Table 1.
Completed and ongoing clinical trials of programmed cell death protein 1 (PD-1), PD-ligand(L)1 inhibitors in AML.
| Disease Stage | Therapeutic Agents | Study Design | Participants | References |
|---|---|---|---|---|
| AML/HR MDS 18–60 years or >60 eligible for intense chemotherapy | cytarabine 1.5 g/m2 by 24 h continuous infusion daily on days 1–4 (3 days in patients > 60 years) and idarubicin 12 mg/m2 daily on days 1–3. nivolumab 3 mg/kg, day 24 every 2 weeks, 1 year for responders | Single-arm, phase II part of the phase I/II study | n = 44 | [86] |
| R/R AML > 18 years | azacitidine iv/sc 75 mg/m2 days 1–7 + nivolumab iv 3 mg/kg days 1 and 14, every 4 to 6 weeks | Non-randomized, open-label, phase II study | n = 70 | [83] |
| Newly diagnosed patients with TP53 mutated AML | Induction: nivolumab iv day 15 of cycle 1 and days 1 and 15 of subsequent cycles, decitabine 1–10 of induction cycle 1 and venetoclax orally daily on days 1–21 Maintenance: nivolumab iv: days 1 and 15, decitabine iv: days 1–5, and venetoclax po: days 1–21 | Non-randomized, open-label, pilot study | n = 13 | [107] |
| AML patients in first CR/CRi after intense chemotherapy not candidates for HSCT | nivolumab iv every 2 weeks for 46 cycles vs. clinical observation | Randomized, open-label, phase II study | n = 82 | [90] |
| AML/HR MDS 18–60 years or >60 eligible for intense chemotherapy or R/R AML/MDS for phase I | Phase I: nivolumab iv 1 mg/kg on day 24 of a 28 days cycle and after cycle 2, nivolumab iv every 2 weeks, 1 year + idarubicin 12 mg/m2 IV days 1–3 + cytarabine iv 1.5 g/m2 days 1–4 + solumedrol 50 mg/dexamethasone iv 10 mg days with 1–4. Phase II: nivolumab maximum tolerated dose | Non-randomized, open label, phase I/II study | n = 75 | [108] |
| R/R AML or MDS patients following allogenic HSCT | nivolumab iv, days 1 and 15 vs. ipilimumab iv day 1 vs. nivolumab iv, days 1, 14, and 28 + ipilimumab iv, day 1 | Non-randomized, open label, phase I study | n = 55 | [95] |
| AML patients ≥ 55–85 years, in first/second CR, suitable for haploidentical transplant | cytarabine iv 500–1000 mg/m2 bid days-2–4 + G-CSF, day 0 + nivolumab 40 mg, day 5 vs. cytarabine iv 500–1000 mg/m2 bid days 1–3 + nivolumab 40 mg day 1 | Randomized, open-label, phase II study | n = 16 | [109] |
| R/R AML/biphenotypic patients or newly diagnosed ≥ 65 years AML patients, unfit for in high dose chemotherapy | azacitidine iv/sc, days 1–7 or days 1–4 and 7–9 + nivolumab iv, days 1 and 14 (cycle 1–4) and day 1 (cycle 5 and subsequent) vs. same regimen + ipilimumab iv day 1 and then every 6–12 weeks | Non-randomized, open label, phase II study | n = 182 | [110] |
| HR of relapse in AML patients in CR/CRi/CRp/PR | nivolumab iv, days 1 and 15. (cycles 1–5) and nivolumab iv, day 1, (cycle 6–12), and nivolumab iv, day 1(every 3 cycles starting from cycle 12) or continue nivolumab days 1 and 15 if progressive disease | Non-randomized, open label, phase II study | n = 30 | [111] |
| R/R AML/HR-MDS, IDH1 mutated | ivosidenib PO 500 mg/day + nivolumab 480mg on day 1 cycle 2. | Non-randomized, open label, phase II study | n = 45 | [112] |
| 18–70 years AML/HR MDS eligible for HSCT | nivolumab iv (1 mg/kg or 3 mg/kg), 12 doses, day 1 every 3 weeks, 12 cycles vs. Ipilimumab (0.3 mg/kg/1.0 mg/kg/3.0 mg/kg), day 1, every 3 weeks, 6 cycles vs. nivolumab iv (3 mg/kg), 12 doses, day 1 every 3 weeks, 12 cycles + ipilimumab (0.3 mg/kg/0.6 mg/kg/1.0 mg/kg), day 1, every 3 weeks, 6 cycles | Non-randomized, open label, phase I study | n = 21 | [113] |
| IPSS-1, IPSS-2, HR MDS, low blast count AML | DEC-205/NY-ESO-1 fusion protein CDX-1401 intracutaneously + poly ICLC sc, day-14 and day 15 (cycle 1–4), and day 1 of every 4 courses (cycle 5 and after) + nivolumab iv days 1 and 15 and decitabine iv, days 1–5 | Non-randomized, open label, phase I study | n = 8 | [114] |
| Recurrent AML/ALL/CLL/CML BCR-ABL+/HL/MM/non-Hodgkin Lymphoma/MDS/MPN/Other hematologic malignancies after allo-HSCT | Induction: ipilimumab iv, day 1+ nivolumab iv, day 1. (cycles of 21 days). Maintenance: ipilimumab iv every 12 weeks + nivolumab iv every 2 weeks in the absence of progressive disease or toxicity. | Non-randomized, open label, phase I/IB study | n = 71 | [115] |
| HR AML in remission not eligible for HSCT | nivolumab 3 mg/kg iv every 2 weeks for 6 months. After 6 months nivolumab was given every 4 weeks until 12 months on the study, and every 3 months until relapse | Non-randomized, open label, phase II study | n = 8 | [116] |
| R/R AML who have exhausted standard of care options | flotetuzumab in step-up dose, followed by continuous infusion flotetuzumab, starting at week 2 of cycle 1 and continuing through each 28-day cycle. MGA012 every two weeks. | Non-randomized phase I study | [117] | |
| R/R AML | atezolizumab iv on day 22 of cycle 1 and on days 8 and 22 on subsequent cycles + Hu5F9-G4 1 mg/kg on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on day 11, and continue with 30 mg/kg every week | Non randomized, Open-label phase Ib study | n = 21 | [118] |
| R/R or newly diagnosed patients with AML unfit for intensive chemotherapy | atezolizumab 840 mg iv on days 8 and 22 + guadecitabine 60 mg/m2 sc on Days 1–5 | Non randomized, open-label phase Ib study | n = 40 | [119] |
| ≥60 years AML patients in CR/CRi, MRD+ not eligible for HSCT | BL-8040 SC 1.25 mg/kg days 1–3 of each cycle + atezolizumab 1200 mg iv on Day 2 of every cycle. |
Non-randomized, phase Ib/II, Multicenter, single arm, open-label study | n = 60 | [120] |
| R/R AML patients FLT3+ | Phase I: establishing the right dose for gilteritinib Phase II: gilteritinib + atezolizumab |
Non-randomized, phase I/II, open-label study | n = 61 | [121] |
| Relapsed AML/MDS/ALL after allo-HSCT | pembrolizumab 200 mg iv every 3 weeks | Non-randomized, open-label, phase IB study | n = 20 | [122] |
| Untreated AML, unfit for intensive chemotherapy | decitabine 20 mg/m2 iv day 1–5, every 28 days and avelumab was given at 10 mg/kg iv day 1, every 14 days | Non-randomized, single arm, open label phase I study | n = 7 | [123] |
| R/R AML | azacitidine sc/iv days 1–7 or on days 1–5 and 8–9 + avelumab iv days 1 and 14 for 4 courses or until CR and on day 1 for subsequent courses. | Non-randomized, open-label phase Ib/II study | n = 19 | [124] |
| MDS patients ≥ 18 years with IPSS-R intermediate, high, and very high or AML patients ≥ 65 years ineligible for intense chemotherapy | azacitidine 75 mg/m2 sc, days 1–7 and durvalumab 1500 mg iv on Day 1 every four weeks vs. azacitidine alone | Randomized, open-label, international, multicenter, phase II study | n = 213 | [125] |
| R/R AML | pembrolizumab iv 200 mg, day 1 of every three-week cycle + decitabine 20 mg/m2, days 8–12 and 15–19 | Single-arm open-label, phase I/II study | n = 10 | [84] |
| R/R AML patients and newly diagnosed elderly (≥65 Years) AML patients | azacitidine 75 mg/m2 iv/sc on days 1–7 every 28 days + pembrolizumab 200 mg iv every 3 weeks starting on day 8 of cycle 1 | Multicenter, nonrandomized, open-label phase II study | n = 40 | [43] |
| ≥60 years AML patients ineligible/refuse intensive chemotherapy | azacitadine iv/sc days 1–7 and venetoclax po days 1–28 of cycle 1 and days 21–28 vs. pembrolizumab iv day 8 cycle 1 and every 3 weeks in cycle 2–6 + azacitadine iv/sc days 1–7 + venetoclax po days 1–28 of cycle 1 and days 21–28 of subsequent cycles. | Randomized phase II, open-label trial | n = 76 | [88] |
| ≥60 years AML patients in CR not eligible for HSCT | pembrolizumab 200 mg iv once every three weeks | Non-randomized, open-label, phase II trial | n = 40 | [126] |
| 18–70 years R/R AML patients | Age-adjusted HiDAC followed by pembrolizumab 200 mg iv on day 14 in R/R AML patients | Non-randomized, open-label, phase II trial | n = 37 | [127] |
| Newly-diagnosed AML patients | Induction phase: 3 + 7 + pembrolizumab (day 8) vs. 3 + 7. Consolidation phase: HiDAC + pembrolizumab vs. HiDAC. Maintenance phase: pembrolizumab every 3 weeks for up to 2 years |
Randomized phase II, open-label trial | n = 124 | [89] |
| R/R AML patients or newly diagnosed AML patients not suitable for high-dose chemotherapy or HR MDS or newly diagnosed MDS | AML: pembrolizumab iv days 1 and 22 and decitabine iv days 1–10 MDS: Pembrolizumab iv days 1 and 22 and decitabine on days 1–5. | Non-randomized, open-label, phase Ib trial | n = 54 | [128] |
| NPM1 mutated AML patients in CR or MRD positivity or patients not eligible for high-dose chemotherapy or HSCT | pembrolizumab 200 mg iv + azacitidine 75 mg/m2 sc | Non-randomized, open-label, phase II trial | n = 28 | [129] |
| HR AML (18–78 years) |
fludarabine + melphalan+ Autologous HSCT followed by pembrolizumab on day +1 | Non-randomized, open-label, phase II trial | n = 20 | [130] |
| AML/MDS/cHL, B cell NHL relapsed after alloHSCT | pembrolizumab 200 mg iv every 3 weeks | Non-randomized, open-label, phase I pilot study | n = 26 | [131] |
RFS—Relapse Free Survival, MTD—Maximum Tolerated Dose, MRD-CR—minimal/measurable residual disease negativity and complete remission, ALL—acute lymphoblastic leukemia, DOR—duration of response, DFS—Disease-Free Survival, bid—bis in die, CRp—complete response with incomplete platelet recovery, MPN—myeloproliferative neoplasm, CML—chronic myeloid leukemia, ADA—anti-drug-antibodies, HiDAC—high dose Cytarabine.