ASH 2018

SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.

137680_Maude_Shannon_web.jpg

Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.

The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).

Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.

[embed:render:related:node:157494]

Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.

Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”

However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”

[embed:render:related:node:87963]

Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.

“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.

The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.

[embed:render:related:node:168292]

Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.

“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.

These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.

Dr. Maude reported financial ties to Novartis.

sworcester@mdedge.com

SOURCE: Li AM et al. ASH 2018, Abstract 556.

SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.

137680_Maude_Shannon_web.jpg

Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.

The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).

Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.

[embed:render:related:node:157494]

Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.

Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”

However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”

[embed:render:related:node:87963]

Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.

“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.

The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.

[embed:render:related:node:168292]

Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.

“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.

These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.

Dr. Maude reported financial ties to Novartis.

sworcester@mdedge.com

SOURCE: Li AM et al. ASH 2018, Abstract 556.

SAN DIEGO – Checkpoint inhibition can be used safely and effectively with CD19-directed chimeric antigen receptor (CAR) T-cell therapy in children with relapsed B-cell acute lymphoblastic leukemia (ALL), and it may bolster CAR T-cell effects and persistence, suggest the findings in a series of 14 patients at the Children’s Hospital of Philadelphia.

137680_Maude_Shannon_web.jpg

Combined programmed death-1 (PD-1) blockade and CAR T-cell therapy appeared to have particular benefit in patients with early B-cell recovery and in those with bulky extramedullary disease, Shannon Maude, MD, PhD, reported during a press conference at the annual meeting of the American Society of Hematology.

The patients, aged 4-17 years with heavily pretreated relapsed B-ALL (13 patients) or B lymphoblastic lymphoma (1 patient), were treated with CD19-directed CAR T-cell therapy, including CTL019 in 4 patients and CTL119 in 10 patients, followed by pembrolizumab (in 13 patients) or nivolumab (in 1 patient).

Six patients received the combination therapy because of early B-cell recovery after initial CAR T-cell infusion, four patients had relapsed or refractory (R/R) bulky extramedullary disease, and four patients had failed to respond or relapsed after initial CAR T-cell therapy.

[embed:render:related:node:157494]

Three of the six with poor persistence of response reestablished B-cell aplasia (a reflection of CAR T-cell function) after reinfusion of the CAR T-cell product followed by infusion with PD-1 blockade, and they have “sustained CR [complete response] with B-cell aplasia, showing continued persistence of their CAR T cells,” said Dr. Maude, an attending physician in the Cancer Center at Children’s Hospital of Philadelphia.

Of the four patients with R/R bulky extramedullary disease, two patients had a partial response and two patients had CR, she said, explaining that it was hypothesized that the “PD-1 checkpoint pathway may be activated through the microenvironment in that extramedullary situation.”

However, all four patients who had partial or no response to initial CAR T-cell therapy progressed after PD-1 administration, she said, noting that “in one patient, this progression was marked by reduced CD19 expression, which was probably the mode of escape from CD19 CAR T cells.”

[embed:render:related:node:87963]

Prior studies have shown that patients who respond to CAR T-cell therapy have persistence of CD19 CAR T cells, whereas those with loss of CD19 CAR T cells within 6 months of infusion have a higher rate of relapse, Dr. Maude explained.

“Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, that one such pathway – PD-1 – may be involved in early loss of CD19 CAR T cells and therefore that the combination [of CD19 CAR T-cell therapy] with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence,” she said.

The combined approach was well tolerated in this study, she said, noting that mild cytokine release syndrome symptoms and fever typical of CAR T-cell proliferative responses were observed in three patients within 2 days of starting pembrolizumab.

[embed:render:related:node:168292]

Other adverse effects associated with PD-1 inhibition, including acute pancreatitis, hypothyroidism, arthralgias, and urticaria, occurred in one patient each. There were four cases of grade 3-4 cytopenias that were deemed tolerable or reversible upon discontinuation.

“We show that PD-1 checkpoint inhibitors can be safely combined with CD19 CAR T-cell therapy and that this mechanism may be useful to improve CAR T-cell persistence,” Dr. Maude said.

These findings, which showed particular benefit in patients with poor persistence marked by early B-cell recovery and in those with R/R bulky extramedullary disease, should help inform future use of checkpoint inhibitors after CAR T-cell therapy, she added.

Dr. Maude reported financial ties to Novartis.

sworcester@mdedge.com

SOURCE: Li AM et al. ASH 2018, Abstract 556.

SAN DIEGO – Minimal residual disease (MRD) response at the end of induction correlates with outcomes in previously untreated follicular lymphoma patients who receive obinutuzumab- or rituximab-based immunochemotherapy, according to updated results from the phase 3 GALLIUM study.

After 57 months of follow-up, and regardless of treatment arm, 564 MRD-evaluable patients who were MRD negative at the end of induction had significantly greater probability of progression-free survival (PFS) than did 70 patients who were MRD positive at the end of induction (about 80% vs. 50%; hazard ratio, 0.38), Christiane Pott, MD, reported at the annual meeting of the American Society of Hematology.

GALLIUM participants were adults with follicular lymphoma requiring treatment. They were randomized to receive standard chemotherapy in combination with 6-8 cycles of either intravenous obinutuzumab at a dose of 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of the remaining cycles or intravenous rituximab at a dose of 375mg/m² on day 1 of each cycle. Responders in each group received their assigned antibody as maintenance every 2 months for up to 2 years, said Dr. Pott, of University Hospital of Schleswig‐Holstein, Kiel, Germany.

Of 324 MRD-evaluable patients in the obinutuzumab arm who continued on maintenance treatment, 300 (92.6%) were MRD-negative at the end of induction, compared with 264 of 310 (85.2%) in the rituximab arm.

The majority of the MRD-negative patients remained negative during maintenance, including 67% of patients receiving obinutuzumab and 63.2% of patient receiving rituximab, she said. There was no difference seen in the relapse rate between groups – 6.3% vs. 6.1%, respectively.

The rate of disease progression or death was 11.4% in the obinutuzumab arm and 15.5% in the rituximab arm.

Additionally, 24 patients in the obinutuzumab arm and 46 in the rituximab arm were MRD positive at the end of induction but were eligible for maintenance therapy based on clinical response; of these, 22 (92%) and 36 (78%), respectively, achieved MRD negativity during maintenance, with 18 and 27 patients in the arms, respectively, achieving MRD negativity within the first 4 months of maintenance therapy, she said.

[embed:render:related:node:189200]

Of the 12 patients who never achieved an MRD response, 8 progressed or died within 7 months after the end of induction, 1 progressed after 15 months, 1 progressed after 26 months, and 2 remained MRD positive during maintenance up to month 8 and month 12, respectively, but had no documented tumor progression until day 1,348 and day 1,709.

“MRD status reflects the depth of response to treatment and provides insight regarding prognosis after first-line therapy in patients with follicular lymphoma,” Dr. Pott said in an interview, adding that “the findings of the current analysis demonstrate the prognostic value of MRD response assessments in previously untreated follicular lymphoma patients receiving immunochemotherapy.”

Further, the finding that a majority of patients who were MRD positive at the end of induction achieved MRD negativity during the first 4 months of maintenance is likely indicative of the efficacy of continued treatment, and it also suggests that response kinetics can be slower than in patients with an early MRD response at midinduction, she said.

“Also, responses that are beyond the sensitivity of the MRD assay may be less deep,” she added, noting that patients who failed to achieve MRD negativity at the end of induction or during early maintenance had a high chance of experiencing early progression or death.

The findings have implications for individualized treatment based on patient response, as well as for future clinical trial design, she said.

For example, MRD status could allow for earlier identification of patients with poor prognosis who aren’t likely to benefit from maintenance therapy. In clinical trials, it could be used to assess the efficiency of new treatments and to stratify patients based on the likelihood of response, allowing for the evaluation of different treatments in those groups, she explained.

“That would be a very important step in the direction of tailored therapies,” she said, adding that patients with follicular lymphoma tend to have very long PFS, and earlier outcomes parameters or tools beyond clinical parameters for assessing treatment efficiency are needed.

“I hope that future trials will address MRD-based treatment stratification as the adverse prognosis we detect by residual disease might be overcome by an MRD-based switch of patients to more effective and efficient treatments, including novel drugs,” she said.

The GALLIUM study is supported by F. Hoffmann–La Roche. Dr. Pott reported having no financial disclosures.

sworcester@mdedge.com

SOURCE: Pott C et al. ASH 2018, Abstract 396.

SAN DIEGO – Minimal residual disease (MRD) response at the end of induction correlates with outcomes in previously untreated follicular lymphoma patients who receive obinutuzumab- or rituximab-based immunochemotherapy, according to updated results from the phase 3 GALLIUM study.

After 57 months of follow-up, and regardless of treatment arm, 564 MRD-evaluable patients who were MRD negative at the end of induction had significantly greater probability of progression-free survival (PFS) than did 70 patients who were MRD positive at the end of induction (about 80% vs. 50%; hazard ratio, 0.38), Christiane Pott, MD, reported at the annual meeting of the American Society of Hematology.

GALLIUM participants were adults with follicular lymphoma requiring treatment. They were randomized to receive standard chemotherapy in combination with 6-8 cycles of either intravenous obinutuzumab at a dose of 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of the remaining cycles or intravenous rituximab at a dose of 375mg/m² on day 1 of each cycle. Responders in each group received their assigned antibody as maintenance every 2 months for up to 2 years, said Dr. Pott, of University Hospital of Schleswig‐Holstein, Kiel, Germany.

Of 324 MRD-evaluable patients in the obinutuzumab arm who continued on maintenance treatment, 300 (92.6%) were MRD-negative at the end of induction, compared with 264 of 310 (85.2%) in the rituximab arm.

The majority of the MRD-negative patients remained negative during maintenance, including 67% of patients receiving obinutuzumab and 63.2% of patient receiving rituximab, she said. There was no difference seen in the relapse rate between groups – 6.3% vs. 6.1%, respectively.

The rate of disease progression or death was 11.4% in the obinutuzumab arm and 15.5% in the rituximab arm.

Additionally, 24 patients in the obinutuzumab arm and 46 in the rituximab arm were MRD positive at the end of induction but were eligible for maintenance therapy based on clinical response; of these, 22 (92%) and 36 (78%), respectively, achieved MRD negativity during maintenance, with 18 and 27 patients in the arms, respectively, achieving MRD negativity within the first 4 months of maintenance therapy, she said.

[embed:render:related:node:189200]

Of the 12 patients who never achieved an MRD response, 8 progressed or died within 7 months after the end of induction, 1 progressed after 15 months, 1 progressed after 26 months, and 2 remained MRD positive during maintenance up to month 8 and month 12, respectively, but had no documented tumor progression until day 1,348 and day 1,709.

“MRD status reflects the depth of response to treatment and provides insight regarding prognosis after first-line therapy in patients with follicular lymphoma,” Dr. Pott said in an interview, adding that “the findings of the current analysis demonstrate the prognostic value of MRD response assessments in previously untreated follicular lymphoma patients receiving immunochemotherapy.”

Further, the finding that a majority of patients who were MRD positive at the end of induction achieved MRD negativity during the first 4 months of maintenance is likely indicative of the efficacy of continued treatment, and it also suggests that response kinetics can be slower than in patients with an early MRD response at midinduction, she said.

“Also, responses that are beyond the sensitivity of the MRD assay may be less deep,” she added, noting that patients who failed to achieve MRD negativity at the end of induction or during early maintenance had a high chance of experiencing early progression or death.

The findings have implications for individualized treatment based on patient response, as well as for future clinical trial design, she said.

For example, MRD status could allow for earlier identification of patients with poor prognosis who aren’t likely to benefit from maintenance therapy. In clinical trials, it could be used to assess the efficiency of new treatments and to stratify patients based on the likelihood of response, allowing for the evaluation of different treatments in those groups, she explained.

“That would be a very important step in the direction of tailored therapies,” she said, adding that patients with follicular lymphoma tend to have very long PFS, and earlier outcomes parameters or tools beyond clinical parameters for assessing treatment efficiency are needed.

“I hope that future trials will address MRD-based treatment stratification as the adverse prognosis we detect by residual disease might be overcome by an MRD-based switch of patients to more effective and efficient treatments, including novel drugs,” she said.

The GALLIUM study is supported by F. Hoffmann–La Roche. Dr. Pott reported having no financial disclosures.

sworcester@mdedge.com

SOURCE: Pott C et al. ASH 2018, Abstract 396.

SAN DIEGO – Minimal residual disease (MRD) response at the end of induction correlates with outcomes in previously untreated follicular lymphoma patients who receive obinutuzumab- or rituximab-based immunochemotherapy, according to updated results from the phase 3 GALLIUM study.

After 57 months of follow-up, and regardless of treatment arm, 564 MRD-evaluable patients who were MRD negative at the end of induction had significantly greater probability of progression-free survival (PFS) than did 70 patients who were MRD positive at the end of induction (about 80% vs. 50%; hazard ratio, 0.38), Christiane Pott, MD, reported at the annual meeting of the American Society of Hematology.

GALLIUM participants were adults with follicular lymphoma requiring treatment. They were randomized to receive standard chemotherapy in combination with 6-8 cycles of either intravenous obinutuzumab at a dose of 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of the remaining cycles or intravenous rituximab at a dose of 375mg/m² on day 1 of each cycle. Responders in each group received their assigned antibody as maintenance every 2 months for up to 2 years, said Dr. Pott, of University Hospital of Schleswig‐Holstein, Kiel, Germany.

Of 324 MRD-evaluable patients in the obinutuzumab arm who continued on maintenance treatment, 300 (92.6%) were MRD-negative at the end of induction, compared with 264 of 310 (85.2%) in the rituximab arm.

The majority of the MRD-negative patients remained negative during maintenance, including 67% of patients receiving obinutuzumab and 63.2% of patient receiving rituximab, she said. There was no difference seen in the relapse rate between groups – 6.3% vs. 6.1%, respectively.

The rate of disease progression or death was 11.4% in the obinutuzumab arm and 15.5% in the rituximab arm.

Additionally, 24 patients in the obinutuzumab arm and 46 in the rituximab arm were MRD positive at the end of induction but were eligible for maintenance therapy based on clinical response; of these, 22 (92%) and 36 (78%), respectively, achieved MRD negativity during maintenance, with 18 and 27 patients in the arms, respectively, achieving MRD negativity within the first 4 months of maintenance therapy, she said.

[embed:render:related:node:189200]

Of the 12 patients who never achieved an MRD response, 8 progressed or died within 7 months after the end of induction, 1 progressed after 15 months, 1 progressed after 26 months, and 2 remained MRD positive during maintenance up to month 8 and month 12, respectively, but had no documented tumor progression until day 1,348 and day 1,709.

“MRD status reflects the depth of response to treatment and provides insight regarding prognosis after first-line therapy in patients with follicular lymphoma,” Dr. Pott said in an interview, adding that “the findings of the current analysis demonstrate the prognostic value of MRD response assessments in previously untreated follicular lymphoma patients receiving immunochemotherapy.”

Further, the finding that a majority of patients who were MRD positive at the end of induction achieved MRD negativity during the first 4 months of maintenance is likely indicative of the efficacy of continued treatment, and it also suggests that response kinetics can be slower than in patients with an early MRD response at midinduction, she said.

“Also, responses that are beyond the sensitivity of the MRD assay may be less deep,” she added, noting that patients who failed to achieve MRD negativity at the end of induction or during early maintenance had a high chance of experiencing early progression or death.

The findings have implications for individualized treatment based on patient response, as well as for future clinical trial design, she said.

For example, MRD status could allow for earlier identification of patients with poor prognosis who aren’t likely to benefit from maintenance therapy. In clinical trials, it could be used to assess the efficiency of new treatments and to stratify patients based on the likelihood of response, allowing for the evaluation of different treatments in those groups, she explained.

“That would be a very important step in the direction of tailored therapies,” she said, adding that patients with follicular lymphoma tend to have very long PFS, and earlier outcomes parameters or tools beyond clinical parameters for assessing treatment efficiency are needed.

“I hope that future trials will address MRD-based treatment stratification as the adverse prognosis we detect by residual disease might be overcome by an MRD-based switch of patients to more effective and efficient treatments, including novel drugs,” she said.

The GALLIUM study is supported by F. Hoffmann–La Roche. Dr. Pott reported having no financial disclosures.

sworcester@mdedge.com

SOURCE: Pott C et al. ASH 2018, Abstract 396.

SAN DIEGO – Thrombin generation may edge out baseline factor activity as a biomarker for predicting bleeding severity among patients with mild and moderate hemophilia, according to a study of 81 patients with nonsevere hemophilia.

Both baseline factor activity and thrombin generation had a similar correlation with bleeding severity, but thrombin generation had a higher sensitivity when differentiating between bleeding severities, Fadi Nossair, MD, of Children’s Hospital of King’s Daughters in Norfolk, Va., reported in a poster at the annual meeting of the American Society of Hematology.

Nonsevere cases of hemophilia A and B account for about half of all hemophilia cases in which factor level does not consistently correlate with bleeding phenotype. That makes it difficult to determine prophylaxis or surgery and highlights the need for a predictive biomarker, the investigators noted.

In the study, 81 patients had their bleeding assessed using standardized, self-administered and investigator-administered questionnaires. Bleeding phenotypes were also collected from EMRs.

One-time venous blood samples were collected after a washout period, when applicable. Additionally, platelet poor plasma was obtained to measure thrombin generation, phospholipid-dependent factor Xa initiated clotting time, factor VIII and IX activities, and von Willebrand factor.

Nearly three-quarters of patients in the study had a low bleeding score.

Both baseline factor level and thrombin generation values obtained with a regular reagent (5 pM of tissue factor) demonstrated a significant correlation with bleeding score (P less than .05). Values obtained with other reagents and biomarkers did not show a significant correlation, according to the researchers.

However, a sensitivity and specificity analysis that helped the researchers narrow down the optimal cutoff values for differentiating between bleeding severities also found that thrombin generation had superior sensitivity, compared with baseline factor level. All thrombin generation values had a higher sensitivity to predict bleeding severity, compared with baseline factor level (57%-62% versus 29%).

“Long-term prospective studies should evaluate the utility of this approach in predicting bleeding severity in this population,” the researchers said.

The study was supported by grants from Novo Nordisk. Dr. Nossair reported financial disclosures related to Novo Nordisk.

mschneider@mdedge.com

SOURCE: Nossair F et al. ASH 2018, Poster 3788.

SAN DIEGO – Thrombin generation may edge out baseline factor activity as a biomarker for predicting bleeding severity among patients with mild and moderate hemophilia, according to a study of 81 patients with nonsevere hemophilia.

Both baseline factor activity and thrombin generation had a similar correlation with bleeding severity, but thrombin generation had a higher sensitivity when differentiating between bleeding severities, Fadi Nossair, MD, of Children’s Hospital of King’s Daughters in Norfolk, Va., reported in a poster at the annual meeting of the American Society of Hematology.

Nonsevere cases of hemophilia A and B account for about half of all hemophilia cases in which factor level does not consistently correlate with bleeding phenotype. That makes it difficult to determine prophylaxis or surgery and highlights the need for a predictive biomarker, the investigators noted.

In the study, 81 patients had their bleeding assessed using standardized, self-administered and investigator-administered questionnaires. Bleeding phenotypes were also collected from EMRs.

One-time venous blood samples were collected after a washout period, when applicable. Additionally, platelet poor plasma was obtained to measure thrombin generation, phospholipid-dependent factor Xa initiated clotting time, factor VIII and IX activities, and von Willebrand factor.

Nearly three-quarters of patients in the study had a low bleeding score.

Both baseline factor level and thrombin generation values obtained with a regular reagent (5 pM of tissue factor) demonstrated a significant correlation with bleeding score (P less than .05). Values obtained with other reagents and biomarkers did not show a significant correlation, according to the researchers.

However, a sensitivity and specificity analysis that helped the researchers narrow down the optimal cutoff values for differentiating between bleeding severities also found that thrombin generation had superior sensitivity, compared with baseline factor level. All thrombin generation values had a higher sensitivity to predict bleeding severity, compared with baseline factor level (57%-62% versus 29%).

“Long-term prospective studies should evaluate the utility of this approach in predicting bleeding severity in this population,” the researchers said.

The study was supported by grants from Novo Nordisk. Dr. Nossair reported financial disclosures related to Novo Nordisk.

mschneider@mdedge.com

SOURCE: Nossair F et al. ASH 2018, Poster 3788.

SAN DIEGO – Thrombin generation may edge out baseline factor activity as a biomarker for predicting bleeding severity among patients with mild and moderate hemophilia, according to a study of 81 patients with nonsevere hemophilia.

Both baseline factor activity and thrombin generation had a similar correlation with bleeding severity, but thrombin generation had a higher sensitivity when differentiating between bleeding severities, Fadi Nossair, MD, of Children’s Hospital of King’s Daughters in Norfolk, Va., reported in a poster at the annual meeting of the American Society of Hematology.

Nonsevere cases of hemophilia A and B account for about half of all hemophilia cases in which factor level does not consistently correlate with bleeding phenotype. That makes it difficult to determine prophylaxis or surgery and highlights the need for a predictive biomarker, the investigators noted.

In the study, 81 patients had their bleeding assessed using standardized, self-administered and investigator-administered questionnaires. Bleeding phenotypes were also collected from EMRs.

One-time venous blood samples were collected after a washout period, when applicable. Additionally, platelet poor plasma was obtained to measure thrombin generation, phospholipid-dependent factor Xa initiated clotting time, factor VIII and IX activities, and von Willebrand factor.

Nearly three-quarters of patients in the study had a low bleeding score.

Both baseline factor level and thrombin generation values obtained with a regular reagent (5 pM of tissue factor) demonstrated a significant correlation with bleeding score (P less than .05). Values obtained with other reagents and biomarkers did not show a significant correlation, according to the researchers.

However, a sensitivity and specificity analysis that helped the researchers narrow down the optimal cutoff values for differentiating between bleeding severities also found that thrombin generation had superior sensitivity, compared with baseline factor level. All thrombin generation values had a higher sensitivity to predict bleeding severity, compared with baseline factor level (57%-62% versus 29%).

“Long-term prospective studies should evaluate the utility of this approach in predicting bleeding severity in this population,” the researchers said.

The study was supported by grants from Novo Nordisk. Dr. Nossair reported financial disclosures related to Novo Nordisk.

mschneider@mdedge.com

SOURCE: Nossair F et al. ASH 2018, Poster 3788.

SAN DIEGO – A small study of infants with severe hemophilia A revealed that there are four distinct patient subgroups based on their unique antibody signatures.

hemophilia_a_web.jpg

Bagirath Gangadharan, PhD, and his colleagues reported the results of HIPS, the Hemophilia Inhibitor Previously Untreated Patient Study, in a poster at the annual meeting of the American Society of Hematology.

The findings included data on 23 infants who had a baseline Factor VIII coagulant activity of less than 0.01 IU/mL at enrollment in the study. All patients received a single type of recombinant FVIII replacement therapy (Advate by Baxalta) with the dose, frequency, and regimen at the discretion of the treating physician.

Patients with prior exposure to clotting factor concentrates or blood products, another clinically significant chronic disease, and those participating in another investigational drug study were excluded.

The researchers discovered that patients fell into four distinct subgroups based on their antibody characteristics after 50 days’ exposure to FVIII infusions:

• Subgroup one, which included seven patients, had no detectable FVIII-specific antibodies and no FVIII inhibitors.
• Subgroup two – also made up of seven patients – had FVIII-specific IgG1, no detectable IgG class–switched antibodies, and no FVIII inhibitors.
• The third subgroup included just two patients. These patients had FVIII-specific IgG1, no detectable IgG class–switched antibodies, but low-titer FVIII inhibitors.
• The final subgroup, which had seven patients, had FVIII-specific IgG1, high-affinity IgG class–switched antibodies (IgG3, IgG4, and IgG2), and FVIII inhibitors.

The researchers concluded that high-affinity FVIII-specific class-switched antibodies precede clinical FVIII inhibitor detection, adding to the evidence of their “potential role as suitable predictive biomarkers for inhibitor development.”

The study is funded by Baxalta, a part of Shire. Dr. Gangadharan is employed by Shire and other authors reported financial disclosures related to the study sponsor.

mschneider@mdedge.com

SOURCE: Gangadharan B et al. ASH 2018, Poster 3774.

SAN DIEGO – A small study of infants with severe hemophilia A revealed that there are four distinct patient subgroups based on their unique antibody signatures.

hemophilia_a_web.jpg

Bagirath Gangadharan, PhD, and his colleagues reported the results of HIPS, the Hemophilia Inhibitor Previously Untreated Patient Study, in a poster at the annual meeting of the American Society of Hematology.

The findings included data on 23 infants who had a baseline Factor VIII coagulant activity of less than 0.01 IU/mL at enrollment in the study. All patients received a single type of recombinant FVIII replacement therapy (Advate by Baxalta) with the dose, frequency, and regimen at the discretion of the treating physician.

Patients with prior exposure to clotting factor concentrates or blood products, another clinically significant chronic disease, and those participating in another investigational drug study were excluded.

The researchers discovered that patients fell into four distinct subgroups based on their antibody characteristics after 50 days’ exposure to FVIII infusions:

• Subgroup one, which included seven patients, had no detectable FVIII-specific antibodies and no FVIII inhibitors.
• Subgroup two – also made up of seven patients – had FVIII-specific IgG1, no detectable IgG class–switched antibodies, and no FVIII inhibitors.
• The third subgroup included just two patients. These patients had FVIII-specific IgG1, no detectable IgG class–switched antibodies, but low-titer FVIII inhibitors.
• The final subgroup, which had seven patients, had FVIII-specific IgG1, high-affinity IgG class–switched antibodies (IgG3, IgG4, and IgG2), and FVIII inhibitors.

The researchers concluded that high-affinity FVIII-specific class-switched antibodies precede clinical FVIII inhibitor detection, adding to the evidence of their “potential role as suitable predictive biomarkers for inhibitor development.”

The study is funded by Baxalta, a part of Shire. Dr. Gangadharan is employed by Shire and other authors reported financial disclosures related to the study sponsor.

mschneider@mdedge.com

SOURCE: Gangadharan B et al. ASH 2018, Poster 3774.

SAN DIEGO – A small study of infants with severe hemophilia A revealed that there are four distinct patient subgroups based on their unique antibody signatures.

hemophilia_a_web.jpg

Bagirath Gangadharan, PhD, and his colleagues reported the results of HIPS, the Hemophilia Inhibitor Previously Untreated Patient Study, in a poster at the annual meeting of the American Society of Hematology.

The findings included data on 23 infants who had a baseline Factor VIII coagulant activity of less than 0.01 IU/mL at enrollment in the study. All patients received a single type of recombinant FVIII replacement therapy (Advate by Baxalta) with the dose, frequency, and regimen at the discretion of the treating physician.

Patients with prior exposure to clotting factor concentrates or blood products, another clinically significant chronic disease, and those participating in another investigational drug study were excluded.

The researchers discovered that patients fell into four distinct subgroups based on their antibody characteristics after 50 days’ exposure to FVIII infusions:

• Subgroup one, which included seven patients, had no detectable FVIII-specific antibodies and no FVIII inhibitors.
• Subgroup two – also made up of seven patients – had FVIII-specific IgG1, no detectable IgG class–switched antibodies, and no FVIII inhibitors.
• The third subgroup included just two patients. These patients had FVIII-specific IgG1, no detectable IgG class–switched antibodies, but low-titer FVIII inhibitors.
• The final subgroup, which had seven patients, had FVIII-specific IgG1, high-affinity IgG class–switched antibodies (IgG3, IgG4, and IgG2), and FVIII inhibitors.

The researchers concluded that high-affinity FVIII-specific class-switched antibodies precede clinical FVIII inhibitor detection, adding to the evidence of their “potential role as suitable predictive biomarkers for inhibitor development.”

The study is funded by Baxalta, a part of Shire. Dr. Gangadharan is employed by Shire and other authors reported financial disclosures related to the study sponsor.

mschneider@mdedge.com

SOURCE: Gangadharan B et al. ASH 2018, Poster 3774.

SAN DIEGO – A chimeric antigen receptor (CAR) targeting both CD19 and CD22 shows promising safety and efficacy for the treatment of relapsed or refractory B-cell malignancies in adults, according to early findings from a phase 1 trial of the novel bispecific CAR.

Of six patients with diffuse large B-cell lymphoma (DLBCL) and two patients with B-cell acute lymphoblastic leukemia (B-ALL) enrolled in the single-institution dose escalation study and available for safety analysis after the bispecific CAR T-cell infusion, five developed reversible grade 1 cytokine release syndrome (CRS) and one developed grade 2 CRS requiring treatment with tocilizumab, Nasheed Hossain, MD, reported at the annual meeting of the American Society of Hematology.

Additionally, two patients developed grade 1 neurotoxicity, and one developed grade 2 neurotoxicity requiring treatment with dexamethasone.

“But no dose-limiting toxicities have been encountered thus far,” said Dr. Hossain of Loyola University Medical Center, Chicago. “With regard to efficacy, the DLBCL overall response rate is 60%, with 1 [complete response] and 2 [partial responses] at day 28 and day 90, and the ALL overall response rate is 100%, with 1 CR and 1 PR at day 28.

“With longer follow-up, five patients have relapsed and biopsies at the time of progression all showed ongoing CD19 expression,” he said, adding that all enrolled patients are alive, except for one patient who died from disease progression.
[embed:render:related:node:192074]

Study participants were adults aged 35-75 years with DLBCL or B-ALL that was refractory to standard therapies.

“Our primary objectives are twofold: One is to determine the feasibility of making our CAR ... and [the other] is to assess the safety using an escalating CAR dose following standard cyclophosphamide/fludarabine conditioning,” Dr. Hossain said.

The dose assessed in the current analysis was 1 x 10⁶ CAR T cells/kg; other planned doses include 3 x 10⁶ CAR T cells/kg and 1 x 10⁷ CAR T cells/kg, he said.

All patients underwent lymphodepletion with cyclophosphamide (500 mg/m² daily x 3 doses) and fludarabine (30 mg/m² daily x 3 doses) followed by CAR T-cell infusion 2 days later.

The findings of this ongoing study – the first in-human study of a bispecific loop CAR in the United States – suggest that the novel CAR has low toxicity and promising efficacy, Dr. Hossain said.

Currently approved therapies target CD19 alone, he said, noting that they all use the same anti-CD19 domain, but different costimulatory domains, and have good clinical efficacy of greater than 70% CRs in ALL and up to 52% CRs in DLBCL.

“But questions remain about determining the durability of response and the causes of therapy failure,” he said.

One common cause of treatment failure is CD19 antigen loss, and efforts to reduce such antigen loss using bispecific loop CARs targeting both CD19 and CD22 have shown promise. The CAR construct evaluated in this study was developed to target CD19 and CD22 with intracellular signaling domains incorporating 4-1BB and CD3-zeta to overcome CD19 immune escape.

“We have now escalated the dose to 3 x 10⁶ CAR T cells/kg ... and an expansion study of 60 patients will follow,” Dr. Hossain said.

A companion phase 1 pediatric trial using the same CAR construct is also underway, with preliminary data presented at the ASH meeting demonstrating safety and tolerability in children with relapsed or refractory B-cell ALL.

Dr. Hossain reported having no financial disclosures.

sworcester@mdedge.com

SOURCE: Hossain N et al. ASH 2018, Abstract 490.

SAN DIEGO – A chimeric antigen receptor (CAR) targeting both CD19 and CD22 shows promising safety and efficacy for the treatment of relapsed or refractory B-cell malignancies in adults, according to early findings from a phase 1 trial of the novel bispecific CAR.

Of six patients with diffuse large B-cell lymphoma (DLBCL) and two patients with B-cell acute lymphoblastic leukemia (B-ALL) enrolled in the single-institution dose escalation study and available for safety analysis after the bispecific CAR T-cell infusion, five developed reversible grade 1 cytokine release syndrome (CRS) and one developed grade 2 CRS requiring treatment with tocilizumab, Nasheed Hossain, MD, reported at the annual meeting of the American Society of Hematology.

Additionally, two patients developed grade 1 neurotoxicity, and one developed grade 2 neurotoxicity requiring treatment with dexamethasone.

“But no dose-limiting toxicities have been encountered thus far,” said Dr. Hossain of Loyola University Medical Center, Chicago. “With regard to efficacy, the DLBCL overall response rate is 60%, with 1 [complete response] and 2 [partial responses] at day 28 and day 90, and the ALL overall response rate is 100%, with 1 CR and 1 PR at day 28.

“With longer follow-up, five patients have relapsed and biopsies at the time of progression all showed ongoing CD19 expression,” he said, adding that all enrolled patients are alive, except for one patient who died from disease progression.
[embed:render:related:node:192074]

Study participants were adults aged 35-75 years with DLBCL or B-ALL that was refractory to standard therapies.

“Our primary objectives are twofold: One is to determine the feasibility of making our CAR ... and [the other] is to assess the safety using an escalating CAR dose following standard cyclophosphamide/fludarabine conditioning,” Dr. Hossain said.

The dose assessed in the current analysis was 1 x 10⁶ CAR T cells/kg; other planned doses include 3 x 10⁶ CAR T cells/kg and 1 x 10⁷ CAR T cells/kg, he said.

All patients underwent lymphodepletion with cyclophosphamide (500 mg/m² daily x 3 doses) and fludarabine (30 mg/m² daily x 3 doses) followed by CAR T-cell infusion 2 days later.

The findings of this ongoing study – the first in-human study of a bispecific loop CAR in the United States – suggest that the novel CAR has low toxicity and promising efficacy, Dr. Hossain said.

Currently approved therapies target CD19 alone, he said, noting that they all use the same anti-CD19 domain, but different costimulatory domains, and have good clinical efficacy of greater than 70% CRs in ALL and up to 52% CRs in DLBCL.

“But questions remain about determining the durability of response and the causes of therapy failure,” he said.

One common cause of treatment failure is CD19 antigen loss, and efforts to reduce such antigen loss using bispecific loop CARs targeting both CD19 and CD22 have shown promise. The CAR construct evaluated in this study was developed to target CD19 and CD22 with intracellular signaling domains incorporating 4-1BB and CD3-zeta to overcome CD19 immune escape.

“We have now escalated the dose to 3 x 10⁶ CAR T cells/kg ... and an expansion study of 60 patients will follow,” Dr. Hossain said.

A companion phase 1 pediatric trial using the same CAR construct is also underway, with preliminary data presented at the ASH meeting demonstrating safety and tolerability in children with relapsed or refractory B-cell ALL.

Dr. Hossain reported having no financial disclosures.

sworcester@mdedge.com

SOURCE: Hossain N et al. ASH 2018, Abstract 490.

SAN DIEGO – A chimeric antigen receptor (CAR) targeting both CD19 and CD22 shows promising safety and efficacy for the treatment of relapsed or refractory B-cell malignancies in adults, according to early findings from a phase 1 trial of the novel bispecific CAR.

Of six patients with diffuse large B-cell lymphoma (DLBCL) and two patients with B-cell acute lymphoblastic leukemia (B-ALL) enrolled in the single-institution dose escalation study and available for safety analysis after the bispecific CAR T-cell infusion, five developed reversible grade 1 cytokine release syndrome (CRS) and one developed grade 2 CRS requiring treatment with tocilizumab, Nasheed Hossain, MD, reported at the annual meeting of the American Society of Hematology.

Additionally, two patients developed grade 1 neurotoxicity, and one developed grade 2 neurotoxicity requiring treatment with dexamethasone.

“But no dose-limiting toxicities have been encountered thus far,” said Dr. Hossain of Loyola University Medical Center, Chicago. “With regard to efficacy, the DLBCL overall response rate is 60%, with 1 [complete response] and 2 [partial responses] at day 28 and day 90, and the ALL overall response rate is 100%, with 1 CR and 1 PR at day 28.

“With longer follow-up, five patients have relapsed and biopsies at the time of progression all showed ongoing CD19 expression,” he said, adding that all enrolled patients are alive, except for one patient who died from disease progression.
[embed:render:related:node:192074]

Study participants were adults aged 35-75 years with DLBCL or B-ALL that was refractory to standard therapies.

“Our primary objectives are twofold: One is to determine the feasibility of making our CAR ... and [the other] is to assess the safety using an escalating CAR dose following standard cyclophosphamide/fludarabine conditioning,” Dr. Hossain said.

The dose assessed in the current analysis was 1 x 10⁶ CAR T cells/kg; other planned doses include 3 x 10⁶ CAR T cells/kg and 1 x 10⁷ CAR T cells/kg, he said.

All patients underwent lymphodepletion with cyclophosphamide (500 mg/m² daily x 3 doses) and fludarabine (30 mg/m² daily x 3 doses) followed by CAR T-cell infusion 2 days later.

The findings of this ongoing study – the first in-human study of a bispecific loop CAR in the United States – suggest that the novel CAR has low toxicity and promising efficacy, Dr. Hossain said.

Currently approved therapies target CD19 alone, he said, noting that they all use the same anti-CD19 domain, but different costimulatory domains, and have good clinical efficacy of greater than 70% CRs in ALL and up to 52% CRs in DLBCL.

“But questions remain about determining the durability of response and the causes of therapy failure,” he said.

One common cause of treatment failure is CD19 antigen loss, and efforts to reduce such antigen loss using bispecific loop CARs targeting both CD19 and CD22 have shown promise. The CAR construct evaluated in this study was developed to target CD19 and CD22 with intracellular signaling domains incorporating 4-1BB and CD3-zeta to overcome CD19 immune escape.

“We have now escalated the dose to 3 x 10⁶ CAR T cells/kg ... and an expansion study of 60 patients will follow,” Dr. Hossain said.

A companion phase 1 pediatric trial using the same CAR construct is also underway, with preliminary data presented at the ASH meeting demonstrating safety and tolerability in children with relapsed or refractory B-cell ALL.

Dr. Hossain reported having no financial disclosures.

sworcester@mdedge.com

SOURCE: Hossain N et al. ASH 2018, Abstract 490.

SAN DIEGO – Ibrutinib treatment continued before, during, and after infusion of the CD19-specific chimeric antigen receptor (CAR) T-cell therapy JCAR014 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) appears to improve patient responses and decrease the risk of severe cytokine release syndrome.

Gauthier_Jordan_SEATTLE_web.jpg

The findings come from a comparison of sequential cohorts from a phase 1/2 study.

At 4 weeks after infusion, the approach was highly efficacious; overall response rates by 2008 International Workshop on CLL (IWCLL) criteria were 83% in 24 patients who received the uninterrupted ibrutinib regimen along with the JCAR014 therapy – a combination of CD4 and CD8 T cells – and 65% in 19 patients from a prior cohort who did not receive continuous ibrutinib, Jordan Gauthier, MD, reported at the annual meeting of the American Society of Hematology.

Concurrent ibrutinib was generally well tolerated, with 13 of 19 patients in the ibrutinib cohort receiving treatment as planned without discontinuation. The rates of grade 1 or higher cytokine release syndrome (CRS) were statistically similar in the ibrutinib and no-ibrutinib cohorts (74% and 92%, respectively). However, the rates of severe CRS (grade 3 or higher) were, strikingly, 0% and 25%, respectively, said Dr. Gauthier, a senior fellow in the Turtle Lab at Fred Hutchinson Cancer Center, Seattle.

Neurotoxicity occurred in 32% and 42% of patients in the groups; severe neurotoxicity occurred in 26% and 29%, respectively.

In the ibrutinib cohort, one patient with grade 2 CRS developed fatal presumed cardiac arrhythmia; in the no-ibrutinib cohort, one patient died from a CAR T cell–related toxicity.

Notably, a trend toward better expansion of CD8 CAR T cells and a significantly greater expansion of CD4 CAR T cells was observed in the ibrutinib cohort, he said.

The study was designed to assess JCAR014, and based on the initial cohort findings published in 2017, established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 infusion at 2 x 10⁶ CAR T cells/kg. The study was not a randomized, head-to-head comparison but the groups were similar with respect to both patient and disease characteristics, Dr. Gauthier noted.

The outcomes in the first cohort were then compared retrospectively with those from the subsequent cohort of patients who received Cy/Flu with 2 x 10⁶ CAR T cells/kg with concurrent ibrutinib administered at 420 mg per day from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion.

The rationale for uninterrupted ibrutinib in relapsed/refractory CLL patients receiving JCAR014 included potential prevention of tumor flare, mobilization of CLL cells into the blood from the lymph nodes, improvement of CAR T-cell function, and a decrease in CAR T-cell related toxicity, he said.

The concurrent administration of ibrutinib and JCAR014 was feasible for most patients. “[It] induced high response rates and deep responses early on at 4 weeks, and it was associated with higher in vivo expansion of CD4 CAR T cells and with lower rates of severe toxicity,” Dr. Gauthier said. “The next step is to hopefully validate these findings in a prospective phase 1/2 study.”

Dr. Gauthier reported having no financial disclosures.

sworcester@mdedge.com

SOURCE: Gauthier J et al. ASH 18, Abstract 299.

SAN DIEGO – Ibrutinib treatment continued before, during, and after infusion of the CD19-specific chimeric antigen receptor (CAR) T-cell therapy JCAR014 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) appears to improve patient responses and decrease the risk of severe cytokine release syndrome.

Gauthier_Jordan_SEATTLE_web.jpg

The findings come from a comparison of sequential cohorts from a phase 1/2 study.

At 4 weeks after infusion, the approach was highly efficacious; overall response rates by 2008 International Workshop on CLL (IWCLL) criteria were 83% in 24 patients who received the uninterrupted ibrutinib regimen along with the JCAR014 therapy – a combination of CD4 and CD8 T cells – and 65% in 19 patients from a prior cohort who did not receive continuous ibrutinib, Jordan Gauthier, MD, reported at the annual meeting of the American Society of Hematology.

Concurrent ibrutinib was generally well tolerated, with 13 of 19 patients in the ibrutinib cohort receiving treatment as planned without discontinuation. The rates of grade 1 or higher cytokine release syndrome (CRS) were statistically similar in the ibrutinib and no-ibrutinib cohorts (74% and 92%, respectively). However, the rates of severe CRS (grade 3 or higher) were, strikingly, 0% and 25%, respectively, said Dr. Gauthier, a senior fellow in the Turtle Lab at Fred Hutchinson Cancer Center, Seattle.

Neurotoxicity occurred in 32% and 42% of patients in the groups; severe neurotoxicity occurred in 26% and 29%, respectively.

In the ibrutinib cohort, one patient with grade 2 CRS developed fatal presumed cardiac arrhythmia; in the no-ibrutinib cohort, one patient died from a CAR T cell–related toxicity.

Notably, a trend toward better expansion of CD8 CAR T cells and a significantly greater expansion of CD4 CAR T cells was observed in the ibrutinib cohort, he said.

The study was designed to assess JCAR014, and based on the initial cohort findings published in 2017, established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 infusion at 2 x 10⁶ CAR T cells/kg. The study was not a randomized, head-to-head comparison but the groups were similar with respect to both patient and disease characteristics, Dr. Gauthier noted.

The outcomes in the first cohort were then compared retrospectively with those from the subsequent cohort of patients who received Cy/Flu with 2 x 10⁶ CAR T cells/kg with concurrent ibrutinib administered at 420 mg per day from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion.

The rationale for uninterrupted ibrutinib in relapsed/refractory CLL patients receiving JCAR014 included potential prevention of tumor flare, mobilization of CLL cells into the blood from the lymph nodes, improvement of CAR T-cell function, and a decrease in CAR T-cell related toxicity, he said.

The concurrent administration of ibrutinib and JCAR014 was feasible for most patients. “[It] induced high response rates and deep responses early on at 4 weeks, and it was associated with higher in vivo expansion of CD4 CAR T cells and with lower rates of severe toxicity,” Dr. Gauthier said. “The next step is to hopefully validate these findings in a prospective phase 1/2 study.”

Dr. Gauthier reported having no financial disclosures.

sworcester@mdedge.com

SOURCE: Gauthier J et al. ASH 18, Abstract 299.

SAN DIEGO – Ibrutinib treatment continued before, during, and after infusion of the CD19-specific chimeric antigen receptor (CAR) T-cell therapy JCAR014 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) appears to improve patient responses and decrease the risk of severe cytokine release syndrome.

Gauthier_Jordan_SEATTLE_web.jpg

The findings come from a comparison of sequential cohorts from a phase 1/2 study.

At 4 weeks after infusion, the approach was highly efficacious; overall response rates by 2008 International Workshop on CLL (IWCLL) criteria were 83% in 24 patients who received the uninterrupted ibrutinib regimen along with the JCAR014 therapy – a combination of CD4 and CD8 T cells – and 65% in 19 patients from a prior cohort who did not receive continuous ibrutinib, Jordan Gauthier, MD, reported at the annual meeting of the American Society of Hematology.

Concurrent ibrutinib was generally well tolerated, with 13 of 19 patients in the ibrutinib cohort receiving treatment as planned without discontinuation. The rates of grade 1 or higher cytokine release syndrome (CRS) were statistically similar in the ibrutinib and no-ibrutinib cohorts (74% and 92%, respectively). However, the rates of severe CRS (grade 3 or higher) were, strikingly, 0% and 25%, respectively, said Dr. Gauthier, a senior fellow in the Turtle Lab at Fred Hutchinson Cancer Center, Seattle.

Neurotoxicity occurred in 32% and 42% of patients in the groups; severe neurotoxicity occurred in 26% and 29%, respectively.

In the ibrutinib cohort, one patient with grade 2 CRS developed fatal presumed cardiac arrhythmia; in the no-ibrutinib cohort, one patient died from a CAR T cell–related toxicity.

Notably, a trend toward better expansion of CD8 CAR T cells and a significantly greater expansion of CD4 CAR T cells was observed in the ibrutinib cohort, he said.

The study was designed to assess JCAR014, and based on the initial cohort findings published in 2017, established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 infusion at 2 x 10⁶ CAR T cells/kg. The study was not a randomized, head-to-head comparison but the groups were similar with respect to both patient and disease characteristics, Dr. Gauthier noted.

The outcomes in the first cohort were then compared retrospectively with those from the subsequent cohort of patients who received Cy/Flu with 2 x 10⁶ CAR T cells/kg with concurrent ibrutinib administered at 420 mg per day from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion.

The rationale for uninterrupted ibrutinib in relapsed/refractory CLL patients receiving JCAR014 included potential prevention of tumor flare, mobilization of CLL cells into the blood from the lymph nodes, improvement of CAR T-cell function, and a decrease in CAR T-cell related toxicity, he said.

The concurrent administration of ibrutinib and JCAR014 was feasible for most patients. “[It] induced high response rates and deep responses early on at 4 weeks, and it was associated with higher in vivo expansion of CD4 CAR T cells and with lower rates of severe toxicity,” Dr. Gauthier said. “The next step is to hopefully validate these findings in a prospective phase 1/2 study.”

Dr. Gauthier reported having no financial disclosures.

sworcester@mdedge.com

SOURCE: Gauthier J et al. ASH 18, Abstract 299.

SAN DIEGO – Investigational SPK-8011 gene transfer results in safe, durable, dose-dependent Factor VIII (FVIII) expression in patients with severe or moderately severe hemophilia A, according to preliminary findings from an ongoing phase 1/2 study.

George_Lindsey_A_PHILA_web.jpg

An overall reduction of 97% was seen in both the annualized bleeding rate (ABR) and annualized infusion rate (AIR) in the first 12 patients treated with SPK-8011, which is a Spark Therapeutics product that consists of a bioengineered AAV capsid expressing B domain-deleted FVIII under the control of a liver-specific promoter, principal investigator Lindsey A. George, MD, reported at the annual meeting of the American Society of Hematology.

Study subjects were men aged 18-52 years, including 11 with severe disease and 1 with moderately severe disease, who received a single infusion of either 5E11 vg/kg (2 patients), 1E12 vg/kg (3 patients), or 2E12 vg/kg (7 patients).

“All vector doses led to expression of FVIII levels adequate to prevent bleeding and allow cessation of prophylaxis,” said Dr. George, associate professor of pediatrics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and an attending physician in the division of hematology at Children’s Hospital of Philadelphia.

In the two men in the 5E11 dose cohort, mean FVIII levels beginning 12 weeks after infusion were 13%, and neither experienced bleeding events, had elevated transaminase levels, or required steroids, she said, noting that FVIII expression remained stable for at least 66 weeks (and up to 78 weeks in one patient).

The three men in the 1E12 dose cohort had mean FVIII levels of 15% beginning at 12 weeks post infusion, and the levels were stable for at least 46 weeks.

The first patient was infused with a single dose of factor concentrate for a spontaneous joint bleed at day 159, and the second patient received multiple infusions for a traumatic bleed beginning at day 195. Both received a successful course of tapering steroids, at 12 and 7 weeks after infusion, respectively, for declining FVIII levels, Dr. George said.

The third subject had no bleeding and did not receive factor infusions or steroids, she added.

[embed:render:related:node:191656]

In the highest dose cohort (2E12), five of seven subjects had FVIII levels between 16% and 49%.

Steroids were required and given between 6 and 11 weeks after infusion in five of the seven patients in that cohort for either declining FVIII levels, a rise in alanine aminotransferase (ALT) above baseline, or elevated IFN-g ELISPOTs to AAV capsid. The steroids normalized ALT levels and extinguished the ELISPOT signal in all cases.

In two patients, FVIII levels showed limited stabilization, and fell to less than 6%. This was most likely due to the immune response, Dr. George explained, noting that in one of the two patients no bleeds were reported through 12 weeks of follow-up, while the other experienced four bleeds through 37 weeks of observation.

SPK-8011 was well tolerated in this study, which had cumulative follow-up of 506 weeks at the time of Dr. George’s presentation. No inhibitor formation was noted in the safety analysis and the only serious adverse event – the immune response to AAV capsid – has resolved, she said.

Data from the lowest dose cohort (5E11) are consistent with published natural history data indicating FVIII:C 12% is adequate to prevent spontaneous bleeding events, she said. However, she noted that the loss of some FVIII expression in two patients in the 2E12 dose cohort (which eventually stabilized on steroids), and the fact that five of seven subjects in this cohort required steroids, suggests a possible role for prophylactic steroid administration in patients treated with SPK-8011.

“Gene transfer for hemophilia A offers the potential for a one-time disease-altering treatment that eliminates bleed risk and could free patients from the burden of lifelong chronic therapy,” Dr. George said.

A phase 3 run-in study is planned, she added.

Spark Therapeutics sponsored the study. Dr. George reported equity ownership related to the University of Pennsylvania and consultancy for Pfizer.

sworcester@mdedge.com

SOURCE: High K et al., ASH 2018, Abstract 487.

SAN DIEGO – Investigational SPK-8011 gene transfer results in safe, durable, dose-dependent Factor VIII (FVIII) expression in patients with severe or moderately severe hemophilia A, according to preliminary findings from an ongoing phase 1/2 study.

George_Lindsey_A_PHILA_web.jpg

An overall reduction of 97% was seen in both the annualized bleeding rate (ABR) and annualized infusion rate (AIR) in the first 12 patients treated with SPK-8011, which is a Spark Therapeutics product that consists of a bioengineered AAV capsid expressing B domain-deleted FVIII under the control of a liver-specific promoter, principal investigator Lindsey A. George, MD, reported at the annual meeting of the American Society of Hematology.

Study subjects were men aged 18-52 years, including 11 with severe disease and 1 with moderately severe disease, who received a single infusion of either 5E11 vg/kg (2 patients), 1E12 vg/kg (3 patients), or 2E12 vg/kg (7 patients).

“All vector doses led to expression of FVIII levels adequate to prevent bleeding and allow cessation of prophylaxis,” said Dr. George, associate professor of pediatrics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and an attending physician in the division of hematology at Children’s Hospital of Philadelphia.

In the two men in the 5E11 dose cohort, mean FVIII levels beginning 12 weeks after infusion were 13%, and neither experienced bleeding events, had elevated transaminase levels, or required steroids, she said, noting that FVIII expression remained stable for at least 66 weeks (and up to 78 weeks in one patient).

The three men in the 1E12 dose cohort had mean FVIII levels of 15% beginning at 12 weeks post infusion, and the levels were stable for at least 46 weeks.

The first patient was infused with a single dose of factor concentrate for a spontaneous joint bleed at day 159, and the second patient received multiple infusions for a traumatic bleed beginning at day 195. Both received a successful course of tapering steroids, at 12 and 7 weeks after infusion, respectively, for declining FVIII levels, Dr. George said.

The third subject had no bleeding and did not receive factor infusions or steroids, she added.

[embed:render:related:node:191656]

In the highest dose cohort (2E12), five of seven subjects had FVIII levels between 16% and 49%.

Steroids were required and given between 6 and 11 weeks after infusion in five of the seven patients in that cohort for either declining FVIII levels, a rise in alanine aminotransferase (ALT) above baseline, or elevated IFN-g ELISPOTs to AAV capsid. The steroids normalized ALT levels and extinguished the ELISPOT signal in all cases.

In two patients, FVIII levels showed limited stabilization, and fell to less than 6%. This was most likely due to the immune response, Dr. George explained, noting that in one of the two patients no bleeds were reported through 12 weeks of follow-up, while the other experienced four bleeds through 37 weeks of observation.

SPK-8011 was well tolerated in this study, which had cumulative follow-up of 506 weeks at the time of Dr. George’s presentation. No inhibitor formation was noted in the safety analysis and the only serious adverse event – the immune response to AAV capsid – has resolved, she said.

Data from the lowest dose cohort (5E11) are consistent with published natural history data indicating FVIII:C 12% is adequate to prevent spontaneous bleeding events, she said. However, she noted that the loss of some FVIII expression in two patients in the 2E12 dose cohort (which eventually stabilized on steroids), and the fact that five of seven subjects in this cohort required steroids, suggests a possible role for prophylactic steroid administration in patients treated with SPK-8011.

“Gene transfer for hemophilia A offers the potential for a one-time disease-altering treatment that eliminates bleed risk and could free patients from the burden of lifelong chronic therapy,” Dr. George said.

A phase 3 run-in study is planned, she added.

Spark Therapeutics sponsored the study. Dr. George reported equity ownership related to the University of Pennsylvania and consultancy for Pfizer.

sworcester@mdedge.com

SOURCE: High K et al., ASH 2018, Abstract 487.

SAN DIEGO – Investigational SPK-8011 gene transfer results in safe, durable, dose-dependent Factor VIII (FVIII) expression in patients with severe or moderately severe hemophilia A, according to preliminary findings from an ongoing phase 1/2 study.

George_Lindsey_A_PHILA_web.jpg

An overall reduction of 97% was seen in both the annualized bleeding rate (ABR) and annualized infusion rate (AIR) in the first 12 patients treated with SPK-8011, which is a Spark Therapeutics product that consists of a bioengineered AAV capsid expressing B domain-deleted FVIII under the control of a liver-specific promoter, principal investigator Lindsey A. George, MD, reported at the annual meeting of the American Society of Hematology.

Study subjects were men aged 18-52 years, including 11 with severe disease and 1 with moderately severe disease, who received a single infusion of either 5E11 vg/kg (2 patients), 1E12 vg/kg (3 patients), or 2E12 vg/kg (7 patients).

“All vector doses led to expression of FVIII levels adequate to prevent bleeding and allow cessation of prophylaxis,” said Dr. George, associate professor of pediatrics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and an attending physician in the division of hematology at Children’s Hospital of Philadelphia.

In the two men in the 5E11 dose cohort, mean FVIII levels beginning 12 weeks after infusion were 13%, and neither experienced bleeding events, had elevated transaminase levels, or required steroids, she said, noting that FVIII expression remained stable for at least 66 weeks (and up to 78 weeks in one patient).

The three men in the 1E12 dose cohort had mean FVIII levels of 15% beginning at 12 weeks post infusion, and the levels were stable for at least 46 weeks.

The first patient was infused with a single dose of factor concentrate for a spontaneous joint bleed at day 159, and the second patient received multiple infusions for a traumatic bleed beginning at day 195. Both received a successful course of tapering steroids, at 12 and 7 weeks after infusion, respectively, for declining FVIII levels, Dr. George said.

The third subject had no bleeding and did not receive factor infusions or steroids, she added.

[embed:render:related:node:191656]

In the highest dose cohort (2E12), five of seven subjects had FVIII levels between 16% and 49%.

Steroids were required and given between 6 and 11 weeks after infusion in five of the seven patients in that cohort for either declining FVIII levels, a rise in alanine aminotransferase (ALT) above baseline, or elevated IFN-g ELISPOTs to AAV capsid. The steroids normalized ALT levels and extinguished the ELISPOT signal in all cases.

In two patients, FVIII levels showed limited stabilization, and fell to less than 6%. This was most likely due to the immune response, Dr. George explained, noting that in one of the two patients no bleeds were reported through 12 weeks of follow-up, while the other experienced four bleeds through 37 weeks of observation.

SPK-8011 was well tolerated in this study, which had cumulative follow-up of 506 weeks at the time of Dr. George’s presentation. No inhibitor formation was noted in the safety analysis and the only serious adverse event – the immune response to AAV capsid – has resolved, she said.

Data from the lowest dose cohort (5E11) are consistent with published natural history data indicating FVIII:C 12% is adequate to prevent spontaneous bleeding events, she said. However, she noted that the loss of some FVIII expression in two patients in the 2E12 dose cohort (which eventually stabilized on steroids), and the fact that five of seven subjects in this cohort required steroids, suggests a possible role for prophylactic steroid administration in patients treated with SPK-8011.

“Gene transfer for hemophilia A offers the potential for a one-time disease-altering treatment that eliminates bleed risk and could free patients from the burden of lifelong chronic therapy,” Dr. George said.

A phase 3 run-in study is planned, she added.

Spark Therapeutics sponsored the study. Dr. George reported equity ownership related to the University of Pennsylvania and consultancy for Pfizer.

sworcester@mdedge.com

SOURCE: High K et al., ASH 2018, Abstract 487.

SAN DIEGO – The next-generation anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy bb21217 shows encouraging efficacy for relapsed/refractory multiple myeloma, according to early findings from the phase 1 CRB-402 study.

CAR T cells_web.jpg

At a median follow-up of 26 weeks, an objective response was seen in 10 of 12 patients (83%) treated with bb21217 at a dose of 150 x 10⁶ CAR+ T cells, Nina Shah, MD, reported at the annual meeting of the American Society of Hematology.

Immunomodulatory CAR T-cell therapy directed against BCMA has shown promising results for the treatment of relapsed/refractory multiple myeloma (RRMM) in several phase 1 clinical studies in patients with advanced disease; bb21217 is based on the investigational therapy bb2121, said Dr. Shah, a hematologist-oncologist at the University of California, San Francisco.

“It uses the same CAR construct design as bb2121. However, it is cultured in the presence of a pan-[phosphoinositide] 3 kinase inhibitor known as bb007 to enrich for T cells displaying a memory-like phenotype,” she said. “CAR T cells enriched with this phenotype may persist and function longer than nonenriched CAR T cells, and the persistence of functional CAR T cells after infusion may be one determinant of the duration of response.”

Preclinical data have supported this approach and CRB-402 – a first-in-human dose-ranging study – was designed to assess the safety, pharmacokinetics, efficacy, and duration of effect of bb21217, Dr. Shah said.

She presented only the data for the 150 x 10⁶ cell dose.

Study subjects were adults with RRMM who had received at least three prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, and who had at least 50% expression of BCMA on the plasma cells in bone marrow samples at screening. They had a median age of 63 years, and 58% had high-risk cytogenetic features.

“Patients tended to be pretty heavily pretreated with a median number of lines of treatment of seven,” Dr. Shah said, noting that almost all patients had prior autologous stem cell transplantation, 58% had been exposed to all five available therapies for RRMM, and 17% were refractory to all five therapies.

The patients underwent collection of peripheral blood mononuclear cells via leukapheresis and underwent lymphodepletion with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) daily for 3 days prior to receiving the single bb21217 infusion.

Grade 3 or higher adverse events occurring in more than one patient were predominantly cytopenias, which is to be expected in a clinical trial such as this, Dr. Shah said, adding that some hypophosphatemia also occurred.

In those with cytopenias, 58% recovered their absolute neutrophil count (ANC) to greater than 1,000 by day 32, and of the remaining five patients, four of them recovered by day 65.

“Therefore, 11 out of 12 had full ANC recovery by day 65,” she said.

[embed:render:related:node:174944]

Thrombocytopenia was seen in half of the patients, and in those six patients, two recovered platelet counts to more than 50,000 by day 32, and two more by day 65.

Overall, 10 out of 12 patients had platelet recovery to greater than 50,000 by day 65, she said.

Other adverse events of clinical interest included cytokine release syndrome (CRS) and neurotoxicity.

CRS was usually grade 1 or 2 and occurred in 8 of the 12 patients (67%). One grade 3 CRS event occurred.

“The median time to onset of the CRS was 4.5 days, and this was fairly manageable with or without tocilizumab,” she said.

Neurotoxicity occurred in 3 of 12 patients (25%), and a dose-limiting grade 4 encephalopathy and prolonged grade 3 CRS occurred in one patient with a high tumor burden and rapidly accelerating disease at baseline.

“Because of this, the dose level was expanded and we included patients equally who had high tumor burden and low tumor burden to further understand the contribution of this to this phenomenon. However, no other [dose-limiting toxicities] occurred,” she noted.

Additionally, one patient experienced a grade 3 catheter-related infection, but no other severe infections have been reported, Dr. Shah said, adding that four patients experienced one or more serious adverse events, but no deaths have occurred to date.

[embed:render:related:node:164295]

Of the 10 patients who achieved an objective response to bb21217, 3 had a complete response (CR) or stringent CR, and 6 patients achieved at least a very good partial response or better.

Some responses deepened over time, therefore some CRs were achieved as late as month 10. Responses are ongoing in all but one responding patient, and the first patient who was dosed continues to respond more than 1 year after treatment.

Of those with good minimal residual disease (MRD) samples available, four were responders, and all four were MRD negative. In contrast, both nonresponders who had tissue available for MRD analysis were MRD positive.

Correlative data show that bone marrow plasma cell clearance was observed early, by day 15, in these representative samples, Dr. Shah said.

“There was a dramatic decline in serum free light chain and serum BCMA ... in all responders by month 1. However, the M protein decline did have some delay, which we would expect based on the half-life, and this resulted in an evolving International Myeloma Working Group response over time,” she said.

Sustained serum BCMA suppression was observed up to month 9, which is likely consistent with ongoing plasma cell aplasia resulting from functional CAR T cell persistence, she explained.

An in vivo examination of the phenotype of the infused CAR T cells showed that while the numbers are small, “so far there seems to be an enrichment for memorylike T cells within the CAR T cell population in the blood post infusion – at least by looking at CD62-ligand T cells.”

There also was a robust and consistent CAR T cell expansion post infusion, which was independent of tumor burden.

“CAR T cells have been detectable up to 9 months post infusion,” she said.

However, the follow-up so far has been very short, she noted. “This action may be underrepresenting the true persistence of these T cells,” she added, explaining that there is only one patient at month 9, whereas all three at month 6 were positive for vector copy.

CRB-402 is ongoing with plans to enroll up to 50 patients. A 300 x 10⁶ dosing cohort has been opened, and doses of 450, 800, and 1200 x 10⁶ CAR+ T cells are planned.

“But longer-term follow-up in a larger patient population will further clarify the depth and durability of the bb21217 tumor response and dose response,” she said.

This study is sponsored by Bluebird Bio. Dr. Shah reported research funding from Bluebird Bio and equity ownership in Indapta Therapeutics, as well as research funding and consulting relationships with other companies.

sworcester@mdedge.com

SOURCE: Shah N et al. ASH 2018, Abstract 488.

SAN DIEGO – The next-generation anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy bb21217 shows encouraging efficacy for relapsed/refractory multiple myeloma, according to early findings from the phase 1 CRB-402 study.

CAR T cells_web.jpg

At a median follow-up of 26 weeks, an objective response was seen in 10 of 12 patients (83%) treated with bb21217 at a dose of 150 x 10⁶ CAR+ T cells, Nina Shah, MD, reported at the annual meeting of the American Society of Hematology.

Immunomodulatory CAR T-cell therapy directed against BCMA has shown promising results for the treatment of relapsed/refractory multiple myeloma (RRMM) in several phase 1 clinical studies in patients with advanced disease; bb21217 is based on the investigational therapy bb2121, said Dr. Shah, a hematologist-oncologist at the University of California, San Francisco.

“It uses the same CAR construct design as bb2121. However, it is cultured in the presence of a pan-[phosphoinositide] 3 kinase inhibitor known as bb007 to enrich for T cells displaying a memory-like phenotype,” she said. “CAR T cells enriched with this phenotype may persist and function longer than nonenriched CAR T cells, and the persistence of functional CAR T cells after infusion may be one determinant of the duration of response.”

Preclinical data have supported this approach and CRB-402 – a first-in-human dose-ranging study – was designed to assess the safety, pharmacokinetics, efficacy, and duration of effect of bb21217, Dr. Shah said.

She presented only the data for the 150 x 10⁶ cell dose.

Study subjects were adults with RRMM who had received at least three prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, and who had at least 50% expression of BCMA on the plasma cells in bone marrow samples at screening. They had a median age of 63 years, and 58% had high-risk cytogenetic features.

“Patients tended to be pretty heavily pretreated with a median number of lines of treatment of seven,” Dr. Shah said, noting that almost all patients had prior autologous stem cell transplantation, 58% had been exposed to all five available therapies for RRMM, and 17% were refractory to all five therapies.

The patients underwent collection of peripheral blood mononuclear cells via leukapheresis and underwent lymphodepletion with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) daily for 3 days prior to receiving the single bb21217 infusion.

Grade 3 or higher adverse events occurring in more than one patient were predominantly cytopenias, which is to be expected in a clinical trial such as this, Dr. Shah said, adding that some hypophosphatemia also occurred.

In those with cytopenias, 58% recovered their absolute neutrophil count (ANC) to greater than 1,000 by day 32, and of the remaining five patients, four of them recovered by day 65.

“Therefore, 11 out of 12 had full ANC recovery by day 65,” she said.

[embed:render:related:node:174944]

Thrombocytopenia was seen in half of the patients, and in those six patients, two recovered platelet counts to more than 50,000 by day 32, and two more by day 65.

Overall, 10 out of 12 patients had platelet recovery to greater than 50,000 by day 65, she said.

Other adverse events of clinical interest included cytokine release syndrome (CRS) and neurotoxicity.

CRS was usually grade 1 or 2 and occurred in 8 of the 12 patients (67%). One grade 3 CRS event occurred.

“The median time to onset of the CRS was 4.5 days, and this was fairly manageable with or without tocilizumab,” she said.

Neurotoxicity occurred in 3 of 12 patients (25%), and a dose-limiting grade 4 encephalopathy and prolonged grade 3 CRS occurred in one patient with a high tumor burden and rapidly accelerating disease at baseline.

“Because of this, the dose level was expanded and we included patients equally who had high tumor burden and low tumor burden to further understand the contribution of this to this phenomenon. However, no other [dose-limiting toxicities] occurred,” she noted.

Additionally, one patient experienced a grade 3 catheter-related infection, but no other severe infections have been reported, Dr. Shah said, adding that four patients experienced one or more serious adverse events, but no deaths have occurred to date.

[embed:render:related:node:164295]

Of the 10 patients who achieved an objective response to bb21217, 3 had a complete response (CR) or stringent CR, and 6 patients achieved at least a very good partial response or better.

Some responses deepened over time, therefore some CRs were achieved as late as month 10. Responses are ongoing in all but one responding patient, and the first patient who was dosed continues to respond more than 1 year after treatment.

Of those with good minimal residual disease (MRD) samples available, four were responders, and all four were MRD negative. In contrast, both nonresponders who had tissue available for MRD analysis were MRD positive.

Correlative data show that bone marrow plasma cell clearance was observed early, by day 15, in these representative samples, Dr. Shah said.

“There was a dramatic decline in serum free light chain and serum BCMA ... in all responders by month 1. However, the M protein decline did have some delay, which we would expect based on the half-life, and this resulted in an evolving International Myeloma Working Group response over time,” she said.

Sustained serum BCMA suppression was observed up to month 9, which is likely consistent with ongoing plasma cell aplasia resulting from functional CAR T cell persistence, she explained.

An in vivo examination of the phenotype of the infused CAR T cells showed that while the numbers are small, “so far there seems to be an enrichment for memorylike T cells within the CAR T cell population in the blood post infusion – at least by looking at CD62-ligand T cells.”

There also was a robust and consistent CAR T cell expansion post infusion, which was independent of tumor burden.

“CAR T cells have been detectable up to 9 months post infusion,” she said.

However, the follow-up so far has been very short, she noted. “This action may be underrepresenting the true persistence of these T cells,” she added, explaining that there is only one patient at month 9, whereas all three at month 6 were positive for vector copy.

CRB-402 is ongoing with plans to enroll up to 50 patients. A 300 x 10⁶ dosing cohort has been opened, and doses of 450, 800, and 1200 x 10⁶ CAR+ T cells are planned.

“But longer-term follow-up in a larger patient population will further clarify the depth and durability of the bb21217 tumor response and dose response,” she said.

This study is sponsored by Bluebird Bio. Dr. Shah reported research funding from Bluebird Bio and equity ownership in Indapta Therapeutics, as well as research funding and consulting relationships with other companies.

sworcester@mdedge.com

SOURCE: Shah N et al. ASH 2018, Abstract 488.

SAN DIEGO – The next-generation anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy bb21217 shows encouraging efficacy for relapsed/refractory multiple myeloma, according to early findings from the phase 1 CRB-402 study.

CAR T cells_web.jpg

At a median follow-up of 26 weeks, an objective response was seen in 10 of 12 patients (83%) treated with bb21217 at a dose of 150 x 10⁶ CAR+ T cells, Nina Shah, MD, reported at the annual meeting of the American Society of Hematology.

Immunomodulatory CAR T-cell therapy directed against BCMA has shown promising results for the treatment of relapsed/refractory multiple myeloma (RRMM) in several phase 1 clinical studies in patients with advanced disease; bb21217 is based on the investigational therapy bb2121, said Dr. Shah, a hematologist-oncologist at the University of California, San Francisco.

“It uses the same CAR construct design as bb2121. However, it is cultured in the presence of a pan-[phosphoinositide] 3 kinase inhibitor known as bb007 to enrich for T cells displaying a memory-like phenotype,” she said. “CAR T cells enriched with this phenotype may persist and function longer than nonenriched CAR T cells, and the persistence of functional CAR T cells after infusion may be one determinant of the duration of response.”

Preclinical data have supported this approach and CRB-402 – a first-in-human dose-ranging study – was designed to assess the safety, pharmacokinetics, efficacy, and duration of effect of bb21217, Dr. Shah said.

She presented only the data for the 150 x 10⁶ cell dose.

Study subjects were adults with RRMM who had received at least three prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, and who had at least 50% expression of BCMA on the plasma cells in bone marrow samples at screening. They had a median age of 63 years, and 58% had high-risk cytogenetic features.

“Patients tended to be pretty heavily pretreated with a median number of lines of treatment of seven,” Dr. Shah said, noting that almost all patients had prior autologous stem cell transplantation, 58% had been exposed to all five available therapies for RRMM, and 17% were refractory to all five therapies.

The patients underwent collection of peripheral blood mononuclear cells via leukapheresis and underwent lymphodepletion with fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) daily for 3 days prior to receiving the single bb21217 infusion.

Grade 3 or higher adverse events occurring in more than one patient were predominantly cytopenias, which is to be expected in a clinical trial such as this, Dr. Shah said, adding that some hypophosphatemia also occurred.

In those with cytopenias, 58% recovered their absolute neutrophil count (ANC) to greater than 1,000 by day 32, and of the remaining five patients, four of them recovered by day 65.

“Therefore, 11 out of 12 had full ANC recovery by day 65,” she said.

[embed:render:related:node:174944]

Thrombocytopenia was seen in half of the patients, and in those six patients, two recovered platelet counts to more than 50,000 by day 32, and two more by day 65.

Overall, 10 out of 12 patients had platelet recovery to greater than 50,000 by day 65, she said.

Other adverse events of clinical interest included cytokine release syndrome (CRS) and neurotoxicity.

CRS was usually grade 1 or 2 and occurred in 8 of the 12 patients (67%). One grade 3 CRS event occurred.

“The median time to onset of the CRS was 4.5 days, and this was fairly manageable with or without tocilizumab,” she said.

Neurotoxicity occurred in 3 of 12 patients (25%), and a dose-limiting grade 4 encephalopathy and prolonged grade 3 CRS occurred in one patient with a high tumor burden and rapidly accelerating disease at baseline.

“Because of this, the dose level was expanded and we included patients equally who had high tumor burden and low tumor burden to further understand the contribution of this to this phenomenon. However, no other [dose-limiting toxicities] occurred,” she noted.

Additionally, one patient experienced a grade 3 catheter-related infection, but no other severe infections have been reported, Dr. Shah said, adding that four patients experienced one or more serious adverse events, but no deaths have occurred to date.

[embed:render:related:node:164295]

Of the 10 patients who achieved an objective response to bb21217, 3 had a complete response (CR) or stringent CR, and 6 patients achieved at least a very good partial response or better.

Some responses deepened over time, therefore some CRs were achieved as late as month 10. Responses are ongoing in all but one responding patient, and the first patient who was dosed continues to respond more than 1 year after treatment.

Of those with good minimal residual disease (MRD) samples available, four were responders, and all four were MRD negative. In contrast, both nonresponders who had tissue available for MRD analysis were MRD positive.

Correlative data show that bone marrow plasma cell clearance was observed early, by day 15, in these representative samples, Dr. Shah said.

“There was a dramatic decline in serum free light chain and serum BCMA ... in all responders by month 1. However, the M protein decline did have some delay, which we would expect based on the half-life, and this resulted in an evolving International Myeloma Working Group response over time,” she said.

Sustained serum BCMA suppression was observed up to month 9, which is likely consistent with ongoing plasma cell aplasia resulting from functional CAR T cell persistence, she explained.

An in vivo examination of the phenotype of the infused CAR T cells showed that while the numbers are small, “so far there seems to be an enrichment for memorylike T cells within the CAR T cell population in the blood post infusion – at least by looking at CD62-ligand T cells.”

There also was a robust and consistent CAR T cell expansion post infusion, which was independent of tumor burden.

“CAR T cells have been detectable up to 9 months post infusion,” she said.

However, the follow-up so far has been very short, she noted. “This action may be underrepresenting the true persistence of these T cells,” she added, explaining that there is only one patient at month 9, whereas all three at month 6 were positive for vector copy.

CRB-402 is ongoing with plans to enroll up to 50 patients. A 300 x 10⁶ dosing cohort has been opened, and doses of 450, 800, and 1200 x 10⁶ CAR+ T cells are planned.

“But longer-term follow-up in a larger patient population will further clarify the depth and durability of the bb21217 tumor response and dose response,” she said.

This study is sponsored by Bluebird Bio. Dr. Shah reported research funding from Bluebird Bio and equity ownership in Indapta Therapeutics, as well as research funding and consulting relationships with other companies.

sworcester@mdedge.com

SOURCE: Shah N et al. ASH 2018, Abstract 488.

SAN DIEGO – Looking to get your study published in a top medical journal? Bob Löwenberg, MD, PhD, editor-in-chief of Blood, says to start thinking about what appeals to readers.

Lowenberg_Bob_NETH_web.jpg

“What do readers want? They want important information with impact in a clinical or biological sense,” Dr. Löwenberg of Erasmus University Rotterdam (the Netherlands) said at the annual meeting of the American Society of Hematology. “Usually they want to get novel information – new and cutting-edge insights, if possible. And readers want to receive access to information that is right. This is about quality.”

Dr. Löwenberg offered several tips for getting published:
 

• Make sure your paper has a “clear message” that comes across in both its title and a concisely written abstract. “When your colleagues are going to scan the journal, they should say ‘Hey, this is an interesting title’ or ‘This is an interesting abstract,’ ” Dr. Löwenberg said.
• Avoid jargon and slang. And don’t fill your paper with abbreviations because that will make it unreadable.
• Don’t just cut and paste the abstract from your meeting submission. Update the information and rewrite it before submitting it. “The abstract is so important because it is the part of your manuscript that’s copied by reference systems,” Dr. Löwenberg said. “It’s more broadly published than your manuscript. Write it in such a way that it tells your entire story in a minimal number of words, without changing the overall message of your paper, and in clear language.”
• Focus on providing important background in the introduction, which usually summarizes existing research.
• “Distill the essentials” in the discussion section. “Don’t repeat the results. Discuss the importance of your findings in relation to the state-of-the-art information that you have presented in the introduction,” he said.
• Beware of plagiarism, which includes “self-plagiarism” – duplicating your own previous research without acknowledgment.
• Understand new rules regarding data-sharing requirements developed by the International Committee of Medical Journal Editors. In order to be considered for publication by the committee’s member journals, clinical trials that begin enrolling participants as of Jan. 1, 2019, must include a data-sharing plan in the trial’s registration.
• Don’t be surprised if your paper is turned down. “We all have experience with rejected papers,” he said. “This is part of the game.”

If you are rejected, you may wish to send a rebuttal – a form of appeal – to the journal. Consider this option if the journal “clearly misunderstood or misrepresented the paper,” he said. “Be polite, try to be unemotional and clear, and never [write] it the same day as when you are still angry about this decision.” Once you send a rebuttal, wait for at least a week for a response. If one doesn’t come, he said, feel free to submit the paper elsewhere.

Dr. Löwenberg reported having no relevant financial disclosures.

SAN DIEGO – Looking to get your study published in a top medical journal? Bob Löwenberg, MD, PhD, editor-in-chief of Blood, says to start thinking about what appeals to readers.

Lowenberg_Bob_NETH_web.jpg

“What do readers want? They want important information with impact in a clinical or biological sense,” Dr. Löwenberg of Erasmus University Rotterdam (the Netherlands) said at the annual meeting of the American Society of Hematology. “Usually they want to get novel information – new and cutting-edge insights, if possible. And readers want to receive access to information that is right. This is about quality.”

Dr. Löwenberg offered several tips for getting published:
 

• Make sure your paper has a “clear message” that comes across in both its title and a concisely written abstract. “When your colleagues are going to scan the journal, they should say ‘Hey, this is an interesting title’ or ‘This is an interesting abstract,’ ” Dr. Löwenberg said.
• Avoid jargon and slang. And don’t fill your paper with abbreviations because that will make it unreadable.
• Don’t just cut and paste the abstract from your meeting submission. Update the information and rewrite it before submitting it. “The abstract is so important because it is the part of your manuscript that’s copied by reference systems,” Dr. Löwenberg said. “It’s more broadly published than your manuscript. Write it in such a way that it tells your entire story in a minimal number of words, without changing the overall message of your paper, and in clear language.”
• Focus on providing important background in the introduction, which usually summarizes existing research.
• “Distill the essentials” in the discussion section. “Don’t repeat the results. Discuss the importance of your findings in relation to the state-of-the-art information that you have presented in the introduction,” he said.
• Beware of plagiarism, which includes “self-plagiarism” – duplicating your own previous research without acknowledgment.
• Understand new rules regarding data-sharing requirements developed by the International Committee of Medical Journal Editors. In order to be considered for publication by the committee’s member journals, clinical trials that begin enrolling participants as of Jan. 1, 2019, must include a data-sharing plan in the trial’s registration.
• Don’t be surprised if your paper is turned down. “We all have experience with rejected papers,” he said. “This is part of the game.”

If you are rejected, you may wish to send a rebuttal – a form of appeal – to the journal. Consider this option if the journal “clearly misunderstood or misrepresented the paper,” he said. “Be polite, try to be unemotional and clear, and never [write] it the same day as when you are still angry about this decision.” Once you send a rebuttal, wait for at least a week for a response. If one doesn’t come, he said, feel free to submit the paper elsewhere.

Dr. Löwenberg reported having no relevant financial disclosures.

SAN DIEGO – Looking to get your study published in a top medical journal? Bob Löwenberg, MD, PhD, editor-in-chief of Blood, says to start thinking about what appeals to readers.

Lowenberg_Bob_NETH_web.jpg

“What do readers want? They want important information with impact in a clinical or biological sense,” Dr. Löwenberg of Erasmus University Rotterdam (the Netherlands) said at the annual meeting of the American Society of Hematology. “Usually they want to get novel information – new and cutting-edge insights, if possible. And readers want to receive access to information that is right. This is about quality.”

Dr. Löwenberg offered several tips for getting published:
 

• Make sure your paper has a “clear message” that comes across in both its title and a concisely written abstract. “When your colleagues are going to scan the journal, they should say ‘Hey, this is an interesting title’ or ‘This is an interesting abstract,’ ” Dr. Löwenberg said.
• Avoid jargon and slang. And don’t fill your paper with abbreviations because that will make it unreadable.
• Don’t just cut and paste the abstract from your meeting submission. Update the information and rewrite it before submitting it. “The abstract is so important because it is the part of your manuscript that’s copied by reference systems,” Dr. Löwenberg said. “It’s more broadly published than your manuscript. Write it in such a way that it tells your entire story in a minimal number of words, without changing the overall message of your paper, and in clear language.”
• Focus on providing important background in the introduction, which usually summarizes existing research.
• “Distill the essentials” in the discussion section. “Don’t repeat the results. Discuss the importance of your findings in relation to the state-of-the-art information that you have presented in the introduction,” he said.
• Beware of plagiarism, which includes “self-plagiarism” – duplicating your own previous research without acknowledgment.
• Understand new rules regarding data-sharing requirements developed by the International Committee of Medical Journal Editors. In order to be considered for publication by the committee’s member journals, clinical trials that begin enrolling participants as of Jan. 1, 2019, must include a data-sharing plan in the trial’s registration.
• Don’t be surprised if your paper is turned down. “We all have experience with rejected papers,” he said. “This is part of the game.”

If you are rejected, you may wish to send a rebuttal – a form of appeal – to the journal. Consider this option if the journal “clearly misunderstood or misrepresented the paper,” he said. “Be polite, try to be unemotional and clear, and never [write] it the same day as when you are still angry about this decision.” Once you send a rebuttal, wait for at least a week for a response. If one doesn’t come, he said, feel free to submit the paper elsewhere.

Dr. Löwenberg reported having no relevant financial disclosures.

SAN DIEGO – Research into hundreds of babies with Down syndrome is providing valuable insight into the genetic roots of leukemia and offering a route to identify newborns at high risk.

Roberts_Irene_UK_web.jpg

“We can now identify children at high risk of developing myeloid leukemia within 4 years” through blood or genetic tests, Irene Roberts, MD, a pediatric hematologist at the University of Oxford’s (England) MRC Weatherall Institute of Molecular Medicine, said at the annual meeting of the American Society of Hematology.

About 2%-3% of children with Down syndrome will develop acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML), according to the National Cancer Institute, rates that are much higher than in the general population.

Research suggests that among children aged 0-4 years with Down syndrome, the standardized incidence ratio (SIR) of AML is 114, compared with other children, Dr. Roberts said. The SIR of ALL is 27 in children aged 1-4 years, she said.

For people with Down syndrome aged 0-60 years, the SIRs are 12 and 13 in AML and ALL, respectively, she said.

In her presentation, Dr. Roberts focused on AML that appears before age 4 years and is preceded by a neonatal preleukemia – transient abnormal myelopoiesis (TAM) – that only occurs in Down syndrome. In most cases, TAM, which occurs with GATA1 mutations, resolves on its own after birth, she said. But in others, the GATA1 mutations continue and cause AML to develop.

Dr. Roberts highlighted her institution’s Oxford Down Syndrome Cohort Study and offered an update to a 2013 report (Blood. 2013 Dec 5;122[24]:3908–17). The study recruited 471 neonates with Down syndrome and followed them for up to 4 years: 341 with no GATA1 mutation and 130 (28%) with the mutation. Dr. Roberts called the latter number a “very high frequency.”

Of those with the mutation, 7 patients (5%) developed AML at a median age of 16 months. None of those without the mutation developed AML.

Also, among the 130 neonates with the mutation, 42% were considered to have “clinical” TAM (more than 10% blasts) and 58% were considered to have “silent” TAM (fewer than 10% blasts).

“We predicted that these babies with clinical TAM would have more severe clinical disease ... and that in fact turned out to be the case,” Dr. Roberts said.

Why is the GATA1 mutation so significant? Research suggests that platelet production is abnormal in neonates with Down syndrome, compared with neonates without it, regardless of whether they have the mutation, Dr. Roberts said.

The mutation doesn’t reduce further platelet count, but does disrupt megakaryopoiesis – the process of the production of platelets. As a result, giant platelets and megakaryocyte fragments are more common, she explained.

Moving forward, research data can be used to identify which children are most at risk, Dr. Roberts said. Newborns with Down syndrome are more likely to survive without leukemia if they have silent TAM, compared with those who have clinical TAM, and if they have an estimated variant allele frequency above 15%, according to findings from the Oxford study.

Children at high risk of AML before age 4 years can be identified by analyzing the percentage of blasts on a smear and/or by analyzing mutation of GATA1, according to Dr. Roberts. However, this cannot be accomplished by the use of a complete blood count (CBC) test, she said, which is used to check for leukemia.

Dr. Roberts called for the development of more guidelines for screening newborns with Down syndrome for leukemia risk. The British Society for Haematology issued testing guidelines, coauthored by Dr. Roberts, in 2018 (Br J Haematol. 2018 Jul;182[2]:200-11).

Dr. Roberts reported having no financial disclosures.

SAN DIEGO – Research into hundreds of babies with Down syndrome is providing valuable insight into the genetic roots of leukemia and offering a route to identify newborns at high risk.

Roberts_Irene_UK_web.jpg

“We can now identify children at high risk of developing myeloid leukemia within 4 years” through blood or genetic tests, Irene Roberts, MD, a pediatric hematologist at the University of Oxford’s (England) MRC Weatherall Institute of Molecular Medicine, said at the annual meeting of the American Society of Hematology.

About 2%-3% of children with Down syndrome will develop acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML), according to the National Cancer Institute, rates that are much higher than in the general population.

Research suggests that among children aged 0-4 years with Down syndrome, the standardized incidence ratio (SIR) of AML is 114, compared with other children, Dr. Roberts said. The SIR of ALL is 27 in children aged 1-4 years, she said.

For people with Down syndrome aged 0-60 years, the SIRs are 12 and 13 in AML and ALL, respectively, she said.

In her presentation, Dr. Roberts focused on AML that appears before age 4 years and is preceded by a neonatal preleukemia – transient abnormal myelopoiesis (TAM) – that only occurs in Down syndrome. In most cases, TAM, which occurs with GATA1 mutations, resolves on its own after birth, she said. But in others, the GATA1 mutations continue and cause AML to develop.

Dr. Roberts highlighted her institution’s Oxford Down Syndrome Cohort Study and offered an update to a 2013 report (Blood. 2013 Dec 5;122[24]:3908–17). The study recruited 471 neonates with Down syndrome and followed them for up to 4 years: 341 with no GATA1 mutation and 130 (28%) with the mutation. Dr. Roberts called the latter number a “very high frequency.”

Of those with the mutation, 7 patients (5%) developed AML at a median age of 16 months. None of those without the mutation developed AML.

Also, among the 130 neonates with the mutation, 42% were considered to have “clinical” TAM (more than 10% blasts) and 58% were considered to have “silent” TAM (fewer than 10% blasts).

“We predicted that these babies with clinical TAM would have more severe clinical disease ... and that in fact turned out to be the case,” Dr. Roberts said.

Why is the GATA1 mutation so significant? Research suggests that platelet production is abnormal in neonates with Down syndrome, compared with neonates without it, regardless of whether they have the mutation, Dr. Roberts said.

The mutation doesn’t reduce further platelet count, but does disrupt megakaryopoiesis – the process of the production of platelets. As a result, giant platelets and megakaryocyte fragments are more common, she explained.

Moving forward, research data can be used to identify which children are most at risk, Dr. Roberts said. Newborns with Down syndrome are more likely to survive without leukemia if they have silent TAM, compared with those who have clinical TAM, and if they have an estimated variant allele frequency above 15%, according to findings from the Oxford study.

Children at high risk of AML before age 4 years can be identified by analyzing the percentage of blasts on a smear and/or by analyzing mutation of GATA1, according to Dr. Roberts. However, this cannot be accomplished by the use of a complete blood count (CBC) test, she said, which is used to check for leukemia.

Dr. Roberts called for the development of more guidelines for screening newborns with Down syndrome for leukemia risk. The British Society for Haematology issued testing guidelines, coauthored by Dr. Roberts, in 2018 (Br J Haematol. 2018 Jul;182[2]:200-11).

Dr. Roberts reported having no financial disclosures.

SAN DIEGO – Research into hundreds of babies with Down syndrome is providing valuable insight into the genetic roots of leukemia and offering a route to identify newborns at high risk.

Roberts_Irene_UK_web.jpg

“We can now identify children at high risk of developing myeloid leukemia within 4 years” through blood or genetic tests, Irene Roberts, MD, a pediatric hematologist at the University of Oxford’s (England) MRC Weatherall Institute of Molecular Medicine, said at the annual meeting of the American Society of Hematology.

About 2%-3% of children with Down syndrome will develop acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML), according to the National Cancer Institute, rates that are much higher than in the general population.

Research suggests that among children aged 0-4 years with Down syndrome, the standardized incidence ratio (SIR) of AML is 114, compared with other children, Dr. Roberts said. The SIR of ALL is 27 in children aged 1-4 years, she said.

For people with Down syndrome aged 0-60 years, the SIRs are 12 and 13 in AML and ALL, respectively, she said.

In her presentation, Dr. Roberts focused on AML that appears before age 4 years and is preceded by a neonatal preleukemia – transient abnormal myelopoiesis (TAM) – that only occurs in Down syndrome. In most cases, TAM, which occurs with GATA1 mutations, resolves on its own after birth, she said. But in others, the GATA1 mutations continue and cause AML to develop.

Dr. Roberts highlighted her institution’s Oxford Down Syndrome Cohort Study and offered an update to a 2013 report (Blood. 2013 Dec 5;122[24]:3908–17). The study recruited 471 neonates with Down syndrome and followed them for up to 4 years: 341 with no GATA1 mutation and 130 (28%) with the mutation. Dr. Roberts called the latter number a “very high frequency.”

Of those with the mutation, 7 patients (5%) developed AML at a median age of 16 months. None of those without the mutation developed AML.

Also, among the 130 neonates with the mutation, 42% were considered to have “clinical” TAM (more than 10% blasts) and 58% were considered to have “silent” TAM (fewer than 10% blasts).

“We predicted that these babies with clinical TAM would have more severe clinical disease ... and that in fact turned out to be the case,” Dr. Roberts said.

Why is the GATA1 mutation so significant? Research suggests that platelet production is abnormal in neonates with Down syndrome, compared with neonates without it, regardless of whether they have the mutation, Dr. Roberts said.

The mutation doesn’t reduce further platelet count, but does disrupt megakaryopoiesis – the process of the production of platelets. As a result, giant platelets and megakaryocyte fragments are more common, she explained.

Moving forward, research data can be used to identify which children are most at risk, Dr. Roberts said. Newborns with Down syndrome are more likely to survive without leukemia if they have silent TAM, compared with those who have clinical TAM, and if they have an estimated variant allele frequency above 15%, according to findings from the Oxford study.

Children at high risk of AML before age 4 years can be identified by analyzing the percentage of blasts on a smear and/or by analyzing mutation of GATA1, according to Dr. Roberts. However, this cannot be accomplished by the use of a complete blood count (CBC) test, she said, which is used to check for leukemia.

Dr. Roberts called for the development of more guidelines for screening newborns with Down syndrome for leukemia risk. The British Society for Haematology issued testing guidelines, coauthored by Dr. Roberts, in 2018 (Br J Haematol. 2018 Jul;182[2]:200-11).

Dr. Roberts reported having no financial disclosures.