Final results of a phase 2, open-label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome

Cancer. 2018 Jul 1;124(13):2758-2765. doi: 10.1002/cncr.31398. Epub 2018 Apr 16.

Abstract

Background: Indisulam possesses anticancer properties through down-regulation of various cell-cycle checkpoint molecules, thereby blocking the phosphorylation of retinoblastoma protein and inducing p53 and p21. Indisulam exhibits synergy with nucleoside analogs and topoisomerase inhibitors.

Methods: The authors designed a phase 2 study of indisulam in combination with idarubicin and cytarabine in patients who had relapsed/refractory acute myeloid leukemia AML and high-risk myelodysplastic syndrome. In stage 1, patients received intravenous indisulam at 400 mg/m2 on days 1 and 8 of a 28-day cycle. If they had no response, then patients received same dose schedule of indisulam followed by intravenous idarubicin 8 mg/m2 daily for 3 days and cytarabine 1.0 g/m2 over 24 hours daily on days 9 through 12 (for those aged < 60 years) or days 9 through 11 (for those aged > 60 years) of a 28-day cycle. Primary endpoints included the overall response rate, and secondary objectives included overall survival.

Results: Forty patients were enrolled. Of the 37 evaluable patients, 31 received indisulam with chemotherapy. Of these, 11 (35%) responded for a median duration of 5.3 months. The estimated 1-year overall survival rate was 51% for responders compared with 8 % for nonresponders (P < .001). The most common grade ≥3 nonhematologic toxicities were electrolyte abnormalities (50%) and febrile neutropenia (28%).

Conclusions: The combination of indisulam with idarubicin and cytarabine yielded a 35% response rate in heavily pretreated patients with AML. With emerging data identifying the expression of DCAF15 (DDB1 and CUL4-associated factor 15) as a potential biomarker for activity, the combination of indisulam with idarubicin and cytarabine should be studied in a biomarker-driven trial or in patients who have splicing factor mutations. Cancer 2018;124:2758-65. © 2018 American Cancer Society. Cancer 2018;124:2758-2765. © 2018 American Cancer Society.

Keywords: acute myeloid leukemia (AML); biomarker; cytarabine; idarubicin; indisulam; relapsed/refractory.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cytarabine / pharmacology
  • Cytarabine / therapeutic use
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Febrile Neutropenia / chemically induced
  • Febrile Neutropenia / epidemiology
  • Female
  • Humans
  • Idarubicin / pharmacology
  • Idarubicin / therapeutic use
  • Kaplan-Meier Estimate
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Middle Aged
  • Mutation
  • Myelodysplastic Syndromes / drug therapy*
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / mortality
  • Myelodysplastic Syndromes / pathology
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / mortality
  • RNA Splicing Factors / genetics
  • Remission Induction / methods*
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Treatment Outcome
  • Water-Electrolyte Balance / drug effects

Substances

  • N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide
  • RNA Splicing Factors
  • Sulfonamides
  • Cytarabine
  • Idarubicin