Table 2.

Phase I/II trials with combination treatment of HDACi and hypomethylating agents, in AML and MDS, sometimes including CMML. OS = overall survival, ORR = overall response rate, CR = complete remission. In the studies by Uy et al., and Tan et al., there was no control arm thus a comparison of efficacy to monotherapy could not be made. Out of five evaluable studies, none showed an advantage of combination therapy. ¹ Azacitidine 75 mg/m² Day 1–5/28, ² panobinostat 3 days/w 7 doses/28 days, phase II 30 mg oral daily Day 1–7/28, ³ decitabine 20 mg/m² iv Day 1–5, ⁴ valproic acid 50 mg/kg oral Day 1–7/28, ⁵ azacitidine 75 mg/m² Day 1–7/28, ⁶ vorinostat 300 mg twice daily Day 3–9/28, ⁷ panobinostat 20–40 mg Day 3, 5, 8, 10, 12, 15, in phase IIb 40 mg, ⁸ pracinostat 60 mg or placebo oral every 2 days Day 1–21/28, ⁹ azacitidine 50 mg/m² 10 days, ¹⁰ entinostt 4 mg/m² Day 3, 10/28, ¹¹ panobinostat three times/week during two weeks/4, phase I dose escalation to 50 mg, phase II 40 mg.

Study, Trial Number and Reference	Disease, Phase	Additive Clinical Effect of HDACi	Drugs	Clinical Response	Molecular Markers Analyzed
Tan [62], ACTRN12610000924055, Open label, phase Ib/II	Higher risk MDS, AML. n = 39	NA	Azacitidine 1, Panobinostat 2	ORR 31% in AML, 50% in MDS. Median OS 8 months in AML, 16 months in MDS.	Total PBMC histone H3 and H4 acetylation higher in responders. NUR77 and p21 markers of treatment efficacy [59]
Issa [68], NCT00414310, Randomized, Phase II	Higher risk MDS, AML. n = 149	NO	Decitabine 3, valproic acid 4	No improvement in CR or OS with adding valproic acid.	NO
Sekeres [69], NCT01522976, Randomized, Phase II	Higher risk MDS, CMML. n = 184	NO	Azacitidine 5, Vorinostat 6	ORR 38% monotherapy, 27% combination (p = 0.16). Study not powered for calculating OS.	NGS. ORR was higher in DNMT3A mutated patients. ORR lower for SRSF2 and ASXL1. Response duration low in TET2 and TP53 mutated patients.
Garcia-Manero [70], NCT00946647, Randomized phase Ib/II	MDS, CMML AML with 20–30% blasts. n = 113	NO	Panobinostat 7, Azacitidine 5	CR 27.5% in the combination arm, 14.3% in monotherapy. No difference in OS or time to progression.	NGS data on 24 myeloid mutations, no clear correlation between mutation pattern and response.
Garcia-Manero [71], NCT01873703, Randomized phase II, double blinded	MDS (up to 30% blasts). n = 102	NO	Azacitidine 5, Pracinostat 8	CR 18% in the combination group, 33% in monotherapy group (p = 0.07). No difference in OS (16 vs. 19 months).	NO
Prebet [72], NCT00313586, Prebet [73], Open label phase II	MDS, CMML, MDS/AML. n = 149	NO	Azacitidine 9, entinostat 10	OS 18 months for monotherapy, 13 for combination.	No correlation between overall methylation decrease and clinical response, or with treatment arm. Possible correlation of SOCS1 methylation and response.
Uy [74], NCT00691938, Open label observational phase I/II	AML, MDS. n = 52	NA	Decitabine 3, panobinostat 11	ORR 11/37 AML and 7/14 MDS, total 36% ORR. Median OS 6.4 months.	Extensive sequencing, complex patterns. Mutations persist during complete remission.