Acute Myelogenous Leukemia (AML)Acute myelogenous leukemia (AML) is a fast-growing cancer of the blood and bone marrow. In AML, the bone marrow

makes many unformed cells called blasts. Blasts normally develop into white blood cells that fight infection. However, the

blasts are abnormal in AML. They do not develop and cannot fight infections. The bone marrow may also make abnormal

red blood cells and platelets. 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.

On this page: Acute myelogenous leukemia symptoms and diagnosis    Treatment options for acute myelogenous leukemia    Chemotherapy for AML    Bone marrow or cord blood transplant for AML    Making treatment decisions  

  Acute myelogenous leukemia symptoms and diagnosisAML is the most common type of acute leukemia. More than 11,900 new cases occur in the United States each year, mostly

in older adults. The average age of a person with AML is 65 years. Fewer than 10% of people with AML are children. Acute

myelogenous leukemia is also called acute myeloblastic leukemia, acute myeloid leukemia, acute granulocytic leukemia or

acute nonlymphocytic leukemia.

Symptoms

The symptoms of AML are caused by low numbers of healthy blood cells and high numbers of leukemia cells.

White blood cells fight infection. Low numbers can lead to fever and frequent infections.

Red blood cells carry oxygen throughout the body. Low numbers can lead to anemia — feeling tired or weak, being short of breath and looking pale.

Platelets control bleeding. Low numbers can lead to easy bleeding or bruising and tiny red spots under the skin (petechiae).

High numbers of leukemia cells may cause pain in the bones or joints.

A person with AML may feel generally unwell and run-down. He or she may also have other, less common symptoms.

Diagnosis

AML is diagnosed when blood and bone marrow samples show a large number of leukemia cells. AML has eight subtypes,

labeled M0 through M7. The subtypes are based on the type of blood cells affected. To find out the sub type and how well

the leukemia might respond to treatment, the samples are looked at to find:

The number of healthy blood cells.

The size and number of leukemia cells.

The changes that appear in the chromosomes of the leukemia cells. This is called cytogenetics.

Other genetic abnormalities, e.g., FLT3 mutation, N-RAS. 

Doctors also examine the patient to find out if leukemia cells have spread outside the blood and bone marrow. Doctors may

use a chest X-ray and an ultrasound of the abdomen to look at the organs and tissues inside. They may also use a test

called a lumbar puncture (spinal tap) to find out whether there are leukemia cells in the fluid around the brain and spinal

cord.

 Treatment options for acute myelogenous leukemiaAML can get worse quickly, so doctors usually begin treatment right away. To plan treatment, doctors look at a patient's

risk factors (also called prognostic factors). Risk factors are patient and disease traits that clinical studies have linked to

better or worse outcomes from treatment. Examples of risk factors are a patient's age and subtype of AML. To learn more

about AML risk factors as well as how treatment options may differ for children or for adults older than age 60, see Risk

Factors for Planning Treatment of AML. 

For a patient with AML, the treatment plan may include: Chemotherapy  — drugs that destroy cancer cells or stop them from growing (described below). A bone marrow or cord blood transplant (described below).

All-trans retinoic acid (ATRA) if he or she has the subtype of AML known as promyelocytic leukemia.

Other newer treatments that were recently developed or are still being studied in clinical trials — you can ask your doctor whether any newer treatments may be options for you.

Whichever treatment you and your doctor choose, you may be asked to be part of a clinical trial. Even standard treatments

continue to be studied in clinical trials. These studies help doctors learn more about which treatments work best for which

patients.  

 Chemotherapy for AML

Induction chemotherapy

For most patients, the standard first phase of AML treatment is induction chemotherapy. The goal of induction

chemotherapy is to bring the disease into remission. Remission is when the patient's blood counts return to normal and

bone marrow samples show no sign of disease (less than 5% of cells are leukemia cells). 

Induction chemotherapy is very intense. It usually lasts one week, followed by three or more weeks for the patient to

recover from the treatment. Often two drugs are used:

Cytarabine (ara-C)

An anthracycline drug such as daunorubicin (Daunomycin) or idarubicin (Idamycin)

Some patients may also be given additional drugs or different drugs. Patients who have the AML subtype promyelocytic

leukemia also are given all-trans retinoic acid (ATRA).

If one week of treatment does not bring a remission, treatment may be repeated once or twice. Induction brings a complete

remission in: 

 

About 70% to 80% of adults under age 60.

About 50% of adults over age 60.

More than 90% of children.

Successful induction chemotherapy destroys most of the leukemia cells, but a few will be left in the body. If these cells are

not destroyed, they can cause a relapse of the disease. More treatment is needed to destroy the remaining leukemia cells.

The next step may be consolidation chemotherapy or a transplant, depending on the treatment plan.

Consolidation chemotherapy

The second phase of chemotherapy is often called consolidation chemotherapy. The goal of consolidation chemotherapy is

to destroy any remaining leukemia cells. A common treatment is high doses of cytarabine (ara-C) given in three or more

cycles. Doctors may also use different drugs and schedules.

Consolidation chemotherapy is used to treat many patients with AML. It is the standard treatment at first remission for

adults with low-risk cytogenetic factors (changes in the chromosomes of leukemia cells), especially adults younger than

age 60.

   Bone marrow or cord blood transplant for AMLFor 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 serious side effects, so it is not used for all patients with AML. A transplant is

used when chemotherapy alone is unlikely to provide a long-term remission.Autologous transplant

An autologous transplant uses blood-forming cells collected from the patient. If an autologous transplant is a treatment

option for you, you will have blood-forming cells collected from your blood stream. The cells are usually collected after one

or two cycles of consolidation treatment. The cells are frozen until you are ready for transplant. You may receive an

autologous transplant soon after your induction therapy is completed, or your cells may be saved as a backup option in

case you relapse after receiving consolidation chemotherapy.

Autologous transplants have risks of serious side effects, but these risks are lower than for allogeneic transplants. However,

a patient has higher risks of a leukemia relapse after an autologous transplant. This is because leukemia cells may be

returned to the patient along with his or her blood-forming cells.

Allogeneic transplant

An allogeneic transplant replaces the abnormal cells in a patient's bone marrow with healthy blood-forming cells from a

family member or unrelated donor or cord blood unit. An allogeneic transplant has a higher risk of serious side effects than

consolidation chemotherapy or an autologous transplant. However, the risk of relapse is lower after an allogeneic

transplant.

Choosing a donor or cord blood unit

If an allogeneic transplant may be an option for you, your doctor will do a test to find out your HLA tissue type. Your doctor

will also test possible donors in your family to find out if they are a suitable match for you.

In adults in good health with standard AML and a matched sibling, an allogeneic transplant may be considered after

remission with induction therapy.

If you do not have a suitable donor in your family, your doctor can work with the National Marrow Donor

Program® to search for an unrelated donor or cord blood unit for you from our Be The Match Registry® and other registries

around the world. To save time, your doctor may check for potential donors on the registry at the same time he or she is

testing for donors in your family.

The closeness of the donor match can affect a patient's chances of a good transplant outcome. In general, transplants

using matched sibling donors have had the best results. However, outcomes for unrelated donor transplants have improved

in the last decade. For some groups of patients, outcomes for sibling donor and unrelated donor transplants are similar.

Reduced-intensity and non-myeloablative transplants

For some people with AML, an allogeneic transplant may offer the best chance for a long-term remission. However, more

than half of people with AML are over age 60. Many people older than age 60 are unable to tolerate the intense treatment

of a standard transplant. People with other health problems, such as heart disease or organ damage from previous

chemotherapy, may also be unable to tolerate a standard transplant. An allogeneic transplant using less intense treatment

may be an option for some of these patients. This type of transplant is called areduced-intensity transplant or non-

myeloablative transplant.Transplant success rates

Transplants have risks of serious complications, but a transplant offers some patients the best chance for a long-term

remission. If transplant is an option for you, your doctor can talk with you about the possible risks and benefits of a

transplant. For statistics showing patients' results after transplant, see AML Transplant Outcomes.  

 Making treatment decisionsAML is an acute disease that can get worse quickly. Most patients begin treatment with induction chemotherapy soon after

diagnosis. Many patients reach remission, but relapse of AML is common. All patients need a second phase of treatment to

try to prevent relapse. The second phase of treatment is based on a patient's risk factors. (For more information, see Risk

Factors for Planning Treatment of AML.) It is important to discuss your risk factors and your treatment options with a doctor

who is experienced in treating AML.Planning for a possible transplant

All patients with AML may want to talk with their doctors about including the possibility of a transplant in their treatment

plan. A transplant may be the first choice or it may be a backup plan. When transplant is not the first treatment, early

planning may allow for more flexibility in treatment options and a quicker transplant later, if it is needed. In general, to

prepare for the possibility of transplant:

Patients with AML should be HLA tissue typed at diagnosis.

Patients should be referred to a transplant doctor for consultation at an appropriate time based on risk factors.

Family members who might be suitable donors should be tested at the same time as the patient or soon after.

Doctors can take an early look at potential unrelated donors and cord blood units on the Be The Match Registry as soon as they know the patient's HLA tissue type. This first look is free of charge.

Patients who have no suitable related donor and few potential unrelated donors may want to discuss storing their own blood-forming cells for a possible autologous transplant.

The only patients who may not benefit from this planning are those who would clearly be unable to tolerate even a

reduced-intensity transplant. Some older patients and patients who have organ damage or other health problems may be

unable to tolerate a transplant. If you want to consider a transplant, a transplant doctor can examine you to see whether a

transplant is a good option.

It is important to talk about your treatment options with a doctor who is experienced in treating AML. Your doctor can

discuss your specific risk factors and treatment options with you. For more information to help you talk to your doctor about

whether a transplant is an option for you, you can share the referral guidelines (PDF) from the Physician Resources section

of this Web site with your doctor.

Introduction: a statement of the problem

Acute myelogenous leukemia (AML) in older adults is the most frequent form of AML and has a dismal long-term prognosis. The median age of patients with AML is around 64 years, and the incidence increases with age and rises from approximately 5 per 100000 at age 60 to 17 per 100000 at age 80.1

Older adults generally have more unfavorable prognostic factors at presentation and their treatment is made more difficult by their inability to withstand the intensity of chemotherapy. Further, the type of post-remission therapy that they receive is generally considered sub-optimal even for the less poor prognostic groups seen in younger adults. In essence, that is the crux of the problem; a biologically unfavorable disease that gets treated sub-optimally (Table 1).

The long-term prognosis is indeed dismal. A recent update by the Eastern Cooperative Oncology Group (ECOG) reviewed the long-term survival of 2882 patients treated between 1973 and 1996. All patients who entered these studies are included regardless whether or not they completed protocol therapy. The median survival for all 2882 patients was 11 months (Figure 1). However, for patients older than 55 years the median survival (944 patients) was 6 months with a 5-year survival of only 7.6% (Figure 2).

Published data from other groups show similar dismal long-term outcome. A recent update of the EORTCHOVON data for AML patients over 60 years reported a median survival of 9 months and a 5-year survival of 8%.2Data from the Fourth International Workshop on Chromosomes in Leukemia reported a 5-year survival for patients over 60 of less than 5%3 and a recent update from the Cancer and Leukemia Group B (CALGB) of almost 400 older patients treated intensively on consecutive protocols reported a 5-year survival of only 5%.4

Of interest, the published data are probably overly optimistic and misleading. As early as 1982, data published from the University of Chicago demonstrated that the incidence of specific translocations is highest in younger adults whereas the incidence of more unfavorable cytogentics, such as deletions of whole or part of chromosomes 5 or 7, as well as complex karyotypes, are more common in older adults.5 Yet, the reported data from cooperative group studies do not always reflect this. The leaders of rigorous cytogenetic monitoring and central review have been the CALGB, and if one observes their published data (Table 2), the incidence of unfavorable cytogenetics, surprisingly, is not significantly higher in older adults suggesting, perhaps, that many patients with unfavorable cytogenetics are not even entered on standard protocols even though there are no data that anything else is superior.

Thus, it seems that the published data are probably not representative of community practice, partly because the degree of patient selection is usually not described and, in any event, older patients referred to leukemia treatment centers are already a pre-selected group.

Intrinsic prognostic factors among older adults

Some superb analyses by the Southwestern Oncology Group (SWOG) reported a very high frequency of intrinsic multi-drug resistance (MDR1) among AML patients over 55 even among those considered as classically de novo.8 Specifically, the MDR1 was expressed in more than 70% of the patients. This was highly predictable of complete remission; that is a negative prediction. Those who had high MDR1 expression were less likely to go into complete remission, and the presence of MDR1 expression was also very significantly associated with resistant disease. In contrast, MDR1 was expressed in only 30% of AML patients younger than 55 years.

One of the hallmarks of secondary leukemias is the fact that they arise in a setting of trilineage dysplasia;9 a morphologic finding that is associated with more resistant disease.10 A close examination of patients in SWOG also described the occurrence of trilineage dysplasia in 64% of patients over 55 with apparent de novo AML.11

Finally, among the so-called de novo AML in older patients there is a striking preponderance of intermediate or unfavorable karyotypic abnormalities  most important being deletions of chromosome 7 or 5 as well as other monosomies, trisomies and complex karyotypes. These typical morphologic, immunophenotypic and genetic profiles among older adults are common among patients presenting with myelodysplasia (MDS) or AML that follows myelodysplasia or therapy-related AML. In other words, the prognostic factors of AML in older adults make it often indistinguishable from classic secondary leukemia.

Older adults are unable to withstand the intensity of therapy that is usually administered to younger adults and thus receive inadequate post-remission therapy. As an example of this problem, the CALGB (Table 3) reported that among almost 400 patients, even though half the patients responded, the long-term survival at 5 years was only 5%.4 Thus, although an increasing number of patients can achieve a good initial response, most relapse and the real challenge may be to maintain a response once this is achieved. The problem is somewhat analogous to Ph-positive ALL where although most patients can achieve a complete remission, with standard therapy virtually everyone relapses.

Therapeutic modulation: is there real progress?

Attempts to improve the therapy of older adults focuses on developments in induction, post-remission therapy, maintenance therapy, immunotherapy, MDR modulation and supportive care (Table 4).

Is there a best induction regimen?

The short answer is that this is probably not known, but certain things are clear. While most regimens include an anthracycline and cytosine arabinoside, the optimal anthracycline and dose has not been established. There have been three convincing trials in younger adults showing that idarubicin is better than 45 mgm2 of daunorubicin.12,13,14 Similar results have also been shown using other anthracyclines such as amsacrine,15mitoxantrone16 or aclacinomycin A.17 In other words, probably any anthracycline is better than 45 mgm2 of daunorubicin. What is not known is whether this represents a true biologic advantage or is merely a question of dose equivalence. At the same time the data in older adults  even for 45 mgm2 of daunorubicin  are equivocal and do not confirm this superiority.18,19

A recently completed trial by the Eastern Cooperative Oncology Group prospectively compared three induction regimens  daunorubicin 45 mgm2vs idarubicin 12 mgm2 vs mitoxantrone 12 mgm2  all given intravenously for 3 days  together with an identical dose of cytosine arabinoside, 100 mgm2 for 7 days, as well as an identical consolidation regimen. In this prospective trial among older adults there was no difference in efficacy between the three anthracyclines and no statistically significant difference in toxicity, although there may have been a trend for a lower therapy-related mortality using mitoxantrone.20 It should thus be noted that for those patients not on any specific study there are very few data that justify the continued use of 45 mgm2 of daunorubicin as standard induction therapy. On the other hand, although there has never been a prospective comparison between 45 mgm2 and 60 or 70 mgm2 of daunorubicin, sequential studies from both SWOG and ECOG very strongly suggest that a dose of 6070 mgm2 is both safe and more efficacious than 45 mgm2.21,22 These data also do not suggest that a higher dose of daunorubicin is more toxic in older adults.21

Is intensive post-remission therapy appropriate in older adults?

Over the past two decades there has been some debate whether older adults should indeed receive intensive induction therapy rather than an

attenuated form of therapy, or, no therapy at all.

The studies are small and limited, often not prospectively randomized. Nevertheless, they provide important information. A European study published in 198923 described older patients (median age 71) who were randomized to receive standard therapy at diagnosis vs those who followed a 'wait and see' approach whereby chemotherapy was only given when there was a clinical deterioration. The overall response rate was dramatically different  58% complete remission rate for those patients receiving standard therapy at diagnosis vs 0% for those only treated upon deterioration. The overall survival was similarly better.

Another study in older adults (median age 71) compared24 standard induction therapy vs low-dose cytarabine at presentation and demonstrated a better complete response rate for patients receiving standard therapy (52%vs 32%).

The overall data on the use of low-dose cytarabine were summarized in 1986.25 A detailed retrospective analysis of 751 patients demonstrated an unimpressive overall response rate. It should also be noted that when the low-dose cytarabine has been given with an intent to achieve a complete remission  using a 15- to 21-day course  such therapy is severely myelosuppressive with a long nadir. Thus, the preponderance of the data do not support the routine use of low-dose cytarabine, or other similar form of therapy, for remission induction in older adults who are biologically fit (Table 5).

How much post-remission therapy can be safely given?

It has become almost uniformly accepted that high-dose cytarabine is essential for post-remission therapy especially if bone marrow transplantation is not used. Perhaps this is so, but it is important to recall the data from the MRC trial  the largest published randomized study of adult AML  which shows a disease-free survival of 40% using chemotherapy alone.26 Even if children are excluded from this analysis, the disease-free survival is still 38%. Although these data are presented somewhat differently, they are still as good as anything else that has been published by anyone and importantly do not include what is typically considered as high-dose cytarabine (the highest dose used was 1 gm2 in only one of the consolidation courses). Thus, while there is no question that high-dose cytarabine is an effective post-remission therapy,27 it is not clear if one needs to subscribe to a dogma that it is a critical element of post-remission therapy.

As for safety, data now exist on over 300 older adults who have

received 12 doses of 1.5 gm2 of cytarabine as consolidation therapy in ECOG trials (only six doses for patients over 70). Such post-remission doses of cytarabine are very well tolerated and with a mortality rate of only 2%.21Furthermore, using such a consolidation course in older adults the median survival at 2 years is over 30%. Thus, the time may have come to critically evaluate and ask the question of whether a dose of 3 gm2, which is often administered and is far more toxic, is really necessary. Although not the topic of this discussion, the same question may apply among younger adults.

Another issue that often arises is how many cycles of high-dose cytarabine are needed as optimal post-remission therapy. The published data range from one to four or five cycles, often an impossible target among older adults. However, there have been no prospective evaluations of the optimal number of cycles of high-dose cytarabine needed for consolidation therapy at any age and thus, the number of cycles of high-dose cytarabine required in standard post-remission therapy is something that is presently unknown and needs to be studied. A current prospective study is being conducted by ECOG (E7996) which randomizes older adults to one or more courses of high-dose cytarabine.

What is the role of maintenance therapy?

The entire issue of maintenance therapy appears to be under-rated and does not give proper consideration to the existing data, especially in the context of an older adult population in whom it may be difficult to administer standard intensive post-remission therapy. A study by the ECOG in 1983 used standard induction therapy and was followed by post-induction randomization to allogeneic bone marrow transplantation if a donor was available; if not, patients were randomized to receive no therapy, maintenance therapy or consolidation therapy. In this study, maintenance therapy consisted of 6-thioguanine, 40 mgm2 for 4 days, followed by cytosine arabinoside on day 5 and this was repeated weekly for 2 years.28 A part of this study was closed early because the observation arm was significantly worse than those patients who received maintenance therapy. This was the first prospective study that demonstrated the need for some form of post-remission therapy and, importantly, showed that maintenance therapy was definitely effective in AML. It did not appear to be as effective as intensive consolidation, but it nevertheless was definitely effective. Similar data from the German Acute Leukemia Group29 described patients who were randomized following consolidation therapy to receive maintenance therapy or not receive maintenance therapy. The disease-free survival at 3 years was 30% for patients who received maintenance therapy vs 17%

on the observation arm (P = 0.003). Thus, maintenance therapy in AML is clearly effective. It is doubtful whether it has a role in younger adults who are able to tolerate intensive post-remission therapy but it is likely to have a role among older adults. This is clearly under-utilized and needs to be more rigorously and prospectively investigated.

What is the role of immunotherapy?

One of the areas of greatest promise, and one that often minimizes the stresses of myeloablation is immunotherapy. It is likely that the greatest progress, especially for older adults, is going to come from this area although one need not belittle its potential effect also for younger adults.

Monoclonal antibodies

Initial work on the development of monoclonal antibodies had led to the hopes that this would lead directly to an effective anti-tumor therapy. For two decades the clinical studies have been mostly disappointing. However, refinements to the initial technology and recent developments have put monoclonal antibody-based immunotherapy back in the forefront of some of the most exciting innovations in the therapy of AML. Current interest has focused on the antibody conjugate, calicheamicin gamma, which is a novel, very toxic drug moiety conjugated to anti-CD33 antibody.30 Because the CD33 antigenic expression is almost exclusively limited to the hematopoietic system, and occurs mostly on AML cells but not in normal hematopoietic elements, this has become a very attractive conjugate with the potential to inhibit growth of AML cell lines and growth of leukemic colony-forming cells.31 This conjugate, now known as CMA-676, is the drug antibody conjugate under greatest focus. Recent data32 reported on 23 relapsed AML patients among whom 43% responded; three went into complete remission and seven also went into remission except that they did not have the required 100000 l platelets that is usually mandated for a definition of the complete response. However, they met all the other criteria for complete remission and certainly established the efficacy of this single agent in the therapy of relapsed AML such that clinical trials in de novo AML will shortly be undertaken. Clearly, this represents one of the most novel and potentially exciting approaches to the therapy of AML and one may expect to hear much more about the CMA-676 conjugate.

IL-2

IL-2 has been around for a long time and has almost become accepted as

an important immunomodulator in AML post therapy.33 Rather surprisingly, despite the wealth of phase I and phase II information, there has never been a convincing phase III study that has shown its effect post remission in AML. Several such cooperative group studies have been launched but have closed early due to inadequate patient accrual. A current ongoing phase III study conducted by the CALGB (9720) is prospectively evaluating IL-2 post remission in patients over 60 years. It is hoped that this study will meet its accrual goal and will give a definitive answer as to the precise role of IL-2 in this setting.

An interesting international effort is underway evaluating the role of IL-2 and histamine. The rationale for this combination is based on the fact that IL-2 is generally thought to act by activation of NK cells as well as cytotoxic lymphocytes. It is also known that monocytes inhibit IL-2-induced activation of NK cells and of lymphocytes. The inhibition of cytotoxicity by monocytes is thought to be due to the monocyte-derived reactive oxygen metabolites. Histamine is known to inhibit production of these reactive oxygen metabolites and therefore is a candidate for an ongoing prospective phase III study, especially after promising preliminary phase III data that were published 2 years ago.34

Flt3 ligand

One of the most intriguing and interesting immunotherapeutic agents that have been developed in the past few years is Flt3 ligand (Flt3L) and this too has enormous potential for the therapy of AML.35,36,37,38

Flt3L is a growth factor with structural similarity to stem cell factor and CSF1. Flt3L stimulates human and mouse hematopoietic progenitor cells to proliferate and it stimulates the generation of human and mouse dentritic cells. One of the problems in the past has been the very small number of dendritic cells that was available for any demonstrable clinical efficacy.

Flt3L-generated dendritic cells have been shown to be imunophenotypically negative for CD1a, CD3, CD14, CD19, CD56, CD34 and positive for CD33, CD11c, CD86 and HLA-DR. They have characteristic veiled and dendritic processes and they stimulate the mixed lymphocyte response. A fundamental property of Flt3L in tumor therapy has been its remarkable ability to expand the number of functioning dendritic cells and increase the uptake and presentation of tumor-associated antigens. In addition, it stimulates tumor-specific cytotoxic lymphocytes. Importantly, Flt3-generated dendritic cells are as functionally competent as freshly isolated dendritic cells from untreated mice. Flt3 is also a very safe molecule, as shown by investigations in

healthy human volunteers.39 Table 6 schematically outlines a phase III study that is under development by the Eastern Cooperative Oncology Group which essentially will prospectively look at patients in remission and compare them giving six cycles of Flt3L vs observation only and see what effect this has on increasing or delaying disease progression.

What is the role of MDR modulation?

Ongoing studies are in progress on several potential multidrug resistance (MDR) modulators.40 It is fair to say, however, that the predominant current focus is on PSC833 which is at present the mostly widely studied MDR modulator. It is a non-immunosuppressive and a non-nephrotoxic cyclosporine analog. It is two- to 10-fold more potent than cyclosporine in modulating MDR and at the present time there are major ongoing phase III studies both in de novo (CALGB 9720) and in advanced AML (ECOG 2995). Although this is one of the areas under most intensive focus at the present time, caution here is in order as most of the preliminary reported data while confirming the in vitro MDR modulation  have not demonstrated striking clinical evidence of its efficacy.41,42 The importance of the current studies by the CALGB and ECOG is that pharmacokenetic considerations have been factored into the randomization such that patients who received PSC833 receive significantly lower doses of anthracyclines and VP-16  the primary target of MDR modulation. The problem with analyzing several ongoing, and recently published studies43 is the difficulty in interpreting the effect of an MDR modulator vs an effectively increased serum and cellular concentration of an anthracycline and VP-16.

What is the role of cytokines in AML?

It is surprising that despite 14 major controlled trial of growth factors after induction therapy for AML (Table 7), controversies still abound.21,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58 Virtually all the studies, with the exception of one very small report, have shown a significant reduction in the days to neutrophil recovery of 500 l to 1000 l and some of them have documented reduced morbidity. Data now exist on close to 3500 patients followed in these 14 well-controlled clinical trials. It is unfortunate that lingering doubts remain, in publications or in clinical practice, regarding the safety of cytokines in AML. However, the preponderance of the data have convincingly shown that cytokines are safe when used in induction or consolidation therapy. The problem in assessing outcome is that one is looking for major differences in survival or in response rate of AML, and failing to demonstrate that in many studies, seems to be a reason for hesitation in the use of cytokines. It is important to think of cytokines as supportive care measures like, for

example, central venous catheters which are probably not cost-effective; increase rather than decrease infection and yet there are very few individuals or centers who do not use them, owing to the benefit for the overall well being of the patients. Cytokines are similarly an important supportive care measure that significantly reduce the period of neutropenia. Studies of cost-effectiveness, using yeast-derived GM-CSF or G-CSF have also shown the benefit of growth factors.59,60,61,62,63 An exception has been a cost-effectiveness study using the more toxic E. coli-derived GM-CSF in AML.64 Thus, cytokines should be routinely used, following induction therapy for acute leukemia, at least in those patients with anticipated high risk for therapy-related morbidity.

Summary

The overall strategy for the treatment of older adults is summarized in Table 8. Soon after the birth of effective chemotherapy for acute leukemia, the perspective for all patients was summarized as follows: 'With all humility it may be claimed that there are, at least, grounds for hope and encouragement in this recently acquired ability occasionally to halt for a while the formerly unrelenting malignant process known as acute leukemia'.65 In reviewing the overall survival data for older adults one may feel that we are at a similar juncture in assessing the outcome for this particular population. It is hoped that some of the potential advances may provide greater hope and improved results over the next decade.

1.1. Latar belakang

       Leukemia adalah suatu keadaan di mana terjadi pertumbuhan yang bersifat irreversibel dari sel induk dari darah. Pertumbuhan dimulai dari mana sel itu berasal. Sel-sel tesebut, pada berbagai stadium akan membanjiri aliran darah. Pada kasus Leukemia (kanker darah), sel darah putih tidak merespon kepada tanda/signal yang diberikan. Akhirnya produksi yang berlebihan tidak terkontrol (abnormal) akan keluar dari sumsum tulang dan dapat ditemukan di dalam darah perifer atau darah tepi. Jumlah sel darah putih yang abnormal ini bila berlebihan dapat mengganggu fungsi normal sel lainnya, Seseorang dengan kondisi seperti ini (Leukemia) akan menunjukkan beberapa gejala seperti; mudah terkena penyakit infeksi, anemia dan perdarahan. (Hematologi Klinik Ed. 2.106).

Acute myeloid leukaemia (AML), yaitu leukemia yang terjadi pada seri myeloid, meliputi (neutrofil, eosinofil, monosit, basofil, megakariosit dan lain - lain). Di negara maju seperti Amerika Serikat, LMA merupakan 32% dari seluruh kasus leukemia. Penyakit ini lebih sering ditemukan pada dewasa (85%) dari pada anak (15%). (Buku Ajar Ilmu Penyakit Dalam Jilid II, Ed. IV.1234).

1.2.Tujuan dan manfaat

Tujuan penulisan referat ini adalah agar penulis atau pembaca dapat mengerti tentang Leukemia mieloblastik akut (LMA) meliputi penyebab, penyebaran, pengertian, perjalanan penyakit, gejala penyakit, komplikasi dan penatalaksanaan penyakit ini. Serta sebagai syarat untuk mengikuti ujian akhir blok.

  Manfaat dari referat ini antara lain mahasiswa bisa lebih mengerti akan suatu penyakit karena secara langsung membuat dan menyusun referat, serta mampu menerangkan tentang kasus yang didapat.

BAB 2

PEMBAHASAN

LEUKEMIA MIELOBLASTIK AKUT

2.1. Anatomi dan Fisiologi DarahA.       Pengertian

     Darah adalah cairan di dalam pembuluh darah yang mempunyai fungsi mentransportasikan oksigen, karbohidrat dan metabolit; mengatur keseimbangan asam dan basa; mengatur suhu tubuh dengan cara konduksi (hantaran), membawa panas tubuh dari pusat produksi panas (hepar dan otot) untuk mendistribusikan ke seluruh tubuh; dan pengaturan hormone dengan membawa dan menghantarkan kelenjar ke sasaran.

B.       Fungsi Darah

         Bekerja dari system transport dari tubuh, mengantarkan semua bahan kimia, oksigen dan zat kimia yang diperlukan untuk tubuh supaya fungsi normalnya dapat dijalankan dan menyingkirkan karbon dioksida dan hasil buangan lainnya.

         Sel darah merah mengantarkan oksigen ke jaringan dan menyingkirkan sebagian dari karbon dioksida.

         Sel darah putih menyediakan banyak baha pelindung dan arena gerakan fagositosis dari beberapa sel maka melindungi tubuh dari serangan bakteri.

         Plasma membagi protein yang diperlukan untuk pembentukan jaringan; menyegarkan cairan jaringan karena melalui cairan ini semua sel tubuh menerima makanannya. Dan merupakan kendaraan untuk mengangkut bahan buangan ke berbagai organ exkretorik untuk dibuang.

         Hormon dan enzim diantarkan dari organ ke organ dengan perantaraan darah.

C.    Bagian-Bagian Darah         Sel darah merah

Jika dilihat di bawah mikroskop, bentuk darah merah seperti saluran bikokaf tersebut mempunyai inti, warnanya kuning kemerah-merahan, sifatnya kenyal sehingga bias berubah bentuk sesuai dengan pembuluh darah.Sel darah merah atau eritrosit berupa saluran kecil , cebung pada kedua sisinya sehingga dilihat dari samping tampak seperti dua buah bulan sabit yang saling bertolak belakang.

         Sel darah putihBentuknya bening dan tidak berwarna ukurannya lebih besar dari pritosit, bentuknya lebih besar 2X sel darah merah, tetapi juga bermacam-macam inti sel dan banyak.Sel polimorfonulitear dan monosit normal dibentuk hanya dalam sumsum tulang, sebaliknya limfosit dan sel plasma dihasilkan dalam berbagai organ limfogen termasuk kelenjar limpa, limpa kelenjar timus forsit dan sisa limfoid yang terletak dalam usus dan ditempat lain.

         TrombositTrombosit adalah sel kecil kira-kira sepertiga ukuran sel darah merah. Peranannya penting dalam penggumpalan darah.

       Trombosit merupakan benda-benda kecil yang mati. Bentuk dan ukurannya bermacam-macam, ada yang bulat dan ada yang lonjong, warnanya putih. Trombosit bukanlah sel melainkan berbentuk keping-keping yang merupakan bagian-bagian terkecil dari sel besar. Trombosit dibuat di susunan tulang, paru-paru dan limpa dengan ukuran kira-kira 2 – 4 miliron umur peredarannya sekitra 10 hari.

2.2. Definisi

   Leukimia mieloblastik akut (LMA) adalah suatu penyakit yang ditandai dengan transformasi neoplastik dan gangguan diferensiasi sel-sel progenitor dari seri mieloid. Bila tidak diobati, penyakit ini akan mengakibatkan kematian secara cepat dalam waktu beberapa minggu sampai bulan sesudah diagnosis. Sebelum tahun 1960 pengobatan LMA terutam bersifat paliatif,

tetapi sejak sekitar 40 tahun yang lalu pengobatan penyakit ini berkembang secara cepat dan dewasa ini banyak pasien LMA yang dapat disembuhkan dari penyakitnya. Kemajuan pengobatan LMA ini dicapai dengan regimen kemoterapi yang lebih baik, kemoterapi dosis tinggi dengan dukungan cangkok sumsum tulang dan terapi suportif yang lebih baik seperti antibiotik generasi baru dan transfusi komponen darah untuk mengatasi efek samping pengobatan. (Buku Ajar Ilmu Penyakit Dalam Jilid II, Ed. IV.1234). 

2.3. Etiologi

       Pada sebagian besar kasus, etiologi dari LMA tidak diketahui. Meskipun demikian ada beberapa faktor yang diketahui dapat menyebabkan atau setidaknya menjadi faktor prediposisi LMA pada populasi tertentu. Benzene, suatu senyawa kimia yang banyak digunakan pada insidens penyamakan kulit di negara berkembang, diketahui merupakan zat leukomogenik untuk LMA. Selain itu radiasi ionik juga diketahui dapat menyebabkan LMA. Ini diketahui dari penelitian tentang tingginya insidensi kasus leukemia, termasuk LMA, pada orang-orang yang selamat bom atom di Hirosima dan Nagasaki pada 1945. Efek leukomogenik dari paparan ion radiasi tersebut mulai tampak sejak 1,5 tahun sesudah pengeboman dan mencapai puncaknya 6 atau 7 tahun sesudah pengeboman. Faktor lain yang diketahui sebagai predisposisi untuk LMA adalah trisomi kromosom 21 yang dijumpai pada penyakit herediter sindrom down. Pasien Sindrom Down  dengan trisommi kromosom 21 mempunyai resiko 10 hingga 18 kali lebih tinggi untuk menderita leukemia, khususnya LMA tipe M7. Selain itu pada beberapa pasien sindrom genetik seperti sindrom bloom dan anemia Fanconi juga diketahui mempunyai resiko yang jauh lebih tinggi dibandingkan populasi normal untuk menderita LMA.

Faktor lain yang dapat memicu terjadinya LMA adalah pengobatan dengan kemoterapi sitotoksik pada pasien tumor padat. LMA akibat terapi adalah komplikasi jangka panjang yang serius dari pengobatan limfoma, mieloma multipel, kanker payudara, kanker ovarium, dan kanker testis. Jenis terapi yang paling sering memicu timbulnya LMA adalah golongan alkylating agent dan topoisomerase II inhibitor.

2.4. Patogenesis

       Patogenesis utama LMA adalah adanya blokade maturitas yang menyebabkan proses diferensiasi sel-sel seri mieloid terhenti pada sel-sel muda (blast) dengan akibat terjadi akumulasi blast di sumsum tulang. Akumulasi

Blast di dalam sumsum tulang akan menyebabkan gangguan hematopoesis normal dan pada gilirannya akan mengakibatkan sindrom kegagalan sumsum tulang (bone marrow failure syndrome) yang ditandai dengan adanya sitopenia ( anemia, leukopeni, trombositopeni). Adanya anemia akan menyebabkan pasien mudah lelah dan pada kasus yang lebih berat akan sesak nafas, adanya trombositopenia akan menyebabkan tanda-tanda perdarahan, sedang adanya leukopenia akan menyebabkan pasien rentan terhadap infeksi, termausk infeksi oportunis dari flora normal bakteri yang ada di dalam tubuh manusia. Selain itu, sel-sel blast yang terbentuk juga punya kemampuan untuk migrasi keluar sumsum tulang dan berinfiltrasi ke organ-organ lain seperti kulit, tulang, jaringan lunak dan sistem syaraf pusat dan merusak organ-organ tersebut dengan segala akibatnya.

Gambar. Hematopoiesis

Sel ganas pada AML myeloblast tersebut. Dalam hematopoiesis normal, myeloblast merupakan prekursor belum matang myeloid sel darah putih, sebuah myeloblast yang normal secara bertahap akan tumbuh menjadi sel darah dewasa putih. Namun, dalam AML, sebuah myeloblast tunggal akumulasi perubahan genetik yang "membekukan" sel dalam keadaan imatur dan mencegah diferensiasi.Seperti mutasi saja tidak menyebabkan leukemia, namun ketika seperti "penangkapan diferensiasi" dikombinasikan dengan mutasi gen lain yang mengganggu pengendalian proliferasi, hasilnya adalah pertumbuhan tidak terkendali dari klon belum menghasilkan sel, yang mengarah ke entitas klinis AML.Sebagian besar keragaman dan heterogenitas AML berasal dari kenyataan bahwa transformasi leukemia dapat terjadi di sejumlah langkah yang berbeda di sepanjang jalur diferensiasi. Skema klasifikasi modern untuk AML mengakui bahwa karakteristik dan perilaku dari sel leukemia (dan leukemia) mungkin tergantung pada tahap di mana diferensiasi dihentikan.

Spesifik sitogenetika kelainan dapat ditemukan pada banyak pasien dengan AML, jenis kelainan kromosom sering memiliki makna prognostik.Para translokasi kromosom yang abnormal menyandikan protein fusi, biasanya faktor transkripsi yang mengubah sifat dapat menyebabkan "penangkapan diferensiasi." Sebagai contoh, pada leukemia promyelocytic akut, t (15; 17) translokasi menghasilkan protein fusi PML-RARα yang mengikat ke reseptor unsur asam retinoat dalam beberapa promotor myeloid-gen spesifik dan

menghambat diferensiasi myeloid. Klinis tanda dan gejala hasil AML dari kenyataan bahwa, sebagai klon leukemia sel tumbuh, ia cenderung untuk menggantikan atau mengganggu perkembangan sel-sel darah normal dalam sumsum tulang. Hal ini menyebabkan neutropenia, anemia, dan trombositopenia.

2.5. Gejala klinis

       Berbeda dengan anggapan umum selama ini, pada pasien LMA tidak selalu dijumpai leukositosis. Leukositosis terjadi pada sekitar 50% kasus LMA, sedang 15% pasien  mempunyai angka leukosit yang normal dan sekitar 35% mengalami netropenia. Meskipun demikian, sel-sel blast dalam jumlah yang signifikan di darah tepi akan ditemukan pada 85% kasus LMA. Oleh karena itu sangat penting untuk memeriksa rincian jenis sel-sel leukosit di darah tepi sebagai pemeriksaan awal, untuk menghindari kesalahan diagnosis pada orang yang diduga menderita LMA.

       Tanda dan gejala utama LMA adalah adanya rasa lelah, perdarahan dan infeksi yang disebabkan oleh sindrom kegagalan sumsum tulang sebagaimana telah disebutkan di atas. Perdarahan biasanya terjadi dalam bentuk purpura atau petekia yang sering dijumpai di ekstremitas bawah atau berupa epistaksis, perdarahan gusi dan retina. Perdarahan yang lebih berat jarang terjadi kecuali pada kasus yang disertai dengan DIC. Kasus DIC ini pling sering dijumpai pada kasus LMA tipe M3. Infeksi sering terjadi di tenggorokan, paru-paru, kulit dan daerah peri rektl, sehingga organ-organ tersebut harus diperiksa secara teliti pada pasien LMA dengan demam.

       Pada pasien dengan angka leukosit yang sangat tinggi (lebih dari 100 ribu/mm3), sering terjadi leukositosis, yaitu gumpalan leukosit yang menyumbat aliran pembuluh darah vena maupun arteri. Gejala leukositosis sangat bervariasi, tergantung lokasi sumbatannya. Gejala yang sering dijumpai adalah gangguan kesadaran, sesak nafas, nyeri dada dan priapismus.

    Infiltrasi sel-sel blast akan menyebabkan tanda/gejala yang bervariasi tergantung organ yang di infiltrasi. Infiltrasi sel-sel blast di kulit akan menyebabkan leukemia kutis yaitu berupa benjolan yang tidak berpigmen dan tanpa rasa sakit, sedang infiltrasi sel-sel blast di jaringan lunak akan menyebabkan nodul di bawah kulit (kloroma). Infiltrasi sel-sel blast di dalam tulang akan meninbulkan nyeri tulang yang spontan atau dengan stimulasi ringan. Pembengkakkan gusi sering dijumpai sebagai manifestasi infiltrasi sel-sel blast ke dalam gusi. Meskipun jarang, pada LMA juga dapat dijumpai infiltrasi sel-sel blast ke daerah menings dan untuk penegakan diagnosis diperlukan pemeriksaan sitologi dari cairan serebro spinal yang diambil melalui prosedur pungsi lumbal.

2.6. Diagnosis

       Secara klasik diagnosis LMA ditegakkan berdasarkan pemeriksaan fisik, morfologi sel dan pengecatan sitokimia. Seperti sudah disebutkan, sejak sekitar dua dekade tahun yang lalu berkembang 2 (dua) teknik pemeriksaan terbaru: immunophenotyping dan analisis sitogenik. Berdasarkan pemeriksaan morfologi sel dan pengecatan sitokimia, gabungan ahli hematologi Amerika, Perancis dan Inggris pada tahun 1976 menetapkan klasifikasi LMA yang terdiri dari 8 subtipe (M0 sampai dengan M7). Klasifikasi ini dikenal dengan nama klasifikasi FAB (French American British). Klasifikasi FAB hingga saat ini masih menjadi diagnosis dasar LMA. Pengecatan sitokimia yang penting untuk pasien LMA adalah Sudan Black B (SSB) dan mieloperoksidase (MPO). Kedua pengecatan sitokimia tersebut akan memberikan hasil positif pada pasien LMA tipe M1, M2, M3, M4, dan M6.

      Pertama, tes darah dilakukan untuk menghitung jumlah setiap jenis sel darah yang berbeda dan melihat apakah mereka berada dalam batas normal. Dalam AML, tingkat sel darah merah mungkin rendah, menyebabkan anemia, tingkat-tingkat platelet mungkin rendah, menyebabkan perdarahan dan memar, dan tingkat sel darah putih mungkin rendah, menyebabkan infeksi.      Biopsi sumsum tulang atau aspirasi (penyedotan) dari sumsum tulang mungkin dilakukan jika hasil tes darah abnormal. Selama biopsi sumsum tulang, jarum berongga dimasukkan ke tulang pinggul untuk mengeluarkan sejumlah kecil dari sumsum dan tulang untuk pengujian di bawah mikroskop. Pada aspirasi sumsum tulang, sampel kecil dari sumsum tulang ditarik melalui cairan injeksi.     Pungsi lumbal, atau tekan tulang belakang, dapat dilakukan untuk melihat apakah penyakit ini telah menyebar ke dalam cairan cerebrospinal, yang mengelilingi sistem saraf pusat atau sistem saraf pusat (SSP) - otak dan sumsum

tulang belakang. Tes diagnostik mungkin termasuk flow cytometry penting lainnya (dimana sel-sel melewati sinar laser untuk analisa), imunohistokimia (menggunakan antibodi untuk membedakan antara jenis sel kanker), Sitogenetika (untuk menentukan perubahan dalam kromosom dalam sel), dan studi genetika molekuler (tes DNA dan RNA dari sel-sel kanker).      Penyakit Leukemia dapat dipastikan dengan beberapa pemeriksaan, diantaranya adalah ; Biopsy, Pemeriksaan darah {complete blood count (CBC)}, CT or CAT scan, magnetic resonance imaging (MRI), X-ray, Ultrasound, Spinal tap/lumbar puncture.

Kelainan hematologis

  Anemia dengan jumlah eritrosit yang menurun sekitar 1-3 x 106/mm3.

  Leukositosis dengan jumlah leukosit antara 50-100 x 103 /mm3. Leukosit yang ada dalam darah

tepi terbanyak adalah myeloblas.

  Trombosit jumlah menurun. Mieloblas yang tampak kadang-kadang mengandung “badan auer”

suatu kelainan yang pathogonomis untuk LMA.

    

   Sumsum tulang hiperseluler karena mengandung mieloblas yang masif, sedang megakariosit dan pronormoblas dijumpai sangat jarang. Kelainan sumsum tulang ini sudah akan jelas meskipun myeloblas belum tampak dalam darah tepi. Jadi kadang-kadang ditemukan kasus dengan pansitopenia perifer akan tetapi sumsum tulang sudah jelas hiperseluler karena infiltrasi dengan myeloblas. Kadan-kadang ditemukan “Auer body” dalam mieloblas. Kadang manifestasi pertama sebagai eritroleukemia (ploriferasi eritroblas dan mieloblas dalam sumsum tulang) yang berlangsung beberapa bulan/tahun sebelum fambaran mieloblastiknya menjadi jelas benar.

2.7. Dignosis banding

       Leukemia mieloblastik akut harus dibuat diagnosa banding dan semua leukemia akut dan anemia aplastik. Apabila ditemukan “Auer body” maka diagnosabandin g tidak sulit ditegakkan, oleh karena kelainan ini patogonomis untuk leukemia mieloblastik akut.

       Apabila tidak ditemukan Auer body maka harus dikerjakan reaksi peroksidase dimana pada mieloblas pereksidase akan positif.

       Anemia aplastik dengan mieloblastik akut yang alekemik di bedakan atas dasar pemeriksaan sumsum tulang. Secara klinis endokarditis bakterialis mirip leukemia mieloblastik akaut karena adanya febris, anemi, splenomegali, dan ptechiae. Tentu adanya riwayat penyakit jantung, splenomegali yang lebih besar dan tidak adanya kelainan pada gusi dapat membedakan kedua keadaan ini.

Anemia pernisiosa yang disertai splenomegali dan ptechiae dapat menyerupai leukemia mieloblastik akut.

       Pada anemia pernisiosa biasanya pasien tidak tampak sakit berat, terdapat ikterus dan tidak ada kelainan pada gusi.

Gambar. Auer Body pada LMA

Gambar. Leukemia Myelogenous akut

2.8.Komplikasi

      Dua macam komplikasi yang sering bersifat fatal yaitu perdarahan serebelar dan infeksi. Komplikasi yang jarang terjadi adalah keluhan akibat tekanan oleh suatu tumor leukemia.

2.9.Penatalaksanaan

      Perbaiki keadaan umum yaitu : anemia diberikan tranfusi darah dengan PCR (Packed red cell) atau darah lengkap. Trombositopeni yang mengancam diatasi dengan transfusi konsetrat trombosit. Apa bila ada infeksi diberikan antibiotika yang adekwat. Terapi spesifik seperti terapi leukemia pada umumnya dimulai dengan tahap induksi dengan : Doxorubicin 40 mg/mm2 berat badan hari 1-5. Dilanjutkan denagan Ara C 100 mg IV, tiap 12 jam hari 1-7. Untuk pasien usia di atas 50 tahun dosis dikurangi dengan Adriamycin hanya 3 hari dan Ara C 5 hari. Obat pengganti adriamycin adalah Farmorubicin. Dilakukan evaluasi klinis dan hematologis. Pemeriksaan sumsum tulang pada akhir mimggu ketiga. Apabila tidak terjadi remisi atau remisi hanya bersifat parsiil maka terapi harus diganti dengan regimen lain.

       Apabila terjadi remisi lengkap (klinis dan hematologis) maka dimulai tahap konsolidasi. Pada tahap ini diberikan doxorubicin 40 mg/mm2 hari 1-2 dan Ara C 1-5. Refimen ini diberikan 2 kali dengan interval 4 minggu.

      Apabila keadaan memungkinkan maka diberikan cangkok sumsum tulang pada saat terjadi remisi lengkap. (Hematologi Klinik Ed. 2.113).

      Terapi standar adalah kemoterapi induksi dengan regimen sitarabin dan daunorubisin dengan protokol sitarabin 100 mg/m2 diberikan secara infus kontinyu selama 7 hari dan daunorubisin 45-60 mg/m2/hari iv selama 3 hari. Sekitar 30-40% pasien mengalami remisi komplit dengan terapi sitarabin dan dounorubisin yang diberikan sebagai obat tunggal, sedangkan bila diberikan sebagai obat kombinasi remisi komplit dicapai oleh lebih dari 60% pasien. (Buku Ajar Ilmu Penyakit Dalam Jilid II, Ed. IV.1238).2.10.Prognosis        Dengan terapi agresif, 40 -50 % penderita yang mencapai remisi akan hidup lama (30-40 % angka kesembuhan keseluruhan). Penderit yang mengalami relaps setelah mendapat kemoterapi atau transplantasi autolog dapat diterapi dengan CST allogenetik sebagai terapi penyelamatan. Beberapa subtipe morfologi atau genetik LMA mempunyai prognosis lebih baik.

BAB 3

PENUTUP

3.1.Kesimpula

      Leukemia (kanker darah) adalah jenis penyakit kanker yang menyerang sel-sel darah putih yang diproduksi oleh sumsum tulang (bone marrow). Sumsum tulang atau bone marrow ini dalam tubuh manusia memproduksi tiga type sel darah diantaranya sel darah putih (berfungsi sebagai daya tahan tubuh melawan infeksi), sel darah merah (berfungsi membawa oxygen kedalam tubuh) dan platelet (bagian kecil sel darah yang membantu proses pembekuan darah).     Sampai saat ini penyebab penyakit leukemia belum diketahui secara pasti, akan tetapi ada beberapa faktor yang diduga mempengaruhi frekuensi terjadinya leukemia :1. Radiasi. Hal ini ditunjang dengan beberapa laporan dari beberapa riset yang menangani kasus Leukemia bahwa Para pegawai radiologi lebih sering menderita leukemia, Penerita dengan radioterapi lebih sering menderita leukemia, Leukemia ditemukan pada korban hidup kejadian bom atom Hiroshima dan Nagasaki, Jepang.2. Leukemogenik. Beberapa zat kimia dilaporkan telah diidentifikasi dapat mempengaruhi frekuensi leukemia, misalnya racun lingkungan seperti benzena, bahan kimia industri seperti insektisida, obat-obatan yang digunakan untuk kemoterapi.3. Herediter. Penderita Down Syndrom memiliki insidensi leukemia akut 20 kali lebih besar dari orang normal.4. Virus. Beberapa jenis virus dapat menyebabkan leukemia, seperti retrovirus, virus leukemia feline, HTLV-1 pada dewasa.

      Sistem Terapi yang sering digunakan dalam menangani penderita leukemia adalah kombinasi antara Chemotherapy (kemoterapi) dan pemberian obat-obatan yang berfokus pada pemberhentian produksi sel darah putih yang abnormal dalam bone marrow. Selanjutnya adalah

penanganan terhadap beberapa gejala dan tanda yang telah ditampakkan oleh tubuh penderita dengan monitor yang komprehensive.

3.2.Saran

     Leukemia salah satu penyakit yang berbahaya, sehingga harus diwaspadai dengan cermat, maka sangatlah penting untuk mencegah penyakit ini dengan cara menghindari faktor resiko dan menjaga pola hidup sehat sedini mungkin.

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