Table 2.
Targeted therapy in acute lymphoblastic leukemia
| Group | Drug | Mechanism of action | usage |
|---|---|---|---|
| Kinase inhibitors [62] | Imatinib [63] | Binds to ATP binding site of ABL tyrosine kinase | Ph + ALL |
| Dasatinib [63] | Binds to ATP binding site of ABL tyrosine kinase. Also inhibits Serine kinase inhibitor | Ph + ALL. Useful in Imatinib resistant ALL. Also inhibits cKIT and PDGFRB | |
| MK0457 [64] | Binds to Aurora family serine-threonine kinases | Phase II study for T315I mutant CML and Ph + ALL | |
| Fms-like tyrosine kinase inhibitors (FLT3) inhibitors | Lestaurtinib (CEP-701) [65] | Inhibits FLT3, JAK2 and tropomyosin receptor kinases | FDA approved (Orphan drug) in AML |
| Sunitinib [66] | Targets receptors for PDGF and VEGF | FDA approved for Renal cell Carcinoma and imatinib resistant GIST | |
| Proteasome inhibitor [67] | Bortezomib (Velcade) [68] | Induces G2–M cell cycle arrest and apoptosis by causing Bcl-2 phosphorylation and cleavage | FDA approved for multiple myeloma |
| Carfilzomib [69] | Inhibits MAPK signaling, increased sensitivity to chemotherapy | FDA approved for multiple myeloma | |
| JAK2 inhibitor [70] | Ruxolitinib [71] | Binds JAK2 kinase domain in both wild and mutated JAK2 | FDA approved for intermediate & high risk myelofibrosis |
| Monoclonal antibodies [72] | Rituximab (Rituxan) [73] | Monoclonal Antibody against CD20. Direct signaling, complement dependent cellular cytotoxicity and antibody dependent cellular cytotoxicity | FDA approved in NHL |
| Epratuzumab [74] | Monoclonal Antibody against CD22. Antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and direct induction of apoptosis | Under clinical trial for ALL | |
| Blinatumomab [75] | Bispecific Ab (BiTE), T cell engager Ab, Directs CD3+ against CD19+ B-ALL | US FDA approved drug for B-ALL in first or second complete remission with MRD ≥ 0.1% | |
| Histone deacetylase inhibitors [76] | Depsipeptide (FK228) [77] | Synergistic with DNA methyl transferase inhibitors; Upregulates CDKN2A (p21). Down regulates cyclin D1 and D2 | FDA approved for CTCL |
| Vorinostat (Zolinza) [78] | Chelator for Zinc ions in active site of histone deacetylases | FDA approved for CTCL | |
| Nucleoside analogue [79] | Forodesine [80] | Purine nucleoside phosphorylase (PNP) inhibitor | Orphan drug designation for use in T-ALL |
| Clofarabine [81] | Deoxyadenosine analogue. Direct inhibition of DNA synthesis | US FDA approved to treat patients age 1 to 21, relapsed or refractory B-ALL | |
| Nelarabine [82] | Pro drug of ara-G | Approved third line treatment for T-ALL | |
| Gamma secretase inhibitors [83] | MK-0752 [84] | NOTCH1 inhibitor; in T-ALL | Phase I clinical trials for T-ALL |
| mTOR inhibitors | Sirolimus [85] | Induce cell cycle arrest | US FDA approved for lymphangioleiomyomatosis (LAM) |
| CDk4/6 inhibitors | Palbociclib [51] | Ensures inhibition of cyclin D1-CDK4/6 complex formation | FDA approved for HR+, Her2− breast carcinoma |