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NEWPORT BEACH, CALIF. – Adding pembrolizumab after high-dose cytarabine in patients with relapsed or refractory acute myeloid leukemia (AML) appears safe and feasible and shows promising efficacy, according to early results from a multicenter phase 2 study.
The overall response rate to this novel treatment approach in 19 evaluable patients (of 20 enrolled to date) was 42%, with 7 patients (37%) achieving a complete response or complete response with incomplete blood count recovery, and 1 (5%) achieving a partial response, reported Joshua Zeidner, MD, in a poster at the Acute Leukemia Forum of Hemedicus.
Those who went on to allogeneic stem cell transplant included three patients in complete response and one of the five who received pembrolizumab maintenance. That patient on pembrolizumab maintenance went to transplant after two cycles, three others on it relapsed after a median duration of 2.8 months in complete response, and one initially achieved a partial response and had stable disease for a “pretty remarkable” 12 cycles before progressing, he said.
Preliminary analyses in the first six patients, including three with complete response and three nonresponders, showed increased posttreatment diversity of the T-cell receptor repertoire versus baseline in peripheral blood CD8+ T cells in the complete response patients, compared with nonresponders. This suggests that T-cell diversity at baseline is a promising biomarker for programmed death-1 (PD-1) blockade response, Dr. Zeidner noted.
PD-1 suppresses immune activation, and the PD-1 pathway is exploited by AML cells to evade immune surveillance, Dr. Zeidner explained. PD-1 blockade has been shown to have antileukemic effects in vivo, there is expression of multiple coinhibitory receptors in AML patients at the time of diagnosis (that persists in refractory AML), and the ligand for PD-1 is up-regulated on AML blasts, particularly in relapsed/refractory disease, he added.
He and his colleagues hypothesized that targeting PD-1 with pembrolizumab after high-dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T cell–mediated antileukemic immune response and lead to improved efficacy in patients with relapsed or refractory AML.
The ongoing study, with planned enrollment of 37 patients, includes patients aged 18-70 years with relapsed/refractory AML (median age of first 20 enrolled is 54 years). Those under age 60 years receive 2 g/m2 of intravenous HiDAC every 12 hours on days 1-5, and those over age 60 years receive 1.5 g/m2 every 12 hours on days 1-5. In both age groups, this is followed by intravenous pembrolizumab given at 200 mg on day 14.
Overall responders receive maintenance phase intravenous pembrolizumab at 200 mg every 3 weeks for up to 2 years until relapse or progression. Patients are allowed to proceed to stem cell transplant before or after the maintenance phase.
A number of correlative studies, including serial peripheral blood and bone marrow flow cytometry and T-cell receptor clonality studies, also are being conducted to look for predictive biomarkers of response, Dr. Zeidner said.
The study population to date is a relatively young, very-high-risk subgroup of AML patients; European LeukemiaNet-2017 genetic risk status was favorable in only 3 of the first 20 patients (15%), intermediate in 7 (35%), and adverse in 10 (50%). Treatment has been well tolerated; toxicities have been rare and manageable. “Overall, there have been no unexpected toxicities,” he said.
The most common overall toxicities included febrile neutropenia in 70% of patients; transaminitis (including one grade 3 case) in 50%, hyperbilirubinemia in 35%, and fatigue, increased alkaline phosphatase, and rash in 25% each.
Novel therapies for relapsed/refractory AML are urgently needed, and these early results demonstrated the safety and feasibility of adding pembrolizumab after HiDAC chemotherapy in relapsed/refractory AML patients. The preliminary finding that broadening of the immune repertoire, which may occur via increasing T-cell responses beyond endogenous viral responses, was associated with complete response was particularly encouraging, Dr. Zeidner said. The investigators hope to determine predictors of response to immune checkpoint blockade in AML through a comprehensive immune biomarker discovery approach, he added.
This study was funded by Merck. Dr. Zeidner reported having no financial disclosures. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
SOURCE: Zeidner J et al. ALF 2018, Poster Session.
NEWPORT BEACH, CALIF. – Adding pembrolizumab after high-dose cytarabine in patients with relapsed or refractory acute myeloid leukemia (AML) appears safe and feasible and shows promising efficacy, according to early results from a multicenter phase 2 study.
The overall response rate to this novel treatment approach in 19 evaluable patients (of 20 enrolled to date) was 42%, with 7 patients (37%) achieving a complete response or complete response with incomplete blood count recovery, and 1 (5%) achieving a partial response, reported Joshua Zeidner, MD, in a poster at the Acute Leukemia Forum of Hemedicus.
Those who went on to allogeneic stem cell transplant included three patients in complete response and one of the five who received pembrolizumab maintenance. That patient on pembrolizumab maintenance went to transplant after two cycles, three others on it relapsed after a median duration of 2.8 months in complete response, and one initially achieved a partial response and had stable disease for a “pretty remarkable” 12 cycles before progressing, he said.
Preliminary analyses in the first six patients, including three with complete response and three nonresponders, showed increased posttreatment diversity of the T-cell receptor repertoire versus baseline in peripheral blood CD8+ T cells in the complete response patients, compared with nonresponders. This suggests that T-cell diversity at baseline is a promising biomarker for programmed death-1 (PD-1) blockade response, Dr. Zeidner noted.
PD-1 suppresses immune activation, and the PD-1 pathway is exploited by AML cells to evade immune surveillance, Dr. Zeidner explained. PD-1 blockade has been shown to have antileukemic effects in vivo, there is expression of multiple coinhibitory receptors in AML patients at the time of diagnosis (that persists in refractory AML), and the ligand for PD-1 is up-regulated on AML blasts, particularly in relapsed/refractory disease, he added.
He and his colleagues hypothesized that targeting PD-1 with pembrolizumab after high-dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T cell–mediated antileukemic immune response and lead to improved efficacy in patients with relapsed or refractory AML.
The ongoing study, with planned enrollment of 37 patients, includes patients aged 18-70 years with relapsed/refractory AML (median age of first 20 enrolled is 54 years). Those under age 60 years receive 2 g/m2 of intravenous HiDAC every 12 hours on days 1-5, and those over age 60 years receive 1.5 g/m2 every 12 hours on days 1-5. In both age groups, this is followed by intravenous pembrolizumab given at 200 mg on day 14.
Overall responders receive maintenance phase intravenous pembrolizumab at 200 mg every 3 weeks for up to 2 years until relapse or progression. Patients are allowed to proceed to stem cell transplant before or after the maintenance phase.
A number of correlative studies, including serial peripheral blood and bone marrow flow cytometry and T-cell receptor clonality studies, also are being conducted to look for predictive biomarkers of response, Dr. Zeidner said.
The study population to date is a relatively young, very-high-risk subgroup of AML patients; European LeukemiaNet-2017 genetic risk status was favorable in only 3 of the first 20 patients (15%), intermediate in 7 (35%), and adverse in 10 (50%). Treatment has been well tolerated; toxicities have been rare and manageable. “Overall, there have been no unexpected toxicities,” he said.
The most common overall toxicities included febrile neutropenia in 70% of patients; transaminitis (including one grade 3 case) in 50%, hyperbilirubinemia in 35%, and fatigue, increased alkaline phosphatase, and rash in 25% each.
Novel therapies for relapsed/refractory AML are urgently needed, and these early results demonstrated the safety and feasibility of adding pembrolizumab after HiDAC chemotherapy in relapsed/refractory AML patients. The preliminary finding that broadening of the immune repertoire, which may occur via increasing T-cell responses beyond endogenous viral responses, was associated with complete response was particularly encouraging, Dr. Zeidner said. The investigators hope to determine predictors of response to immune checkpoint blockade in AML through a comprehensive immune biomarker discovery approach, he added.
This study was funded by Merck. Dr. Zeidner reported having no financial disclosures. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
SOURCE: Zeidner J et al. ALF 2018, Poster Session.
NEWPORT BEACH, CALIF. – Adding pembrolizumab after high-dose cytarabine in patients with relapsed or refractory acute myeloid leukemia (AML) appears safe and feasible and shows promising efficacy, according to early results from a multicenter phase 2 study.
The overall response rate to this novel treatment approach in 19 evaluable patients (of 20 enrolled to date) was 42%, with 7 patients (37%) achieving a complete response or complete response with incomplete blood count recovery, and 1 (5%) achieving a partial response, reported Joshua Zeidner, MD, in a poster at the Acute Leukemia Forum of Hemedicus.
Those who went on to allogeneic stem cell transplant included three patients in complete response and one of the five who received pembrolizumab maintenance. That patient on pembrolizumab maintenance went to transplant after two cycles, three others on it relapsed after a median duration of 2.8 months in complete response, and one initially achieved a partial response and had stable disease for a “pretty remarkable” 12 cycles before progressing, he said.
Preliminary analyses in the first six patients, including three with complete response and three nonresponders, showed increased posttreatment diversity of the T-cell receptor repertoire versus baseline in peripheral blood CD8+ T cells in the complete response patients, compared with nonresponders. This suggests that T-cell diversity at baseline is a promising biomarker for programmed death-1 (PD-1) blockade response, Dr. Zeidner noted.
PD-1 suppresses immune activation, and the PD-1 pathway is exploited by AML cells to evade immune surveillance, Dr. Zeidner explained. PD-1 blockade has been shown to have antileukemic effects in vivo, there is expression of multiple coinhibitory receptors in AML patients at the time of diagnosis (that persists in refractory AML), and the ligand for PD-1 is up-regulated on AML blasts, particularly in relapsed/refractory disease, he added.
He and his colleagues hypothesized that targeting PD-1 with pembrolizumab after high-dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T cell–mediated antileukemic immune response and lead to improved efficacy in patients with relapsed or refractory AML.
The ongoing study, with planned enrollment of 37 patients, includes patients aged 18-70 years with relapsed/refractory AML (median age of first 20 enrolled is 54 years). Those under age 60 years receive 2 g/m2 of intravenous HiDAC every 12 hours on days 1-5, and those over age 60 years receive 1.5 g/m2 every 12 hours on days 1-5. In both age groups, this is followed by intravenous pembrolizumab given at 200 mg on day 14.
Overall responders receive maintenance phase intravenous pembrolizumab at 200 mg every 3 weeks for up to 2 years until relapse or progression. Patients are allowed to proceed to stem cell transplant before or after the maintenance phase.
A number of correlative studies, including serial peripheral blood and bone marrow flow cytometry and T-cell receptor clonality studies, also are being conducted to look for predictive biomarkers of response, Dr. Zeidner said.
The study population to date is a relatively young, very-high-risk subgroup of AML patients; European LeukemiaNet-2017 genetic risk status was favorable in only 3 of the first 20 patients (15%), intermediate in 7 (35%), and adverse in 10 (50%). Treatment has been well tolerated; toxicities have been rare and manageable. “Overall, there have been no unexpected toxicities,” he said.
The most common overall toxicities included febrile neutropenia in 70% of patients; transaminitis (including one grade 3 case) in 50%, hyperbilirubinemia in 35%, and fatigue, increased alkaline phosphatase, and rash in 25% each.
Novel therapies for relapsed/refractory AML are urgently needed, and these early results demonstrated the safety and feasibility of adding pembrolizumab after HiDAC chemotherapy in relapsed/refractory AML patients. The preliminary finding that broadening of the immune repertoire, which may occur via increasing T-cell responses beyond endogenous viral responses, was associated with complete response was particularly encouraging, Dr. Zeidner said. The investigators hope to determine predictors of response to immune checkpoint blockade in AML through a comprehensive immune biomarker discovery approach, he added.
This study was funded by Merck. Dr. Zeidner reported having no financial disclosures. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
SOURCE: Zeidner J et al. ALF 2018, Poster Session.
REPORTING FROM ALF 2018
Key clinical point:
Major finding: The overall response rate was 42%; 37% of patients achieved complete response or CR with incomplete blood count recovery, and 5% achieved partial response.
Study details: A multicenter, phase 2 study with early results from the first 20 patients enrolled.
Disclosures: This study was funded by Merck. Dr. Zeidner reported having no financial disclosures. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
Source: Zeidner J et al. ALF 2018, Poster Session.