Cytarabine plays a crucial role in the treatment of acute myeloid leukemia (AML). It is administered alongside anthracyclines during induction therapy and at higher dosages during consolidation therapy for AML patients. The combination of cytarabine with purine nucleoside analogs, like fludarabine and cladribine, has been extensively studied for the treatment of relapsed or refractory AML patients. However, in recent years, there has been a significant shift towards the use of targeted therapies that are both novel and effective. These therapies include inhibitors that target mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase (IDH), as well as venetoclax, a B-cell lymphoma 2 inhibitor, and glasdegib, a hedgehog pathway inhibitor. In older patients, a combination of a hypomethylating agent or low-dose cytarabine with venetoclax has shown promising results, achieving response rates similar to standard induction regimens in similar populations. However, this combination therapy may come with reduced toxicity and lower risk of early mortality [70]–[72].

For over 40 years, daunorubicin, an anthracycline drug, has been widely used alongside cytarabine as a standard induction therapy for adult patients with acute myeloid leukemia (AML). This treatment approach, commonly referred to as the “3+7 regimen,” involves administering daunorubicin for three days followed by seven days of cytarabine. Recently, a phase 2 trial examined the effectiveness and safety of combining venetoclax with the 3+7 regimen in adult AML patients. The results demonstrated an impressive composite complete remission rate of 91% after just one cycle of treatment [73]–[75].

Mercaptopurine, a potent chemotherapy medication, is primarily utilized in the treatment of acute lymphoblastic leukemia (ALL), a type of cancer affecting the white blood cells. Additionally, it can be employed to address acute myeloid leukemia (AML), as well as the rare form of AML known as acute promyelocytic leukemia. This medication acts as a pro-drug, resembling the structure of purine analogues, and disrupts the synthesis and recycling of nucleotides within the body. For the successful eradication of ALL, it is crucial to undergo maintenance therapy (MT) involving the administration of oral methotrexate (MTX) and 6-mercaptopurine (6-MP). The primary method by which this drug exerts its cytotoxic effects is through the integration of thioguanine nucleotides (TGNs) into the DNA molecule. This process may be further intensified due to the inhibition of the production of new purines by other metabolites derived from MTX/6-MP [76]–[78].

Vincristine, an effective chemotherapy medication, is frequently administered alongside other drugs for the treatment of acute lymphoblastic leukemia (ALL). This compound works by interfering with the normal functioning of microtubules, thereby halting the cell cycle. In order to assess the possibility of discontinuing pulse therapy with vincristine and dexamethasone beyond one year of treatment for childhood ALL, a study was conducted to determine if this approach would have any negative impact on the outcome of any risk subgroup within this population [79]–[82].

Methotrexate is a chemotherapy drug commonly used to treat acute lymphoblastic leukemia (ALL). This medication works by depleting reduced folates and inhibiting key steps in nucleotide synthesis, which are necessary for the production of thymidine and purine. Maintenance therapy, consisting of oral methotrexate and 6-mercaptopurine, is crucial for successfully curing ALL. These drugs disrupt nucleotide synthesis and salvage pathways, and their primary method of killing cancer cells involves incorporating thioguanine nucleotides into DNA. This process can be further enhanced by the inhibition of de novo purine synthesis by other metabolites of methotrexate and 6-mercaptopurine [83]–[87].

Busulfan, a chemotherapy medication, is utilized alongside other drugs to prepare patients with leukemia for allogeneic marrow transplantation. For individuals with acute myeloid leukemia or myelodysplastic syndrome who are deemed unfit for intense conditioning treatments, a widely accepted reduced-intensity conditioning regimen involves a lower dosage of intravenous busulfan combined with the purine analogue fludarabine [88]–[92].

Cyclophosphamide, a chemotherapy medication, has shown potential in enhancing the effectiveness of treatment for patients with acute lymphoblastic leukemia (ALL). Despite its promising results, there remains a lack of clarity when it comes to assessing the overall efficacy and safety of this drug for ALL patients [93], [94].

Doxorubicin has been proven to be a highly effective chemotherapy medication in the treatment of acute lymphoblastic leukemia (ALL) in children. However, recent developments in the form of bispecific antibodies (BsAbs) have further enhanced its effectiveness by improving its ability to target leukemia cell lines and patient samples. This is particularly beneficial as these samples often consist of varying immunophenotypes and represent high-risk subtypes of childhood leukemia. Moreover, the use of a clinically approved and low-toxic PEGylated liposomal formulation of doxorubicin, known as Caelyx, in combination with BsAbs has shown promising results in increasing the cytotoxic activity against these leukemia cells [95]–[97].

Asparaginase, an enzyme known for its ability to reduce the levels of the amino acid L-asparagine in the bloodstream, plays a crucial role in the treatment of acute lymphoblastic leukemia (ALL). By depriving leukemic cells of this amino acid, which they are unable to produce themselves, asparaginase effectively induces cell death. Moreover, this enzyme has the unique capability of reconfiguring the metabolic and energy-producing pathways within leukemia cells, thereby triggering both anti-leukemic and pro-survival mechanisms [98]–[100].

Tretinoin, also known as all-trans-retinoic acid (ATRA), is a medication utilized to induce remission in individuals diagnosed with acute promyelocytic leukemia (APL) who possess a specific gene mutation known as the t(15;17) translocation, resulting in the formation of the PML::RARα fusion gene. This medication is not prescribed for maintenance therapy. Researchers have examined the combination of arsenic trioxide and tretinoin (AsO/ATRA) as a potential treatment approach for APL. For individuals newly diagnosed with APL and exhibiting low-risk disease (with a white blood cell count [WBC] of ≤10,000/mcL), AsO/ATRA is the preferred induction regimen. Additionally, patients with high-risk disease (WBC >10,000/mcL) who are unable to tolerate anthracyclines are advised to undergo the AsO/ATRA induction regimen [101]–[103].

Imatinib, a targeted inhibitor of BCR-ABL1 kinase, has significantly enhanced the outlook for chronic myeloid leukemia (CML) patients. Examining the efficacy and safety data from over a decade of follow-up on CML patients treated with imatinib as their initial therapy, it is evident that imatinib’s effectiveness remains consistent over time. Furthermore, long-term use of imatinib does not lead to any concerning cumulative or delayed toxic effects [104], [105].

Idarubicin, an anthracycline medication, demonstrates remarkable efficacy in combating acute myeloid leukemia (AML). Its oral administration capability allows for the development of anti-leukemic treatment plans that can be conveniently administered via oral intake. This feature proves invaluable, particularly for elderly AML patients who are deemed unfit for conventional intensive therapies [106]–[108].

Etoposide, a potent anticancer medication, has demonstrated effectiveness as a standalone treatment for acute myeloid leukemia (AML). Nevertheless, the administration of high dosages or prolonged use of etoposide may lead to the development of therapy-related leukemia [109]–[111].

Thioguanine, a potent anti-cancer medication primarily utilized in leukemia treatment, is now being investigated through a study called Thiopurine Enhanced ALL Maintenance (TEAM). The objective of this study is to assess the potential enhancement in disease-free survival by incorporating a minute quantity of 6-thioguanine into the maintenance therapy based on 6-mercaptopurine/methotrexate. The study focuses on both pediatric and adult patients, ranging from 0 to 45 years of age, who have recently been diagnosed with B-cell precursor or T-cell acute lymphoblastic leukemia. These patients are being treated in accordance with the intermediate risk-high group of the ALLTogether1 protocol [86], [112]–[114].

The combination of arsenic trioxide and all-trans retinoic acid (ATRA) has proven to be highly effective in treating acute promyelocytic leukemia (APL), leading to significant advancements in patient outcomes. As a result, APL has emerged as the most easily treatable form of acute myeloid leukemia [101], [102], [115], [116].

Fludarabine, an antineoplastic drug, is widely employed in the management of hematological malignancies, specifically chronic lymphocytic leukemia (CLL) and indolent B-cell lymphoma. Due to its ability to suppress the immune system, fludarabine has been incorporated into reduced intensity conditioning regimens [27], [117]–[119].

Amsacrine, an antineoplastic agent, has shown promising results in treating acute leukemias. However, it is important to note that using Amsacrine-based induction therapy in patients with cardiac comorbidities should not be considered as an alternative to the standard induction treatment for acute myeloid leukemia (AML) [120]–[123].

Mitoxantrone is a potent therapeutic agent widely employed in the management of acute leukemia. In various clinical investigations involving individuals with refractory and relapsed acute myeloid leukemia (AML), a combination of Mitoxantrone and etoposide has been utilized, yielding notable rates of complete remission (CR) ranging from 16% to 61% [109], [124], [125].

Cytosine arabinoside, which is commonly referred to as cytarabine, holds significant value as a medication for addressing acute myeloid leukemia (AML). It plays a crucial role in induction therapy when combined with anthracyclines and in consolidation therapy at elevated doses for AML patients³. Although high-dose cytarabine (ranging from 2000 to 3000 mg per square meter of body-surface area) can be toxic, it yields superior rates of relapse-free survival compared to the traditional dosage of 100 to 400 mg per square meter [71], [126], [127].

The effectiveness of Recombinant Interleukin-3 (IL-3) in combating leukemia has been explored through research. Specifically, a new fusion protein called DT388IL3 has been developed for this purpose. DT388IL3 is a combination of the catalytic and translocation domains of diphtheria toxin (DT388) and human interleukin 3 (IL-3), connected by a Met-His linker. In order to assess its potential in treating differentiated human acute myeloid leukemia (AML), DT388IL3 was tested in an in vivo model [128]–[131].

Transplant conditioning stands as a critical component in the treatment procedure for leukemia. Prior to the transplant, medical professionals employ chemotherapy, radiation therapy, or a combination of the two, aiming to eliminate as many cancerous cells as feasible. This phase of treatment not only weakens the immune system to minimize the chances of transplant rejection but also creates space for the introduction of fresh stem cells. Conditioning regimens assume an integral role in the complete eradication of leukemic cells [88], [132]–[134].

Myeloablative conditioning is a preparative regimen employed prior to a stem cell transplant, aimed at achieving sufficient immunosuppression to prevent rejection of the transplanted graft and eliminate the underlying disease. When treating acute lymphoblastic leukemia (ALL), myeloablative conditioning typically involves the use of total-body irradiation (TBI) or busulfan. TBI-based regimens are particularly effective in eradicating leukemia cells in hard-to-reach areas, and as a result, cyclophosphamide and TBI are currently the preferred myeloablative regimen for ALL [132], [135]–[137].

The preparative regimen, also referred to as the conditioning regimen, plays a crucial role in the hematopoietic cell transplant (HCT) procedure. Its primary objectives are twofold: to ensure adequate immunosuppression to prevent the rejection of the transplanted graft and to eliminate the disease for which the transplant is being conducted. There are two main types of preparative regimens: standard-intensity and reduced-intensity. The standard-intensity regimen involves the administration of high doses of chemotherapy, sometimes combined with high doses of radiation, and is commonly known as a myeloablative regimen. On the other hand, the reduced-intensity regimen employs lower doses of chemotherapy, possibly with lower doses of radiation, and is commonly referred to as a non-myeloablative regimen [138].

Anthracyclines, which are chemotherapy drugs derived from various strains of Streptomyces bacteria, enjoy extensive usage in the treatment of a wide range of cancers. These include leukemias, lymphomas, as well as cancers affecting the breast, stomach, uterus, ovary, and lung, among other locations. The mechanism of action for anthracyclines involves the infliction of DNA damage upon cancer cells, ultimately leading to their demise before they can undergo cell division. Numerous variations of anthracycline drugs are employed in chemotherapy, with certain medications exhibiting remarkable efficacy in targeting specific cancer types [139].

Filgrastim is a pharmaceutical drug employed to bolster the production of white blood cells in individuals undergoing chemotherapy for acute myeloid leukemia (AML). Its purpose is twofold: to expedite recovery from fever and to minimize the risk of infection in patients with neutropenia resulting from specific types of chemotherapy, including those prescribed for AML [140].

Prednisolone, a potent steroid, serves a dual purpose in medical applications - combating leukemia cells and alleviating allergic reactions caused by certain chemotherapy medications. Its primary function is to curtail inflammation and modulate the body’s immune response. Prednisone, a popular glucocorticoid, has emerged as the standard treatment for individuals diagnosed with acute lymphoblastic leukemia (ALL). Typically administered for a duration of four consecutive weeks, it is complemented by a combination of other chemotherapy drugs [121], [141], [142].

Tyrosine kinase inhibitors (TKIs) are a class of drugs widely recognized as the standard treatment for chronic myeloid leukemia (CML). These medications function by deactivating the tyrosine kinase, which is produced by the BCR-ABL1 gene present in leukemia cells. By doing so, they effectively halt or slow down the abnormal production of white blood cells in the bone marrow. Notable examples of TKIs employed in the management of CML encompass Imatinib (Gleevec), Dasatinib (Sprycel), Nilotinib (Tasigna), Bosutinib (Bosulif), Ponatinib (Iclusig), and Asciminib (Scemblix) [15], [17], [143]–[145].

Azacitidine, a prescribed medication, serves as an effective remedy for specific leukemia forms, such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). This medication is specifically formulated to impede the excessive growth of leukemia cells while simultaneously promoting the production of healthy and fully functioning cells in the bone marrow. The primary objectives of this therapy encompass elevating blood cell counts, mitigating the susceptibility to infections, reducing the dependency on blood transfusions, and minimizing the risk of bleeding. Notably, Azacitidine is highly recommended as the initial course of treatment for elderly AML patients who are unsuitable candidates for intensive treatment regimens [146]–[148].

Clofarabine, a second-generation purine analog, is a highly effective medication prescribed for the treatment of acute lymphoblastic leukemia (ALL) in children and young adults, specifically those aged between 1 and 21 years, who have undergone at least two unsuccessful treatment methods. Typically administered as a last resort, this potent drug exerts its therapeutic effects by strongly impeding DNA synthesis while exhibiting a favorable pharmacologic profile [149], [150].

Aclarubicin is a pharmaceutical utilized for the therapeutic management of acute non-lymphocytic leukemia, a malignancy affecting the blood and bone marrow. In the context of acute myeloid leukemia (AML), this medication has been administered as an induction therapy for patients who have shown resistance to initial chemotherapy or have experienced a relapse [151], [152].

Dasatinib, a second-generation BCR-ABL1 kinase inhibitor, is an effective medication prescribed for the treatment of specific forms of leukemia, such as chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). It is particularly approved as an initial therapy for CML and for adult patients who no longer derive benefits from alternative leukemia medications, such as imatinib (Gleevec), or for those who are unable to tolerate them due to adverse reactions [153]–[155].

Tetradecanoylphorbol Acetate (TPA) is a highly effective tumor promoter frequently utilized in the field of biomedical research to activate the signal transduction enzyme protein kinase C (PKC)². Furthermore, TPA has demonstrated remarkable potential as a powerful inducer of differentiation in human promyelocytic leukemia cells¹. Notably, TPA has proven successful in treating patients with myelocytic leukemia, resulting in therapeutic effects and temporary remission. However, further investigation is required to determine the optimal dosing regimens of TPA and assess whether it can lead to long-lasting or even permanent remissions of myelocytic leukemia [156]–[158].

Venetoclax, a pharmaceutical medication, has obtained official approval for the treatment of newly diagnosed acute myeloid leukemia (AML). Specifically designed for individuals aged 75 years and older, as well as adults who are unable to undergo intensive induction chemotherapy, this drug is administered alongside azacitidine, decitabine, or low-dose cytarabine. Furthermore, Venetoclax has exhibited considerable potential in addressing AML cases characterized by heightened Bcl-2 levels [73], [107], [159].

Objectives

Despite the existence of various studies on useful drugs for leukemia, the reasons shown in Figure 1 have led to lack of comprehensive statistical research on the subject. The use of artificial intelligence, on the other hand, has been considered in various medical applications in recent years, from protein folding [160], medical imaging[161], [162], cohort studies[163], until core fundamental changes in neural networks[164].

The goal of this research is suggesting drug combinations to manage/treat Leukemia using the RAIN protocol, which employs artificial intelligence to recommend drug combinations for managing or treating diseases [165]. The RAIN protocol has been used in recent years to propose medicinal compounds for diseases such as cancers [165]–[170].