Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: north American intergroup study swog s1117

Mikkael A. Sekeres, Megan Othus, Alan F. List, Olatoyosi Odenike, Richard M. Stone, Steven D. Gore, Mark R Litzow, Rena Buckstein, Min Fang, Diane Roulston, Clara D. Bloomfield, Anna Moseley, Aziz Nazha, Yanming Zhang, Mario R. Velasco, Rakesh Gaur, Ehab Atallah, Eyal C. Attar, Elina K. Cook, Alyssa H. CullMichael J. Rauh, Frederick R. Appelbaum, Harry P. Erba

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Abstract

Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m2/day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR. Results Of 277 patients from 90 centers, 92 received azacitidine, 93 received azacitidine plus lenalidomide, and 92 received azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31%) were female, and 53 patients (19%) had CMML. Serious adverse events were similar across arms, although combination-arm patients were more likely to undergo nonprotocol-defined dose modifications (P, .001).With a median follow-up of 23 months (range, 1 to 43 months), the ORR was 38% for patients receiving azacitidine, 49% for azacitidine plus lenalidomide (P = .14 v azacitidine), and 27% for azacitidine plus vorinostat (P = .16 v azacitidine). For patients with CMML, ORR was higher for azacitidine plus lenalidomide versus azacitidine (68% v 28%, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. ORR was higher with mutations in DNMT3A and lower for SRSF2, whereas ORR duration improved with fewer mutations. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio, 1.30; P = .05). Conclusion Patients with higher-risk MDS treated with azacitidine-based combinations had similar ORR to azacitidine monotherapy, although patients with CMML benefitted from azacitidine plus lenalidomide. The efficacy of combination regimens may have been affected by dose modifications.

Original languageEnglish (US)
Pages (from-to)2745-2753
Number of pages9
JournalJournal of Clinical Oncology
Volume35
Issue number24
DOIs
StatePublished - Aug 20 2017
Externally publishedYes

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Leukemia, Myelomonocytic, Chronic
Azacitidine
Myelodysplastic Syndromes
vorinostat
lenalidomide

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia : north American intergroup study swog s1117. / Sekeres, Mikkael A.; Othus, Megan; List, Alan F.; Odenike, Olatoyosi; Stone, Richard M.; Gore, Steven D.; Litzow, Mark R; Buckstein, Rena; Fang, Min; Roulston, Diane; Bloomfield, Clara D.; Moseley, Anna; Nazha, Aziz; Zhang, Yanming; Velasco, Mario R.; Gaur, Rakesh; Atallah, Ehab; Attar, Eyal C.; Cook, Elina K.; Cull, Alyssa H.; Rauh, Michael J.; Appelbaum, Frederick R.; Erba, Harry P.

In: Journal of Clinical Oncology, Vol. 35, No. 24, 20.08.2017, p. 2745-2753.

Research output: Contribution to journalArticle

Sekeres, MA, Othus, M, List, AF, Odenike, O, Stone, RM, Gore, SD, Litzow, MR, Buckstein, R, Fang, M, Roulston, D, Bloomfield, CD, Moseley, A, Nazha, A, Zhang, Y, Velasco, MR, Gaur, R, Atallah, E, Attar, EC, Cook, EK, Cull, AH, Rauh, MJ, Appelbaum, FR & Erba, HP 2017, 'Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: north American intergroup study swog s1117', Journal of Clinical Oncology, vol. 35, no. 24, pp. 2745-2753. https://doi.org/10.1200/JCO.2015.66.2510
Sekeres, Mikkael A. ; Othus, Megan ; List, Alan F. ; Odenike, Olatoyosi ; Stone, Richard M. ; Gore, Steven D. ; Litzow, Mark R ; Buckstein, Rena ; Fang, Min ; Roulston, Diane ; Bloomfield, Clara D. ; Moseley, Anna ; Nazha, Aziz ; Zhang, Yanming ; Velasco, Mario R. ; Gaur, Rakesh ; Atallah, Ehab ; Attar, Eyal C. ; Cook, Elina K. ; Cull, Alyssa H. ; Rauh, Michael J. ; Appelbaum, Frederick R. ; Erba, Harry P. / Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia : north American intergroup study swog s1117. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 24. pp. 2745-2753.
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abstract = "Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m2/day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR. Results Of 277 patients from 90 centers, 92 received azacitidine, 93 received azacitidine plus lenalidomide, and 92 received azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31{\%}) were female, and 53 patients (19{\%}) had CMML. Serious adverse events were similar across arms, although combination-arm patients were more likely to undergo nonprotocol-defined dose modifications (P, .001).With a median follow-up of 23 months (range, 1 to 43 months), the ORR was 38{\%} for patients receiving azacitidine, 49{\%} for azacitidine plus lenalidomide (P = .14 v azacitidine), and 27{\%} for azacitidine plus vorinostat (P = .16 v azacitidine). For patients with CMML, ORR was higher for azacitidine plus lenalidomide versus azacitidine (68{\%} v 28{\%}, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. ORR was higher with mutations in DNMT3A and lower for SRSF2, whereas ORR duration improved with fewer mutations. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio, 1.30; P = .05). Conclusion Patients with higher-risk MDS treated with azacitidine-based combinations had similar ORR to azacitidine monotherapy, although patients with CMML benefitted from azacitidine plus lenalidomide. The efficacy of combination regimens may have been affected by dose modifications.",
author = "Sekeres, {Mikkael A.} and Megan Othus and List, {Alan F.} and Olatoyosi Odenike and Stone, {Richard M.} and Gore, {Steven D.} and Litzow, {Mark R} and Rena Buckstein and Min Fang and Diane Roulston and Bloomfield, {Clara D.} and Anna Moseley and Aziz Nazha and Yanming Zhang and Velasco, {Mario R.} and Rakesh Gaur and Ehab Atallah and Attar, {Eyal C.} and Cook, {Elina K.} and Cull, {Alyssa H.} and Rauh, {Michael J.} and Appelbaum, {Frederick R.} and Erba, {Harry P.}",
year = "2017",
month = "8",
day = "20",
doi = "10.1200/JCO.2015.66.2510",
language = "English (US)",
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TY - JOUR

T1 - Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia

T2 - north American intergroup study swog s1117

AU - Sekeres, Mikkael A.

AU - Othus, Megan

AU - List, Alan F.

AU - Odenike, Olatoyosi

AU - Stone, Richard M.

AU - Gore, Steven D.

AU - Litzow, Mark R

AU - Buckstein, Rena

AU - Fang, Min

AU - Roulston, Diane

AU - Bloomfield, Clara D.

AU - Moseley, Anna

AU - Nazha, Aziz

AU - Zhang, Yanming

AU - Velasco, Mario R.

AU - Gaur, Rakesh

AU - Atallah, Ehab

AU - Attar, Eyal C.

AU - Cook, Elina K.

AU - Cull, Alyssa H.

AU - Rauh, Michael J.

AU - Appelbaum, Frederick R.

AU - Erba, Harry P.

PY - 2017/8/20

Y1 - 2017/8/20

N2 - Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m2/day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR. Results Of 277 patients from 90 centers, 92 received azacitidine, 93 received azacitidine plus lenalidomide, and 92 received azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31%) were female, and 53 patients (19%) had CMML. Serious adverse events were similar across arms, although combination-arm patients were more likely to undergo nonprotocol-defined dose modifications (P, .001).With a median follow-up of 23 months (range, 1 to 43 months), the ORR was 38% for patients receiving azacitidine, 49% for azacitidine plus lenalidomide (P = .14 v azacitidine), and 27% for azacitidine plus vorinostat (P = .16 v azacitidine). For patients with CMML, ORR was higher for azacitidine plus lenalidomide versus azacitidine (68% v 28%, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. ORR was higher with mutations in DNMT3A and lower for SRSF2, whereas ORR duration improved with fewer mutations. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio, 1.30; P = .05). Conclusion Patients with higher-risk MDS treated with azacitidine-based combinations had similar ORR to azacitidine monotherapy, although patients with CMML benefitted from azacitidine plus lenalidomide. The efficacy of combination regimens may have been affected by dose modifications.

AB - Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m2/day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR. Results Of 277 patients from 90 centers, 92 received azacitidine, 93 received azacitidine plus lenalidomide, and 92 received azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31%) were female, and 53 patients (19%) had CMML. Serious adverse events were similar across arms, although combination-arm patients were more likely to undergo nonprotocol-defined dose modifications (P, .001).With a median follow-up of 23 months (range, 1 to 43 months), the ORR was 38% for patients receiving azacitidine, 49% for azacitidine plus lenalidomide (P = .14 v azacitidine), and 27% for azacitidine plus vorinostat (P = .16 v azacitidine). For patients with CMML, ORR was higher for azacitidine plus lenalidomide versus azacitidine (68% v 28%, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. ORR was higher with mutations in DNMT3A and lower for SRSF2, whereas ORR duration improved with fewer mutations. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio, 1.30; P = .05). Conclusion Patients with higher-risk MDS treated with azacitidine-based combinations had similar ORR to azacitidine monotherapy, although patients with CMML benefitted from azacitidine plus lenalidomide. The efficacy of combination regimens may have been affected by dose modifications.

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