Review

. 2021 Dec 24;14(1):87.

doi: 10.3390/cancers14010087.

FDA-Approved Drugs for Hematological Malignancies-The Last Decade Review

Aleksandra Sochacka-Ćwikła¹, Marcin Mączyński¹, Andrzej Regiec¹

Affiliations

PMID: 35008250
PMCID: PMC8750348
DOI: 10.3390/cancers14010087

Review

FDA-Approved Drugs for Hematological Malignancies-The Last Decade Review

Aleksandra Sochacka-Ćwikła et al. Cancers (Basel). 2021.

. 2021 Dec 24;14(1):87.

doi: 10.3390/cancers14010087.

Authors

Aleksandra Sochacka-Ćwikła¹, Marcin Mączyński¹, Andrzej Regiec¹

Affiliation

¹ Department of Organic Chemistry and Drug Technology, Faculty of Pharmacy, Wroclaw Medical University, 211A Borowska Street, 50-556 Wroclaw, Poland.

PMID: 35008250
PMCID: PMC8750348
DOI: 10.3390/cancers14010087

Abstract

Hematological malignancies, also referred to as blood cancers, are a group of diseases involving abnormal cell growth and persisting in the blood, lymph nodes, or bone marrow. The development of new targeted therapies including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally, Chimeric Antigen Receptor T (CAR-T) cells has improved the clinical outcomes for blood cancers. In this review, we summarized 52 drugs that were divided into small molecule and macromolecule agents, approved by the Food and Drug Administration (FDA) in the period between 2011 and 2021 for the treatment of hematological malignancies. Forty of them have also been approved by the European Medicines Agency (EMA). We analyzed the FDA-approved drugs by investigating both their structures and mechanisms of action. It should be emphasized that the number of targeted drugs was significantly higher (46 drugs) than chemotherapy agents (6 drugs). We highlight recent advances in the design of drugs that are used to treat hematological malignancies, which make them more effective and less toxic.

Keywords: EMA; FDA; hematological malignancies; macromolecule agents; small molecule agents.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Mode of action of tyrosine kinase (TK) inhibitors such as non-receptor BTK and Src/Abl inhibitors. **BCR**: B-cell receptor. **RTK**: tyrosine kinase receptor. **RAF**: proto-oncogene serine/threonine-protein kinase. **MEK**: mitogen-activated protein kinase kinase. **ERK**: mitogen-activated protein kinase. **Src**: non-receptor Sarcoma kinase. Abl: Abelson kinase. **Rac**: Ras-related C3 botulinum toxin substrate. **JNK**: c-Jun N-terminal kinase. SYK: spleen tyrosine kinase. **BCAP**: B cell adapter for PI3K. **DAG**: diacylglycerol. **PKC**: protein kinase C. **IKK**: IκB kinase. **NF-κB**: nuclear factor kappa-light-chain-enhancer of activated B cells. **Lyn**: tyrosine-protein kinase Lyn. **BTK**: Bruton’s tyrosine kinase. **PLC**: phospholipase C. **IP3**: inositol trisphosphate. **NFAT**: nuclear factor of activated T-cells. Created with BioRender.com based on information in [37,38].

**Figure 2**
Schematic representation of the signaling pathways that can potentially be inhibited by multi kinase inhibitors. **BCR**: B-cell receptor. **PDGFR**: platelet-derived growth factor receptor. **FLT3**: FMS-like tyrosine kinase-3. **AXL**: AXL receptor tyrosine kinase. **ALK**: anaplastic lymphoma kinase. **VEGFR**: vascular endothelial growth factor receptor. **FGFR**: fibroblast growth factor receptor. **RET**: receptor tyrosine kinase rearranged during transfection. **c-Kit**: mast/stem cell growth factor receptor. **TIE2**: tunica interna endothelial cell kinase 2. **PI3K**: phosphatidylinositol 3-kinase. **PIP2**: phosphatidylinositol 4,5-bisphosphate. **PIP3**: phosphatidylinositol-3,4,5-trisphosphate. **PTEN**: phosphatase and tensin homolog deleted on chromosome ten. **PDK**: 3-phosphoinositide-dependent protein kinase. **AKT**: protein kinase B. mTORC1: mammalian target of rapamycin complex 1. **4E-BP1**: 4E-binding protein 1. **eIF4E**: eukaryotic translation initiation factor 4E. **S6K**: p70S6 kinase. S6: S6 protein. **RAF**: proto-oncogene serine/threonine-protein kinase. **MEK**: mitogen-activated protein kinase kinase. **ERK**: mitogen-activated protein kinase. **Src**: non-receptor Sarcoma kinase. **Abl**: Abelson kinase. **Rac**: Ras-related C3 botulinum toxin substrate. **JNK**: c-Jun N-terminal kinase. **CDK**: cyclin-dependent kinase. **SYK**: spleen tyrosine kinase. **BCAP**: B cell adapter for PI3K. **DAG**: diacylglycerol. **PKC**: protein kinase C. **IKK**: IκB kinase. **NF-κB**: nuclear factor kappa-light-chain-enhancer of activated B cells. **Lyn**: tyrosine-protein kinase Lyn. **BTK**: Bruton’s tyrosine kinase. **PLC**: phospholipase C. **IP3**: inositol trisphosphate. **NFAT**: nuclear factor of activated T-cells. Created with BioRender.com based on information in [37,38,50,51].

**Figure 3**
Mechanism of action of PI3K inhibitors. **RTK**: receptor tyrosine kinase. **PI3K**: phosphatidylinositol 3-kinase. **PIP2**: phosphatidylinositol 4,5-bisphosphate. **PIP3**: phosphatidylinositol-3,4,5-trisphosphate. **PTEN**: phosphatase and tensin homolog deleted on chromosome ten. **PDK**: 3-phosphoinositide-dependent protein kinase. **AKT**: protein kinase B. mTORC1: mammalian target of rapamycin complex 1. **4E-BP1**: 4E-binding protein 1. **eIF4E**: eukaryotic translation initiation factor 4E. **S6K**: p70S6 kinase. S6: S6 protein. Created with BioRender.com based on information in [51,79].

**Figure 4**
Mode of action of various enzymes inhibitors. **HDAC**: histone deacetylase. **RNMT**: RNA methyltransferase. **DNMT**: DNA methyltransferase. **EZH2**: enhancer of zeste homolog 2. **mIDH1**: mutant isocitrate dehydrogenase 1. **mIDH2**: mutant isocitrate dehydrogenase 2. **NADPH**: nicotinamide-adenine dinucleotide phosphate (reduced form). **NADP⁺**: nicotinamide-adenine dinucleotide phosphate. **αKG**: α-ketoglutarate. **D2-HG**: D-2-hydroxyglutarate. Me: methyl group. Ac: acetyl group. **DNA**: deoxyribonucleic acid. **tRNA**: transfer ribonucleic acid. Created with BioRender.com.

**Figure 5**
Glasdegib inhibition of the Hedgehog signaling pathway. HH: Hedgehog. **PTCH**: Patched receptor. **SMO**: smoothened receptor. **SUFU**: suppressor of fused protein. **GLI**: glioma-associated oncogene protein. **GLIr**: repressor form of GLI. Created with BioRender.com based on information in [128].

**Figure 6**
The four types of protein inhibitors in the treatment of hematological malignancies and their mechanisms of action. **BCL-2**: B-cell leukemia/lymphoma-2. **Bim**: BCL-2-like protein 11. **BAX**: BCL-2-associated X protein. **BAK**: BCL-2 antagonist/killer 1. **MOMP**: mitochondrial outer membrane permeabilization. **XPO1**: exportin-1. **TSP**: tumor suppressor protein. Ub: ubiquitin. **ADP**: adenosine diphosphate. Created with BioRender.com.

**Figure 7**
Schematic representation of major mechanisms of action for omacetaxine mepesuccinate. **BCR-ABL**: BCR-ABL fusion protein. **MCL1**: myeloid cell leukemia 1. **mRNA**: messenger ribonucleic acid. **tRNA**: transfer ribonucleic acid. **Hsp90**: heat shock protein 90. Created with BioRender.com.

**Figure 8**
Scheme of metabolism and mode of action of mercaptopurine (6-MP). **SLC**: solute carrier. **6-MP**: mercaptopurine. XO: xanthine oxidase. **TPMT**: thiopurine methyltransferase. **Me-MP**: methylmercaptopurine. **HPGRT**: hypoxanthine-guanine phosphoribosyltransferase. **TIMP**: thioinosine monophosphate. Me-TIMP: methyl thioinosine monophosphate. **IMPDH**: inosine monophosphate dehydrogenase. **6-TGMP**: 6-thioguanosine monophosphate. **6-TGDP**: 6-thioguanosine diphosphate. **6-dTGTP**: deoxy-6-thioguanine triphosphate. **6-TGTP**: 6-thioguanosine triphosphate. **Rac1**: ras-related C3 botulinum toxin substrate 1. **DNA**: deoxyribonucleic acid. **RNA**: ribonucleic acid. Created with BioRender.com based on information in [167].

**Figure 9**
Mode of action of monoclonal antibodies. **ADCC**: antibody-dependent cellular cytotoxicity. NK: natural killer. **ADCP**: antibody-dependent cellular phagocytosis. **CDC**: complement-dependent cytotoxicity. **mAb**: monoclonal antibody. **C1q**: complement component 1q. **PD-1**: programmed death-1 protein. **PD-L1**: programmed death ligand-1. **PD-1 Ab**: monoclonal antibody directed against PD-1. **TCR**: T-cell receptor. **MHC**: major histocompatibility complex. Created with BioRender.com based on information in [197].

**Figure 10**
Blinatumomab mechanism of action. **CD19**: cluster of differentiation 19. **CD3**: cluster of differentiation 3. **Gzm**: granzymes. PFN: perforin. **IFNγ**: interferon gamma. **TNFα**: tumor necrosis factor alpha. Created with BioRender.com.

**Figure 11**
General mechanism of action of antibody-drug conjugates. **ADC**: antibody-drug conjugate. Adapted from “Intracellular layout—endocytosis pathway,” by BioRender.com (2021). Retrieved from https://app.BioRender.com/biorender-templates (accessed on: 8 December 2021).

**Figure 12**
Intoxication of cell by moxetumomab pasudotox. **ADP**: adenosine diphosphate. **ADPr**: adenosine diphosphate ribose. **EF-2**: elongation factor-2. Figure based on the following reference [275]. Adapted from “Intracellular layout—endocytosis pathway,” by BioRender.com (2021). Retrieved from https://app.BioRender.com/biorender-templates (accessed on: 8 December 2021).

**Figure 13**
Schematic representation of mechanism of action for asparaginases such as asparaginase *Erwinia chrysanthemi* and calaspargase pegol-mknl. Created with BioRender.com.

**Figure 14**
The immune-mediated cytotoxic mechanism of CAR-T cell. **PFN**: perforin. **Gzm**: granzymes. **CD19**: cluster of differentiation 19. **IFNγ**: interferon gamma. **TNF**: tumor necrosis factor. **CAR-T**: chimeric antigen receptor T. Created with BioRender.com.

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FDA-Approved Drugs for Hematological Malignancies-The Last Decade Review

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FDA-Approved Drugs for Hematological Malignancies-The Last Decade Review

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