Immune Checkpoint Inhibition in Acute Myeloid Leukemia

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This entry is adapted from the peer-reviewed paper 10.3390/cancers15205060

Immune based treatments (ITs) represent one of the most important strategies in the treatment of acute myeloid leukemia (AML), like allogeneic stem cell transplant. however, ITs clinical development in AML is still in its infancy. This work provides up to date information on current research in the field.

acute myeloid leukemia immunotherapy checkpoint inhibitors

1. PD-1/PDL-1 Blockade

The PD-L1/PD-1 axis has been thoroughly studied over the past few decades, and recent data indicate that CD34+ blasts from MDS and AML patients cause the upregulation of PDL-1, while PD-1 expression is raised in effector T cells and Tregs ^[1]^[2]^[3]^[4]. Furthermore, activated T cells upregulate the antagonistic co-receptor PD-1. As the PDL-1/PD-1 interaction dampens anti-tumor T cell responses ^[5]^[6]^[7], the disruption of this pathway by anti-PD-1/PDL-1 monoclonal antibodies can revive worn-out T cells and prompt anti-tumor responses ^[8]^[9]. Although this strategy has provided striking data in the context of solid malignancies, its action in the context of AML and MDS needs to be further clarified (Table 1).

2. PD-1 Inhibitors

2.1. Nivolumab

In a phase II study, 70 patients with R/R AML were treated with a combination of nivolumab (3 mg/Kg) on days 1 and 14 as well as azacitidine at 75 mg/m² for one week, every 4 to 6 weeks. The median age of patients was 70 years (range: 22–90); the median number of previous therapies was two (range: one to seven). The overall response rate (ORR) was 33%, with 7 patients reaching hematologic improvement that lasted for more than 6 months and 15 (22%) achieving full remission or complete remission with insufficient count recovery. Six patients (9%) showed stable disease for more than six months. When comparing hypomethylating agent (HMA)-naive patients (n = 25) and HMA-pretreated patients (n = 45), the derived ORR values were 58% and 22%, respectively. Eight (11%) patients experienced immune-related side effects graded 3 to 4. The pretreatment of bone marrow and peripheral blood with CD3+ and CD8+ T cells strongly predicted the response. Interestingly, after two and four doses of the drug, non-responder patients showed increased CTLA-4 expression on CD4 T cell effectors ^[10]. On this basis, the protocol was amended, with the introduction of a second cohort, wherein 31 R/R AML patients with high CTLA-4 expression were treated with anti-CTLA-4 moAb ipilimumab, together with azacitidine and nivolumab, to further improve T cell responses. With a median OS of 10.5 months, the ORR rate among patients for whom efficacy could be evaluated (n = 24) was 46% (CR/CRi rate: 36%), which compares favorably with the result for azacitidine plus nivolumab. As anticipated, 25% of patients experienced grade 3–4 immune-related adverse events (ir-AEs), which is higher than that seen in the azacitidine plus nivolumab cohort ^[11].

Nivolumab was also investigated by Davids et al., who focused on recurrent hematologic malignancies following allogeneic transplantation (10 AML cases out of 28). This multicenter phase I trial evaluated the effectiveness, the immunologic activity, the maximum tolerated dose and the safety of the drug. Nivolumab was given out every two weeks until the occurrence of either progression or intolerable side effects. The initial dose level was 1 mg/kg, with the option to reduce it to 0.5 mg/kg or increase it to 3 mg/kg. The 1-year PFS rate was 23% and the OS rate was 56%, with a median follow-up of 11 months. Among the 28 patients enrolled, 3 patients could not be evaluated for the efficacy of response, whereas 25 patients could be, owing to early toxicity. Of the 25, 20 received treatment at 0.5 mg/kg, while 5 received treatment at 1 mg/kg. As regards the efficacy at both levels, the ORR was 32%. The median OS for all patients was 21.4 months, and the overall patient 1-year OS rate ^[12] was 56%. Two of the six patients treated at 1 mg/kg experienced dose-limiting toxicity (DLT) from ir-AEs. In total, 22 patients were treated at 0.5 mg/kg, and four DLTs occurred, including two ir-AEs and two fatal GVHD.

A phase 2 trial tested the use of nivolumab in combination with idarubicin + cytarabine in frontline disease treatment in patients with newly diagnosed AML (n = 42) and HR-MDS (n = 2). The composite CR rate was 78%, of which 79% showed no evidence of measurable residual disease (MRD), assessed using multiparameter flow cytometry (MFC). In total, 19 patients underwent allo-SCT, with 13 patients developing GVHD (68%). The chemo-immunotherapy regimen showed a tolerable toxicity without the extensive incidence of ir-AEs. Overall, the median OS was 18.5 months, and for those who received allo-SCT, this was prolonged to 25 months. Importantly, responders who were continued on nivolumab treatment after remission and those who were bridged to allo-SCT showed similar OS values, suggesting that nivolumab may play a role in restoring anti-tumor immune surveillance and eliminating MRD ^[13].

As confirmed by observations in certain lymphoma treatment subgroups, Liu et al. ^[13] postulated that immunomodulation with checkpoint inhibitors (CIs) might induce an anti-leukemia immune response avoiding or postponing a potential disease relapse in intermediate/poor-risk AML. NCT02275533 comprised a phase II trial to assess maintenance using nivolumab in patients with AML in first CR or CR with incomplete hematologic recovery (CRi), as assessed by bone marrow biopsies within 2 months from the last chemotherapy, and who were not eligible for HSCT. Eighty patients were randomized to placebo or nivolumab treatment (3 mg/kg every 2 weeks for forty-six doses). The 2-year PFS values were identical—30.3% and 30% in the nivolumab arm and the observation arm, respectively (p = 0.38). The median OS values were 53.9 and 30.9 months in the two subgroups; however, the 2-year OS values were 60.0% and 52.8% in the nivolumab and observation arm, respectively (p = 0.23). As expected, AEs were more common in the nivolumab arm, with 27 (71.0%) experiencing grade 3 or higher toxicity, while only 5 patients in the placebo group showed the same (12.2%) (p < 0.001) ^[14]. These findings show that nivolumab maintenance did not benefit high- and intermediate-risk AML patients after chemotherapy, as it failed to improve the 2-year PFS or the OS, and it increased the incidence of AEs.

To describe transplantation outcomes with regard to GvHD and the effects of various GvHD prophylaxis strategies, Oran and colleagues conducted a clinical trial of patients with AML and MDS patients treated with either PD-1 (nivolumab) and/or CTLA-4 (ipilimumab) inhibitors before undergoing an allo-HSCT. Of the 43 patients enrolled, 9 received ipilimumab and 34 received nivolumab. Nivolumab was administered to the patients in 2 cases as a monotherapy, in 19 cases in combination with chemotherapy, and in the remaining cases in combination with HMAs. Of the 43 patients, 24 experienced CR, 6 experienced CRi, 5 showed hematologic improvement, and 1 experienced a PR. At the time of best response, 27 of these patients discontinued CI therapy and proceeded to allo-HSCT. Tacrolimus and mini-methotrexate with or without anti-thymocyte globulin were used as part of the GvHD prophylaxis in 21 patients, while post-HSCT cyclophosphamide (PTCy) or tacrolimus with or without mycophenolate mofetil was used in 22 individuals. The application of prophylaxis in the patients was based on donor type. Both the baseline disease and transplantation characteristics were comparable between PTCy patients and no-PTCy patients—32% and 10%, respectively. Matched control analyses using patients with no prior exposure to Cis unfortunately showed increased aGVHD (grade 3–4) in those exposed to CI ^[15].

2.2. Pembrolizumab

The combination of pembrolizumab and azacitidine was evaluated in a phase 2 trial including de novo and R/R AML. Patients received azacitidine at 75 mg/m² on days 1–7, with pembrolizumab (200 mg) beginning on day 8 and every 3 weeks thereafter. Among the 37 R/R AML patients, 29 were evaluable for response and showed an ORR of 55%, with 14% CR/CRi; among the 22 patients with de novo AML who were ineligible for intensive chemotherapy, 17 were evaluable for response, and showed an ORR of 94% with 47% CR/CRi. The median OS for this cohort was 13.1 months ^[16]. In another trial (NCT02996474), pembrolizumab was given with 10 days of decitabine to 10 patients with R/R AML. The median OS was 10 months with responses observed in six patients: two achieved CR, one showed a morphologic leukemia-free state and three experienced stable disease ^[17]. A US group conducted a phase II trial providing high-dose cytarabine followed by pembrolizumab at 200 mg on day 14 to assess whether this combination could improve outcomes of R/R AML. Thirty-seven patients were enrolled, with a median age of 54 years; the majority showed either refractory (43%) or relapsed disease with a CR duration of <1 year (43%). The median OS of the entire cohort was 11.1 months, with ORR and composite CR values of 48% and 38%, respectively. Among the patients showing refractoriness/early relapse and those who received this combination approach as the first salvage therapy, there were encouraging outcomes (median OS, 13.2 and 11.3 months, respectively). Rare grade ≥ 3 ir-AEs after pembrolizumab administration included maculopapular rash (n = 2; 5%), aminotransferase elevation (n = 2; 5%), and after the failure of HMAs, lymphocytic infiltration shown on liver biopsy (n = 1; 3%) ^[18]. In a small phase 2 study conducted on 20 patients affected by intermediate-risk (60%) and high-risk AML in CR, pembrolizumab was administered as the consolidation after autologous-SCT in eight doses. The study met the planned objective of a leukemia-free survival rate of 48.4% at 2 years, and the two-year OS, NRM and CIR values were 68%, 5% and 46%, respectively ^[19].

The use of pembrolizumab was also investigated in high-risk and HMA-resistant MDS to define its potential efficacy in myeloid malignancies. The phase 1b KEYNOTE-013 study evaluated the use of pembrolizumab as a monotherapy in 28 patients with high-risk MDS following HMA treatment failure. No patient achieved CR or PR; 5 patients (19%) showed a complete bone marrow response, 12 (44%) showed stable disease, 10 (37%) showed progressive disease, 6 (22%) showed a cytogenetic response, and 5 (19%) showed hematologic improvement. The median OS was 6.0 months with a 2-year OS rate of 17% ^[20]. Another phase 2 study explored the use of pembrolizumab and azacitidine in patients with both de novo and intermediate- to high-risk MDS who did not respond to HMAs. After a median follow-up of 12.8 months, the median OS was not reached, and the ORR and CR rate were 76% and 18%, respectively, in HMA-naïve patients (n = 17). In the 20 patients for whom HMA treatment failed, the ORR was 25%, with a CR rate of 5% and a median OS of 5.8 months ^[21]. According to these data, pembrolizumab appeared to be ineffective in patients with high-risk MDS and in those who were HMA-resistant, both when used as a monotherapy and in combination regimens.

2.3. Tislelizumab

Tislelizumab is an experimental humanized immunoglobulin G4 monoclonal antibody that has a high affinity for the PD-1 protein. It is constituted in such a way as to reduce binding to the Fc receptor on macrophages to prevent antibody-dependent phagocytosis, which is a potential mechanism of resistance to anti-PD-1 therapy ^[22]. Tislelizumab as a monotherapy or in combination with chemotherapy exhibited antitumor effectiveness in patients with solid tumors in early-phase clinical studies, and it also displayed a safety profile similar to thos of other anti-PD-1 antibodies ^[23]^[24].

In a phase 2, single-arm study, R/R AML patients received azacitidine or decitabine plus CAG regimen (cytarabine, aclarubicin, G-CSF) with tislelizumab. In total, 27 patients were enrolled; the ORR was 63% (14 CR/Cri, 3 PR, 10 no response). The median OS and EFS were 9.7 and 9.2 months, respectively, with grade 2–3 ir-AEs observed in four patients (14.8%) ^[25].

3. PD-L1 Inhibitors

The phase 2 study FUSION-AML-001 was designed to evaluate the activity and safety of durvalumab, a PDL-1 inhibitor, in combination with azacitidine in untreated patients with AML aged ≥65 years. Patients were randomized to receive azacitidine at 75 mg/m² on days 1–7, either with (Arm A, n = 64) or without (Arm B, n = 65) durvalumab (1500 mg on day 1), repeated every 4 weeks. This combination regimen failed to significantly improve ORR (Arm A, 31.3%; Arm B, 35.4%), duration of response (Arm A, 24.6 weeks; Arm B, 51.7 weeks) or OS (Arm A, 13.0 months; Arm B, 14.4 months) ^[26]. Another PDL-1 antibody, avelumab, that has been approved by the FDA for treating Merkel cell carcinoma, renal cell carcinoma, and urothelial carcinoma was tested on untreated and R/R AML. A phase 1 study was conducted to evaluate the combination of avelumab and decitabine as the frontline treatment for AML patients unfit for intensive chemotherapy (n = 7). The response rate was unsatisfactory, with only one patient who reached CR and three who reached stable disease as the best responses to the therapy ^[27]. Avelumab was also investigated in association with azacitidine in the R/R setting. In a phase 1b/2 trial, 19 patients received azacitidine at 75 mg/m² on days 1–7 in combination with avelumab on days 1 and 14, repeated every 28 days (avelumab was given at 3 mg/kg to the first 7 patients and increased to 10 mg/kg for the other 12 patients). The median age was 66 years; 100% showed adverse-risk disease (European LeukemiaNet 2017), and 63% had previously received a hypomethylating agent. The median OS was 4.8 months and responses with full or incomplete bone marrow recovery were seen in 10.5%, which result is similar to the historical CR/CRi rate of 16% observed with the application of HMA ^[28]^[29]. A further analysis in these studies confirmed that the overexpression of PD-L2 in myeloid blasts and the monocyte-restricted increase in PDL-1 expression with therapy are the most important causes of inactivity related to PDL-1 inhibitors in patients with AML ^[26]^[28].

No benefits related to the employment of anti-PDL-1 inhibitors were seen in MDS patients.

A phase 2 study addressing frontline azacitidine plus the ICI durvalumab (Arm A) versus azacitidine monotherapy (Arm B) in 84 HR-MDS patients was conducted. The ORR values were 61.9% and 47.6% in Arm A and Arm B (p= 0.18), respectively, with median OS values of 11.6 months and 16.7 months (p= 0.74), confirming the inefficacy of PDL-1 inhibitors in the MDS scenario as well ^[30].

Table 1. Trials including PD-1 inhibitors in patients with AML.

Reference	Therapeutic Approach	Type of AML	Number of Patients	Response	Survival	AEs
Daver et al. ^[10]	Azacitidine + nivolumab	R/R AML	70	ORR: 33% CR/CRi: 22%	Median OS: 9.2 months	irAEs grade 3–4: 11% (n = 8)
Daver et al. ^[11]	Azacitidine + nivolumab + ipilimumab	R/R AML	24	ORR: 46% CR/CRi: 36%	/	NA
Davids et al. ^[12]	Nivolumab	AML and myeloid malignancies after transplant	10 AML 19 myeloid malignancies	/	Median OS: 21.4 months 1-year OS: 56%	DLTs 1 mg/kg (ir-AE): 33% (n = 2/6) DLTs 0.5 mg/kg (ir-AE): 18% (n = 4/22) ir-AEs: 9% (n = 2/22) fatal GVHD: 9% (n = 2/22)
Ravandi et al. ^[13]	Nivolumab + idarubicin + cytarabine	ND-AML and HR-MDS	42 AML 2 HR-MDS	composite CR: 78%	Median OS: 18.5 months	Early mortality: 5% irAEs grade 3/4: 13% 19 patients underwent allo-SCT GVHD: 68% (n = 13)
Liu et al. ^[14]	Nivolumab	Maintenance on AML in first CR, CR or CRi	26	/	Median OS: 53.9 months; 2-year OS: 60.0%	ORR: 32% Os rate 1 year: 56%
Gojo et al. ^[16]	Pembrolizumab + azacitidine	Newly diagnosed AML and R/R AML	37 R/R AML 22 de novo AML	ORR: 55%, with 14% CR/CRi in R/R AML ORR: 94% with 47% CR/CRi in de novo AML	Median OS for de novo AML: 13.1 months	irAE n: 9 (24%) and 5 (11%) pts in Cohort 1, and 3 (14%) and 4 (18%) pts in Cohort 2
Goswami et al. ^[17]	Pembrolizumab + decitabine	R/R AML	10	/	Median OS: 10 months	irAE n: 9. Trhombocytopenia: 80%. Neutropenia: 30%.
Zeidner et al. ^[18]	Pembrolizumab + high-dose cytarabine	R/R AML	37	ORR: 48% with a composite CR 38%	median OS: 13.2 months	Rare grade ≥ 3 ir-AEs after pembrolizumab: maculopapular rash (n = 2; 5%)
Gao et al. ^[25]	Tislelizumab + azacitidine or decitabine + CAG regimen (cytarabine, aclarubicin, G-CSF)	R/R AML	27	ORR: 63%	Median OS: 9.7 months	Grade 2–3 ir-AEs: 14.8% (n = 4)
Zeidan et al. ^[30]	Arm A: Azacitidine + durvalumab Arm B: Azacitidine	Untreated MDS or Elderly AML $(\geq$ 65 year)	129	ORR Arm A: 31.3% Arm B: 35.4% DoR Arm A: 24.6 weeks Arm B: 51.7 weeks	mOS: Arm A: 13.0 month Arm B: 14.4 month	Arm A: constipation (57.8%) and thrombocytopenia (42.2%)
Zeng ^[27]	Avelumab + decitabine	De novo AML r/r AML	7	CR: 14% (n = 1) SD: 42% (n = 3)		febrile neutropenia (86%), hypoxia (57%), heart failure (29%), and pneumonitis (29%)
Saxena ^[28]	Avelumab + azacitidine	r/r AML	19	CR/Cri: 10.5%	median OS: 4.8 months	trAEs grade ≥ 3: neutropenia, 10% (n = 2) Anemia: 10% (n = 2) irAEs grade 2/3: 10% (n = 2)

References

Williams, P.; Basu, S.; Garcia-Manero, G.; Hourigan, C.S.; Oetjen, K.A.; Cortes, J.E.; Ravandi, F.; Jabbour, E.J.; Al-Hamal, Z.; Konopleva, M.; et al. The Distribution of T-Cell Subsets and the Expression of Immune Checkpoint Receptors and Ligands in Patients with Newly Diagnosed and Relapsed Acute Myeloid Leukemia. Cancer 2019, 125, 1470–1481.
Tamura, H.; Dan, K.; Tamada, K.; Nakamura, K.; Shioi, Y.; Hyodo, H.; Wang, S.-D.; Dong, H.; Chen, L.; Ogata, K. Expression of Functional B7-H2 and B7.2 Costimulatory Molecules and Their Prognostic Implications in de Novo Acute Myeloid Leukemia. Clin. Cancer Res. 2005, 11, 5708–5717.
Zhang, Z.-F.; Zhang, Q.-T.; Xin, H.-Z.; Gan, S.-L.; Ma, J.; Liu, Y.-F.; Xie, X.-S.; Sun, H. Expression of Programmed Death Ligand-1 (PD-L1) in Human Acute Leukemia and Its Clinical Significance. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2015, 23, 930–934.
Krönig, H.; Kremmler, L.; Haller, B.; Englert, C.; Peschel, C.; Andreesen, R.; Blank, C.U. Interferon-Induced Programmed Death-Ligand 1 (PD-L1/B7-H1) Expression Increases on Human Acute Myeloid Leukemia Blast Cells during Treatment. Eur. J. Haematol. 2014, 92, 195–203.
Blank, C.; Brown, I.; Peterson, A.C.; Spiotto, M.; Iwai, Y.; Honjo, T.; Gajewski, T.F. PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells. Cancer Res. 2004, 64, 1140–1145.
Chemnitz, J.M.; Parry, R.V.; Nichols, K.E.; June, C.H.; Riley, J.L. SHP-1 and SHP-2 Associate with Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation. J. Immunol. 2004, 173, 945–954.
Dong, H.; Strome, S.E.; Salomao, D.R.; Tamura, H.; Hirano, F.; Flies, D.B.; Roche, P.C.; Lu, J.; Zhu, G.; Tamada, K.; et al. Tumor-Associated B7-H1 Promotes T-Cell Apoptosis: A Potential Mechanism of Immune Evasion. Nat. Med. 2002, 8, 793–800.
Zhang, L.; Gajewski, T.F.; Kline, J. PD-1/PD-L1 Interactions Inhibit Antitumor Immune Responses in a Murine Acute Myeloid Leukemia Model. Blood 2009, 114, 1545–1552.
Zhou, Q.; Munger, M.E.; Highfill, S.L.; Tolar, J.; Weigel, B.J.; Riddle, M.; Sharpe, A.H.; Vallera, D.A.; Azuma, M.; Levine, B.L.; et al. Program Death-1 Signaling and Regulatory T Cells Collaborate to Resist the Function of Adoptively Transferred Cytotoxic T Lymphocytes in Advanced Acute Myeloid Leukemia. Blood 2010, 116, 2484–2493.
Daver, N.; Garcia-Manero, G.; Basu, S.; Boddu, P.C.; Alfayez, M.; Cortes, J.E.; Konopleva, M.; Ravandi-Kashani, F.; Jabbour, E.; Kadia, T.; et al. Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study. Cancer Discov. 2019, 9, 370–383.
Daver, N.G.; Garcia-Manero, G.; Konopleva, M.Y.; Alfayez, M.; Pemmaraju, N.; Kadia, T.M.; DiNardo, C.D.; Cortes, J.E.; Ravandi, F.; Abbas, H.; et al. Azacitidine (AZA) with Nivolumab (Nivo), and AZA with Nivo + Ipilimumab (Ipi) in Relapsed/Refractory Acute Myeloid Leukemia: A Non-Randomized, Prospective, Phase 2 Study. Blood 2019, 134, 830.
Davids, M.S.; Kim, H.T.; Costello, C.; Herrera, A.F.; Locke, F.L.; Maegawa, R.O.; Savell, A.; Mazzeo, M.; Anderson, A.; Boardman, A.P.; et al. A Multicenter Phase 1 Study of Nivolumab for Relapsed Hematologic Malignancies after Allogeneic Transplantation. Blood 2020, 135, 2182–2191.
Ravandi, F.; Assi, R.; Daver, N.; Benton, C.B.; Kadia, T.; Thompson, P.A.; Borthakur, G.; Alvarado, Y.; Jabbour, E.J.; Konopleva, M.; et al. Idarubicin, Cytarabine, and Nivolumab in Patients with Newly Diagnosed Acute Myeloid Leukaemia or High-Risk Myelodysplastic Syndrome: A Single-Arm, Phase 2 Study. Lancet Haematol. 2019, 6, e480–e488.
Liu, H.; Sharon, E.; Karrison, T.G.; Zha, Y.; Fulton, N.; Streicher, H.; Sweet, K.; Yaghmour, G.; Liu, J.J.; Jonas, B.A.; et al. Randomized Phase II Study to Assess the Role of Nivolumab As Single Agent to Eliminate Minimal Residual Disease and Maintain Remission in Acute Myelogenous Leukemia (AML) Patients after Chemotherapy (NCI9706 Protocol; REMAIN Trial). Blood 2022, 140, 1716–1719.
Oran, B.; Garcia-Manero, G.; Saliba, R.M.; Alfayez, M.; Al-Atrash, G.; Ciurea, S.O.; Jabbour, E.J.; Mehta, R.S.; Popat, U.R.; Ravandi, F.; et al. Posttransplantation Cyclophosphamide Improves Transplantation Outcomes in Patients with AML/MDS Who Are Treated with Checkpoint Inhibitors. Cancer 2020, 126, 2193–2205.
Gojo, I.; Stuart, R.K.; Webster, J.; Blackford, A.; Varela, J.C.; Morrow, J.; DeZern, A.E.; Foster, M.C.; Levis, M.J.; Coombs, C.C.; et al. Multi-Center Phase 2 Study of Pembroluzimab (Pembro) and Azacitidine (AZA) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) and in Newly Diagnosed (≥65 Years) AML Patients. Blood 2019, 134, 832.
Goswami, M.; Gui, G.; Dillon, L.W.; Lindblad, K.E.; Thompson, J.; Valdez, J.; Kim, D.-Y.; Ghannam, J.Y.; Oetjen, K.A.; Destefano, C.B.; et al. Pembrolizumab and Decitabine for Refractory or Relapsed Acute Myeloid Leukemia. J. Immunother. Cancer 2022, 10, e003392.
Zeidner, J.F.; Vincent, B.G.; Ivanova, A.; Moore, D.; McKinnon, K.P.; Wilkinson, A.D.; Mukhopadhyay, R.; Mazziotta, F.; Knaus, H.A.; Foster, M.C.; et al. Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia. Blood Cancer Discov. 2021, 2, 616–629.
Solomon, S.R.; Solh, M.M.; Morris, L.E.; Holland, H.K.; Bachier-Rodriguez, L.; Zhang, X.; Guzowski, C.; Jackson, K.C.; Brown, S.; Bashey, A. Phase 2 Study of PD-1 Blockade Following Autologous Transplantation for Patients with AML Ineligible for Allogeneic Transplant. Blood Adv. 2023, 7, 5215–5224.
Garcia-Manero, G.; Ribrag, V.; Zhang, Y.; Farooqui, M.; Marinello, P.; Smith, B.D. Pembrolizumab for Myelodysplastic Syndromes after Failure of Hypomethylating Agents in the Phase 1b KEYNOTE-013 Study. Leuk. Lymphoma 2022, 63, 1660–1668.
Chien, K.S.; Kim, K.; Nogueras-Gonzalez, G.M.; Borthakur, G.; Naqvi, K.; Daver, N.G.; Montalban-Bravo, G.; Cortes, J.E.; DiNardo, C.D.; Jabbour, E.; et al. Phase II Study of Azacitidine with Pembrolizumab in Patients with Intermediate-1 or Higher-risk Myelodysplastic Syndrome. Br. J. Haematol. 2021, 195, 378–387.
Zhang, T.; Song, X.; Xu, L.; Ma, J.; Zhang, Y.; Gong, W.; Zhang, Y.; Zhou, X.; Wang, Z.; Wang, Y.; et al. The Binding of an Anti-PD-1 Antibody to FcγRΙ Has a Profound Impact on Its Biological Functions. Cancer Immunol. Immunother. 2018, 67, 1079–1090.
Desai, J.; Deva, S.; Lee, J.S.; Lin, C.-C.; Yen, C.-J.; Chao, Y.; Keam, B.; Jameson, M.; Hou, M.-M.; Kang, Y.-K.; et al. Phase IA/IB Study of Single-Agent Tislelizumab, an Investigational Anti-PD-1 Antibody, in Solid Tumors. J. Immunother. Cancer 2020, 8, e000453.
Shen, L.; Guo, J.; Zhang, Q.; Pan, H.; Yuan, Y.; Bai, Y.; Liu, T.; Zhou, Q.; Zhao, J.; Shu, Y.; et al. Tislelizumab in Chinese Patients with Advanced Solid Tumors: An Open-Label, Non-Comparative, Phase 1/2 Study. J. Immunother. Cancer 2020, 8, e000437.
Gao, X.-N.; Su, Y.-F.; Li, M.; Jing, Y.; Wang, J.; Xu, L.; Zhang, L.-L.; Wang, A.; Wang, Y.-Z.; Zheng, X.; et al. Single-Center Phase 2 Study of PD-1 Inhibitor Combined with DNA Hypomethylation Agent + CAG Regimen in Patients with Relapsed/Refractory Acute Myeloid Leukemia. Cancer Immunol. Immunother. 2023, 72, 2769–2782.
Zeidan, A.M.; Boss, I.; Beach, C.L.; Copeland, W.B.; Thompson, E.; Fox, B.A.; Hasle, V.E.; Hellmann, A.; Taussig, D.C.; Tormo, M.; et al. A Randomized Phase 2 Trial of Azacitidine with or without Durvalumab as First-Line Therapy for Older Patients with AML. Blood Adv. 2022, 6, 2219–2229.
Zheng, H.; Mineishi, S.; Claxton, D.; Zhu, J.; Zhao, C.; Jia, B.; Ehmann, W.C.; Rybka, W.B.; Naik, S.; Songdej, N.; et al. A Phase I Clinical Trial of Avelumab in Combination with Decitabine as First Line Treatment of Unfit Patients with Acute Myeloid Leukemia. Am. J. Hematol. 2021, 96, E46.
Saxena, K.; Herbrich, S.M.; Pemmaraju, N.; Kadia, T.M.; DiNardo, C.D.; Borthakur, G.; Pierce, S.A.; Jabbour, E.; Wang, S.A.; Bueso-Ramos, C.; et al. A Phase 1b/2 Study of Azacitidine with PD-L1 Antibody Avelumab in Relapsed/Refractory Acute Myeloid Leukemia. Cancer 2021, 127, 3761–3771.
Stahl, M.; DeVeaux, M.; Montesinos, P.; Itzykson, R.; Ritchie, E.K.; Sekeres, M.A.; Barnard, J.D.; Podoltsev, N.A.; Brunner, A.M.; Komrokji, R.S.; et al. Hypomethylating Agents in Relapsed and Refractory AML: Outcomes and Their Predictors in a Large International Patient Cohort. Blood Adv. 2018, 2, 923–932.
Zeidan, A.M.; Salimi, T.; Epstein, R.S. Real-World Use and Outcomes of Hypomethylating Agent Therapy in Higher-Risk Myelodysplastic Syndromes: Why Are We Not Achieving the Promise of Clinical Trials? Future Oncol. 2021, 17, 5163–5175.

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Matteo Molica

Salvatore Perrone

Costanza Andriola

Marco Rossi

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Update Date: 23 Jan 2024

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