Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome

Jorge E. Cortes, Florian H. Heidel, Andrzej Hellmann, Walter Fiedler, B Douglas Smith, Tadeusz Robak, Pau Montesinos, Daniel A. Pollyea, Pierre DesJardins, Oliver Ottmann, Weidong Wendy Ma, M. Naveed Shaik, A. Douglas Laird, Mirjana Zeremski, Ashleigh O’Connell, Geoffrey Chan, Michael Heuser

Research output: Contribution to journalArticle

Abstract

Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9–9.9) months with glasdegib/LDAC and 4.9 (3.5–6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39–0.67, P = 0.0004). Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit–risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy.

Original languageEnglish (US)
JournalLeukemia
DOIs
StateAccepted/In press - Jan 1 2018

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Myelodysplastic Syndromes
Cytarabine
Acute Myeloid Leukemia
Pneumonia
Confidence Intervals
Drug Therapy
Survival
Cytogenetics
Causality
Multicenter Studies
Fatigue

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. / Cortes, Jorge E.; Heidel, Florian H.; Hellmann, Andrzej; Fiedler, Walter; Smith, B Douglas; Robak, Tadeusz; Montesinos, Pau; Pollyea, Daniel A.; DesJardins, Pierre; Ottmann, Oliver; Ma, Weidong Wendy; Shaik, M. Naveed; Laird, A. Douglas; Zeremski, Mirjana; O’Connell, Ashleigh; Chan, Geoffrey; Heuser, Michael.

In: Leukemia, 01.01.2018.

Research output: Contribution to journalArticle

Cortes, JE, Heidel, FH, Hellmann, A, Fiedler, W, Smith, BD, Robak, T, Montesinos, P, Pollyea, DA, DesJardins, P, Ottmann, O, Ma, WW, Shaik, MN, Laird, AD, Zeremski, M, O’Connell, A, Chan, G & Heuser, M 2018, 'Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome', Leukemia. https://doi.org/10.1038/s41375-018-0312-9
Cortes, Jorge E. ; Heidel, Florian H. ; Hellmann, Andrzej ; Fiedler, Walter ; Smith, B Douglas ; Robak, Tadeusz ; Montesinos, Pau ; Pollyea, Daniel A. ; DesJardins, Pierre ; Ottmann, Oliver ; Ma, Weidong Wendy ; Shaik, M. Naveed ; Laird, A. Douglas ; Zeremski, Mirjana ; O’Connell, Ashleigh ; Chan, Geoffrey ; Heuser, Michael. / Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. In: Leukemia. 2018.
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abstract = "Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80{\%} confidence interval [CI]) overall survival was 8.8 (6.9–9.9) months with glasdegib/LDAC and 4.9 (3.5–6.0) months with LDAC (hazard ratio, 0.51; 80{\%} CI, 0.39–0.67, P = 0.0004). Fifteen (17.0{\%}) and 1 (2.3{\%}) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7{\%}) and fatigue (14.3{\%}) with glasdegib/LDAC and pneumonia (14.6{\%}) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit–risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy.",
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AU - Cortes, Jorge E.

AU - Heidel, Florian H.

AU - Hellmann, Andrzej

AU - Fiedler, Walter

AU - Smith, B Douglas

AU - Robak, Tadeusz

AU - Montesinos, Pau

AU - Pollyea, Daniel A.

AU - DesJardins, Pierre

AU - Ottmann, Oliver

AU - Ma, Weidong Wendy

AU - Shaik, M. Naveed

AU - Laird, A. Douglas

AU - Zeremski, Mirjana

AU - O’Connell, Ashleigh

AU - Chan, Geoffrey

AU - Heuser, Michael

PY - 2018/1/1

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N2 - Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9–9.9) months with glasdegib/LDAC and 4.9 (3.5–6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39–0.67, P = 0.0004). Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit–risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy.

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