L1 means the childhood form of ALL; lots of small lymphocytes.
L2 means the adult form of ALL; lymphocytes are larger.
L3 Burkitt's lymphoma-- rare-- most aggressive type.

The most favorable type is L1, the least favorable is L3, with L2 intermediate. ALL can then be further subclassified by immunophenotyping, to see if the cells are or"B" or"T" origin. Their surface proteins can be analyzed to determine how "mature" the cells are. For instance, "B" lymphocytes normally develop in a progression from"early pre-B" to "pre-B" to"B" ;in general the less mature the lymphocyte the less "surface immunoglobulin" (protein) it produces, and the easier it is to treat successfully.

AML arises from any blood cell beside lymphocytes, so it's classification is even more complicated, and divided into 7 "M"categories by the FAB system, and followed by their relative proportions making up adult acute leukemia:

M1 "myeloblastic" cells, very immature can be confused with L2; 20%
M2 "myeloblastic" cells with maturation, larger cells, 30%
M3 "promyelocytic" cells are further developed than M1 or M2 10%
M4 "myelomonocytic" more mature looking like monocytes 30%
M5 "monocytic"-- the cells look just like monocytes. 10%
M6 "erythocytic " means it comes from red blood cell lineage <5%
M7 "megakaryoblastic" -- it comes from platelet making cells <5%

Sometimes the acute leukemias start off as one form and seem to develop into another. For instance, M6, "erythroleukemia", usually "progresses" to M2 or M4. This occurs as the unstable DNA within the leukemic clone changes form. Also, the altered biochemical conditions fostered by one leukemic clone might encourage another different leukemia to arise, in the patient already predisposed to develop leukemias, and so more than one type may be seen in that patient.

What are the Factors Influencing Outcome in Leukemia?

Factors influencing predicted outcome and survival in disease are called "prognostic factors" and these have been identified for acute leukemia:

ALL worsening characteristics:

a) Types L2 or L3 as opposed to L1 ; production of mature surface proteins.
b) Being Male, or Adult (children ages 3 to 7 do best).
c) "T" cell leukemia as opposed to "B" cell.
d) High White Blood Cell count (over 25,000); severe anemia, low platelets.
e) Organ or Glandular swelling, mass in the center of chest ("mediastinum").
f) Involvement of the spinal fluid, brain linings, or eyes. ("CNS leukemia").
g) Presence of Philadelphia Chromosome, especially after treatment.

AML worsening characteristics:

a) Age older than 60 years, Down's syndrome, infant-age children.
b) Secondary AML , after treatment for ALL or another cancer.
c) AML arising out of a long standing "myelodysplastic" syndrome.
d) Presence of the Philadelphia Chromosome, especially after treatment.

What is the Survival From Acute Leukemia?

This will depend upon many factors, including the particular type of leukemia, the condition of the patient, and the therapy selected. According to textbooks, prior to discovery of chemotherapy everyone with acute leukemia died within 2 years. The following results are seen with conventional therapy still used today:

For ALL the cure rate is currently 40% for adults and 60% for children.
For AML the cure rate is currently 20%, overall.

No one can predict how long any individual patient will live, we are not "M.Dieties". Recall that many patients live longer than expected, and lead high quality lives, with their cancer.

What is the Conventional Treatment for Acute Leukemia?

The most important thing in treating leukemia is the induction of a "complete remission" in the patient. A "complete remission" is defined as:

1) No sign of leukemic cells in the patients blood or bone marrow, the bone marrow should have less than 5% "blasts" (young cells).
2) Normal white blood cell, red blood cell, and platelet counts.
3) No residual organ, testicle or glandular swelling.
4) Ability of patient to return to previous normal activities.

Unfortunately, "complete remission" does not mean getting rid of every last leukemia cell, it does mean there are too few to be detected with our current technology. In practice, the number of leukemia cells is probably reduced from a trillion to a billion with induction therapy. This is enough to resolve all symptoms.
After successful induction of remission, the next step is to"consolidate" the remission with "intensification therapy" given over several months. After this, the remission may be"maintained" with "maintenance therapy" spanning out over several years. Only after the patient has been kept in complete remission for several years can the total discontinuance of therapy be considered, although close follow up will be essential to at least 5 years. Cancer doctors speak in terms of "phases" of therapy for leukemia-- "induction, consolidation, intensification, maintenance" to describe each stage of the treatment, and to be able to compare the results of various regimens. The refinements in the treatment of leukemia have been by examining the results of side-effects of each of these particular phases and trying to improve upon them. Improvement may actually mean that the therapy becomes less aggressive. For instance, radiation to the brain used to be used for most children with leukemia, but now is only used for those with high risk factors. Treatment for acute leukemia always includes chemotherapy, and may additionally use radiation therapy, immune therapy, and bone-marrow transplant. Preventative therapies ("prophylaxis"), may be necessary for "sanctuary sites" (i.e. nervous system). Treatments used will depend upon the type of leukemia, how extensive it is, the condition of the patient, and the available local facilities.

We will now consider the standard therapies for ALL and AML:

For ALL the standard "Remission Induction" phase is:

Vincristine and Prednisone will produce remission in 90% of children and 50% of adults. Each agent used alone is only half as effective. Adding L-asparaginase ups remission to 95%. in children and 80% in adults. Doxorubicin (adriamycin) can be added instead. The use of more than 3 drugs has not improved success rates. A bone-marrow biopsy after 7 days of treatment is useful to predict if the regimen is working. If it doesn't work by 6 weeks, there is no use continuing that particular therapy.

Side- Effects of ALL Remission Induction Drugs:

Vincristine derived from the periwinkle plant and given by injection. It can cause "peripheral neuropathy", meaning pain and numbness from nerve damage, as well as kidney damage and hearing loss. It lowers blood cell counts which can lead to anemia and infection. The risk of these side effects depends upon the dose and what other drugs are being used. Many patients have minimal side effects.

Prednisone is a cortisone derivative that can be taken as a pill. This"steroid" drug reduces the white blood cell count, and over time will increase the risk for infection, thin bone, raise the chance of internal
bleeding and cause a "Cushinoid" appearance (fat face and body, thin limbs, hair growth, 'buffalo hump' on back). It is usually very well tolerated over short courses (e.g. a few weeks), and the side effects
become more prominent with higher doses over a longer time.

L-Asparaginase is from the amino acid asparigine and is given into the veins ("I.V."). It causes nerve damage and nausea.

Doxorubicin (Adriamycin) is a brilliant red color "anthracycline" (from coal) and is always given I.V. It's main side-effect is heart damage (no more than 500 mg. per square meter of body area are given, and
a heart test ("MUGA") is gotten first). Also, it can cause lung damage, and the skin to become redder than normal with radiation. It causes hair loss (usually temporary), and decreased blood counts.

For ALL the "Consolidation and Intensification" phase, and "Prophylaxis" is:

Cytarabine (ARA-C) with or without intermittent "pulses" of vincristine and prednisone. The idea here is to further reduce the presumed one billion or so leukemic cells remaining after remission induction.

CNS Prophylaxis is mandatory in children after complete remission and the methods of clearing the Central Nervous System of actual or presumed leukemia cells have been subject to much study. If no CNS prophylaxis is given to children, it will be the first site of relapse 50% of the time. While adolescents and adults usually get prophy laxis, it has not been shown to improve survival for them. Previously radiation therapy used to be always used; it is now only used in high risk patients and those with actual CNS leukemia. Instead, most patients get "Intrathecal Chemotherapy" -- directly into the spinal canal given with a spinal tap. The drug most used is Methotrexate. In low risk patients, Methotrexate alone is sufficient therapy, reducing CNS relapse from 30% to just 5%. In those with high risk disease, it
is appropriate to add "cranial" radiation (10 treatments totaling 18.0 Gray) to reduce the CNS relapse risk from over 50% to 5%. Treating the entire spinal column with radiation (in addition to the skull) used to be common, but this "cranial-spinal" irradiation is now almost always avoided since it is doesn't help survival, and causes growth deformity, nutrition problems, and bone marrow damage in children. The only current use for cranial-spinal irradiation is to treat florid re lapse in the CNS. In an patient getting both Methotrexate and Radiation, it is critical to give the Radiation first, and then the Methotrexate, since this causes less brain damage than vice-versa.

Side Effects of Consolidation and CNS Prophylaxis:

Cytarabine (ARA-C) can also be used in CNS prophylaxis for those not responsive to Methotrexate. It very powerfully lowers blood counts. It is given as an injection. It can cause liver and kidney damage.
The side effects of the other drugs used for consolidation are above.

Cranial Irradiation: Is given to each side of the head, while using a block to protect the lens of the eye. It is also called "whole brain" irradiation. The treatment is given with a Linear Accelerator (Linac)
with high-energy photons. The therapy takes about 3 minutes per day for 10 days, Monday through Friday. The therapy itself if painless, small children may need short-acting anesthesia to hold still. Radia tion causes the scalp hair to fall out (temporarily) and the patient to be tired during treatment. Long term, children who receive radiation may develop a syndrome of acute fatigue and lethargy which slowly improves as the brain heals. They tend to have somewhat lower IQ scores and more propensity to behavioral problems, but it is hard to separate out the contributions of radiation, chemotherapy, and just
the trauma of being diagnosed and treated for leukemia. Recent studies have shown no worse brain functioning in children who got both cranial radiation and methotrexate versus just methotrexate.

For ALL the "Maintenance" phase is:

6-Mercaptopurine (6-MP) used daily is added to oral methotrexate weekly, and sometimes with prednisone and the other drugs above. 6-MP is given as a pill, lowers blood counts and can cause some
back up in the liver. The question of how long to continue maintainance is controversial, but in childhood ALL it's at least 30 months.

Side-Effects of Maintenance Therapy:

6-MP and Methotrexate must be given in sufficient dose to lower blood counts ("hematosuppression") to be effective. This means the patient will be at risk for anemia and infections. Also, these drugs can cause mouth sores ("stomatitis"), diarrhea, and liver and kidney function (that must be closely monitored). Giving these drugs to children can cause growth problems and bone weakness ("osteoporosis"). As mentioned, children are often socially underdeveloped due to the stresses of the disease and it's treatment.

For AML (except M3) the Remission Induction Drugs are:

Cytarabine and Idarubicin (or Daunorubicin) are typical induction drugs. It is mandatory to give these drugs until almost complete bone marrow shutdown, which occurs within 10 - 14 days after treatment begins. The regimen will need to be repeated if a complete remission is not gotten. About 75% of patients will have a complete remission within a month of starting treatment. However, this remission alone is temporary.

Side effects of AML Remission Induction Drugs:

Cytarabine and Idarubicin together are a very powerful combination. The treatment lowers blood counts so drastically that the patient must be very carefully monitored for anemia, infection and internal bleeding. Temporary baldness, nausea and vomiting, and mouth sores occur. The regimen can cause heart damage and even heart failure. A certain type of "port" (catheter) must be put into a major vein to give the drugs, and local tissue damage will occur if the drugs seep out of the port into the surrounding tissues. The port itself is subject to infections and may "clot-off", necessitating putting through streptokinase or some other clot-dissolving agent. Not all patients can tolerate such aggressive induction, it is especially difficult on the elderly or very young. The elderly may opt for lower doses of these drugs, or oral drugs like hydroxyurea which has less cure, but also less early deaths from therapy and better quality of life. If the elderly do get the standard remission drugs in full doses, their remission rates are the same as for younger patients.

For AML type M3 (Promyelocytic) the Remission Induction Is:

Trans-Retinoic Acid, a vitamin A derivative, given as pills twice per day for about 2 months. Nearly all patients get a complete remission, without problem of blood count lowering. However, after the remission standard intensive chemotherapy will still be needed (as described below) to help prevent relapse. The problem of inappropriate blood clotting is seen in over 80% of patients with the M3 type; this must be carefully monitored.

AML After-Remission Therapy:

It is essential to continue treating the patient with AML after a complete remission is obtained, since over 95% of patients would relapse without more therapy. The appropriate treatment to maintain complete remission is dependent upon the condition, tolerance and wishes of the patient and what's available. The
doses of drugs given may have to be reduced if they are causing excessive blood count lowering or otherwise sickening the patient. In general, after remission therapy ("post-remission") is given after the patient's blood counts have recovered from the induction phase. The post-remission drugs are given for at least 4 cycles, but long-term "maintenance" chemotherapy has not been shown to improve survival, and definitely hampers quality of life. The drugs commonly used:

Cytarabine (ARA-C) is given by vein alone or again in combination with a drug like Daunorubicin. While the duration for giving this treatment is controversial there is no question that patients who complete one or more "consolidation courses" (cycles) with these drugs have a longer survival than those who do
not. These drugs severely depress blood counts, of both leukemic and normal cells, and some considerations of this are:

a) Replacement Therapy of critical blood components, that is transfusions, will be necessary if the hemoglobin drops below 8 or the platelets below 20,000. It gets harder to transfuse successfully as the patient develops antibodies to donor blood cells and platelets, and the immune system destroys them. If the white blood cell count falls to under 500 and the patient has a fever, they get l "granulocyte transfusions" and antibiotics.
b) Supportive Therapy includes giving proper nutrition and fluids to keep metabolism balanced, and drugs like Allopurinol which help excrete that excess uric acid released from killed blood cells, preventing it from building up and causing gout. A remarkable advance in support has been the development of Growth Factors which stimulate new blood cells to form, specifically erythropoetin to stimulate red blood cells and neupogen (GM-CSF) to stimulate white blood cell development. We are working on
a growth factor to stimulate platelet growth, but don't have it yet. Giving Growth Factors can reduce anemia and infections without transfusions.

Results of Conventional Therapy for AML:

Without any treatment, the average survival for AML patients is just 3 months. When giving chemotherapy, replacement and supportive therapy as described above, above, the average survival increases to about 18 months. This means some patients live much longer, and about 20% of patients are alive and disease free at 5 years. The most common causes of demise in patients are infections and hemorrhage resulting from the disease, it's therapy, or both. The longest survivals from conventional treatment are from studies that use intensive consolidation chemotherapy after complete remission is achieved by induction.

Latest Effective Treatments for Acute Leukemia.

Bone Marrow Transplant is the most exciting practical development for both ALL and AML. We first describe the process and side effects, then the latest results. It is important to note that the success rates have been increasing, and the complication rates decreasing, as more Bone Marrow Transplants are done. While the procedures used to be limited to only the most advanced University Hospitals, there is now a push for some to be done at smaller Community Hospitals given increased safety and success with experience and new drugs.

The rationale for Bone Marrow Transplant is that it allows much higher doses of chemotherapy to be given than otherwise possible, wiping out not only the cancer cells but also the patient's entire ability to manufacture new blood cells. If the blood-forming cells were not replaced, this would be lethal. Basically, Bone Marrow transplant is merely a method of replacing the blood forming cells after intensive chemotherapy. There are two distinct types of Bone Marrow Transplant, the first being using the patient's own blood forming cells which have been "harvested" and stored ("autologous transplant") and the second is using "donor" blood-forming cells from another person ("allogeneic transplant") . When using donor blood forming cells, the donor is usually a very close relative since the cells must be closely matched to those of the patient, for the transplant to a success. To match marrow a sample must be taken by needle, usually from a hip bone, and the sample is "HLA matched" see how similar it is to the patients. Only identical twins would have identical marrow, but the closer of a match that can be obtained, the less chance for rejection in the patient. Using donor marrow is fraught with more difficulties than using the patient's own stored marrow, so "autologous" transplants are generally preferred, provided the patient's stored marrow can be "purged" of the leukemic clone. It makes no sense to give the patient back his own leukemia cells and re-initiate the disease!

For both autologous and allogeneic transplants, there are two basic ways that the blood-forming cells can be collected.The first and older technique is to "harvest" bone marrow from the iliac wing bones, that is the hip area. The patient or matched donor is taken taken to the operating room and commonly put under general anesthesia. About 50 punctures are made with a special bone-boring needle into the bone above each buttock, and the marrow from this area sucked out ("aspirated"). There is no significant danger (besides anesthesia risk) to the donor, this marrow is expendable, but some scarring is common in the harvest area. The marrow is stored in glass jars. If it comes from the patient, then it may be cleaned ("purged") of leukemia cells; this process is unnecessary if it comes from a healthy donor. New techniques have improved the success of purging, but it still remains a risk to give the patient back there their disease in the transplant. The second and newer method is less invasive and does not take actual marrow, but instead"stem cells" circulating in the bloodstream. These "stem cells" can form new marrow, all crucial blood cells, and "reconstitute" the blood.

For stem-cell collection, the procedure is not called a "Bone-Marrow" transplant but instead a "Peripheral Stem Cell Transplant". Since currently this procedure is used with patient's own stem-cells, the full name is "Autologous Peripheral Stem Cell Transplant". For this, the patient comes in several times and has a needle ("catheter") inserted into an arm vein. Blood is drawn out and processed through a special machine which collects stem cells, and then returns the residual blood back to the patient. The cells removed are centrifuged to remove the circulating stem cells, which are packaged and stored. The process of separating specific white blood cells is called "leukophoresis" and ideally will remove the cancerous clone, while preserving the healthy stem cells to re-infuse.

The next step for any Bone Marrow Transplant is for the patient's own marrow to be destroyed by chemotherapy ("cytotoxic marrow ablation"). This is to annihilate the leukemic clone, and as a consequence destroys every other blood forming cell at the same time. Sometimes, part of the "preparative regimen" for Bone Marrow Transplant is the addition of "whole body radiation" . For this, the patient is sent down to the Radiation Oncology Department for initial measurements of body thickness, and to make appropriate physics calculations. During the Marrow Ablation phase (and while receiving the chemotherapy) about 6 whole body radiation treatments are given over 3 days (so two treatments per day about 6 hours apart). The patient, on a cart, is usually placed against a wall in the treatment room and the Linear Accelerator is turned on for about 10 minutes per treatment. They are commonly treated from each side, with their arms at their sides to help lower the dose to the lungs. A plexiglass "scatter screen" is placed between the patient and the machine, which helps boost up the dose to the skin. This is because leukemic cells can hide in the lower skin layers. The actual radiation treatment is painless, and the patient is then returned to their room.

The side-effects of the "preparative regimen" for Bone Marrow Transplant are due to a killing of all the rapidly dividing cells in the body. The side-effects will depend on whether just chemotherapy is used, or whether whole-body radiation is added also. The chemotherapy side-effects are the same as noted above for when these drugs are used a primary treatment, but for marrow ablation higher doses are given. The dose is, in fact, "super-lethal", since the patient will die if the bone marrow is not replaced. The first cells to disappear from the bloodstream are those with the shortest normal life-- white cells often only live 10 hours! Next, the platelets, with an average life of 10 days, will disappear, and finally the red blood cells with an average life of 120 days. Thus, if not replaced, we would expect to see, in order, infection, hemorrage, and then anemia develop from the marrow ablative therapy. In practice, the patient will not live long enough to develop anemia, first dying from infection and hemorrhage. It takes a while for the re-infused bone marrow or stem cells to "take", and start producing new blood cells. This is a critical time for supportive transfusions and preventing infections.

The side effects of whole body radiation are divided into "acute" and "late" categories. Acute reactions, seen during the treatment period, include nausea, vomiting, swelling of the salivary glands (looks like mumps), sore throat, hair loss and fatigue. Some skin redness may develop. These acute reactions will resolve with time. Late reactions take weeks to years to manifest and include sterility, a thickening of the skin, cataract formation of the eyes, and possible heart, lung and liver damage. The most worrisome possible complications are "radiation pneumonitis" from overdose to the lungs, and "venoocclusive" disease of the liver. These may range from mild to fatal. The treatment is broken up into about 6 "fractions" to help reduce the risk of these late reactions, which used to be much more common when the whole treatment was given at one sitting. It is sometimes hard to thresh out which side-effects came from the chemotherapy and which from radiation. Generally, however, the preparative regimen is well tolerated, and the patient can be supported with anti-nauseants and other medicines for comfort.

Once the "preparative" regimen has been completed, the stored blood-forming cells are infused into a ordinary vein. They circulate through the bloodstream and find their way into the center of the bones, sticking onto the bone "spicules" there. They (hopefully)"engraft", meaning take and start forming new blood cells. If they don't, the patient will die of "aplastic anemia" unless given constant transfusions. Happily, the cells do usually take, although new blood cell formation may at first be a very slow process. The patient is given antibiotics to prevent infection, and daily blood counts are taken to check for engraftment. If the transplant is from another person ("allogeneic") who is not an identical twin, then anti-rejection drugs like Cyclosporine and Thymosin will be given to help prevent rejection. An unusual situation may arise when people are given foreign bone marrow. Instead of the body rejecting the transplant, as is seen with kidney or liver transplants, the transplanted bone marrow rejects the body it is put into! This is called "Graft versus Host Disease, or "GVH" for short. GVH manifests as skin rashes, fatigue and organ swelling, and low blood counts. Sometimes a liver or skin biopsy is necessary to make the diagnosis. It is treated by increasing the amount of anti-rejection drugs the patient receives. Ironically, some GVH actually helps ensure that the transplant is a success, by killing off any remaining leukemic cells in the patients body! Thus, doctors may not wish to suppress GVH totally, although it can be fatal if it is uncontrolled. Normally, patients are ready to go home after several weeks in the hospital, and can return to regular activities. If the patient relapses after bone-marrow transplant, it can be tried again, but the whole body radiation is only given once in the life of each patient, either on the first transplant or afterward.

In conclusion, new technology like growth factors, retinoin, bone-marrow transplant and anti-rejection drugs are giving more hope than ever to patients with acute leukemia. It is crucial to get an opinion from doctors at a University Academic Medical Center, familiar with open protocols you may wish to participate in. Acute Leukemia is an aggressive disease which requires aggressive therapy. It is advisable to take a multi-faceted approach, and not just rely upon the conventional treatment. This means not only listening to an oncologist you trust for the primary treatment, but also taking an active role in the therapy. A reasonable alternative therapy, which is not overtly toxic or overly expensive, should be sought as well as programs of nutrition and exercise. "Mind over Cancer" thoughts can be helpful, along with keeping a positive attitude, even in the face of setbacks. Studies have shown than patients with positive attitudes and a strong will to live do better than those who have a depressed and complacent attitude. Living each day fully, and using all the tools available to fight the disease, will enhance your quality of life, and give you the peace-of-mind knowing that you have done everything possible to help ensure a happy outcome.

This is the full transcript, offered freely in the spirit of internet sharing, of CancerAnswers' report on Acute Leukemia. Much more, including latest additional treatments for Acute Leukemia can be found on our order page. Thank you for using CancerAnswers as your information resource.