Sruman Bandaru.
B.Pharm.
#2-10-711, Teachers Colony
Phase –I, Subedari,
Hanamkonda
Dist: Warangal
State: Andhra Pradesh,
India, PIN - 506370
E-mail: sruman.bandaru@gmail.com
Dr.P.Nanda Kishore.
MD.Fellowship (U.K)
Oncologist and clinical hematologist
Director of Life Line Hospitals
Hanamkonda
Dist: Warangal
State: Andra Pradesh
India.
Abstract:
The article focuses on four major types of leukemia along with their etiopathogenesis, treatment, chemotherapy, with different combinations, recent advances in chemotherapy, future directions for better understanding the disease and to research different combination of drugs so has to improve the survival rate of leukemia patients.
INTRODUCTION:
Lukemia is cancer of blood characterised by an uncontrolled proliferation of blood forming cells in the bone marrow.
There are four major types of leukemia
a) Acute myelogenous leukemia(AML)
b) Chronic myelogenous leukemia(CML)
c) Acute lympho blastic leukemial(ALL)
d) Chronic lymphocytic leukemai(CLL)
(Note: myleogenous and lymphocytic refer to the type of cell affected.).
ETIOPATHOGENESIS OF LEUKEMIA:
Acute leukemia progresses much more rapidly than the chronic disease. In acute leukemia genetic mutations in the blood forming cells result in a excesses of immature blood cells in the bone marrow and blood, essentially at the cost of the production of healthy marrow cells. As a result, the marrow cannot produce enough red blood cells, white blood cells and blood platelets, leaving individuals anemic, susceptable to infection and bleeding diathesis.in chronic lukemia greater number of more mature cells are produced.
ALL and aml are marked by the accumulation of immature cells called blasts, which fail to function as normal blood cells.
Cll is charcetrised by an overproduction mature lymphiod cells
Cml (and some cases of ALL) is caused by a genetic anamoly in the blood –forming cells known as translocation, in which part of one chromosome breaks off and attaches to another chromosome. In this case a section of chromosome 9 tears away and connects onto a section of chromosome 22,resulting in the fusion of two genes BCR and ABL, which are normally separate.
The new BCR-ABL gene produces an abnormal enzyme that results in the uncontrolled growth of white blood cells, i.e, blood cancer.
ACUTE MYELOID LUKEMIA:
Acute myeloid leukemia (AML) is an aggressive cancer of the white blood cells the cancerous white blood cells or blasts are abnormal, immature white blood cells, which occupy the bon emarrow and replace the normal components involved in the formation of normal blood cells. Because of this, the normal white cells, red cells and platelets are decreased, this leads to symptoms of anaemia (weakness, shortness of breath on exerction etc), infections and bleeding or symptoms of stroke or hearts disease.
Aml is more common in older adults.while this disease occurs in less than 1/1 lac individuals less than 30 years of age, the frequncy is greater than 11 /1 lac individuals more than 30 years of age.
TREATMENT:
Conventional treatment of AML consists of chemotherapy-a combination of medications usually given through vein or more commonly a “catheter” that is placed in the chest. Most chemotherapy regimes consists of combination of drugs “cytosine arabinoside”(Ara-c (or) cytarabine) and one of the drugs in the family of “anthracyclines.”(Daunorubicin, Idorubicin, Mitoxantron etc). In the recent years, various combination therapies have achieved remission rates of nearly 80% in young-adult patients with AML. Though there are patients who achieve remission, still 60% eventually experiencing a relapse of this disease.
Stem cell transplantation (or bone marrow transplantation) offers the opportunity to treat leukemia with the back up of high doses of chemotherapy or combinations of chemotherapy and radiotherapy.
The goal of high dose chemotherapy or radiotherapy before transplantation is to permanently kill the leukemia cell population. Transplanted stem cells from a matched donor provide the seeds to replenish the normal blood cells.
RECENT ADVANCES:
The following are some of the recent advances in the treatment of AML:
(a) Monoclonal antibodies are proteins that target specific markers on the tumor cells and destroy them. These agents have the advantage of sparing the normal cells and therefore have fewer side effects like hair loss or damage to the heart, which may be seen with chemotherapy.
A monoclonal antibody is now available against the CD33 antigen that is located on the surface of the most AML cells. The FDA has approved the drug mylotarg, which is a combination of this antibody with a very toxic agent called calichamycin. When the antibody attaches to the CD33 marker,the calichamycin is released in the cell and destroys it combination of chemotherapy with mylotarg is being tried as an investigational treatment in many centers in united states and other countries.
(b) A new drug called clofarabine is being a tried in-patient with AML at selected institutions in USA in clinical clinic. This drug is given intravenously in the out patient clinic. This drug is tolerated by patients well and is showing a lot of promise in the treatment of AML. Another drug i.e being tried is 5-azacytidine that was recently shown to significantly benefit patients with pre-leukemia. Troxacitabine is yet another investigational chemotherapy agent, which is being tested for the treatment of AML.
(c) In-patients, who are eligible for bone marrow or stem cell transplantation, newer modalities of therapy include “Mini” transplants or “non-myeloblative stem cell transplantation”. These modalities utilize less intensive “conditioning” therapy prior to transplantaion. Because of less intensive therapy, this procedure may be tolerated better than conventional transplantaion, particularly by patients who are near the upper age limits for transplantation.
Future prospects of AML:
A myriad of new agent is now available which, when administered either alone (ATRA or arsenic trioxide in APL) or in combinations with each other or with conventional cytotoxic chemotherapy, have the potential to reduce the disease patients with AML. Combinations of several agents targetting, more than one gene mutation, signal transduction pathway or antigenic determinant may be the most effective.
The challenge will be to detemine the specific pathway responsible for the propagation of the leukemia cells from a specific clone. This can be achieved with correct strategy and combinations of different agents.
CHRONIC MYELOID LEUKEMIA:
Chronic Myeloid Leukemia (Chronic myelogenous leukemia, CML) is a disease characterized by increased WBC, anemia and enlarged spleen. The disease usually occurs in older persons but may occur at any age. The patient may complain with symptoms of anemia (pallor, fatigue or tiredness) or that of enlarged spleen (fullness of abdomen, early satiety or abdominal discomfort) or the diagnosis may result from the investigation of an incidental finding of a big spleen. The presence of Philadelphia (ph’) chromosome in the leukemic cells in the blood or bone marrow.
TREATMENT:
The only known “curative” procedure for CML is the stem cell transplantation from a matched donor. The results of this treatment are best in the chronic phase especially if it is done in the first year after diagnosis. Out side this various treatment options are available with drugs like vinorelbine tartrate (navelbine), Imatinib mesylate (Gilvec), samarium-153, ethylene diaminetetramethylene phosphate (EDTMP), Temazepam (euhypnos).
Interferon alfa is a drug that is very effective in the chronic phase of CML. However, more than half of the patients has significant side effects from the drug.
Imatinib mesylate (Gleevec) has revelutionized the therapy of CML. There is evidence that this drug is superior to other conventonal therapy options in CML including Interferon-alfa, with significantly less toxicity.
FUTURE PROSPECTUS:
Although much has been achieved, many important issues pertaning to the biology and treatment of CML remain unresolved. To mention just a few, we know little of the mechanisms that cause the chromosomal rearrgement. We still need to clarify how deregulation of signal transduction by the BCR-ABL oncoprotien leads to the proliferative advantage of the ph-positive clone. We need to have a much better understanding of the molecular basis of disease progression, which is of tremendous value. In therapeutic terms we need to define the true clinical potential of imatinib and to acertain whether combining this agent with other signal-transduction inhibitors, other cytotoxic drugs or differntiating agents can improve its efficacy. We need to know whether immunizing patients with CML can prolong their survival or contribute to the eradication of disease. It seems that atleast some of these problems will be solved within the next five years.
ACUTE LYMPHOBLASTIC LEUKEMIA:
Acute lymphoblastic leukemia (ALL) is a fast-growing cancer of the white blood cells. Lymphocytes are a type of white blood cell, which fight the infections. In ALL, the bone marrow makes lots of unformed cells called blasts that normally develop into lymphocytes. However, the blasts are abnormal. They do not develop and cannot fight infections. The number of abnormal cells (or leukemia cells) grows quickly. They crowd out the normal red blood cells, white blood cells and platelets the body needs.
It appears most often in childern younger than 10 years of age. ALL is the most common leukemia in children. However, it can appear in people of any age. About one third of cases are adults. ALL may also be called acute lymphoid leukemia.
Signs and symptoms:
(a) Reduced red blood cells, which lead to anemia-feeling tiredness or weak, with shortness of breath and looking pale.
(b) Reduced number of white blood cells, which lead to fever and frequent infections that are difficult to treat.
(c) Reduced platelets which leads to easy brusing or bleeding and tiny red spots under the skin(petechiae)
(d) Increased leukemic cells cause pain in the joints, lack of appetite, headache or vomitting. These symptoms are less common.
Treatment:
Chemotherapy for acute lymphoblastic leukemia:
There are 3 phases of chemotherapy treatment for ALL: induction, consolidation and maintenance. Many patients also receive treatment called intrathecal chemotherapy to prevent leukemia from spreading to the central nervous system.
Induction chemotherapy:
Most patients with ALL are given induction chemotherapy. The goal of induction therapy is to bring the disease into remission. Remission is when the patient’s blood counts return to normal and bone marrow samples show no signs of disease. Induction therapy achieves a remission in more than 95% of childern and is about 75% to 89% of adults. Induction therapy is usually very intense and lasts about one month.
Consolidation therapy:
Consolidation therapy, the second phase of chemotherapy is also intense, it lasts about 4 to 8 months. The goal of consolidation therapy is to reduce the number of disease cells left in the body. The drugs and doses used during consolidation therapy depend on the patient’s risk factors.
Maintenance thearpy:
If a patient stays in remission after induction and consolidation therapy, maintenance therapy begins. The goal is to destroy disease cells that remain so that the leukemia is completely gone. Maintenance therapy is less intense than the other two phases. It may last two or three years.
Intrathecal chemotherapy:
During all three phases of chemotherapy treatment, many patients receive extra chemotherapy to destroy leukemia cells that may have spread to the central nervous system (the brain and spinal cord). This chemotherapy is injected right into the spinal fluid using a lumber punture (spinal tap) or an omaya reservoir (a device placed under the scalp). It is called intrathecal chemotherapy.
Bone marrow or cord blood transplant for acute lymphoblastic leukemia:
For some patients a bone marrow or cord blood transplant may offer the best chance for a long-term remission. A transplant is a strong treatment with risks of side effects, so it is not used for all patients with ALL. Transplant are used when chemotherapy alone is unlikely to provide a long-term remission.
Allogenic transplants for ALL:
The most suitable transplants for ALL are allogenic. An allogenic transplant from a family member, unrelated donor or cord blood unit replaces the abnormal cells in the patients bone marrow with healthy blood-forming cells Patients may receive an allogenic transplant in first remission, in second or third remission. It can also be employed after a relapse or while the disease is active if they do not reach remission.
Autologous transplants for ALL:
Another option for some patients may be an autologous transplant, which uses the patients own blood-forming cells. Autologous transplants have risks of serious side effects, but these risks are lower than allogenic transplants. However, patients have a higher risk of relapse of this leukemia after autologous transplants. This is because leukemia cells may retrun to the patient along with his or her blood forming cells.
Drugs used: fludarabine phosphate (fludara).
CHRONIC LYMPHOCYTIC LEUKEMIA:
Chronic lymphocytic leukemia as CLL in short, is a type of leukemia in which too many lymphocytes are produced. Although the malignant lymphocytes in CLL may look normal and mature, these cells may not cope effectively with infection.
CLL is the most common form of leukemia in adults. Men are twice as likely to develop CLL as women. However, the risk factor is aging over 50 years. More then 7,000 new cases of CLL are diagnosed in the U.S each year.
Patients with CLL show the symptoms such as lymphnodes, most commonly in the cervical (neck) area. Other symptoms, patients complain are the so-called “B symptoms” of lymphoma that include weight loss, fever, night sweats and extreme fatigue.
Treatment:
While it is generally considered that CLL is incurable it progresses slowly in most cases. Many people with CLL lead normal and active life for many years in some cases for decades. Because of slow onset, early stage CLL is generally not treated. Since it is believed that early intervention does not imporve survival time or quality of life, the condition is monitored over time.
The decision to start CLL treatment is taken when the patient’s clinical symptoms or blood counts indcate that the disease has progressed to a point where it may affect the patient’s quality of life. Clinical “staging sytems” such as the Rai4-stage system and the Binet classification can help to determine when and how to treat the patient.
CLL treatment focuses on controlling the disease and its symptoms rather then on an outright cure. Chemotherapy, radiation therapy, and biological therapy or bone marrow transplantation are used to treat CLL. Symptoms are some times treated surgically (splenotomy: removal of enlarged spleen) or by radiation therapy (“de-bulking” of swollen lymph nodes). Intial CLL treatments vary depending on the exact diagnosis and the progression of the disease and even with the preference and experience of health care practitioner. There are dozens of agents used in the treatment of CLL, and there is considerable research activity studying them individually or in combination with each other. For example, although the purine analogue fludarabine was shown to give superior response rates than chlorambucil as primary therapy, there is no evedence that early use of fludarabine improves over all survival, and some clinicians prefer to reserve fludarabine for relapsed disease. Combination chemistry regimens such as fludarabine with cyclophosphamide, FCR (fludarabine, cyclophosphamide and rituximab) and CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) are effective in both newly diagnosed and relapsed CLL. Allogenic bone marrow (stem cell) transplantation is rarely used as first line treatment for CLL due to its risk.
“Refractory” CLL is the CLL no longer responds favourably to treatment. In this case more aggressive therapies, including bone marrow (stem cell) transplantation, are considered. The monoclonal antibody, alemtuzumab (directed against CD52) may be used in-patients with refractory and bone marrow based disease. There is increasing intrest in the use of reduced intensity allogenic stem cell transplantation, which offers prospect of cure for selected patients with a suitable donor.
CONCLUSION:
Survival of patients with leukemia has improved dramatically over the years. From 1960 to 1963, an individual with leukemia, had a 14% chnace of living five years, by 1995 to 2000 the number had jumped to 46%.
Leukemia in gendral is 10 times more common in adults then in children, with the noteable exception of ALL, which accounts for approximately 78% among children. AML and CLL are the most common adult leukemia (approx.10, 980 and approximately 8,900 expected cases, respectively in 2005). The incidence of AML, CLL and CML increases drastically after age of 40 and is highest in those 60 years of age and older. The statistics regarding how long individuals live with leukemia vary according to the type of disease. Only about 20% of those with AML live for five years (approx) where as 70% of individuals who have CLL live that long. Survival numbers have raisen dramatically for those with ALL in the past several decades, largely due to advances in therapies for childeren. In the 1970’s, the five-year relative survival rate was 38%. By the late 90’s, it had reached 65%. In children with ALL, the survival rate in that period went from 53% to 85%. The vast majority of cases of CML occur in adults, and its frequency esculates with age. It is estimated that only one in one millon children upto age 10 develops CML, rising to one in 100,000 by age 50 and to one in 10,000 by age 80. The five-year survival rate between 1995 and 2000 was approxmately 37%.
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