One step further in targeting acute leukemia by combining antibody-based immunotherapies and small molecule inhibitors.

Introduction

One kind of blood malignancy is acute leukemia which progresses rapidly and usually affects the bone marrow and peripheral blood. The classification is based on the lineage of the affected progenitor cells the type of progenitor involved; depending on the myeloid or lymphoid progenitors engaged, it is termed acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL), respectively. Acute leukemia is characterized by the derangement of the normal process of maturation of blood cells, which results in the uncontrolled proliferation and excessive growth of the immature myeloid cells as myeloblasts in AML and overproduction of immature lymphocytes, known as lymphoblasts, in ALL. This disruption diminishes the production of normal blood cells, causing several symptoms, including fatigue, frequent infections, fever, thrombocytopenia, bruising or bleeding, skeletal pains, swollen lymph nodes or spleen, loss of appetite, and weight loss. Acute leukemia is usually aggressive and genetically heterogeneous; hence, treatment for it is extremely difficult [ 1 , 2 ].

The conventional approach to chemotherapy involves attacking the growing cancer cells to eliminate them but inadvertently impacting both cancerous and healthy cells in the process which results in adverse effects such as extreme tiredness from anemia, vulnerability to infections due to neutropenia, increased risk of bleeding due to thrombocytopenia, hair loss, and feelings of nausea [ 3 , 4 ]. These side effects can be highly debilitating, significantly impairing the patient’s overall health and quality of life. Most chemotherapy treatments will eventually build up a resistance to the treatment over time, a process that diminishes the effectiveness of the drug [ 3 , 5 ]. To improve outcomes and reduce treatment-related complications, there was a serious need for newer and more effective treatment approaches that aim to attack cancer cells while preserving normal cells. Macromolecular approaches and small molecule inhibitors (SMIs) impede specific molecular pathways in leukemic cells. Macromolecular therapies include monoclonal antibodies, bispecific T-cell engagers (BiTEs), chimeric antigen receptor (CAR), and antibody–drug conjugates (ADCs) [ 6 , 7 ]. Targeted therapy has many advantages yet disadvantages abound. These are: restriction with long-term stimulation, off-target effects from SMIs, efficient macromolecule distribution to target areas, and cytokine release syndrome [ 8 ]. Recent studies have demonstrated that the growth and proliferation of tumor cells utilize mechanisms related to the production of inhibitory ligands, secretion of anti-inflammatory cytokines, and establishment of an immunosuppressive environment. One of the elements reducing the effectiveness of targeted therapy is the escape mechanisms of tumor cells [ 9 , 10 ]. One of the ways to overcome tumor escape mechanisms and also to increase the effectiveness of targeted treatment and reduce its side effects is to use combination therapy [ 11 ]. In this review, we discuss the state of targeted therapy as well as the potential for combining antibody-based treatments and SMIs to treat acute leukemia in a more advanced manner.

Antibody-based therapy

Monoclonal antibodies are designed to specifically attach to antigens on cancer cell surfaces and trigger leukemic cell death via antibody-dependent cell cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Furthermore, the efficacy of antibody-based treatments may be enhanced when standard monoclonal antibodies are modified to bind to T cells and conjugate drugs [ 12 ]. For better understanding, we will separately discuss the monoclonal antibodies , ADCs, immune checkpoint inhibitors (ICIs), and BiTEs (Fig. 1 ). Fig. 1 Overview of the main targets of antibody-based immunotherapies in acute leukemia. CD cluster of differentiation, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, PD-1 programmed cell death protein 1, PD-L1 Programmed death-ligand 1, TIM-3 T-cell immunoglobulin and mucin-domain containing-3, CLL-1 C-type lectin-like molecule-1, Gal-9 Galectin-9, EpCAM Epithelial cell adhesion molecule

Monoclonal antibodies in acute leukemia

Anti-CD19

CD19 is a pan-B-cell antigen with the abnormal expression in subsets of AML being rare. It transmits B-cell receptor (BCR) signaling activation through PI3K/AKT and MAPK to promote cell survival. Engagement of CD19 on cell surface receptors by monoclonal antibody has anti-tumor effects by activating signaling pathways that regulate the progression of the cell cycle and programmed cell death [ 13 ]. Tafasitamab is a monoclonal antibody that has been engineered to improve its affinity for effector cell receptors and CD19 by modifying its Fab and Fc domains. It is Food and Drug Administration (FDA)-approved in combination with lenalidomide for the treatment of adults with diffuse large B-cell lymphoma (DLBCL) that has relapsed or is refractory [ 14 ]. Loncastuximab tesirine is an antibody–drug conjugate targeting CD19 that has been given FDA approval to treat DLBCL. In 2020, thirty-five individuals with B-cell ALL were treated with Loncastuximab Tesirine. Adverse effects observed included nausea, febrile neutropenia, and reversible liver function test abnormalities [ 15 ].

Anti-CD20

CD20 is expressed in Mature B-lymphocytes and B-lymphoblasts in B-ALL, while not in AML myeloblasts. CD20 mediates activation of B cells and calcium signaling. CD20 is successfully targeted in CD20 + ALL, but is not in AML. Rituximab, a monoclonal antibody against CD20, has shown positive results across many B cell malignancies [ 16 ]. Maury et al. demonstrated that the combination of rituximab with the chemotherapy protocol for CD20-positive young adults' and absence of the Philadelphia chromosome (Ph) ALL improved outcomes. Rituximab was generally well tolerated, without an unforeseen increase in major adverse effects from the control group, except for the easily controlled infusion-related reactions [ 17 ]. Ofatumumab is a new generation of fully human monoclonal antibody against CD20, targeting a small extracellular loop of CD20 with greater complement-dependent toxicity compared to rituximab. Results of a phase 2 study also reported that Hyper-CVAD plus ofatumumab has the potential to result in reduced intensity and duration of chemotherapy in patients with Ph-negative, CD20-positive B-ALL. Ofatumumab was tolerated generally well; although infections were common throughout induction and consolidation, no deaths were treatment-related due to the antibody itself [ 18 ].

Anti-CD22

CD22 is expressed on precursor B cells and lymphoblasts, specifically in B-ALL. It is a negative regulator of BCR signaling by recruiting SHP-1. It’s not expressed in AML, so it is B-ALL selective as a therapeutic target. In B-ALL, most blast cells (60–90%) express CD22. Epratuzumab is a humanized anti-CD22 monoclonal antibody, and it is internalized after binding to cell surface CD22 and modulates B-cell activation and signaling in contrast to eliciting direct cytotoxicity. A phase 2 clinical study results showed that the combinational therapy with epratuzumab as anti-CD22 and a conventional re-induction chemotherapy significantly improved overall survival (OS) and 2-year event-free survival (EFS) [ 19 ]. An anti-CD22 monoclonal antibody that has been humanized and conjugated to the cytotoxic antibiotic calicheamicin is called inotuzumab ozogamicin, or InO. In a phase 3 trial conducted by Kantarjian, et al. 326 patients were enrolled. Patients were divided into two groups: one receiving standard chemotherapy and the other receiving Inotuzumab ozogamicin (InO). The results showed that compared to normal treatment, the rate of complete remission was greater with InO [ 20 ]. Another study conducted on children with ALL demonstrated that InO is an effective and tolerable treatment for children with relapsed ALL, but it may be associated with side effects [ 21 ].

Anti-CD33

CD33 is a sialic acid-binding Ig-like lectin that is expressed at high levels on myeloblasts in AML, but not on lymphoblasts in ALL patients. It transmits inhibitory signals through ITIM motifs, and is the target of drugs such as gemtuzumab ozogamicin. Gemtuzumab ozogamicin, an antibody against CD33 combines the cytotoxic agent calicheamicin approved by the FDA in 2017. Gemtuzumab ozogamicin is associated with hepatotoxic effects, particularly manifesting as veno-occlusive disease [ 22 ]. Lintuzumab (SGN-33) is a humanized monoclonal antibody against CD33 but has significant toxicity. Rosenblat et al. exploited Actinium-225-lintuzumab (225Ac-lintuzumab), a radioimmunoconjugate that targets CD33 in AML and emits alpha particles. Its safety and anti-leukemic effects in relapsed/refractory AML patients have been proven in phase 1 trials [ 23 ]. Satomaa et al. demonstrated that the GLK-33 as antibody–drug conjugates has significant antitumor activity and reduced viability AML cell line and in contrast to earlier ADCs, it responded against leukemic cells that were multi-drugs resistant [ 24 ]. Phase 1/2 trial by Fiedler et al. showed BI 836858, a fully human unconjugated anti-CD33 monoclonal antibody, in combination with decitabine had a manageable tolerability profile and showed potential signals of efficacy in elderly patients with AML and those with relapsed/refractory AML [ 25 ].

Anti-CD38

CD38 is a transmembrane glycoprotein that operates both as a receptor and enzyme in cell activation, proliferation, differentiation, and cell adhesion, and is widely expressed in both types of acute leukemia, especially T-ALL [ 26 ]. Due to its broad distribution on immune cells and expression in acute leukemia, CD38 has been considered for a long time as a potential target for therapy [ 26 ]. Daratumumab, a human monoclonal antibody that targets CD38 and is approved for the treatment of multiple myeloma. According to research by Hogan et al., patients with relapsed/refractory T-ALL or lymphoblastic lymphoma demonstrated when daratumumab was added to the chemotherapeutic regimen, improved response rates compared to chemotherapy alone with a manageable safety profile [ 27 ]. Clinical trial studies of daratumumab are ongoing, which are mentioned in Table 1 . Isatuximab monotherapy in T-ALL patients showed low efficacy along with a high rate of complications [ 28 ] but when combined with chemotherapy, response rates were 42.9% in the B-ALL, 33.3% in the T-ALL, and 50.0% in the AML [ 29 ]. Table 1 Ongoing clinical trials based on antibody immunotherapies and small molecule inhibitors in acute leukemia Investigators (Start date) Study title Target Intervention Phase of clinical trial Participants Conditions Clinical trials Gov. Identifier Current status (Completion date) Marc Bernard (2024-05) Escalation of Doses of Daratumumab in Combination with Chemotherapy (Idarubicin and Cytarabine) in patients of 60 Years Old or More with Adverse Risk AML CD38 Daratumumab Phase 1 12 AML NCT05749276 Not yet recruiting (2028-01) Jeffrey Y Wong (2024-06) 225Ac-DOTA-Anti-CD38 Daratumumab Monoclonal Antibody with Fludarabine, Melphalan and Total Marrow and Lymphoid Irradiation as Conditioning Treatment for Donor Stem Cell Transplant in Patients with High-Risk AML, ALL and Myelodysplastic Syndrome CD38 Daratumumab Fludarabine Phase 1 15 ALL-AML-MDS NCT06287944 Not yet recruiting (2027-02) Sabina Chiaretti (2024-05) Daratumumab in VHR T-ALL Treated According to the ALL-National Treatment Program CD38 Daratumumab plus chemotherapy Phase 2 31 T-ALL NCT06253637 Not yet recruiting (2029-01) Alice S Mims (2024-06) Testing the Addition of an Anti-cancer Drug, SNDX-5613, to the Standard Chemotherapy Treatment (Daunorubicin and Cytarabine) for Newly Menin Revumenib Phase1 28 AML NCT05886049 Recruiting (2027-12) Guru Subramanian Guru Murthy (2024-05) Venetoclax-Navitoclax with Cladribine-based Salvage Therapy in Patients with Relapsed/Refractory AML BCL-2 Navitoclax Cladribine Venetoclax Phase1 36 AML NCT06007911 Not yet recruiting (2027-04) Kelly E Faulk (2024-04) A Study of SNDX-5613 in Combination with Chemotherapy for Patients Diagnosed with Relapsed or Refractory Leukemia Menin Revumenib Phase 2 78 AML-ALL NCT05761171 Recruiting (2027-12) Shira Dinner (2023-05) Daratumumab for Chemotherapy-Refractory Minimal Residual Disease in T Cell ALL CD38 Daratumumab Hyaluronidase Phase 2 20 T-ALL NCT05289687 Recruiting (2027-10) Publique Hôpitaux de Paris (2023-03) Combination of an Anti-PD1 Antibody with Tisagenlecleucel Reinfusion in Children, Adolescents and Young Adults with ALL After Loss of Persistence PD-1 Nivolumab Phase 1/2 26 B-ALL NCT05310591 Recruiting (2027-03) Xijing Hospital (2023-11) Olverembatinib Plus Venetoclax and Dexamethasone for Treatment-naïve Ph + ALL BCL-2 Olverembatinib Venetoclax Dexamethasone Phase 1/2 30 Ph + ALL NCT06082934 Recruiting (2026-11) Lori Muffly (2023-10) Study of Brexucabtagene Autoleucel Plus Dasatinib in Adults with ALL BCR-ABL Dasatinib Phase 1 20 Lymphoblastic Leukemia NCT05993949 Recruiting (2025-08) Miriam Garcia (2023-04) Phase II Study to Evaluate Safety and Efficacy of CB-103 With Venetoclax in Adolescent and Young Adult Patients with Relapsed/Refractory T-ALL or T-LBL BCL-2 CB-103 Venetoclax Phase 2 30 Lymphoblastic Leukemia NCT05464836 Recruiting (2026-07) Jianxiang Wang (2022-10) Pediatric-inspired Regimen Combined with Venetoclax for Adolescent and Adult Patients With de Novo Philadelphia Chromosome-Negative ALL BCL-2 Venetoclax Vincristine Daunorubicin Phase 2 100 Lymphoblastic Leukemia Lymphoma NCT05660473 Recruiting (2027-12) Sabina Chiaretti (2022-10) Ponatinib Plus Chemotherapy in ALL Patients BCR-ABL Ponatinib Phase 2 32 ALL NCT05306301 Recruiting (2028-07) Seth E. Karol (2022-08) Trial Treating Relapsed ALL with Venetoclax and Navitoclax BCL-2 CD19 Venetoclax Navitoclax Dasatinib Blinatumomab Phase 1/2 98 ALL NCT05192889 Active not recruiting (2029-07) Jae Park (2022-06) A Study of Venetoclax in Combination with Chemotherapy to Treat Newly Diagnosed ALL BCL-2 Venetoclax Early Phase1 12 ALL NCT05386576 Active not recruiting (2025-05) Jain Nitin (2022-06) A Phase II Study of the Combination of Ponatinib with Mini-hyper CVD Chemotherapy and Venetoclax in Patients with Relapsed or Refractory T-cell ALL BCR-ABL BCL-2 Ponatinib Venetoclax Phase 2 26 ALL NCT05268003 Recruiting (2026-10) Soochow University (2022-04) Study of Venetoclax Combined with Azacitidine Regimen in Newly Diagnosed T-ALL Patients BCL-2 Venetoclax Azacitidine Phase 2 28 T-ALL NCT05376111 Recruiting (2024-05) Jonathan Webster (2022-10) Post-transplant Flotetuzumab for AML CD123 Flotetuzumab Phase 1 16 AML NCT05506956 Recruiting (2027-12) Anthony Stein (2022-07) Navitoclax, Venetoclax, and Decitabine for the Treatment of Relapsed or Refractory AML Previously Treated with Venetoclax BCL-2 Navitoclax Venetoclax Decitabine Phase 1 17 AML NCT05222984 Active not recruiting (2025-01) Jacqueline S Garcia (2022-07) Combination Navitoclax, Venetoclax and Decitabine for Advanced Myeloid Neoplasms BCL-2 Navitoclax Venetoclax Decitabine Phase 1 36 AML-MDS-MF-MPN NCT05455294 Recruiting (2026-12) Nicole McNeer (2022-03) A Study of Revumenib in Combination with Chemotherapy in Participants With R/R Acute Leukemia Menin Revumenib Phase 1 30 AML-ALL NCT05326516 Active not recruiting (2024-07) Adam J Lamble (2022-01) Flotetuzumab for the Treatment of Pediatric Recurrent or Refractory AML CD123 Cytarabine Flotetuzumab Phase 1 16 AML NCT04158739 Active not recruiting (2024-09) Matthew Christopher (2021-05) Flotetuzumab for Relapsed AML and MDS Following Allogeneic Hematopoietic Cell Transplantation CD123 Flotetuzumab Phase 2 25 AML NCT04582864 Recruiting (2029-06) Childhood Leukemia Consortium (2019–-) Nivolumab in Combination With 5-azacytidine in Childhood Relapsed/Refractory AML PD-1 Nivolumab 5-azacytidine Phase 1/2 13 AML NCT03825367 Active not recruiting (2024-03) John Koreth (2019-07) A Phase 1 Trial of CD25/Treg-depleted DLI Plus Ipilimumab for Myeloid Disease Relapse After Matched-HCT CTLA-4 Ipilimumab Phase 1 25 AML-MDS NCT03912064 Active not recruiting (2024-07) Lihua Budde (2019-08) Pembrolizumab and Blinatumomab in Treating Participants with Recurrent or Refractory ALL PD-1 Blinatumomab| Pembrolizumab Phase 1/2 36 Ph + ALL NCT03512405 Recruiting (2024-10) M. Raaijmakers (2019-12) A Study of Gilteritinib Versus Midostaurin in Combination with Induction and Consolidation Therapy Followed by One-year Maintenance in Patients with Newly Diagnosed AML or MDS with Excess Blasts-2 With FLT3 Mutations Eligible for Intensive Chemotherapy FLT3 Gilteritinib Midostaurin Phase 3 777 AML-MDS NCT04027309 Active not recruiting (2033-06) Angela R Smith (2019-11) A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation Menin Revumenib Phase 1/2 413 AML-ALL NCT04065399 Recruiting (2024-12) Takeda (2018-10) A Study of Ponatinib Versus Imatinib in Adults with ALL BCR-ABL Ponatinib Imatinib Vincristine Phase 3 245 Ph + ALL NCT03589326 Active not recruiting (2027-07) Neil Palmisiano (2018-08) Venetoclax and Vincristine Liposomal in Treating Patients with Relapsed or Refractory T-cell or B-cell ALL BCL-2 Venetoclax Vincristine Liposomal Phase 1/2 74 ALL NCT03504644 Recruiting (2028-12) Arog Pharmaceuticals (2018-08) Study of Crenolanib vs Midostaurin Following Induction Chemotherapy and Consolidation Therapy in Newly Diagnosed FLT3 Mutated AML FLT3 Crenolanib Midostaurin Phase 3 510 AML NCT03258931 Recruiting (2024-11) Eunice Wang (2018-06) Study Investigating the Efficacy of Crenolanib with Chemotherapy vs Chemotherapy Alone in R/R FLT3 Mutated AML FLT3 Crenolanib Chemotherapy Phase 3 322 AML NCT03250338 Recruiting (2024-10) Seoul National University Hospital (2018-05) The Role of Ruxolitinib in Secondary AML Evolving from Myeloproliferative Neoplasm JAK Ruxolitinib Phase 1/2 17 AML NCT03558607 Recruiting (2024-08) Tapan M Kadia (2017-07) Palbociclib and Sorafenib, Decitabine, or Dexamethasone in Treating Patients with R/R Leukemia RAF kinase receptor Decitabine Palbociclib Sorafenib Phase 1 54 ALL-AML NCT03132454 Recruiting (2024-12) Jacqueline S Garcia (2017-09) Ipilimumab and Decitabine in Treating Patients with Relapsed or Refractory MDS or AML CTLA-4 Decitabine Ipilimumab Phase 1 48 AML-MDS NCT02890329 Active not recruiting (2024-07) Matthew Wieduwilt (2017-08) Blinatumomab and Pembrolizumab for Adults with Relapsed/Refractory B-cell ALL with High Marrow Lymphoblasts PD-1 CD19 Blinatumomab Pembrolizumab Phase 1/2 16 ALL NCT03160079 Active not recruiting (2025-12) Ivana Gojo (2017-10) Blinatumomab and Nivolumab with or Without Ipilimumab in Treating Patients with Poor-Risk Relapsed or Refractory CD19 + Precursor B-Lymphoblastic Leukemia CTLA-4 PD-1 CD19 Ipilimumab Nivolumab Blinatumomab Phase 1 24 ALL NCT02879695 Active not recruiting (2024-09) Maro Ohanian (2017-08) Combination Chemotherapy in Treating Patients with Relapsed or Refractory ALL, Lymphoblastic Lymphoma, Burkitt Lymphoma/Leukemia, or Double-Hit Lymphoma/Leukemia CD20 Ofatumumab Rituximab Bortezomib Phase 2 42 ALL Lymphoma NCT03136146 Recruiting (2026-08) AstraZeneca (2015-02) ACP-196 (Acalabrutinib) in Combination with Pembrolizumab, for Treatment of Hematologic Malignancies PD-1 BTK Pembrolizumab Acalabrutinib Phase 1/2 161 FL-NHL-MM-HL NCT02362035 Active not recruiting (2026-04) Jae Park (2015-06) Adding Ruxolitinib to a Combination of Dasatinib Plus Dexamethasone in Remission Induction Therapy in Newly Diagnosed Ph + ALL Patients JAK1, 2 BCR-ABL Ruxolitinib Dasatinib Phase 1 12 ALL NCT02494882 Active not recruiting (2025-06) Wendy Stock (2015-07) Testing Nivolumab to Prevent Disease from Coming Back After Treatment in Patients with AML PD-1 Nivolumab Phase 2 82 AML NCT02275533 Active not recruiting (2024-08) Astellas Pharma Global Development (2015-10) A Study of ASP2215 Versus Salvage Chemotherapy in Patients with Relapsed or Refractory AML With FLT3 Mutation FLT3 Gilteritinib Phase 3 371 AML NCT02421939 Active not recruiting (2024-07) Mikkael A Sekeres (2012-03) Azacitidine With or Without Lenalidomide or Vorinostat in Treating Patients with Higher-Risk MDS or CML HDAC Azacitidine Lenalidomide Vorinostat Phase 2 282 AML-CML-CMML-MDS NCT01522976 Active not recruiting (2025-03) Carlos Ramos (2009-02) CD19 Chimeric Receptor Expressing T Lymphocytes In B-Cell Non-Hodgkin's Lymphoma, ALL & CLL CTLA-4 CD19 CAR T cells Ipilimumab Phase 1 14 B Cell Lymphoma-ALL NCT00586391 Active not recruiting (2029-07) Lewis R Silverman (2006-11) Vorinostat and Azacitidine in Treating Patients with MDS or AML HDAC Vorinostat Azacitidine Phase 1/2 135 AML-MDS NCT00392353 Active not recruiting (2024-09) ALL acute lymphocytic leukemia, AML acute myeloid leukemia, CML chronic myeloid leukemia, CMML Chronic myelomonocytic leukemia, MDS myelodysplastic syndromes, FL Follicular lymphoma, MM multiple myeloma, NHL Non-Hodgkin lymphoma, HL Hodgkin lymphoma, MF Myelofibrosis, MPN Myeloproliferative neoplasms, DLBCL diffuse large B cell lymphoma, CTLA-4 cytotoxic T-lymphocyte antigen-4, PD-1 programmed death-1, HDAC Histone deacetylase, FLT3 fms like tyrosine kinase 3, JAK Janus kinase, BTK Bruton tyrosine kinase, BCL-2 B-cell lymphoma 2

Anti-CD52

CD52 is present on mature lymphocytes and on leukemic blasts in ALL and AML. It is not clearly known what its function is, but it is an immune regulatory glycoprotein. Overexpression of CD52 is an unfavorable prognostic factor for acute leukemia. Alemtuzumab is a monoclonal antibody against the CD52 antigen on the surface of blast cells. Alemtuzumab monotherapy has limited activity in treating leukemia and should be combined with other therapeutic agents [ 30 ]. A phase 2 clinical trial indicates that alemtuzumab has acceptable but short-term effects in patients with acute HTLV-1-associated adult T-cell leukemia. Therefore, including alemtuzumab in multi-drug treatments for patients with Adult T-cell Leukemia could play an effective role in their recovery [ 31 ].

Anti-CD123

CD123 is considered the alpha subunit of the interleukin-3 receptor. It is a novel cell membrane protein identified as a therapeutic target and is expressed in AML (50–75.6%) and ALL (75–88.6%), and it is utilized for response evaluation and assessment of residual disease. It induces activation of the JAK/STAT and PI3K/AKT pathways, taking part in proliferation and cell survival [ 32 ]. Pivekimab sunirine (IMGN632) is an antibody against CD123 conjugate novel indolinobenzodiazepine pseudodimer payload. Daver et al. investigated the phase 1/2 study IMGN632 in relapsed or refractory AML patients, their results showed tolerance and efficacy are encouraging and supporting further research for combination therapy [ 33 ]. Result of phase 2/3 study talacotuzumab, a humanized anti-CD123 monoclonal antibody, combined with decitabine did not showed to be more effective than decitabine alone in complete response rate or overall survival [ 34 ].

Immune checkpoint inhibitors (ICIs) in acute leukemia

Various immune checkpoint pathways with immunosuppressive properties are activated by tumor cells. ICIs have shown to be an efficient strategy for boosting the effector activity and therapeutic impact of anti-tumor T cells in the context of cancer, where negative T cell regulatory pathways are frequently hyperactive [ 35 ].

Anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4)

One of the best stimulatory signals for T cells is provided by the CD28 family of proteins. The binding of CD28 to its ligands, B7-1 and B7-2, leads to T cell proliferation and the production of IL-2 and anti-apoptotic factors. Due to the structural similarity between CTLA-4 and CD28 and the higher affinity of CTLA4, it can compete with CD28 and bind to B7, thereby reducing T cell function. Two monoclonal antibodies that attach to CTLA-4 and prevent it from functioning are ipilimumab and tremelimumab [ 36 ]. The results of a phase 1 clinical trial by Garcia et al. showed that the combination of ipilimumab and decitabine therapy has a significant therapeutic effect and an acceptable safety profile in patients with R/R MDS/AML [ 37 ].

Anti-programmed cell death-1 (PD-1)

PD-1 as an inhibitory receptor on T cells interacts with the tyrosine phosphatase SHP2, leading to the dephosphorylation of downstream TCR molecules, thereby inhibiting TCR activation, IL-2 production, and T cell proliferation [ 38 , 39 ]. Ruan, et al. conducted a study on 53 AML patients, 44 ALL patients, and 28 healthy controls, their results demonstrated that aberrant expression of PD-1 is associated with acute leukemia. Therefore, the use of PD-1 inhibitors could be a promising strategy for treating patients with AML and ALL [ 40 ]. The FDA has approved anti-PD-1, including nivolumab, pembrolizumab, and cemiplimab but did not approve them for acute leukemia [ 41 ]. Assouline et al. conducted a randomized controlled trial study in which some AML patients treated with nivolumab and azacitidine experienced complications such as pneumonitis, fever, diarrhea, and hemodynamic instability. Overall, due to higher mortality in the nivolumab and azacitidine group compared to the group receiving only azacitidine, the use of combinational treatment with nivolumab and azacitidine for AML is not recommended [ 42 ]. Another phase 2 randomized trial study evaluated the efficacy of nivolumab in AML patients, after 24 months follow-up revealed that nivolumab post-chemotherapy failed to raise overall and progression-free survival [ 43 ].

Anti-T cell immunoglobulin and mucin domain 3 (Tim-3)

Tim-3 is an inhibitory receptor that is produced by leukemic stem/progenitor cells, blasts, and different immune cells. It may be possible to enhance AML outcomes, alter the immune system, and eradicate leukemic stem cells (LSCs), by focusing on Tim-3 [ 44 ]. The clinical trial's outcomes indicated that AML patients' bone marrow had substantially higher Tim-3 expression than their peripheral blood. In addition, targeting the Tim-3/Galectin-9 axis in combination with chemotherapy could enhance the likelihood of complete remission in these patients [ 45 ]. A clinical trial study demonstrated that the hematopoietic stem cell transplantation was generally favorable in patients with high-risk MDS and AML after combinational therapy with sabatolimab as anti-Tim-3 [ 46 ]. In another study, Brunner et al. indicated that the treatment with sabatolimab and hypomethylating agents (HMA) were well-tolerated in patients with AML and higher-risk MDS when compared to monotherapy with HMA; however, this treatment strategy showed promising and durable anti-leukemic activity [ 47 ].

Anti-CD47

In acute leukemia (ALL and AML) blasts, CD47 is expressed more frequently, which can promote the disease by sending out a "don't eat me" signal by interacting with SIRPα present on macrophages. Magrolimab is a humanized monoclonal antibody against CD47. The final result of phase 1b showed that when used in combination with magrolimab and azacitidine demonstrated a favorable safety profile and potential effectiveness in treating patients with untreated higher-risk MDS [ 48 ].

Bispecific T-cell engagers (BiTEs)

Bispecific antibodies are a useful substitute treatment platform for immunotherapy. These engineered synthetic antibodies can recognize two epitopes from one antigen or two different antigens, offering stronger and more appropriate immune targeting compared to the capabilities of naturally occurring antibodies. BiTE compounds are extensively employed in immunotherapy for cancer to retarget T lymphocytes to cancerous cells or cells related to cancer in the tumor microenvironment. BiTEs target both tumor-associated antigen expressed by tumor cells and CD3 on T-cells and establish a cytolytic synapse so as to facilitate synergistic dual targeting and enhance anti-tumor immune responses. Using scFv fragments from two distinct monoclonal antibodies joined by a peptide linker, they are able to maintain the binding activity of each antibody when assembled [ 49 ]. The approval of catumaxomab (anti-EpCAM and anti-CD3) and blinatumomab (anti-CD19 and anti-CD3), in order to treat B-cell precursor ALL, in 2014 marked a milestone in the development of bispecific antibodies [ 50 ]. Nevertheless, Catumaxomab has recently been withdrawn from the European market to revise its informational content. A phase 3 clinical trial reported that the overall survival in the treatment group with blinatumomab was higher than in the chemotherapy group in adults with B-cell ALL. The 12-month survival rate was 31% in the blinatumomab group compared to 12% in the chemotherapy group [ 51 ]. In another study on infants with ALL, it was shown that combination treatment with blinatumomab and chemotherapy appeared safe and demonstrated a high level of efficacy [ 52 ]. Gökbuget et al. indicated that the treatment B-cell precursor ALL patients with blinatumomab resulted in the majority of patients achieving a complete minimal residual disease (MRD) response. However, these patients had longer overall survival and relapse-free survival compared to the other treatment group. But, some patients experienced grade 3 or 4 neurological complications and cytokine release syndrome [ 53 ].

In the context of (AML), the CLL-1 biomarker has garnered significant scholarly interest owing to its expression on neoplastic cells while remaining undetected on normal hematopoietic stem cells, as well as the CD123 marker which is characterized by its heightened expression in malignant cellular populations. In AML, MCLA-117, an innovative bispecific antibody designed to redirect T cells, emerged as a promising approach for treating AML by targeting CD3 on T cells and CLL-1 on leukemic cells. Van Loo et al. demonstrated that MCLA-117 can efficiently eliminate AML blasts from primary patient samples by activation of T cells [ 54 ]. XmAb18968 is a bispecific antibody directed against CD38 and CD3 and incorporates an Fc domain modification that reduces binding to Fc γ receptors and nonspecific T cell activation, resulting in lower cytokine release without compromising the efficacy in the eradication of target cells. A phase 1 trial study has shown promising tolerability, safety, and efficacy results for the treatment of AML by XmAb18968 [ 55 ]. In addition, flotetuzumab and XmAb14045 are CD123/CD3 targeting bispecific antibodies. A phase 1 study showed that Flotetuzumab has preliminary anti-leukemic activity and a controllable safety profile in relapsed/refractory AML and MDS [ 56 ].

Small molecule inhibitors (SMIs)

Over the past two decades, SMIs have emerged as one of the major breakthroughs in the management of acute leukemia. Because of their small size, they can easily penetrate the cells to target the disrupted proteins and signaling pathways in cancer cells. Among the key advantages of these agents are their high selectivity and reduced off-target toxicity compared to conventional chemotherapeutic regimens. By inhibiting key signaling proteins, they can prevent tumor growth and induce cell death [ 57 ]. Protein kinases act as cords in the complicated world of cellular communication. There are three primary categories of protein kinases: tyrosine kinases (which comprise receptor and non-receptor variants), serine/threonine kinases, and enzymes that resemble tyrosine kinases [ 58 ]. In addition, SMIs target epigenetic regulators, anti-apoptotic proteins, and the smoothened signaling pathway. These classes will be further elaborated in the next sections (Fig. 2 ). Fig. 2 Overview of the main targets of small molecule inhibitors in acute leukemia. BCR B cell receptor, FLT3 fms like tyrosine kinase 3, SMO Smoothened, JAK Janus kinase, BTK Bruton tyrosine kinase, IDH Isocitrate dehydrogenases, Bcl-2 B-cell lymphoma 2, Bcl-XL B-cell lymphoma-extra large, LSD1 Lysine-specific demethylase 1, HMT Histone methyltransferases, BRD Bromodomains, HDAC Histone deacetylase, NF-Κb Nuclear factor kappa-light-chain-enhancer of activated B cells, PI3K Phosphoinositide 3 kinase, mTOR mammalian target of rapamycin

Receptor tyrosine kinases (RTKs) inhibitors

RTKs which are integral proteins with an extracellular domain, function as docking sites for a variety of signaling molecules, including growth factors and cytokines [ 59 ]. They have been identified as a target for cancer cell inhibition because of their important role in the vital pathways of the cells. There are multiple mutant RTKs found in acute leukemia, here we are talking about FLT3 (fms like tyrosine kinase 3) and KIT [ 60 ].

FLT3 inhibitors

FLT3 is a class III receptor tyrosine kinase essential for blood cell formation. Approximately 30% of AML patients have a mutation in FLT3. Continuously activated mutant receptor causes acute leukemia to proliferate and progression [ 61 ]. Innovative pharmacological therapies that specifically inhibit FLT3 have been used for treatment and mitigating the adverse consequences of AML caused by FLT3 mutations [ 62 ]. Midostaurin and gilteritinib were given FDA approval in 2017 and 2018, respectively, for the treatment of relapsed or resistant AML patients with FLT3 mutations [ 63 ]. Similarly, Halpern et al. demonstrated that the combinational treatment with sorafenib as FLT3 inhibitors and standard chemotherapy dramatically increased AML patients' event-free survival [ 64 ].

KIT inhibitors

KIT, a class III receptor tyrosine kinase, is essential for signal transmission. AML has been associated with mutations in the KIT gene, especially in a particular kind called core-binding factor (CBF) leukemia [ 65 ]. KIT mutations are particularly relevant in certain subtypes of ALL, such as Ph-negative ALL and some cases of high-risk ALL [ 66 ]. Imatinib and dasatinib are other FDA-approved tyrosine kinase inhibitors used mainly for Ph-positive ALL [ 67 ]. Ripretinib as a KIT and PDGFRA receptor tyrosine kinase inhibitor, has shown effectiveness in early clinical data in preclinical cancer models indicating it can inhibit a wide range of KIT mutants in patients with drug-resistant gastrointestinal stromal tumors [ 68 ].

Non-receptor tyrosine kinases (NRTK) inhibitors

A subclass of tyrosine kinases, the NRTKs are internal proteins located in the cytoplasm which may trigger intracellular impulses derived from external receptors and participate in several biological processes, like cell division, proliferation, and survival. These can be classified into nine groups mainly according to structural similarities within the kinase domains. Some NRTKs including BCR-ABL, JAK, and BTK are frequently involved in acute leukemia [ 69 ].

BCR-ABL inhibitors

Due to a component of DNA translocation between chromosomes 9 and 22, known as t (9;22), this chromosome is abnormally short and dysfunctional. This encodes a complex protein that is a constantly active tyrosine kinase signaling peptide which disrupts the integrity of the genes to cause the invincible proliferation of cells. The p190, p210, and p230 types of the aberrant protein are produced by the BCR-ABL combination gene. Although p210 is more frequently connected to chronic myeloid leukemia (CML) but may happen in ALL and AML, p190 is generally associated with ALL [ 70 ]. The BCR-ABL inhibitors imatinib (Gleevec), dasatinib (Sprycel), ponatinib (Iclusig), and nilotinib (Tasigna) have mainly been approved for use in the treatment of CML and Ph + ALL by the FDA [ 71 ]. Kantarjian et al. conducted a clinical trial in which it was observed that bafetinib can act as an effective treatment option as a BCR-ABL inhibitor in the case of Ph + ALL patients [ 72 ]. Another trial study by Jabbour et al. showed that with ponatinib, the rate of MRD-negative complete remission was noticeably greater (34.4%) compared to imatinib (16.7%) in Ph + ALL [ 73 ]. As of the latest updates, unlike CML and ALL, BCR-ABL inhibitors are not FDA-approved for the treatment of AML.

Bruton tyrosine kinase (BTK) inhibitors

BTK, a non-receptor tyrosine kinase, is essential for lymphoid development. Insufficient BTK signaling has been implicated to result in defective immune function and potentially leukemogenesis in AML and B-ALL pathogenesis. High quantities of enabled BTK (phosphorylated at Y223) and BTK upregulation were found in AML specimens [ 74 ]. BTK is a key factor in driving leukemia development, especially in B-cell ALL, by supporting cell growth and survival. The substantial impact of BTK on leukemogenesis is especially relevant considering the poor outcomes and high recurrence rates observed in B-ALL patients [ 75 ]. A recent study by Rice et al. has interestingly shown that loxeptinib, a known pan-FLT3/pan-BTK in AML, also inhibits other kinases involved in cancer cell survival [ 76 ]. Ibrutinib has been shown in clinical studies to be effective in treating B-ALL, but occasionally, these medications might have negative reactions. Acalbrutinib and zanubrutinib are two of the more recent BTK inhibitors that are being researched because they could have fewer adverse consequences [ 77 , 78 ]. Another study by Soltanshahi et al. exhibited a combination of ibrutinib and mTOR inhibitor, everolimus, decreased the expression of the immune checkpoint ligands PD-L1 and CD155 and modulating the immune evasion mechanisms in breast cancer cells [ 79 ].

JAK inhibitors

JAK1, JAK2, JAK3, and TYK2 are the four subgroups of the JAK class of non-receptor tyrosine kinases that are currently recognized. Hematological malignancies are the ones that have most effectively articulated abnormal JAK/STAT excessive stimulation and its function in the pathology of cancer. There is growing evidence linking the process involving JAK and STAT to the etiology of AML and ALL [ 80 ]. In certain B-ALL patients, especially those who do not respond well to traditional treatments, mutations in JAK3 or abnormal activation of the JAK-STAT system are highlighted. T-ALL is associated with mutations and aberrations in the JAK-STAT pathway, particularly in JAK1 [ 81 ]. JAK excessive stimulation and pathway dysfunction have been demonstrated in AML, and blocking JAK/STAT in AML cells led to the suppression of cell growth, regardless of the cause of genetic or epigenetics of the JAK/STAT system's alterations. Due to the modest prevalence of activating changes in JAK1 within AML, JAK2 inhibitors that also block JAK1, such as CYT387 and ruxolitinib, maybe the best option in this situation [ 82 ]. The unique JAK inhibitor ruxolitinib received FDA approval for myelofibrosis in 2011, and studies in acute leukemia are still ongoing (Table 1 ) [ 83 ]. Pemmaraju et al. in a phase 1/2 study of the ruxolitinib in patients with relapsed or refractory AML performed in 27 patients observed that after seven lines of drugs, a patient who had relapsed several times experienced a complete remission [ 84 ].

Serine/threonine kinase inhibitors

Serine/threonine protein kinases are a family of enzymes that phosphorylate the hydroxyl group of serine or threonine residues in proteins. Such phosphorylation is indispensable for many biological functions, including cell division, apoptosis, and reproduction [ 85 ].

Cyclin-dependent kinases (CDKs) inhibitors

These CDKs are an important family of serine/threonine protein kinases in the regulation of cell cycle progression and require complex formation with cyclins for their activation to phosphorylate target proteins. To date, at least 20 identified CDKs and 29 cyclins have been identified in humans. Of these, especially CDK4, CDK6, and CDK9 play an important role in controlling the growth signals that promote the transition from G1 to S phase in the cell cycle [ 86 ]. The CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib have also been explored for treatment in solid tumors and homological malignancies [ 87 ]. However, clinical trials are underway to assess the effect of these drugs on acute leukemia. By inhibiting CDK9 and CDK7 by alvocidib, the expression of cyclin D1, c-MYC, and MCL-1 were down-regulated, which is crucial for AML cell survival and proliferation [ 88 ]. In newly diagnosed AML patients, phase 1 research combining alvocidib with 7 + 3 (cytarabine + daunorubicin) induction therapy produced a 69% complete remission rate and 89% of those individuals had no detectable residual illness [ 89 ]. For patients with relapsed/refractory and newly diagnosed AML, a combination of palbociclib, a selective CDK4/6 inhibitor and CPX-351, an encapsulated version of cytarabine plus daunorubicin, proved to be highly beneficial in phase 1/2 trial participants [ 90 ].

Phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) inhibitors

The serine/threonine kinase-mediated PI3K/AKT/mTOR signaling pathway is considered important in cell growth, proliferation, survival, apoptosis, and motility and is usually triggered in human cancers. Compared to children, adults show more increased expression of mTOR in T-ALL, while PI3K/Akt/mTOR signaling network is usually hyper-activated in B-ALL, which suggests worse prognosis and drug resistance in both adults and children [ 91 ]. In 60% of AML patients, this pathway is continuously activated, and this activation is associated with a decrease in overall survival [ 92 ]. Sirolimus (rapamycin), temsirolimus, and everolimus are approved for treating a range of cancers, but none are approved for treating acute leukemia [ 58 ]. Pikman et al. observed effective synergy with the CDK4/6 inhibitor ribociclib when combined with everolimus and glucocorticoids in T- and B-ALL patients [ 93 ]. In a phase 2 study, combining temsirolimus with clofarabine in elderly AML patients led to an overall remission rate of 21% and a median disease-free survival of 3.5 months [ 94 ]. The in vitro study by Taghiloo et al. showed that when idelalisib as a PI3K inhibitor, MK-2206 as an Akt inhibitor, and everolimus as an mTOR inhibitor were combined, it led to decreased proliferation and increased apoptosis of AML cells [ 95 ]. Recent studies indicated that the combination of R848 (a TLR7/8 agonist) and BEZ235 (a PI3K/mTOR inhibitor) inhibited the proliferation and development of WEHI-3 murine leukemia cells and that this was more effective than monotherapy and in the AML murine model, improvements of anti-tumor immunity [ 96 , 97 ].

Epigenetic inhibitors

Independent of DNA sequence, heritable effects on gene expression are termed epigenetic modifications, including DNA methylation, histone modification, and chromatin remodeling [ 98 ]. Together, these epigenetic inhibitors represent a rapidly evolving class of targeted therapies in acute leukemia, with several showing promise in early clinical trials, particularly in genetically defined patient subsets.

Histone methyltransferases (HMTs) inhibitors

HMTs are epigenetic regulators that methylate lysine or arginine residues on histone proteins, influencing gene expression. The site and number of methyl groups determine whether genes are activated or silenced. HMTs are classified by their domain architecture and effect on gene expression. The main class contains a SET domain, using S-adenosyl-L-methionine (SAM) for methylation, with EZH2 as a key example catalyzing the polycomb repressive complex 2 (PRC2) [ 99 ]. Another group, like DOT1L, lacks the SET domain and methylates histone H3 at lysine 79 (H3K79) using a unique AdoMet-binding mechanism. DOT1L has been identified as a contributing factor to the development of multiple leukemia, including mixed lineage leukemia (MLL), ALL, and AML [ 100 ]. In T-cell ALL, EZH2 is commonly mutated and overexpressed. Moreover, recent studies indicate that post-translational inactivation of EZH2 leads to chemoresistance in AML [ 101 ]. Two patients in the trial by Stein et al. experienced complete remissions, supporting the idea that patients with MLL can experience clinically meaningful responses when pinometostat as a DOT1L inhibitor. Although the efficacy of pinometostat as a monotherapy was limited [ 102 ].

Histone deacetylase (HDACs) inhibitors

There are four subtypes for HDACs with distinct intracellular sites and protein preferences, deacetylate lysine residues on a variety of proteins, including those implicated in cell division and death [ 103 ]. In AML, mutations in HDAC genes have not been detected; however, abnormal fusion proteins like PML-RARα, PLZF-RARα, or AML1-ETO can recruit HDAC proteins to gene promoters, silencing genes and contributing to leukemia [ 98 ]. Therefore, HDAC inhibitors have the potential as an AML treatment since they can promote differentiation, cell cycle arrest, and death in cancer cells [ 104 ]. The first discovered HDAC inhibitor is hydroximates, which boast strong activity despite their simple structures. Panobinostat is an another HDAC inhibitor that exhibited modest efficacy as a monotherapy in initial clinical trials involving advanced hematological malignancy including AML, with notably low rates of overall and partial responses [ 105 ]. In phase 2 clinical carried out by Schaefer, the monotherapy with vorinostat showed limited effectiveness in AML patients [ 106 ]. Finally, belinostat as an HDAC inhibitor efficiently inhibits proliferation, induces cell cycle arrest, and stimulates apoptosis in AML cells. However, a phase 2 clinical trial indicated that the effectiveness of monotherapy of belinostat for AML patients was negligible [ 107 ].

Menin inhibitors

Menin is a nuclear protein that functions as a scaffold and affects many biological processes encoded by the MEN1 gene. The control of myeloid cell proliferation and hematopoiesis are two of these processes [ 108 ]. Menin interacts with the KMT2A proto-oncogene, crucial for development and blood cell formation. Menin inhibitors block this interaction, preventing overexpression of HOX and MEIS1 genes, and thus hindering leukemia development [ 109 ]. Accordingly, a phase 1 clinical trial indicated that revumenib as a menin inhibitor can be effective in AML patients [ 110 ]. Another phase 1 study by Erba et al., displayed that a tolerable safety profile and initial efficacy for ziftomenib in relapsed or refractory AML patients [ 111 ]. Leukemic cells in AML patients with NUP98 rearrangements, which are addicted to the interaction of menin with Mixed Lineage Leukemia 1 (KMT2A), are also addicted to aberrant kinase signaling via CDK6 and/or FLT3 pathways. Recent in vitro experiments have demonstrated that the limited activity of single agent treatments can be overcome by co-targeting menin and critical kinases. Specifically, the anti-leukemic activity of menin inhibitors is greatly enhanced in combination with CDK6 or FLT3 inhibitors, revealing a promising avenue for future combination therapy strategies in genetically defined AML subtypes [ 112 ].

Bromodomains (BRDs) inhibitors

BRDs, are protein segments involved in gene expression regulation by recruiting molecular partners. Bromodomain and extraterminal (BET) is a family of proteins with BRDs, which consists of BRD2, BRD3, BRD4, BRD9, and BRDT [ 113 ]. Due to the ability of BET inhibitor including OTX015, mivebresib, and molibresib to suppress cell growth and trigger apoptosis in leukemia cell lines, is being investigated in clinical trials as a potential treatment for AML [ 114 , 115 ]. In a phase 1 clinical study conducted by Borthakur et al. the anti-leukemic activity of mivebresib monotherapy was moderate, indicating that its usage in treating relapsed or resistant AML would have a limited impact but when combined with venetoclax showed higher efficacy [ 116 ]. Another study displayed that the treatment of high-risk MDS, cutaneous T-cell lymphoma (CTCL), and AML patients with molibresib exhibited anti-tumor activity, and was well-tolerated with no unexpected side effects [ 117 ].

Isocitrate dehydrogenases (IDH) inhibitors

IDH are essential NADP + dependent enzymes in the Krebs cycle that catalyze the conversion of isocitrate to α-ketoglutarate. There are three different forms, IDH1, IDH2, and IDH3. Mutations in IDH1 and IDH2 are seen in cytogenetically normal AML but are uncommon in other subtypes [ 118 ]. IDH2 mutations in AML are more common than IDH1 and become even more frequent in intermediate-risk and older patients [ 119 ]. The FDA has approved ivosidenib, an IDH1 inhibitor, and enasidenib, an IDH2 inhibitor, for the treatment of AML patients with the IDH1 and IDH2 mutation, respectively [ 120 ]. In a phase 3 clinical trial using enasidenib, the primary endpoint of overall survival was not met, the study demonstrated that enasidenib offers significant benefits in EFS, TTF, and response rates in a heavily pretreated older population with mutant-IDH2 AML [ 121 ]. In another research conducted by Montesinos et al. the combination of ivosidenib and azacitidine demonstrated notable clinical advantages compared to placebo and azacitidine in newly diagnosed IDH1-mutated AML patient [ 122 ].

Lysine-specific demethylase 1 (LSD1) inhibitors

LSD1 demethylates histone H3 at lysine 4, thereby influencing epigenetic mechanisms [ 123 ]. Despite the absence of LSD1 mutations in acute leukemia, this enzyme is found to be overexpressed in AML and ALL patients. According to Niebel et al. 60% of patients with AML showed the up-regulation of LSD1 [ 124 ]. This overexpression points towards LSD1 as a possible target for therapeutic intervention in leukemia. Using the structural homology between LSD1 and monoamine oxidase (MAO) to explore MAO inhibitors in developing targeted molecules against LSD1. Tranylcypromine (TCP) emerged as the first compound that was capable of inhibiting LSD1 catalytic activity [ 125 ]. In one study, Tayari et al. reported that trans-retinoic acid combined with TCP (ATRA-TCP) synergistically increased the differentiation and cell death of AML cells by modulating gene sets that predict clinical response [ 126 ].

B-cell lymphoma 2 (BCL-2) inhibitors

The BCL-2 protein family plays a critical role in cell survival and the intrinsic apoptotic process. BCL-2, which is an anti-apoptotic protein, can be excessively expressed in the AML and ALL leukemia cells to support therapy resistance and persistence of the disease. This aberrant expression causes a poor prognosis and treatment resistance [ 127 ]. Bcl-2 inhibitor, venetoclax is highly selective and orally bioavailable and was approved in combination with chemotherapy for the treatment of AML in 2018. In a phase 2 trial, venetoclax was initially assessed as a stand-alone treatment for patients with relapsed or resistant AML or those unable to receive intense chemotherapy. According to this study, single-agent venetoclax showed high tolerability and anti-tumor efficacy in AML [ 128 ]. Another phase 1 trial examined combining venetoclax with chemotherapy, exhibiting 37.5% of patients achieved an MRD-negative complete remission by the end of induction I, and 83% of patients who completed induction II achieved MRD-negative complete remission [ 129 ]. Besides venetoclax, another BCL-2 family inhibitor, navitoclax, was also investigated and showed favorable outcomes. Navitoclax (ABT-263) has potential as a treatment for AML patients with MLL rearrangement [ 130 ]. The data from a phase 2a study of the effect of navitoclax on patients with relapsed or refractory lymphoid malignancies demonstrated overall objective response rate was 23.1% and the median overall survival was 24.8 months [ 131 ].

Smoothened (SMO) inhibitors

As a highly conserved and regulated pathway, Hedgehog (Hh) signaling is crucial for embryogenesis and stem cell functions. When its components become dysregulated, leukemic stem cells (LSCs) develop and expand. SMO inhibitors can disrupt this dormancy, prompting LSC differentiation through cell-cycle activation [ 132 ]. The first cyclopamine derivative and drug targeting the Hh pathway approved for treating metastatic basal cell carcinoma was vismodegib. A study by Bixby et al. carried out the evaluation of vismodegib safety and effectiveness in treating relapsed or resistant AML. Their results showed that in patients with relapsed or resistant AML, vismodegib as a single drug had only a minimally beneficial effect. A phase Ib trial, 20 patients with relapsed or refractory AML, demonstrated that vismodegib monotherapy was of modest clinical activity with only partial disease stabilization, although the drug was well tolerated overall [ 133 ]. Glasdegib is another SMO inhibitor approved for newly diagnosed AML patients who are either 75 years old or older, or unsuitable for intensive induction chemotherapy, and in a common treatment regimen, it is usually combined with low-dose cytarabine [ 128 ]. A phase 1 trial by Martinelli et al. with 47 patients with myeloid malignancy revealed that glasdegib has a favorable safety and tolerability profile, dose-proportional pharmacokinetics, and on-target side effects, and early indications of clinical efficacy in patients with AML, CML, MDS, and myelofibrosis [ 134 ].

Challenges of monotherapy

Despite the positive effects of antibodies in treating acute leukemia, this type of treatment faces several challenges. Many current monoclonal antibodies (mAbs) need to be administered in high doses, about 5–20 mg/kg per injection, to be effective, which further increases the treatment cost. Most mAbs have to be administered intravenously, requiring a hospital setting with advanced equipment and skilled staff [ 135 , 136 ]. The use of mAbs can lead to side effects such as immune reactions like acute anaphylaxis, serum sickness, and antibody production. Moreover, there are several adverse effects associated with mAbs, depending on their specific targets, including infections, autoimmune diseases, and cardiac toxicity [ 137 ]. For example, blinatumomab is most commonly associated with cytokine release syndrome (CRS) and neurologic toxicities [ 138 ]. On the other hand, rituximab is associated with infusion reactions and an increased risk of infections [ 139 , 140 ]. Gemtuzumab ozogamicin has hepatotoxicity, specifically veno-occlusive disease [ 141 ]. Accordingly, individuals receiving ICIs for advanced cancers have a higher chance of experiencing immune-related neurological side effects, such as myasthenia gravis, inflammatory myopathies, acute and chronic demyelinating polyradiculoneuropathies, vasculitic neuropathies, and isolated cranial neuropathies, and hypophysitis [ 142 ]. A review of clinical trials shows that the incidence of grade 3 or higher infections is significantly higher among patients treated with bispecific antibodies. In addition, high rates of neutropenia and fever were also observed with the use of BsAbs in myeloid malignancies [ 143 ]. On the other hand, SMIs have achieved significant progress in targeted cancer therapy, especially acute leukemia, yet these drugs face some challenges. One major challenge is interacting with molecules in normal cells throughout the body. Studies have shown that SMIs usually interact with at least 6–11 other targets in addition to their primary intended target. These unintentional interactions, sometimes referred to as off-target effects, may result in negative consequences [ 144 ]. For instance, it is currently reported that cardiovascular toxicity is a prominent undesirable effect of some medications, such as tyrosine kinase inhibitors (TKIs) [ 145 ]. Nilotinib and ponatinib were shown to have the greatest amounts of raised liver enzymes [ 146 ]. In addition, pleural effusion is a significant long-term adverse event, associated with some BCR-ABL inhibitors, especially dasatinib [ 147 ]. Also, over 70% of individuals have been shown to experience a variety of mild to significant skin responses after using TKIs [ 148 ].

One of the most important major problems with targeted anti-cancer drugs is drug resistance. Resistance can occur with mutations in the target gene itself (e.g. FLT3 mutations render FLT3 inhibitors inactive) [ 149 ], activation of an independent survival signaling cascade (e.g. signal by-passes upstream blockade through the PI3K/Akt/mTOR pathway) [ 150 ], or downregulation and modulation of the antigen (e.g. after treatment with blinatumomab, decrease in expression of CD19) [ 151 ]. Almost all drugs mentioned above develop resistance after a period of clinical use, and the main cause of this resistance is gene mutations. There are two perspectives on drug-resistant gene mutations; the first holds that the mutations are preexisting, and the second holds that the drugs induce the mutations [ 58 ]. Therefore, one effective way to overcome the challenges in immunotherapy with SMIs is the combination therapeutic strategy.

Combination therapy

Cancer treatment has changed dramatically due to antibody-based therapeutics and SMIs, some of which have been approved by the FDA; however, we still face challenges in treating acute leukemia. One of the primary causes is that cancer cells employ a variety of escape strategies, such as the recruitment of immunosuppressive cells, the up-regulation of inhibitory immune checkpoint ligands, the decrease in MHC class I expression, the increase in anti-apoptotic protein expression, and the secretion of anti-inflammatory cytokines. Furthermore, the use of various alternative mechanisms to develop resistance to targeted therapy has led to additional difficulties and decreased efficacy. A further drawback of utilizing monoclonal antibodies, which was noted in the previous section, was the requirement for a high dose in order to achieve optimal efficiency. However, this problem can be resolved with combination therapy because the synergistic effects of the medications work together [ 152 , 153 ]. Therefore, it is anticipated that the use of monoclonal antibodies and SMIs together, two treatment approaches with different mechanisms of action, when combined, can lead to less adverse effects and drug resistance as well as greater efficacy. Accordingly, in this section, we review several studies on combination therapy. Li et al. demonstrated that the combinational of venetoclax, a BCL-2 inhibitor, and TJC4, an anti-CD47 antibody, had a synergistic effect that promotes phagocytosis of B-cell lymphoma cells and enhances anti-tumor activity [ 154 ]. Similarly, Mistry et al. examined an AML mouse model and found that treating the mice with a combination of both venetoclax and daratumumab had much slower progression of the tumor and lessened leukemia growth over time [ 155 ]. Furthermore, Yuen et al. presented results from a phase 2 clinical trial showing a promising response rate in patients with DLBCL or relapsed/refractory follicular lymphoma treated with a combination of venetoclax with rituximab and polatuzumab vedotin (a CD79b-directed antibody–drug conjugate) [ 156 ]. After pretreating AML cells with venetoclax, Mu-Mosley et al. employed a CD123-specific BiTE. The results demonstrated that venetoclax increased the cytolytic activity of CD123-specific BiTE-secreting T-cells in a dose-dependent manner [ 157 ]. In addition, recent study indicated that the treatment strategy with anti-PD-1 plus dasatinib was the most successful combination to increase survival in a mouse model of Ph + ALL when compared to either treatment alone [ 158 ]. The data presented by Leclercq et al. support the use of dasatinib to quickly and reversibly prevent the negative consequences of T cell bispecific antibodies, such as cytokine production [ 159 ]. In this line, dasatinib and anti-OX40 antibody worked better together than they did separately, and this was linked to an increase in the amount of tumor-specific T cells within the tumor as well as decreased Treg function and elevated expression of chemokines that draw in cytotoxic T cells and improve tumor-specific T cell infiltration [ 160 ]. Another Phase 2 clinical trial, demonstrated that in individuals with newly diagnosed ALL that was relapsed or refractory to treatment, ponatinib with blinatumomab produced significant rates of complete molecular response [ 161 ]. A phase 1 trial of MGA012, an anti-PD-1 antibody, in combination with flotetuzumab, a CD123/CD3 bispecific protein, in patients with relapsed or refractory AML, showed that in combinational therapy group were increased T-cell mediated cytotoxicity against AML cells compared to monotherapy groups [ 162 ].

Conclusion and discussion

Treatment regimen development for acute leukemia has progressively shifted from conventional cytotoxic therapy to targeted therapies including monoclonal antibodies and small molecule inhibitors (SMIs). Monotherapies, although on both fronts, have been plagued by a series of issues including brief duration of response, drug resistance development, and toxicity-related side effects. As the paragraphs above have noted, such restrictions have sparked growing interest in logical combination therapies, which synergistically act on numerous leukemogenesis and immune evasion pathways and Due to its ability to simultaneously inhibit multiple signaling pathways, combination therapy has gained a lot of attention recently.

However, converting combination therapies from theoretical models to the bedside is problematic. The use of more than one drug conventionally results in overlapping toxicities, treatment cost escalation, and practical inconvenience in drug scheduling, monitoring, and compliance by the patient. Combination regimens also may require complex diagnostic equipment—such as next-generation sequencing and immunophenotyping—to select proper candidates, especially if distinctive mutations or immune escape mechanisms are involved. Regulatory hurdles and design of multi-arm clinical trials make it even more difficult for wide spread use. Therefore, while combination strategies are promising, they will succeed only based on personalized strategies, rational dosing, and stringent risk–benefit considerations.

A novel concept is to personalize combination therapy based upon molecular subtyping. For instance, patients harboring FLT3 mutations would be treated with dual inhibition of proliferation and immune escape through the combination of FLT3 inhibitors and immune checkpoint blockade. Similarly, relapsed or refractory AML patients with or without epigenetic dysregulation may be treated better using epigenetic modifiers with SMIs that have the capability of reeducating the tumor microenvironment and inducing immune-mediated clearance. Therapy approaches tailored to these subsets can transform outcomes with very little unnecessary exposure to unhelpful therapies. Speculatively, the future holds the integration of AI-based treatment planning, biomarker-guided combination algorithms, and nano-delivery platforms for enhanced drug targeting and reduced systemic toxicity. Further, combination regimens with immune modulators, metabolic inhibitors, and microbiome-targeted adjuncts can expand the therapeutic armamentarium. Ultimately, while monotherapies have set the stage for targeted therapy in acute leukemia, the future lies in smart, patient-specific combinations that strike multiple fronts of the disease simultaneously.

In this review, we examined the studies that used combination therapy. The results looked promising and supported the concurrent use of SMIs and monoclonal antibodies. Though encouraging, it is also evident that combined treatment faces many hurdles in optimizing drug combinations, managing toxicity, and developing effective delivery techniques; these will require further studies and research in the field to fully exploit the potential of this therapeutic modality by overcoming the barriers. Finally, one could focus specifically on the combination of antibody-based treatment and SMIs in further treatment steps of acute leukemia.

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Author contributions

A.DJ. contributed to the study design as well as writing of the manuscript. E.R, S.F, N.J, S.G, and M.T contributed to writing of the manuscript. S.T and T.K. supervised the study, and contributed to the study concept, editing, and final approval of the manuscript.

Funding

This paper was not funded.

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.

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