Regarding the critical role of glycolysis pathway in the growth and proliferation of cancer cells, myeloid leukemia cells also upregulate this metabolic pathway. Numerous genetic studies in mouse models have implicated the importance of glycolysis and high expression of glycolysis-associated enzymes in the initiation and maintenance of myeloid malignancies. They have proved that deletion of glycolytic enzymes such as pyruvate kinase (PKM2) or lactate dehydrogenase A (LDHA) can considerably extenuate the initiation and maintenance of murine CML and AML (53). Raised glycolytic activity not only gives rise to a decreased level of autophagy leading to more aggressive leukemia, but also is associated with drug resistance (54, 55). In AML cells, higher mTORC1 activity and FLT3-ITD-mediated signaling contribute to the continuance of glycolysis and leukemic cells survival and therefore, render therapeutic sensitivity to glycolytic inhibition ( Figure 1 ) (56, 57). 2-Deoxyglucose, as an inhibitor of the glycolysis pathway, has shown beneficial effects in AML treatment (47, 58). Moreover, leukemic cells are significantly dependent on the pentose phosphate pathway (PPP) which provides ribonucleotides for nucleic acid synthesis and NADPH for lipid synthesis. Redox homeostasis and glucose-6-phosphate dehydrogenase (G6PD) overexpression are the key regulators of this pathway and correlate with an adverse prognosis in AML ( Figure 1 ). Therefore, inhibition of G6PD activity can be a promising therapeutic target in AML and its beneficial effects have been demonstrated in FLT3-ITD-mutated AML (56, 59, 60). Additionally, synergic effects of G6PD and 6-phosphogluconate dehydrogenase (6PGD) inhibition with cytarabine to produce anti-leukemic activities in AML have been proven (42). BCR‐ABL fusion oncogene in CML also increases glucose transport and renders cells more glycolytic compared with normal counterparts (61). It has been demonstrated that continuous exposure of K562, a CML cell line, with imatinib which decreases glucose uptake and inactivates glycolytic enzymes, can lead to induction of autophagy in CML cells by mechanisms involving activation of AMPK and suppression of S6K1 (62).

OXPHOS and mitochondrial metabolism also have a significant role in myeloid leukemia. According to Krtić et al, oxygen consumption rate and mitochondrial mass are increased in AML cells compared with normal hematopoietic progenitors (63). Furthermore, amplification of mitochondrial DNA (mtDNA) levels in AML has been indicated in various studies (64, 65). Noteworthily, different AML cell lines exhibit a different preference on glycolysis or mitochondrial OXPHOS for energy demand. For instance, NB4 was proved to be a “glycolytic” cell line while THP-1 was identified to be dependent on OXPHOS, even though they are all AML cell lines (66). Further mechanism investigation revealed that AMPK is responsible for the bioenergetic production difference, highlighting that the oncogene background of leukemia cells, at least partly, determines their metabolism preference. Furthermore, leukemia continuously reprograms to adapt to environmental pressures and alteration of growth conditions, resulting in the ratio between glycolysis and OXPHOS are continuously changing (67). Due to higher mitochondrial biogenesis and higher dependency on mitochondrial oxidation in leukemia myeloblasts, it has been indicated that metformin suppresses leukemia cell survival, proliferation, and clonogenic activity in both AML and CML (68, 69). The compound CPI-613, as an inhibitor of pyruvate dehydrogenase (PDH) and α-KG dehydrogenase (KDH), has clinical benefits through decreasing oxygen consumption rate in AML cells (70). An unexpected high remission rate has been observed in relapsed and refractory AML patients after co-administration of CPI-613 with high-dose Ara-C (71). Several OXPHOS or ETC complexes inhibitors including Tigecycline, Metformin, 2’3’-Dideoxycytidine, IACS-010759, and A2-32-01 have revealed clinical benefits in AML and CML (63, 65, 72, 73). Metformin, as a widely used anti-diabetic drug, has interestingly exhibited anti-leukemic activities in some leukemias such as AML. However, regarding its pharmacokinetics and maximum efficient dose, it is usually administered in association with other remedies but not alone in clinical settings. Regarding that AML cells are strongly dependent on mitochondrial metabolism, metformin is administered in doses which could inhibit ETC complex I (69, 74). It has been proven that in order to eliminate disease persistence in CML patients, a combination of tigecycline and imatinib can serve as a suitable clinical approach (75).

One of the most important and well-known metabolism-related hallmarks of AML is a mutation of isocitrate dehydrogenases. These are crucial enzymes of the TCA cycle. In their wild-type form, these isoforms oxidatively decarboxylate isocitrate to 2-KG and generate NADPH. However, their mutant forms oxidize NADPH and produce the oncometabolite 2-hydroxyglutarate (2-HG) from α-KG ( Figure 1 ) (76–78). This alteration has been found approximately in 20% of AML patients and has been proven to be a promising therapeutic point. In 2018, ivosidenib (formerly known as AG120), an allosteric IDH1^R132 inhibitor, was firstly approved by the FDA for patients with relapsed or refractory IDH1-mutated AML. Additionally, it is considered as front-line therapy for newly diagnosed patients who are 75 years or older and also some patients who are ineligible to receive intensive chemotherapy (79, 80). Enasidenib (formerly known as AG-221) that has gained FDA approval for IDH2 mutant AML patients, is a small molecule that selectively inhibits mIDH2 (IDH2^R140Q and IDH2^R172K) via binding to its allosteric site and prevents the conformation change requiring for the catalytic action and the R-2-hydroxyglutarate (R2HG) production. Its clinical benefits in AML treatment have been demonstrated in both in-vitro studies and clinical trials (80–82). Furthermore, Vorasidenib (AG-881) is under investigation in phase I for the treatment of AML patients with a mutation in IDH1 and/or IDH2 (83).

Amino acids not only serve as essential building blocks of protein biosynthesis but also are considered as a significant source of carbon and nitrogen on nucleotide synthesis and therefore they contribute to cancer cells’ growth and proliferation. According to numerous studies, it seems that three amino acids glutamine, arginine, and tryptophan have prominent roles in hematological malignancies particularly in myeloid leukemia. The importance of branched−chain amino acids (BCAAs) metabolism in myeloid leukemia has also been studied. Accordingly, in several leukemic cell lines, glutamine depletion can induce significant apoptosis (84–86). AML primary cells have indicated a higher level of glutamine dependence than normal CD34+ cells because this amino acid controls OXPHOS in these cells (87). Small molecule inhibitors such as BPTES and CB-839 that are glutaminase (GLS) inhibitors, can lead to cell proliferation arrest and apoptosis in AML and BCR–ABL-positive CML cells (88, 89). CB-839 can also inhibit glutathione production and cause accumulation of mitochondrial ROS and eventually apoptotic cell death in AML (90). Recent research showed that high-risk MDS patients can benefit from the combination of CB-839 and 5-azacitidine due to the rapid reduction of BM blasts (91). Moreover, GLS inhibition and BCL-2 inhibitor Venetoclax have displayed synergic effects in AML ( Figure 1 ) (86).

Various studies also described a strong dependence of myeloid leukemia cells on arginine. Arginine is a semi-essential amino acid that is involved in many biochemical processes and can be considered as a potential therapeutic cancer target (92–94). Because of defects in the arginine-recycling pathway enzymes like argininosuccinate synthase and ornithine transcarbamylase, AML blast cells are mostly dependent on arginine uptake by the CAT-1 and CAT-2B arginine transporters. In addition, the plasma arginine levels are significantly higher in AML patients compared with healthy counterparts. Hence, BCT-100, a PEGylated human recombinant arginase that can deplete extracellular arginine, has resulted in proliferation arrest, apoptosis, and decreased AML engraftment in vivo. Generally, the cultivation of AML blasts or AML cell lines in an arginine-free media can lead to their apoptosis (94).

Tryptophan metabolism and its conversion to kynurenine, have an important role in a variety of malignant tissues, such as ovarian cancer, melanoma, and head and neck cancer (95). Increased kynurenine/tryptophan ratio in AML patient sera which negatively correlates with their OS, also indicates its importance in myeloid leukemia (96). In fact, in more than 50% of the cases tested at diagnosis, AML blasts constitutively express IDO (Indoleamine-2,3-dioxygenase) and so can promote the formation of regulatory T cells (Tregs) (97).

leucine, isoleucine, and valine are known as BCAAs synthesized by the BCAA transaminases 1 (BCAT1) and 2 (BCAT2) in a reversible transamination reaction. A quantitative expression proteomics analysis detected significant BCAT1 overexpressed in AML LSCs but not in the non-LSC bulk population. A high level of BCAT1 is involved in AML biology (98). Furthermore, Hattori et al. have indicated highly elevated BCAA levels in CML-initiating cells isolated from a BC-CML mouse model using amino acid-specific fluorescent markers. They also have shown that BCAT1 inhibition impairs CML blast crisis propagation in vitro and in vivo (99).

In a general perspective, lipids are considered as central players in cancer biology due to their critical roles in cell growth and proliferation. Therefore, extensive rewiring of lipid metabolism, which is driven by both oncogenic and tumor microenvironmental cues, is a significant hallmark of cancer cells. Indeed, these metabolic reprogramming and specific lipid profiles of cancer cells are so important that can be regarded as disease biomarkers, with diagnostic, prognostic, and predictive values. Lipids and their metabolism are emerging as promising tools and targets for anti-cancer therapies and numerous natural or synthetic compounds targeting lipid metabolism have been discovered with curative effects against cancer (100, 101). Interestingly, bone marrow-resident LSCs express higher fatty acid transporter CD36 than normal HSCs and hence, they can induce lipolysis in BM adipocytes to fuel FAO in leukemic cells. It seems to be that BM-resident adipocytes remarkably impair the anti-leukemia effect of various chemotherapeutic agents and obese mice compared to normal-weight counterparts show higher rates of relapse after chemotherapy (102). It has been proven that cell growth and survival of AML monocytes are strongly supported by BM adipocytes, which promote their fatty acid β-oxidation (103). Firstly, a study in 2010 showed that pharmacological inhibition of the carnitine palmitoyltransferase 1 (CPT1) which catalyzes one of the rate-limiting steps in FAO, enhanced AML sensitivity to apoptosis ( Figure 1 ) (104). Moreover, other pharmacologic agents that inhibit fatty acid oxidation, such as Etomoxir or Ranolazine, restrain AML cell proliferation and sensitize human leukemia blasts to apoptosis (104). Even some more common lipid targeting drugs like statins are also clinically useful in AML treatment in combination with chemotherapy. Some studies have demonstrated that statin treatment can enhance complete remission rates in favorable-risk AML groups, but had a less clear role in high-risk AML (105, 106).

Lipids are not only a source of energy to produce ATP, NAD(P)H, and building blocks for cell membrane, but also are essential signaling molecules. This group of lipids including prostaglandins, leukotrienes, and eicosanoids has a critical role in several processes like inflammation, and carcinogenesis (107). Chen and colleagues have demonstrated that mRNAs for both Alox5 and Alox15 (arachidonic acid lipoxygenase enzymes) are highly expressed in CML stem cells and their overexpression is vital for their survival. Additionally, they showed that in vivo administration of PD146176 (an Alox15 inhibitor) and/or zileuton (an Alox5 inhibitor) can diminish the relapse of CML disease in WT CML model mice (108, 109). Another study has indicated that increased expression of the enzyme Gdpd3 (lysophospholipase D), which activates lysophospholipid metabolism, can eventually lead to stem cell quiescence and TKI resistance in CML. These observations suggest that targeting Gdpd3 or other enzymes that are involved in lysophospholipid metabolism can contribute in reducing CML disease relapse (110).

Although different hematological malignancies harbor individual genetical alterations and locate in a diverse microenvironment, ALL shows a conserved symptom of high consumption of glucose as myeloid leukemia does (111). B precursor ALL lymphoblasts exhibit a preferential upregulation of genes related to glycolysis compared to the TCA cycle, indicating the dominant position of aerobic glycolysis in glucose metabolism of ALL (111). However, in contrast to ALL, CLL shows a relatively low uptake of 2-Deoxy-2-[¹⁸F] fluoroglucose (FDG) and low sensitivity of positron emission tomography-FDG, demonstrating that the glycolytic pathway might not be a critical role in CLL cells’ metabolism (112, 113). As the glucose transporter, GLUT promotes the uptake of glucose extracellularly in ALL cells, and after deletion, a decrease in proliferation and a limited degree of apoptosis was observed in B cell ALL lymphoblasts harboring the BCR-ABL1 tyrosine kinase fusion oncogene (114). Moreover, inhibition of rate-limiting enzymes that catalyze the metabolic intermediates during glycolysis, such as HK2, PKM2, and LDHA, induces apoptosis, blocks proliferation, and even attenuates drug resistance in ALL cells. Therefore, opens a potential therapeutic window for ALL treatment by targeting crucial enzymes in the glycolysis pathway (114, 115). Numerous oncogenic pathways, such as MYC, PI3K/Akt, AMPK, and Notch, have been reported to participate in the glycolysis procedure in lymphoid leukemia, upregulating the expression of glucose transporters and glycolytic enzymes or balancing glycolysis and mitochondrial metabolism (116–118).

The PPP, which branches from glycolysis, produces NADPH and ribose-5-phosphate after an oxidative phase and plays an unreplaceable role in lipids generation and redox homeostasis in lymphoid leukemia (119). G6PD, the first enzyme in the PPP pathway, can serve as a prognostic biomarker of ALL (120). Furthermore, in B cell ALL, the serine/threonine-protein phosphatase 2A (PP2A) switches glucose carbon utilization from glycolysis to the PPP to cope with oxidative stress, implicating the possibility to remove the gatekeeper function of PP2A in the PPP by inhibiting this molecule in ALL (121).

Despite the roles of aerobic glycolysis as a predominant pathway for providing a source of energy and anabolic precursors for tumorigenesis in most hematopoietic malignancies, some subsets of leukemia, like CLL, satisfy from increasing energy demands during growth by upregulating mitochondrial OXPHOS activity. For instance, an increase in the number of mitochondria, the total mitochondrial mass, and mitochondrial biogenesis was evidenced in CLL cells, in comparison to normal B lymphocytes (122). Elevated mitochondrial oxidative activity generates a proper high level of ROS, contributing to tumor progression by mediating the tumor microenvironment and protecting cells from apoptosis. When compared with normal B cells, the level of mitochondria-derived ROS in CLL cells is higher due to a more active mitochondrial activity, thereby promoting the progression of leukemia (40, 122). Metformin, an inhibitor of mitochondrial complex I, has been proved to suppress cell cycle progression and cell proliferation via disruption of mitochondrial OXPHOS in CLL and ALL (123, 124). Furthermore, a synergetic antileukemia effect has been observed when combining metformin with daunorubicin or vincristine, which are extensively used to treat leukemia clinically. This has revealed that, revealing that targeting mitochondrial OXPHOS could be a potent adjuvant therapy strategy for lymphoid leukemia treatment (125, 126).

Glutamine provides a rich resource of carbon and nitrogen, which can be used to produce amino acids, nucleotides, and fuel mitochondrial activity via offering α-KG. Thus, many cancer cells become addicted to glutamine and rely heavily on glutaminolysis for rapid growth. Likewise, ALL cells show an active utilization of glutamine for leukemogenesis, while suppression of glutaminolysis enhances the antileukemic effects in mice harboring T cell ALL (127). Genetic or pharmacological targeting ASCT2 molecule, a transporter of neutral amino acids, especially glutamine, decreases leukemia initiation and maintenance driven by the oncogene MLL-AF9 or Pten deficiency (128). Furthermore, glutaminase (GLS), An enzyme that catalyzes glutamine into glutamate, has proved to be a potential therapeutic target in the treatment of ALL (129, 130).

Asparagine synthetase (ASNA) catalyzes the conversion from aspartate to asparagine in most tissues. However, due to the low expression of ASNA, ALL cells are auxotrophic for asparagine and highly sensitive to asparaginase treatment, which degrades extracellular asparagine systematically and blocks the cell growth of ALL cells (131, 132). Taking advantage of this unusual metabolic dependency on an exogenous supply of asparagine in ALL cells, asparaginase has become one of the standard therapeutic regimens in ALL treatment. Asparaginase already exhibited a synergetic and profound antileukemia effect when combining with chemotherapies for ALL treatment in clinical practice (133, 134). Intriguingly, asparaginase diminishes not only asparagine but also glutamine in the intracellular pool (130). Moreover, asparaginase reduces glucose uptake and glycolysis and hampers pyrimidine synthesis in ALL cells (135). Altogether, asparaginase can fulfill its antileukemia function in a comprehensive method.

Arginine is a semi-essential amino acid, which is critical for the synthesis of protein, nitric oxide, and other amino acids. Arginine can be synthesized from citrulline intracellularly while taking up exogenous arginine is also necessary to meet the cellular demands in leukemias. Increasing studies have shown the potential therapeutic benefit of pegylated-human-arginase I (peg-Arg I) in ALL treatment. By depleting the existence of arginine and starving ALL cells of it, peg-Arg I induces a decreased progression of the cell cycle via impairing the expression of cyclin D3 (136). Further study suggested the central role of phosphorylation of the eukaryotic-translation-initiation factor 2 alpha signaling in the antileukemia effects induced by peg-Arg I (137). Interestingly, although endogenous or genetic upregulation of argininosuccinate synthase or ornithine transcarbamylase rescues ALL survival from a moderately low arginine condition, these enzymes cannot prevent the cytotoxic effects of peg-Arg I towards ALL (138).

Lipids serve as fundamental building blocks for the construction of membranes. Cancer cells satisfy the high demands of lipids for the biosynthesis of membrane structure via synthesizing fatty acids themselves, rather than absorbing lipids from the blood. Fatty acid synthase (FASN), a large enzyme with multiple catalytic domains, carboxylates malonyl-CoA into fatty acid chains. An elevated level of FASN was evidenced in drug-resistant ALL and correlated with a poor prognosis, while inhibition of FASN increases apoptosis rates and overcomes dexamethasone resistance (139). Moreover, not only the suppression of FASN inhibits ALL cells growth but also produces a remarkable impairment of PD-L1 expression, indicating the potential role of FASN inhibitors in antileukemia immunotherapy (140).

FAO in the mitochondria degrades fatty acids and generates acetyl-CoA for OXPHOS and energy production in cancer cells. The transportation of fatty acids into mitochondria for FAO requires the assistance of CPT, an enzyme located in the outer membrane of mitochondria. CLL cells exhibit elevated levels of CPT1 and CPT2, while inhibition of CPT induces compromised FAO activity due to ineffective transportation of fatty acids into mitochondria, subsequently leading to massive CLL cell death (141).

Lipoprotein lipase (LPL), a water-soluble enzyme that hydrolyzes triglycerides in lipoproteins, has found to be abnormally expressed in CLL cells (142). Moreover, the elevated expression of LPL is associated with a poor prognosis and an aggressive disease stage of CLL (142, 143). LPL displays its oncogenic function via storing lipids in cytoplasmic vacuoles and fueling fatty acids for energy production, reprograming CLL cells to utilize fatty acids as the major energy resource (144). Furthermore, this unique metabolic feature of CLL cells is driven by STAT3, an oncogenic pathway that endows CLL cells’ survival advantages by binding and activating the promotors of LPL (145, 146). Additionally, further study has revealed that LPL in aggressive CLL cells generates activating ligands for the nuclear receptor PPARα and allows fatty acids to be employed as fuel (147). Thus, STAT3-mediated aberrant LPL in CLL can serve as an ideal targeted marker for blocking lipid metabolism.

Generally, most of the glucose consumed by leukemia cells is catabolized through glycolysis. Thus, preventing glucose uptake and glycolysis will be an effective strategy to struggle against leukemia. GLUT mediates the glucose uptake and transportation of leukemia cells. By inhibiting GLUT4, protease inhibitor ritonavir exhibits similar toxic effects on CLL cells as glucose deprivation does in vitro (173). Furthermore, when co-incubating with metformin, an inhibitor of mitochondrial complex I activity, ritonavir-resistant CLL cells are sensitized, resulting in the elimination of CLL cells via perturbation of glucose metabolism. Promising antileukemia results have also been evidenced by targeting rate-limiting enzymes related to glycolysis and the PPP, such as HK2 (174), G6PD (175), PKM2 (176). Leukemia cells prefer shunting pyruvate into lactate production to adjust to rapid energy consumption rather than into the TCA cycle for further OXPHOS, providing a probability to target LDH to inhibit the production of lactate in leukemia cells. The LDHA inhibitor oxamate fulfills its antileukemia effects by arresting ALL cells in G0/G1 phase and inducing apoptosis (177). Further mechanism exploration revealed that blocking LDHA also leads to the inactivation of the c-Myc and PI3K signaling pathway, suggesting that targeting LDH is an ideal selection to achieve antitumor benefits when applying in vitro. Last but not least, prohibiting monocarboxylate transporters (MCTs), the transporter of lactate, will results in the accumulation of glycolytic end-products including lactate and H⁺, which consequently, lead to intracellular acidification and apoptosis. A recent study demonstrated that AR-C155858 and syrosingopine, inhibitors of MCT1 and MCT4, exert an anti-proliferative effect and enhance AML cells’ sensitivity to chemotherapeutic agents (178). Altogether, the results highlight the important role of targeting the glycolysis pathway in the treatment of leukemia. Regretfully, clinical results concerning glycolysis-related inhibitors to cure leukemia are rare up to now so far. The bio-safe and efficacy of glycolysis-related inhibitors for leukemia treatment are eager to explore clinically.

The current development of targeted agents against glutamine metabolism of cancer cells focuses on membrane glutamine transporter inhibition, GLS inhibition, and glutamine depletion. ASCT2 mediates the entry of glutamine and other amino acids into cells. ASCT2 inhibitor GPNA showed potential in decreasing survival and promoting apoptosis of AML cells in vitro. In AML mice, GPNA treatment effectively suppressed leukemia progression. Attenuated splenomegaly and hepatomegaly, and reduced AML cells infiltration were observed. Notably, the impact of GPNA on normal blood cell formation was limited (128). As a selective and irreversible inhibitor of GLS, CB-839 has shown ideal antileukemia effects on AML and ALL cells in vivo (129). Furthermore, a completed phase I clinical trial also evidenced the potential role of CB-839 to combat leukemias (NCT02071927) (179). Eighteen patients, including AML (n=16), ALL (n=1) and mixed leukemia (n=1), were enrolled in this trial. Results showed that CB-839 was well tolerated in advanced leukemia patients. One AML patient achieved a complete remission (CR) and has been on study for more than 10 months, while four additional patients remained on study for at least 12 weeks. Another Phase Ib/II clinical trial has demonstrated that CB-839 is safe and effective in combination with azacitidine in patients with advanced myelodysplastic syndrome (MDS) (NCT03047993) (91). Among ten patients with MDS, seven patients achieved CR, two patients had stable disease (SD), while one patient had no response, suggesting that GLS inhibition may induce a robust effect against hematopoietic malignancies synergetically when combining with other conventional treatments.

Asparaginase has been approved by FDA as the frontline therapeutic agent used in ALL. A previous clinical trial revealed that 357 patients with ALL reached a 68% of four-year continuous CR rate after receiving asparaginase treatment, while the rate was only 55% in patients without asparaginase (180). The overall one-sided logrank test favors the asparaginase group over the control in ALL treatment. Toxicities related to asparaginase were manageable.

Many types of cancer cells, including AML disease, depend on the exogenous supply of arginine due to the defects in arginine synthetase (189, 190). Therefore, arginine depletion is a possible therapeutic option for leukemia cure. A phase II clinical trial reported that two patients reached CR while seven patients achieved SD among 21 argininosuccinate synthetase (ASS)-deficient AML patients after receiving arginine deiminase (ADI-PEG20) (NCT01910012) (181). The median progression-free survival (PFS) and overall survival (OS) were 1.8 months and 7.9 months, respectively. Clinical outcomes and further transcriptome sequencing implied that ADI-PEG20 monotherapy is required but not sufficient for ASS-deficient leukemia treatment. A rational combination with other targeted or conventional drugs may improve the efficacy of the antileukemia response as a whole. Recently, another phase I study combining ADI-PEG20 and low-dose cytarabine for the treatment of AML has completed and encouraging outcomes have been observed (NCT02875093) (182). Results revealed that the overall response rate (ORR) in 18 patients was 44.4%, with a median OS of 8.0 months. In seven treatment-naive patients, the ORR was 71.4% and the CR rate was 57.1%. Moreover, patients suffered limited fatal side effects after receiving the combination of ADI-PEG20 and cytarabine. Taken together, ADI-PEG20 shows the superior clinical performance when cooperating with conventional clinical agents for AML therapy, and the underlying mechanism of combination warrants further explorations.

Increased IDO activity results in T cells inactivation and immunosuppression (191). Even though IDO inhibitors are mainly being tested in solid tumors, clinical trials have also started to test this potential biomarker in AML (NCT02835729) (183). Among 25 AML patients who received more than one dose of indoximod, a small-molecule inhibitor of the IDO pathway, 21 AML patients attained disease remission. Furthermore, ten patients experience measurable residual disease (MRD) negative among twelve patients with MRD available in remission. When combining with standard AML induction therapy, indoximod is well tolerated. These promising results indicated that indoximod could serve as an ideal targeted agent to combat leukemia by inhibiting IDO activity.

To meet the exquisite demands of cell growth and proliferation, leukemia cells exhibit high dependence on FA metabolism, making it possible to target this metabolic vulnerability to eliminate leukemia cells (192). Currently, FAO inhibitors are being tested in preclinical trials. Imatinib induces the inactivation of BCR-ABL, thereby suppressing glycolysis in CML cells. However, compensatory FAO activation rescued glucose-independent CML cells’ survival after imatinib treatment. AIC-47 suppressed the expression of CPT 1 and directly fatty acid metabolism, contributing to the complementary attack on CML energy metabolism when combining with imatinib (184). Moreover, another CPT 1 inhibitor, etomoxir, has been reported to exhibit significant antiproliferative effects on AML cells and sensitize AML cells to apoptosis induced by ABT-737 in vitro (185). Although FAO inhibitors have not been practiced clinically, preclinical studies already reveal the feasibility of appliance of FAO inhibitors in leukemia treatment.

In CLL, LPL has been identified as a specific biomarker, which indicates an unfavorable prognosis in patients (193, 194). Via targeting LPL molecule, orlistat induced apoptosis of CLL cells, while limited cytotoxicity was demonstrated in healthy B cells and peripheral blood mononuclear cells (186). Moreover, the antileukemia effects of orlistat on CLL cells strengthened when incubated with fludarabine, simultaneously.

Retrospective studies claim that the IDH mutation was associated specifically with a poorer prognosis in AML (195–197). Currently, ivosidenib and enasidenib, inhibitors of IDH1 and IDH2, have become the first FDA-approved metabolism targeting drugs for AML. In a phase I/II trial, the efficacy of enasidenib was examined in patients with mutant-IDH2 advanced myeloid malignancies (187). The median overall survival among patients with relapsed/refractory AML was 9.3 months while patients who reached CR or partial remission had a median survival of 19.7 months or 14.4 months, respectively. The ORR for all relapsed/refractory AML patients was 40.3%, with a median response duration of 5.8 months. This study proved that daily enasidenib therapy induces antileukemia responses and is well-tolerated in patients who failed in conventional treatment previously. Ivosidenib, a mutant IDH1 specific inhibitor, has been evaluated in a phase I trial (NCT02074839) (188). Thirty four patients with AML were enrolled in this trial and their median overall survival was 12.6 months with a median follow-up period of 23.5 months. CR plus CR with partial hematologic recovery rate was 42.4%. The most commonly reported therapy-related serious adverse event was IDH differentiation syndrome. These results demonstrated that enasidenib and ivosidenib induce durable remissions and are safe in mutant IDH AML treatment.