

Still, more work is needed, Dr. Shah said.

“This DRI will need to be prospectively tested and compared to other established risk factors. For instance, minimal residual disease alone can be further stratified and has a significant role in establishing risk for posttransplant relapse. And the development of acute graft-versus-host disease also plays an important role in posttransplant relapse.”

Dr. Shah went on to outline potential areas of improvement.

“[F]uture directions for this study could include incorporation of early posttransplant events like graft-versus-host disease, potential stratification of the minimal residual disease results among those patients in complete remission, and potential application of this DRI to the adolescent and young adult population, which may have slight variation even from the adult DRI.”The study was funded by the National Institutes of Health. The investigators disclosed no conflicts of interest

SOURCE: Qayed M et al. ASCO 2020, Abstract 7503.

A disease risk index is now available for pediatric patients with acute myeloid leukemia or acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation.

The model, which was developed and validated using data from more than 2,000 patients, stratifies probabilities of leukemia-free survival (LFS) into four risk groups for acute myeloid leukemia (AML) and three risk groups for acute lymphoblastic leukemia (ALL), reported lead author Muna Qayed, MD, of Emory University, Atlanta, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“The outcome of stem cell transplantation for hematologic malignancy is influenced by disease type, cytogenetics, and disease status at transplantation,” Dr. Qayed said. “In adults, these attributes were used to develop the disease risk index, or DRI, that can stratify patients for overall survival for purposes such as prognostication or clinical trial entry.”

But no such model exists for pediatric patients, Dr. Qayed said, noting that the adult DRI was found to be inaccurate when applied to children.

“[T]he [adult] DRI did not differentiate [pediatric] patients by overall survival,” Dr. Qayed said. “Therefore, knowing that pediatric AML and ALL differ biologically from adult leukemia, and further, treatment strategies differ between adults and children, we aimed to develop a pediatric-specific DRI.”

This involved analysis of data from 1,135 children with AML and 1,228 children with ALL who underwent transplantation between 2008 and 2017. All patients had myeloablative conditioning, and 75% received an unrelated donor graft. Haploidentical transplants were excluded because of small sample size.

Analyses were conducted in AML and ALL cohorts, with patients in each population randomized to training and validation subgroups in a 1:1 ratio. The primary outcome was LFS. Cox regression models were used to identify significant characteristics, which were then integrated into a prognostic scoring system for the training groups. These scoring systems were then tested in the validation subgroups. Maximum likelihood was used to identify age cutoffs, which were 3 years for AML and 2 years for ALL.

In both cohorts, disease status at transplantation was characterized by complete remission and minimal residual disease status.

In the AML cohort, approximately one-third of patients were in first complete remission with negative minimal residual disease. Risk was stratified into four groups, including good, intermediate, high, and very high risk, with respective 5-year LFS probabilities of 81%, 56%, 44%, and 21%. Independent predictors of poorer outcome included unfavorable cytogenetics, first or second complete remission with minimal residual disease positivity, relapse at transplantation, and age less than 3 years.

In the ALL cohort, risk was stratified into three risk tiers: good, intermediate, and high, with 5-year LFS probabilities of 68%, 50%, and 15%, respectively. Independent predictors of poorer outcome included age less than 2 years, relapse at transplantation, and second complete remission regardless of minimal residual disease status.

The models for each disease also predicted overall survival.

For AML, hazard ratios, ascending from good to very-high-risk tiers, were 1.00, 3.52, 4.67, and 8.62. For ALL risk tiers, ascending hazard ratios were 1.00, 2.16, and 3.86.

“In summary, the pediatric disease risk index validated for leukemia-free survival and overall survival successfully stratifies children with acute leukemia at the time of transplantation,” Dr. Qayed said.

She concluded her presentation by highlighting the practicality and relevance of the new scoring system.

“The components included in the scoring system used information that is readily available pretransplantation, lending support to the deliverability of the prognostic scoring system,” Dr. Qayed said. “It can further be used for improved interpretation of multicenter data and in clinical trials for risk stratification.”

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., first emphasized the clinical importance of an accurate disease risk index for pediatric patients.

“When going into transplant, the No. 1 question that all parents will ask is: ‘Will my child be cured?’ ” she said.

According to Dr. Shah, the risk model developed by Dr. Qayed and colleagues is built on a strong foundation, including adequate sample size, comprehensive disease characterization, exclusion of patients that did not undergo myeloablative conditioning, and use of minimal residual disease status.

Still, more work is needed, Dr. Shah said.

“This DRI will need to be prospectively tested and compared to other established risk factors. For instance, minimal residual disease alone can be further stratified and has a significant role in establishing risk for posttransplant relapse. And the development of acute graft-versus-host disease also plays an important role in posttransplant relapse.”

Dr. Shah went on to outline potential areas of improvement.

“[F]uture directions for this study could include incorporation of early posttransplant events like graft-versus-host disease, potential stratification of the minimal residual disease results among those patients in complete remission, and potential application of this DRI to the adolescent and young adult population, which may have slight variation even from the adult DRI.”The study was funded by the National Institutes of Health. The investigators disclosed no conflicts of interest

SOURCE: Qayed M et al. ASCO 2020, Abstract 7503.

A disease risk index is now available for pediatric patients with acute myeloid leukemia or acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation.

The model, which was developed and validated using data from more than 2,000 patients, stratifies probabilities of leukemia-free survival (LFS) into four risk groups for acute myeloid leukemia (AML) and three risk groups for acute lymphoblastic leukemia (ALL), reported lead author Muna Qayed, MD, of Emory University, Atlanta, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“The outcome of stem cell transplantation for hematologic malignancy is influenced by disease type, cytogenetics, and disease status at transplantation,” Dr. Qayed said. “In adults, these attributes were used to develop the disease risk index, or DRI, that can stratify patients for overall survival for purposes such as prognostication or clinical trial entry.”

But no such model exists for pediatric patients, Dr. Qayed said, noting that the adult DRI was found to be inaccurate when applied to children.

“[T]he [adult] DRI did not differentiate [pediatric] patients by overall survival,” Dr. Qayed said. “Therefore, knowing that pediatric AML and ALL differ biologically from adult leukemia, and further, treatment strategies differ between adults and children, we aimed to develop a pediatric-specific DRI.”

This involved analysis of data from 1,135 children with AML and 1,228 children with ALL who underwent transplantation between 2008 and 2017. All patients had myeloablative conditioning, and 75% received an unrelated donor graft. Haploidentical transplants were excluded because of small sample size.

Analyses were conducted in AML and ALL cohorts, with patients in each population randomized to training and validation subgroups in a 1:1 ratio. The primary outcome was LFS. Cox regression models were used to identify significant characteristics, which were then integrated into a prognostic scoring system for the training groups. These scoring systems were then tested in the validation subgroups. Maximum likelihood was used to identify age cutoffs, which were 3 years for AML and 2 years for ALL.

In both cohorts, disease status at transplantation was characterized by complete remission and minimal residual disease status.

In the AML cohort, approximately one-third of patients were in first complete remission with negative minimal residual disease. Risk was stratified into four groups, including good, intermediate, high, and very high risk, with respective 5-year LFS probabilities of 81%, 56%, 44%, and 21%. Independent predictors of poorer outcome included unfavorable cytogenetics, first or second complete remission with minimal residual disease positivity, relapse at transplantation, and age less than 3 years.

In the ALL cohort, risk was stratified into three risk tiers: good, intermediate, and high, with 5-year LFS probabilities of 68%, 50%, and 15%, respectively. Independent predictors of poorer outcome included age less than 2 years, relapse at transplantation, and second complete remission regardless of minimal residual disease status.

The models for each disease also predicted overall survival.

For AML, hazard ratios, ascending from good to very-high-risk tiers, were 1.00, 3.52, 4.67, and 8.62. For ALL risk tiers, ascending hazard ratios were 1.00, 2.16, and 3.86.

“In summary, the pediatric disease risk index validated for leukemia-free survival and overall survival successfully stratifies children with acute leukemia at the time of transplantation,” Dr. Qayed said.

She concluded her presentation by highlighting the practicality and relevance of the new scoring system.

“The components included in the scoring system used information that is readily available pretransplantation, lending support to the deliverability of the prognostic scoring system,” Dr. Qayed said. “It can further be used for improved interpretation of multicenter data and in clinical trials for risk stratification.”

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., first emphasized the clinical importance of an accurate disease risk index for pediatric patients.

“When going into transplant, the No. 1 question that all parents will ask is: ‘Will my child be cured?’ ” she said.

According to Dr. Shah, the risk model developed by Dr. Qayed and colleagues is built on a strong foundation, including adequate sample size, comprehensive disease characterization, exclusion of patients that did not undergo myeloablative conditioning, and use of minimal residual disease status.

Still, more work is needed, Dr. Shah said.

“This DRI will need to be prospectively tested and compared to other established risk factors. For instance, minimal residual disease alone can be further stratified and has a significant role in establishing risk for posttransplant relapse. And the development of acute graft-versus-host disease also plays an important role in posttransplant relapse.”

Dr. Shah went on to outline potential areas of improvement.

“[F]uture directions for this study could include incorporation of early posttransplant events like graft-versus-host disease, potential stratification of the minimal residual disease results among those patients in complete remission, and potential application of this DRI to the adolescent and young adult population, which may have slight variation even from the adult DRI.”The study was funded by the National Institutes of Health. The investigators disclosed no conflicts of interest

SOURCE: Qayed M et al. ASCO 2020, Abstract 7503.

Addressing local supply constraints may be insufficient to improve poorer outcomes among women who need a liver transplant, based on a large retrospective analysis.

Sex-based disparities in liver allocation were more strongly associated with liver size mismatch and MELD (Model for End-stage Liver Disease) score than geographic factors, reported lead author Jayme E. Locke, MD, of the University of Alabama at Birmingham, and colleagues.

“Currently, the transplant community is considering geographic redistribution ... to redefine local organ supply by replacing donor service areas with fixed concentric circles around donor hospitals,” the investigators wrote in JAMA Surgery. “However, newly proposed geographic models rely on the same metric for medical urgency, the MELD score, and offer no solution for candidates with small body stature who may appear at the top of the match run yet are routinely skipped secondary to discrepancies in donor-recipient size.”

To further investigate the driving forces behind sex-based disparities, the investigators conducted the first national study of its kind, involving 81,357 adults who were wait-listed for liver transplant. Primary outcomes included deceased donor liver transplant and wait list mortality. Using multivariate regression models and inverse odds ratio weighting, the investigators determined proportions of disparity shared across MELD score, candidate anthropometric and liver measurements, and geographic location.

Compared with men, women were 14.4% less likely to receive a transplant, and 8.6% more likely to die on the wait list.

The only geographic factor significantly associated with the increased disparity between female sex and wait list mortality was organ procurement organization, which was associated with a 22% increase. The disparity between rates of transplant receipt was not linked with any geographic factors.

In contrast, MELD score accounted for increases in disparity of 10.3% and 50.1% for organ receipt and wait list mortality, respectively. Candidate anthropometric and liver measurements played an even greater role, raising disparity by 49.0% for organ receipt and 125.8% for wait list mortality.

“Size mismatch between the donor and intended recipient and incorrect assessments of liver disease severity were more strongly associated with the observed sex disparity in wait list mortality than local supply of organs,” the investigators wrote.

Dr. Locke and colleagues noted that ongoing debates about geographic disparity hinge upon the assumption that the MELD score accurately measures disease severity, despite known shortcomings, including reliance upon serum creatinine level, which is influenced by muscle mass and therefore overestimates kidney function in women, and sex-based differences in size, which the MELD score does not incorporate whatsoever.

As such, the investigators suggested that addressing issues with the MELD score and organ size mismatch should be part of a more comprehensive approach to fixing sex-based disparities among candidates for liver transplant.

“Although geographic factors matter, examining geographic access alone may be insufficient,” they concluded.

James F. Markmann, MD, PhD, chief of the division of transplantation at Massachusetts General Hospital, Boston, who has previously published research in support of geographic redistribution, said in an interview that the study by Dr. Locke and colleagues “highlights a well-known problem in the liver transplant field.”

“The cause of this disparity is nicely illustrated by Dr. Locke’s work, which shows multiple contributing factors,” Dr. Markmann said.

While Dr. Markmann agreed with Dr. Locke and colleagues’ proposal that estimated glomerular filtration rate, instead of creatinine, could be used to more accurately measure renal function across sexes, he suggested that the disparities uncovered by their analysis are more likely driven by body size than sex.

“A more impactful factor and one obvious to those performing transplants is that on average the smaller body habitus of females makes more organs unsuitable due to size mismatch,” Dr. Markmann said. “In general, it is technically much less of a barrier to put a small liver into a large patient, than a large liver in a small patient. But, the same disparity in access almost certainly applies to small males; unfortunately, the authors did not examine this point. If allocation changes are envisioned to gain greater fairness in organ access, at least for the recipient size issue, it should be a size issue and not a sex issue.”

Dr. Markmann went on to explain that steps are currently being taken to make liver access more equitable.

“As of February 4th of this year, a broader sharing program for deceased donor livers was implemented,” he said. “This will make more organs available to those in greatest need. It will also potentially increase the number of liver offers to sick patients with a small body habitus and will hopefully reduce the excess morbidity and mortality they suffer.”

According to Willscott E. Naugler, MD and Susan L. Orloff, MD, of Oregon Health & Science University, Portland, novel clinical strategies need to be reinforced with a broader mindset in order to close the gap between men and women.

“A change in the MELD score is unlikely to fix this problem,” they wrote in an accompanying JAMA Surgery editorial, “but it is not hard to think of solutions; one could imagine, for example, allowing women of small stature to access pediatric livers while ramping up liver splits to increase contributions to the pediatric pool.”

Dr. Naugler and Dr. Orloff went on to suggest that barriers to equity may be culturally insidious.

“It is likely that the same unconscious biases that lead us to pay women surgeons less account for the lack of will to make these simple changes,” they wrote. “Not mentioned are multiple sociocultural elements that favor men over women in organ transplant. ... These realities cannot be fixed with changes to the MELD score, and we must be mindful not to let such notions distract from the essential hard work of creating long-lasting cultural changes that underpin a true path forward.”

The investigators disclosed relationships with Sanofi, Hansa Medical, Natera, and others.

SOURCE: Locke JE et al. JAMA Surg. 2020 May 20. doi: 10.1001/jamasurg.2020.1129.

Addressing local supply constraints may be insufficient to improve poorer outcomes among women who need a liver transplant, based on a large retrospective analysis.

Sex-based disparities in liver allocation were more strongly associated with liver size mismatch and MELD (Model for End-stage Liver Disease) score than geographic factors, reported lead author Jayme E. Locke, MD, of the University of Alabama at Birmingham, and colleagues.

“Currently, the transplant community is considering geographic redistribution ... to redefine local organ supply by replacing donor service areas with fixed concentric circles around donor hospitals,” the investigators wrote in JAMA Surgery. “However, newly proposed geographic models rely on the same metric for medical urgency, the MELD score, and offer no solution for candidates with small body stature who may appear at the top of the match run yet are routinely skipped secondary to discrepancies in donor-recipient size.”

To further investigate the driving forces behind sex-based disparities, the investigators conducted the first national study of its kind, involving 81,357 adults who were wait-listed for liver transplant. Primary outcomes included deceased donor liver transplant and wait list mortality. Using multivariate regression models and inverse odds ratio weighting, the investigators determined proportions of disparity shared across MELD score, candidate anthropometric and liver measurements, and geographic location.

Compared with men, women were 14.4% less likely to receive a transplant, and 8.6% more likely to die on the wait list.

The only geographic factor significantly associated with the increased disparity between female sex and wait list mortality was organ procurement organization, which was associated with a 22% increase. The disparity between rates of transplant receipt was not linked with any geographic factors.

In contrast, MELD score accounted for increases in disparity of 10.3% and 50.1% for organ receipt and wait list mortality, respectively. Candidate anthropometric and liver measurements played an even greater role, raising disparity by 49.0% for organ receipt and 125.8% for wait list mortality.

“Size mismatch between the donor and intended recipient and incorrect assessments of liver disease severity were more strongly associated with the observed sex disparity in wait list mortality than local supply of organs,” the investigators wrote.

Dr. Locke and colleagues noted that ongoing debates about geographic disparity hinge upon the assumption that the MELD score accurately measures disease severity, despite known shortcomings, including reliance upon serum creatinine level, which is influenced by muscle mass and therefore overestimates kidney function in women, and sex-based differences in size, which the MELD score does not incorporate whatsoever.

As such, the investigators suggested that addressing issues with the MELD score and organ size mismatch should be part of a more comprehensive approach to fixing sex-based disparities among candidates for liver transplant.

“Although geographic factors matter, examining geographic access alone may be insufficient,” they concluded.

James F. Markmann, MD, PhD, chief of the division of transplantation at Massachusetts General Hospital, Boston, who has previously published research in support of geographic redistribution, said in an interview that the study by Dr. Locke and colleagues “highlights a well-known problem in the liver transplant field.”

“The cause of this disparity is nicely illustrated by Dr. Locke’s work, which shows multiple contributing factors,” Dr. Markmann said.

While Dr. Markmann agreed with Dr. Locke and colleagues’ proposal that estimated glomerular filtration rate, instead of creatinine, could be used to more accurately measure renal function across sexes, he suggested that the disparities uncovered by their analysis are more likely driven by body size than sex.

“A more impactful factor and one obvious to those performing transplants is that on average the smaller body habitus of females makes more organs unsuitable due to size mismatch,” Dr. Markmann said. “In general, it is technically much less of a barrier to put a small liver into a large patient, than a large liver in a small patient. But, the same disparity in access almost certainly applies to small males; unfortunately, the authors did not examine this point. If allocation changes are envisioned to gain greater fairness in organ access, at least for the recipient size issue, it should be a size issue and not a sex issue.”

Dr. Markmann went on to explain that steps are currently being taken to make liver access more equitable.

“As of February 4th of this year, a broader sharing program for deceased donor livers was implemented,” he said. “This will make more organs available to those in greatest need. It will also potentially increase the number of liver offers to sick patients with a small body habitus and will hopefully reduce the excess morbidity and mortality they suffer.”

According to Willscott E. Naugler, MD and Susan L. Orloff, MD, of Oregon Health & Science University, Portland, novel clinical strategies need to be reinforced with a broader mindset in order to close the gap between men and women.

“A change in the MELD score is unlikely to fix this problem,” they wrote in an accompanying JAMA Surgery editorial, “but it is not hard to think of solutions; one could imagine, for example, allowing women of small stature to access pediatric livers while ramping up liver splits to increase contributions to the pediatric pool.”

Dr. Naugler and Dr. Orloff went on to suggest that barriers to equity may be culturally insidious.

“It is likely that the same unconscious biases that lead us to pay women surgeons less account for the lack of will to make these simple changes,” they wrote. “Not mentioned are multiple sociocultural elements that favor men over women in organ transplant. ... These realities cannot be fixed with changes to the MELD score, and we must be mindful not to let such notions distract from the essential hard work of creating long-lasting cultural changes that underpin a true path forward.”

The investigators disclosed relationships with Sanofi, Hansa Medical, Natera, and others.

SOURCE: Locke JE et al. JAMA Surg. 2020 May 20. doi: 10.1001/jamasurg.2020.1129.

Addressing local supply constraints may be insufficient to improve poorer outcomes among women who need a liver transplant, based on a large retrospective analysis.

Sex-based disparities in liver allocation were more strongly associated with liver size mismatch and MELD (Model for End-stage Liver Disease) score than geographic factors, reported lead author Jayme E. Locke, MD, of the University of Alabama at Birmingham, and colleagues.

“Currently, the transplant community is considering geographic redistribution ... to redefine local organ supply by replacing donor service areas with fixed concentric circles around donor hospitals,” the investigators wrote in JAMA Surgery. “However, newly proposed geographic models rely on the same metric for medical urgency, the MELD score, and offer no solution for candidates with small body stature who may appear at the top of the match run yet are routinely skipped secondary to discrepancies in donor-recipient size.”

To further investigate the driving forces behind sex-based disparities, the investigators conducted the first national study of its kind, involving 81,357 adults who were wait-listed for liver transplant. Primary outcomes included deceased donor liver transplant and wait list mortality. Using multivariate regression models and inverse odds ratio weighting, the investigators determined proportions of disparity shared across MELD score, candidate anthropometric and liver measurements, and geographic location.

Compared with men, women were 14.4% less likely to receive a transplant, and 8.6% more likely to die on the wait list.

The only geographic factor significantly associated with the increased disparity between female sex and wait list mortality was organ procurement organization, which was associated with a 22% increase. The disparity between rates of transplant receipt was not linked with any geographic factors.

In contrast, MELD score accounted for increases in disparity of 10.3% and 50.1% for organ receipt and wait list mortality, respectively. Candidate anthropometric and liver measurements played an even greater role, raising disparity by 49.0% for organ receipt and 125.8% for wait list mortality.

“Size mismatch between the donor and intended recipient and incorrect assessments of liver disease severity were more strongly associated with the observed sex disparity in wait list mortality than local supply of organs,” the investigators wrote.

Dr. Locke and colleagues noted that ongoing debates about geographic disparity hinge upon the assumption that the MELD score accurately measures disease severity, despite known shortcomings, including reliance upon serum creatinine level, which is influenced by muscle mass and therefore overestimates kidney function in women, and sex-based differences in size, which the MELD score does not incorporate whatsoever.

As such, the investigators suggested that addressing issues with the MELD score and organ size mismatch should be part of a more comprehensive approach to fixing sex-based disparities among candidates for liver transplant.

“Although geographic factors matter, examining geographic access alone may be insufficient,” they concluded.

James F. Markmann, MD, PhD, chief of the division of transplantation at Massachusetts General Hospital, Boston, who has previously published research in support of geographic redistribution, said in an interview that the study by Dr. Locke and colleagues “highlights a well-known problem in the liver transplant field.”

“The cause of this disparity is nicely illustrated by Dr. Locke’s work, which shows multiple contributing factors,” Dr. Markmann said.

While Dr. Markmann agreed with Dr. Locke and colleagues’ proposal that estimated glomerular filtration rate, instead of creatinine, could be used to more accurately measure renal function across sexes, he suggested that the disparities uncovered by their analysis are more likely driven by body size than sex.

“A more impactful factor and one obvious to those performing transplants is that on average the smaller body habitus of females makes more organs unsuitable due to size mismatch,” Dr. Markmann said. “In general, it is technically much less of a barrier to put a small liver into a large patient, than a large liver in a small patient. But, the same disparity in access almost certainly applies to small males; unfortunately, the authors did not examine this point. If allocation changes are envisioned to gain greater fairness in organ access, at least for the recipient size issue, it should be a size issue and not a sex issue.”

Dr. Markmann went on to explain that steps are currently being taken to make liver access more equitable.

“As of February 4th of this year, a broader sharing program for deceased donor livers was implemented,” he said. “This will make more organs available to those in greatest need. It will also potentially increase the number of liver offers to sick patients with a small body habitus and will hopefully reduce the excess morbidity and mortality they suffer.”

According to Willscott E. Naugler, MD and Susan L. Orloff, MD, of Oregon Health & Science University, Portland, novel clinical strategies need to be reinforced with a broader mindset in order to close the gap between men and women.

“A change in the MELD score is unlikely to fix this problem,” they wrote in an accompanying JAMA Surgery editorial, “but it is not hard to think of solutions; one could imagine, for example, allowing women of small stature to access pediatric livers while ramping up liver splits to increase contributions to the pediatric pool.”

Dr. Naugler and Dr. Orloff went on to suggest that barriers to equity may be culturally insidious.

“It is likely that the same unconscious biases that lead us to pay women surgeons less account for the lack of will to make these simple changes,” they wrote. “Not mentioned are multiple sociocultural elements that favor men over women in organ transplant. ... These realities cannot be fixed with changes to the MELD score, and we must be mindful not to let such notions distract from the essential hard work of creating long-lasting cultural changes that underpin a true path forward.”

The investigators disclosed relationships with Sanofi, Hansa Medical, Natera, and others.

SOURCE: Locke JE et al. JAMA Surg. 2020 May 20. doi: 10.1001/jamasurg.2020.1129.

Erythema associated with chronic graft-versus-host disease (GVHD) after allogenic stem cell transplantation is likely to resolve regardless of when it appears, while sclerosis that develops more than 3 months after a chronic GVHD diagnosis is less likely to resolve, according to research presented during a plenary session at the annual meeting of the Society for Investigative Dermatology, held virtually.

In addition, greater improvement in erythema, as measured by body surface area (BSA) in the study was significantly associated with higher patient survival, Laura X. Baker, BS, a medical student at Vanderbilt University, and coinvestigators at Vanderbilt Dermatology Translational Research Clinic in Nashville, Tenn., said in her presentation.

This new significant association between erythema response and survival could inform future studies,” she said. “Our findings highlight the importance of thorough skin exams in chronic GVHD patients.”

Ms. Baker and colleagues performed a prospective, observational study of 242 patients with chronic GVHD and cutaneous manifestations, enrolled in the Chronic GVHD Consortium across nine centers between 2007 and 2012.

Patients had either erythema or sclerosis at the time of enrollment, which was considered incident if erythema or sclerosis appeared less than 3 months after diagnosis of chronic GVHD, or prevalent if erythema or sclerosis appeared 3 months or later after a chronic GVHD diagnosis. All patients were enrolled in the Chronic GVHD Consortium within 3 years of a transplant and were receiving systemic immunosuppressive therapy.

Transplant clinicians examined patients every 6 months, assessing clinical parameters such as skin involvement. Ms. Baker and colleagues used the 2005 National Institutes of Health (NIH) criteria to assess a complete response, a partial response, or no cutaneous response using measurements made by the transplant clinicians. The NIH criteria recommend calculating the change in BSA at the first follow-up visit to determine these changes (Pavletic S et al. Biol Blood Marrow Transplant. 2006 Mar;12[3]:252-66). Researchers also developed a Cox regression model to evaluate overall survival and non-relapse mortality.

Among those with erythema, 133 patients had incident cases and 52 had prevalent cases of cutaneous chronic GVHD. At first follow-up after a finding of cutaneous involvement, the mean BSA was 4.5%, but the median BSA was zero, “meaning that more than half of the patients had complete disappearance of any erythema by the first follow-up,” Ms. Baker said. By the second follow-up visit, 74% of patients with erythema had complete responses, 9% achieved a partial response, and 18% had no response. A similar complete response rate was seen among patients with prevalent cases.

Among patients with sclerosis, there were 43 incident and 47 prevalent cases. Among patients with incident sclerosis, 68% achieved a clear response, 2% a partial response, and 30% no response. But only 28% of those with prevalent sclerosis had a complete response, 4% had a partial response, and 68% had no response.

Most erythema showed a complete response by the first follow-up, and it was not dependent on time from cGVHD diagnosis, Ms. Baker said. However, while most sclerosis within 3 months of cGVHD diagnosis showed a response, sclerosis present beyond the initial 3 months did not generally respond by the first follow-up.

“These findings could inform clinical care and expectations in addition to guiding the selection of outcome measures and endpoint definitions in clinical trials,” she added.

The researchers also looked at overall survival and nonrelapse mortality among patients with incident and prevalent erythema. After adjustment for age and BSA at enrollment, patients with incident cases of erythema with a complete response had significantly better odds of overall survival compared with patients who had no clinical response (hazard ratio, 0.50; 95% confidence interval; 0.25-1.00; P = .05).

Overall survival was greater in patients with prevalent cases of erythema (HR, 0.29; 95% CI, 0.09-0.87; P = .03). Nonrelapse mortality was also significantly lower among prevalent cases with complete or partial clinical response for erythema (HR, 0.19; 95% CI, 0.06-0.64; P = .01).

In a subgroup analysis, 113 patients with incident cases of erythema that had other organ cGVHD had significantly greater overall survival than did patients without a clinical response (HR, 0.20; 95% CI, 0.08-0.46; P < .005). Median survival distance after the first follow-up between patients with and without a clinical response was 28.9 months among incident cases, and 33.7 months among prevalent erythema cases.

“We knew that erythema is not a direct cause of mortality,” Ms. Baker said. Our results suggest the association between erythema response and survival is important and could inform future study.”

The researchers noted their study was limited by transplant clinicians measuring BSA rather than dermatologists, patients being treated at top transplant centers, and their GVHD diagnosis being within 3 years of a transplant, which could limit generalizability of the findings.

This study was funded by a career development award from the U.S. Department of Veterans Affairs and grants from the National Institutes of Health/National Cancer Institute.

SOURCE: Baker L. SID 2020, Abstract 434.

Erythema associated with chronic graft-versus-host disease (GVHD) after allogenic stem cell transplantation is likely to resolve regardless of when it appears, while sclerosis that develops more than 3 months after a chronic GVHD diagnosis is less likely to resolve, according to research presented during a plenary session at the annual meeting of the Society for Investigative Dermatology, held virtually.

In addition, greater improvement in erythema, as measured by body surface area (BSA) in the study was significantly associated with higher patient survival, Laura X. Baker, BS, a medical student at Vanderbilt University, and coinvestigators at Vanderbilt Dermatology Translational Research Clinic in Nashville, Tenn., said in her presentation.

This new significant association between erythema response and survival could inform future studies,” she said. “Our findings highlight the importance of thorough skin exams in chronic GVHD patients.”

Ms. Baker and colleagues performed a prospective, observational study of 242 patients with chronic GVHD and cutaneous manifestations, enrolled in the Chronic GVHD Consortium across nine centers between 2007 and 2012.

Patients had either erythema or sclerosis at the time of enrollment, which was considered incident if erythema or sclerosis appeared less than 3 months after diagnosis of chronic GVHD, or prevalent if erythema or sclerosis appeared 3 months or later after a chronic GVHD diagnosis. All patients were enrolled in the Chronic GVHD Consortium within 3 years of a transplant and were receiving systemic immunosuppressive therapy.

Transplant clinicians examined patients every 6 months, assessing clinical parameters such as skin involvement. Ms. Baker and colleagues used the 2005 National Institutes of Health (NIH) criteria to assess a complete response, a partial response, or no cutaneous response using measurements made by the transplant clinicians. The NIH criteria recommend calculating the change in BSA at the first follow-up visit to determine these changes (Pavletic S et al. Biol Blood Marrow Transplant. 2006 Mar;12[3]:252-66). Researchers also developed a Cox regression model to evaluate overall survival and non-relapse mortality.

Among those with erythema, 133 patients had incident cases and 52 had prevalent cases of cutaneous chronic GVHD. At first follow-up after a finding of cutaneous involvement, the mean BSA was 4.5%, but the median BSA was zero, “meaning that more than half of the patients had complete disappearance of any erythema by the first follow-up,” Ms. Baker said. By the second follow-up visit, 74% of patients with erythema had complete responses, 9% achieved a partial response, and 18% had no response. A similar complete response rate was seen among patients with prevalent cases.

Among patients with sclerosis, there were 43 incident and 47 prevalent cases. Among patients with incident sclerosis, 68% achieved a clear response, 2% a partial response, and 30% no response. But only 28% of those with prevalent sclerosis had a complete response, 4% had a partial response, and 68% had no response.

Most erythema showed a complete response by the first follow-up, and it was not dependent on time from cGVHD diagnosis, Ms. Baker said. However, while most sclerosis within 3 months of cGVHD diagnosis showed a response, sclerosis present beyond the initial 3 months did not generally respond by the first follow-up.

“These findings could inform clinical care and expectations in addition to guiding the selection of outcome measures and endpoint definitions in clinical trials,” she added.

The researchers also looked at overall survival and nonrelapse mortality among patients with incident and prevalent erythema. After adjustment for age and BSA at enrollment, patients with incident cases of erythema with a complete response had significantly better odds of overall survival compared with patients who had no clinical response (hazard ratio, 0.50; 95% confidence interval; 0.25-1.00; P = .05).

Overall survival was greater in patients with prevalent cases of erythema (HR, 0.29; 95% CI, 0.09-0.87; P = .03). Nonrelapse mortality was also significantly lower among prevalent cases with complete or partial clinical response for erythema (HR, 0.19; 95% CI, 0.06-0.64; P = .01).

In a subgroup analysis, 113 patients with incident cases of erythema that had other organ cGVHD had significantly greater overall survival than did patients without a clinical response (HR, 0.20; 95% CI, 0.08-0.46; P < .005). Median survival distance after the first follow-up between patients with and without a clinical response was 28.9 months among incident cases, and 33.7 months among prevalent erythema cases.

“We knew that erythema is not a direct cause of mortality,” Ms. Baker said. Our results suggest the association between erythema response and survival is important and could inform future study.”

The researchers noted their study was limited by transplant clinicians measuring BSA rather than dermatologists, patients being treated at top transplant centers, and their GVHD diagnosis being within 3 years of a transplant, which could limit generalizability of the findings.

This study was funded by a career development award from the U.S. Department of Veterans Affairs and grants from the National Institutes of Health/National Cancer Institute.

SOURCE: Baker L. SID 2020, Abstract 434.

Erythema associated with chronic graft-versus-host disease (GVHD) after allogenic stem cell transplantation is likely to resolve regardless of when it appears, while sclerosis that develops more than 3 months after a chronic GVHD diagnosis is less likely to resolve, according to research presented during a plenary session at the annual meeting of the Society for Investigative Dermatology, held virtually.

In addition, greater improvement in erythema, as measured by body surface area (BSA) in the study was significantly associated with higher patient survival, Laura X. Baker, BS, a medical student at Vanderbilt University, and coinvestigators at Vanderbilt Dermatology Translational Research Clinic in Nashville, Tenn., said in her presentation.

This new significant association between erythema response and survival could inform future studies,” she said. “Our findings highlight the importance of thorough skin exams in chronic GVHD patients.”

Ms. Baker and colleagues performed a prospective, observational study of 242 patients with chronic GVHD and cutaneous manifestations, enrolled in the Chronic GVHD Consortium across nine centers between 2007 and 2012.

Patients had either erythema or sclerosis at the time of enrollment, which was considered incident if erythema or sclerosis appeared less than 3 months after diagnosis of chronic GVHD, or prevalent if erythema or sclerosis appeared 3 months or later after a chronic GVHD diagnosis. All patients were enrolled in the Chronic GVHD Consortium within 3 years of a transplant and were receiving systemic immunosuppressive therapy.

Transplant clinicians examined patients every 6 months, assessing clinical parameters such as skin involvement. Ms. Baker and colleagues used the 2005 National Institutes of Health (NIH) criteria to assess a complete response, a partial response, or no cutaneous response using measurements made by the transplant clinicians. The NIH criteria recommend calculating the change in BSA at the first follow-up visit to determine these changes (Pavletic S et al. Biol Blood Marrow Transplant. 2006 Mar;12[3]:252-66). Researchers also developed a Cox regression model to evaluate overall survival and non-relapse mortality.

Among those with erythema, 133 patients had incident cases and 52 had prevalent cases of cutaneous chronic GVHD. At first follow-up after a finding of cutaneous involvement, the mean BSA was 4.5%, but the median BSA was zero, “meaning that more than half of the patients had complete disappearance of any erythema by the first follow-up,” Ms. Baker said. By the second follow-up visit, 74% of patients with erythema had complete responses, 9% achieved a partial response, and 18% had no response. A similar complete response rate was seen among patients with prevalent cases.

Among patients with sclerosis, there were 43 incident and 47 prevalent cases. Among patients with incident sclerosis, 68% achieved a clear response, 2% a partial response, and 30% no response. But only 28% of those with prevalent sclerosis had a complete response, 4% had a partial response, and 68% had no response.

Most erythema showed a complete response by the first follow-up, and it was not dependent on time from cGVHD diagnosis, Ms. Baker said. However, while most sclerosis within 3 months of cGVHD diagnosis showed a response, sclerosis present beyond the initial 3 months did not generally respond by the first follow-up.

“These findings could inform clinical care and expectations in addition to guiding the selection of outcome measures and endpoint definitions in clinical trials,” she added.

The researchers also looked at overall survival and nonrelapse mortality among patients with incident and prevalent erythema. After adjustment for age and BSA at enrollment, patients with incident cases of erythema with a complete response had significantly better odds of overall survival compared with patients who had no clinical response (hazard ratio, 0.50; 95% confidence interval; 0.25-1.00; P = .05).

Overall survival was greater in patients with prevalent cases of erythema (HR, 0.29; 95% CI, 0.09-0.87; P = .03). Nonrelapse mortality was also significantly lower among prevalent cases with complete or partial clinical response for erythema (HR, 0.19; 95% CI, 0.06-0.64; P = .01).

In a subgroup analysis, 113 patients with incident cases of erythema that had other organ cGVHD had significantly greater overall survival than did patients without a clinical response (HR, 0.20; 95% CI, 0.08-0.46; P < .005). Median survival distance after the first follow-up between patients with and without a clinical response was 28.9 months among incident cases, and 33.7 months among prevalent erythema cases.

“We knew that erythema is not a direct cause of mortality,” Ms. Baker said. Our results suggest the association between erythema response and survival is important and could inform future study.”

The researchers noted their study was limited by transplant clinicians measuring BSA rather than dermatologists, patients being treated at top transplant centers, and their GVHD diagnosis being within 3 years of a transplant, which could limit generalizability of the findings.

This study was funded by a career development award from the U.S. Department of Veterans Affairs and grants from the National Institutes of Health/National Cancer Institute.

SOURCE: Baker L. SID 2020, Abstract 434.