TBD Meeting (5328-19)

HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.

Novartis

These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.

In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).

However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.

Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).


ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.

Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.

In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.

Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.

Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.

“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.

Neurotoxicity

In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).

Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.

Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.

CRS

In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).

Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.

Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
 

Potential modifications

The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.

Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.

“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.

Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”

One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.

Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.

Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.

A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.

“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”

Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.

[email protected]

HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.

Novartis

These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.

In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).

However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.

Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).


ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.

Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.

In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.

Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.

Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.

“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.

Neurotoxicity

In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).

Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.

Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.

CRS

In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).

Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.

Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
 

Potential modifications

The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.

Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.

“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.

Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”

One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.

Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.

Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.

A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.

“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”

Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.

[email protected]

HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.

Novartis

These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.

In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).

However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.

Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).


ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.

Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.

In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.

Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.

Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.

“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.

Neurotoxicity

In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).

Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.

Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.

CRS

In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).

Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.

Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
 

Potential modifications

The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.

Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.

“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.

Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”

One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.

Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.

Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.

A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.

“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”

Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.

[email protected]

HOUSTON – Acute lymphoblastic leukemia patients with measurable residual disease (MRD) negativity prior to hematopoietic cell transplantation achieve better outcomes than do those who are MRD positive, particularly when total body irradiation (TBI)–based conditioning is used, a large retrospective study suggests.

Of 2,780 ALL patients who underwent hematopoietic cell transplantation (HCT) in first or second complete remission (CR), and who were included in the study, 1,816 were MRD negative before transplantation and 964 were MRD positive.

Overall, with follow-up of 40-44 months, MRD positivity was a significant independent predictor of lower overall survival (OS; hazard ratio, 1.19), leukemia-free survival (LFS; HR, 1.26), and higher relapse incidence (RI; 1.51), Arnon Nagler, MD, reported at the Transplantation & Cellular Therapy Meetings.

Conditioning was TBI-based in 76% of the patients; when these patients were compared with those who received chemotherapy-based conditioning, they were found to have better OS, LFS, and RI (HRs, 0.75, 0.70, and 0.60, respectively), said Dr. Nagler, director of both the division of hematology and the bone marrow transplantation and cord blood bank at the Chaim Sheba Medical Center, Tel-Hashomer, and professor of medicine at Tel Aviv University, both in Israel.

“There was no significant interaction between the MRD status and the conditioning,” he said.


On multivariate analysis, MRD positivity was found to be associated with lower OS and LFS (HRs, 1.26 and 1.3), and higher RI (HR, 1.53) in the TBI group, and with higher RI (HR 1.58) in the chemotherapy group, he said. There was no significant association between MRD and other outcomes in this last cohort, he added, noting that TBI-based conditioning was associated with improved OS, LFS, and RI in both MRD-negative and MRD-positive patients.

“MRD is an extremely important prognostic factor for ALL,” he said, noting that its prognostic value in this setting has been established in multiple studies, and that MRD measured at the end of induction is increasingly used to guide further therapy.

However, although MRD detectable immediately before HCT is known to be associated with poor outcomes, it has been unclear if – or to what extent – this differs with different types of conditioning, he added.

“So the aim of this study was to explore if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in adult patients receiving myeloablative conditioning, either TBI or chemotherapy based,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Patients included in the analysis had a median age of 38 years and underwent HCT between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. None received blinatumomab or inotuzumab, Dr. Nagler said, adding that more patients are likely to achieve MRD negativity with these agents.

It will be interesting to see if the prognostic value of MRD will remain as strong with the new agents, and if TBI will be “a strong factor in overall survival and disease-free survival” with modern immunotherapy, he concluded.

The study was conducted on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Dr. Nagler reported having no relevant financial disclosures.

[email protected]

SOURCE: Nagler A et al. TCT 2019, Abstract 7.

HOUSTON – Acute lymphoblastic leukemia patients with measurable residual disease (MRD) negativity prior to hematopoietic cell transplantation achieve better outcomes than do those who are MRD positive, particularly when total body irradiation (TBI)–based conditioning is used, a large retrospective study suggests.

Of 2,780 ALL patients who underwent hematopoietic cell transplantation (HCT) in first or second complete remission (CR), and who were included in the study, 1,816 were MRD negative before transplantation and 964 were MRD positive.

Overall, with follow-up of 40-44 months, MRD positivity was a significant independent predictor of lower overall survival (OS; hazard ratio, 1.19), leukemia-free survival (LFS; HR, 1.26), and higher relapse incidence (RI; 1.51), Arnon Nagler, MD, reported at the Transplantation & Cellular Therapy Meetings.

Conditioning was TBI-based in 76% of the patients; when these patients were compared with those who received chemotherapy-based conditioning, they were found to have better OS, LFS, and RI (HRs, 0.75, 0.70, and 0.60, respectively), said Dr. Nagler, director of both the division of hematology and the bone marrow transplantation and cord blood bank at the Chaim Sheba Medical Center, Tel-Hashomer, and professor of medicine at Tel Aviv University, both in Israel.

“There was no significant interaction between the MRD status and the conditioning,” he said.


On multivariate analysis, MRD positivity was found to be associated with lower OS and LFS (HRs, 1.26 and 1.3), and higher RI (HR, 1.53) in the TBI group, and with higher RI (HR 1.58) in the chemotherapy group, he said. There was no significant association between MRD and other outcomes in this last cohort, he added, noting that TBI-based conditioning was associated with improved OS, LFS, and RI in both MRD-negative and MRD-positive patients.

“MRD is an extremely important prognostic factor for ALL,” he said, noting that its prognostic value in this setting has been established in multiple studies, and that MRD measured at the end of induction is increasingly used to guide further therapy.

However, although MRD detectable immediately before HCT is known to be associated with poor outcomes, it has been unclear if – or to what extent – this differs with different types of conditioning, he added.

“So the aim of this study was to explore if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in adult patients receiving myeloablative conditioning, either TBI or chemotherapy based,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Patients included in the analysis had a median age of 38 years and underwent HCT between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. None received blinatumomab or inotuzumab, Dr. Nagler said, adding that more patients are likely to achieve MRD negativity with these agents.

It will be interesting to see if the prognostic value of MRD will remain as strong with the new agents, and if TBI will be “a strong factor in overall survival and disease-free survival” with modern immunotherapy, he concluded.

The study was conducted on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Dr. Nagler reported having no relevant financial disclosures.

[email protected]

SOURCE: Nagler A et al. TCT 2019, Abstract 7.

HOUSTON – Acute lymphoblastic leukemia patients with measurable residual disease (MRD) negativity prior to hematopoietic cell transplantation achieve better outcomes than do those who are MRD positive, particularly when total body irradiation (TBI)–based conditioning is used, a large retrospective study suggests.

Of 2,780 ALL patients who underwent hematopoietic cell transplantation (HCT) in first or second complete remission (CR), and who were included in the study, 1,816 were MRD negative before transplantation and 964 were MRD positive.

Overall, with follow-up of 40-44 months, MRD positivity was a significant independent predictor of lower overall survival (OS; hazard ratio, 1.19), leukemia-free survival (LFS; HR, 1.26), and higher relapse incidence (RI; 1.51), Arnon Nagler, MD, reported at the Transplantation & Cellular Therapy Meetings.

Conditioning was TBI-based in 76% of the patients; when these patients were compared with those who received chemotherapy-based conditioning, they were found to have better OS, LFS, and RI (HRs, 0.75, 0.70, and 0.60, respectively), said Dr. Nagler, director of both the division of hematology and the bone marrow transplantation and cord blood bank at the Chaim Sheba Medical Center, Tel-Hashomer, and professor of medicine at Tel Aviv University, both in Israel.

“There was no significant interaction between the MRD status and the conditioning,” he said.


On multivariate analysis, MRD positivity was found to be associated with lower OS and LFS (HRs, 1.26 and 1.3), and higher RI (HR, 1.53) in the TBI group, and with higher RI (HR 1.58) in the chemotherapy group, he said. There was no significant association between MRD and other outcomes in this last cohort, he added, noting that TBI-based conditioning was associated with improved OS, LFS, and RI in both MRD-negative and MRD-positive patients.

“MRD is an extremely important prognostic factor for ALL,” he said, noting that its prognostic value in this setting has been established in multiple studies, and that MRD measured at the end of induction is increasingly used to guide further therapy.

However, although MRD detectable immediately before HCT is known to be associated with poor outcomes, it has been unclear if – or to what extent – this differs with different types of conditioning, he added.

“So the aim of this study was to explore if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in adult patients receiving myeloablative conditioning, either TBI or chemotherapy based,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Patients included in the analysis had a median age of 38 years and underwent HCT between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. None received blinatumomab or inotuzumab, Dr. Nagler said, adding that more patients are likely to achieve MRD negativity with these agents.

It will be interesting to see if the prognostic value of MRD will remain as strong with the new agents, and if TBI will be “a strong factor in overall survival and disease-free survival” with modern immunotherapy, he concluded.

The study was conducted on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Dr. Nagler reported having no relevant financial disclosures.

[email protected]

SOURCE: Nagler A et al. TCT 2019, Abstract 7.

HOUSTON – Secondary acute myeloid leukemia (sAML) predicts outcomes after stem cell transplantation in first complete remission, whereas factors such as age, cytogenetics, and performance status are more relevant predictors of outcomes in patients with de novo AML, according to a large, registry-based analysis.

Sharon Worcester/MDedge News

Of 11,439 patients with de novo AML and 1,325 with sAML identified in the registry, 7,691 and 909, respectively, underwent a stem cell transplant (SCT) in first complete remission (CR1), Bipin Savani, MD, said at the Transplantation & Cellular Therapies Meetings.

The 3-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) rates in those who underwent SCT in CR1 were higher in the sAML versus de novo AML groups (35% vs. 28.5% for CIR and 23.4% vs. 16.4% for NRM, respectively), said Dr. Savani, professor of medicine, director of the Long-Term Transplant Clinic, and medical director of the Stem Cell Transplant Processing Laboratory at Vanderbilt University Medical Center & Veterans Affairs Medical Center, Nashville, Tenn.

The 3-year overall survival (OS), leukemia-free survival (LFS), and graft-versus-host disease/relapse-free survival (GRFS) were significantly lower in the sAML group versus the de novo AML group (46.7% vs. 60.8% for OS; 41.6% vs. 55.1% for LFS; and 28.4% vs. 28.6% for GRFS).


Multivariate analysis controlling for risk factors and stratified by disease stage at SCT showed that sAML in CR1 was significantly associated with higher NRM (hazard ratio, 1.32) and CIR (HR, 1.28), and with lower LFS (HR, 1.30), OS (HR, 1.32) and GRFS (HR, 1.20).

Other significant predictors of OS in the model were age, cytogenetics, patient/donor sex combination, Karnofsky performance status (KPS), and donor, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

In the patients who underwent SCT for primary refractory AML (607 with de novo AML and 199 with sAML) or relapsed AML (1,009 with de novo AML and 124 with sAML), the outcomes were generally inferior to those seen with SCT in CR1. However, sAML in those patients did not predict outcomes, Dr. Savani said, noting that outcome in those cases were predicted by age, cytogenetics, and KPS.

In an analysis of 877 pairs matched for age, disease stage at SCT, KPS, conditioning, in vivo/ex vivo T-cell depletion, donor, donor/recipient sex and cytomegalovirus-status combination, cytogenetics, and graft source, the finding that sAML was associated with significantly higher NRM, and lower LFS, OS, and GRFS overall was confirmed.

However, stratification by stage at the time of SCT again showed that the differences between groups were only seen among those transplanted in CR1, and not in those with advanced disease at the time of transplant.

Patients included in the study were adults aged 18 years and older who underwent SCT for de novo or sAML from a matched related, unrelated, or T-cell replete haploidentical donor between 2000 and 2016.

The findings confirm the general belief that the prognosis in AML secondary to another hematologic neoplasia or malignant disease is poorer than that for de novo AML, and clarify the role of this difference for SCT, Dr. Savani said.

“These data may help to improve risk stratification and prognostic estimates after allogeneic hematopoietic cell transplantation for acute myeloid leukemia,” he concluded.

Dr. Savani reported having no financial disclosures.

[email protected]

SOURCE: Savani B et al. TCT 2019, Abstract 12.

HOUSTON – Secondary acute myeloid leukemia (sAML) predicts outcomes after stem cell transplantation in first complete remission, whereas factors such as age, cytogenetics, and performance status are more relevant predictors of outcomes in patients with de novo AML, according to a large, registry-based analysis.

Sharon Worcester/MDedge News

Of 11,439 patients with de novo AML and 1,325 with sAML identified in the registry, 7,691 and 909, respectively, underwent a stem cell transplant (SCT) in first complete remission (CR1), Bipin Savani, MD, said at the Transplantation & Cellular Therapies Meetings.

The 3-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) rates in those who underwent SCT in CR1 were higher in the sAML versus de novo AML groups (35% vs. 28.5% for CIR and 23.4% vs. 16.4% for NRM, respectively), said Dr. Savani, professor of medicine, director of the Long-Term Transplant Clinic, and medical director of the Stem Cell Transplant Processing Laboratory at Vanderbilt University Medical Center & Veterans Affairs Medical Center, Nashville, Tenn.

The 3-year overall survival (OS), leukemia-free survival (LFS), and graft-versus-host disease/relapse-free survival (GRFS) were significantly lower in the sAML group versus the de novo AML group (46.7% vs. 60.8% for OS; 41.6% vs. 55.1% for LFS; and 28.4% vs. 28.6% for GRFS).


Multivariate analysis controlling for risk factors and stratified by disease stage at SCT showed that sAML in CR1 was significantly associated with higher NRM (hazard ratio, 1.32) and CIR (HR, 1.28), and with lower LFS (HR, 1.30), OS (HR, 1.32) and GRFS (HR, 1.20).

Other significant predictors of OS in the model were age, cytogenetics, patient/donor sex combination, Karnofsky performance status (KPS), and donor, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

In the patients who underwent SCT for primary refractory AML (607 with de novo AML and 199 with sAML) or relapsed AML (1,009 with de novo AML and 124 with sAML), the outcomes were generally inferior to those seen with SCT in CR1. However, sAML in those patients did not predict outcomes, Dr. Savani said, noting that outcome in those cases were predicted by age, cytogenetics, and KPS.

In an analysis of 877 pairs matched for age, disease stage at SCT, KPS, conditioning, in vivo/ex vivo T-cell depletion, donor, donor/recipient sex and cytomegalovirus-status combination, cytogenetics, and graft source, the finding that sAML was associated with significantly higher NRM, and lower LFS, OS, and GRFS overall was confirmed.

However, stratification by stage at the time of SCT again showed that the differences between groups were only seen among those transplanted in CR1, and not in those with advanced disease at the time of transplant.

Patients included in the study were adults aged 18 years and older who underwent SCT for de novo or sAML from a matched related, unrelated, or T-cell replete haploidentical donor between 2000 and 2016.

The findings confirm the general belief that the prognosis in AML secondary to another hematologic neoplasia or malignant disease is poorer than that for de novo AML, and clarify the role of this difference for SCT, Dr. Savani said.

“These data may help to improve risk stratification and prognostic estimates after allogeneic hematopoietic cell transplantation for acute myeloid leukemia,” he concluded.

Dr. Savani reported having no financial disclosures.

[email protected]

SOURCE: Savani B et al. TCT 2019, Abstract 12.

HOUSTON – Secondary acute myeloid leukemia (sAML) predicts outcomes after stem cell transplantation in first complete remission, whereas factors such as age, cytogenetics, and performance status are more relevant predictors of outcomes in patients with de novo AML, according to a large, registry-based analysis.

Sharon Worcester/MDedge News

Of 11,439 patients with de novo AML and 1,325 with sAML identified in the registry, 7,691 and 909, respectively, underwent a stem cell transplant (SCT) in first complete remission (CR1), Bipin Savani, MD, said at the Transplantation & Cellular Therapies Meetings.

The 3-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) rates in those who underwent SCT in CR1 were higher in the sAML versus de novo AML groups (35% vs. 28.5% for CIR and 23.4% vs. 16.4% for NRM, respectively), said Dr. Savani, professor of medicine, director of the Long-Term Transplant Clinic, and medical director of the Stem Cell Transplant Processing Laboratory at Vanderbilt University Medical Center & Veterans Affairs Medical Center, Nashville, Tenn.

The 3-year overall survival (OS), leukemia-free survival (LFS), and graft-versus-host disease/relapse-free survival (GRFS) were significantly lower in the sAML group versus the de novo AML group (46.7% vs. 60.8% for OS; 41.6% vs. 55.1% for LFS; and 28.4% vs. 28.6% for GRFS).


Multivariate analysis controlling for risk factors and stratified by disease stage at SCT showed that sAML in CR1 was significantly associated with higher NRM (hazard ratio, 1.32) and CIR (HR, 1.28), and with lower LFS (HR, 1.30), OS (HR, 1.32) and GRFS (HR, 1.20).

Other significant predictors of OS in the model were age, cytogenetics, patient/donor sex combination, Karnofsky performance status (KPS), and donor, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

In the patients who underwent SCT for primary refractory AML (607 with de novo AML and 199 with sAML) or relapsed AML (1,009 with de novo AML and 124 with sAML), the outcomes were generally inferior to those seen with SCT in CR1. However, sAML in those patients did not predict outcomes, Dr. Savani said, noting that outcome in those cases were predicted by age, cytogenetics, and KPS.

In an analysis of 877 pairs matched for age, disease stage at SCT, KPS, conditioning, in vivo/ex vivo T-cell depletion, donor, donor/recipient sex and cytomegalovirus-status combination, cytogenetics, and graft source, the finding that sAML was associated with significantly higher NRM, and lower LFS, OS, and GRFS overall was confirmed.

However, stratification by stage at the time of SCT again showed that the differences between groups were only seen among those transplanted in CR1, and not in those with advanced disease at the time of transplant.

Patients included in the study were adults aged 18 years and older who underwent SCT for de novo or sAML from a matched related, unrelated, or T-cell replete haploidentical donor between 2000 and 2016.

The findings confirm the general belief that the prognosis in AML secondary to another hematologic neoplasia or malignant disease is poorer than that for de novo AML, and clarify the role of this difference for SCT, Dr. Savani said.

“These data may help to improve risk stratification and prognostic estimates after allogeneic hematopoietic cell transplantation for acute myeloid leukemia,” he concluded.

Dr. Savani reported having no financial disclosures.

[email protected]

SOURCE: Savani B et al. TCT 2019, Abstract 12.

HOUSTON – Haploidentical stem cell transplantation (Haplo-HSCT) outperforms chemotherapy for the treatment of adults with acute lymphoblastic leukemia (ALL) in first complete remission, findings from a prospective multicenter trial suggest.

Sharon Worcester/MDedge News

The 2-year leukemia-free survival (LFS) was about 70% in 49 patients in first remission who received haplo-HSCT vs. 40% in 40 patients who received chemotherapy, and 2-year overall survival (OS) was about 80% vs. 50% in the groups, respectively, Meng Lv, MD, PhD, of Peking University People’s Hospital in Beijing reported at the Transplantation & Cellular Therapy Meetings.

“This result is comparable to results of our previous reports,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

He noted that the findings also support those from other institutions.

Study subjects initially included 112 newly diagnosed standard-risk ALL patients aged 18-39 years without high-risk features who achieved complete remission (CR) after one or two cycles of induction. They were consecutively enrolled at five centers in China, including high-volume centers, between July 2014 and June 2017 and were followed for a median of 24.6 months.

Subjects without a suitable HLA-matched sibling donor (MSD) or HLA-matched unrelated donor after two cycles of consolidation with hyper-CVAD chemotherapy were eligible for haplo-HSCT or further hyper-CVAD chemotherapy.

The final analysis included 89 patients after 23 were excluded because of early relapse (6 patients) or a decision to undergo MSD HSCT (16 patients), or unrelated donor-HSCT (1 patient), Dr. Lv said, noting that landmark analysis was used when comparing the outcomes of patients receiving haplo-HSCT with those receiving chemotherapy.

Multivariate analysis with adjustment for a propensity score calculated for each patient showed that treatment (haplo-HSCT vs. chemotherapy) independently predicted LFS (hazard ratio, 0.388), OS (HR, 0.346), and cumulative incidence of relapse (CIR; HR, 0.247). Minimal residual disease (MRD) positivity after the first consolidation was an independent risk factor for LFS (HR, 2.162) and CIR (HR, 3.667). Additionally, diagnosis (T- vs. B-cell) was an independent risk factor for OS (HR, 2.267), Dr. Lv said, adding that nonrelapse mortality was similar in the groups in the propensity score–adjusted analysis.

The findings overall show that haplo-HSCT has variable impact on survival in standard-risk ALL, when compared with traditional chemotherapy, with subgroup analyses showing MRD-positive patients deriving the greatest benefit, he said. Future studies are planned to look more closely at MRD-positive disease and the possible benefits of postponing transplant until the second CR.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Lv reported having no financial disclosures.

[email protected]

SOURCE: Lv M et al. TCT 2019, Abstract 8.

HOUSTON – Haploidentical stem cell transplantation (Haplo-HSCT) outperforms chemotherapy for the treatment of adults with acute lymphoblastic leukemia (ALL) in first complete remission, findings from a prospective multicenter trial suggest.

Sharon Worcester/MDedge News

The 2-year leukemia-free survival (LFS) was about 70% in 49 patients in first remission who received haplo-HSCT vs. 40% in 40 patients who received chemotherapy, and 2-year overall survival (OS) was about 80% vs. 50% in the groups, respectively, Meng Lv, MD, PhD, of Peking University People’s Hospital in Beijing reported at the Transplantation & Cellular Therapy Meetings.

“This result is comparable to results of our previous reports,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

He noted that the findings also support those from other institutions.

Study subjects initially included 112 newly diagnosed standard-risk ALL patients aged 18-39 years without high-risk features who achieved complete remission (CR) after one or two cycles of induction. They were consecutively enrolled at five centers in China, including high-volume centers, between July 2014 and June 2017 and were followed for a median of 24.6 months.

Subjects without a suitable HLA-matched sibling donor (MSD) or HLA-matched unrelated donor after two cycles of consolidation with hyper-CVAD chemotherapy were eligible for haplo-HSCT or further hyper-CVAD chemotherapy.

The final analysis included 89 patients after 23 were excluded because of early relapse (6 patients) or a decision to undergo MSD HSCT (16 patients), or unrelated donor-HSCT (1 patient), Dr. Lv said, noting that landmark analysis was used when comparing the outcomes of patients receiving haplo-HSCT with those receiving chemotherapy.

Multivariate analysis with adjustment for a propensity score calculated for each patient showed that treatment (haplo-HSCT vs. chemotherapy) independently predicted LFS (hazard ratio, 0.388), OS (HR, 0.346), and cumulative incidence of relapse (CIR; HR, 0.247). Minimal residual disease (MRD) positivity after the first consolidation was an independent risk factor for LFS (HR, 2.162) and CIR (HR, 3.667). Additionally, diagnosis (T- vs. B-cell) was an independent risk factor for OS (HR, 2.267), Dr. Lv said, adding that nonrelapse mortality was similar in the groups in the propensity score–adjusted analysis.

The findings overall show that haplo-HSCT has variable impact on survival in standard-risk ALL, when compared with traditional chemotherapy, with subgroup analyses showing MRD-positive patients deriving the greatest benefit, he said. Future studies are planned to look more closely at MRD-positive disease and the possible benefits of postponing transplant until the second CR.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Lv reported having no financial disclosures.

[email protected]

SOURCE: Lv M et al. TCT 2019, Abstract 8.

HOUSTON – Haploidentical stem cell transplantation (Haplo-HSCT) outperforms chemotherapy for the treatment of adults with acute lymphoblastic leukemia (ALL) in first complete remission, findings from a prospective multicenter trial suggest.

Sharon Worcester/MDedge News

The 2-year leukemia-free survival (LFS) was about 70% in 49 patients in first remission who received haplo-HSCT vs. 40% in 40 patients who received chemotherapy, and 2-year overall survival (OS) was about 80% vs. 50% in the groups, respectively, Meng Lv, MD, PhD, of Peking University People’s Hospital in Beijing reported at the Transplantation & Cellular Therapy Meetings.

“This result is comparable to results of our previous reports,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

He noted that the findings also support those from other institutions.

Study subjects initially included 112 newly diagnosed standard-risk ALL patients aged 18-39 years without high-risk features who achieved complete remission (CR) after one or two cycles of induction. They were consecutively enrolled at five centers in China, including high-volume centers, between July 2014 and June 2017 and were followed for a median of 24.6 months.

Subjects without a suitable HLA-matched sibling donor (MSD) or HLA-matched unrelated donor after two cycles of consolidation with hyper-CVAD chemotherapy were eligible for haplo-HSCT or further hyper-CVAD chemotherapy.

The final analysis included 89 patients after 23 were excluded because of early relapse (6 patients) or a decision to undergo MSD HSCT (16 patients), or unrelated donor-HSCT (1 patient), Dr. Lv said, noting that landmark analysis was used when comparing the outcomes of patients receiving haplo-HSCT with those receiving chemotherapy.

Multivariate analysis with adjustment for a propensity score calculated for each patient showed that treatment (haplo-HSCT vs. chemotherapy) independently predicted LFS (hazard ratio, 0.388), OS (HR, 0.346), and cumulative incidence of relapse (CIR; HR, 0.247). Minimal residual disease (MRD) positivity after the first consolidation was an independent risk factor for LFS (HR, 2.162) and CIR (HR, 3.667). Additionally, diagnosis (T- vs. B-cell) was an independent risk factor for OS (HR, 2.267), Dr. Lv said, adding that nonrelapse mortality was similar in the groups in the propensity score–adjusted analysis.

The findings overall show that haplo-HSCT has variable impact on survival in standard-risk ALL, when compared with traditional chemotherapy, with subgroup analyses showing MRD-positive patients deriving the greatest benefit, he said. Future studies are planned to look more closely at MRD-positive disease and the possible benefits of postponing transplant until the second CR.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Lv reported having no financial disclosures.

[email protected]

SOURCE: Lv M et al. TCT 2019, Abstract 8.

HOUSTON – Compared with weight-based dosing, pharmacokinetic-directed therapeutic dose monitoring of busulfan used in combination with cyclophosphamide and etoposide reduced relapse risk in non-Hodgkin lymphoma (NHL) patients undergoing autologous stem cell transplantation (ASCT), according to a review of 336 cases.

Sharon Worcester/MDedge News

This was particularly true in patients with less than a complete response at the time of transplant, Brian T. Hill, MD, PhD, reported at the Transplantation & Cellular Therapy Meetings.

The relapse rate at 24 months after ASCT was 19% in 78 adult NHL patients who underwent ASCT with pharmacokinetic-guided therapeutic dose monitoring (PK-TDM), compared with 38% in 258 patients who received weight-based-dosing (WBD) of busulfan with cyclophosphamide and etoposide.

Progression-free survival (PFS) improved with PK-TDM vs. WBD (69% vs. 55%) but overall survival (OS) did not differ between the groups, most likely because of subsequent therapy given at the time of relapse, said Dr. Hill, director of the lymphoid malignancies program and a staff physician at the Cleveland Clinic Taussig Cancer Institute, Ohio.

The findings are from a retrospective comparison of outcomes in patients treated between 2014 and 2017 when PK-TDM was the standard practice, and patients treated between 2007 and 2013 when fixed weight-based dosing was standard, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“In 2013 we began a program of therapeutic dose monitoring at our site,” Dr. Hill said, explaining that with TDM the goal is to eliminate the low and high levels seen with weight-based dosing, and “to get the maximum number of patients into the therapeutic zone.”

TDM became the preferred approach for busulfan dosing because of the drug’s “unpredictable and widely variable pharmacokinetics,” and ASBMT guidelines now call for consideration of TDM with first-line busulfan to minimize the potential complications, he noted.

“But it’s noteworthy that ... there are really no data to show that TDM can reduce the rates of relapse,” he added.

For this study, WBD busulfan dosing was 2.8 mg/kg every 24 hours on day –9 to –6 of ASCT. For PK-TDM, plasma busulfan concentration was serially determined using a previously described and externally validated in-house liquid chromatography–tandem mass spectrometry assay, he said, explaining that busulfan area under the curve (AUC) after first dose was calculated for each patient and used to adjust subsequent doses to target a daily AUC of 4,500 micromol/min.

To account for baseline differences in the two groups, including a higher number of prior chemotherapy regimens in the WBD group and a higher proportion of aggressive B-cell and T-cell lymphoma in the TDM group, two propensity-matched cohorts of 47 patients each were derived via logistic regression analysis.

“In the propensity-matched cohorts we saw a similar pattern, with therapeutic dose monitoring patients having lower relapse and improved progression-free survival, but no change in the nonrelapse mortality or the overall survival,” Dr. Hill said.

Notably, PFS did not differ between the groups when the researchers looked only at those in complete remission at transplant, but a significant improvement in PFS was seen in the TDM vs. WBD cohorts when they looked only at patients with partial remission, stable disease, or progressive disease (collectively considered as those in less than CR at transplant), he said (P = .79 vs. .08, respectively).

On multivariate analysis, less than CR status was associated with an increased risk of relapse after ASCT (hazard ratio, 2.0), and TDM vs. WBD was associated with a decreased risk of relapse (HR, 0.5).

No differences were seen between the groups with respect to changes in pulmonary or liver function from baseline, or in treatment-related mortality rates, Dr. Hill noted.

The findings support the use of PK-TDM for NHL patients undergoing ASCT with busulfan, but further study is needed, he concluded.

Dr. Hill reported having no relevant financial disclosures.

[email protected]

SOURCE: Hill B et al. TCT 2019, Abstract 39.

HOUSTON – Compared with weight-based dosing, pharmacokinetic-directed therapeutic dose monitoring of busulfan used in combination with cyclophosphamide and etoposide reduced relapse risk in non-Hodgkin lymphoma (NHL) patients undergoing autologous stem cell transplantation (ASCT), according to a review of 336 cases.

Sharon Worcester/MDedge News

This was particularly true in patients with less than a complete response at the time of transplant, Brian T. Hill, MD, PhD, reported at the Transplantation & Cellular Therapy Meetings.

The relapse rate at 24 months after ASCT was 19% in 78 adult NHL patients who underwent ASCT with pharmacokinetic-guided therapeutic dose monitoring (PK-TDM), compared with 38% in 258 patients who received weight-based-dosing (WBD) of busulfan with cyclophosphamide and etoposide.

Progression-free survival (PFS) improved with PK-TDM vs. WBD (69% vs. 55%) but overall survival (OS) did not differ between the groups, most likely because of subsequent therapy given at the time of relapse, said Dr. Hill, director of the lymphoid malignancies program and a staff physician at the Cleveland Clinic Taussig Cancer Institute, Ohio.

The findings are from a retrospective comparison of outcomes in patients treated between 2014 and 2017 when PK-TDM was the standard practice, and patients treated between 2007 and 2013 when fixed weight-based dosing was standard, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“In 2013 we began a program of therapeutic dose monitoring at our site,” Dr. Hill said, explaining that with TDM the goal is to eliminate the low and high levels seen with weight-based dosing, and “to get the maximum number of patients into the therapeutic zone.”

TDM became the preferred approach for busulfan dosing because of the drug’s “unpredictable and widely variable pharmacokinetics,” and ASBMT guidelines now call for consideration of TDM with first-line busulfan to minimize the potential complications, he noted.

“But it’s noteworthy that ... there are really no data to show that TDM can reduce the rates of relapse,” he added.

For this study, WBD busulfan dosing was 2.8 mg/kg every 24 hours on day –9 to –6 of ASCT. For PK-TDM, plasma busulfan concentration was serially determined using a previously described and externally validated in-house liquid chromatography–tandem mass spectrometry assay, he said, explaining that busulfan area under the curve (AUC) after first dose was calculated for each patient and used to adjust subsequent doses to target a daily AUC of 4,500 micromol/min.

To account for baseline differences in the two groups, including a higher number of prior chemotherapy regimens in the WBD group and a higher proportion of aggressive B-cell and T-cell lymphoma in the TDM group, two propensity-matched cohorts of 47 patients each were derived via logistic regression analysis.

“In the propensity-matched cohorts we saw a similar pattern, with therapeutic dose monitoring patients having lower relapse and improved progression-free survival, but no change in the nonrelapse mortality or the overall survival,” Dr. Hill said.

Notably, PFS did not differ between the groups when the researchers looked only at those in complete remission at transplant, but a significant improvement in PFS was seen in the TDM vs. WBD cohorts when they looked only at patients with partial remission, stable disease, or progressive disease (collectively considered as those in less than CR at transplant), he said (P = .79 vs. .08, respectively).

On multivariate analysis, less than CR status was associated with an increased risk of relapse after ASCT (hazard ratio, 2.0), and TDM vs. WBD was associated with a decreased risk of relapse (HR, 0.5).

No differences were seen between the groups with respect to changes in pulmonary or liver function from baseline, or in treatment-related mortality rates, Dr. Hill noted.

The findings support the use of PK-TDM for NHL patients undergoing ASCT with busulfan, but further study is needed, he concluded.

Dr. Hill reported having no relevant financial disclosures.

[email protected]

SOURCE: Hill B et al. TCT 2019, Abstract 39.

HOUSTON – Compared with weight-based dosing, pharmacokinetic-directed therapeutic dose monitoring of busulfan used in combination with cyclophosphamide and etoposide reduced relapse risk in non-Hodgkin lymphoma (NHL) patients undergoing autologous stem cell transplantation (ASCT), according to a review of 336 cases.

Sharon Worcester/MDedge News

This was particularly true in patients with less than a complete response at the time of transplant, Brian T. Hill, MD, PhD, reported at the Transplantation & Cellular Therapy Meetings.

The relapse rate at 24 months after ASCT was 19% in 78 adult NHL patients who underwent ASCT with pharmacokinetic-guided therapeutic dose monitoring (PK-TDM), compared with 38% in 258 patients who received weight-based-dosing (WBD) of busulfan with cyclophosphamide and etoposide.

Progression-free survival (PFS) improved with PK-TDM vs. WBD (69% vs. 55%) but overall survival (OS) did not differ between the groups, most likely because of subsequent therapy given at the time of relapse, said Dr. Hill, director of the lymphoid malignancies program and a staff physician at the Cleveland Clinic Taussig Cancer Institute, Ohio.

The findings are from a retrospective comparison of outcomes in patients treated between 2014 and 2017 when PK-TDM was the standard practice, and patients treated between 2007 and 2013 when fixed weight-based dosing was standard, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“In 2013 we began a program of therapeutic dose monitoring at our site,” Dr. Hill said, explaining that with TDM the goal is to eliminate the low and high levels seen with weight-based dosing, and “to get the maximum number of patients into the therapeutic zone.”

TDM became the preferred approach for busulfan dosing because of the drug’s “unpredictable and widely variable pharmacokinetics,” and ASBMT guidelines now call for consideration of TDM with first-line busulfan to minimize the potential complications, he noted.

“But it’s noteworthy that ... there are really no data to show that TDM can reduce the rates of relapse,” he added.

For this study, WBD busulfan dosing was 2.8 mg/kg every 24 hours on day –9 to –6 of ASCT. For PK-TDM, plasma busulfan concentration was serially determined using a previously described and externally validated in-house liquid chromatography–tandem mass spectrometry assay, he said, explaining that busulfan area under the curve (AUC) after first dose was calculated for each patient and used to adjust subsequent doses to target a daily AUC of 4,500 micromol/min.

To account for baseline differences in the two groups, including a higher number of prior chemotherapy regimens in the WBD group and a higher proportion of aggressive B-cell and T-cell lymphoma in the TDM group, two propensity-matched cohorts of 47 patients each were derived via logistic regression analysis.

“In the propensity-matched cohorts we saw a similar pattern, with therapeutic dose monitoring patients having lower relapse and improved progression-free survival, but no change in the nonrelapse mortality or the overall survival,” Dr. Hill said.

Notably, PFS did not differ between the groups when the researchers looked only at those in complete remission at transplant, but a significant improvement in PFS was seen in the TDM vs. WBD cohorts when they looked only at patients with partial remission, stable disease, or progressive disease (collectively considered as those in less than CR at transplant), he said (P = .79 vs. .08, respectively).

On multivariate analysis, less than CR status was associated with an increased risk of relapse after ASCT (hazard ratio, 2.0), and TDM vs. WBD was associated with a decreased risk of relapse (HR, 0.5).

No differences were seen between the groups with respect to changes in pulmonary or liver function from baseline, or in treatment-related mortality rates, Dr. Hill noted.

The findings support the use of PK-TDM for NHL patients undergoing ASCT with busulfan, but further study is needed, he concluded.

Dr. Hill reported having no relevant financial disclosures.

[email protected]

SOURCE: Hill B et al. TCT 2019, Abstract 39.

HOUSTON – A novel anti-CD45 targeted conditioning regimen is feasible for use in older patients with relapsed or refractory acute myeloid leukemia undergoing transplant, according to preliminary results of a randomized, phase 3 trial.

Treatment with iodine-131 apamistamab (Iomab-B) has thus far has resulted in successful engraftment for all patients who have received it and gone on to transplant, despite active disease and high bone marrow blast burden prior to transplantation, according to Sergio A. Giralt, MD, of Memorial Sloan Kettering Cancer Center, New York.

There has been no nonrelapse mortality related to the novel regimen in the ongoing trial, which compares Iomab-B as targeted conditioning prior to allogeneic hematopoietic stem cell transplant (HCT) with standard of care regimens, Dr. Giralt said in an update on the trial, known as SIERRA.

SIERRA is the only ongoing, randomized, phase 3 clinical trial to offer a transplant option in patients aged 55 years or older with active relapsed or refractory acute myeloid leukemia (AML), Dr. Giralt said at the Transplantation & Cellular Therapy Meetings.

“This is an underserved population in which traditional transplant techniques have very poor results, and there are limited options for patients with active disease,” Dr. Giralt said. “Of note, many transplant centers today do not consider these patients eligible for transplant.”

A total of 150 patients are to be enrolled in SIERRA and randomized either to investigator’s choice of salvage induction chemotherapy including approved targeted agents or to the experimental arm, which consists of an individualized dose of Iomab-B 12 days prior to HCT with fludarabine and total body irradiation as transplant conditioning.

Dr. Giralt presented an update on the first 38 patients in SIERRA, representing 25% of the total enrollment target.

Of 18 patients randomized to Iomab-B and transplanted, the median number of days to absolute neutrophil count engraftment was 13, Dr. Giralt said.

In the control arm, 15 of 19 (79%) failed to achieve complete remission, and of those 10 crossed over to receive Iomab-B and transplant. Days to engraftment, full donor chimerism, and dose delivered to the bone marrow were all similar in the crossover group, compared with those initially randomized to the novel therapy.

Nonhematologic grade 3 or 4 toxicities were similar between the Iomab-B arm and the conventional care arm, and included febrile neutropenia, stomatitis, and other side effects typical for these patients.

There were no grade 3 or 4 Iomab-B infusion-related reactions, and four mild cases of chronic graft-versus-host disease occurred in Iomab-B treated patients.

Nonrelapse mortality was “extremely low” with no cases in the 100 days post transplant in those initially randomized to Iomab-B, and only one case in a crossover patient, Dr. Giralt said.

“These results are encouraging, and can broaden transplant eligibility and improve outcomes,” he added.

The meeting is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

The SIERRA study is supported by Actinium Pharmaceuticals. Dr. Giralt reported disclosures related to Actinium and several other companies.

SOURCE: Giralt SA et al. TCT 2019, Abstract LBA3.

HOUSTON – A novel anti-CD45 targeted conditioning regimen is feasible for use in older patients with relapsed or refractory acute myeloid leukemia undergoing transplant, according to preliminary results of a randomized, phase 3 trial.

Treatment with iodine-131 apamistamab (Iomab-B) has thus far has resulted in successful engraftment for all patients who have received it and gone on to transplant, despite active disease and high bone marrow blast burden prior to transplantation, according to Sergio A. Giralt, MD, of Memorial Sloan Kettering Cancer Center, New York.

There has been no nonrelapse mortality related to the novel regimen in the ongoing trial, which compares Iomab-B as targeted conditioning prior to allogeneic hematopoietic stem cell transplant (HCT) with standard of care regimens, Dr. Giralt said in an update on the trial, known as SIERRA.

SIERRA is the only ongoing, randomized, phase 3 clinical trial to offer a transplant option in patients aged 55 years or older with active relapsed or refractory acute myeloid leukemia (AML), Dr. Giralt said at the Transplantation & Cellular Therapy Meetings.

“This is an underserved population in which traditional transplant techniques have very poor results, and there are limited options for patients with active disease,” Dr. Giralt said. “Of note, many transplant centers today do not consider these patients eligible for transplant.”

A total of 150 patients are to be enrolled in SIERRA and randomized either to investigator’s choice of salvage induction chemotherapy including approved targeted agents or to the experimental arm, which consists of an individualized dose of Iomab-B 12 days prior to HCT with fludarabine and total body irradiation as transplant conditioning.

Dr. Giralt presented an update on the first 38 patients in SIERRA, representing 25% of the total enrollment target.

Of 18 patients randomized to Iomab-B and transplanted, the median number of days to absolute neutrophil count engraftment was 13, Dr. Giralt said.

In the control arm, 15 of 19 (79%) failed to achieve complete remission, and of those 10 crossed over to receive Iomab-B and transplant. Days to engraftment, full donor chimerism, and dose delivered to the bone marrow were all similar in the crossover group, compared with those initially randomized to the novel therapy.

Nonhematologic grade 3 or 4 toxicities were similar between the Iomab-B arm and the conventional care arm, and included febrile neutropenia, stomatitis, and other side effects typical for these patients.

There were no grade 3 or 4 Iomab-B infusion-related reactions, and four mild cases of chronic graft-versus-host disease occurred in Iomab-B treated patients.

Nonrelapse mortality was “extremely low” with no cases in the 100 days post transplant in those initially randomized to Iomab-B, and only one case in a crossover patient, Dr. Giralt said.

“These results are encouraging, and can broaden transplant eligibility and improve outcomes,” he added.

The meeting is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

The SIERRA study is supported by Actinium Pharmaceuticals. Dr. Giralt reported disclosures related to Actinium and several other companies.

SOURCE: Giralt SA et al. TCT 2019, Abstract LBA3.

HOUSTON – A novel anti-CD45 targeted conditioning regimen is feasible for use in older patients with relapsed or refractory acute myeloid leukemia undergoing transplant, according to preliminary results of a randomized, phase 3 trial.

Treatment with iodine-131 apamistamab (Iomab-B) has thus far has resulted in successful engraftment for all patients who have received it and gone on to transplant, despite active disease and high bone marrow blast burden prior to transplantation, according to Sergio A. Giralt, MD, of Memorial Sloan Kettering Cancer Center, New York.

There has been no nonrelapse mortality related to the novel regimen in the ongoing trial, which compares Iomab-B as targeted conditioning prior to allogeneic hematopoietic stem cell transplant (HCT) with standard of care regimens, Dr. Giralt said in an update on the trial, known as SIERRA.

SIERRA is the only ongoing, randomized, phase 3 clinical trial to offer a transplant option in patients aged 55 years or older with active relapsed or refractory acute myeloid leukemia (AML), Dr. Giralt said at the Transplantation & Cellular Therapy Meetings.

“This is an underserved population in which traditional transplant techniques have very poor results, and there are limited options for patients with active disease,” Dr. Giralt said. “Of note, many transplant centers today do not consider these patients eligible for transplant.”

A total of 150 patients are to be enrolled in SIERRA and randomized either to investigator’s choice of salvage induction chemotherapy including approved targeted agents or to the experimental arm, which consists of an individualized dose of Iomab-B 12 days prior to HCT with fludarabine and total body irradiation as transplant conditioning.

Dr. Giralt presented an update on the first 38 patients in SIERRA, representing 25% of the total enrollment target.

Of 18 patients randomized to Iomab-B and transplanted, the median number of days to absolute neutrophil count engraftment was 13, Dr. Giralt said.

In the control arm, 15 of 19 (79%) failed to achieve complete remission, and of those 10 crossed over to receive Iomab-B and transplant. Days to engraftment, full donor chimerism, and dose delivered to the bone marrow were all similar in the crossover group, compared with those initially randomized to the novel therapy.

Nonhematologic grade 3 or 4 toxicities were similar between the Iomab-B arm and the conventional care arm, and included febrile neutropenia, stomatitis, and other side effects typical for these patients.

There were no grade 3 or 4 Iomab-B infusion-related reactions, and four mild cases of chronic graft-versus-host disease occurred in Iomab-B treated patients.

Nonrelapse mortality was “extremely low” with no cases in the 100 days post transplant in those initially randomized to Iomab-B, and only one case in a crossover patient, Dr. Giralt said.

“These results are encouraging, and can broaden transplant eligibility and improve outcomes,” he added.

The meeting is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

The SIERRA study is supported by Actinium Pharmaceuticals. Dr. Giralt reported disclosures related to Actinium and several other companies.

SOURCE: Giralt SA et al. TCT 2019, Abstract LBA3.

HOUSTON – Use of an alemtuzumab/fludarabine conditioning regimen – without any radiation or alkylating agents – was effective in patients with a systemic regenerative disease who experienced myeloid failure after allogeneic transplantation, according to an investigator.

Of the 20 patients with dyskeratosis congenita who received the regimen, 19 achieved primary engraftment within 42 days of transplant, according to Suneet Agarwal, MD, PhD, of Dana-Farber/Boston Children’s Cancer & Blood Disorders Center and Harvard Medical School, Boston.

However, these findings may have broader implications beyond this rare disease, as this is the first reported series of patients undergoing allogeneic bone marrow transplant to achieve durable myeloid engraftment without receiving alkylating agents or radiation, Dr. Agarwal said at the Transplantation & Cellular Therapy Meetings.

In a late-breaking clinical trial presentation of the results, Dr. Agarwal noted that patients in this study all had telomere disease, defined by clinical syndrome, gene mutation, or short lymphocyte telomere length. That’s because the investigators hypothesized that telomere defects would result in a “replicative disadvantage” in hematopoietic and immune cells, which would favor engraftment.

Dyskeratosis congenita is a prototypic telomere biology disorder caused by mutations that impair telomere maintenance, he said, adding that the disease has high rates of cancer, pulmonary disease, and hepatic disease.

While allogeneic transplants are curative in the disorder, outcomes after transplantation are typically poor, with high rates of bone marrow failure, he added. By eliminating radiation and alkylator exposure, the investigators hoped salvage bone marrow transplant would be more feasible, with lower risks of organ failure and secondary malignancy.

The 20 patients Dr. Agarwal reported on were aged from 30 months to 65 years. They all received alemtuzumab/fludarabine conditioning starting at day 9 before bone marrow graft, along with graft-versus-host disease (GVHD) prophylaxis through the pre- to posttransplant period. Two had matched siblings, while 18 had unrelated donors.

Of those 20 patients, 19 achieved primary engraftment at a median of 22 days after transplant, Dr. Agarwal reported. There was no acute GVHD and four cases of chronic GVHD that resolved with oral or topical steroids.

Of the 20 patients, 18 were alive at a median follow-up of 24 months, which compares favorably with historically reported cases, according to the investigator. There was one disease-related death and one treatment-related death caused by fungal infection at 3 months post transplant, he said.

These results suggest the radiation- and alkylator-free conditioning regimen is “effective,” Dr. Agarwal said, adding that exposure to those modalities is not required for myeloid engraftment in certain clinical settings.

The meeting is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Agarwal reported having no conflicts of interest.

SOURCE: Agarwal S et al. TCT 2019, Abstract LBA2.

HOUSTON – Use of an alemtuzumab/fludarabine conditioning regimen – without any radiation or alkylating agents – was effective in patients with a systemic regenerative disease who experienced myeloid failure after allogeneic transplantation, according to an investigator.

Of the 20 patients with dyskeratosis congenita who received the regimen, 19 achieved primary engraftment within 42 days of transplant, according to Suneet Agarwal, MD, PhD, of Dana-Farber/Boston Children’s Cancer & Blood Disorders Center and Harvard Medical School, Boston.

However, these findings may have broader implications beyond this rare disease, as this is the first reported series of patients undergoing allogeneic bone marrow transplant to achieve durable myeloid engraftment without receiving alkylating agents or radiation, Dr. Agarwal said at the Transplantation & Cellular Therapy Meetings.

In a late-breaking clinical trial presentation of the results, Dr. Agarwal noted that patients in this study all had telomere disease, defined by clinical syndrome, gene mutation, or short lymphocyte telomere length. That’s because the investigators hypothesized that telomere defects would result in a “replicative disadvantage” in hematopoietic and immune cells, which would favor engraftment.

Dyskeratosis congenita is a prototypic telomere biology disorder caused by mutations that impair telomere maintenance, he said, adding that the disease has high rates of cancer, pulmonary disease, and hepatic disease.

While allogeneic transplants are curative in the disorder, outcomes after transplantation are typically poor, with high rates of bone marrow failure, he added. By eliminating radiation and alkylator exposure, the investigators hoped salvage bone marrow transplant would be more feasible, with lower risks of organ failure and secondary malignancy.

The 20 patients Dr. Agarwal reported on were aged from 30 months to 65 years. They all received alemtuzumab/fludarabine conditioning starting at day 9 before bone marrow graft, along with graft-versus-host disease (GVHD) prophylaxis through the pre- to posttransplant period. Two had matched siblings, while 18 had unrelated donors.

Of those 20 patients, 19 achieved primary engraftment at a median of 22 days after transplant, Dr. Agarwal reported. There was no acute GVHD and four cases of chronic GVHD that resolved with oral or topical steroids.

Of the 20 patients, 18 were alive at a median follow-up of 24 months, which compares favorably with historically reported cases, according to the investigator. There was one disease-related death and one treatment-related death caused by fungal infection at 3 months post transplant, he said.

These results suggest the radiation- and alkylator-free conditioning regimen is “effective,” Dr. Agarwal said, adding that exposure to those modalities is not required for myeloid engraftment in certain clinical settings.

The meeting is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Agarwal reported having no conflicts of interest.

SOURCE: Agarwal S et al. TCT 2019, Abstract LBA2.

HOUSTON – Use of an alemtuzumab/fludarabine conditioning regimen – without any radiation or alkylating agents – was effective in patients with a systemic regenerative disease who experienced myeloid failure after allogeneic transplantation, according to an investigator.

Of the 20 patients with dyskeratosis congenita who received the regimen, 19 achieved primary engraftment within 42 days of transplant, according to Suneet Agarwal, MD, PhD, of Dana-Farber/Boston Children’s Cancer & Blood Disorders Center and Harvard Medical School, Boston.

However, these findings may have broader implications beyond this rare disease, as this is the first reported series of patients undergoing allogeneic bone marrow transplant to achieve durable myeloid engraftment without receiving alkylating agents or radiation, Dr. Agarwal said at the Transplantation & Cellular Therapy Meetings.

In a late-breaking clinical trial presentation of the results, Dr. Agarwal noted that patients in this study all had telomere disease, defined by clinical syndrome, gene mutation, or short lymphocyte telomere length. That’s because the investigators hypothesized that telomere defects would result in a “replicative disadvantage” in hematopoietic and immune cells, which would favor engraftment.

Dyskeratosis congenita is a prototypic telomere biology disorder caused by mutations that impair telomere maintenance, he said, adding that the disease has high rates of cancer, pulmonary disease, and hepatic disease.

While allogeneic transplants are curative in the disorder, outcomes after transplantation are typically poor, with high rates of bone marrow failure, he added. By eliminating radiation and alkylator exposure, the investigators hoped salvage bone marrow transplant would be more feasible, with lower risks of organ failure and secondary malignancy.

The 20 patients Dr. Agarwal reported on were aged from 30 months to 65 years. They all received alemtuzumab/fludarabine conditioning starting at day 9 before bone marrow graft, along with graft-versus-host disease (GVHD) prophylaxis through the pre- to posttransplant period. Two had matched siblings, while 18 had unrelated donors.

Of those 20 patients, 19 achieved primary engraftment at a median of 22 days after transplant, Dr. Agarwal reported. There was no acute GVHD and four cases of chronic GVHD that resolved with oral or topical steroids.

Of the 20 patients, 18 were alive at a median follow-up of 24 months, which compares favorably with historically reported cases, according to the investigator. There was one disease-related death and one treatment-related death caused by fungal infection at 3 months post transplant, he said.

These results suggest the radiation- and alkylator-free conditioning regimen is “effective,” Dr. Agarwal said, adding that exposure to those modalities is not required for myeloid engraftment in certain clinical settings.

The meeting is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Agarwal reported having no conflicts of interest.

SOURCE: Agarwal S et al. TCT 2019, Abstract LBA2.

HOUSTON – The ROCK2 inhibitor KD025 produced durable and clinically meaningful responses in patients with steroid-dependent or steroid-refractory chronic graft-versus-host disease (cGVHD), according to a speaker at the Transplantation & Cellular Therapy Meetings.

In an ongoing phase 2 trial (NCT02841995), KD025 produced an overall response rate of 59%. Responses occurred in all affected organ systems, and 72% of responders experienced an improvement in Lee Symptom Scale (LSS) score.

The median duration of response was 28 weeks, but durability data are still maturing, according to Madan Jagasia, MBBS, of Vanderbilt University in Nashville, Tenn.

Dr. Jagasia and his colleagues evaluated KD025 in 54 adults who had persistent, active cGVHD after at least 2 months of steroid therapy. Sixty-seven percent of patients had received at least two prior lines of therapy, and 48% had involvement in four or more organs.

KD025 was given at three doses: 200 mg once daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg once daily (cohort 3). Patients also received glucocorticoid therapy, with or without calcineurin inhibitor therapy.

Cohort 1 included 17 patients who had a median age of 50 years (range, 20-63). They received KD025 for a median of 37 weeks, and six patients were still receiving KD025 at last follow-up.

Cohort 2 included 16 patients who had a median age of 55 years (range, 30-75). They received KD025 for a median of 33 weeks, and three patients were still receiving KD025 at last follow-up.

Cohort 3 included 21 patients who had a median age of 46 years (range, 25-75). They received KD025 for a median of 27 weeks, and 11 patients were still receiving KD025 at last follow-up.

The ORR was 59% (32/54) across the study, 65% (11/17) in cohort 1, 63% (10/16) in cohort 2, and 52% (11/21) in cohort 3. Three patients in cohort 3 didn’t reach the first response assessment, so the ORR in response-evaluable patients was 61% (11/18).

The ORR was 58% in patients who had received two or more prior lines of therapy, 55% in patients with severe cGVHD, and 62% in patients who had four or more organs involved.

“Responses were observed across all affected organ systems,” Dr. Jagasia said. “CRs [complete responses] were seen in all organs except the lung, and there were two partial responses observed in the lung.”

The median duration of response was 28 weeks. Eighty-two percent of responders in cohort 1, 50% of responders in cohort 2, and 36% of responders in cohort 3 had responses lasting 20 weeks or more.

“Keep in mind, the median duration of follow-up in cohort 3 is still short, and the durability data will continue to mature,” Dr. Jagasia said.

Most responders (72%) had at least a 7-point reduction in LSS score. Considering responders and nonresponders together, 65% of patients in cohort 1, 56% in cohort 2, and 52% in cohort 3 had an improvement in LSS score.

In all, 69% of patients stopped or reduced their use of steroids or other immunosuppressants. Seven patients completely discontinued steroids.

Forty-four percent of patients (n = 24) had a treatment-related adverse event (AE), but none of these AEs were considered serious. Four percent of patients (n = 2) had a related AE that led to treatment discontinuation, and 15% (n = 8) had grade 3/4 related AEs.

“The AEs were, overall, consistent with those expected in chronic graft-versus-host disease patients receiving corticosteroids,” Dr. Jagasia said. “Most important to note, there was no apparent increased risk of infection. Specifically, there was no CMV [cytomegalovirus] infection.”

The most common AEs were upper respiratory tract infection, fatigue, nausea, AST/ALT increase, and diarrhea. The most common grade 3/4 AEs were gamma-glutamyltransferase increase, hyperglycemia, anemia, and dyspnea.

There were three on-study deaths, all considered unrelated to KD025. One patient died of leukemia relapse, one died of lung infection, and one died of cardiac arrest.

Dr. Jagasia presented these results at the Transplantation & Cellular Therapy Meetings, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: the American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Jagasia reported relationships with Kadmon Holdings, Mallinckrodt, and Janssen. The trial was sponsored by Kadmon Holdings.

[email protected]

SOURCE: Jagasia M et al. TCT 2019, Abstract 36.

HOUSTON – The ROCK2 inhibitor KD025 produced durable and clinically meaningful responses in patients with steroid-dependent or steroid-refractory chronic graft-versus-host disease (cGVHD), according to a speaker at the Transplantation & Cellular Therapy Meetings.

In an ongoing phase 2 trial (NCT02841995), KD025 produced an overall response rate of 59%. Responses occurred in all affected organ systems, and 72% of responders experienced an improvement in Lee Symptom Scale (LSS) score.

The median duration of response was 28 weeks, but durability data are still maturing, according to Madan Jagasia, MBBS, of Vanderbilt University in Nashville, Tenn.

Dr. Jagasia and his colleagues evaluated KD025 in 54 adults who had persistent, active cGVHD after at least 2 months of steroid therapy. Sixty-seven percent of patients had received at least two prior lines of therapy, and 48% had involvement in four or more organs.

KD025 was given at three doses: 200 mg once daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg once daily (cohort 3). Patients also received glucocorticoid therapy, with or without calcineurin inhibitor therapy.

Cohort 1 included 17 patients who had a median age of 50 years (range, 20-63). They received KD025 for a median of 37 weeks, and six patients were still receiving KD025 at last follow-up.

Cohort 2 included 16 patients who had a median age of 55 years (range, 30-75). They received KD025 for a median of 33 weeks, and three patients were still receiving KD025 at last follow-up.

Cohort 3 included 21 patients who had a median age of 46 years (range, 25-75). They received KD025 for a median of 27 weeks, and 11 patients were still receiving KD025 at last follow-up.

The ORR was 59% (32/54) across the study, 65% (11/17) in cohort 1, 63% (10/16) in cohort 2, and 52% (11/21) in cohort 3. Three patients in cohort 3 didn’t reach the first response assessment, so the ORR in response-evaluable patients was 61% (11/18).

The ORR was 58% in patients who had received two or more prior lines of therapy, 55% in patients with severe cGVHD, and 62% in patients who had four or more organs involved.

“Responses were observed across all affected organ systems,” Dr. Jagasia said. “CRs [complete responses] were seen in all organs except the lung, and there were two partial responses observed in the lung.”

The median duration of response was 28 weeks. Eighty-two percent of responders in cohort 1, 50% of responders in cohort 2, and 36% of responders in cohort 3 had responses lasting 20 weeks or more.

“Keep in mind, the median duration of follow-up in cohort 3 is still short, and the durability data will continue to mature,” Dr. Jagasia said.

Most responders (72%) had at least a 7-point reduction in LSS score. Considering responders and nonresponders together, 65% of patients in cohort 1, 56% in cohort 2, and 52% in cohort 3 had an improvement in LSS score.

In all, 69% of patients stopped or reduced their use of steroids or other immunosuppressants. Seven patients completely discontinued steroids.

Forty-four percent of patients (n = 24) had a treatment-related adverse event (AE), but none of these AEs were considered serious. Four percent of patients (n = 2) had a related AE that led to treatment discontinuation, and 15% (n = 8) had grade 3/4 related AEs.

“The AEs were, overall, consistent with those expected in chronic graft-versus-host disease patients receiving corticosteroids,” Dr. Jagasia said. “Most important to note, there was no apparent increased risk of infection. Specifically, there was no CMV [cytomegalovirus] infection.”

The most common AEs were upper respiratory tract infection, fatigue, nausea, AST/ALT increase, and diarrhea. The most common grade 3/4 AEs were gamma-glutamyltransferase increase, hyperglycemia, anemia, and dyspnea.

There were three on-study deaths, all considered unrelated to KD025. One patient died of leukemia relapse, one died of lung infection, and one died of cardiac arrest.

Dr. Jagasia presented these results at the Transplantation & Cellular Therapy Meetings, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: the American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Jagasia reported relationships with Kadmon Holdings, Mallinckrodt, and Janssen. The trial was sponsored by Kadmon Holdings.

[email protected]

SOURCE: Jagasia M et al. TCT 2019, Abstract 36.

HOUSTON – The ROCK2 inhibitor KD025 produced durable and clinically meaningful responses in patients with steroid-dependent or steroid-refractory chronic graft-versus-host disease (cGVHD), according to a speaker at the Transplantation & Cellular Therapy Meetings.

In an ongoing phase 2 trial (NCT02841995), KD025 produced an overall response rate of 59%. Responses occurred in all affected organ systems, and 72% of responders experienced an improvement in Lee Symptom Scale (LSS) score.

The median duration of response was 28 weeks, but durability data are still maturing, according to Madan Jagasia, MBBS, of Vanderbilt University in Nashville, Tenn.

Dr. Jagasia and his colleagues evaluated KD025 in 54 adults who had persistent, active cGVHD after at least 2 months of steroid therapy. Sixty-seven percent of patients had received at least two prior lines of therapy, and 48% had involvement in four or more organs.

KD025 was given at three doses: 200 mg once daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg once daily (cohort 3). Patients also received glucocorticoid therapy, with or without calcineurin inhibitor therapy.

Cohort 1 included 17 patients who had a median age of 50 years (range, 20-63). They received KD025 for a median of 37 weeks, and six patients were still receiving KD025 at last follow-up.

Cohort 2 included 16 patients who had a median age of 55 years (range, 30-75). They received KD025 for a median of 33 weeks, and three patients were still receiving KD025 at last follow-up.

Cohort 3 included 21 patients who had a median age of 46 years (range, 25-75). They received KD025 for a median of 27 weeks, and 11 patients were still receiving KD025 at last follow-up.

The ORR was 59% (32/54) across the study, 65% (11/17) in cohort 1, 63% (10/16) in cohort 2, and 52% (11/21) in cohort 3. Three patients in cohort 3 didn’t reach the first response assessment, so the ORR in response-evaluable patients was 61% (11/18).

The ORR was 58% in patients who had received two or more prior lines of therapy, 55% in patients with severe cGVHD, and 62% in patients who had four or more organs involved.

“Responses were observed across all affected organ systems,” Dr. Jagasia said. “CRs [complete responses] were seen in all organs except the lung, and there were two partial responses observed in the lung.”

The median duration of response was 28 weeks. Eighty-two percent of responders in cohort 1, 50% of responders in cohort 2, and 36% of responders in cohort 3 had responses lasting 20 weeks or more.

“Keep in mind, the median duration of follow-up in cohort 3 is still short, and the durability data will continue to mature,” Dr. Jagasia said.

Most responders (72%) had at least a 7-point reduction in LSS score. Considering responders and nonresponders together, 65% of patients in cohort 1, 56% in cohort 2, and 52% in cohort 3 had an improvement in LSS score.

In all, 69% of patients stopped or reduced their use of steroids or other immunosuppressants. Seven patients completely discontinued steroids.

Forty-four percent of patients (n = 24) had a treatment-related adverse event (AE), but none of these AEs were considered serious. Four percent of patients (n = 2) had a related AE that led to treatment discontinuation, and 15% (n = 8) had grade 3/4 related AEs.

“The AEs were, overall, consistent with those expected in chronic graft-versus-host disease patients receiving corticosteroids,” Dr. Jagasia said. “Most important to note, there was no apparent increased risk of infection. Specifically, there was no CMV [cytomegalovirus] infection.”

The most common AEs were upper respiratory tract infection, fatigue, nausea, AST/ALT increase, and diarrhea. The most common grade 3/4 AEs were gamma-glutamyltransferase increase, hyperglycemia, anemia, and dyspnea.

There were three on-study deaths, all considered unrelated to KD025. One patient died of leukemia relapse, one died of lung infection, and one died of cardiac arrest.

Dr. Jagasia presented these results at the Transplantation & Cellular Therapy Meetings, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: the American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Jagasia reported relationships with Kadmon Holdings, Mallinckrodt, and Janssen. The trial was sponsored by Kadmon Holdings.

[email protected]

SOURCE: Jagasia M et al. TCT 2019, Abstract 36.

HOUSTON – Lentiviral gene therapy appears safe and was potentially effective in a rare primary immunodeficiency disease known as X-linked chronic granulomatous disease, said Donald B. Kohn, MD, of the University of California, Los Angeles.

Seven of nine patients treated were “alive and well” at 12 months’ follow-up after receiving lentiviral vector transduced CD34+ cells, Dr. Kohn reported in a late-breaking clinical trial session at the Transplantation & Cellular Therapy Meetings.

Most patients were able to discontinue antibiotic prophylaxis for this disease, which is associated with severe, recurrent, and prolonged life-threatening infections, he said.

Results of the small study provide “proof of concept” for use of the gene therapy in the disease, though additional studies are needed to formally assess the clinical safety and efficacy of the approach, he said.

The estimated incidence of chronic granulomatous disease is 1 in 200,000 births in the United States, and the X-linked form is most common, occurring in about 60% of patients, Dr. Kohn told attendees of the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Most of these patients are treated with antibacterial or antifungal prophylaxis. While allogeneic hematopoietic stem cell transplantation is also an option, according to Dr. Kohn, the approach is limited by a lack of matched donors and graft-versus-host disease.

Dr. Kohn reported results for nine patients in the United States and the United Kingdom who were treated with the same G1XCGD lentiviral vector. The patients, who ranged in age from 2 to 27 years, underwent CD34+ cell mobilization or bone marrow isolation, transduction with the lentiviral vector, busulfan conditioning, and autologous transplantation.

All patients had confirmed X-linked chronic granulomatous disease, and had had at least one severe infection or inflammatory complication requiring hospitalization.

There were no infusion-related adverse events, and one serious adverse event, which was an inflammatory syndrome that resolved with steroids. Two patients died from complications unrelated to gene therapy, Dr. Kohn reported.

“The other patients are basically doing quite well,” he said.

Of the seven patients alive at the 12-month follow up, six were reported as “clinically well” and off antibiotic prophylaxis, according to Dr. Kohn, while the seventh patient was clinically well and receiving antimicrobial support.

Dr. Kohn is a scientific advisory board member for Orchard Therapeutics, which licensed the lentiviral gene therapy for X-CGD discussed in his presentation. He is also an inventor of intellectual property related to the therapy that UCLA has licensed to Orchard.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

SOURCE: Kohn DB et al. TCT 2019, Abstract LBA1.

HOUSTON – Lentiviral gene therapy appears safe and was potentially effective in a rare primary immunodeficiency disease known as X-linked chronic granulomatous disease, said Donald B. Kohn, MD, of the University of California, Los Angeles.

Seven of nine patients treated were “alive and well” at 12 months’ follow-up after receiving lentiviral vector transduced CD34+ cells, Dr. Kohn reported in a late-breaking clinical trial session at the Transplantation & Cellular Therapy Meetings.

Most patients were able to discontinue antibiotic prophylaxis for this disease, which is associated with severe, recurrent, and prolonged life-threatening infections, he said.

Results of the small study provide “proof of concept” for use of the gene therapy in the disease, though additional studies are needed to formally assess the clinical safety and efficacy of the approach, he said.

The estimated incidence of chronic granulomatous disease is 1 in 200,000 births in the United States, and the X-linked form is most common, occurring in about 60% of patients, Dr. Kohn told attendees of the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Most of these patients are treated with antibacterial or antifungal prophylaxis. While allogeneic hematopoietic stem cell transplantation is also an option, according to Dr. Kohn, the approach is limited by a lack of matched donors and graft-versus-host disease.

Dr. Kohn reported results for nine patients in the United States and the United Kingdom who were treated with the same G1XCGD lentiviral vector. The patients, who ranged in age from 2 to 27 years, underwent CD34+ cell mobilization or bone marrow isolation, transduction with the lentiviral vector, busulfan conditioning, and autologous transplantation.

All patients had confirmed X-linked chronic granulomatous disease, and had had at least one severe infection or inflammatory complication requiring hospitalization.

There were no infusion-related adverse events, and one serious adverse event, which was an inflammatory syndrome that resolved with steroids. Two patients died from complications unrelated to gene therapy, Dr. Kohn reported.

“The other patients are basically doing quite well,” he said.

Of the seven patients alive at the 12-month follow up, six were reported as “clinically well” and off antibiotic prophylaxis, according to Dr. Kohn, while the seventh patient was clinically well and receiving antimicrobial support.

Dr. Kohn is a scientific advisory board member for Orchard Therapeutics, which licensed the lentiviral gene therapy for X-CGD discussed in his presentation. He is also an inventor of intellectual property related to the therapy that UCLA has licensed to Orchard.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

SOURCE: Kohn DB et al. TCT 2019, Abstract LBA1.

HOUSTON – Lentiviral gene therapy appears safe and was potentially effective in a rare primary immunodeficiency disease known as X-linked chronic granulomatous disease, said Donald B. Kohn, MD, of the University of California, Los Angeles.

Seven of nine patients treated were “alive and well” at 12 months’ follow-up after receiving lentiviral vector transduced CD34+ cells, Dr. Kohn reported in a late-breaking clinical trial session at the Transplantation & Cellular Therapy Meetings.

Most patients were able to discontinue antibiotic prophylaxis for this disease, which is associated with severe, recurrent, and prolonged life-threatening infections, he said.

Results of the small study provide “proof of concept” for use of the gene therapy in the disease, though additional studies are needed to formally assess the clinical safety and efficacy of the approach, he said.

The estimated incidence of chronic granulomatous disease is 1 in 200,000 births in the United States, and the X-linked form is most common, occurring in about 60% of patients, Dr. Kohn told attendees of the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Most of these patients are treated with antibacterial or antifungal prophylaxis. While allogeneic hematopoietic stem cell transplantation is also an option, according to Dr. Kohn, the approach is limited by a lack of matched donors and graft-versus-host disease.

Dr. Kohn reported results for nine patients in the United States and the United Kingdom who were treated with the same G1XCGD lentiviral vector. The patients, who ranged in age from 2 to 27 years, underwent CD34+ cell mobilization or bone marrow isolation, transduction with the lentiviral vector, busulfan conditioning, and autologous transplantation.

All patients had confirmed X-linked chronic granulomatous disease, and had had at least one severe infection or inflammatory complication requiring hospitalization.

There were no infusion-related adverse events, and one serious adverse event, which was an inflammatory syndrome that resolved with steroids. Two patients died from complications unrelated to gene therapy, Dr. Kohn reported.

“The other patients are basically doing quite well,” he said.

Of the seven patients alive at the 12-month follow up, six were reported as “clinically well” and off antibiotic prophylaxis, according to Dr. Kohn, while the seventh patient was clinically well and receiving antimicrobial support.

Dr. Kohn is a scientific advisory board member for Orchard Therapeutics, which licensed the lentiviral gene therapy for X-CGD discussed in his presentation. He is also an inventor of intellectual property related to the therapy that UCLA has licensed to Orchard.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

SOURCE: Kohn DB et al. TCT 2019, Abstract LBA1.

HOUSTON – Allogeneic hematopoietic stem cell transplantation (allo-HCT) following a novel reduced-intensity conditioning regimen was largely successful in a heterogeneous cohort of 29 adults and children with primary immunodeficiency in a prospective clinical trial.

Sharon Worcester/MDedge News

At 1 year after transplant, overall survival was 98% and the estimated graft failure–free and graft-versus-host disease (GVHD)–free survival was 82% among the participants, who had various underlying primary immunodeficiencies (PIDs), Dimana Dimitrova, MD, reported at the Transplantation and Cellular Therapy Meetings.

GVHD-free survival was defined in this National Institutes of Health study as the absence of steroid-refractory grade 3-4 acute GVHD and chronic GVHD, noted Dr. Dimitrova of the NIH.

All patients, including 19 adults and 10 children (median age, 25 years), received a serotherapy-free, radiation-free, reduced-intensity conditioning regimen designed to optimize immune reconstitution, minimize toxicity and GVHD, reduce the risk of infectious complications, and enable successful use of alternative donors.

The conditioning platform included pentostatin on day –11 and day –7 at 4 mg/m² along with 8 days of low-dose cyclophosphamide and 2 days of pharmacokinetically dosed busulfan at 4,600 mmol/min. GVHD prophylaxis included posttransplantation cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus.

All patients received T cell–replete bone marrow or peripheral blood stem cell allografts; 72% received alternative donor grafts, Dr. Dimitrova said.

Two patients died, including one with bacterial sepsis and invasive aspergillosis who died on day +44 and one with presumed viral encephalitis who died on day +110. The patients were high risk overall (median HCT–comorbidity index score of 3, with a range of 0-11), and the two who died had HCT-CI scores of 6 and 8, respectively.

An additional accidental death occurred at 18 months after transplant “in the setting of continued remission, good graft function, and no transplant-related complications,” she said.

Neutrophil recovery occurred at a median of 17 days after transplant; three patients experienced graft failure, including one primary failure with autologous recovery on day +14 and two secondary graft failures.

“Two patients with known underlying difficult-to-engraft diseases required second transplants using different nonmyeloabalative platforms, and nevertheless required donor lymphocyte infusions to avoid threatened secondary graft failure,” she said. “The third patient actually had sufficiently improved infectious disease control and has not needed a second transplant to date.”

Overall GVHD incidence using the novel platform has been extremely low, she said, noting that 14% of patients had grade 2-4 GVHD and 3% had grade 3-4 acute GVHD. There was no steroid-refractory GVHD or chronic GVHD.

Among the infectious complications, other than those that led to the two deaths, were cytomegalovirus reactivation in 7 of 16 patients at risk, BK virus–associated hemorrhagic cystitis in 19 of 22 patients at risk, and a suspected case of viral cardiomyopathy that ultimately resolved.

“Importantly, although many patients had Epstein-Barr virus [EBV] control issues prior to transplant, no patients received preemptive EBV-directed therapy, and no patients had EBV-PTLD [posttransplant lymphoproliferative disorder],” she said.

Additionally, blood stream infections were detected in five patients, there were two cases of confirmed aspergillosis, and one child developed cutaneous candidiasis. Other complications and toxicities appeared to relate to underlying pretransplant issues in the affected organ or exuberant immune responses to existing infection.

“Phenotype reversal was evident to some degree in all evaluable patients, even in those with mixed chimerism or unknown underlying genetic defect,” Dr. Dimitrova said.

All 10 patients with malignancy or lymphoproliferative disease as an additional indication for allo-HCT remain in remission, and most patients who required immunoglobulin replacement therapy prior to transplant have been able to discontinue it, she noted.

The findings of this study are of note, because while it has been known for decades that allo-HCT is a potentially curative therapy for patients with PIDs that arise from defects in cells of hematopoietic origin, it frequently fails because of complicating factors or is not an option, Dr. Dimitrova said.

“These patients will often enter transplant with multiple comorbidities and disease sequelae, particularly as diagnosis of PIDs increases in older children and adults following years of illness,” she explained, adding that related donor options may be limited if family members are also affected.

For this reason, and with the goal of improving access to allo-HCT to all who require it, the novel conditioning platform used in this study was developed.

The platform was well tolerated overall, Dr. Dimitrova said, emphasizing the “notably low” GVHD rates.

“Currently we are investigating reduced MMF with the goal of promoting earlier immune reconstitution, and a separate protocol has opened that includes several modifications to this platform aimed at patients with increased risk of graft failure who may not tolerate mixed chimerism early on,” she said, noting that both protocols are currently enrolling.

The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Dimitrova reported having no financial disclosures.

[email protected]

SOURCE: Dimitrova D et al. TCT 2019, Abstract 54.

HOUSTON – Allogeneic hematopoietic stem cell transplantation (allo-HCT) following a novel reduced-intensity conditioning regimen was largely successful in a heterogeneous cohort of 29 adults and children with primary immunodeficiency in a prospective clinical trial.

Sharon Worcester/MDedge News

At 1 year after transplant, overall survival was 98% and the estimated graft failure–free and graft-versus-host disease (GVHD)–free survival was 82% among the participants, who had various underlying primary immunodeficiencies (PIDs), Dimana Dimitrova, MD, reported at the Transplantation and Cellular Therapy Meetings.

GVHD-free survival was defined in this National Institutes of Health study as the absence of steroid-refractory grade 3-4 acute GVHD and chronic GVHD, noted Dr. Dimitrova of the NIH.

All patients, including 19 adults and 10 children (median age, 25 years), received a serotherapy-free, radiation-free, reduced-intensity conditioning regimen designed to optimize immune reconstitution, minimize toxicity and GVHD, reduce the risk of infectious complications, and enable successful use of alternative donors.

The conditioning platform included pentostatin on day –11 and day –7 at 4 mg/m² along with 8 days of low-dose cyclophosphamide and 2 days of pharmacokinetically dosed busulfan at 4,600 mmol/min. GVHD prophylaxis included posttransplantation cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus.

All patients received T cell–replete bone marrow or peripheral blood stem cell allografts; 72% received alternative donor grafts, Dr. Dimitrova said.

Two patients died, including one with bacterial sepsis and invasive aspergillosis who died on day +44 and one with presumed viral encephalitis who died on day +110. The patients were high risk overall (median HCT–comorbidity index score of 3, with a range of 0-11), and the two who died had HCT-CI scores of 6 and 8, respectively.

An additional accidental death occurred at 18 months after transplant “in the setting of continued remission, good graft function, and no transplant-related complications,” she said.

Neutrophil recovery occurred at a median of 17 days after transplant; three patients experienced graft failure, including one primary failure with autologous recovery on day +14 and two secondary graft failures.

“Two patients with known underlying difficult-to-engraft diseases required second transplants using different nonmyeloabalative platforms, and nevertheless required donor lymphocyte infusions to avoid threatened secondary graft failure,” she said. “The third patient actually had sufficiently improved infectious disease control and has not needed a second transplant to date.”

Overall GVHD incidence using the novel platform has been extremely low, she said, noting that 14% of patients had grade 2-4 GVHD and 3% had grade 3-4 acute GVHD. There was no steroid-refractory GVHD or chronic GVHD.

Among the infectious complications, other than those that led to the two deaths, were cytomegalovirus reactivation in 7 of 16 patients at risk, BK virus–associated hemorrhagic cystitis in 19 of 22 patients at risk, and a suspected case of viral cardiomyopathy that ultimately resolved.

“Importantly, although many patients had Epstein-Barr virus [EBV] control issues prior to transplant, no patients received preemptive EBV-directed therapy, and no patients had EBV-PTLD [posttransplant lymphoproliferative disorder],” she said.

Additionally, blood stream infections were detected in five patients, there were two cases of confirmed aspergillosis, and one child developed cutaneous candidiasis. Other complications and toxicities appeared to relate to underlying pretransplant issues in the affected organ or exuberant immune responses to existing infection.

“Phenotype reversal was evident to some degree in all evaluable patients, even in those with mixed chimerism or unknown underlying genetic defect,” Dr. Dimitrova said.

All 10 patients with malignancy or lymphoproliferative disease as an additional indication for allo-HCT remain in remission, and most patients who required immunoglobulin replacement therapy prior to transplant have been able to discontinue it, she noted.

The findings of this study are of note, because while it has been known for decades that allo-HCT is a potentially curative therapy for patients with PIDs that arise from defects in cells of hematopoietic origin, it frequently fails because of complicating factors or is not an option, Dr. Dimitrova said.

“These patients will often enter transplant with multiple comorbidities and disease sequelae, particularly as diagnosis of PIDs increases in older children and adults following years of illness,” she explained, adding that related donor options may be limited if family members are also affected.

For this reason, and with the goal of improving access to allo-HCT to all who require it, the novel conditioning platform used in this study was developed.

The platform was well tolerated overall, Dr. Dimitrova said, emphasizing the “notably low” GVHD rates.

“Currently we are investigating reduced MMF with the goal of promoting earlier immune reconstitution, and a separate protocol has opened that includes several modifications to this platform aimed at patients with increased risk of graft failure who may not tolerate mixed chimerism early on,” she said, noting that both protocols are currently enrolling.

The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Dimitrova reported having no financial disclosures.

[email protected]

SOURCE: Dimitrova D et al. TCT 2019, Abstract 54.

HOUSTON – Allogeneic hematopoietic stem cell transplantation (allo-HCT) following a novel reduced-intensity conditioning regimen was largely successful in a heterogeneous cohort of 29 adults and children with primary immunodeficiency in a prospective clinical trial.

Sharon Worcester/MDedge News

At 1 year after transplant, overall survival was 98% and the estimated graft failure–free and graft-versus-host disease (GVHD)–free survival was 82% among the participants, who had various underlying primary immunodeficiencies (PIDs), Dimana Dimitrova, MD, reported at the Transplantation and Cellular Therapy Meetings.

GVHD-free survival was defined in this National Institutes of Health study as the absence of steroid-refractory grade 3-4 acute GVHD and chronic GVHD, noted Dr. Dimitrova of the NIH.

All patients, including 19 adults and 10 children (median age, 25 years), received a serotherapy-free, radiation-free, reduced-intensity conditioning regimen designed to optimize immune reconstitution, minimize toxicity and GVHD, reduce the risk of infectious complications, and enable successful use of alternative donors.

The conditioning platform included pentostatin on day –11 and day –7 at 4 mg/m² along with 8 days of low-dose cyclophosphamide and 2 days of pharmacokinetically dosed busulfan at 4,600 mmol/min. GVHD prophylaxis included posttransplantation cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus.

All patients received T cell–replete bone marrow or peripheral blood stem cell allografts; 72% received alternative donor grafts, Dr. Dimitrova said.

Two patients died, including one with bacterial sepsis and invasive aspergillosis who died on day +44 and one with presumed viral encephalitis who died on day +110. The patients were high risk overall (median HCT–comorbidity index score of 3, with a range of 0-11), and the two who died had HCT-CI scores of 6 and 8, respectively.

An additional accidental death occurred at 18 months after transplant “in the setting of continued remission, good graft function, and no transplant-related complications,” she said.

Neutrophil recovery occurred at a median of 17 days after transplant; three patients experienced graft failure, including one primary failure with autologous recovery on day +14 and two secondary graft failures.

“Two patients with known underlying difficult-to-engraft diseases required second transplants using different nonmyeloabalative platforms, and nevertheless required donor lymphocyte infusions to avoid threatened secondary graft failure,” she said. “The third patient actually had sufficiently improved infectious disease control and has not needed a second transplant to date.”

Overall GVHD incidence using the novel platform has been extremely low, she said, noting that 14% of patients had grade 2-4 GVHD and 3% had grade 3-4 acute GVHD. There was no steroid-refractory GVHD or chronic GVHD.

Among the infectious complications, other than those that led to the two deaths, were cytomegalovirus reactivation in 7 of 16 patients at risk, BK virus–associated hemorrhagic cystitis in 19 of 22 patients at risk, and a suspected case of viral cardiomyopathy that ultimately resolved.

“Importantly, although many patients had Epstein-Barr virus [EBV] control issues prior to transplant, no patients received preemptive EBV-directed therapy, and no patients had EBV-PTLD [posttransplant lymphoproliferative disorder],” she said.

Additionally, blood stream infections were detected in five patients, there were two cases of confirmed aspergillosis, and one child developed cutaneous candidiasis. Other complications and toxicities appeared to relate to underlying pretransplant issues in the affected organ or exuberant immune responses to existing infection.

“Phenotype reversal was evident to some degree in all evaluable patients, even in those with mixed chimerism or unknown underlying genetic defect,” Dr. Dimitrova said.

All 10 patients with malignancy or lymphoproliferative disease as an additional indication for allo-HCT remain in remission, and most patients who required immunoglobulin replacement therapy prior to transplant have been able to discontinue it, she noted.

The findings of this study are of note, because while it has been known for decades that allo-HCT is a potentially curative therapy for patients with PIDs that arise from defects in cells of hematopoietic origin, it frequently fails because of complicating factors or is not an option, Dr. Dimitrova said.

“These patients will often enter transplant with multiple comorbidities and disease sequelae, particularly as diagnosis of PIDs increases in older children and adults following years of illness,” she explained, adding that related donor options may be limited if family members are also affected.

For this reason, and with the goal of improving access to allo-HCT to all who require it, the novel conditioning platform used in this study was developed.

The platform was well tolerated overall, Dr. Dimitrova said, emphasizing the “notably low” GVHD rates.

“Currently we are investigating reduced MMF with the goal of promoting earlier immune reconstitution, and a separate protocol has opened that includes several modifications to this platform aimed at patients with increased risk of graft failure who may not tolerate mixed chimerism early on,” she said, noting that both protocols are currently enrolling.

The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Dimitrova reported having no financial disclosures.

[email protected]

SOURCE: Dimitrova D et al. TCT 2019, Abstract 54.