**2. Molecular diagnosis in hematological malignancies**

Hematological malignancies are heterogeneous in both clinical and biological aspects. The association of genomic profile changes associated with hematological malignancies is complex and variable including translocations, karyotypic improvements, transformations and adjustments of post-translational alteration and some genetic changes are needed, to induce the onset of disease. This proof in relationship with the development of molecular techniques has prompted an alteration of the current authoritative opinion concentrating on a solitary quality or single pathway analysis [4].

The advancement in molecular biology techniques has not just permitted the individualized molecular diagnosis of hematological malignancies but have also prompted the disclosure of genetic or targeted therapeutic schemes with cytotoxic, anti-metabolic or immunomodulatory properties [4].

Utilizing karyotype analysis and the new technique of polymerase chain reaction (PCR), chromosomal microarrays (CMA), fluorescence in situ hybridization (FISH) and new generation sequencing technique (NGS), it is conceivable to configuration better hazard stratification classes and decide if there is complete remission or presence of minimal residual disease (MRD).

New molecular and cytogenetic methods have been connected to determination of diagnosis and treatment. As to, the reasonableness of those strategies expands the precision and the speed of results while screening can be even more successfully performed. In regard to treatments, immunomodulatory and target therapies assurance better outcomes with less hematological side effects.

The molecular basis of hematological malignancies has developed aberrant genes expression and/or pathological expression of natural genes [5]. Also other new somatic mutations detected by Next Generation Sequencing NGS have prompted the revelation of already unknown molecular and pathological genes as well as diagnostic and therapeutic value [6].

Genetic changes plays a vital role to diagnose and classify the stage of disease and determine the prognosis of diseases and choice of treatment in most hematological malignancies [7–9]. Molecular diagnostic technology in patients with HMs is useful for diagnosis and prognosis and selecting the proper treatment, and to monitor the degree of response to new therapies [5, 8].

The majority of leukemia, specifically predictable by gene expression profiles [9]. Vulnerability tests are being developed through the explicit treatment of targeted therapies such as imatinib in acute lymphoblastic leukemia BCR-ABL positive (ALL) and farnesyltransferase inhibitors in acute myeloblastic leukemia (AML) [10].

Myelodysplastic syndrome (MDS) and acute leukemia (AML and ALL) are intensely influenced by epigenetics [11]. Targeted epigenetic therapies may be particularly attractive as long-term treatment in post remission period, if they could target certain subclones once standard chemotherapy has produced targeted cytoreduction to induce remission of acute leukemia [12]. Personalized targeted therapy have just upset treatment results in some HMs, especially, chronic myeloid leukemia (CML), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) and acute promyelocytic leukemia (APL) [12, 13].

### **3. Detection of molecular markers in hematologic malignancies**

**The molecular markers and genetic studies in hematologic malignancies include**: (1) **AML**: FLT3-ITD, CEBPA, RUNX1, NPM1, PML-RARA, *ASXL1*, IDH1, IDH2, DNMT3A, TET2 and BCR-ABL1; (2) **ALL**: IKFZ1, CDKN2A/B, BCR-ABL1, BCR-ABL1-like, NOTCH1, ETV6, and RUNX1; (3) **chronic myeloproliferative** (CMPNs): CAL-R, MPL, JAK2, SRSF2, SETBP1, *TP53*, CSF3R and ASXL1; (4) **CML**: BCR-ABL1; (5) **MDS**: RUNX1, *JAK2*, EZH2, SF3B1, IDH1/2, *N-RAS*, TP53, TET2, *KIT*, SRSF2, and ASXL1; (6) **CLL**: ATM, TP53, BIRC3, del11q, SF3B1 and NOTCH1 mut; (7) **Hodgkin's lymphoma (HL):** BCL6, SOC1, JUNB, MAP3K14, STAT6, MDM2, JAK2, XPO1, NFKBIE, GNA13, MAFB,IKBA, TNFIP3, BCL3, NFKBIA, PD-L1, PD-L2, and REL6; (8) **B-cell lymphomas**: MYC/BCL2, MYC/BCL2/BLC6, SOX11, CCND1/2, *CCND3* and *TCF3*; (9) **T-cell lymphomas**: TP63, IRF4, DUSP22 and ALK; (10) **Hairy cell leukemia (HCL)**: BRAFV600E, *IGHV4-34*, *MAP2K1*; and (11) **MM**: KRAS, CCND1, CCND2, CCND3, TP53, DI53, NRAS, MAF, FAM46C and BRAF [5, 10, 14–17].

#### **4. Personalized target therapy: Monoclonal antibodies**

In the late 1970s, the technology development of monoclonal antibody (MoAb) was possible to produce antibodies targeting specific antigens to the surface of cancer cells. The antibodies target an antigen present at high concentrations on cancer cells

**3**

*Introductory Chapter: Advances in Hematologic Malignancies*

and missing or present at low fixations on typical cells. The MoAbs, is given as monotherapy or target therapy with chemotherapy, have excellent outcome in different types of neoplasm's with improve quality of life and survival rate and time. An assortment of components has been proposed that would allow monoclonal antibodies to kill cancer cells, including apoptosis, inhibition of cell growth, cellular cytotoxicity. The development of molecular and genetic technology play important role in the modernization and modification of the (2016 WHO Edition) for classification of tumors of hematopoietic and lymphoid tissues, is being published by World Health Organization, the aims to provide these data with essential clinical characteristics, morphology and immunophenotyping relevant to targeted and novel therapies

The targeted and novel therapies currently used in the treatment of hematological malignancies are: (1) Acute myeloblastic leukemia subtypes: lintuzumab, midostaurin, gemtuzumab, ulocuplumab, sorafinib, navitoclax, panobinostat, vorinostat, Dr383-IL3 and lestaurtinib; (2) acute myeloblastic leukemia (promyelocytic type): all trans-retinoic acid gemtuzumab ozogamicin and arsenic trioxide; (3) acute lymphoblastic leukemia: tyrosine kinase inhibitors, rituximab, inotuzumab ozogamicin, nelarabine, blinatumomab, and CAR T-cells; (4) myelodysplastic syndrome: azacitidine, decitabine, and lenalidomide; (5) chronic myeloid leukemia: imatinib, nilotinib, dasatinib and ponatinib; (6) chronic myeloproliferative neoplasms: ruxolitinib; (7) chronic lymphatic leukemia (CLL): rituximab, idelalisib, ibrutinib, venetoclax obinutuzumab, and duvelisib; (8) HL: brentuximabvedotin, nivolumab, rituximab and everolimus; (9) B-cell lymphomas: tositumomab, rituximab, ibritumomab tiuxetan and CAR T-cells; (10) T-cell lymphomas: romidepsin, alemtuzumab, epratuzumab, denileukin and nelarabine; (11) hairy cell leukemia: vemurafenib; and (12) multiple myeloma: bortezomib, carfilzomib, lenalidomide,

pomalidomide, daratumumab milatuzumab, and ixazomib [17–26].

therapies have proven to be a great success.

**5.1 Enasidenib for** *IDH***-mutated AML**

**5. Examples of advance treatment in AML**

**5.2 Gemtuzumab ozogamicin for CD33+ AML**

The targeted treatments are directed to the cancer cell and do not harm or affect the healthy cell, which is of course a breakthrough in the treatment of hematological malignancies, but is still in the process of research despite the success of the experiments, which have been conducted and targeted therapies exist for many types of cancers, including: Chronic leukemia and lymphoma is used in making there are opportunities for no need for bone marrow transplantation, and targeted

Mutations in isocitrate dehydrogenase (IDH) occur in 20% of AML cases and are also found in gliomas and cholangiocarcinomas. Enasidenib was approved in August 2017 by FDA for treatment acute myeloblastic leukemia patients (AML) refractory or relapsed to chemotherapy with presence of IDH2 mutation. IDH2 mutations are relatively common in hematological malignancies, which occur in ~12% of AML patients [27]. The follow up of patients for a period of 6.6 months, 23% of patients experienced a complete remission [28]. The dose of enasidenib is

Gemtuzumab ozogamicin (Mylotarg) is an antibody-drug conjugate to treat patients who are more than 60 years old in first relapse AML with CD33+ and not candidates for chemotherapy and also for pediatric patients, more than 2 years old

100 mg once daily and continuously was chosen for the extension stage.

*DOI: http://dx.doi.org/10.5772/intechopen.88777*

against incurable diseases [18].

*Introductory Chapter: Advances in Hematologic Malignancies DOI: http://dx.doi.org/10.5772/intechopen.88777*

*Advances in Hematologic Malignancies*

ence of minimal residual disease (MRD).

well as diagnostic and therapeutic value [6].

acute promyelocytic leukemia (APL) [12, 13].

ance better outcomes with less hematological side effects.

monitor the degree of response to new therapies [5, 8].

and new generation sequencing technique (NGS), it is conceivable to configuration better hazard stratification classes and decide if there is complete remission or pres-

The molecular basis of hematological malignancies has developed aberrant genes expression and/or pathological expression of natural genes [5]. Also other new somatic mutations detected by Next Generation Sequencing NGS have prompted the revelation of already unknown molecular and pathological genes as

Genetic changes plays a vital role to diagnose and classify the stage of disease and determine the prognosis of diseases and choice of treatment in most hematological malignancies [7–9]. Molecular diagnostic technology in patients with HMs is useful for diagnosis and prognosis and selecting the proper treatment, and to

The majority of leukemia, specifically predictable by gene expression profiles [9]. Vulnerability tests are being developed through the explicit treatment of targeted therapies such as imatinib in acute lymphoblastic leukemia BCR-ABL positive (ALL) and farnesyltransferase inhibitors in acute myeloblastic leukemia (AML) [10]. Myelodysplastic syndrome (MDS) and acute leukemia (AML and ALL) are intensely influenced by epigenetics [11]. Targeted epigenetic therapies may be particularly attractive as long-term treatment in post remission period, if they could target certain subclones once standard chemotherapy has produced targeted cytoreduction to induce remission of acute leukemia [12]. Personalized targeted therapy have just upset treatment results in some HMs, especially, chronic myeloid leukemia (CML), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) and

**3. Detection of molecular markers in hematologic malignancies**

**4. Personalized target therapy: Monoclonal antibodies**

**The molecular markers and genetic studies in hematologic malignancies include**: (1) **AML**: FLT3-ITD, CEBPA, RUNX1, NPM1, PML-RARA, *ASXL1*, IDH1, IDH2, DNMT3A, TET2 and BCR-ABL1; (2) **ALL**: IKFZ1, CDKN2A/B, BCR-ABL1, BCR-ABL1-like, NOTCH1, ETV6, and RUNX1; (3) **chronic myeloproliferative** (CMPNs): CAL-R, MPL, JAK2, SRSF2, SETBP1, *TP53*, CSF3R and ASXL1; (4) **CML**: BCR-ABL1; (5) **MDS**: RUNX1, *JAK2*, EZH2, SF3B1, IDH1/2, *N-RAS*, TP53, TET2, *KIT*, SRSF2, and ASXL1; (6) **CLL**: ATM, TP53, BIRC3, del11q, SF3B1 and NOTCH1 mut; (7) **Hodgkin's lymphoma (HL):** BCL6, SOC1, JUNB, MAP3K14, STAT6, MDM2, JAK2, XPO1, NFKBIE, GNA13, MAFB,IKBA, TNFIP3, BCL3, NFKBIA, PD-L1, PD-L2, and REL6; (8) **B-cell lymphomas**: MYC/BCL2, MYC/BCL2/BLC6, SOX11, CCND1/2, *CCND3* and *TCF3*; (9) **T-cell lymphomas**: TP63, IRF4, DUSP22 and ALK; (10) **Hairy cell leukemia (HCL)**: BRAFV600E, *IGHV4-34*, *MAP2K1*; and (11) **MM**: KRAS, CCND1, CCND2, CCND3, TP53, DI53, NRAS, MAF, FAM46C and BRAF [5, 10, 14–17].

In the late 1970s, the technology development of monoclonal antibody (MoAb) was possible to produce antibodies targeting specific antigens to the surface of cancer cells. The antibodies target an antigen present at high concentrations on cancer cells

New molecular and cytogenetic methods have been connected to determination of diagnosis and treatment. As to, the reasonableness of those strategies expands the precision and the speed of results while screening can be even more successfully performed. In regard to treatments, immunomodulatory and target therapies assur-

**2**

and missing or present at low fixations on typical cells. The MoAbs, is given as monotherapy or target therapy with chemotherapy, have excellent outcome in different types of neoplasm's with improve quality of life and survival rate and time. An assortment of components has been proposed that would allow monoclonal antibodies to kill cancer cells, including apoptosis, inhibition of cell growth, cellular cytotoxicity.

The development of molecular and genetic technology play important role in the modernization and modification of the (2016 WHO Edition) for classification of tumors of hematopoietic and lymphoid tissues, is being published by World Health Organization, the aims to provide these data with essential clinical characteristics, morphology and immunophenotyping relevant to targeted and novel therapies against incurable diseases [18].

The targeted and novel therapies currently used in the treatment of hematological malignancies are: (1) Acute myeloblastic leukemia subtypes: lintuzumab, midostaurin, gemtuzumab, ulocuplumab, sorafinib, navitoclax, panobinostat, vorinostat, Dr383-IL3 and lestaurtinib; (2) acute myeloblastic leukemia (promyelocytic type): all trans-retinoic acid gemtuzumab ozogamicin and arsenic trioxide; (3) acute lymphoblastic leukemia: tyrosine kinase inhibitors, rituximab, inotuzumab ozogamicin, nelarabine, blinatumomab, and CAR T-cells; (4) myelodysplastic syndrome: azacitidine, decitabine, and lenalidomide; (5) chronic myeloid leukemia: imatinib, nilotinib, dasatinib and ponatinib; (6) chronic myeloproliferative neoplasms: ruxolitinib; (7) chronic lymphatic leukemia (CLL): rituximab, idelalisib, ibrutinib, venetoclax obinutuzumab, and duvelisib; (8) HL: brentuximabvedotin, nivolumab, rituximab and everolimus; (9) B-cell lymphomas: tositumomab, rituximab, ibritumomab tiuxetan and CAR T-cells; (10) T-cell lymphomas: romidepsin, alemtuzumab, epratuzumab, denileukin and nelarabine; (11) hairy cell leukemia: vemurafenib; and (12) multiple myeloma: bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab milatuzumab, and ixazomib [17–26].

The targeted treatments are directed to the cancer cell and do not harm or affect the healthy cell, which is of course a breakthrough in the treatment of hematological malignancies, but is still in the process of research despite the success of the experiments, which have been conducted and targeted therapies exist for many types of cancers, including: Chronic leukemia and lymphoma is used in making there are opportunities for no need for bone marrow transplantation, and targeted therapies have proven to be a great success.

### **5. Examples of advance treatment in AML**

#### **5.1 Enasidenib for** *IDH***-mutated AML**

Mutations in isocitrate dehydrogenase (IDH) occur in 20% of AML cases and are also found in gliomas and cholangiocarcinomas. Enasidenib was approved in August 2017 by FDA for treatment acute myeloblastic leukemia patients (AML) refractory or relapsed to chemotherapy with presence of IDH2 mutation. IDH2 mutations are relatively common in hematological malignancies, which occur in ~12% of AML patients [27]. The follow up of patients for a period of 6.6 months, 23% of patients experienced a complete remission [28]. The dose of enasidenib is 100 mg once daily and continuously was chosen for the extension stage.

#### **5.2 Gemtuzumab ozogamicin for CD33+ AML**

Gemtuzumab ozogamicin (Mylotarg) is an antibody-drug conjugate to treat patients who are more than 60 years old in first relapse AML with CD33+ and not candidates for chemotherapy and also for pediatric patients, more than 2 years old with relapsed or refractory CD33+ AML. Subsequent studies with positive findings resulted in the resurrection of gemtuzumab ozogamicin and its approval in 2017.
