See also Cancer Treatment See also DNA Methylation and Demethylation See also Histone Acetylation
Introduction:
Leukemia (also spelled leukaemia) is a group of cancers that typically starts in the bone marrow and results in high number of abnormal white blood cells. These white blood cells are not fully developed and are called blasts or leukemia cells. (Arnatt, US 2018/0289671A1)
In 2012, leukemia developed in 352k people gobally and casued 265k deaths. It is the most common type of cancer in children, with 3/4 of leukemia cases in chldren being the acute lymphoblastic type. Howev er, about 90% of all luekemias are diagnosed in adults, with AML and CLL being most common in adulsts. It occurs more commonly in the developed world. (Arnatt, US 2018/0289671A1)
Symptoms may include blooeding and bruising problems, feeling tired, fever and an increased risk of infections. These symptoms corru due to a lack of normal blood cells. (Arnatt, US 2018/0289671A1)
Cuases of leukemia are unkonw. Different kinds of luekemia are believed to ahve different casues. Both inherited and environmental factors are believed to be invovled. Risk factors include smoking, ionizing radiation, some ehcmemicals (such as benzene), prior chemotherapy and Down syndrome. (Arnatt, US 2018/0289671A1)
Diagnosis is typically made by blood tests or bone marrow biopsy. (Arnatt, US 2018/0289671A1)
Treatment: may involve some combiation of chemotherapy, radiation therapy, targeted therapy and bone marrow transplant. (Arnatt, US 2018/0289671A1)
Acute Lymphoblastic Leukemia (ALL)
ALL is an acute form of leukemia (cancer of the white blood cells) characterized by the overproduction and accumulation of cancerous, immature white blood cells (lymphoblasts). In ALL, lymphoblasts are overproduced in the bone marrow and continuously multiply, causing damage and death by inhibiting the production of normal cells such as red blood cells, other white blood cells and platelets. ALL is most common in childhood with a peak incidence at 2-5 years of age, and another peak in old age. The crowding that resutls form such cells makes the bone marrow unable to produce healthy blood cells. Immedaite treatment is required in acute leukemia becasue of the rapid progression and accumulation of the malignant cells, which then spill over into the blodstream and spread to otehr organs of the body. (Arnatt, US 2018/0289671A1)
Causes: The efinitive cause of most cases of B cell ALL is not known, although in many cases, the disease results from acquired genetic alterations in the DNA of a single cell, causing it to become abnormal and multiply continously. (Hagal, WO 02/059264)
Symptoms: include fever, increased risk of infection, shortness of breath, chest pain, cough, vomiting, and changes in bowel or bladder habits, increased tenedcy to bleed (due to thrombocytopenia) and signs indicative of anemia such as pallor, tachycardia (high heart rate), fatigue and headache. These sytpoms are indicative of a reduced production of functional blood cells, because the leukemia wastes the resources of the bone marrow, which are normally used to produce new fuunctioning blood cells.
Diagnosis: begins with physical examination, complete blood count and blood smears. Bast cells are seen on blood smear in the majority of casesA bone marrow biopsy is conclusive proof of ALL. Pathological examination, cytogenetics such as the presence of the Philadelphia chromosome and immunophenotyping establish whether myloblastic (neutrophils, eosinophils or basophils) or lymphoblastic (B or T lymphocytes) are the problem.
Types: Luekemia is subdivided into a variety of large groups. The frist division is between its acute and chronic forms. Acute leukemia is characterized by a rpaid increase in the number of immature blood cells. Chronic leukemia is characteirzed by the excessive buildup of relatively mature, but still abnormla, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal, resutlign in many abnormal whtie blood cells. (Arnatt, US 2018/0289671A1)
Acute Myeloid Leukemia (AML)
Introduction: AML is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal whtie blood cells that accumulate in the bone marrow and interferes with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. It accounts for about 1.2% of cancer deaths in the US.
Symptoms: include fatigue, shortness of breath, easy bruising and bleeding, and increased risk of infection. The syptoms are caused by replacement of normal bone marrow with leukemic cells, which causes a drop in red blood cells, platelets and normal white blood cells. A lack of normal white blood cell production makes the patient susceptible to infections, while the leukemic cells themselves have no infeciton fighting capacity. A drop in red blood cell count (anemia) can cause fatigue, paleness and shortness of breath. A lack of platelets can lead to easy brusing or bleeding with minor trauma.
Some patients with AML may experience swelling of the gums because of infiltration of leukemic cells into the gum tissue. Rarely, the first sign of leukemia may be the development of a solid luekmic mass or tumor outside of the bone marrow, called a chloroma.
Detection: An abnormal result on a complete blood count is a first sign of AML. An excess of abnormal white blood cells (leukocytosis) is a common finding. AML can also present with isolated decreases in platelets, red blood cells or even with a low white blood cell count (leukpenia). A presumptive diagnosis of AML can be made via examination of a peripheral blood smear when there are cirulating leukemic blasts. A definitive diagnosis usually requires an adequate bone marrow aspiration and biopsy.
Marrow or blood is exmained via ligh microscopy as well as flow cytometry to diagnose the presence of leukemia and to differentiate AML from other types of leukemia such as acute lymphblastic luekemia (ALL) and to also classify the subtye of disease.
Pathology:
In the pathogenesis fo AML, multicple mechanisms involving genetic alterations and epigenetic deregulations collaborate to casue aberrant maturation arrest, grwoth and survival of ealry myeloid progenitor cells. Among the deregulated epigenetic mechanisms, in addition to DNA methylation and histone (H) de-acetylation, alternations in histone H3 lysin (K) specific methylation are involved in promoting the aberrant gene expression or “transcriptome” in AML cells, which includes the deregulated epxression of oncogenes and tumor suppressor genes. (Fiskus, “Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells” Leukemia, 2014, 28(111).
Treatment: varies among subtypes. AML is treated initial with chemotherapy aimed at inducing a remission. Patients may go on to receive additional chemotherapy or a hematopoietic stem cell transplant.
–Antibodies:
—-AntiCD33: Acute myeloid leukemia (AML) has served as paradigm for teh therapeutic use of monoclonal antibodies becasue of well-defined cell surface antigens adn easy tumor accessbility. The most investigated target so far is CD33, a sialic-acid-dependent cytoadhesion molecule known as a mheloid differentation antigne found on AML blasts in most patients, and, perhaps leukemic stem cells in some. (Walter, US 2016/0317657A1)
——AntiCD33 + Epigenetic factor: Walter, US 2016/0317657A1 discloses a pharmacetucial composition that includes a CD33 targeting compound at at elast one epigenetic factor such as a HDAC inhibitor, DNA methyltransferase (DNMT) I inhibitor or histone methyltrasnferase (HMT) inhibitor.
–Hematopoietic Cell Transplantation (HCT): can result in long term survival in about 30-40% of pateintes with relapsed AMl. Howeve,r many patietns are not approprirate candidates because of age, comorbidities, or lack of a suitable donor.
–Chemotherapy:
Chemotherapy uses cytotoxic drugs to interfere with cellular processes. This often affects rapidly dividing cells throughout the body. This results in DNA synthesis inhibition, DNA damage, or disruption of cell division.
Following standard chemotherapy, while complete remissions are rutinely acheived, a majority of patients with AML eventaully suffer relapse with treatment-refractory disease. Consequently, the overall 5 year survival of AML patients remains about 23%. (Fiskus, “Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells” Leukemia, 2014, 28(111).
—-Cytarabine (Ara-C) is a chemotherapy drug primarily used to treat certain types of leukemia, particularly acute myeloid leukemia (AML). It is an antimetabolite, specifically a pyrimidine nucleoside analog, that interferes with DNA synthesis in rapidly dividing cells.
–Radioimmunotherapy:
Radioimmunotherapy uses radioactive isotopes attached to antibodies. The antibody targets a specific antigen on cancer cells. The ionizing radiation damages cellular DNA.
To date, most radioimmunotherpy trails for AML have used beta-particle emitting isotopes. Early studies showed that M195, a murine anti-CD33 mAb, and its humanized counterpart, lintuzumb, labeled with iodine-131 (131I) could eliminate large luekemic burdens in preparation for hematopoietic cell transplantation (HCT). Becaseu alpha-particles have a shorter range and a higher liner engery transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the ptoential for mroe efficient tumor cell killing while sparing surrounding normal cells. To date, clinical studies of alpha-particle immunotherapy for AML have focused on the myeloid cell surface antigen CD33 as a target using the humanized mAb lintuzumab. A phase I trail demosntrated that 22Ac-lintuzumab in combination wtih a low dose cytarabine 9LDAC) is udner investigation for the management of older patietns with untreated AML in a mutlicenter trail. (Jurcic, “Targeted alpha-particle immunotherapy for acute myeloid leukemia” American Soceity of Clinical Oncology, 2014).
–Histone Demethnlase Inhibitors:
Treatment with the LSD1 antagonist SP2509 attenuated the binding of LSD1 with the co-repressor CoREST, increased the permissive H3K4Me3 mark on the target gene promotes, and increased the levels of p21, p27 and C/EBPalpha in cultures AML cells. (Fiskus, “highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetyale inhibiotr against human AML cells”Leukemia, 214, 28(11).
–in conjunction with Radioisotope/Antibody radioconjugates: Ludwig (US 2025/0121105 A1) discloses a method for treating a human subject afflicted with acute myeloid leukemia that includes admisntiering a PARP inhibitor such as olaparib, niraparib, rucaparib and talazoparib in cinjunction with 225A-labeled HuM 195, which when admisntiered in conjunciton with one another are therapeutically effective. Ludwig also disclsoes an ant8-HER2 antibody albeled with a radioisotpe such as 225AC albed trastuzumab (also known as Herceptin®.
Chronic Lymphocytic Leukemia (CLL):
CLL most often affects adults over 55. It sometimes occurs in younger adults, but it almost enver affects children. Two-third of affected people are men. The 5- year survival rate is 75%. I is incurable, but there are many effective treatments. One subtype is aB-cell prolymphocytic leukemia, a more aggressive disease. (Arnatt, US 2018/0289671A1)
Hairy cell leukemia (HCL): is soemtimes considered a subset of CLL but does not fit neatly into this category. About 80% of affected people are adult men. Survival is 96-100% at ten years. (Arnatt, US 2018/0289671A1)
Chronic Myelogenous Luekemia (CML)
CML occurs mainly in adutls. I tis treated with imatinib or other drugs. The 5 eyar survival rate is 90%. One subtype is chronic myelomoncytic leukemia. (Arnatt, US 2018/0289671A1)
The Philadelphia chromosome is a genetic abnormality in chromosome 22 in luekemia cells. The gene is the ABL1 gene of chromosome 9 justaposed onto the BCR gene on chromosome 22 coding for a hybrid protein; a tyrosome kinase signalling protein which is always “turned on” as a result of the abnormality, causing the cell to divide uncontrallably.
Treatments:
–Tyrosine kinase inhibitors:
—-Imatinib (Glivec): was approved by the FDA in 2001 for the treatment of chronic myelogenous leukemia (CML), a rare form of cancer that affects certain type of white blood cells. Since approval, its use has been approved for pateitns with several types of gastrointestinal tumors. The drug has been described as a miracle drug in that it has a phenomenal success rate. Its development started in the late 1950s when researches notice that cancer cells chromosomal abnormality in that individuals with CML had an atypical small chromosome #22 which was called the “philadelphia chromosome”. The long arm had transferred to chromosome 9. Ten years later scientists determined the actual genes involved in the translocation labeled as human c-abl oncogene located in the region of chromosome 9 that translocates to become part of the Philadelphia chromosome. Then, the scientists idnetifed a breakpoint cluster region in which all of chromosome 22 breaponts seemed to occur in CML pateitns. Later scientists from the Whitehead Institute in Cambridge infected bone marrow cells with a retrovirus encoding the fusion gene and demonstrated that the presence of an iactive bcr-abl gene initials CML like symptoms. Later researches identified the fuction of the bcr-abl fusion gene: production of an abnormal tyrosine kinase protein that is not properly regulated. This proliferation resutls int he overproduction and accumulation of immature white blood cells, which is the ahllmoark of CML. Research at Ciba-Geigy (which later become Novartis) identified kinase blocking inhibitors using computer models to predict which molecule structures might fit the ATP binding site of the fusion protein. One compound was particularly pormosing. kills cancer cells by turning of tyrosine kinase. It is marketed by Novartis. It is on the World Health Orgnization List of essential medicines.
T-cell prolymphocytic Leukemia (T-PLL):
T-PLL is a very rare and aggressive leukemia affecting adults, somewhat more men than woemn are diagnosed. It is the most common type of mature T cell luekemia (nearly all other keukemias invovle B cells). It is difficult to treat and the median survival is measured in months. (Arnatt, US 2018/0289671A1)