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Phase I study of oral 5-azacytidine and romidepsin in patients with PTCL

Nov 21, 2019

In a recent articleon Lymphoma Hub, the use of oral 5-azacytidine (AZA) and romidepsin (ROMI) to target epigenetic dysregulation in the treatment of peripheral T-cell lymphoma (PTCL) was discussed. The article centered on the phase II portion of a phase I/II trial ( NCT01998035) which was presented at the International Conference on Malignant Lymphoma (ICML) in June 2019. Owen O’Connor, Columbia University Medical Center, US, and team have now published the phase I part of the study in Blood. 1

This phase I trial assessed the effect of AZA plus ROMI in the treatment of relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) and Hodgkin Lymphoma (HL), with emphasis on patients with PTCL. The primary objectives were to determine the dose-limiting toxicity (DLT) of the combined treatment in the first cycle and the maximum tolerated dose (MTD), which is defined as the highest dose level resulting in less than a third of the treatment cohort experiencing DLT in the first cycle.

Study design

  • A total of 26 patients were enrolled initially and a further five patients with PTCL were recruited as an ‘expansion cohort’
  • Patients had been pre-treated with a median of six prior therapies (range, 1–15), with 14 (54%) and five (19%) having had autologous (A) hematopoietic stem cell therapy (HSCT) and allogeneic (allo-) HSCT, respectively
  • Treatment:
    • Cohort 1 (n= 6), 21-day cycles: AZA 100mg Days 1–14, ROMI 10mg/m 2Days 8 and 15
    • Cohort 2 (n= 3), 21-day cycles: AZA 200mg Days 1–14, ROMI 10mg/m 2Days 8 and 15
    • Cohort 3 (n= 3), 28-day cycles: AZA 200mg Days 1–14, ROMI 10mg/m 2Days 8 and 15
    • Cohort 4 (n= 3), 28-day cycles: AZA 300mg Days 1–14, ROMI 10mg/m 2Days 8 and 15
    • Cohort 5 (n= 3), 28-day cycles: AZA 300mg Days 1–14, ROMI 14mg/m 2Days 8 and 15
    • Cohort 6 (n= 3 plus five participants with PTCL), 35-day cycles: AZA 300mg Days 1–14, ROMI 14mg/m 2Days 8, 15, and 22 (MTD)
    • Cohort 7 (n= 5), 35-day cycles: AZA 300mg Days 1-21, ROMI 14mg/m 2Days 8, 15, and 22 (Maximum administered dose)


  • No patients had dose reductions, 2 patients discontinued treatment due to toxicity (1 had nausea and vomiting; 1 had sepsis)
  • The most common grade ≥3 treatment emergent adverse events included cytopenias (typically lymphocytopenia [42%] and thrombocytopenia [27%]), hypotension (12%), febrile neutropenia (8%), hyponatremia (8%), and sepsis (4%)


  • Objective response achieved in 10 (32%) patients
  • Complete response (CR) achieved in seven (23%) patients
  • Patients with PTCL responded better than patients with non-T-cell lymphoma, with 73% of them achieving a response (55% achieved CR) vs10% of non-T-cell lymphoma group (5% achieved CR), a significant difference (overall response rate, p= 0.001; CR, p= 0.01)
  • Tumor burden was shown to decrease in 16 out of 25 measurable cases (64%), with the three patients with angioimmunoblastic T-cell lymphoma (AITL) showing 100% tumor shrinkage
  • At 15.3 months follow-up, median progression free survival (PFS) was 3.6 months (95% confidence interval [CI], 1.9–3) for all patients. Median PFS for patients with PTCL was not reached, and in those with non-T-cell lymphomas, PFS was 2.5 months (95% CI, 0.4–4.6)
  • Global DNA methylation scores decreased in four of the five patients in the PTCL expansion cohort by Day 8 of Cycle 1, but did not correlate with clinical response
  • Patterns of demethylation between baseline and each timepoint post-treatment found five significantly differentially demethylated regions at Day 15 of Cycle 1, rising to 24 regions at Day 22 of Cycle 2
  • Next generation sequencing of nine patients with PTCL

O’Connor and colleagues concluded that the results of this study highlight the utility of this combination treatment for patients with R/R PTCL due to the high CR rates seen in such a heavily pre-treated group, enabling them to be considered for AHSCT. The study also suggests that this treatment may work well for AITL, but this would need validating in a larger sample. They go on to state that although the number of patients included was low, the phase II results and validation of these findings is ongoing and should confirm these findings.


  1. O’Connor O.A. et al., Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study. Blood.2019 Oct 24; 134(17):1395–1405. DOI: 10.1182/blood.2019001285.