Table 3.
Selected clinical trials of HMA in combination therapy.
| Combination therapy | Phase | Patient population | Intervention | Outcomes | Ref. |
|---|---|---|---|---|---|
| AZA + venetoclax | I/II | R/R myeloid patients [AML (91%), MDS (5%), or blastic plasmacytoid dendritic cell neoplasm (5%)] | Combination of venetoclax with AZA or LDAC | (1) ORR: 21% (2 CRs, 3 CRi, and 4 morphologic leukemia-free
state) (2) Median OS 3.0 months, estimated 6-mo survival 24%. |
DiNardo et al.68 |
| AZA or DEC + venetoclax | I/II | 57 newly diagnosed AML patients >65 years of age | venetoclax and IV decitabine 20 mg/m2 [D1–5 of each 28-day cycle]), venetoclax and subcutaneous or intravenous azacitidine 75 mg/m2 [D1–7 of each 28d cycle] | 35 (61%) of 57 pts with CR or CRi | DiNardo et al.69 |
| AZA + venetoclax | Ib | 59 untreated MDS patients | Venetoclax dose ramp-up to 400 mg daily + AZA 75 mg/m2, subcutaneously or IV D1–7 of each 28d cycle | 31.6% CR, 38.6% mCR; 74% 18-month OS estimate Median duration of response, progression-free and OS not reached |
Wei et al.70 |
| AZA + venetoclax | I | 46 HMA-refractory MDS patients | Venetoclax monotherapy or in combination with AZA | (1) Venetoclax monotherapy: ORR 7% (1 out of 16; mCR), 75%
(12 out of 16) with SD; (2) Venetoclax + AZA: ORR 50% (12 out of 24; 13% CR, 38% mCR) |
Zeidan et al.71 |
| AZA + pevonedistat | II | 23 HMA refractory patients (21 MDS, 2 MDS/MPN overlap) | AZA 75mg/m2 daily on days 1–5 + pevonedistat 20mg/m2 iv on days 1, 3 and 5 of each 28-day cycle | (1) ORR (CR, PR, hematologic improvement and clinical
benefit): 42.9% (9/21 patients), with 23.8% CR rate (1
CR + 4 marrow CR) (2) median duration of response of 8.7 months (range 2.8–15.7months) |
Moyo et al.72 |
| AZA, nivolumab or ipilimumab | I/II | MDS patients in frontline (n = 41) and HMA-refractory setting (n = 35) | Pts were divided into front-line and HMA-failure cohorts. Front-line pts treated with: AZA + nivolumab and AZA + ipilimumab. Pts in HMA failure cohort treated with single agent nivolumab or ipilimumab (AZA added after 6 cycles) | ORR in 15/20 (75%), 15/21 (71%), 2/15 (13%), and 7/20 (35%) of patients with median OS of 12 months, not reached, 8 months, and 8 months treated with AZA + nivolumab, AZA + ipilimumab, nivolumab alone, or ipilimumab alone respectively | Garcia-Manero et al.73 |
| AZA + magrolimab | Ib | Untreated higher-risk MDS (n = 39) or AML ineligible for intensive chemotherapy (n = 29) | magrolimab priming/intrapatient dose escalation regimen (1–30 mg/kg weekly or biweekly starting in cycle 3) + AZA 75mg/m2 days 1–7 | (1) MDS cohort: ORR 91% (42% CR, 24% marrow CR (4/8 with
HI), 3% PR, 21% HI alone) (2) AML cohort: ORR 64% (40% CR, 16% CRi, 4% PR) |
Sallman et al.74 |
| AZA + APR-246 | Ib/II | Untreated MDS (n = 40), AML-MRC (n = 11), or CMML/MDS-MPN (n = 4) with TP53 mutation | APR-246 4500 mg IV (days 1–4) + AZA 75 mg/m2 SC/IV x 7 days (days 4–10 or 4–5 and 8–12) each 28-day cycle | (1) Combined: ORR 87% (53% CR, 18% mCR+HI) (2) MDS cohort: 61% CR |
Sallman et al.75 |
| AZA + APR-246 | II | HMA-naïve, TP53-mutated MDS (n = 34) or AML (n = 19) | APR-246 4500 mg IV/d (days 1–4) + AZA 75 mg/m²/d (days 4–10) in 28 day cycles | 16 evaluable patients with ORR of 75% (56% CR; 19% mCR) | Cluzeau et al.76 |
| Quizartinib + 5-AZA or LDAC | I/II | 59 ND and R/R-AML, MDS, CMML | Assignment by physician choice to AZA 75 mg/m2 for 7 days per 28-day cycle, or LDAC for 10 days per cycle + daily quizartinib at 60 mg or 90 mg daily | (1) Untreated: ORR: 92%, median OS: 18.6 months (2) Pretreated: ORR: 68%; median OS: 11.25 months |
Swaminathan et al.77 |
| 5-AZA + midostaurin | I/II | 54 patients with R/R-AML, ND-AML, HR-MDS, s-AML | AZA 75 mg/m2 on D1–7 and midostaurin 25 mg or 50 mg twice daily on D8–21 during the first cycle and continuously thereafter | ORR: 26% Median OS: 22 weeks |
Strati et al.78 |
AML, acute myeloid leukemia; AZA, azacitidine; CMML, chronic myelomonocytic leukemia; CR, complete remission; Cri, complete remission with incomplete cell count recovery; DEC, decitabine; HI, hematologic improvement; HMA, hypomethylating agent; HR-MDS, high-risk myelodysplastic syndrome; LDAC, low-dose cytarabine; ND, new diagnosis; ORR, overall response rate; OS, overall survival; Ref, reference; R/R, relapsed/refractory; s-AML, secondary AML; SD, stable disease.