**2. Development of target therapy**

The outcome after revolution of target therapy was improved in lymphoma, myeloma and chronic leukemia. Imatinib as first generation of TKI has had an excellent outcome on chronic myeloid leukemia, bortezomib and rituximab, which has also high percentage of remission in myeloma and lymphoma, respectively [7, 8]. In patients with multiple myeloma preclinical studies have informed the rational use of combination therapies, such as bortezomib with lenalidomide to trigger both intrinsic and extrinsic apoptotic signaling [9].

Chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL) and idiopathic myelofibrosis (IM) fundamentally influence elderly patients, numerous of whom have therapeutic comorbidities that constrain the utilize of standard chemotherapy. Treatment with target therapy such as imatinib and rituximab are frequently less harmful and superior endured than conventional chemotherapy, advertising these patients extra treatment choices [10].

## **3. Acute myeloid leukemia (AML)**

The targeted therapy for patients with AML in recent years maybe most outstanding within the molecularly targeted *therapy* against its *specific* genetic abnormality of acute promyelocytic leukemia (APL). The initial (induction) *treatment of APL* with all-trans-retinoic acid (ATRA) play role in cells differentiation in patients with APL with *t*(*15*;*17*)(q22;q21) and has driven to disease-free survival and/or cure in 75% of patients with APL [11].

The introduction of ATRA in patients works to differentiation blast of acute promyelocytic leukemia (APL) to AML blast. The retinoic acid disorder is the most common complication characterized by fever, disseminated intravascular coagulation and cardiac, respiratory and renal function disorders. These disorders, which are seen in some patients, particularly patients associated with leukocytosis, can be treated or improved with chemotherapy or corticosteroids.

The current standard treatment of APL in induction and consolidation, include introduction of ATRA simultaneously with cytarabine and anthracycline and pursued by maintenance in combination with low-dose chemotherapy [12, 13].

**121**

**Table 1.**

*Target Therapy in Hematological Malignancies DOI: http://dx.doi.org/10.5772/intechopen.84696*

affectability according to type of target therapy [21].

and CD33+ treated with GO.

with CD33+.

Moreover, in an endeavor to maintain a strategic distance from routine chemotherapy, the addition of ATRA in combination with gemtuzumab ozogamicin has been utilized as induction with achievement of remissions (**Table 1**) [14]. Gemtuzumab ozogamicin (GO; Mylotarg) is a selective anti CD33 anti-body conjugated with calicheamicin facilitated against CD33 surface marker and communicated by more than 90% of myeloid leukemic blasts and is harmful to DNA calicheamicin. The overall response (OR) rate reported in 30% patients with AML

The rate of myelosuppression as common side effects of chemotherapy, was less with GO, in spite of the fact that acute *respiratory distress syndrome* and pulmonary edema have been experienced in patients with leukocytosis but less than 30,000/mL [15]. In May 2000, FDA have approved "GO" for patients above 60 years and after relapsing or for patients not fit for intensive chemotherapy [15–19]. On September 1, 2017, the (FDA) also approved "GO" for adult patients newly diagnosed AML

Ulocuplumab (BMS-936564/MDX-1338) may be a monoclonal antibodies agent which inhibits the official of the CXC chemokine receptor 4 (CXCR4) to fortify relocation from the bone marrow to peripheral blood stromal cell-derived chemokine CXC theme ligand 12 (CXCL12). In patients with refractory and relapsed AML, ulocuplumab in combination with mitoxantrone, etoposide and cytarabine driven to CR with partial recovery of bone marrow cell lines (CRi) in 51% patients studied [20]. The mutations of FLT 3 appear to be free destitute prognosticators in AML. The *Mutation in FLT3 gene* (FMS-like tyrosine kinase-3) occurs in 30% of FLT3-ITD and 7% of FLT3-TDK with AML. The FLT3 kinase inhibitors may be divided into 1st- and 2nd-generation drugs. 1st-generation: sorafenib, sunitinib, estaurtinib, midostaurin l, tandutinib, pacritinib; 2nd-generation: gliteritinib, quizartinib, crenolamid, ponatinib, JH-IX-179, PLX3397. The mutated *FLT3* gene has variable

Isocitrate dehydrogenase (IDH) takes place in lipid metabolism and the Krebs cycle, and it catalyzes the change of isocitrate to α-ketoglutarate. In AML the gene mutations IDH1 occur in 11% and IDH2 in 12% of cases. Enasidenib (AG-221/ CC-90007) is the first single-agent selective IDH2 inhibitor to induce the differentiation of leukemic cells and orally well tolerated. AML in patients with refractory or relapsed with mutant-*IDH2* induced hematologic responses, and have more than

9 months median survival reported after treatment with Enasidenib [22].

**Target Drug Group**

drugs CD33, CD3 AMG 330

FLT3 1st-generation: sorafenib, midostaurin, lestaurtinib, sunitinib,

tandutinib, pacritinib

gliteritinib, JH-IX-179

BCL2 Navitoclax, venetoclax

HDAC Pabinostat, vorinostat

Topoisomerase II Vosaroxin

*Targeted drugs in AML treatment.*

CD33 Gemtuzumab ozogamycin, lintuzumab, vadastuximab talirine High molecular mass

2nd-generation: quizartinib, crenolamid, ponatinib, PLX3397,

IDH Cenasidenib Cell pathway Inhibitors

LSD1 ORY-1001, GSK2879552 Epigenetic modulators

Tyrosine kinase inhibitors

*Target Therapy in Hematological Malignancies DOI: http://dx.doi.org/10.5772/intechopen.84696*

*Advances in Hematologic Malignancies*

Personalized targeted therapy is a drug that squares the cancer cells development by interfering with particular molecule needed for carcinogenesis and growth of tumors [2] instead of essentially interfering with quickly isolating dividing cells. The personalized target therapy for cancer diseases has been a noteworthy stimulus for the advancing field of pharmacogenomics. Moreover it is characterized as pharmacogenomics can envelop germline and significant (infection) gene and protein estimations utilized to expect the probability that a patient's tumor will react to an explicit singleagent or multiagent chemotherapy protocols and the chance of hurtful side effects [3]. Besides the *US Food and Drug Administration* (FDA) has considered target treatment as a personalized therapy approved and named with a specific reference to at the same time or as of now asserted illustrative test that must be performed some time recently

the persistent can be considered qualified to get the target therapy agents [4].

for patients who have gotten cancer target therapy [5, 6].

**2. Development of target therapy**

intrinsic and extrinsic apoptotic signaling [9].

**3. Acute myeloid leukemia (AML)**

in 75% of patients with APL [11].

advertising these patients extra treatment choices [10].

treated or improved with chemotherapy or corticosteroids.

Personalized targeted therapy begun modern transformation approximately the improvement of cancer treatment to a person patient's tumor, the financial matters of cancer care around the world. As expanded of analyzed patients with cancer and as these patients live longer, essential care clinics will make strides wellbeing care

The outcome after revolution of target therapy was improved in lymphoma, myeloma and chronic leukemia. Imatinib as first generation of TKI has had an excellent outcome on chronic myeloid leukemia, bortezomib and rituximab, which has also high percentage of remission in myeloma and lymphoma, respectively [7, 8]. In patients with multiple myeloma preclinical studies have informed the rational use of combination therapies, such as bortezomib with lenalidomide to trigger both

Chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL) and idiopathic myelofibrosis (IM) fundamentally influence elderly patients, numerous of whom have therapeutic comorbidities that constrain the utilize of standard chemotherapy. Treatment with target therapy such as imatinib and rituximab are frequently less harmful and superior endured than conventional chemotherapy,

The targeted therapy for patients with AML in recent years maybe most outstanding within the molecularly targeted *therapy* against its *specific* genetic abnormality of acute promyelocytic leukemia (APL). The initial (induction) *treatment of APL* with all-trans-retinoic acid (ATRA) play role in cells differentiation in patients with APL with *t*(*15*;*17*)(q22;q21) and has driven to disease-free survival and/or cure

The introduction of ATRA in patients works to differentiation blast of acute promyelocytic leukemia (APL) to AML blast. The retinoic acid disorder is the most common complication characterized by fever, disseminated intravascular coagulation and cardiac, respiratory and renal function disorders. These disorders, which are seen in some patients, particularly patients associated with leukocytosis, can be

The current standard treatment of APL in induction and consolidation, include

introduction of ATRA simultaneously with cytarabine and anthracycline and pursued by maintenance in combination with low-dose chemotherapy [12, 13].

**120**

Moreover, in an endeavor to maintain a strategic distance from routine chemotherapy, the addition of ATRA in combination with gemtuzumab ozogamicin has been utilized as induction with achievement of remissions (**Table 1**) [14]. Gemtuzumab ozogamicin (GO; Mylotarg) is a selective anti CD33 anti-body conjugated with calicheamicin facilitated against CD33 surface marker and communicated by more than 90% of myeloid leukemic blasts and is harmful to DNA calicheamicin. The overall response (OR) rate reported in 30% patients with AML and CD33+ treated with GO.

The rate of myelosuppression as common side effects of chemotherapy, was less with GO, in spite of the fact that acute *respiratory distress syndrome* and pulmonary edema have been experienced in patients with leukocytosis but less than 30,000/mL [15]. In May 2000, FDA have approved "GO" for patients above 60 years and after relapsing or for patients not fit for intensive chemotherapy [15–19]. On September 1, 2017, the (FDA) also approved "GO" for adult patients newly diagnosed AML with CD33+.

Ulocuplumab (BMS-936564/MDX-1338) may be a monoclonal antibodies agent which inhibits the official of the CXC chemokine receptor 4 (CXCR4) to fortify relocation from the bone marrow to peripheral blood stromal cell-derived chemokine CXC theme ligand 12 (CXCL12). In patients with refractory and relapsed AML, ulocuplumab in combination with mitoxantrone, etoposide and cytarabine driven to CR with partial recovery of bone marrow cell lines (CRi) in 51% patients studied [20].

The mutations of FLT 3 appear to be free destitute prognosticators in AML. The *Mutation in FLT3 gene* (FMS-like tyrosine kinase-3) occurs in 30% of FLT3-ITD and 7% of FLT3-TDK with AML. The FLT3 kinase inhibitors may be divided into 1st- and 2nd-generation drugs. 1st-generation: sorafenib, sunitinib, estaurtinib, midostaurin l, tandutinib, pacritinib; 2nd-generation: gliteritinib, quizartinib, crenolamid, ponatinib, JH-IX-179, PLX3397. The mutated *FLT3* gene has variable affectability according to type of target therapy [21].

Isocitrate dehydrogenase (IDH) takes place in lipid metabolism and the Krebs cycle, and it catalyzes the change of isocitrate to α-ketoglutarate. In AML the gene mutations IDH1 occur in 11% and IDH2 in 12% of cases. Enasidenib (AG-221/ CC-90007) is the first single-agent selective IDH2 inhibitor to induce the differentiation of leukemic cells and orally well tolerated. AML in patients with refractory or relapsed with mutant-*IDH2* induced hematologic responses, and have more than 9 months median survival reported after treatment with Enasidenib [22].


#### **Table 1.**

*Targeted drugs in AML treatment.*

Navitoclax is BCL2 inhibitor by ABT-199 with multiple anti-apoptotic of AML. Its antitumor activity is restricted by adverse effects, which is registered by the FDA for treating chronic lymphocytic leukemia (CLL) and AML [23].

Vosaroxin could be a topoisomerase II inhibitor which is one of the important randomized trials exploring therapeutic options for refractory and relapsed AML to date and considered basic for cell survival. Vosaroxin induces DNA destruction and is most successful among elderly patients more than 60 years of age with myelodysplastic disorder (MDS) or acute myeloid leukemia (AML) [24].

Lysine-specific demethylase 1 (LSD1) is a histone demethylase. LSD1 inhibition leads to the inhibition of growth and metastasis of tumor and also regulates the differentiation of stem cells and has potential novel treatment in acute myeloid leukemia (AML).

Panobinostat (LBH589) induces AML cell apoptosis in vitro by inhibiting the expression of repair proteins (e.g., BRCA1, CHK1 and RAD51), increasing the efficiency of cytarabine and daunorubicin, and it is promising in t(8;21) AML due to the pathological AML1/ETO protein that recruits histone deacetylases and in combination with Azacitidine (AZA) doubled the rate of response in high risk patients with CMML, MDS or AML not candidate for stem cell transplantation [25].

Vorinostat (suberoylanilidehydroxamic acid [SAHA]) advances cell cycle inhibition of growth and induces differentiation and cell apoptosis of AML and reported favorable overall survival in AML patients with FLT3 ITD mutations [26].
