**5. Conventional therapeutic approaches and novel agents in future development**

The treatment of AML comprises of two phases, initially induction therapy to achieve complete response and consolidation therapy after achieving CR.

#### **5.1. Induction therapy**

low for meaningful analysis, in particular to compare the different post-remission strategies (chemotherapy versus autologous SCT versus allogeneic SCT) [74]. Therefore, the prognostic

MLL partial tandem duplication (PTD) is exclusively found in normal karyotype (CN)-AML with an incidence reported from 5% to 11%. There are no clinical features differentiating MLL-PTD positive versus MLL wild-type patients [78]. Approximately 30–40% of MLL-PTDpositive patients consist of FLT3-ITD mutations, whereas combined existence of CEBPA with NPM1 mutations is rare. MLL-PTD is linked with shorter complete remission duration or worse RFS; however, in these studies, MLL-PTD did not show any effect on OS [77]. Recently, the CALGB reported relationship of MLL-PTD in young adults who received autologous SCT in the first complete remission. Clinical outcomes between the MLL-PTD-positive and the MLL wild-type groups were equivalent. WT1 mutations were reported in 10–12.6% in CN-AML. However, variable results have been mentioned about the prognostic significance of WT1 mutations. Both CALGB and MRC studies reported the prognostic impact of WT1 mutations in young adults with CN-AML. In both studies, patients with WT1 mutations were an independent adverse prognostic factor with inferior RFS and OS in multivariate analysis. This is in contrast to the findings of Gaidzik et al. who did not observe any decreased RFS and OS in relation with WT1 mutations on RFS and OS neither in univariate nor multivariate analysis. Of note, when performing exploratory subset analysis on FLT3-ITD samples, the WT1mut/FLT3-ITD pos genotype appeared to be associated with worse clinical course. One major difference between the three studies is different doses of cytarabine used. Cumulative dose of cytarabine was significantly higher in the trial reported by Gaidzik et al. (in preparation), suggesting that the negative impact ofWT1 mutations reported by others may be overcome by the use of high-dose cumulative cytarabine. On the basis of the current data, the prognostic impact of WT1 mutation remains unclear and its impact on treatment remains to

Although the majority of studied related to CN patients contained at least one of the already mentioned genetic alterations. In a study of AML done by one group, almost a quarter of patients did not have FLT3-ITD, FLT3-TKD, MLL-PTD, or mutations in the CEBPA or NPM1 genes [77]. Thus, it is likely that unidentified novel gene mutations and/or abnormal gene expression with prognostic significance will be discovered in the future. Expression of the meningioma 1 (MN1) gene might become such a novel prognostic factor. Same group in study reported also high expression of the MN1 gene related to inferior RFS and OS and a higher risk of relapse in CN aged 60 years or younger with de novo or secondary AML. This observa-

**5. Conventional therapeutic approaches and novel agents in future** 

The treatment of AML comprises of two phases, initially induction therapy to achieve com-

marker CEBPA mut cannot actually be used as a predictive marker.

be elucidated in future studies.

74 Myeloid Leukemia

**development**

tion needs confirmation before implementation.

plete response and consolidation therapy after achieving CR.

The primary objective of induction therapy is attainment of normal bone marrow function. The criteria of CR are a platelet count of >100 × 109/L, neutrophil count of >1 × 109/L and a bone marrow examination with <5% blasts. Patients with persistent >5% blasts in the bone marrow following induction chemotherapy have a poor overall survival (OS) [79, 80]. Despite multiple trials, the standard remission induction therapy consisting of three daily infusions of an anthracycline and cytarabine given as continuous infusion for 7 days (7 + 3 regimen) has not changed much over the years.

#### **5.2. Post-remission consolidation chemotherapy**

After achieving complete remission(CR) after induction therapy, disease relapse is a certainly virtual. Median disease-free survival (DFS) in this circumstance is estimated at only 4–8 months. Options for post-remission consolidation therapy include high-dose chemotherapy allogeneic HSCT [81].

#### **5.3. Response assessment**

After conventional induction therapy with 3 days of an anthracycline and 7 days of cytarabine ("3 + 7") or other recommended regimens according to guidelines, response assessment is commonly performed between day 21 and 28 after the start of therapy [81].

#### **5.4. Response assessment during follow-up period**

Repeat bone marrow examination is recommended every 3 months for the first 2 years; in some cases, it continues every 6 months for the following 2–3 years. Most relapses occur within 1–3 years after the completion of treatment. Standardized schedule is necessary if MRD monitoring is advised. Blood counts should be repeated every 1–3 months for the initial 2 years and then every 3–6 months up to 5 years [77].

#### **5.5. Role of HSCT as a consolidation strategy**

Prospective single institution studies comparing allogeneic HSCT as a consolidation treatment in the 1980s and the early 1990s showed lower relapse rates of 181 and improved DFS with allogeneic HSCT in AML patients in CR1, but none conclusively demonstrated a survival advantage [81]. Subsequently, six cooperative group trials prospectively addressed the role of HSCT in AML in CR1 in 1995 [91]. Patients with HLA-identical sibling donors were offered allogeneic transplantation ("Genetic randomization"). Remaining patients were randomized to autologous transplantation, intensive consolidation chemotherapy (ICC) or (depending on individual trial design) no further treatment.

Among these trials, the landmark European Organization for Research and Treatment of Cancer (EORTC)-Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) trial showed superior 4-year leukemia-free survival (LFS) with allogeneic (55%) and autologous (48%) HSCT compared to ICC (30%) [81]. However, despite this improved LFS and higher relapse rate in patients getting ICC, OS was similar in the three groups, since majority of patients relapsing after ICC successfully salvaged with autologous HSCT.

**7. Conclusion**

eases and poor cytogenetic features.

**Author details**

**References**

2007;**138**:687-699

Zeeshan Ansar Ahmed1

AML is a biologically and clinically heterogeneous disease. Established therapies have given some survival benefit according to risk stratification but overall long-term survival remains poor. Most of the patients on diagnosis are elderly, and they have adverse cytogenetic profile. At the same time, these patients are susceptible for transplant-related complications. The novel targeted therapies may have a good antileukemic activity with reduced toxicity versus available chemotherapeutic options. However, given the molecular diversity of AML, it is unlikely that targeted therapies such as FLT3 tyrosine kinase inhibitors will provide a sole treatment option in FLT3-mutated patients. With improved diagnostic genetic profiling, risk

Genomics of Acute Myeloid Leukemia http://dx.doi.org/10.5772/intechopen.72757 77

Furthermore, the identification of cell-specific surface antigens can provide another targetable therapeutic option for recombinant monoclonal antibodies. But now difficulty in selecting to target leukemic myeloid cells while sparing non-malignant myeloid precursors. Lastly, the development of well-tolerated oral therapies, such as clofarabine, will increasingly broaden the range of available treatment for elderly patients at a higher risk of mortality from standard chemotherapy regimens. It is the beginning of a new era in the treatment of AML to make them survive with novel agents with little toxicity, particularly in relapsed or refractory dis-

and Sadia Sultan<sup>3</sup>

stratification will result in incremental gains in remission and survival.

\*, Imran Ahmed Siddqui<sup>2</sup>

1 Molecular Pathology Section, Department of Pathology and Laboratory Medicine, Aga

[1] Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and

[2] Small D. FLT3 mutations: Biology and treatment. Hematology American Society of

[3] Knapper S. FLT3 inhibition in acute myeloid leukemia. British Journal of Haematology.

acute leukemia: Rationale and important changes. Blood. 2009;**114**:937-951

Address all correspondence to: zeeshan.ansar@aku.edu

Hematology Education Program. 2006:178-184

Khan University Hospital, Karachi, Pakistan 2 Memon Medical Institute, Karachi, Pakistan 3 National Medical Complex, Karachi, Pakistan

#### **5.6. Novel agents in development**

Currently is the era of targeted agents for treatment of malignancies. These targeted therapies for each AML patient are based on unique molecular features. Hypothesis -based study designs can give us proper risk stratification for prognosis and predictive treatment options in AML. In the following section, promising novel agents in development are described:

