Advancement of Drugs for Myeloid Leukaemia: An Overview in the Developmental Process

Special Article - Acute and Chronic Myeloid Leukaemia

Ann Hematol Oncol. 2017; 4(6): 1153.

Advancement of Drugs for Myeloid Leukaemia: An Overview in the Developmental Process

Roy S, Bhaduri A* and Singh M*

Department of Biotechnology, Haldia Institute of Technology, India

*Corresponding author: Bhaduri A, Department of Biotechnology, Haldia Institute of Technology, HIT Campus, Purba Medinipur, Haldia (West Bengal), India

Singh M, Department of Biotechnology, Haldia Institute of Technology, HIT Campus, Purba Medinipur, Haldia (West Bengal), India

Received: April 20, 2017; Accepted: May 15, 2017; Published: May 29, 2017


Every year millions of people are being freshly diagnosed with cancer and a healthy amount is diagnosed with some form of myeloid leukaemia. Few decades ago treatment options for myeloid leukaemia were not so diverse and mortality rate amongst patients were very high. Things have changed dramatically due to the introduction of various treatment options; patients are being able to lead a healthy life prior to their medication period. Though conventional chemotherapy is still used but there are a variety of drugs that have been introduced which could replace chemotherapy and stem cell transplantation in near future as these new generation of drugs have a very specific mode of action and they have a minimal side effect. For example Tyrosine Kinase Inhibitor brought a revolution in the field of treatment for Chronic Myeloid Leukaemia as they bind to the ATP binding site of BCR-ABL gene, thus inhibiting the signaling process of cell division and controlling the number of tumor cell. Though Acute Myeloid Leukaemia has a higher mortality rate than Chronic Myeloid Leukaemia but some of the recent developments in the field of Immunotherapy are showing very promising result. Artificially modified T lymphocyte cell is used to differentiate the tumor cells thus controlling the cancer via body’s own immune system. Some of the treatment options are still in developmental stage and some of them are not affordable by people all over the world, but the ongoing development shows a promising future in the treatment of myeloid leukaemia.

Keywords: Acute myeloid leukaemia; Chronic myeloid leukaemia; BCRABL; Tyrosine kinase inhibitor; CAR-T cell immunotherapy; Chemotherapy


AML: Acute Myeloid Leukaemia; CML: Chronic Myeloid Leukaemia; APL: Acute Promyelocytic Leukaemia; RBC: Red Blood Cell; WBC: White Blood Cell; TKI: Tyrosine Kinase Inhibitior; IFN: Interferon; BCR: Break Point Clusture Gene; ABL: Abelson Tyrosine Kinase Gene; CAR: Chimeric Antigen Receptor; SOS: Sinusoidal Occlusive Syndrome; ATRA: All-trans Retinoic Acid; ATO: Arsenic Trioxide; GSH: Glutathione; TCR: T cell Receptor; scFV: Single Chain Antibody FV; TYK: Tyrosine Protein Kinase; JAK: Janus Kinase; GO: Gemtuzuma Ozogamicin


Acute Myeloid Leukaemia or AML is a rare type of disease mostly affecting adults and its incidence increases with the increase in ages, although about 1.2% of cancer deaths are caused by AML [1]. It’s also known as acute myelocytic, myelogenous or granulocytic leukaemia. AML is primarily caused by outgrowth and build-up of abnormal white blood cells in the bone marrow which reduces the number of RBC, platelets and normal WBC. There are also several risk factors resulting in some chromosomal abnormalities which could be responsible for AML but the real reason is still a mystery. General symptoms consist of easy bruising, bleeding, anaemia, tiredness, prone to infection. AML could be fatal if left untreated and it has a very fast growth rate. Due to the several subtypes of AML, prognosis could vary. AML has a better survival rate for people aging less than 60 years with 35-40% comparing to the 5-15% aging more than 60 years [2]. There are some pre leukemic blood disorders such as myeloproliferative disease (MPS) and myelodysplastic syndrome (MDS) that can mature and turn into AML [3]. Prolonged exposure to several chemotherapy agents such as alkylating agents [4], epipodophyllotoxins and anthracyclines [5] have been known to increase the risk of AML. Chromosomal translocation between 8 & 21 and 15 & 16 and inversion of 16 brings some cytogenetic changes which results in a subtype of AML known as Acute Promyelocytic Leukaemia (M3 or APL) [6]. Chronic Myeloid Leukaemia or CML is a rare myeloproliferative neoplasm or myelodysplastic syndrome typically caused by outgrowth and accumulation of abnormal WBC in bone marrow just as AML. CML affects relatively less number of people and they have a longer incubation time than AML but it is difficult to cure a CML than AML. Generally CML is caused by the translocation of chromosomes which activates oncogenes or deactivates tumor suppressor genes [7]. Other form of chromosomal defects contains deletion. Another main cause of CML is the deformation in Philadelphia chromosomes [8].

There are several treatments available regarding CML. Five distinct and well known treatment for CML available are Tyrosine Kinase Inhibitor (TKIs), Bone Marrow Transplant, Interferon alpha-2b (IFN-a2b), Myelosuppressive or Leukopheresis therapy and Splenectomy [9]. Most of the times the growth of a tumor cell in CML depends upon the activation of break point clusture gene (BCR) at chromosome 22 and Abelson tyrosine kinase gene (ABL) at chromosome 9, together known as BCR-ABL tyrosine kinase complex which forms the deformities in the Philadelphia chromosome. Imatinib (Gleevec) is considered as the very first drug that inhibits BCR-ABL Tyrosine kinase [10]. Dasatinib is an also a TKI more specifically BCR-ABL TKI which is used orally to prevent CML in those patients who are intolerant to Imatinib [11]. Nilotinib (AMN107) is also a TKI used in case of Imatinib intolerance. Radotinib (IY5511) [12] and Bosutinib (SKI-606) [13,14] are recently developed in case to the intolerance of the prior treatment. Sometimes BCR-ABL genes undergo a specific kind of mutation (T315I) which alters the protein binding site of Imatinib and other similar drugs, thus resulting in a futile treatment. Omacetaxine mepesuccinate or homoharringtonine (HHT) is used for in case of adult patients when multiple TKIs are intolerant by the patients [15]. It is a type of natural drug obtained from Cephalotaxus harringtonia. IFN-a2b is one of the oldest methods for treatment of CML but due to its higher toxicity comparing to TKIs, it is almost obsolete nowadays [16].

Chemotherapy is the main way of treating AML. It is divided into three phase, Induction chemotherapy, Post-remission chemotherapy and Consolidation chemotherapy. Alone a chemotherapy is not that much effective so a Stem cell transplantation or a bone marrow transplantation is recommended (only if the patients is able to tolerate a transplantation) in most of the times. Allogeneic (ALLO) stem cell transplantation (i.e. using donated stem cell) is done in case of patients suffering from AML [17]. This induction chemotherapy is given with (except in case of M3 subtype of AML) cytarabine (ara-C) and an anthracycline [18]. The induction Chemotherapy routine is also denoted by “7+3” because the cytarabine is given to the patients continuous IV infusions for 7 days consecutively and as IV push, anthracycline is given for 3 days consecutively [19]. Acute promyelocytic leukaemia (APL) or the M3 subtype of AML is treated with all-trans-retinoic acid (ATRA) with addition to induction chemotherapy, almost universally [20]. For older people aging over 60 years with relapsed AML who are unable to withstand high dosages of chemotherapy, Gemtuzumab Ozogamicin (Mylotarg), a monoclonal antibody linked cytotoxic agent is being used as a replacement [21] but the drug was withdrawn from the market by its manufacturer, Pfizer in the year of 2010 [22]. US FDA approved Arsenic trioxide for the treatment of relapsed APL and this compound is specific to the M3 subtype of AML like ATRA [23]. Another more recent advancement in the field of treatment of AML is Immunotherapy by CAR-T cell. The T-cells in patients body is modified so that they could produce special receptors on their surface which is known as chimeric antigen receptors (CARs). CARs are protein in nature which detect a specific kind of antigen released by the tumor cell and destroy them. They are generally produced in laboratory to expand rapidly and then after rapid growth they are infused in the patient’s body to kill the cancer cells and when present in the patient’s body, they can also multiply [24].

Acute myeloid leukaemia

AML is a fatal form of myeloid leukaemia affecting almost all the age groups. Accumulation of abnormal WBC in bone marrow results in AML. AML has a very fast growth rate and patients die very quickly if left untreated, prior to the diagnosis. Anaemia, tiredness, bruising, bleeding and prone to infection are some of the very common side effects rather symptoms in case of AML. There are some pre occurred diseases which could turn in to AML. Chemotherapy was the main mode of treatment alongside stem cell transplantation. As the science advances there are a lot of new treatment options introduced in the market which are proving a lot more efficient than conventional stem cell transplantation or chemotherapy. The lists of drugs in use and under development are enlisted in table 1.