**5.2 Dasatinib (Sprycel)**

Dasatinib is approved in 2006 as a kinase inhibitor of thiazole carboximide agent and molecular formula C22H26CIN7O2S.H2O with highly powerful dual Abl/Src kinase inhibitor against most imatinib-resistant mutants. Dasatinib considering the excellent treatment option for CML cases in chronic phase and other CML phases who develop resistance or fails response to imatinib and for cases with Ph+ALL [39]. Dasatinib is more than 300 times as powerful as imatinib in restraining unmutated BCR-ABL transcripts in vitro. The incidence of resistance to dasatinib is less than other TKI and the disease progression may be reduced among CML cases treated with dasatinib [40].

### **5.3 Nilotinib (Tasigna)**

Nilotinib is a small molecule tyrosine kinase inhibitor in the form of hydrochloride monohydrate salt and is 20–30 times as potent as imatinib and can be replaced instead of imatinib. In 2007 nilotinib approved by (FDA) for utilize as a particular treatment for *Philadelphia chromosome-positive CML (Ph+CML).* Nilotinib was statistically superior in both complete cytogenetic response (CCyR) and major molecular response (MMR) (p < 0.001) [41].

### **5.4 Bosutinib (Bosulif )**

FDA approved bosutinib in September 2012, for adult patients with all phases of chronic myeloid leukemia confirmed positive BCR-ABL. Bosutinib is an oral double ABL/SRC kinase inhibitor that is dynamic against numerous BCR-ABL transformations related with imatinib resistance. Bosutinib had the lowest rates of severe side effects, except for diarrhea. In especially, severe cardiovascular side effects were significantly less common in the bosutinib. They experience not complicated to develop blast crisis and progress to accelerated phase in 4% of cases. The overall survival at 2 years were 97% [42].

The suggested dosage of bosutinib is 500 mg oral daily dose with nourishment. The treatment will be proceeded concurring to plan take after up until progression of disease or intolerance of drug.

#### **5.5 Ponatinib (Iclusig)**

Ponatinib is approved in December 2012 by the US-FDA as a third generation TKI. Ponatinib is indicated for all phases of CML patients develop resistant to nilotinib or dasatinib or not tolerate to nilotinib or dasatinib and for ALL patients with Philadelphia chromosome positive and resistant to imatinib, dasatinib or nilotinib.

Patients with severely leukocytosis and patients with monocytosis, are less response to tyrosine kinase inhibitors, and have a higher risk of transformation to accelerated and blast phase [43]. The dose of ponatinib recommended daily is 45 mg with modification according to side effects. The recommendations for treatment of CML according to European LeukemiaNet summarized in **Table 2**.

#### **5.6 Monitoring therapeutic response in CML**

The target treatment checking can be performing concurring to inquire about laboratory recommendations for scoring molecular response by utilizing either a cytogenetic or molecular tests, or both, depending on the open facilities. The molecular response to TKI treatment of patients with CML is exceptionally imperative component of CML management with standard take after up each 3 months agreeing to ELN guidelines to realize early molecular response playing an imperative part in helpful decision making (**Table 3**) [45].

The TKI response is the foremost vital prognostic figure. The forecast for CML patients in accelerated and blast phases (AP and BP) is less than that seen in chronic stage (CP). The treatment responses are characterized as optimal, suboptimal or failure. Complete remission accomplished with optimal response which is the most excellent result comparable with that of the common populace. Failure implies that the understanding ought to get a distinctive treatment to restrain the chance of progression of disease and death [46]. Fractional abatement or the problematic response is the intermediate zone between optimal response and failure and usually considered as "warning" for moving to moment line TKI **Table 3**.

**125**

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

2nd line, intolerance to

Second line, failure of imatinib first line

2nd line, dasatinib failure

3rd line, intolerance or failure to 2 TKIs

marrow metaphases by karyotyping.

2nd line, failure of nilotinib first line

the first TKI

as first line

**Table 2.**

**Table 3.**

daily)

major route CCA/Ph+)

HLA type patients and siblings

Bosutinib or Nilotinib or ponatinib

*CCA/Ph+; clonal chromosome abnormalities in Ph+ cells, alloSCT; allogenic stem cell transplantation.*

*Target therapy recommendations for chronic myeloid leukemia modified of Abdul Hamid et al. [34].*

**Complete hematological response (CHR):** complete blood counts normalization and spleen return to

**Complete cytogenetic response (CCyR)**: absence of Philadelphia chromosome (Ph) in 20 of 20 bone

**Major cytogenetic response (MCyR)**: presence of Philadelphia chromosome in 0–35% of 20 metaphases. **Molecular response**: by follow up of quantitative real time PCR (qRT-PCR) analysis, the *BCR-ABL1*/control gene transcript ratio is determined using the International Scale (IS) standardized baseline. ≥3log10 reduction

**Optimal response**: complete hematological response (CHR) and ≤65% Ph+ metaphases at 3 months of imatinib therapy, ≤35% Ph+ metaphases at 6 months, CCyR at 12 months and MMR at 18 months. **Suboptimal response:** There is no fulfilling criteria for either optimal response or failure. The suboptimal response according to ELN recommendations implies that the long term benefits of imatinib are doubtful. **Failure**: There is no complete hematological response at 3 months of imatinib therapy, >95% Ph+ metaphases at 6 months, >35% Ph+ metaphases at 12 months and no MMR at 18 months. Absence of CHR, BCR-ABL1

Any line, T315I mutation Ponatinib/omacitaxine; consider AlloSCT and search for an unrelated stem cell

consider AlloSCT

normal with disappearance of chronic myeloid leukemia (CML) manifestations

in *BCR-ABL1* transcripts (≤0.10% IS) is major molecular response (MMR).

mutations, clonal cytogenetic evolution, define failure at any time during treatment.

donor

**6. Chronic lymphocytic leukemia (CLL)**

**6.1 Treatment of chronic lymphoyctic leukemia**

and the male to female ratio 2:1 [47].

*Criteria of therapeutic response [44].*

Chronic lymphocytic leukemia (chronic lymphoid leukemia CLL), is a heterogeneous disease characterized by the proliferation of functionally incompetent in the peripheral blood, bone marrow, spleen and lymph nodes. CLL is a disease of adult the elder age group as with a median onset at initial diagnosis of 70 and 75 years old

First line Imatinib (400 mg daily) or nilotinib (300 mg twice daily) or dasatinib (100 mg

HLA type patients and siblings only in case of baseline warnings (high risk,

Anyone of the other TKIs approved first line (imatinib 400 mg twice daily,

Dasatinib or nilotinib or bosutinib 500 mg daily or ponatinib (45 mg daily)

Bosutinib or dasatinib or ponatinib; search for an unrelated stem cell donor;

HLA type patients and siblings; search for an unrelated stem cell donor;

Anyone of the remaining TKIs; alloSCT recommended in all eligible patients

nilotinib 400 mg twice daily, dasatinib (70 mg twice daily)

consider AlloSCT and prepare HLA type patients and siblings

The CLL disease extent and prognosis according to Rai and Binet staging systems. Early stages (0, I, II) and symptomatic patient keep for observation and


#### **Table 2.**

*Advances in Hematologic Malignancies*

molecular response (MMR) (p < 0.001) [41].

Nilotinib is a small molecule tyrosine kinase inhibitor in the form of hydrochloride monohydrate salt and is 20–30 times as potent as imatinib and can be replaced instead of imatinib. In 2007 nilotinib approved by (FDA) for utilize as a particular treatment for *Philadelphia chromosome-positive CML (Ph+CML).* Nilotinib was statistically superior in both complete cytogenetic response (CCyR) and major

FDA approved bosutinib in September 2012, for adult patients with all phases of chronic myeloid leukemia confirmed positive BCR-ABL. Bosutinib is an oral double ABL/SRC kinase inhibitor that is dynamic against numerous BCR-ABL transformations related with imatinib resistance. Bosutinib had the lowest rates of severe side effects, except for diarrhea. In especially, severe cardiovascular side effects were significantly less common in the bosutinib. They experience not complicated to develop blast crisis and progress to accelerated phase in 4% of cases. The overall

The suggested dosage of bosutinib is 500 mg oral daily dose with nourishment. The treatment will be proceeded concurring to plan take after up until progression

Ponatinib is approved in December 2012 by the US-FDA as a third generation TKI. Ponatinib is indicated for all phases of CML patients develop resistant to nilotinib or dasatinib or not tolerate to nilotinib or dasatinib and for ALL patients with Philadelphia chromosome positive and resistant to imatinib, dasatinib or nilotinib. Patients with severely leukocytosis and patients with monocytosis, are less response to tyrosine kinase inhibitors, and have a higher risk of transformation to accelerated and blast phase [43]. The dose of ponatinib recommended daily is 45 mg with modification according to side effects. The recommendations for treatment of

The target treatment checking can be performing concurring to inquire about laboratory recommendations for scoring molecular response by utilizing either a cytogenetic or molecular tests, or both, depending on the open facilities. The molecular response to TKI treatment of patients with CML is exceptionally imperative component of CML management with standard take after up each 3 months agreeing to ELN guidelines to realize early molecular response playing an impera-

The TKI response is the foremost vital prognostic figure. The forecast for CML patients in accelerated and blast phases (AP and BP) is less than that seen in chronic stage (CP). The treatment responses are characterized as optimal, suboptimal or failure. Complete remission accomplished with optimal response which is the most excellent result comparable with that of the common populace. Failure implies that the understanding ought to get a distinctive treatment to restrain the chance of progression of disease and death [46]. Fractional abatement or the problematic response is the intermediate zone between optimal response and failure and usually

CML according to European LeukemiaNet summarized in **Table 2**.

considered as "warning" for moving to moment line TKI **Table 3**.

**5.6 Monitoring therapeutic response in CML**

tive part in helpful decision making (**Table 3**) [45].

**5.3 Nilotinib (Tasigna)**

**5.4 Bosutinib (Bosulif )**

survival at 2 years were 97% [42].

of disease or intolerance of drug.

**5.5 Ponatinib (Iclusig)**

**124**

*Target therapy recommendations for chronic myeloid leukemia modified of Abdul Hamid et al. [34].*

**Complete hematological response (CHR):** complete blood counts normalization and spleen return to normal with disappearance of chronic myeloid leukemia (CML) manifestations

**Complete cytogenetic response (CCyR)**: absence of Philadelphia chromosome (Ph) in 20 of 20 bone marrow metaphases by karyotyping.

**Major cytogenetic response (MCyR)**: presence of Philadelphia chromosome in 0–35% of 20 metaphases. **Molecular response**: by follow up of quantitative real time PCR (qRT-PCR) analysis, the *BCR-ABL1*/control gene transcript ratio is determined using the International Scale (IS) standardized baseline. ≥3log10 reduction in *BCR-ABL1* transcripts (≤0.10% IS) is major molecular response (MMR).

**Optimal response**: complete hematological response (CHR) and ≤65% Ph+ metaphases at 3 months of imatinib therapy, ≤35% Ph+ metaphases at 6 months, CCyR at 12 months and MMR at 18 months. **Suboptimal response:** There is no fulfilling criteria for either optimal response or failure. The suboptimal response according to ELN recommendations implies that the long term benefits of imatinib are doubtful. **Failure**: There is no complete hematological response at 3 months of imatinib therapy, >95% Ph+ metaphases at 6 months, >35% Ph+ metaphases at 12 months and no MMR at 18 months. Absence of CHR, BCR-ABL1 mutations, clonal cytogenetic evolution, define failure at any time during treatment.

#### **Table 3.**

*Criteria of therapeutic response [44].*
