Safety, Outcomes, and T-Cell Characteristics in Patients with Relapsed or Refractory MDS or CMML Treated with Atezolizumab in Combination with Guadecitabine
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Safety, Outcomes, and T-Cell Characteristics in Patients with Relapsed or Refractory MDS or CMML Treated with Atezolizumab in Combination with Guadecitabine. / O'Connell, Casey L.; Baer, Maria R.; Ørskov, Andreas Due; Saini, Sunil Kumar; Duong, Vu H.; Kropf, Patricia; Hansen, Jakob Werner; Tsao-Wei, Denice; Jang, Hyo Sik; Emadi, Ashkan; Holmberg-Thyden, Staffan; Cowland, Jack; Brinker, Brett T.; Horwood, Kristin; Burgos, Ryan; Hostetter, Galen; Youngblood, Benjamin A.; Hadrup, Sine Reker; Issa, Jean Pierre; Jones, Peter; Baylin, Stephen B.; Siddiqi, Imran; Grønbaek, Kirsten.
In: Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 28, No. 24, 2022, p. 5306-5316.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Safety, Outcomes, and T-Cell Characteristics in Patients with Relapsed or Refractory MDS or CMML Treated with Atezolizumab in Combination with Guadecitabine
AU - O'Connell, Casey L.
AU - Baer, Maria R.
AU - Ørskov, Andreas Due
AU - Saini, Sunil Kumar
AU - Duong, Vu H.
AU - Kropf, Patricia
AU - Hansen, Jakob Werner
AU - Tsao-Wei, Denice
AU - Jang, Hyo Sik
AU - Emadi, Ashkan
AU - Holmberg-Thyden, Staffan
AU - Cowland, Jack
AU - Brinker, Brett T.
AU - Horwood, Kristin
AU - Burgos, Ryan
AU - Hostetter, Galen
AU - Youngblood, Benjamin A.
AU - Hadrup, Sine Reker
AU - Issa, Jean Pierre
AU - Jones, Peter
AU - Baylin, Stephen B.
AU - Siddiqi, Imran
AU - Grønbaek, Kirsten
N1 - Publisher Copyright: ©2022 American Association for Cancer Research.
PY - 2022
Y1 - 2022
N2 - PURPOSE: We hypothesized that resistance to hypomethylating agents (HMA) among patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) would be overcome by combining a programmed death-ligand 1 antibody with an HMA. PATIENTS AND METHODS: We conducted a Phase I/II, multicenter clinical trial for patients with MDS not achieving an International Working Group response after at least 4 cycles of an HMA ("refractory") or progressing after a response ("relapsed") with 3+ or higher risk MDS by the revised International Prognostic Scoring System (IPSS-R) and CMML-1 or -2. Phase I consisted of a 3+3 dose-escalation design beginning with guadecitabine at 30 mg/m2 and escalating to 60 mg/m2 Days 1 to 5 with fixed-dose atezolizumab: 840 mg intravenously Days 8 and 22 of a 28-day cycle. Primary endpoints were safety and tolerability; secondary endpoints were overall response rate (ORR) and survival. RESULTS: Thirty-three patients, median age 73 (range 54-85), were treated. Thirty patients had MDS and 3 had CMML, with 30% relapsed and 70% refractory. No dose-limiting toxicities were observed in Phase I. There were 3 (9%) deaths in ≤ 30 days. Five patients (16%) came off study for drug-related toxicity. Immune-related adverse events (IRAE) occurred in 12 (36%) patients (4 grade 3, 3 grade 2, and 5 grade1). ORR was 33% [95% confidence interval (CI), 19%-52%] with 2 complete remission (CR), 3 hematologic improvement, 5 marrow CR, and 1 partial remission. Median overall survival was 15.1 (95% CI, 8.5-25.3) months. CONCLUSIONS: Guadecitabine with atezolizumab has modest efficacy with manageable IRAEs and typical cytopenia-related safety concerns for patients with relapsed or refractory MDS and CMML.
AB - PURPOSE: We hypothesized that resistance to hypomethylating agents (HMA) among patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) would be overcome by combining a programmed death-ligand 1 antibody with an HMA. PATIENTS AND METHODS: We conducted a Phase I/II, multicenter clinical trial for patients with MDS not achieving an International Working Group response after at least 4 cycles of an HMA ("refractory") or progressing after a response ("relapsed") with 3+ or higher risk MDS by the revised International Prognostic Scoring System (IPSS-R) and CMML-1 or -2. Phase I consisted of a 3+3 dose-escalation design beginning with guadecitabine at 30 mg/m2 and escalating to 60 mg/m2 Days 1 to 5 with fixed-dose atezolizumab: 840 mg intravenously Days 8 and 22 of a 28-day cycle. Primary endpoints were safety and tolerability; secondary endpoints were overall response rate (ORR) and survival. RESULTS: Thirty-three patients, median age 73 (range 54-85), were treated. Thirty patients had MDS and 3 had CMML, with 30% relapsed and 70% refractory. No dose-limiting toxicities were observed in Phase I. There were 3 (9%) deaths in ≤ 30 days. Five patients (16%) came off study for drug-related toxicity. Immune-related adverse events (IRAE) occurred in 12 (36%) patients (4 grade 3, 3 grade 2, and 5 grade1). ORR was 33% [95% confidence interval (CI), 19%-52%] with 2 complete remission (CR), 3 hematologic improvement, 5 marrow CR, and 1 partial remission. Median overall survival was 15.1 (95% CI, 8.5-25.3) months. CONCLUSIONS: Guadecitabine with atezolizumab has modest efficacy with manageable IRAEs and typical cytopenia-related safety concerns for patients with relapsed or refractory MDS and CMML.
U2 - 10.1158/1078-0432.CCR-22-1810
DO - 10.1158/1078-0432.CCR-22-1810
M3 - Journal article
C2 - 36222848
AN - SCOPUS:85144585294
VL - 28
SP - 5306
EP - 5316
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 24
ER -
ID: 341062419