Satyajeet College Of Pharmacy, Mehkar.
Blood cancers, including Leukemia, lymphoma, and multiple myeloma, are complex hematologic malignancies posing significant global health challenges. Recent advancements in targeted therapies have transformed the treatment paradigm, offering precision-based solutions that disrupt specific molecular pathways while minimizing systemic toxicity. This article examines emerging targeted therapies, including tyrosine kinase inhibitors (TKIs), monoclonal antibodies, immune checkpoint inhibitors, bispecific T-cell engagers, and chimeric antigen receptor (CAR) T-cell therapies. These innovations have improved survival outcomes and quality of life for many patients, with notable successes in chronic myeloid leukemia and B-cell malignancies. Despite these advances, challenges remain. Resistance mechanisms, therapy-related toxicities, high costs, and limited accessibility hinder widespread adoption and long-term efficacy. Ongoing research aims to address these limitations through combination regimens, next-generation CAR-T technologies, and novel biomarkers for personalized treatment strategies. This review highlights the current landscape of targeted therapies, emphasizing both achievements and ongoing hurdles. It also explores future directions, such as integrating advanced genomic profiling and artificial intelligence to refine treatment algorithms. By synthesizing recent breakthroughs and identifying critical challenges, this article underscores the potential of targeted therapies to redefine blood cancer management and inspire further innovation in the field.
Hematologic malignancies, or blood cancer, are a broad category of tumors that start in the lymphatic or bone marrow. White blood cells, red blood cells, and platelets are among the blood cell types whose production and function may be impacted by these cancers. Leukemia, lymphoma, and multiple myeloma are examples of hematologic malignancies. The precise kind and stage of hematologic malignancies, in addition to the patient's unique circumstances, determine how they should be treated. Radiation treatment, chemotherapy, immunotherapy, targeted therapy, and stem cell transplantation are all options for treating these cancers. High-energy radiation is used in radiation treatment to target and destroy cancer cells. Chemotherapy uses powerful drugs to either kill or stop the growth of cancer cells.[1] One of the main causes of death in the world today is cancer. It occurs as a result of various bodily issues or illnesses that run in families. According to the World Health Organization (WHO), cancer is the leading cause of death for individuals under 70 in 112 out of 183 nations. Cancer is the third or fourth most common cause of mortality in at least 23 countries. The most prevalent forms of cancer have few effective treatments. Under a microscope, doctors typically examine small samples of tissue to screen for malignancy. However, this method of diagnosing cancer is costly, time-consuming, and occasionally results in an incorrect diagnosis. When aberrant cells multiply unchecked and have the capacity to spread throughout the body, cancer results. Nearly 10 million people died from cancer in 2020, with 19.3 million new cases reported. Each form of cancer has a different chance of survival. For instance, the mortality rates for stomach, breast, and liver cancer were 7.7%, 6.9%, and 8.3%, respectively, whereas the mortality rates from lung and colon cancer were 18% and 9.4%, respectively.([2] Leukemia, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma are among the illnesses that fall under the category of hematological cancers. Acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, and chronic lymphoblastic leukemia are all included in the word "leukaemia." These conditions can afflict children, young people, and the elderly, and their prevalence climbs with age. Acute or chronic diseases with side effects brought on by various treatments are distinct from liquid tumors that travel through the blood or lymphatic system. The way these diseases are treated differs greatly from that of solid tumors, just as they are unique entities. In 1999, leukemias and lymphomas made up around 8% of all adult cancer cases. Depending on the cancer, 5-year survival rates range from 47% to 95%.[3]
The combination of genetic and non-genetic alterations brought on by environmental variables that cause certain genes to be inappropriately activated or inactivated, resulting in neoplastic transformations or aberrant cell proliferation, is what causes cancers. Key cellular events that take place in the early phases of cancer development, as well as the internal and external stimuli that cause these alterations, are not fully understood.
When malignant forms of aberrant cell development develop in one or more body organs, a collection of at least a hundred disorders are collectively referred to as cancer. When the regular checks on cell development are eliminated by a sequence of genetic changes, cancer develops. To create tumors, these cancer cells keep dividing and growing. Adjacent structures may be invaded by cancer cells..[4]Over the past ten years, blood cancer has become a more serious issue, requiring early detection in order to provide prompt and efficient treatment. The current diagnosis approach is expensive and time-consuming and entails a number of tests and medical professionals. Establishing an automated diagnostic system is therefore essential for precise forecasts. The combination of machine learning with leukemia microarray gene data for blood cancer diagnosis is a specific area of attention in medical research Despite extensive research, further advancements are required to achieve the proper levels of efficacy and accuracy. A supervised machine-learning system for predicting blood cancer is presented in this paper. The 22,283-gene leukemia microarray gene data is used in this study. To get around problems with high-dimensional and unbalanced datasets, resampling is utilized. SMOTE-Tomek generates synthetic data to balance the dataset for each target class, and Chi2 selects the most crucial characteristics from 22,283 genes to train the learning models. A new weighted CNN model is put forth for classification, leveraging the capabilities of three distinct CNN models. Extensive tests are conducted on the datasets, including a performance comparison with the most cutting-edge methodologies, in order to assess the significance of the suggested strategy. When combined with SMOTE-Tomek and Chi2 approaches, weighted CNN outperforms other models, attaining an astounding 99.9?curacy rate. K-fold cross-validation results further support the superiority of the suggested model.[5]
Types of blood cancer:
There are mainly three types of blood cancer
Other types of blood cancer include myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN)
Leukaemia:
A frequent cancer in both children and adults, leukemia is brought on by changes in normal cell regulatory systems that lead to the unchecked growth of hematopoietic stem cells in the bone marrow. In the US, the annual age-adjusted incidence rate of leukemia is 12.8 per 100,000 people. Leukemia is more common in white people and men, and its prevalence rises with age. Leukemia affects about one in seventy people at some point in their lives. Primary care doctors most frequently deal with acute lymphoblastic, acute myelogenous, chronic lymphocytic, and chronic myelogenous leukemia. Family doctors should be qualified to provide the initial diagnostic assessment, identify the typical leukemia presentations, and know how to treat leukemia survivors. [6]
There are two types of leukemia: acute and chronic. Acute leukemias are distinguished by their fast growth and immature cell types (blasts), whereas chronic leukemias involve more mature cell types and progress more slowly.[7]
Lymphoma : Based on the normal counterpart, or cell of origin, from which they originate, lymphomas are a highly diverse collection of neoplastic illnesses of lymphocytes. The complexity of the physiologic processes by which common lymphoid precursor cells give rise to multiple lymphoid subsets that vary in lineage and degree of functional maturation to deliver the appropriate immune response at the appropriate time for the wide range of antigenic challenges the body must face is reflected in the diversity of lymphoma subtypes. To make matters more complicated, neoplasms can develop from cells of any of these lineages and stages of development. They can also develop as a result of the acquisition of various genetic abnormalities that contribute to their clinicopathologic characteristics. Lastly, albeit not entirely comprehended yet.[6]
Myeloma : The blood cancer known as myeloma, or more precisely multiple myeloma, arises in plasma cells, a type of white blood cell that makes antibodies. A variety of health problems are brought on by the unchecked proliferation of aberrant plasma cells in myeloma. Anemia, kidney failure, bone discomfort, and heightened vulnerability to infections are a few examples. Although the precise etiology of multiple myeloma is unknown, some risk factors, including age, family history, and chemical exposure, may make the disease more likely to develop. Usually, imaging scans, bone marrow biopsies, and blood tests are used to make the diagnosis.
1.2 rationale for targeted therapies
The secret to increasing overall survival and reducing the unfavorable side effects of cancer treatment is targeted therapy. When compared to patients without matched medicines, patients who received matched targeted therapy demonstrated significantly better overall survival (OS) and progression-free survival (PFS). The paradigm for treating cancer has shifted as a result of focused medicines. However, a lot of individuals become resistant to treatment and eventually pass away due to the growth of their tumors. The development of innovative therapy approaches that target cancers with particular molecular disturbances has advanced remarkably during the last few decades. For a subset of cancer types, including lung cancer, these new therapy options—known as targeted therapies—have changed the way that cancer is treated. The idea of combining targeted medicines with immunotherapy or conventional medications to maximize benefit has been bolstered by new findings.([8]) The primary methods of treating cancer are drug treatment, surgery, radiotherapy, and biotherapy. Chemotherapy, which involves using chemical drugs to kill tumor cells and/or stop their growth and proliferation, was the only method of cancer drug therapy for a long time due to its inability to distinguish between cancer cells and normal cells, which led to significant toxicity and side effects. Over the past 20 years, there has been a significant shift in cancer treatment from broad-spectrum cytotoxic drugs to targeted drugs.1 Compared to traditional chemotherapy drugs, targeted drugs can specifically target cancer cells while sparing normal cells, which results in their high potency and low toxicity. This has been encouraged by the approval of the first small-molecule tyrosine[9]
1.Overview of targeted therapies in blood cancer
molecular targeted therapies: These innovative treatments stop the growth, spread, and metastasis of cancer by interfering with particular molecules. The Food and Drug Administration (FDA) has approved a number of molecular targeted medicines that have shown impressive clinical performance in treating a wide range of cancer types, including lung, ovarian, colorectal, breast, and leukemia. Using medications or other substances that target particular molecules (molecular targets) to stop the growth and spread of cancer cells is known as molecular targeted therapy. Paul Rich first developed the idea of a "magic bullet" in late 1800, which served as the inspiration for focused therapy (Ehrlich, 1906). It was first employed to illustrate a chemical's capacity to selectively target bacteria, but the technique[10])
What is targeted therapy?
Targeted therapy is a medication used to limit the growth and spread of cancer by focusing on particular characteristics of the cancer cells. Although the medications circulate throughout the body, they function more precisely than chemotherapy and frequently have fewer adverse effects. However, not all cancer patients benefit from focused therapy.
How targeted therapy works?
The body produces new cells continuously to support growth, repair damaged tissue, and promote wound healing. Healthy cells divide and decompose in a systematic manner. Cancer cells are unique in that they continue to develop and proliferate more quickly than they should. This occurs as a result of modifications to the cancer cells' genes.[11]
Why targeted therapies are used in blood cancer?
Targeted therapies work by targeting specific proteins or genes that are involved in the growth and survival of cancer cells.
This approach can help to:
Block the growth of cancer cells: Targeted therapies can block the growth of cancer cells by inhibiting the activity of specific proteins or genes that are involved in cell growth and division.
Kill cancer cells: Targeted therapies can kill cancer cells by triggering programmed cell death (apoptosis) or by inhibiting the activity of proteins that are involved in cell survival.
Prevent the spread of cancer cells: Targeted therapies can prevent the spread of cancer cells by inhibiting the activity of proteins that are involved in cell migration and invasion.
list of targeted therapies in blood cancer:
Some examples of targeted therapies in blood cancer include :
Targeted therapies in specific hematologic malignancies:
• Monoclonal antibodies, chimeric antigen receptor T (CAR-T) cells, and small-molecule medications are examples of targeted therapy for hematologic malignancies, also known as blood cancers: Clinical results for blood malignancies have improved with aggressive therapy. Customized targeted therapies are anticipated to become increasingly more crucial in the near future for the treatment of hematological malignancies. When compared to conventional chemotherapy, targeted medicines have improved results and decreased side effects in both acute and chronic leukemias, drastically altering the treatment landscape.
Here’s an overview of some of the key therapies for both types:
Acute Leukemias:
Acute Lymphoblastic Leukemia (ALL):
Tyrosine Kinase Inhibitors (TKIs): For patients with Philadelphia chromosome-positive ALL, drugs like imatinib and dasatinib are used.
Monoclonal Antibodies: Blinatumomab (a bispecific T-cell engager) targets CD19 and can be used for relapsed or refractory ALL.
CAR T-Cell Therapy: Targeting CD19, this therapy has shown promise in treating relapsed/refractory cases.
Acute Myeloid Leukemia (AML):
FLT3 Inhibitors: Midostaurin and gilteritinib target FLT3 mutations common in AML.
IDH Inhibitors: Ivosidenib and enasidenib target IDH1 and IDH2 mutations,
respectively.
Hypomethylating Agents: Azacitidine and decitabine are used in older patients or those unfit for intensive chemotherapy.
Chronic Leukemias
Chronic Lymphocytic Leukemia (CLL):
BTK Inhibitors: Ibrutinib and acalabrutinib are used to inhibit Bruton's tyrosine kinase, which is crucial for CLL cell survival.
BCL-2 Inhibitors: Venetoclax targets BCL-2 and is particularly effective in combination with other therapies.
Monoclonal Antibodies: Agents like obinutuzumab and rituximab target CD20 on CLL cells.
Chronic Myeloid Leukemia (CML):
TKIs: Imatinib was the first TKI approved for CML, with newer options like dasatinib and nilotinib offering improved efficacy and resistance profiles.
Bosutinib and Ponatinib: These are used for patients with resistance to first-line TKIs or those with specific mutations.
Target Therapies For Lymphomas:
1. Monoclonal Antibodies
Rituximab (Rituxan): Targets CD20 on B cells; used in various B-cell lymphomas.
Obinutuzumab (Gazyva): A newer anti-CD20 antibody with improved efficacy.
Brentuximab vedotin (Adcetris): Targets CD30; used for Hodgkin lymphoma and anaplastic large cell lymphoma.
2. Small Molecule Inhibitors
Ibrutinib (Imbruvica): A Bruton's tyrosine kinase inhibitor; effective in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma.
Idelalisib (Zydelig): A PI3K delta inhibitor; used in relapsed CLL and follicular lymphoma.
Venetoclax (Venclexta): BCL-2 inhibitor; particularly effective in CLL and certain types of non-Hodgkin lymphoma.
3. CAR T-cell Therapy
Tisagenlecleucel (Kymriah): Approved for certain types of large B-cell lymphoma.
Axicabtagene ciloleucel (Yescarta): Another CAR T-cell therapy for large B-cell lymphoma.
4. Checkpoint Inhibitors
Nivolumab (Opdivo) and Pembrolizumab (Keytruda): PD-1 inhibitors used for Hodgkin lymphoma and other malignancies.
5. Combination Therapies
Many of these targeted therapies are used in combination with chemotherapy or other agents to enhance efficacy and improve outcomes.
Target therapies for myeloma:
Targeted therapies for lymphomas focus on specific molecular targets involved in the growth and survival of cancer cells. Here are some of the main types:
1. Monoclonal Antibodies
Rituximab: Targets CD20 on B cells, commonly used for non-Hodgkin lymphoma (NHL).
Obinutuzumab: A newer anti-CD20 antibody with enhanced efficacy.
Brentuximab vedotin: Targets CD30, used for Hodgkin lymphoma and anaplastic large cell lymphoma.
2. Small Molecule Inhibitors
Ibrutinib: A Bruton's tyrosine kinase (BTK) inhibitor used for chronic lymphocytic leukemia (CLL) and certain types of NHL.
Idelalisib: A PI3K inhibitor for CLL and indolent NHL.
Venetoclax: A BCL-2 inhibitor that promotes cancer cell death, mainly used in CLL.
3. CAR T-Cell Therapy
Axicabtagene ciloleucel (Yescarta) and Tisagenlecleucel (Kymriah): Engineered T cells targeting CD19, effective in certain aggressive B-cell lymphomas.
4. Checkpoint Inhibitors
Nivolumab and Pembrolizumab: PD-1 inhibitors used in relapsed or refractory Hodgkin lymphoma and some aggressive NHLs.
5. Epigenetic Modulators
Histone deacetylase inhibitors (HDAC inhibitors): Such as romidepsin and vorinostat, used in cutaneous T-cell lymphoma and peripheral T-cell lymphoma.
6. Combination Therapies
Combining targeted therapies with chemotherapy or immunotherapy to enhance efficacy.
5.Mechanism of resistance and stratergies to overcome it:
Changes to the pharmacological targets or changes to drug metabolism (sequestrations or improved detoxification) can result in both primary and acquired resistance (Gottesman, 2002; Gatti and Zunino, 2005; Teicher, 2006; Wilson et al., 2006; Ullah, 2008). Below is a synopsis of these mechanisms backed up by clinically relevant instances (Figure 1). The most researched type of resistance may be related to medication metabolism, including absorption.
efflux, and detoxification. Depending on their chemical makeup, medications enter cells primarily through the employment of transporters, which permit their cellular entry, or receptors, to which they bind and transfer their effects without entering the cell (Gottesman, 2002). At this stage, mutations that alter surface receptor and transporter activity or decrease their expression can lead to resistance. For example, impaired uptake of cyclopamine, nucleoside medications like cytarabine, and toxic folate analogs like methotrexate are caused by mutations or decreased expression of the extracellular receptor smoothened (Yauch et al., 2009; Atwood et al., 2012; Kasper and Toftgard, 2013), nucleoside transporters (Galmarini et al., 2001; Damaraju et al., 2003), or one or both folate transporters (Longo-Sorbello and Bertino, 2001). Conversely, higher expression of ATP binding cassette (ABC) membrane transporters is often responsible for improved drug efflux (Gottesman et al., 2002). P-gp (MDR1 gene product), Multidrug resistance-associated protein 1 (MRP1), and mitoxantrone resistance protein [MXR; also called breast cancer resistance protein (BCRP) or placenta ABC protein (ABCP)] are three of the 48 known ABC transporters in humans whose elevation has been linked to cancer chemoresistance to different drugs (Gottesman, 2002; Gottesman et al., 2002). For example, resistance to a number of hydrophobic anti-cancer medications, including vinblastine, doxorubicin, vincristine, and taxol, has been linked to increased expression of Pgp (Gottesman et al., 2002). However, MRP1 also carries negatively charged natural product medications. As is evident, these elements make up a significant area where medication resistance might arise. Many anti-cancer medications require metabolic activation in order to produce their cytotoxic effects. For example, deoxycytidine kinase must first phosphorylate cytarabine (also known as AraC), a nucleoside medication that is frequently used to treat acute myelogenous leukemia (Sampath et al., 2006), to cytarabinemonophosphate, which must then be phosphorylated to the active form cytarabine triphosphate. Cancer cells become resistant to these medications by decreasing their activation (Kufe and Spriggs, 1985; Bardenheuer et al., 2005). Enzymes implicated in this metabolic pathway, such as deoxycytidine kinase in the case of cytarabine, are downregulated or mutated to cause this (Sampath et al., 2006). GSH conjugation to platinum medicines, such oxaliplatin and cisplatin, which are used to treat different kinds of cancer, can also result in drug inactivation. This makes the drugs substrates for ABC transporters, which increases drug efflux (Meijer et al., 1992; Ishikawa and Ali-Osman, 1993). Additionally, it has been demonstrated that phase I drug metabolizing enzymes, CYP450, inactivate the topoisomerase I inhibitor irinotecan, which is used to treat colon cancer (Xu and VillalonaCalero, 2002). Lastly, another method of drug inactivation involves the binding of platinum medicines, especially cisplatin, to metallothionein (MT), a tiny cysteine-rich protein (Kelley et al., 1988; Kasahara et al., 1991). Many cancer cells develop an overreliance or dependency on an oncogene. This is referred to as oncogene addiction (Arber et al., 1997; Weinstein, 2002; Weinstein and Joe, 2006; Sharma and Settleman, 2007). Targeting such oncogenes, provided a basis for the development of targeted therapies. Examples of such targeted therapies include: (i) imatinib targeting BCR/ABL tyrosine kinase in CML (Hughes et al., 2003), (ii) gefitinib and erlotinib targeting the epidermal growth factor receptor (EGFR) tyrosine kinase domain in non-small cell lung carcinoma (Lynch et al., 2004; Shepherd et al., 2005; Taron et al., 2005), and (iii) trastuzumab targeting human epidermal growth factor receptor-2 (HER-2) receptor in breast carcinomas (Slamon et al., 2001; Piccart-Gebhart et al., 2005). Unfortunately, the long term effectiveness of these drugs is hindered by the development of drug resistance due to mutation of the targeted protein (Gioeli, 2011; Wong and Lee, 2012). Mutations at the gatekeeper residues of the kinase domain, which prevent drug binding, cause resistance to BCR/ABL and EGFR inhibitors (Gorre et al., 2001; Blencke et al., 2003; Kobayashi et al., 2005; Pao et al., 2005; Soverini et al., 2005; Balak et al., 2006; Jabbour et al., 2006, 2008; Nicolini et al., 2006; Apperley, 2007; Costa et al., 2007; Bean et al., 2008; Gioeli, 2011). Additionally, it has been shown that resistance mutations in tiny subpopulations of tumor cells can be identified before treatment, indicating that the targeted therapy was employed to select for these mutant forms (Hofmann et al., 2003; Toyooka et al., 2005; Inukai et al., 2006). Basically, knowing how changes in the target[13]
Emerging Therapies and Future Directions
The standard treatment for acute myeloid leukemia consists of remission induction with regimens combining cytarabine and anthracyclines, followed by consolidation therapy, which may include allogeneic stem cell transplantation, to extend remission. The use of innovative and successful target-directed treatments has significantly increased in recent years. Examples of these include the hedgehog pathway inhibitor glasdegib, the B-cell lymphoma 2 inhibitor venetoclax, and inhibitors of mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase (IDH). Venetoclax, when combined with a hypomethylating drug or low-dose cytarabine, produced composite response rates in older patients that were comparable to those obtained with conventional induction regimens in comparable groups, but with possibly lower toxicity and early mortality. Doublets of venetoclax with inhibitors that target these mutations have demonstrated encouraging clinical activity in early stage trials, and preclinical research points to a synergy between venetoclax and treatments that target FLT3 and IDH. Currently under evaluation are triplet regimens that include the TP53-modulating agent APR-246 and magrolimab, the hypomethylating agent and venetoclax with FLT3 or IDH1/2 inhibitor, myeloid cell leukemia-1 inhibitors, or immune therapies like CD123 antibody-drug conjugates and programmed cell death protein 1 inhibitors. When used in suitable patient subgroups, it is anticipated that these triplets will further increase remission rates and[14]
7 gene therapy and CRISPR
Treatment of several diseases could be revolutionized by the application of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) in cancer therapy. Targeting specific genetic alterations that fuel tumor growth and metastasis is one potential use of CRISPR technology in cancer research, which enables accurate and effective genome manipulation. The application of CRISPR-based gene editing in cancer treatment has been the subject of an increasing amount of research in recent years, with a number of preclinical investigations and clinical trials showing encouraging outcomes. A significant turning point in the field of genome editing was reached in 2012 with the discovery of CRISPR technology. The development of CRISPR tools for studying cancer biology is depicted in Figure 1. Cas9 and other CRISPR-associated enzymes can be programmed.[15]
CAR-T cell therapy innovation.
Designing and building new biological components, tools, and systems as well as redesigning existing biological systems are the primary goals of the burgeoning interdisciplinary area of synthetic biology. Understanding and producing biological events at the molecular level is the ultimate aim of synthetic biology. TCR-T therapy and CAR-T cell therapy are two examples of ACT research-engineered T cells that have gained attention as a result of developments in genetic engineering and synthetic biology. The process by which CARs recognize and attach to particular antigens is known as CAR-T cell therapy. by introducing CAR genes into the T cells, which leads to a more potent antitumor effect on the surfaces of tumor cells (6). A hinge region, transmembrane structural domains, an intracellular signaling peptide domain, and a singlechain variable fragment (scFv) antibody make up the structural components of the CAR. The single-chain variable region of a monoclonal antibody, which includes the light chain variable (VL) and heavy chain variable (VH) sections, is what makes up the scFv component. These areas are connected by a linker region. Tumor-associated antigen (TAA) recognition is the role of the scFv. The hinge region, which is made up of protein sequences from molecules including CD8 a, TCR b, and IgG, is situated between the structural transmembrane domain and the scFv component. The structural domain known as the transmembrane domain, which links the extracellular and intracellular portions of the CAR and guarantees the molecule's localization and stability in the T cell membrane, is generated from proteins like CD4, CD7, CD8, CD28, CD137, and CD3z. The activation signal generated by the interaction of the extracellular Tcell receptor (TCR) region with TAAs is transmitted to downstream targets within the cell by the intracellular signal peptide region, which is typically made up of co-stimulatory molecules (CMs) and immunoreceptor tyrosine-activated modulators (ITAMs), typically TCR/CD3z and Fc?RIg. Therefore, binding to target antigens expressed on the surface of tumor cells can activate CAR-T cells. TCR T cells and CAR-T cells differ primarily in that the former do not causing holes to be created in the cell membranes of the target tumor cells, and then the granzyme enters the target tumor cells through the holes, resulting in a chain reaction of cysteine-aspartate
proteases that cause the tumor cells to lysate, and the CAR-T can autocrine release cytokines to promote its own activity and regulate the tumor microenvironment. Alternatively, it can induce apoptosis of target cells via the Fas-FasL pathway through targeted binding of TNF ligand (tumor necrosis factor) on CAR-T cells[16]
A clinical trial for a cancer drug is developed and led by experienced doctors who specialize in cancer research. They decide on
{ The disease to be treated
{ The treatment that will be tested
{ The goal(s), sometimes called “end point(s),” of the study
{ The type of patient who will be an appropriate participant in the study
{ Ways to protect the patient’s safety
{ Drug dosages or whether other treatments will be given to patients in the trial
{ How long the treatment will be studied in the trial.
current clinical trials
it is divided into 4 phase.
Phase I
The purpose of the study is to
{ Test the safety of the treatment
{ Determine the maximum tolerated dosage/therapeutic dosage
{ Learn how the treatment affects the cancer and the side effects
of that treatment
Information About Phase 1
{ Small group of patients enroll (20 or more)
{ This could be the first time a drug or combination of drugs is tested
in humans; called “first in human”
{ This is the first time a drug is studied as a treatment for a particular
condition.
{ A drug already approved by the Food and Drug Administration (FDA) and in
use for treating one disease, can be tested and evaluated for the first time in
a different disease.
{ This is the first time a treatment administered in a particular regimen (for
example, in a new combination with other drugs) can be evaluated.
Phase 2
The purpose of the study is
{ To test the effectiveness and identify side effects.
Information About Phase II
{ Up to 300 patients enroll
{ This is the first time that doctors and researchers will be looking to see
whether the new drug treatment works for a specific cancer.
{ If the phase II trial shows that the treatment is safe and likely to work, the
drug treatment could be submitted for FDA approval.
{ If researchers are trying to compare the effects of the new drug or
treatment approach to the outcomes of standard treatment, further
research may be undertaken under phase III trial protocols. Research can
be moved to a phase III trial right away or at a later date.
Phase III
The purpose of the study is
{ To look at effectiveness, side effects and determine whether the drug is
beneficial to the specific disease population.
Table 1. Phases of Clinical Trials
Understanding Clinical Trials for Blood Cancers I 13
Information About Phase III
{ Between 300 and several thousand patients enroll
{ Phase III trials are structured so that researchers can determine whether
the study treatment is more effective than standard treatment, has fewer
side effects, or both.
{ A phase III trial looks at a number of different patient groups (referred to
as “arms”). Each patient group is associated with a specific drug treatment
regimen–a different treatment regimen is given to each group. Assigning
people to different groups is called “randomization.”
{ Phase III randomized trials are designed to be “single-blind,” “doubleblind,” or “open label” studies.
{ In a single-blind study, patients do not know whether they are receiving
the study treatment or the standard treatment.
{ In a double-blind study, neither the patients nor the clinicians (doctors
and/or nurses) treating the patients know which participants are receiving
what treatment. A double-blinded randomized study is considered the
gold standard of scientific evidence for a new treatment because this
type of study minimizes the possibility of unintended biases.
{ In an open label clinical trial, both the patient and the doctor and/or
nurse will know what treatment the patient is getting.
{ Not knowing which treatment group they have been assigned to can
be difficult for patients; however, blinded studies reduce the risk that
doctors will be biased in their evaluations of patient outcomes.
{ After the phase III trial is completed, the FDA reviews the trial results.
The FDA will then approve the new treatment if it is
{ More effective than standard treatment
{ Equally effective as standard treatment but has less toxic side effects.
Phase IV
The purpose of the study is
{ To gather long-term data on safety and effectiveness after FDA approval
and the drug is on the market.(16)
Real Evidences:
Real-world evidence (RWE) is increasingly shaping the landscape of targeted therapies for blood cancers, complementing clinical trial data and informing clinical practice. Below are key insights into the role and findings of RWE in this context:
Challenges and consideration:
Side effect and toxicity:
Targeted therapies for blood cancers, such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and CAR-T cell therapies, have revolutionized treatment but are associated with specific side effects and toxicities that vary by drug and mechanism of action. Here's a summary:
Common Side Effects and Toxicities
1.Cytokine Release Syndrome (CRS):
Often seen with immune-based treatments such as bispecific antibodies and CAR-T cells. From mild fever and exhaustion to severe hypotension and organ malfunction, symptoms can vary widely. Excessive immunological activation causes CRS, which needs to be closely watched and managed, frequently with tocilizumab or steroids
2.Neurotoxicity:
Also referred to as immunological effector cell-associated neurotoxicity syndrome (ICANS), it primarily affects CAR-T cell recipients and presents as aphasia, seizures, or confusion. The severity of CRS is correlated with its occurrence.
3.Cardiotoxicity:
Protease inhibitors and anthracyclines are examples of targeted agents that can result in arrhythmias or heart failure. Cardiovascular monitoring is necessary since TKIs (like imatinib) can cause hypertension or left ventricular dysfunction.
4.Hematologic Toxicity:
Anemia, neutropenia, or thrombocytopenia may result from these treatments' suppression of bone marrow activity. These consequences increase the risk of bleeding and infections.
5.Off-Target Effects:
Normal cells may be impacted by TKIs, which could result in adverse effects such skin rashes, diarrhea, or elevated liver enzymes. Monoclonal antibodies may result in hypogammaglobulinemia, exhaustion, or infusion reactions.
6.Specific Toxicities of Emerging Therapies:
Bispecific antibodies (e.g., CD3×CD20): Lower rates of CRS and neurotoxicity compared to CAR-T cells, but still significant in heavily pre-treated patients Antibody-drug conjugates: Linked to cytopenias, neuropathy, and gastrointestinal side effects due to payload delivery
Management Strategies
These side effects underscore the importance of personalized treatment planning, balancing efficacy with toxicity management. Clinicians rely on evolving guidelines and real-world evidence to mitigate risks while optimizing outcomes.[17]
Conclusion And Future Prospective:
CONCLUSION
With alternatives more selective and effective than conventional chemotherapy, targeted treatments have completely changed the treatment landscape for blood malignancies. Many patients' lifespan and quality of life have been enhanced by medications such tyrosine kinase inhibitors, monoclonal antibodies, CAR-T cells, and bispecific antibodies. Drug resistance, off-target effects, and accessibility are still major problems in spite of these developments. Although the use of biomarkers in clinical practice has improved the accuracy of these treatments, it also highlights the need for more study on tumor heterogeneity and changing resistance mechanisms.
Future Perspectives
REFERENCES
Sanchit Armal*, Radheshyam Azade, Om Avhale, Prashant Ingle, Dr. Shivshankar Mhaske, Targeted Therapies in Blood Cancer, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 1, 1531-1544. https://doi.org/10.5281/zenodo.14688977
10.5281/zenodo.14688977
