Molecularly targeted therapy and immunotherapy in leukemias.

Targeted therapies in leukemias

The treatment of hematological malignancies has been a forerunner in targeted therapy, with one of the most famous, and successful targeted treatments by the use of all-trans-retinoic acid (ATRA) in acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML) [ 1 , 2 ]. Today, a multitude of different targets in cancer cells, cancer stem cells, and tumor microenvironment including genes and their genetic or epigenetic modifiers, RNAs and noncoding RNAs, growth factors, receptors, enzymes, and signaling pathways involved in tumor initiation, growth, migration, progression and resistance have been identified [ 3 ] (Fig. 1 , 2 ).

Acute myeloblastic leukemia (AML)

Overview

AML is a heterogeneous group of diseases with a variable response to therapy, due to intrinsic genetic complexity present at diagnosis and/or developing during disease evolution. Recent technological advances have contributed to an increase in the list of AML mutations associated with poor prognosis. In particular, NGS technologies led to the identification of novel molecular abnormalities and have increased the application of minimal residual disease (MRD)-based strategies to a significantly higher number of AML patients, and to the design of individual post-remission protocols and pre-emptive treatments in patients with subclinical relapse [ 4 ]. Patient risk stratification based on genetic abnormalities is given by the ELN2022 [ 5 , 6 ]. Treatment and management of AML have been greatly improved, thanks in particular to novel targeted therapies and immunotherapeutic approaches and HSCT is now restricted to high- and intermediate-risk patients who are fit and, in most centers, under 75 years of age. FDA-approved drugs and clinical trials concerning targeted therapies in AML mentioned below are summarized in Fig. 3 , Tables 1 and 2 .

FLT3 inhibitor

Gain-of-function mutations in the FLT3 gene are found in ~ 30% of younger AML patients and at a lower frequency in older patients. Most FLT3 mutations occur as internal tandem duplications (FLT3-ITD) or as point mutations (FLT3-TKD). Mutant FLT3 proteins constitutively activate prosurvival and proproliferative PI3K/AKT, RAS/MAPK, and JAK/STAT pathways. Type I FLT3 inhibitors, such as midostaurin, gilteritinib, and crenolanib inhibit both FLT3-ITD and FLT3-TKD mutations [ 7 ]. Midostaurin was approved in combination with chemotherapy in the frontline of FLT3-mutated AML [ 8 ]. Gilteritinib was approved as a single-agent in FLT3-mutated relapsed/refractory (RR) AML [ 9 ]. Second-generation FLT3 inhibitors, such as quizartinib and sorafenib, specifically target FLT3-ITD mutations. Clinical evidence demonstrates that combining quizartinib with intensive chemotherapy significantly improves overall survival (OS) compared to intensive chemotherapy alone, with a median OS of 31.9 months in the quizartinib group versus 15.1 months in the placebo group [ 10 ]. FLT3 inhibitors as monotherapy can also enhance long-term survival and reduce relapse rates when used after chemotherapy or allo-HSCT particularly in patients with FLT3-mutated disease confirmed by deep sequencing around the time of transplant. As presented by Xuan et al., the mutlikinase inhibitor sorafenib significantly increased post-transplant leukemia-free survival (70.0% vs. 49.0%) [ 11 , 12 ]. Despite initial success with FLT3 inhibitors, outcomes for FLT3-ITD AML patients remain unsatisfactory. Remission is often short-lived and followed by relapse and drug resistance [ 13 , 14 ]. FLT3 inhibitors have also been evaluated in combination with other agents such as venetoclax [ 15 ], in a triplet strategy with venetoclax/azacitidine [ 16 ], venetoclax/decitabine [ 17 ], venetoclax/ASTX727 (decitabine and cedazuridine, a cytidine deaminase inhibitor) [ 18 ], or with histone deacetylase inhibitors (HDACis) [ 19 ] (Table 2 ).

Isocitrate dehydrogenase 1–2 inhibitors (IDH1-2)

Approximately 20% of AML patients harbor gain-of-function mutations in IDH1 or IDH2, encoding isocitrate dehydrogenase (IDH) enzymes. IDH1 and IDH2 are similar, homodimeric enzymes both involved in the Krebs cycle. Mutant IDH inhibitors, such as enasidenib (IDH2) and ivosidenib (IDH1) have been FDA-approved for relapsed/refractory (R/R) AML in 2017 and 2018, respectively [ 94 , 95 ]. Despite the good initial effectiveness of IDH inhibitors in IDH-mutated AML patients, their long-term use may lead to the development of resistance and relapse [ 96 , 97 ]. Ivosidenib has also been safely associated with azacitidine in a phase 3 study, and showed a significant clinical benefit as compared with placebo and azacitidine with a complete remission (CR) rate of 47% (ivosidenib + azacitidine) vs 15% (placebo + azacitidine), in a cohort of AML patients ineligible for intensive induction chemotherapy [ 20 ] . IDH -mutated AML has also marked dependence on the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) and the combination of venetoclax and IDH1-2 inhibitors has shown synergistic effects in AML [ 98 ]. The triplet association of ivosidenib, venetoclax, and azacitidine has been clinically tested and has demonstrated positive effects in patients with IDH1-mutated myeloid malignancies with a CR rate of 90% (ivosidenib + venetoclax + azacitidine) vs 83% (ivosidenib + venetoclax). In addition, this combination therapy appears to overcome resistance mechanisms observed with single-agent IDH inhibitor use [ 21 ]. Another IDH1 inhibitor, olutasidenib, has been FDA-approved for the treatment of adult patients with R/R IDH1 -mutated AML in December 2022 [ 99 ]. In combination strategies, olutasidenib plus azacitidine induced high response rates with 31% of CRs and durable remissions with a tolerable side effect profile in patients with R/R AML [ 22 ]. All these combinations represent as many options for relapsed or IDH1-mutated AML patients, but unanswered questions remain regarding sequencing to limit resistance emergence and the best combinations to maximize the chance of long-term remission [ 100 ].

DNA and RNA methyltransferases inhibitors/hypomethylating agent (DNMT/HMA)

The DNMT family includes three major members (DNMT1, DNMT3A, and DNMT3B) that have functional methylation activities and play an important role in epigenetic gene regulation. Aberrant DNA methylation due to DNMT dysregulation and mutations is known as an important molecular event in the hematological malignancies, such as DNMT3A mutations in AML [ 101 ]. Two major hypomethylating agents, azacitidine and decitabine, are used in the treatment of hematological malignancies with oral, subcutaneous and parenteral available formulations [ 102 , 103 ]. Azacitidine is a cytidine nucleoside analog that is phosphorylated in cells to its active form. Azacitidine triphosphate reduces both DNA and RNA methylation, inducing activation and expression of genes regulating cancer-suppressing functions and cell differentiation. Azacitidine was initially approved in 2004 as a treatment for myelodysplastic syndromes (MDS), based on clinical trial evidence of decreased red blood cell (RBC) transfusion dependence and improved survival. Patients treated with azacitidine had a median OS of 24.5 months, while patients receiving conventional care had a median OS of 15.0 months [ 104 , 105 ]. In patients with AML, large randomized clinical trials have demonstrated a clinical benefit of HMAs, although no OS improvement was observed [ 106 ]. However, in older patients, median OS was significantly longer with HMAs (14.4 months) compared to high-intensity therapy (10.8 months). The toxicity and mortality associated with intensive chemotherapy and the lack of alternative non-intensive therapies for older AML patients resulted in the adoption of HMAs as the standard of care for this population [ 107 ]. While intravenous azacitidine remains the gold standard for high-risk MDS and AML due to its well-documented efficacy in improving OS, subcutaneous administration also offers a comparable bioavailable alternative with reduced hospitalization burden. Oral azacitidine can also be used as a single agent as an effective maintenance strategy in first-remission patients ineligible for allo-HSCT after intensive chemotherapy to prolong survival in both high-risk and favorable-risk AML patients [ 108 , 109 ].

Considering the lack of significant survival benefit with azacitidine alone in AML patients with higher (≥ 30%) BM blasts, combination therapies have been tested in clinical trials to improve outcomes and expand the therapeutic indications of HMAs. The combination of lenalidomide with HMAs has been investigated due to potential synergistic biological effects. Lenalidomide, an immunomodulatory agent, enhances T-cell and NK-cell activation, increases cytokine production (IL-2, IFN-γ), and exerts antiangiogenic and anti-inflammatory effects. However, initial combinations with immunomodulatory drugs such as thalidomide [ 23 ] or lenalidomide [ 24 ] were not further explored due to modest activity, poor tolerance, and high complication rates. In 2018, the Bcl-2 inhibitor venetoclax, in combination with azacitidine, received accelerated approval for the treatment of newly diagnosed AML in patients aged 75 years or older, or those ineligible for intensive chemotherapy. This combination subsequently became the standard of care for this patient population (Table 2 ) [ 25 , 110 ]. In a recent publication, Lu et al. report results from a randomized clinical trial comparing outcomes of newly-diagnosed younger patients with AML treated with venetoclax-decitabine vs idarubicin-cytarabine induction and found noninferior response rates and superior safety with venetoclax-decitabine. This trial highlights the need for continued investigation of HMA-venetoclax for younger and fit patients to better understand which patients may benefit from this regimen as compared with traditional anthracycline-cytarabine induction [ 26 ]. In adults with newly diagnosed FLT3-mutated AML who were ineligible for intensive chemotherapy, a large phase 3 study combining gilteritinib and azacitidine vs. azacitidine alone in older/unfit patients showed good tolerability and safety profiles but was closed after interim analysis due to futility[ 27 ]. Another drug association combining azacitidine and ivosidenib received FDA approval to treat newly diagnosed patients with IDH1-mutated adult AML who are 75 years or older, or who have comorbidities [ 20 ]. Enasidenib was also evaluated in combination with azacitidine; however, no significant difference in OS was observed compared to azacitidine alone (22 months vs. 22.3 months, respectively), likely due to the study’s crossover design [ 28 ]. APR-246 (eprenetapopt) is a new molecule that can restore the transcriptional activity of mutant p53, leading to death of mutant p53 cells. A phase 2 study was conducted using the combination of eprenetapopt and azacitidine in patients with TP53-mutated MDS and AML. Complete remission rates reached 47% for MDS and 17% for AML [ 29 ]. A large-scale phase 3 clinical trial testing APR-246 and azacitidine or azacitidine alone in MDS has been conducted but failed to meet its primary endpoint of CR ( NCT03745716 ) [ 111 ]. Eprenetapopt combined with venetoclax and azacitidine in TP53-mutated AML has also shown an acceptable safety profile and encouraging activity with 38% of CR, supporting further frontline evaluation of this combination in the treatment of TP53-mutated AML [ 30 ]. Magrolimab, an anti-CD47 monoclonal antibody, is a macrophage immune checkpoint inhibitor that eliminates leukemia stem cells by inducing tumor phagocytosis. This inhibitor has been tested in association with azacitidine in a phase 3, randomized, open-label study in previously untreated patients with TP53-mutant AML. This study did not meet its primary end point of OS in TP53-mutated AML and was prematurely terminated for futility [ 31 ]. Chidamide, which is the first oral selective HDAC inhibitor, was also tested in combination with CAG (cytarabine, aclarubicin, and G-CSF) and venetoclax-azacitidine in patients with newly diagnosed AML [ 32 ]. The 12-month OS rate was 73.4%, and the regimen was well tolerated in elderly patients. Because of their good efficacy and acceptable safety profile in AML, HMAs have become the cornerstone of targeted therapy combination strategies and often constitute the control arm in clinical studies.

Bcl-2 inhibitors

The Bcl -2 family is composed of pro- and antiapoptotic proteins that regulate the delicate balance between programmed cell death and survival. The antiapoptotic Bcl-2, the founding member, was discovered thanks to its dysregulated expression in non-Hodgkin’s lymphoma [ 112 , 113 ]. In AML, high Bcl-2 level is associated with resistance to chemotherapy, decreased rate of CR, and shortened survival [ 114 – 118 ]. Many Bcl-2 inhibitors have been developed, including venetoclax, the most prominent one, which is a selective oral Bcl-2 inhibitor that sequesters Bcl-2, thus precluding its binding to proapoptotic proteins [ 119 ]. Although venetoclax demonstrated antitumor activity in AML with good tolerability as a single-agent [ 33 ], it has been largely tested in combination strategies and has been approved as frontline treatment in combination therapy with azacitidine following the VIALE study showing a CR rate of 36.7% versus 17.9% with azacitidine alone [ 25 ] or low-dose cytarabine for elderly or unfit patients AML achieving a 54% CR rate [ 34 ]. Sensitivity to venetoclax-based therapies depends on molecular subgroups of AML. Patients with NPM1, IDH1/2, TET2 mutations, DDX41 [ 120 ], ASXL1 [ 121 ], spliceosome mutations [ 122 ] and R/R RUNX1-mutated AML have shown enhanced sensitivity to venetoclax. On the contrary, AML patients with mutations in FLT3, TP53, RAS, PTPN11, and those with prior treatment with HMA showed reduced sensitivity to venetoclax [ 5 , 123 ].

Although venetoclax has provided a much-needed step forward in cancer treatments, with a successful impact on patients with chronic lymphocytic leukemia (CLL) and AML, limitations such as toxicities, deep and prolonged cytopenia, and drug resistance remain prominent [ 124 ]. The upregulation of the MCL-1 antiapoptotic protein, which is highly expressed in AML, is one of the most well-known causes of resistance to venetoclax and represents a potential target for overcoming venetoclax resistance. Because preclinical studies have shown synergistic activity between venetoclax and MCL-1 inhibitors, molecules interacting with MCL-1, as reviewed by Wei Y et al . [ 125 ] , such as cyclin-dependent kinase 9 (CDK9) inhibitors, midostaurin or gilteritinib (FLT3 inhibitors that induce downregulation of MCL-1), CUDC-907 (a dual PI3K and histone deacetylase inhibitor that downregulates MCL-1), MEK inhibitors, MDM2 inhibitors, PI3K inhibitors, or inhibitors of the Nedd8-activating enzyme (MLN4924), could boost venetoclax activity to overcome resistance and prolong EFS (event free survival) after Bcl-2 inhibitors treatment [ 5 , 119 , 124 ]. Venetoclax could also be used in combination with azacitidine as a chemo-free bridge to transplantation [ 126 ]. Venetoclax scope of application in combination strategies is expected to be expanded in the near future, for example in fit and younger patients [ 127 ].

Histone deacetylase inhibitor (HDACi)

Histone deacetylase inhibitors (HDACi) act by increasing the acetylated levels of histones, promoting the re-expression of silenced genes in cancer cells [ 128 , 129 ]. Since 2011, two HDACi have been approved as treatments for hematological malignancies, belinostat, for patients with R/R peripheral T-cell lymphoma (PTCL), and panobinostat, for patients with recurrent multiple myeloma who have received at least two prior treatment regimens [ 130 ]. In leukemia, HDACi such as vorinostat, panobinostat, belinostat, or pracinostat have demonstrated the ability to promote growth arrest and cell death in preclinical AML models [ 131 ]. Vorinostat is a broad-spectrum HDACi that targets class I, II, and IV HDAC enzymes. Initially approved for the treatment of cutaneous T-cell lymphoma (CTCL) [ 132 ], its potential has also been explored in AML [ 133 ]. In spite of promising preclinical results, a phase 2 study of vorinostat as a monotherapy showed minimal activity in patients with relapsed AML achieving only 4.5% of CR [ 35 ]. Even if these inhibitors do not seem to be effective as monotherapy, combination strategies with a variety of anticancer drugs have shown significant antileukemic activity such as combination with decitabine, idarubicin, idarubicin plus cytarabine, alvocidib (a flavonoid alkaloid CDK9 kinase inhibitor), gemtuzumab ozogamicin (GO) plus azacitidine, or sorafenib (a multikinase inhibitor) plus bortezomib (a proteasome inhibitor), as reviewed by San José-Enériz E et al. [ 133 ]. Despite the improvement of therapeutic efficacy, the results of such combinations remain modest. Panobinostat is another HDACi active on class I, II, and IV HDAC enzymes. It was first approved for multiple myeloma in 2015 [ 134 ]. Many combinations including panobinostat have been tested in vitro on leukemic cells but only a few of them have been clinically evaluated. Despite the initial data showing 10% of CR in newly diagnosed AML or high-risk MDS [ 36 ], larger clinical trials proposing panobinostat and azacitidine combination in AML did not demonstrate a significant advantage compared to azacitidine alone [ 37 ]. Pracinostat, another potent oral HDACi, was also evaluated in combination with azacitidine in adult patients with newly diagnosed AML ineligible for intensive chemotherapy, but similarly, no significant benefit was observed compared to azacitidine alone [ 38 ]. Despite the data from first phase clinical trials testing HDACi in high-risk AML patients, therapeutic efficacy improvements observed in combination with conventional chemotherapy or other epigenetic inhibitors remain modest.

Hedgehog pathway inhibitor

In AML, components of the hedgehog (Hh) signaling pathway, such as Smoothened (SMO), are implicated in the development, maintenance, expansion of leukemic stem cells (LSCs), sensitization to chemotherapy and development of drug resistance [ 135 , 136 ]. Current findings in hematological malignancies indicate the potential for a synergistic effect when SMO inhibitors are administered in combination with chemotherapy or other investigational agents. Glasdegib, an oral SMO inhibitor, was the first in its class to be approved by the FDA for the treatment of newly diagnosed patients with AML who are ≥ 75 years or unsuitable for treatment with intensive induction chemotherapy, based on the phase 2 BRIGHT AML 1003 trial, wherein glasdegib in combination with low dose cytarabine (LDAC) versus LDAC alone significantly increased OS and response rates (median OS: 8.3 months (glasdegib + LDAC) vs 4.3 months (LDAC)) [ 39 , 40 , 137 ]. However, these results were not confirmed in the placebo-controlled phase 3 BRIGHT AML 1019 clinical trial, where glasdegib was tested in combination with cytarabine and daunorubicin, or with non-intensive chemotherapy (azacitidine), in patients with untreated AML [ 138 ]. The place of SMO inhibitors in the therapeutic arsenal remains to be defined [ 139 ].

Neddylation pathway inhibitors

Neddylation is required for ubiquitination and degradation of select proteins upstream of the proteasome. It is also involved in several signaling pathways that are upregulated in tumorigenesis, promoting cell growth and evasion of programmed cell death through the degradation of tumor suppressor proteins. Pevonedistat acts as an adenosine monophosphate mimetic that can bind to the NEDD8-activating enzyme (NAE) adenylation site, thereby blocking the neddylation process. Pevonedistat is a first-in-class inhibitor of NAE that has been investigated both as monotherapy and in combination regimens in MDS and AML [ 140 ]. Pevonedistat was tested alone in adult patients with AML or high-grade MDS, but only modest clinical activity was observed with only 14% of CR [ 41 ]. Further studies were conducted to test combinations, notably pevonedistat and azacitidine. A randomized phase 2 study showed clinical efficacy vs azacitidine alone in patients with higher-risk MDS (CR: 46.9% vs 22.9%, respectively) [ 42 ]. These results led to a multicenter, randomized, open-label phase 3 study. However this rigorous study failed to show a significant improvement in overall clinical outcomes with pevonedistat plus azacitidine compared to azacitidine alone in AML (CR: 22% vs 32.3%, respectively) [ 43 ]. Pevonedistat has been also associated with belinosat, showing modest activity in heavily treated high risk AML/MDS patients (CR: 5%) [ 44 ]. A recent phase 2 study showed that addition of pevonedistat to azacitidine + venetoclax in a triplet strategy failed to significantly improve response rates or EFS in patients with newly diagnosed AML patients who were ineligible for intensive chemotherapy [ 45 ]. Other therapy combinations reviewed by Snow et al., including decitabine [ 46 ], cytarabine [ 47 ], or multidrug combinations with azacitidine, fludarabine, cytarabine and venetoclax [ 48 ], are currently being tested. Given the modest efficacy of pevonedistat associated strategies, further studies are needed to identify subgroups of patients who may benefit from this approach [ 140 ].

Menin inhibitors

Chromosomal rearrangements involving the lysine-specific N-methyltransferase 2A (KMT2A) define a genetically distinct subtype of acute leukemia (AL), representing about 10% of leukemias. Chromosomal translocations involving the KMT2A locus result in the formation of a chimeric oncogene, in which the N-terminal part of KMT2A is fused to a variety of partners [ 49 ]. Non-rearranged KMT2A-complexes are also crucial for disease development and maintenance in NPM1-mutated and NUP98-rearranged leukemias, broadening the spectrum of KMT2A-targeted therapies. Given that the presence of a KMT2A-rearrangement in patients is associated with adverse outcomes, the development of novel targeted approaches is of high interest in this specific subtype [ 141 ]. KMT2A normally associates with cofactors to form a macromolecular complex that includes menin, the product of the MEN1 tumor suppressor gene. Oncogenic KMT2A fusion proteins retain the ability to associate with menin, a crucial interaction for the initiation and maintenance of KMT2A-mediated leukemogenesis [ 142 ]. Revumenib is an oral menin inhibitor approved for the treatment of R/R KMT2A-rearranged (KMT2Ar) AL in adult and pediatric patients older than 1 year [ 143 ]. The first-in-human clinical trial showed encouraging clinical benefit with 21.2% of CR complete remission with incomplete hematologic recovery (CRi) rate, with deep molecular remissions and minimal toxicity, in pretreated pediatric and adult patients with advanced AL [ 50 , 144 ]. Early-phase clinical trials reviewed by Candoni et al., are investigating the safety and efficacy of two menin inhibitors, revumenib and ziftomenib, alone or in combination with other agents in AML harboring KMT2A or NPM1 mutations [ 145 – 147 ]. In preclinical studies, revumenib was found to downregulate Bcl-2 protein levels in AML cell lines. Combination with venetoclax resulted in synergistic cytotoxicity in AML cells, potentially by re-sensitizing leukemic cells to Bcl-2 inhibition [ 148 ]. Thus, revumenib is being investigated in combination with venetoclax and azacitidine as frontline therapy in patients aged ≥ 60 years old with newly diagnosed KMT2Ar, NPM1m or NUP68r AML ( NCT05735184 ). Another study involving this triplet combination is also open for pediatric and young adult patients ( NCT06177067 ) [ 149 ]. Revumenib was also tested in association with decitabine/cedazuridine (ASTX727) and venetoclax with an acceptable safety profile and efficacy with an ORR of 88% (23/26 pts) in a recent phase 1/2 study [ 51 , 150 ]. Ziftomenib received FDA approval in November 2025 for the treatment of adults with R/R AML harboring a susceptible NPM1 mutation, specifically for those lacking satisfactory alternative treatment options. A study is planned to evaluate the safety profile and preliminary efficacy of ziftomenib in combination with venetoclax + azacitidine or 7 + 3 chemotherapy in patients with untreated NPM1-m or KMT2A-r AML ( NCT07007312 ). Interestingly, preclinical data have demonstrated that the antitumor activity of ziftomenib and other menin-inhibitors was enhanced by the addition of FLT3 inhibitors such as gilteritinib and quizartinib in KMT2A -r and NPM1 -m AML. Based on this observation, a study is planned to evaluate the safety, tolerability and preliminary efficacy of ziftomenib in combination with standard of care regimens including gilteritinb for the treatment of R/R AML with NPM1m or KMT2A translocation [ 52 ]. Menin inhibitors appear to exhibit a synergistic potential with many agents. Nonetheless, further investigation is required to confirm the efficacy, to identify patient subgroups in which these agents may be the most effective, and to determine the optimal dosing and timing of administration for optimal use [ 147 ].

Chronic myeloid leukemias (CML)

Overview

Since the approval of tyrosine kinase inhibitor (TKI) therapy as first-line treatment in 2001, CML has been transformed from a life-threatening disease to a manageable chronic condition for the majority of patients [ 151 , 152 ]. Five tyrosine kinase inhibitors (TKIs), imatinib (first generation), dasatinib, bosutinib, nilotinib (second generation), and ponatinib (third generation), have been approved by the US FDA for CML treatment. Another TKI, named radotinib, was approved in South Korea in 2012. In 2019, flumatinib, a second-generation TKI, was approved in China, followed by olverembatinib in 2021. Allo-HSCT remains an important therapeutic option for CML-CP patients after treatment failure of at least two TKIs, and for all patients in advanced-phase disease [ 153 ]. It should also be considered early in patients with increased blast infiltration [ 154 ]. FDA-approved drugs and clinical trials concerning targeted therapies in CML mentioned below are summarized in Fig. 3 , Tables 3 and 4 .

Tyrosine kinase inhibitors

Five TKIs are FDA-approved for frontline treatment of CML and Ph + ALL: imatinib, dasatinib, bosutinib, nilotinib, and ponatinib. They act via competitive inhibition at the ATP-binding site of the BCR/ABL1 oncoprotein, which results in the inhibition of receptor phosphorylation, and block signal transduction. Imatinib mesylate was the first small-molecule inhibitor found to selectively target protein tyrosine kinases. It was synthesized by Buchdunger et al. in 1996 and approved by the FDA in 2001 for patients with CML [ 164 ]. Dasatinib is an oral, second-generation TKI that is 350-fold more potent than imatinib in vitro [ 165 ]. The superiority of dasatinib compared to imatinib was confirmed in a real-world retrospective study in patients with newly diagnosed CML-CP, with higher rate of MMR (79% vs 65%, respectively) and deeper, faster disease remission [ 154 , 155 , 164 , 165 ]. Because of higher hematologic toxicity compared to imatinib, a lower dose of dasatinib has been tested, and studies proved an equal efficacy with less toxicity at the dose of 50 mg daily compared to 100 mg [ 166 ]. Nilotinib, another second-generation TKI, is a structural analog of imatinib but with higher affinity for the ATP-binding site on BCR::ABL1 in vitro [ 167 ]. Rate of major molecular response (MMR) at 12 months was significantly higher for nilotinib compared to imatinib (44% vs 22%, respectively), but the long-term study revealed higher cumulative incidence of arterio-occlusive/veno-occlusive events. Even if the benefit-risk profile of nilotinib as frontline therapy for patients with CML-CP remains positive, general cardiovascular risk scores should be assessed and managed if nilotinib is needed [ 156 ]. Bosutinib (a second-generation TKI) is a dual SRC/ABL kinase inhibitor, recently approved as first-line treatment for CML-CP. In a multinational phase 3 study comparing bosutinib and imatinib, bosutinib treatment was associated with better MMR at 12 months (47.2% vs 36.9%) [ 157 ]. Bosutinib was also safe and effective when given as second- or third-line therapy for intolerant or refractory CML patients [ 168 ]. Concerning the choice of TKIs as frontline therapy for CML-CP patients, the four TKIs are equivalent if the aim of therapy is to improve survival, but the clinician has to consider patient comorbidities and potential side effects of the chosen TKIs before long-term prescription. If the aim is to obtain faster and durable remission, second-generation TKIs may be preferred, particularly in younger patients with high-risk disease [ 154 ].

The two main issues in CML management remain TKI intolerance [ 169 ] and the acquisition of specific resistance [ 154 , 170 ]. TKI intolerance occurs in 15%–25% of patients at 10 years of treatment and is the most common cause of TKI therapy change [ 154 ]. Disease resistance occurs in about 10% of patients after 10 years of treatment and is defined as BCR::ABL1 transcript levels (IS) > 1% after 12 months of therapy, loss of hematologic or cytogenetic response, or AML transformation [ 170 ]. A common mechanism of resistance involves mutations in the kinase domain of BCR/ABL1 that disrupt the activity of TKIs. Although second-generation TKIs overcome most of the mutations that confer resistance to imatinib, one important mutation, T315I, known as the “gatekeeper” mutation, displays resistance to currently available TKIs, except ponatinib, asciminib [ 171 ], and olverembatinib [ 154 , 158 ]. However, other single or combined mutations have been described as resistant to ponatinib such as E255K/G250E or E255V/T315I. These mutations have been specifically reported in the context of advanced-phase disease or in patients who have received multiple lines of treatment [ 172 – 176 ]. Asciminib is a BCR/ABL1 inhibitor specifically targeting the ABL myristoyl pocket, offering improved efficacy, better safety, and fewer side effects compared to currently available frontline ATP-competitive TKIs. In a recent phase 3 trial, asciminib demonstrated superior efficacy and a favorable safety profile in patients with newly diagnosed CML-CP. A major molecular response after 48 weeks was achieved in 67.7% of patients treated with asciminib compared with 49.0% in the group receiving investigator-selected TKIs. These results highlight asciminib as an efficient alternative, particularly in cases of resistance to 2G TKIs [ 159 ]. Olverembatinib is a new third-generation TKI currently approved and marketed in China for the treatment of adult patients with CML-CP who are resistant to TKIs or carrying the T315I variant. By adding one hydrogen bond in its molecular structure, olverembatinib is able to bind more tightly to both non-phosphorylated and phosphorylated BCR/ABL1, including the T315I variant, than ponatinib [ 177 ]. In a clinical trial involving 80 patients with CML or Ph + ALL resistant or intolerant to at least 2 TKIs, Jabbour et al. showed that, among evaluable patients with CML-CP, complete cytogenetic response occurred in 61% of patients and MMR occurred in 42%. Interestingly, cytogenetic and molecular responses were similar in patients with or without T315I variants. Because of its good safety profile and strong antileukemic effect, olverembatinib provides a viable new treatment option for patients after failure of two or more TKIs [ 158 ].

Investigational combinations

Recent interest has focused on combining asciminib with ATP-competitive TKIs to overcome multidrug resistance by simultaneously targeting the myristoyl-binding and ATP-binding sites, an approach supported by preclinical studies with imatinib [ 178 ], nilotinib [ 179 ], and ponatinib [ 180 ]. Clinical trials of asciminib plus ponatinib in CML-CP are not yet available, but combinations with other TKIs (nilotinib, dasatinib, imatinib) have shown high MMR rates at 48 weeks (31%, 36%, 42%, respectively) [ 181 ]. Targeting BCR/ABL1 and Bcl-2 (venetoclax) may offer synergistic therapeutic benefits in CML that has developed resistance to TKIs. This is because the BCR/ABL1 tyrosine kinase regulates Bcl-2 family proteins, which contribute to apoptosis resistance in CML cells [ 182 ]. However, these preclinical findings have not yet translated into positive clinical outcomes [ 160 ]. Novel combinations of oral decitabine/cedazuridine with low-dose dasatinib ( NCT05007873 ) [ 161 ], as well as strategies involving nilotinib plus pegylated interferon-alpha (IFN-α) [ 162 ], or the addition of ruxolitinib to TKIs [ 163 ], remain under active investigation.

Myelodysplastic syndromes (MDS)

Overview

Historically, MDS classifications were based on morphological criteria and clinical features, but emerging genomic and molecular insights have revealed a broad spectrum of genetic mutations and chromosomal alterations that drive MDS pathogenesis [ 183 ]. Among cytogenetic abnormalities, del(5q), trisomy [ 8 ], del(20q), del(7q), and monosomy 7 are identified in up to 50% of MDS cases [ 184 ], and acquired somatic mutations in genes, such as SF3B1, TET2, ASXL1, SRSF2, RUNX1 , and TP53, are nearly ubiquitous in MDS [ 185 ]. Some of these confer poor prognosis, such as ASXL1, TP53, RUNX1 [ 186 ]. New classification systems from the World Health Organization (WHO) [ 187 ] and the International Consensus Classification (ICC) help physicians to better diagnose and categorize MDS as lower-risk MDS (LR-MDS), intermediate-risk (IR-MDS), or higher-risk disease (HR-MDS), in accordance with the risk of transformation into Als [ 188 ]. FDA-approved drugs and clinical trials concerning targeted therapies in MDS mentioned below are summarized in Fig. 3 and Tables 5 and 6 .

Therapeutic strategies

Concerning treatment, no specific strategy has shown survival benefit in LR-MDS, and the main objective is to improve quality of life and reduce the dependence on transfusions by using erythropoiesis-stimulating agents (ESA), lenalidomide for patients with an isolated del(5q) and anemia [ 198 ], luspatercept [ 199 ], hypomethylating agents (HMAs) [ 104 ], or immunosuppressive therapy (IST). The combination of HMAs such as azacitidine with Bcl-2 inhibitors such as venetoclax has been tested for HR patients without available donors but the global phase 3 VERONA trial evaluating this strategy in the treatment of newly diagnosed HR-MDS did not meet its primary endpoint of OS. The definitive results will be soon available [ 189 , 200 ]. When combined with azacitidine, pevonedistat did not lead to significantly longer median EFS than azacitidine alone [ 190 ]. The triplet combination of pevonedistat, azacitidine, and venetoclax showed 13% of CR in older adults with MDS after the failure of HMA alone [ 191 ]. In R/R MDS patients with IDH-1 mutations, ivosidenib showed a median OS of 35.7 months and 75% of RBC- and platelet transfusion-dependent patients became transfusion-independent [ 192 ]. Since the IDH-2 gene is mutated in approximately 5% of MDS patients, enasidenib has been tested in newly diagnosed IDH-2-mutated MDS patients, both as monotherapy and in combination with azacitidine. The ORR was 74% for the enasidenib + azacitidine combination, compared to 35% for enasidenib alone [ 94 ]. Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression are upregulated in patients with MDS. The combination of pembrolizumab, a monoclonal antibody targeting PD-1, and azacitidine has been evaluated in previously untreated HR-MDS patients. In a phase 2 clinical trial, this regimen was associated with an ORR of 18% [ 193 ], whereas studies testing nivolumab, ipilimumab and atezolizumab (PD-L1 inhibitor) with or without azacitidine were stopped before completion of recruitment due to unexpectedly high rate of early death [ 194 , 195 , 201 ].

Acute lymphoblastic leukemia (ALL)

Overview

The integration of molecular features into risk stratification algorithms has become essential in ALLs and has been added to the clinical and biological pejorative criteria previously used. The early response to chemotherapy, defined as MRD, is the second most important prognostic factor. The main objectives of the risk stratification are: (i) to limit the toxicity of treatments for patients defined as having a good prognosis and therefore to reduce the intensity of chemotherapy, and (ii) to allow early access to immunotherapy, targeted therapies, and cell-based therapies for the cases defined as poor-prognosis or refractory AL. The frontline therapy for ALLs is usually a sequential combination of chemotherapies (steroids, anthracycline, asparaginase, and alkaloids). Allo-HSCT still represents a potentially curative approach for high-risk patients or after relapses. However, the allo-HSCT procedure is a source of acute toxicities and raises the issue of long-term sequelae, especially when applied to young children. FDA-approved drugs and clinical trials concerning targeted therapies in ALL mentioned below are summarized in Fig. 3 , Tables 7 and 8 .

Proteasome inhibitors

Bortezomib is the first-generation proteasome inhibitor to be FDA-approved for the treatment of plasma cell myeloma and mantle cell lymphoma [ 244 ]. The anticancer mechanisms of bortezomib result from the upregulation of proapoptotic proteins, the suppression of the NF-κB signaling pathway, and the inactivation of antiapoptotic proteins (Bcl-XL, Bcl-2, and STAT3) [ 245 ]. In ALL, although bortezomib alone has limited efficacy, various clinical studies utilizing combined treatment strategies, associating bortezomib with standard chemotherapy regimens or targeted drugs as ruxolitinib or venetoclax, have shown efficacy and safety in R/R pediatric ALL [ 202 – 204 , 246 ]. Other combinations have also been tested in pediatric patients, including mitoxantrone, vincristine, and PEG-asparaginase with 80% of CR [ 205 ]. In adults, bortezomib has recently been tested in combination with hyper-CVAD therapy, leading to 65% of CR and high rates of MRD negativity in relapsed ALL or MRD + ALL, indicating its potential use as a first-line treatment strategy [ 206 ]. Carfilzomib, a second-generation proteasome inhibitor, has also been shown to be active against B- and T-ALL in preclinical studies [ 247 ]. When combined with standard chemotherapy, high levels of CR have been obtained in early-phase studies in R/R pediatric ALL (50%) [ 207 ] and in adults (90%) [ 208 ]. However, multiple mechanisms that can lead to resistance to proteasome inhibitors in hematological malignancies have been described [ 248 ]. Interestingly, interferon-γ (IFN-γ) is known to induce immunoproteasome expression, and in vitro studies have demonstrated that IFN-γ can restore bortezomib and carfilzomib sensitivity in T-ALL cells, opening the door to novel combination therapies for resistant patients [ 249 ].

Tyrosine kinase inhibitors

The Philadelphia chromosome (Ph) with the BCR::ABL1 fusion gene occurs in 11%–29% of ALL adult patients. The historically poor prognosis of patients with Ph + ALL has significantly improved with the advent of specific TKI targeting the BCR/ABL1 [ 209 ]. TKIs, initially imatinib, followed by 2nd and 3rd generation agents, have improved OS by approximately 20% and reduced the need for allo-HSCT [ 250 ]. In 2009, large-scale gene expression profiling identified a high-risk B-ALL subtype, termed Philadelphia chromosome-like ALL (Ph-like ALL) that has broadened the scope of indications for targeted therapies in ALL. This subtype displays a heterogeneous genomic expression profile, similar to Ph + ALL, with a high frequency of IKZF1 (IKAROS family zinc finger 1) alterations, but without BCR::ABL1 fusion gene of Ph + ALL [ 251 ]. Genes commonly rearranged in Ph-like ALL include ABL1/2, CRLF2 (cytokine receptor-like factor 2), EPOR (erythropoietin receptor) and JAK2 (Janus kinase 2). As reviewed by Haddad et al., the three generations of TKIs have been successively tested in Ph + ALL [ 250 ]. Compared with imatinib, second-generation TKIs have demonstrated greater efficacy and lower relapse rates in adult and pediatric populations [ 210 ]. However, the emergence of mutations in the ABL1 kinase domain, most notably the T315I mutation, is associated with resistance. On March 19, 2024, the FDA granted accelerated approval to ponatinib, a third-generation TKI effective against T315I and other resistant mutations, for use in adult patients with newly diagnosed Ph + ALL. This approval was based on data of the phase 3, global, open‐label, randomized PhALLCON study ( NCT03589326 ), which compared ponatinib versus imatinib, both administered with reduced‐intensity chemotherapy. The MRD-negative CR rate at the end of induction was 35% in the ponatinib arm versus 17% in the imatinib arm [ 211 ]. Given the high toxicity of TKIs combined with high intensity chemotherapy regimens, chemo-free approaches have emerged in Ph + ALL. For example, the addition of blinatumomab to ponatinib in Ph + ALL yielded complete molecular response in 64% for newly diagnosed ALL patients, 82% for R/R ALL patients and 20% in CML patients [ 212 ]. In a recent metanalysis, Ali MA et al. compared the efficacy of two chemotherapy-free regimens: TKI, plus steroid, and TKI, steroids, and blinatumomab. The addition of blinatumomab significantly improved both response and survival rates in patients with newly diagnosed Ph + ALL. Complete major remission rates were 87% in the ponatinib + blinatumomab + steroids arm, 72% in the dasatinib + blinatumomab + steroids arm, 51% in the dasatinib + steroids arm, 41% in the ponatinib + steroids arm, and 15% in the imatinib + steroids arm [ 209 ].

JAK inhibitors

JAK2 alterations, including rearrangements and gain-of-function mutations, are associated with poor outcomes within the Ph-like ALL subtype(178). In 2011, the semi-selective JAK1/2 inhibitor ruxolitinib became the first JAK2 inhibitor to be FDA-approved for the treatment of myelofibrosis and hydroxyurea-resistant polycythemia vera. Ruxolitinib is the only JAK inhibitor that has been clinically assessed in the ALL setting. High clinical effectiveness of ruxolitinib in combination with multi-agent chemotherapy has already been reported in a few patients with CRLF2r/JAK-mutant or JAK2r ALL [ 252 , 253 ]. Clinical trials ( NCT03117751 , NCT03571321 ) are now investigating, on a large scale, the ruxolitinib/chemotherapy combination in patients with JAK-STAT signaling activation [ 213 , 214 ]. Early results suggest that JAK inhibitors in combination with chemotherapy may improve outcomes for patients with high-risk ALL subtypes, notably Ph-like ALL [ 254 ]. However, because the majority of the genetic alterations that occur in the JAK-STAT pathway are subclonal, the expected clinical benefits for patients are uncertain.

Bcl-2 inhibitors

Overexpression of Bcl-2 has also been widely reported in some subtypes of ALL, suggesting that they might be especially sensitive to Bcl-2 inhibition. The resulting fusion gene KMT2A::AF4 was shown to directly bind to the Bcl-2 gene and upregulate its expression in vitro [ 255 ]. Hypodiploid B-ALL and subtypes with a t [ 17 , 19 ] translocation, which results in the fusion protein TCF3-HLF associated with poor prognosis, are also characterized by elevated expression of Bcl-2 and were highly sensitive to venetoclax in vitro [ 256 , 257 ]. Combinations associating venetoclax with standard chemotherapies have been tested in B-ALL or in early T-cell precursor (ETP-ALL) as reviewed by Aumann et al. Taken together, these studies concluded that the administration of venetoclax in combination with low-dose chemotherapy regimens for Ph-negative B or ETP-ALL seems to be feasible and effective, and could be an alternative in case of R/R ALL subtypes with few available therapeutic options [ 258 ]. In preliminary case reports and early clinical studies, venetoclax has been tested in chemo-free protocols with steroids in elderly patients with poor-prognosis Ph-negative ALL [ 259 ], and in combination with ponatinib and dexamethasone for R/R Ph + ALL (CR: 56% in 9 patients) [ 215 ] or with decitabine [ 260 ]. Recent studies are currently testing venetoclax plus blinatumomab ( NCT05182385 ) [ 216 ], or venetoclax plus inotuzumab ( NCT05016947 ) [ 217 ]. Clinical experience in venetoclax ALL remains limited but demonstrates a favorable safety profile and the ability to induce deep and durable responses, making it a possible bridge-to-transplant option for eligible patients [ 258 ].

Nucleoside analogs

T-ALL represents around 15% of pediatric ALL and is associated with poorer prognosis than B-ALL, with a 5-year EFS of approximately 80% compared to 90% in B-ALL. ETP-ALL is associated with poor outcomes and is used for risk stratification in some treatment protocols [ 261 ]. ETP-ALL derives from a primitive stem cell–like hematopoietic precursor, with genetic and immunophenotypic features close to myeloid leukemias [ 262 ]. Many mutations or alterations in JAK2, Bcl-2 or NOTCH pathways, with available targeted agents, have been described, but only nelarabine, a nucleoside analog, is approved for the treatment of R/R T-ALL [ 263 , 264 ]. Nucleoside analogs have complex and polypharmacologic mechanisms of action. Nelarabine undergoes a cascade of chemical modifications leading to the accumulation of ara-GTP in leukemic blasts, thereby inducing DNA synthesis inhibition and cell death [ 265 ]. Single-agent nelarabine is active for R/R T-ALL achieving 36% of CR, especially for patients in first relapse, and can lead to durable remissions when followed by allo-HSCT consolidation [ 218 ]. Nelarabine has also been tested in combinations with cyclophosphamide (CTX) and etoposide (NECTAR) for R/R T-ALL. Despite contradictory results, nelarabine combination therapy and post-nelarabine allo-HSCT seem to be associated with improved OS compared to nelarabine alone [ 219 , 266 ]. Nelarabine was subsequently evaluated as frontline therapy in both children and young adults with newly diagnosed T-ALL. The study demonstrated a significant improvement in 5-year disease-free survival (DFS), with rates of 88.2% in the nelarabine group compared to 82.1% in the non-nelarabine group. This benefit was observed regardless of patient age and without an increase in toxicity [ 220 ]. Use of nelarabine as a part of initial treatment of T-ALL adults remains limited and continues to be studied [ 267 ]. Recent studies report that adding venetoclax to the hyper-CVAD regimen combined with nelarabine and pegylated asparaginase was well tolerated and resulted in prolonged responses, with 2-year OS of 87.8% and 2-year progression-free survival (PFS) of 87.9% [ 221 ]. The strategy combining pegaspargase, venetoclax and nelarabine can also be useful as a bridge to transplant [ 268 ].

Chronic lymphocytic leukemia (CLL)

Overview

Approximately 80% of all patients with CLL carry at least one of four common chromosomal alterations: a deletion in chromosome 13, 11, 17, or trisomy 12 [ 269 ]. The use of whole exome sequencing has allowed the characterization in depth of the genomic landscape of CLL, and a total number of 44 recurrently mutated genes and 11 recurrent somatic copy number variations have been described in genes, including NOTCH1, MYD88, TP53, ATM, SF3B1, FBXW7, POT1, CHD2, RPS15, IKZF3, ZNF292, ZMYM3, ARID1A, and PTPN11 [ 270 ]. The CLL international prognostic index (CLL‐IPI) integrates genetic, biological, and clinical variables to categorize patients in four distinct risk groups: low risk, intermediate risk, high risk, and very high risk based on the survival at 5 years [ 271 ]. Regarding treatment, only patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy [ 272 , 273 ]. Monotherapy with alkylating agents has served as front‐line therapy for CLL, and chlorambucil was the therapeutic “gold standard” for several decades [ 274 ]. Fludarabine remains the most extensively studied purine analog and demonstrates superior overall response rate (ORR) rates in monotherapy compared to other chemotherapies (40.1% versus 29.6% for CHOP (cyclophosphamide, vincristine, prednisone plus doxorubicin) and 15.2% for CAP (cyclophosphamide, doxorubicin plus prednisone)) [ 275 ]. When relapse occurs, the initial treatment may be repeated if the treatment‐free interval exceeds 3 years. If the leukemia relapses earlier, therapy should be changed using an alternative regimen [ 276 ]. FDA-approved drugs and clinical trials concerning targeted therapies in CLL mentioned below are summarized in Fig. 3 and Tables 9 and 10 .

Bruton’s tyrosine kinase inhibitors

Sustained B-cell receptor (BCR) activation plays an important role in the survival of CLL cells [ 277 ]. BCR signaling is transmitted by different tyrosine kinases, such as Bruton’s tyrosine kinase (BTK) and PI3K. Ibrutinib, acalabrutinib, and zanubrutinib enable irreversible inhibition of BTK activity by forming a covalent bond with a cysteine residue in the BTK active site. This results in blocking B-cell antigen receptor signaling and downstream signaling pathways (i.e., NF-κB pathway and ERK pathway), thus inhibiting the malignant B cells’ proliferation and survival [ 130 , 278 ]. Ibrutinib has been approved in combination with obinutuzumab, an anti-CD20 monoclonal antibody, as the first non-chemotherapy regimen for patients with previously untreated CLL [ 130 , 279 ]. Despite demonstrating excellent clinical activity, with an ORR of 77% as monotherapy and 84% in combination, ibrutinib typically fails to eradicate the disease or induce durable responses without continuous therapy. This limitation is particularly evident in CLL patients with del(17p) and/or complex cytogenetics, which are associated with poor outcomes [ 280 , 281 ]. Although therapy discontinuation is associated with a high risk of resistant relapse with an estimated cumulative incidence of progression at 4 years of 19% [ 282 ], the need for continuous therapy can be problematic for patients who experience adverse effects, often observed with ibrutinib. Acalabrutinib and zanubrutinib are some examples of second-generation BTK inhibitors (BTKi) with greater specificity for BTK, and developed to limit side effects of ibrutinib [ 283 ]. Even though acalabrutinib also received approval to treat patients with CLL or small lymphocytic lymphoma, alone or in combination with obinutuzumab, it does not appear that any of the second-generation “brutinibs” will obviate continuous maintenance therapy [ 284 , 285 ]. Pirtobrutinib is a highly selective but reversible non-covalent BTKi, developed to counteract resistance to second-generation BTKi, notably in patients with the well-described C481S mutation located in the kinase domain of the protein [ 286 ]. A recent study demonstrated that non-covalent BTK inhibitors, such as pirtobrutinib, are effective therapeutic options, achieving an ORR of 62% in patients who are intolerant of or resistant to conventional BTK inhibitors [ 287 ].

PI3K inhibitors

Drugs that target BCR signaling by inhibiting the delta isoform of phosphoinositide 3 kinase (PI3Kδ) have also shown clinical activity in CLL [ 285 ]. Idelalisib was the first PI3Kδ inhibitor approved by the FDA for the treatment of patients with CLL, in combination with rituximab [ 288 ]. However, due to higher incidence of hepatotoxicity and immune dysregulation, the FDA recommended closure of frontline clinical trials of idelalisib [ 289 ]. Duvelisib, a second-generation small molecule inhibitor of both gamma and delta isoforms of PI3K, has shown efficacy in CLL with a favorable safety profile compared to ofatumumab with median OS of 52.3 months (duvelisib) vs 63.3 months (ofatumumab) [ 290 ]. It was approved by the FDA in 2018 for patients with CLL who have received at least two prior therapies [ 291 ]. However, the report of frequent and severe adverse events with PI3K inhibitors, whether used alone or in combinations, has reduced the development of this class of drugs in CLL [ 292 , 293 ].

Bcl-2 inhibitor

Venetoclax is highly effective in patients with R/R CLL, particularly those harboring del(17p) [ 294 ]. Combination therapies incorporating venetoclax with either rituximab or obinutuzumab have demonstrated even greater efficacy in both treatment-naïve and R/R patients. These regimens achieved higher rates of durable responses, including a CR rate of 51% with rituximab [ 295 , 296 ] and a CR/CRi rate of 37% with obinutuzumab in R/R patients [ 297 ] . Based on these findings, the FDA and the National Comprehensive Cancer Network (NCCN) guidelines committee approved venetoclax combined with obinutuzumab as a frontline therapy for patients with CLL [ 298 ]. However, despite the encouraging clinical activity, some patients relapsed even with continuous venetoclax treatment, often due to specific resistance mechanisms, notably the occurrence of mutations in Bcl-2 that impede drug binding to the Bcl-2 protein [ 299 ], and compromise the cytotoxic effectiveness. Combinations of venetoclax with BTKis have demonstrated both a favorable safety profile and high efficacy, achieving response rates exceeding 80% in this setting [ 300 , 301 ]. In a very recent study, 867 untreated fit patients with CLL were randomized to receive acalabrutinib-venetoclax, acalabrutinib-venetoclax-obinutuzumab, or chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab). Fixed-duration acalabrutinib–venetoclax (with or without obinutuzumab) significantly prolonged PFS compared to chemoimmunotherapy. Estimated 36-month PFS at a median follow-up of 40.8 months was 76.5% with acalabrutinib-venetoclax, 83.1% with acalabrutinib-venetoclax-obinutuzumab, and 66.5% with chemoimmunotherapy [ 302 ]. These findings support reconsidering the place of venetoclax-BTKi based regimens in the therapeutic arsenal in fit CLL patients.

Conclusion

Although the development of targeted therapies is booming today in the field of hematology, the emergence of mutations is a recurrent mechanism of treatment escape. For instance, resistance to TKIs urges constant innovation to overcome newly arising mutations. Targeted therapies may also be associated with specific toxicities, avoiding their use for some patients, particularly those with comorbidities. In addition, access to certain targeted drugs remains restricted and their cost may be a barrier to widespread use. Incorporating novel targeted agents into frontline regimens as early as they become available is crucial to optimize therapy. Clinicians need to keep in mind that new drugs may come with their potential side effects, whether used alone or in combination. With the growing number of possible combinations involving two to four molecules, management of drug interactions could rapidly surpass predictions, potentially exposing patients to new risks.

Immunotherapy in leukemias

Immunotherapy for ALL

Immunotherapy, or biological therapy, refers to the treatment of disease by activating or suppressing the immune system of the patient. Hematopoietic stem cell transplant was the first immunotherapeutic approach used for patients with R/R disease. However, monoclonal antibodies or bispecific antibodies, alone or in conjugation, and cellular therapies like CAR-T or CAR-NK cells have since emerged as new standards of care for the difficult-to-treat leukemias [ 303 ] (Fig. 4 , 5 ). FDA-approved drugs and clinical trials concerning immunotherapy in ALL mentioned below are summarized in Fig. 3 , Tables 7 and 8 .

Monoclonal antibodies

The use of monoclonal antibodies in cancer therapy was first introduced in 1997 with rituximab, an anti-CD20 antibody used for treatment of B-cell lymphoma. In this review, we focus only on anti-CD38, the most recently developed in ALL.

Anti-CD38 therapy (daratumumab/isatuximab)

CD38 is a transmembrane protein expressed on various lymphoid and myeloid cells, as well as non-hematopoietic cells. Because of the high expression of CD38 in multiple myeloma (MM) cells, anti-CD38 antibodies, daratumumab and isatuximab, were initially developed and approved for this pathology [ 304 ]. During preclinical development, daratumumab demonstrated strong efficacy in inducing blast cell lysis, with broad potential in the treatment of T-ALL [ 305 ]. Preclinical studies further confirmed that blasts from patients with T-ALL and AML had robust CD38 expression, which remains stable after exposure to multiple chemotherapy treatments, and that daratumumab was effective against these cells [ 305 , 306 ]. In the DELPHINUS phase 2 study, daratumumab was safely combined with standard chemotherapy in children and young adults with T-cell ALL or lymphoblastic lymphoma (LL), leading to CR in 41.7% of T-ALL, and contributed to successful bridging to HSCT [ 222 ]. While isatuximab has shown low efficacy as monotherapy in refractory T-ALL and T-LL patients [ 223 , 224 ], it could represent an interesting therapeutic option in combination with chemotherapy for pediatric patients with R/R ALL or AML, as demonstrated in the ISAKIDS study in which CR rates of 42.9% were achieved in B-ALL, 33.3% in T-ALL, and 50% in AML [ 224 ]. The interest in integrating anti-CD38 mAb as first-line treatment for ALL is currently being explored in large trials such as GRAALL-T 2024 [ 307 ]. In addition to extending use of daratumumab in first-line treatment, combined therapies are currently under evaluation. For example, since ATRA can enhance the lytic capacity of the anti-CD38 mAb by increasing CD38 levels on the target cells, combinations of daratumumab with ATRA have shown promising results in myeloma, which could be transposed in AML [ 306 , 308 ]. Strategies combining antibodies targeting CD47 and CD38 have also shown encouraging results in preclinical T-ALL studies and need to be tested clinically [ 309 , 310 ]. These data suggest that daratumumab is effective in adult and pediatric AL, notably in T-ALL, and could offer alternative options beyond chemotherapy and targeted treatments.

Bi-specific antibodies (BsAbs)

Bi-specific antibodies (BsAb) are engineered antibodies designed to simultaneously bind two different antigens: one on a cytotoxic cell (such as T cell or NK cell), and one on the target tumor cell. Matchmaking, recruitment and activation of immune cells by bi-specific antibodies lead to tumor lysis.

Blinatumomab

Blinatumomab is a bi-specific T-cell-engaging (BiTE) antibody that recognizes CD19 on leukemic cells and CD3 on T cells to activate T-cell cytotoxicity. This forced interference results in a highly effective tumor cell killing through the release of granzymes and perforins in the immunological synapse, activating the caspase pathway and inducing apoptosis [ 311 ]. Blinatumomab was first approved by FDA in 2014 for R/R B-ALL patients [ 312 ], and in 2018 for the treatment of adult and pediatric patients with B-ALL in first or second CR with MRD-positivity (≥ 0.1%) [ 313 ]. After several single-arm trials demonstrating its efficacy and safety in the treatment of heavily pretreated R/R B-ALL patients [ 311 ], a phase 3 study comparing blinatumomab with standard chemotherapy was prematurely stopped due to the higher superiority of blinatumomab in terms of remission rates and OS, which consequently rendered continuation of the chemotherapy control arm unethical (CR: 34% in the blinatumomab group vs 16% in the standard of care group) [ 225 ]. Similar results were observed in pediatric patients with HR first-relapse B-ALL treated before allo-HSCT. The CR rate with negative MRD was 90% in the blinatumomab group compared to 54% in the chemotherapy group [ 226 ]. Similar findings were observed in patients aged 1 to 30 years with high- or intermediate-risk first relapse of B-ALL. After two treatment cycles, the CR rate with negative MRD was 66% in the blinatumomab group, compared to 32% in the chemotherapy group [ 227 ]. MRD clearance is one of the most powerful predictors of long-term survival in B-ALL.

Blinatumomab has been shown to be more effective than chemotherapy in achieving negative MRD after one course in R/R patients, and in prolonging leukemia-free survival [ 228 ]. Because there is no consensual MRD threshold to guide blinatumomab use, studies have been conducted to clarify whether patients with very low MRD levels could also benefit from blinatumomab or not. In a phase 3 trial, 224 patients with Ph-negative BCP-ALL who achieved MRD-negative remission, defined as < 0.01% leukemic cells in bone marrow after induction and intensification chemotherapy, were randomized (112 patients per group) to receive four cycles of blinatumomab with consolidation chemotherapy or four cycles of consolidation chemotherapy alone. At a median follow-up of 43 months, the blinatumomab group demonstrated a clear advantage in 3-year OS compared to the chemotherapy-only group (85% vs. 68%, respectively) [ 229 ].

Blinatumomab was also investigated as first-line therapy in infants with KMT2A-rearranged ALL. A total of 28 patients (93%) either were MRD-negative (16 patients) or had low levels of MRD (< 5 × 10–4, 12 patients) after the blinatumomab infusion. The 2-year DFS rate was 81.6% with blinatumomab, compared to 49.4% in the previous Interfant-06 protocol and OS rates were 93.3% and 65.8%, respectively [ 230 ]. Although long-term follow-up is needed, these results are very encouraging given that 90% of relapses occur within two years of diagnosis for this specific subtype of pediatric leukemia. Efficacy of blinatumomab in first-line treatment has been confirmed in a larger cohort of 1,440 newly diagnosed pediatric standard-risk B-ALL patients. A total of 722 were randomized to receive chemotherapy alone, and 718 to receive blinatumomab in combination with chemotherapy. The study was terminated early after the first interim efficacy analysis due to superior benefit of the blinatumomab arm (DFS of 96.0%) compared to standard chemotherapy alone (87.9%) [ 231 ]. Following these results, the FDA-approved in June 2024, the addition of blinatumomab to consolidation chemotherapy for patients with BCP-ALL who achieve CR with induction chemotherapy regardless of MRD status [ 314 ]. Blinatumomab has also proven to be a highly effective strategy as a bridge to transplant, achieving a 2-year DFS rate of 72.2%. This approach is associated with a low 2-year cumulative incidence of non-relapse mortality (NRM: 2.6%) and does not compromise the efficacy of subsequent salvage immunotherapies, including CAR-T cell therapy [ 232 ].

Despite its good tolerability profile, the addition of blinatumomab to chemotherapy still resulted in added toxicity [ 315 ]. Neurotoxicity with high risk of convulsion and cytokine release syndrome (CRS) are the two major adverse events, requiring careful monitoring during the initial infusions. Due to its limited penetration across the blood–brain barrier, blinatumomab is not optimal for treating CNS involvement. Therefore, additional CNS-directed therapy or prophylaxis remains essential to prevent relapse in this sanctuary site [ 311 ]. Blinatumomab should also be alternated with conventional chemotherapy, as its efficacy and safety are reduced in cases of high blast burden. Other limitations are still under investigation to better understand acquired mechanisms of resistance such as CD19 loss, lineage switch, exhaustion, and immune escape pathways that can disrupt blinatumomab efficacy and other anti-CD19 therapies such as CAR-T cells [ 316 , 317 ]. In Ph + ALL, blinatumomab has also demonstrated the ability to eradicate MRD when associated with TKIs in R/R patients, with a good tolerance profile [ 233 , 318 ]. With the constant aim of improving efficacy and reducing toxicity, promising chemo-free strategies combining steroids, TKIs (dasatinib) and blinatumomab are being explored as first-line treatment for adult Ph + B-ALL [ 209 , 319 ].

The incorporation of blinatumomab into frontline treatment protocols has profoundly reshaped the therapeutic approach in B-ALL. Its efficacy in both Ph + and Ph-negative B-ALL, particularly its activity to achieve MRD negativity, makes it a cornerstone of modern treatment protocols. Blinatumomab has shown a remarkable ability to overcome the negative prognostic value of persistent MRD positivity highlighting the need to re-evaluate indications and timing of allo-HSCT, particularly for patients achieving deep molecular responses. This includes weighing the risks of transplant procedure against the molecular risk factors of the disease and the patient’s response to therapy. Moreover, the development of a subcutaneous formulation of blinatumomab represents a significant advance. The new administration route could facilitate access to treatment, particularly in outpatient settings, and help better manage the logistical challenges posed by continuous intravenous infusion [ 319 ].

Antibody–drug conjugates

Inotuzumab ozogamicin

Antibody–drug conjugates (ADC) are immunoconjugate treatments combining an antibody with a drug, with the aim of delivering the cytotoxic agent directly and specifically to the targeted leukemic cell or its microenvironment. Inotuzumab ozogamicin (InO) is a humanized ADC targeting CD22 (expressed in around 90% of B-ALL cells) conjugated with calicheamicin, a powerful cytotoxic agent. InO is approved for the treatment of R/R adult ALL, based on the results of the INO-VATE trial, which demonstrated a significantly higher rate of CR (CR/CRi: 73.8% with inotuzumab vs 30.9% with standard chemotherapy), a longer PFS (5.0 months vs 1.7 months, respectively), and a longer median OS (7.7 months vs 6.7 months, respectively), regardless of the initial disease burden [ 234 , 235 , 320 ]. The safety and efficacy of InO treatment were also studied in children with R/R ALL, with a high response rate (ORR: 80%) and MRD < 0.01% in two-thirds of responders. In these studies, veno-occlusive liver disease, a serious and potentially fatal liver-related complication, and prolonged cytopenias were the major adverse events and therapeutic limitations associated with InO treatment, notably for patients treated before HSCT [ 236 ]. A large phase 3 study (Alliance A041501) investigated the addition of InO to intensive first-line chemotherapy in young adult patients but did not show a significant benefit in 3-year EFS (69.0% for the InO arm vs. 66.7% for the control), or 3-year OS (79.4% for the InO arm vs. 80.3% for the control). The study was even halted by the safety board because of the increased incidence of severe adverse events in the InO group, especially infections due to prolonged neutropenia [ 237 ]. However, the addition of InO to a low-dose chemotherapy in older patients with Ph-negative ALL was found to be safe [ 238 ]. To limit toxicity and avoid resistance such as the loss of CD22 target, innovative strategies combining InO with targeted therapy have been explored, notably for elderly patients. To allow lower doses of InO, better disease control and a longer delay between the last dose of InO and HSCT, a sequential combination of InO with low-intensity chemotherapy ± blinatumomab in patients with Ph-negative ALL in first relapse was evaluated and showed favorable outcomes with 1-year PFS, and OS of 64%, and 73%, respectively. In this study, the risk of veno-occlusive liver disease was minimized thanks to fractionated low-dose InO and its sequential combination with blinatumomab [ 239 ]. The benefits of InO in younger patients are currently under investigation. Because all patients receiving InO should be considered at high risk for veno-occlusive liver disease, early signs and hepatic symptoms should be closely monitored and modifiable risk factors need to be identified and treated before HSCT [ 321 ].

Immunotherapies for AML

Monoclonal antibodies

Immunotherapies have the potential to overcome both primary and acquired resistance, which is particularly important in patients with R/R AML. CD33, CD123, CD70, and CLL-1` are the main targetable antigens expressed on the surface of AML cells, but also on stem cells, which limit clinical applications because of toxic reactions on normal cells. Monoclonal antibodies targeting CD33 (lintuzumab) [ 53 ] and CD123 (talacotuzumab) [ 54 ] have shown high levels of toxicity without statistically significant improvement in response rate or survival in patients with R/R AML [ 56 ]. Strategies using monoclonal antibodies, such as cusatuzumab (anti-CD70 mAb) in combination with azacitidine or azacitidine + venetoclax, are still in progress [ 57 ]. FDA-approved drugs and clinical trials concerning immunotherapy in AML mentioned below are summarized in Fig. 3 , Tables 1 and 2 .

Bispecific antibodies

AMG330, vibecotamab or flotetuzumab are three examples of human bispecific T cell engagers (BiTEs) that target human CD33 and CD123, respectively, on the tumor cells and CD3Ԑ on T cells. These drugs have shown an acceptable safety profile and antileukemic effect, which need to be evaluated on a larger scale [ 55 , 58 , 59 ].

Antibody–drug conjugates

Gemtuzumab ozogamicin (GO) is a humanized antibody–drug conjugate combining a CD33-antibody with a cytotoxic agent, calicheamicin. Evidence indicates that GO can be safely added to conventional induction therapy on fractionated dosing schedules to achieve significant survival benefits in R/R patients and in newly diagnosed fit or unfit adult and pediatric patients with favorable and intermediate cytogenetic-risk disease [ 60 , 322 ]. In 2017, the FDA-approved GO for the treatment of newly diagnosed CD33-positive AML in adults, as well as for R/R CD33-positive AML in adults and pediatric patients aged 2 years and older [ 323 ]. This approval followed the results of the ALFA-0701 study, which reported an estimated 3-year EFS of 31% in the GO arm versus 19% in the control arm. However, OS data did not demonstrate a significant benefit, with 3-year OS rates of 44% versus 36% in the GO and control arms, respectively [ 324 , 325 ]. GO is also effective and well tolerated when combined with intensive chemotherapy in patients with early relapsed CD33-positive AML following allogeneic HSCT achieving a CR rate of 38% [ 61 ]. Ongoing studies reviewed by Wu et al. [ 326 ] are currently testing GO as first-line treatment for pediatric patients [ 62 , 327 ], and in combination with midostaurin ( NCT04385290 ) [ 65 ], venetoclax ( NCT04070768 ) [ 66 ], and CPX-351 (liposomal daunorubicin and cytarabine) ( NCT03672539 ) [ 63 , 64 ]. Optimal use of GO in the upfront AML setting requires rapid cytogenetic and molecular information in order to select patients with favorable and intermediate risk cytogenetics most likely to benefit from addition of GO. Because of higher risk of toxicity, notably veno-occlusive liver disease, it is important to monitor liver function and control cell counts frequently during therapy, particularly in patients with baseline abnormal liver tests before allo-HSCT [ 322 ]. Tagraxofusp-erzs (SL-401) is also a drug-conjugated antibody targeting CD123 (IMGN632) under investigation, alone or in combination [ 328 ].

In conclusion, GO is an interesting alternative for AML treatment, specifically in patients over 60 years of age who are not eligible for conventional chemotherapy or who have experienced a first relapse. The use of GO as first-line treatment is still under investigation in children. Even if the toxicity profile of GO, mainly hepatic veno-occlusive disease, raises concerns, the fractionated and revised dosing schedule make its management acceptable [ 329 ].

Immune checkpoint inhibitors (ICIs)

Immune checkpoint (IC) receptors are primarily expressed on immune cells, and are able to recognize specific ligands in normal or tumor cells, thereby acting as key regulators of the immune system. When IC receptors are activated by their ligands, they trigger the downregulation of immune effector functions, such as tumor cell cytolysis and the secretion of antitumor cytokines, ultimately leading to immune cell exhaustion. This unresponsiveness facilitates tumor cell evasion, uncontrolled proliferation, and metastatic spread. Immune checkpoint molecules include for examples CTLA-4, PD-1/PD-L1, T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3) [ 330 ]. Immune checkpoint inhibitors (ICIs) are mAbs that target inhibitory checkpoint molecules [ 331 ]. This class of molecules has revolutionized the outcomes of many solid tumors [ 332 ] and nivolumab and pembrolizumab have been approved by FDA for Hodgkin lymphoma [ 333 , 334 ]. PD-1/PD-L1 inhibitors tested in AML clinical trials include nivolumab, pembrolizumab, durvalumab, and avelumab. As a single agent, nivolumab was recently tested in the maintenance phase for AML to prevent relapse but failed to improve PFS and OS in a randomized phase 2 study with an increase of adverse events [ 67 ]. To enhance curative potential and improve patient outcomes particularly for high-risk R/R adult and pediatric patients, combinations of ICIs with HMAs have been investigated. A complete remission rate of 22% was observed when nivolumab was combined with azacitidine [ 68 , 69 ] and the addition of Bcl-2 inhibitors has also been proposed in preclinical studies [ 335 ]. Combination therapies of pembrolizumab (anti-PD-1) with decitabine or azacitidine have shown comparable results to those of azacitidine and nivolumab with CR for 2/10 patients [ 70 ]. On the contrary, combining entinostat (an HDACi) with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity [ 71 ]. Combination strategies involving durvalumab or avelumab (anti–PD-L1 ICIs) with azacitidine have been tested in older patients but did not demonstrate improved clinical efficacy compared with azacitidine alone. The complete remission rates were 17% for durvalumab plus azacitidine versus 21.5% for azacitidine alone, and 10.5% for the combination of azacitidine plus avelumab [ 72 , 73 ]. CTLA-4 expression on the surface of T cells hinders their maturation and differentiation. Ipilimumab, a monoclonal antibody targeting CTLA-4, has demonstrated durable responses as monotherapy, achieving a CR rate of 23% in patients with relapsed AML following allogeneic HSCT [ 74 ]. However, combination strategies comparing ipilimumab, nivolumab, or ipilimumab and nivolumab ± azacitidine in previously untreated MDS patients revealed higher toxicities grades and hospitalization rates in the triplet cohort than in the doublet cohorts, and failed to improve OS (8.9 months for ipilimumab, 8.0 months for nivolumab, and 8.7 months for ipilimumab-nivolumab) [ 75 ]. New ICIs are still under investigation in R/R AML and HR-MDS such as sabatolimab (TIM-3 checkpoint blockades) [ 196 ] in combination with azacitidine, or anti-CD47 mAb (CC-90002) [ 76 ]. However, contrary to solid tumors, ALs have a low mutational burden and ICIs have demonstrated modest effectiveness. The development of ICIs therefore remains in the clinical-trial stage as reviewed by Abaza et al. [ 336 ].

Cancer vaccines

AML vaccination strategies, such as peptide- and dendritic cell-based vaccines, reviewed by Fas et al., have been explored to decrease the risk of relapse and promote leukemia-specific immune responses in AML [ 337 ]. Wilms tumor 1 (WT1) protein has emerged as an encouraging vaccine target in AML due to its overexpression in leukemic blast cells and near absence in normal hematopoietic cells. Maintenance therapy with cancer vaccines targeting WT1, named galinpepimut-S (GPS), showed 16.9 months DFS in patients with AML in first CR by inducing a strong innate immune response against the WT1 antigen and achieving survival durations exceeding 5 years in the reported cohort of patients [ 77 ]. These findings have led to the design of a phase 3 randomized clinical trial, NCT04229979 still in progress, to test GPS in second complete remission (CR2) compared with the best available treatment for AML [ 78 , 338 ].

Dendritic cell (DC) vaccines have recently attracted considerable attention in AML. DCs are an important type of antigen-presenting cell that initiate immune responses (innate and adaptive) by processing antigens, such as necrotic tumor cells residues, to present them to immune effectors through the major histocompatibility complex class I, class II, and class III. Firstly, DCs can directly activate cells of the innate immune system such as natural killer cells, to limit the initial tumoral expansion until the activation of the adaptive immune system. Secondly, DCs establish immunological connections with T cells, allowing the amplification of the adaptive immune response [ 339 ]. DC-based vaccination strategies, including leukemia-derived DCs (DCleu), monocyte-derived DCs (mo-DCs), or hybridomas, have been tested in patients to control MRD and prevent leukemia relapse and have demonstrated variable levels of success [ 340 ].

DCleu derives from AML blasts. It has been described that DCleu vaccine therapy strengthens the immune system, as seen by increased levels of CD4 + and CD8 + T cells, Th1 cytokines, and activated NK cells [ 341 , 342 ]. In a phase 1/2 vaccination clinical trial using a personalized DCleu vaccine, with patient-derived AML cells fused with autologous dendritic cells, 71% of patients remained alive without disease recurrence at a median follow-up of 57 months, demonstrating that this personalized vaccine induces anti-AML cell immunity and provides protection against disease relapse [ 79 , 342 ].

Mo-DCs are an important source of DCs, which can be generated ex vivo from autologous or allogeneic CD14 + cells. Mo-DCs have been shown to be more effective in activating autologous antileukemia T-cell responses than DCleu [ 342 ]. Moreover, mo-DCs can be loaded with whole autologous apoptotic leukemic cells [ 80 ], leukemia cell lysates [ 81 ], or leukemia-associated antigens such as WT1, to improve immune activation. In a phase 2 study, DCs electroporated with WT1 mRNA were injected after remission in 30 patients with AML at very high risk of relapse. The vaccine strategy was well-tolerated and revealed a vaccine-induced relapse reduction rate of 25% and higher relapse-free survival in vaccine responders than in non-responders [ 82 ]. Innovative developments, such as the allogeneic DC vaccine (DCP-001) based on an AML-derived cell line [ 83 ], hybridoma of AML cells and autologous patient-derived DCs [ 79 ], and combination strategies testing DC vaccines with targeted drugs such as HMAs, are still under investigation [ 339 , 343 ]. Challenges remain in optimizing DC vaccine therapy for AML to enhance its clinical application and efficacy. The genetic heterogeneity of AML makes it difficult to identify optimal tumor-associated antigens, the ex vivo production of mo-DCs and generation of DCleu from patient leukemic cells are complex and expensive processes, and the optimal timing and dosage of vaccine injections still need to be clearly established [ 339 ].

Immunotherapy for CLL

Monoclonal antibodies

CD20 was the first target antigen explored in CLL, and the combination of the anti-CD20 mAb rituximab with fludarabine and cyclophosphamide is still often considered a standard treatment for previously untreated fit patients with a low-risk disease [ 344 ]. Ofatumumab, obinutuzumab, and ublituximab are next-generation CD20-targeting antibodies that have shown efficacy in combination strategies with conventional chemotherapy [ 345 ], BTKi [ 346 ], PI3K inhibitors [ 347 ] or venetoclax [ 348 ] (Table 10 ). However, the presence of high levels of circulating soluble CD20 antigen, which interferes with antibody binding, or the selection of antigen-loss variants in rituximab-treated patients, might limit their clinical efficacy [ 348 ].

CD19 is a pan-B surface antigen expressed also on precursor B cells. Even if CD19-directed mAbs did not show sufficient cytotoxic effects, possibly due to the rapid internalization of CD19, tafasitamab, a modified Fc-region anti-CD19 mAb, is being tested in combination with lenalidomide [ 349 ]. Preliminary data from studies combining tafasitamab with ibrutinib or venetoclax in CLL patients refractory to BTK inhibitors have reported CR rates of 9.1% for tafasitamab plus idelalisib versus 38.5% for tafasitamab plus venetoclax [ 350 ].

An interesting target currently under investigation is CD37, a tetraspanin notably expressed on the surface of mature B cells. Anti-CD37 mAbs currently assessed in clinical trials for the treatment of B-cell malignancies, as reviewed by Bobrowicz M et al., include otlertuzumab, naratuximab emtansine, AGS67E, BI 836826, and lilotomab labeled with the beta-emitter 177Lu [ 362 ]. Otlertuzumab demonstrated a CR rate of 9.4% when combined with bendamustine in a phase 2 trial involving patients with R/R CLL [ 351 , 363 ]. BI 836826 in combination with ibrutinib was tested in patients with R/R CLL, with 1 out of 6 patients achieving a CR [ 352 ]. Although substantial evidence supports CD37 as a relevant therapeutic target in B-cell malignancies, its use as a therapeutic target raises some important questions. Because CD37 has been demonstrated as a negative regulator of tumorigenesis in B-cell lymphoma, it is important to investigate whether anti-CD37 immunotherapy might lead to the selection of CD37-deficient clones, as described for other mAb targets [ 362 ].

Monoclonal antibodies targeting CD200, such as samalizumab (a cell surface protein), and receptor tyrosine kinase-like orphan receptor 1 (ROR1, an oncofetal protein), such as zilovertamab vedotin have also demonstrated a favorable safety profile in heavily pretreated patients, but very modest antitumor activity was observed (ORR: 4% for samalizumab and no observed antitumor activity for zilovertamab vedotin) [ 353 , 354 ].

B cell–activating factor (BAFF) is an immunomodulatory cytokine involved in the regulation of B-cell signaling, capable of modulating resistance of CLL cells to new targeted agents by sustaining survival and antiapoptotic signals of leukemic cells [ 364 ]. Interestingly, the anti-BAFF mAb belimumab, approved for treatment of systemic lupus erythematosus, has been shown to increase the sensitivity of the malignant cells to idelalisib, ibrutinib, and venetoclax [ 365 ]. In patients with R/R CLL on ibrutinib, ianalumab, another anti-BAFF monoclonal antibody, demonstrated an acceptable safety profile and promising preliminary activity, achieving a CR rate of 40% when combined with ibrutinib [ 355 ].

Bispecific antibodies

The first bispecific antibody (bsAb) tested in CLL was blinatumomab. Richter transformation is defined as the onset of aggressive lymphoma, mostly diffuse large B-cell lymphoma (DLBCL), in patients with CLL. In a phase 2 study, blinatumomab demonstrated encouraging antitumor activity in patients without CR after two cycles of R-CHOP for Richter transformation, with an ORR of 46% and an acceptable toxicity [ 356 ]. Interestingly, the antileukemic activity of bsAbs has been shown to be potentiated by BTKi, and the efficacy of CD19/CD3 bsAb was increased when used in combination with both ibrutinib and acalabrutinib in CLL models [ 366 ]. Restoration of autologous patient-derived T-cells functions appears to be required to achieve a full antitumor activity of BiTEs [ 348 ].

Innovative combination strategies

Recently, combination strategies have been explored for Richter’s transformation (RT), including ibrutinib (BTKi) with nivolumab (anti-PD1) [ 357 ], the triplet regimen of umbralisib (PI3Ki), ublituximab (anti-CD20), and pembrolizumab (anti-PD1) [ 358 ], as well as the combination of venetoclax (Bcl-2 inhibitor), obinutuzumab (anti-CD20), and atezolizumab (anti-PD-L1) [ 359 ]. These approaches have yielded high response rates in previously untreated RT patients, with ORR of 61%, 89%, and 71%, respectively. All FDA-approved drugs and clinical trials concerning immunotherapy in CLL are summarized in Fig. 3 and Tables 9 and 10 .

Conclusion

To minimize chemotherapy and HSCT and to improve long-term outcomes in patients, immunotherapy combinations designed to reduce drug resistance and enhance drug efficacy are currently ongoing. Chemo-free strategies in Ph + ALL have shown very high levels of CR, allowing to rethink the place of HSCT in this disease [ 212 ]. Research is now focusing on understanding the mechanisms of immune evasion employed by leukemia cells [ 303 ]. However, there is still a significant subset of patients who do not benefit from these approaches. Progress in targeted immunotherapies for B-ALL also raised high expectations for T-ALL therapy. Even if therapies targeting NOTCH1, proteasome inhibitors, JAK inhibitors, Bcl-2 inhibitors, and anti-CD38 antibodies are showing efficacy, T-ALL remains an urgent area of unmet need, with poor survival outcomes in both first-line treatment and relapsed setting [ 367 ].

Adoptive cell therapies in acute leukemia

CAR-T, CAR-NK cells in AML

Chimeric antigen receptor (CAR) T-cells are genetically modified polyclonal T or natural killer (NK) cells engineered with fusion proteins to guide them toward a given molecule on the tumor cell surface. CARs are composed of a single-chain variable fragment that binds tumor antigens, fused to a spacer and transmembrane domain with intracellular costimulatory signaling domains, most commonly CD28 or 4-1BB [ 368 ]. Developing AML-targeted CAR-T therapy is challenging because of the heterogeneity of target antigen expression in leukemic cells, the large number of targets shared by tumor cells and normal hematopoietic cells, posing a high risk of off-target effects, and the immunosuppressive impact of the tumor microenvironment. To date, various targets have been investigated, as reviewed by Deng et al., including CD33, NKG2D, CD123, CLL-1, and CD7. Despite extensive efforts, no CAR-T product has yet reached clinical practice in AML [ 369 , 370 ].

CD33 is a sialic acid receptor that is extensively found on myeloid and progenitor cells and is expressed in 96% of AML cases. This antigen is of major importance on the surface of AML cells and is already effectively targeted by antibody–drug conjugate GO. However, recent interim results of a phase 1/2 clinical study showed that only 2 patients among the 24 who had received autologous anti-CD33 CAR-T cells achieved CR and MRD negativity, with deep aplasia [ 371 ]. In addition to manufacturing challenges and high levels of toxicity, ex vivo-produced CAR-T cells may acquire CD33 expression during the production process, which raises concerns about the relevance of this target for CAR-T cells [ 369 ].

Natural killer group 2, member D (NKG2D) is one of the NK cell-activating receptors crucial for immune recognition and eradication of tumor cells by both NK and T-cells. NKG2D triggers immune activation by recognizing ligands (NKG2D-L) on AML cells [ 372 ]. NKX101 is a NK cell therapy derived from healthy donors and engineered to express a NKG2D ligand-directed CAR. In phase 1 study, 6 patients with R/R AML were enrolled to receive alternative lymphodepletion (LD) regimen using fludarabine and cytarabine (ara-C), followed by NKX101-10 infusion. Results showed that 4 out of 6 patients achieved CR/CRi, with prolonged persistence of CAR-NK cells for up to 3 weeks [ 373 ]. In a larger study, 16 patients with R/R AML or MDS received an autologous CAR-T cells products based on the NKG2D receptor. Among 12 evaluable patients, three showed an objective response. Seven patients experienced grade 3 or 4 treatment-related adverse events. Despite modest efficacy, these studies support the proof of concept of targeting NKG2D ligands with CAR-T cell therapy in R/R AML [ 374 ].

CD123 is the alpha chain of the interleukin-3 receptor, expressed in around 80% of AML patients but also in normal cells, including multipotent progenitors, myeloid, and lymphoid progenitors, as well as immature blood cells [ 375 ]. Allogeneic CD123 CAR-T cells were tested in 16 AML patients. In terms of efficacy, disease was stabilized in two patients, while one achieved morphologic remission, and another achieved negative MRD. Treatment was associated with high levels of toxicity, including CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) [ 376 ]. Because preliminary clinical results for anti-CD123 CAR-T cells are modest and reveal high toxicity, researchers are focusing on CAR constructs that enable selective elimination of CAR-T cells in case of severe adverse effects, by integrating molecular safety switches (such as caspase or CD20) [ 377 ].

Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein that plays a role in immune regulation as an inhibitory receptor. In AML, CLL-1 is detected in approximately 90% of cases on the surface of AML cells, but also on LSCs, granulocytes, monocytes, macrophages, and dendritic cells [ 378 ]. A first-in-human phase 1 study of CLL-1 CAR-T cells was conducted in 10 R/R patients. Although all 10 patients developed CRS, 70% of them achieved Cri [ 379 ]. The recent update of the results confirms both the efficacy and high level of toxicity in the 30 treated patients. Long-term efficacy of CAR-T cells is difficult to assess, because almost all patients were bridged to HSCT [ 380 ]. Anti-CLL-1 CAR-T cells were also tested in pediatric patients, with comparable efficacy and toxicity profiles [ 381 ].

CD7 is a transmembrane protein that belongs to the immunoglobulin superfamily. Because CD7 can be expressed in approximately 30% of AML, CD7 CAR-T cells, initially developed for T-ALL, were tested in AML. Hu et al. reported results for 10 patients. Although 7/10 patients achieved CR in bone marrow and 6 attained MRD-negative CR, responses remained transient and were associated with high levels of toxicity (80% of CRS) [ 382 ].

The development of dual-target CAR-T cells is currently being tested to counteract antigenic escape [ 370 ]. Tandem bispecific CD123/CLL-1 CAR-T cells have demonstrated significant killing effects on both CLL-1( +)/CD123( +) leukemia cell lines and primary AML tumor cells [ 383 ]. In a phase 1 clinical trial evaluating the safety and efficacy of dual-targeted CD33/CLL-1 CAR-T, patients diagnosed with complex karyotype AML achieved MRD-negative CR after treatment [ 384 ]. Clinical trials on dual-targeted CAR-T cells are currently underway ( NCT06110208 , NCT06125652 ) [ 385 ].

CAR-T cells in ALL

CD19, a B-cell surface marker expressed throughout B-cell development, has been chosen as the most suitable target for CAR-T cells in ALL due to its high level of expression on most malignant B cells and its absence on the surface of HSCs, thereby limiting the risk of aplastic anemia. Initial approvals for CAR-T cells targeting CD19 (tisagenlecleucel) were based on the ELIANA trial, which demonstrated efficacy in children and young adults with R/R ALL [ 386 ]. In this study, the ORR within 3 months was 81%, while EFS and OS were 73% and 90% at 6 months, respectively. In 2023, updated data for long-term follow-up demonstrated durable efficacy of tisagenlecleucel with a 36-month RFS, EFS, and OS rates of 52%, 44%, and 63%, respectively [ 387 ]. In the adult population, the ZUMA-3 trial assessed the efficacy and safety of autologous anti-CD19 CAR-T cell therapy in patients with R/R ALL. Seventy-one patients were enrolled and underwent leukapheresis. Anti-CD19 CAR-T cells were successfully manufactured for 65 of them (92%), and at the median follow-up, 39 patients (71%) achieved CR or CRi with manageable toxicity [ 388 ]. CAR-T cells can also migrate to CNS or testes, which are sanctuary sites for leukemic cells, and efficiently clear CNS disease and achieve durable remissions [ 385 ].

The value of CAR-T cells is undeniable in the treatment of B-ALL, but toxicities such as CRS, ICANS, and B-cell aplasia are still associated with a high level of morbidity and mortality. CRS is a systemic inflammatory response that often occurs within 1–4 days after the infusion and can progress to multiple organ failure [ 389 ]. Higher-grade CRS may be effectively treated with the anti-interleukin-6 receptor antibody tocilizumab, but the use of this specific mAb could potentially limit the efficacy of CAR-T cells [ 390 ]. ICANS is also associated with CAR-T cell therapy and may be due to activated CAR-T and endogenous T lymphocytes. It should be considered in the presence of any neurological symptoms following infusion of CAR-T cells. Prophylactic measures such as fractionated CAR-T cell dosing and early therapeutic interventions with tocilizumab and/or corticosteroids for persistent grade 1 or any grade 2 CRS/ICANS may help to reduce the incidence of high grade CRS/ICANS [ 391 ]. Prolonged B-cell aplasia leading to hypogammaglobulinemia and agammaglobulinemia is a damageable consequence of CAR-T cell infusion and exposes patients to an increased risk of severe infections. In addition to antimicrobial and antifungal prophylaxis, immunoglobulin replacement may help to prevent serious bacterial infections [ 303 ]. Although the initial response rate to CAR-T cells is remarkable, a significant number of patients either fail to respond or relapse after treatment, and approximately 50% of CD19-targeted CAR-T cell treated patients relapse within one year [ 368 ]. While B-cell recovery does not always precede relapse, the detection of B-cells in peripheral blood within the first 6 months after infusion has been shown to predict relapse risk and may be an indicator for clinicians to consider subsequent therapy [ 387 ]. In AL, loss of CD19 antigen, due to mechanisms such as selection of CD19-negative subclones, appeared to be a dominant cause of relapse [ 368 ]. To overcome resistance, ongoing studies are investigating the infusion of new products composed of different cell populations expressing various CARs, either simultaneously or sequentially [ 392 ], the design of bicistronic or tricistronic vectors encoding two or three different CARs within a single cell [ 393 , 394 ], or tandem CARs, which combine two different single-chain variable fragments on the same chimeric protein [ 391 ] (Fig. 4 ). To overcome resistance, alternative targets for CAR-T cells are under investigation, including CD20 [ 395 ], CD22 [ 396 ], TSLPR [ 397 ], CD7 [ 398 ], and CD38 [ 306 ], as reviewed by Sheykhhasan et al. [ 368 ]. CAR-T cell exhaustion and inactivation also represent important limitations. Combining checkpoint inhibitor administration with CAR-T cell therapy may enhance CAR-T cell persistence and provide an effective and safe strategy to improve CD19-targeted CAR-T cell therapy in relapsed B-ALL [ 399 , 400 ]. Combination of nivolumab with tisagenlecleucel reinfusion is currently ongoing in a cohort of R/R B-ALL patients, aged 1–25 years old, previously treated by tisagenlecleucel with a demonstrated early loss of B-cell aplasia (within 6 months), a surrogate marker of the loss of CAR T-cells or their non-functionality. (CAPTiRALL, NCT05310591 ). FDA-approved drugs and clinical trials concerning CAR-T cells in ALL are summarized in Fig. 3 , Tables 11 and 12 .

Although CAR-T cell therapy has proven to be curative in a significant proportion of patients with relapsed B-cell lymphoma and B-ALL in patients without need of transplantation, as a bridge to transplant, or in case of relapse after transplantation, its role in T-ALL is less established. In the first-in-human study, autologous CD5-directed CAR-T cells were manufactured from patients with R/R T-cell malignancies. Among the 17 patients treated, CD5 CAR-T treatment achieved an ORR of 44%, with CR in two patients. The most common grade 3 or higher adverse events were cytopenias [ 401 ]. Other potential CAR-T targets include CD3, CD7, CCR4, and CCR8 [ 367 ].

The implementation of CAR-T in clinical practice requires a highly complex organization, from leukapheresis that needs to be done in fragile patients, to reinfusion in specialized departments. Moreover, the associated toxicities can be difficult to manage and contribute to a significant rate of non-relapse mortality. To ensure optimal CAR-T cell expansion, blast proliferation must be controlled throughout the manufacturing process, which can be a major challenge in aggressive diseases. Finally, personalized CAR-T cell manufacturing is time-consuming, technically complex and often conducted at decentralized facilities. Currently, access to CAR-T cells is restricted to FDA-approved indications or inclusion in clinical trials, and limited trial capacity of patient enrollment and the strict inclusion criteria do not allow universal access to this potentially life-saving therapy. “Universal CAR-T cell therapy” refers to the development of off-the-shelf (ready-to-use) CAR-T cells that can be manufactured from healthy donor cells and used in multiple patients. The use of allogeneic immune cells offers advantages over autologous patient-derived cells, such as the ability to generate mass production, reducing costs and wait times, and generating multiple therapeutic cell doses from a single donor, which can be cryopreserved. This makes the allogeneic products cost-effective and readily available for treatment [ 402 ]. In addition to CD19 CAR-T, off-the-shelf CAR-NK cell therapies targeting antigens such as CD7 ( NCT02742727 ) and FLT3 are currently under investigation [ 403 ]. Clinical trials concerning CAR-T cells are summarized in Tables 11 and 12 .

In vivo CAR-T is another promising way of development for adoptive cell therapies in cancer. These methods use engineered nanocarriers or viral vectors to generate CAR-T cells directly within a patient’s T-cells, reducing manufacturing costs and turnaround times compared to ex vivo approaches. Preclinical and nonhuman primate studies have demonstrated the feasibility and effectiveness of in vivo CAR-T cell generation, producing therapeutic CAR-T cells comparable to ex vivo methods and supporting progression to human clinical trials [ 404 – 407 ].

CAR-NK cells in ALL

NK cells are heterogeneous and distinct lymphocyte populations composed of classic cytotoxic cells and cells with regulatory functions. Both NK cell subsets are defined according to the intensity of cell surface expression of CD56 and CD16. In addition to 4-1BB (CD137), NKG2D and CD244 (2B4) are the two costimulatory molecules through which NK cells enhance their cytotoxic capabilities [ 408 ]. NK cells can be obtained from different sources, including donor or autologous peripheral blood mononuclear cells, umbilical cord blood, cell lines (NK-92), or pluripotent stem cells. The main limitations in engineering CAR-NK cells are the low transduction efficiency, poor expansion, and the long-term storage, which decreases cytotoxic potential [ 409 ]. Only a few clinical studies of CAR-NK cell immunotherapy for B-malignancies are ongoing, in which allogeneic NK cell therapies were well tolerated without adverse events such as CRS or ICANS [ 303 , 410 , 411 ]. For example, FT596, an induced pluripotent stem-cell (iPSC)-derived CAR-NK cell therapy, as monotherapy or in combination with rituximab, induces deep and durable responses in patients with indolent and aggressive lymphomas [ 412 ]. Another phase 1/2 trial using cord blood-derived NK cells expressing anti-CD19 CAR and interleukin-15 (CAR19/IL-15) was conducted in 37 patients with CD19 + B-cell malignancies. The 1-year OS and PFS were 68% and 32%, respectively, with no notable toxicities such as CRS, ICANS or graft versus host disease (GVHD) [ 413 ]. FDA-approved drugs and clinical trials concerning CAR-T cells in ALL are summarized in Fig. 3 , Tables 11 and 12 .

TCR-T cell therapy

TCR-T cell therapy is an adoptive cell therapy that genetically engineers T cells to express specific TCRs, enabling recognition of intracellular antigens presented by HLA molecules, unlike CARs, which only target surface antigens. TCRs are highly specific, often restricted to a single HLA subtype. TCR-T products can be derived from autologous or allogeneic sources. As of August 2024, over 400 interventional clinical trials on TCR-T therapies are registered globally, many focusing on leukemia [ 419 ]. Key targets for TCR-T cell therapy include WT1, the preferentially expressed antigen in melanoma (PRAME), human minor histocompatibility antigen 1 or 2 (HA-1/HA-2) and mutated nucleophosmin 1 (mNPM1). In the NCT01640301 trial, 12 AML patients received prophylactic donor-derived EBV-specific CD8 + WT1 TCR-T cells post allo-HSCT, achieving 100% RFS at 44 months [ 414 ]. The NCT01621724 trial treated 7 AML/CML patients with autologous WT1-directed TCR-T cells, with 4 showing disease responsiveness [ 415 ]. In NCT02550535 , all the 6 prophylactically treated AML patients remained in remission at a median follow-up of 12 months [ 416 ]. Three phase 1 trials for AML patients post-allo-HSCT used HA-1-specific T cells. In the EudraCT-2010–024625-20 trial, 5 HA-1 + patients received EBV/CMV-specific CD8 + HA-1 TCR-T cells, and among them 2 remained in remission, with no GVHD or toxicity observed [ 417 ]. In NCT03326921 , a CD8/CD4 HA-1 TCR-T cell product treated 9 relapsed patients, with T-cell persistence in 8 for up to a year, and 4 showing disease responsiveness, including 1 with CR for > 27 months [ 231 , 418 ]. Clinical trials demonstrate few severe adverse events and sustained remissions accompanied by long-term persistence of therapeutic T cells, even at low doses. However, slow patient accrual due to strict HLA and antigen-specificity requirements, as well as challenges in generating products for all enrolled patients, remain significant limitations [ 420 ].

RNA based therapy in AL

RNA-based therapy is an alternative strategy that could expand the therapeutic arsenal for ALs as done for genetic diseases such as Duchenne muscular dystrophy (3 or 4 FDA-approved molecules). Antisense oligonucleotides (ASOs) are short, single-stranded chemically modified RNA or DNA molecules that bind to complementary nucleic acid sequences, thereby impacting the functions of the targeted genes. In the field of hematology, three ASOs have been granted as orphan drugs: oblimersen for CLL, PNT2258 for DLBCL, and cobomarsen for cutaneous T-Cell lymphoma [ 360 ]. Concerning the treatment of acute myeloid or lymphoid leukemias, 11 ASOs have been evaluated in clinical trials in AML or ALL but none has yet been approved [ 421 ] (Tables 2 , 6 , 8 , 10 ).

Clinically tested ASOs in AL

The literature on antisense oligonucleotides (ASOs) in AL demonstrates encouraging results from preclinical experiments and phase 1 clinical trials, but only modest improvements in clinical outcomes have been achieved to date. Imetelstat, an ASO that competitively inhibits telomerase activity by binding to the telomerase RNA component TERC, without interacting with mRNA, was FDA-approved in 2024 for patients with LR-MDS and IR-MDS. This approval followed the IMerge study, which demonstrated a 39.8% rate of ≥ 8-week red blood cell transfusion independence (RBC-TI) in the imetelstat group compared to 15% in the placebo group [ 422 ]. Cobomarsen, targeting miRNA-155, also received FDA approval in 2020 for cutaneous T-cell lymphoma (CTCL) [ 197 , 423 ]. The literature is replete with examples of ‘antisense knockouts’, which demonstrate the utility of such targets under a variety of experimental conditions but only a few of them have been clinically tested. For instance, LY2181308 and EZN-3042, designed to target inhibitors of apoptosis (IAP) BIRC5/Survivin, exhibited variable efficacy. LY2181308 showed clinical benefits in 4 out of 16 R/R AML patients when combined with chemotherapy [ 424 , 425 ], whereas EZN-3042 trials were discontinued due to toxicity [ 84 ]. XIAP, the most potent IAP, was targeted by AEG35156 , which achieved a 47% CR rate in AML [ 426 ]. However, larger phase 2 trials failed to demonstrate significant clinical improvement [ 240 ]. More recently, novel strategies using steric-blocking ASOs targeting BIRC5 have shown promising in vitro results [ 85 ].

Bcl-2 has also been targeted by ASOs. Oblimersen sodium (G3139), the first ASO to demonstrate antisense effects in tumors [ 86 , 427 ], showed early promise in R/R AML/ALL [ 428 , 429 ] but did not improve OS in larger trials when combined with standard chemotherapy (Table 2 ). PNT2258, a liposomal ASO targeting Bcl-2, initially demonstrated an ORR of 53.8% in R/R B-cell malignancies [ 87 ], but these results were not confirmed in a larger phase 2 trial (Wolverine, NCT02226965 ), leading to its discontinuation (response rate: 8.1% in R/R DLBCL) [ 88 , 430 ]. BP1002, a novel liposomal ASO, is currently under investigation in phase 1 trials for R/R AML [ 113 ]. BP-1001, an ASO targeting Grb2, also demonstrated safety and efficacy in preclinical models and phase 1 trials, with 3 out of 6 R/R AML patients achieving CR [ 241 , 242 ]. A phase 2a trial combining BP-1001 with venetoclax and decitabine in untreated and R/R AML ( NCT02781883 ) is currently underway [ 421 ].

Targeting TP53 with Cenersen (OL(1)p53), a specific ASO, represents an innovative approach, as inhibiting the DNA repair system may induce synthetic lethality in cancer cells through the accumulation of genetic aberrations. Cenersen was well-tolerated but showed limited efficacy as monotherapy [ 431 ]. When combined with chemotherapy, 19% of R/R AML patients achieved CR [ 243 ]. Another phase 2 study evaluated Cenersen in combination with fludarabine, cyclophosphamide, and rituximab in HR-CLL, showing tolerable toxicity and 18% of CR [ 426 ]. Other ASOs targeting ribonucleotide reductase (RNR) (GTI-2040) [ 89 , 90 ], DNMT1 (MG98) [ 361 ], and STAT3 (AZD9150/Danvatirsen) [ 91 , 92 ] have shown limited or no significant clinical activity. The modest efficacy of ASOs in hematological malignancies may be partly attributed to their pharmacokinetic limitations, such as rapid clearance, low membrane permeability, and the lack of effective delivery systems. Over the past decade, innovative approaches have been developed to enhance ASO efficacy by modifying their pharmacological properties and improving targeted delivery.

Conclusion

From the historical revolution of ATRA in APL to precision medicine, which allows the production of personalized drugs for each patient, the development of targeted therapy has largely improved outcomes in patients with leukemias and still remains one of the largest areas of current research in the field. Given all the progress in targeted therapies, immunotherapy and RNA-based therapies developed in the last decade, along with new technologies for accurate MRD assessment, the management of leukemias may gradually move away from HSCT, especially for patients at lower risk of relapse. Researchers are now focusing on understanding the mechanisms of relapse and immune evasion employed by leukemia cells in order to develop novel therapeutic strategies to overcome resistance, and are attempting to optimize drug delivery with new vehicles. Future needs will be to help clinicians to choose the best possible combination of drugs for each patient, depending on genetic disease features and patient comorbidities, to optimize treatment sequences, and be able to propose coherent alternatives in case of relapse, based on the identification of resistance mechanisms.

Acknowledgements

The authors thank the Gene Expression and Oncogenesis team, especially Sébastien CORRE, Yuna BLUM, Océane GUEHO, Yanis SI-AHMED, Elfie PERRUDIN, Rose-Marie FRABOULET, Céline MONOT, Laura BACHELOT-PERROT, Diane SCHAUSI-TIFFOCHE, Justine GUILLO, and the Institute of Genetics and Development of Rennes (UMR6290 CNRS) for helpful discussions.

Abbreviations

2’-O-methoxyethyl

Activated B-cell subtype of diffuse large B-cell lymphoma

ATP-binding cassette-B1

Abelson kinase

Acetyl group

Antibody–drug conjugate

Antisense double-stranded DNA oligonucleotide

Adriamycin

Erythroleukemia

Protein kinase B

Allogeneic hematopoietic stem cell transplantation

Acute leukemia

Acute myeloid leukemia

Adenosine monophosphate

Accelerated phase

Acute promyelocytic leukemia

Cytarabine

AT-rich interactive domain-containing protein 1A

Antisense oligonucleotide

Additional sex combs-like 1

Ataxia telangiectasia mutated gene

Arsenic trioxide

Adenosine triphosphate

All-trans retinoic acid

B acute lymphoblastic leukemia

B-cell activating factor of the TGF family

Bcl-2 associated athanogene 3

Bcl-2-associated X protein

B-cell leukemia/lymphoma 2

B-cell lymphoma-extra large

B-cell maturation antigen

B-cell precursor acute lymphoblastic leukemia

Breakpoint cluster region gene/Abelson proto-oncogene

Bcl-2-like protein 11

Baculoviral IAP repeat containing 5

Bi-specific T-cell-engaging

B-cell linker protein

Bone marrow

Blastic phase

Blastic plasmacytoid dendritic cell neoplasia

Bi-specific antibodie

Bruton’s tyrosine kinase

Cellular myelocytomatosis

Chimeric antigen receptor-natural killer cell

Chimeric antigen receptor-T cell

Chemokine receptor 4

Chemokine receptor 8

Cluster of differentiation

Cluster of differentiation 40

Cluster of differentiation 40 ligand

Cyclin-dependent kinase 9

CCAAT/enhancer-binding protein alpha

Chromodomain-helicase-DNA-binding protein 2

Human C-type lectin-like molecule-1

CLL international prognostic index

Chronic lymphocytic leukemia

Chronic myelogenous leukemia

Chronic myelomonocytic leukemia

Complete major response

Central nervous system

Chronic phase

Complete remission

Second complete remission

Complete remission with incomplete hematologic recovery

Cytokine receptor-like factor 2

Cytokine release syndrome

Cutaneous T-cell lymphoma

Cytotoxic T-lymphocyte-associated protein 4

Cyclophosphamide/vincristine/doxorubicin

D-2-hydroxyglutarate

Dendritic cell

Leukemia-derived DCs

Disease-free survival

Diffuse large B-cell lymphoma

Deoxyribonucleic acid

DNA methyltransferase

Deoxynucleoside triphosphate

Cationic lipid 1,2-dioleoyl-3-trimethylammonium propane

Ubiquitin-conjugating enzyme

Transcription factor 3/PBX homeobox 1

Event free survival

Epidermal growth factor receptor tyrosine kinase

Erythropoietin receptor

Mitogen-activated protein kinase

Extracellular signal-regulated kinases 1–2

Erythropoiesis stimulating agents

Early T-cell precursor

Ets variant 6/runt-related transcription factor 1

F-Box and WD repeat domain containing 7

Fludarabine/cyclophosphamide

Fragment crystallizable

Food and drug administration

Fusion gene

Fibroblast growth factor receptor 1

Fms-like tyrosine kinase 3

Fms-like tyrosine kinase 3-Internal tandem duplications

FMS-like tyrosine kinase 3-tyrosine kinase domain

Granulocyte-colony-stimulating factor

Galectin-3

Glioma-associated oncogene protein

Repressor form of GLI

Gemtuzumab ozogamicin

Galinpepimut-S

Growth factor receptor-bound protein 2

Graft versus host disease

Histone deacetylase

Histone deacetylase inhibitor

Heteroduplex oligonucleotide

Hedgehog

Hepatic leukemia factor

Hypomethylating agent

Homeobox A7-10

High risk

Hematopoietic stem cell

Hematopoietic stem and progenitor cell

Human telomerase reverse transcriptase

Inhibitor of apoptosis proteins

Half-maximal inhibitory concentration

Immune effector cell-associated neurotoxicity syndrome

International consensus classification

Immune checkpoint inhibitors

Isocitrate dehydrogenase 1/2

Interferon-α/β

Interferon-γ

IKAROS family zinc finger 1

Interleukin-12

Interleukin-3

Inotuzumab-ozogamicin

Induced pluripotent stem cells

Intermediate risk

Immunosuppressive therapy

Janus kinase

Juvenile myelomonocytic leukemia

Protein kinase C

Lysine-specific N-methyltransferase 2A

Lysine-specific N-methyltransferase 2A/ALF transcription elongation factor 4

KMT2A-rearranged

Lymphocyte-activation gene 3

Lymphodepletion

Low dose cytarabine

Locked nucleic acid

Long non-coding ribonucleic acid

Lipid nanoparticles

Low risk

Leukemic stem cell

Leukemia translocation gene of chromosome 19

Tyrosine-protein kinase Lyn

Monoclonal antibody

Mitogen activated protein kinase

Mitogen-activated protein kinase

MYC-associated factor X

Myeloid cell leukemia-1

Mouse double minute 2

Multidrug resistance 1

Myelodysplastic syndrome

Methyl group

Mitogen-activated protein kinase kinase

Major histocompatibility complex 2

Micro ribonucleic acid

Major molecular response

Monocyte-derived DCs

Minimal residual disease

Messenger ribonucleic acid

Multidrug-resistance protein

Mammalian target of rapamycin

MYC-associated factor X dimerization protein 3

Myeloid differentiation primary response gene 88

Nicotinamide-adenine dinucleotide phosphate

Nicotinamide-adenine dinucleotide phosphate (reduced form)

NEDD8-activating enzyme

National comprehensive cancer network

Neural precursor cell expressed, developmentally downregulated 8

Next generation sequencing

Natural killer

Natural killer group 2D

Natural killer group 2D ligand

Neurogenic locus notch homolog protein

Nucleophosmin 1

Cytoplasmic nucleophosmin 1

Non-relapse mortality

Nucleoside triphosphate

Nucleoporin 98

Overall survival

Overall response rate

Phosphorylated form

Programmed death-1 protein

Programmed death ligand-1

Programmed cell death 4

Platelet-derived growth factor receptor

Patient-derived mouse xenograft

Polyethylene glycol-lipids

Progression free survival

P-glycoprotein

Philadelphia chromosome, acute lymphoblastic leukemia

Philadelphia

Philadelphia chromosome positive, chronic myeloid leukemia

Phosphatidylinositol 3-kinase

Phosphatidylinositol 3,4,5-trisphosphate

Phosphatidylinositol-specific phospholipase Cγ2

Promyelocytic leukemia / retinoic acid receptor-alpha

Phosphorodiamidate morpholino oligomer

Peptide nucleic acid

Protection of telomeres protein 1

Pyrophosphate

Phosphorothioate

Patched receptor

Peripheral T-cell lymphoma

Tyrosine-protein phosphatase non-receptor type 11

Plasmacytoma variant translocation 1

Rituxan (rituximab) – cytoxan (cyclophosphamide) – hydroxydoxorubicine – oncovin (vincristine) – prednisone

Relapsed/refractory

R2 subunit of RNR

Rat sarcoma

Red blood cell

Red blood cell-derived extracellular vesicle

Relapse free survival

Cytokine receptor-like factor 2

Ribonucleic acid

RNA methyltransferase

Ribonucleotide reductase

Receptor tyrosine kinase-like orphan receptor 1

Reactive oxygen species

Ribosomal protein S15

Richter transformation

Runt-related transcription factor 1

S100 calcium binding protein A8

Stearic acid

Severe combined immunodeficient mice

Splicing factor 3b subunit 1

Small interfering RNA

Small lymphocytic leukemia

Second mitochondria-derived activator of caspases

Smoothened receptor

Proto-oncogene tyrosine kinase

Serine and arginine rich splicing factor 2

Signal transducer and activator of transcription

Suppressor of fused protein

Cytoplasmic protein spleen tyrosine kinase

T acute lymphoblastic leukemia

Tricarboxylic acid

Transcription factor 3

T-cell receptor

Telomerase RNA component

Tet methylcytosine dioxygenase 2

Type 1 T helper

T-cell immunoglobulin and mucin containing protein-3

Tyrosine kinase Inhibitors

Tumor protein 53

Transfer ribonucleic acid

Ubiquitin

Vascular adhesion molecule-1

Vascular endothelial growth factor

Very late antigen-4

World health organization

Wilms’ tumor

X-linked inhibitor of apoptosis protein

Zinc finger MYM-type protein 3

Zinc finger protein 2

α-Ketoglutarate

Author contributions

EC conceptualized, wrote, designed figures and edited the manuscript. AP wrote and reviewed the manuscript. MO wrote and designed figures. NT, AQ, AGR reviewed the manuscript. MDG reviewed, and edited the manuscript. VG and FM conceptualized, reviewed and edited the manuscript.

Funding

This work has been funded by the Rennes Hospital FHU CAMin (CHU de Rennes), Brittany Regional Council (Région Bretagne), Comprehensive Cancer Center Eugène Marquis, the Cancer Care Foundation LCC 35 (Ligue Contre le Cancer), La Vannetaise and Manche Leucemie (patient associations).

Data availability

Not applicable

Declarations

Ethics approval

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Data Availability Statement

Not applicable