A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML

Amir T. Fathi, Harry P. Erba, Jeffrey E. Lancet, Eytan M. Stein, Farhad Ravandi, Stefan Faderl, Roland B. Walter, Anjali S. Advani, Daniel J. DeAngelo, Tibor J. Kovacsovics, Anand Jillella, Dale Bixby, Moshe Y. Levy, Megan M. O’Meara, Phoenix A. Ho, Jenna Voellinger, Anthony S. Stein

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 mg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.

Original languageEnglish (US)
Pages (from-to)1125-1133
Number of pages9
JournalBlood
Volume132
Issue number11
DOIs
StatePublished - Sep 13 2018
Externally publishedYes

Fingerprint

Proxy
Acute Myeloid Leukemia
decitabine
Cytogenetics
Toxicity
Therapeutics
Azacitidine
Oncology
Survival
Flow cytometry
Residual Neoplasm
Cytotoxicity
Dimers
Flow Cytometry
Blood
Safety
Recurrence
Recovery
Mortality
Antibodies

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Fathi, A. T., Erba, H. P., Lancet, J. E., Stein, E. M., Ravandi, F., Faderl, S., ... Stein, A. S. (2018). A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML. Blood, 132(11), 1125-1133. https://doi.org/10.1182/blood-2018-03-841171

A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML. / Fathi, Amir T.; Erba, Harry P.; Lancet, Jeffrey E.; Stein, Eytan M.; Ravandi, Farhad; Faderl, Stefan; Walter, Roland B.; Advani, Anjali S.; DeAngelo, Daniel J.; Kovacsovics, Tibor J.; Jillella, Anand; Bixby, Dale; Levy, Moshe Y.; O’Meara, Megan M.; Ho, Phoenix A.; Voellinger, Jenna; Stein, Anthony S.

In: Blood, Vol. 132, No. 11, 13.09.2018, p. 1125-1133.

Research output: Contribution to journalArticle

Fathi, AT, Erba, HP, Lancet, JE, Stein, EM, Ravandi, F, Faderl, S, Walter, RB, Advani, AS, DeAngelo, DJ, Kovacsovics, TJ, Jillella, A, Bixby, D, Levy, MY, O’Meara, MM, Ho, PA, Voellinger, J & Stein, AS 2018, 'A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML', Blood, vol. 132, no. 11, pp. 1125-1133. https://doi.org/10.1182/blood-2018-03-841171
Fathi, Amir T. ; Erba, Harry P. ; Lancet, Jeffrey E. ; Stein, Eytan M. ; Ravandi, Farhad ; Faderl, Stefan ; Walter, Roland B. ; Advani, Anjali S. ; DeAngelo, Daniel J. ; Kovacsovics, Tibor J. ; Jillella, Anand ; Bixby, Dale ; Levy, Moshe Y. ; O’Meara, Megan M. ; Ho, Phoenix A. ; Voellinger, Jenna ; Stein, Anthony S. / A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML. In: Blood. 2018 ; Vol. 132, No. 11. pp. 1125-1133.
@article{f3a28968557e4da69f4c02e05c413c65,
title = "A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML",
abstract = "Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 mg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38{\%}) or intermediate (62{\%}) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2{\%} and 8{\%}, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70{\%}. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.",
author = "Fathi, {Amir T.} and Erba, {Harry P.} and Lancet, {Jeffrey E.} and Stein, {Eytan M.} and Farhad Ravandi and Stefan Faderl and Walter, {Roland B.} and Advani, {Anjali S.} and DeAngelo, {Daniel J.} and Kovacsovics, {Tibor J.} and Anand Jillella and Dale Bixby and Levy, {Moshe Y.} and O’Meara, {Megan M.} and Ho, {Phoenix A.} and Jenna Voellinger and Stein, {Anthony S.}",
year = "2018",
month = "9",
day = "13",
doi = "10.1182/blood-2018-03-841171",
language = "English (US)",
volume = "132",
pages = "1125--1133",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "11",

}

TY - JOUR

T1 - A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML

AU - Fathi, Amir T.

AU - Erba, Harry P.

AU - Lancet, Jeffrey E.

AU - Stein, Eytan M.

AU - Ravandi, Farhad

AU - Faderl, Stefan

AU - Walter, Roland B.

AU - Advani, Anjali S.

AU - DeAngelo, Daniel J.

AU - Kovacsovics, Tibor J.

AU - Jillella, Anand

AU - Bixby, Dale

AU - Levy, Moshe Y.

AU - O’Meara, Megan M.

AU - Ho, Phoenix A.

AU - Voellinger, Jenna

AU - Stein, Anthony S.

PY - 2018/9/13

Y1 - 2018/9/13

N2 - Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 mg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.

AB - Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 mg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.

UR - http://www.scopus.com/inward/record.url?scp=85053117319&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053117319&partnerID=8YFLogxK

U2 - 10.1182/blood-2018-03-841171

DO - 10.1182/blood-2018-03-841171

M3 - Article

VL - 132

SP - 1125

EP - 1133

JO - Blood

JF - Blood

SN - 0006-4971

IS - 11

ER -