**4. Treatment of CML**

Therapy for treatment of CML developed very slowly. Heinrich Lissauer, in 1865, described the use of arsenic in two leukemia patients [42], nothing new in view of the fact that the use of arsenic for cancer therapy had been described in the Indian Ramayana more than 2000 years earlier [43].

In the 1920s, radiotherapy entered clinical practice, and it was soon used for the treatment of CML, and for over 50 years, radiotherapy was considered the standard treatment. Radiation was usually directed to the spleen for symptomatic relief [43–45].

After the Second World War, there was the rapid development of alkylating agents. Thus, busulfan largely replaced radiotherapy in the 1960s. Later, hydroxyurea (hydroxycarbamide) was introduced in the USA (United States of America). Prospective studies showed that patients treated with hydroxyurea survived longer than those treated with busulfan. However, it was not clear whether this was due to the beneficial effect of hydroxyurea or a mitogenic effect of busulfan [44].

In the early 1980s, interferon-α (IFN-α) was introduced for the treatment of CP-CML. Few patients achieved any level of Ph-negative hematopoiesis, and others achieved a complete and lasting Ph-negative hematopoiesis. In rare cases, IFN-α may be discontinued without subsequent relapse. Thus, IFN-α replaced busulfan

and hydroxyurea in the treatment of CP-CML if the patient was not eligible for allogeneic BM transplantation [46].

In 1979, Fefer and colleagues treated four CP-CML patients with high doses of chemoradiotherapy, followed by transfusion of stem cells from their genetically identical twins [47]. At follow-up intervals of 22–31 months, these patients remained well absent of Ph-positive metaphases in their marrow. The previously fatal leukemia brought the possibility of treatment and cure through BM transplantation [45].

Researchers began to treat CP-CML patients with allogeneic BM transplantation between identical HLA siblings. In the beginning, conditioning consisted of the use of cyclophosphamide and full body irradiation. However, years later, it was decided to use busulfan with cyclophosphamide [48]. According to the Center for International Blood & Marrow Transplant Research, allograft-associated transplant-related mortality for CP-CML patients is about 10–20% at 1 year, and the survival at 5 years is about 60% [49]. Most survivors have no evidence of leukemia, but occasional patients relapse early after transplantation [44].

Thus, from the 1990s, the treatment of choice for all relatively young CP-CML patients (under 50 years old) was an allogeneic stem cell transplant (SCT). In France, patients with CML who were not eligible for allograft were treated with IFN-α plus cytarabine [50], although more recent data from Italy cast doubt on this conclusion [51].

#### **4.1 Tyrosine kinase inhibitors**

Accumulated knowledge of action mechanism of BCR-ABL was sufficient to initiate experiments with target molecule designs to be used in the treatment of CML. From the knowledge that tyrosine kinase is the effective portion of oncoprotein, it was evident that its inhibition would be the most attractive target as a therapeutic strategy. The goal was to design a small chemical compound that would compete with ATP binding at the kinase domain site. Thus, with this site occupied by an "ATP-like" molecule, it would not be possible to provide any phosphate group for substrate transfer. With this, the tyrosine residues would remain in the "non-phosphorylated" form, and the protein substrate would not be able to change its conformation so that it could be associated with the effectors described above, resulting in the interruption of oncogenetic signals to the nucleus of cell.

This "ATP-like" molecule, known as imatinib, revolutionized the treatment in oncology and specifically of CML, opening the "era of targeted specific therapy." One of the first studies on the effectiveness of imabinib treatment (the International Randomized Study of Interferon and STI571 [IRIS] trial) estimated the rate of complete cytogenetic response (CCyR) at 12 months in the imatinib arm was 69%. Such responses are in relation to the standard treatment of the time (IFN-α and cytarabine) [52].

One of the last IRIS updates showed an estimated overall survival (OS) rate of 83% at 10 years (20.1% of patients had unknown survival status when data was analyzed). It should be mentioned that, despite these excellent results, 31 and 52% of patients assigned to imatinib discontinued treatment by 5 and 10 years of follow-up, respectively. The main cause of treatment discontinuation was the unsatisfactory therapeutic effect (11%), while only 4% of patients discontinued treatment due to side effects [53].

Treatment with imatinib induces a hematological response in 90% of patients diagnosed in the CP and a cytogenetic response in 80% of them, which made bone

#### *Chronic Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.90604*

marrow transplantation, the only curative treatment for CML, to be indicated only in those patients who develop imatinib resistance, observed in 20–25% of cases [52].

Known mechanisms of imatinib resistance include the presence of mutation point in the BCR-ABL tyrosine kinase domain, amplification of the BCR-ABL gene, overexpression of the multidrug resistance gene known as P-glycoprotein, and low expression of pickup transporters such as SLC22A1 (hOCT1) [54].

The second generation TKIs (2GTKIs), dasatinib, nilotinib, and bosutinib, were initially approved in CML patients who were resistant or intolerant to imatinib. Due to a more potent in vitro inhibition of the unmutated BCR-ABL kinase with a good safety profile, these second generation TKIs were later evaluated and approved in the first-line setting [55].

Dasatinib is an oral, second generation TKI that is 350 times more potent than imatinib in vitro. It also inhibits the Src family of kinases, which may be important in blunting critical cell signaling pathways [56]. Compared to the structure analog of imatinib, nilotinib's affinity for the ATP-binding site on BCR-ABL1 is 30–50 times more potent in vitro [57]. Like dasatinib, nilotinib initially demonstrated the ability to induce hematologic and cytogenetic responses in patients who had failed imatinib [56]. Bosutinib appeared to retain activity across most known mutations that confer imatinib resistance, except for T315I. Responses were independent of whether patients had resistance to or intolerance of imatinib [56].

A subset of patients with CML exhibited either primary or secondary resistance to imatinib. Primary resistance refers to patients never responding to imatinib, whereas secondary resistance occurs when a patient who had an initial response to imatinib eventually loses the response [36]. Although a significant proportion of patients respond to 2GTKI therapy after imatinib failure, most of them (70%, approximately) will eventually discontinue such treatment in the short term due to loss of response or toxicity [55].

There are many treatment mechanisms of resistance, and several of them, mostly in vitro or in selected patient samples, have been reported. However, their individual contribution to this phenomenon has not been completely defined. The most frequently identified mechanism of resistance is the development of mutations in the ABL tyrosine kinase domain [55].

A third generation TKI, ponatinib, is approved in CML patients with refractory CML or Ph-positive acute lymphoblastic leukemia (Ph + ALL) and those harboring the BCR-ABL1T315I mutant [58]. Clinical trials using the approved dose of 45 mg/ day of ponatinib show the main concern with this drug is the increased incidence of cardiovascular complications [55]. **Table 1** shows the target recommendations for CML, according to the American Cancer Society.


#### **Table 1.**

*Target recommendations for CML [4].*

#### *4.1.1 Definition of therapeutic response*

The quality of response to TKI treatment is categorized according to the laboratory method used. Patients are monitored by hematological, cytogenetic, and molecular response, and their terminology has been standardized by the European Leukemia Net [59].

Hematologic response is defined by the presence of platelets <450 × 109 L, without differential immature granulocytes and <5% basophils, and a non-palpable spleen. Cytogenetic response (CyR) is defined according to the proportion of positive Philadelphia chromosome (Ph +) in bone marrow cells. The association between CyR and improved survival made the cytogenetic response the gold standard of CML therapy [36]. **Table 2** shows the cytogenetic response definition.

The IRIS study, conducted in 2003, defined two types of molecular response assessed by real-time PCR: major molecular remission (MMR) and complete molecular remission (CMR). Major molecular remission is defined as a three-log drop of the initial load of BCR-ABL at the time of diagnosis; this value is equal to or less than 0.1%. Complete molecular remission is defined when the BCR-ABL transcript is undetectable [60].

Response to treatment is monitored during the first 3 months through clinical evaluation, blood count, and biochemical exams every 2 weeks. After the third month, cytogenetics is recommended every 6 months until complete CCyR is achieved. From the moment the patient reaches CCyR (Ph + 0%), monitoring is performed through real-time PCR quarterly to detect minimal residual disease [61].

#### **4.2 Allogeneic stem cell transplantation**

For patients who fail frontline therapy, the second-line options include second and third generation TKIs. Even though second and third generation TKIs are potent and selective TKIs, some patients still do not respond to treatment. Allogeneic stem cell transplantation (allo-SCT) remains an important therapeutic option for patients with CML-CP who have failed at least two TKIs and for all patients in advanced phase disease [56].

Patients exposed primarily to TKI treatment do not respond negatively to allo-SCT. Conversely, if patients referred for transplant have the lower CML burden, they may respond better to allo-SCT [62].

Allo-SCT is the only treatment with healing potential. However, it remains associated with substantial risks of morbidity and mortality. For appropriate counselling of patients, a rapid and simple way to assess risk is needed [63]. Pre-allo-SCT risk factors for CML are donor type, disease stage, recipient age, recipient-donor gender combination, and, lastly, time between diagnosis and allo-SCT. **Table 3** presents the risk factors for allo-STC [63–67].


#### **Table 2.**

*Cytogenetic response definition [59].*


#### **Table 3.**

*Risk factors for allo-STC [63–67].*

In the era of TKIs, there is no doubt for the first-line treatment for CML patients. But when allo-SCT is indicated, this scoring system is still of great value in estimating overall disease-free survival and procedure-related mortality.

When considering allo-SCT for CML patients, it is important to know that a poor response to one or more TKIs does not predict a negative transplant response. TKIs pharmacologically block BCR-ABL activity, while allo-SCT depends on graftversus-leukemia (GVL) effect [68].

The challenge of allo-SCT for treatment of leukemia and other malignancies of the hematopoietic system is the prevention of graft-versus-host disease (GVHD) without losing the GVL effect. Depletion of T cells abrogates GVHD and GVL effects. Delayed transfusion of donor lymphocytes into chimeras after T-cell-depleted stem cell transplantation produces a GVL effect without necessarily producing GVHD [69].

Allo-SCT should not be seen as a last resort but as a treatment strategy to be considered viable at the beginning of treatment for patients who have suboptimal responses to TKIs. The key issues for HSCT in CML are those of patient selection, risk stratification, and outcome optimization by means of regimen selection and improved supportive care [68].

#### **5. Conclusions**

CML is a myeloproliferative disease, resulting from clonal expansion of hematopoietic progenitor stem cells, characterized by *BCR-ABL* fusion gene, resulting from reciprocal translocation t (9; 22) (q34; q11) that gives rise to Ph chromosome. All the accumulated knowledge about action mechanisms of BCR-ABL1 has enabled the development of very efficient target-specific drugs, as well as molecular methods for disease monitoring.

Allo-SCT is a possible cure for CML; however, it is associated with mortality and morbidity increased due to complications in the pre- and posttransplantation periods, such as GVHD, immunosuppression, and multiple organ toxicity.

Although great progress has been made for the improvement in clinical treatment during the past decades, it is common for patients to develop resistance to treatments. Therefore, further exploring the novel therapeutic strategies is still crucial for improving disease outcome.
