Immunosuppressive Therapy

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Precautions During Immunosuppressive Therapy
Second ATG Treatment
"Horse" ATG and "Rabbit" ATG
ATG and Lymphocytes
ATG in Older Patients
Immunizations After ATG Treatment
Follow-up After Successful ATG Treatment
ATG to Treat PNH Patients
Starting Cyclosporine
Cyclosporine Duration
Kidney Problems from Cyclosporine
Nausea Associated with Cyclosporine
High Blood Pressure Associated with Treatments
Cyclosporine and Clonal Disease
Other Immunosuppressive Drugs
Pregnancy and Aplastic Anemia
ATG/Cyclosporine and fertility
Drug Interaction with Grapefruit Juice
Concurrent Hepatitis C and Aplastic Anemia
Bloodless Treatment

Precautions During Immunosuppressive Therapy

During immune suppression therapy, what specific actions or steps should a patient take to avoid illness and infection?

A patient is at increased risk for illness and infection while receiving immune suppression. The risk is both internal (we all have germs in our bodies) and external (contact with ill persons). The risk is highest when receiving large doses of immune suppression and when a patient also has low neutrophil counts.

Doctors advise patients who are receiving immunosuppressive drugs to avoid crowded places and to avoid individuals who have any contagious infection. An antibiotic may be given as a precaution. Prompt treatment of cuts is also important. Good dental hygiene is important to reduce the risk of bacterial infection in the mouth or throat. Fever or increased fatigue can be warning signs and should be reported to your doctor promptly.

Report any symptoms to your doctor so that immediate treatment can be administered and medication adjusted as necessary.

Second ATG Treatment

Is there any advantage in undergoing the second ATG treatment within three or four months of the first treatment because the ATG from the second treatment builds upon that which is still in the body from the first treatment?

It can take over 6 months to respond to

ATG is an immunosuppressant, a drug that lowers the body's immune response. Scientists believe that aplastic anemia happens when the immune system attacks and destroys bone marrow stem cells. ATG kills the specific cells that are attacking the bone marrow stem cells. This allows the bone marrow to grow and make new blood cells. ATG may be used to treat other bone marrow failure diseases in some cases. ATG is approved by the U.S. Food and Drug Administration (FDA) for treating moderate and severe aplastic anemia. ATG is commonly used with another drug called cyclosporine.

ATG (anti-thymocyte globulin), somewhat shorter if the ATG is combined with

An immunosuppressant, this drug that lowers the body's immune response. Cyclosporine is used along with antithymocyte globulin (ATG), another immunosuppressant, for treating aplastic anemia and some other forms of bone marrow failure.

cyclosporine. Even in a patient on the combination of ATG and cyclosporine, about half of the patients who respond will take longer than 3 months to do so. Most doctors will wait a few months longer before considering re-treatment.
If the patient is very severely neutropenic (i.e. ANC <300), or thrombocytopenic and not responding to

The smallest type of blood cell. Platelets help the blood to clot and stop bleeding. Also called a thrombocyte.

platelet transfusion, this may be a more urgent situation. If the patient is not responding to an initial course of ATG by 3 months, transplant options will be considered, siblings will be typed, and if necessary an unrelated donor search will be initiated. If no improvement is seen by 6-9 months everything may be made ready for transplantation.
Each patient is different and patients should discuss treatment options and specific risk factors with their doctors. The AA&MDSIF offers a booklet called Managing Treatment Decisions in their information packets. Contact the AA&MDSIF office at help@aamds.org or 800.747.2820 to request an information packet.

"Horse" ATG and "Rabbit" ATG

Is it common to be given rabbit ATG following horse ATG if the horse serum is not effective in treating aplastic anemia? What are the side effects of rabbit ATG? Is it stronger or weaker than horse ATG?

It is common practice to give rabbit

ATG (anti-thymocyte globulin) following the horse (equine) ATG if the horse serum is not effective. Rabbit ATG is more immunosuppressive than horse ATG but well-tolerated, if given slowly over 24 hours.

In younger patients, if there is no response to initial treatment of ATG, many experts would recommend a stem cell transplant. In older patients (>30-40 years old), a second course of ATG may be given. This can be either horse or rabbit ATG.

The side effects are similar and there is a subset of patients who will respond to the rabbit preparation who did not respond to the equine preparation.

We do not yet know which one is better for newly diagnosed patients. The standard care remains to start with the horse preparation. You may refer to a paper published by E DiBona, et al from the British Journal of Hematology, "Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy". Link to an author abstract of this article at www.pubmed.gov.

ATG and Lymphocytes

Why would an aplastic anemia (or MDS) patient receiving ATG have high lymphocyte count if ATG is supposed to suppress lymphocytes?

Until the patient responds, which may take 2-6 months it is very common that the only surviving

Cells in the body that fight disease and infection by attacking and killing germs. There are several types of white blood cells including neutrophils, eosinophils, basophils, lymphocytes and monocytes. Each type of cell fights a different kind of germ. Also called WBC, leukocyte.

white blood cells are lymphocytes. The

A type of white blood cell. B lymphoctyes help make special proteins called antibodies that fight bacteria and viruses (immune response). T lymphocytes help kill tumor cells and help the body's immune response.

lymphocyte count usually drops somewhat after

ATG therapy, but it is not long before it comes back up. It is important to remember that there are many different types of lymphocytes such as T-cells, B-cells, and

a type of cell that lacks B-cell and T-cell receptors and attacks mutant and virus-infected cells

natural killer cells. In patients who respond to ATG, the lymphocyte count also rises but the sub-set of "bad" T-lymphocytes that cause the aplastic anemia does not. You can't tell by doing a CBC the type of lymphocytes that are coming back (i.e. good B-cells and good T-cells that protect from infection vs. the "bad" T-cells). This is a very difficult thing to test for even in academic laboratories. Most patients, including the approximately 75% who respond to ATG, have this same pattern of lymphocytes after ATG therapy is given. ATG is not intended to kill all lymphocytes, just the overactive ones that cause marrow aplasia.

ATG in Older Patients

What is the experience and success rate of ATG treatment in older patients with aplastic anemia?

Provided that older patients do not have significant medical problems that preclude

ATG (anti-thymocyte globulin) administration, it can be given safely with a similar response rate as younger patients. It should be noted that older patients can be at increased risk for falls, which could lead to serious or life-threatening bleeding when severe thrombocytopenia is present. Therefore, the residence should be carefully evaluated to ensure that this risk is minimized.

Immunizations After ATG Treatment

Is it necessary to re-immunize or do you continue immunizations in a child with aplastic anemia treated with combination ATG and cyclosporine?

Re-immunization is not necessary. Doctors will resume immunization only when the patient is off of immune suppression and has stable blood counts for at least 6 months. Live virus vaccines are not used for immunizing aplastic anemia patients.

Follow-up After Successful ATG Treatment

After successful immunosuppressive therapy in a child with aplastic anemia, when should one watch for relapse or disease progression to PNH, MDS, or AML? How often should blood counts be monitored after successful immunosuppressive therapy for aplastic anemia?

Doctors usually recommend following blood counts at gradually increasing intervals (for example, monthly for one year then every 2 months for year 2, every three months for year 3, etc). The greatest risk of relapse is in the first year. Other complications (AML, PNH, MDS) can occur up to 10-20 years later. Repeat counts should be obtained at the time of infections, when taking other drugs, during pregnancy and at other times that might be associated with hematologic problems.

ATG to Treat PNH Patients

What percentage paroxysmal nocturnal hemoglobinuria (PNH) patients have responded to ATG and what clinical factors may predict response?

Immunosuppression with

ATG /

Cyclosporine can successfully be used

as a treatment for low
The smallest type of blood cell. Platelets help the blood to clot and stop bleeding. Also called a thrombocyte.
platelet counts or low
(NOO-truh-fil) The most numerous of the white blood cells, important for helping the body fight infections (particularly bacterial and fungal infections.
neutrophil counts that frequently occur in patients with a diagnosis of PNH (The hemolytic component of PNH responds very little to ATG, at least initially. There may be improvement on the long run).
as a treatment for patients who have a diagnosis of aplastic anemia but also with a PNH clone that is detectable by
(sy-TOM-uh-tree) A laboratory test that gives information about cells, such as size, shape, and percentage of live cells. Flow cytometry is the test doctors use to see if there are any proteins missing from the surface of blood cells. It is the standard test for confirming a diagnosis of paroxysmal nocturnal hemoglobinuria (PNH).
flow cytometry. Patients with a diagnosis of PNH who have hemolytic anemia but whose
An immature red blood cell. Reticulocytes are normally found in the bone marrow. They are present in the bloodstream only in very low numbers.
reticulocyte (immature
The most numerous type of blood cell in healthy people. Red blood cells contain hemoglobin, a protein that picks up oxygen in the lungs and brings it to cells in all parts of the body. Also called erythrocyte, RBC.
red blood cells) count is low or in the low normal range may also respond to immunosuppression, resulting in an increased reticulocyte count and a decreased transfusion requirement.

In an important and widely quoted paper, Paquette et al from UCLA (British Journal of Haematology 96:92-7,1997) have reported a response in 3 out of 7 PNH patients: these 3 responders had low platelets and little hemolysis. This does not mean, however, that patients who have both low platelets and hemolysis will not respond. The experience of physicians with expertise in PNH shows that more than one-half of them do respond.

Patients with PNH who have a normal neutrophil count, platelet count, an elevated reticulocyte count and

(ay-PLASS-tik uh-NEE_mee-uh) A rare and serious condition in which the bone marrow fails to make enough blood cells: red blood cells, white blood cells, and platelets. The term aplastic is a Greek word meaning not to form. Anemia is a condition that happens when red blood cell count is low. Most scientists believe that aplastic anemia happens when the immune system attacks the bone marrow stem cells. Aplastic anemia can be acquired (begin any time in life) or can be hereditary (less common, passed down from parent to child).

anemia due to

(hi-MOL-uh-suss) The destruction of red blood cells.

hemolysis are unlikley to benefit from immunosuppression. The response that can be expected is instead mainly in the neutrophil count and in the platelet count.

In patients with a large PNH cell population, an exacerbation of hemolysis can occur due to activation of complement following ATG infusion. For this reason it makes sense to transfuse

The most numerous type of blood cell in healthy people. Red blood cells contain hemoglobin, a protein that picks up oxygen in the lungs and brings it to cells in all parts of the body. Also called erythrocyte, RBC.

red blood cells starting 1-2 weeks before�sort of an exchange transfusion�to decrease the proportion of PNH red cells prior to giving the ATG. This can be monitored by flow cytometry or by the

(LAK-tate dee-high-DROJ-uh-nase) An enzyme found in the blood and in many of the body's organs. High levels of LDH in the blood can mean that red blood cells are breaking apart (hemolysis) or that there is tissue damage in the body. It is important for patients with paroxysmal nocturnal hemoglobinuria (PNH) to have their LDH monitored regularly. Also called lactic dehydrogenase, LDH.

LDH, which is a surrogate marker for hemolysis and the size of the PNH clone.

Starting Cyclosporine

When treating aplastic anemia or MDS patients with combination ATG/cyclosporine, when is the cyclosporine begun? At the same time as ATG or later date?

Most protocols begin the

cyclosporine AFTER completing the

ATG (anti-thymocyte globulin) infusions. This is related more often to potential toxicities during ATG rather than to data regarding optimal timing or the two drugs. Cyclosporine can be started at the time of diagnosis if there will be some delay in giving the ATG.

Cyclosporine Duration

How long can a patient stay on cyclosporine?

There is no upper limit on the duration of

cyclosporine therapy, as we know from the renal transplant patients. Cyclosporine was originally used in patients receiving solid organ transplants (kidney, liver). These patients have taken cyclosporine for many years to prevent graft rejection.

Most

(hee-muh-TOL-uh-jist) A doctor who specializes in treating blood diseases and disorders of blood producing organs.

Hematologists start to taper cyclosporine 6-12 months after achieving a maximal response. Some patients will then relapse and respond to restarting the drug. In some cases the drug must be discontinued if there is kidney toxicity.

Generally speaking, patients can remain on cyclosporine indefinitely as long as there is evidence that the drug is providing some benefit and no evidence of significant side effects. Some patients require prolonged treatment to prevent or minimize the risk of disease relapse.

Kidney Problems from Cyclosporine

What are the treatment options for aplastic anemia patients who, after many years on cyclosporine, begin to experience kidney problems?

Patients who have

cyclosporine-dependent aplastic anemia should receive the minimum dose of cyclosporine that is required to maintain the response. Periodic discontinuations may also be possible.

There is no substantial data to indicate well-tried treatment options for patients in incipient renal failure. Other immunosuppressives could be tried - steroids,

ATG, or mycophenolate - but there is no data to say they would work as well. Adjusting cyclosporine dose down might be a better approach. Discuss these options with your hematologist.

Nausea Associated with Cyclosporine

Do other aplastic anemia patients experience severe nausea associated with cyclosporine? What should be done?

Nausea could potentially be a sign of liver or kidney toxicity. It is uncommon when standard doses of

cyclosporine are used (5 mg/kg/d or less). If toxicity is observed at standard doses, a tolerable dose should be found and continued. The minimum effective dose of cyclosporine has not been clearly defined and even low doses can potentially be effective. Liver and kidney function should be checked if nausea occurs.

High Blood Pressure Associated with Treatments

Is high blood pressure frequently observed in aplastic anemia patients successfully treated with immunosuppressive therapy?

High blood pressure in a patient being treated for aplastic anemia is likely to be due to the treatments, such as high dose steroids being given at the time of

ATG therapy or cyclosporine. Treatment depends on the severity of hypertension and the need for continued use of the drug. In the case of the latter, if the diastolic is greater than 90 or the systolic greater than 150, the doctor will review the cyclosporine levels to see if it could be decreased. Hypertension due to cyclosporine can be treated with calcium channel blockers, such as diltiazem (Cardizem CD, Cardizem SR, Dilacor XR, Tiazac). These drugs will have the effect of increasing the

Cyclosporine levels, therefore cyclosporine levels should be monitored closely.

Cyclosporine and Clonal Disease

Is there any evidence to suspect that long-term cyclosporine use is a factor in progression to myelodysplastic syndromes or paroxysmal nocturnal hemoglobinuria?

There is no direct effect from

cyclosporine. Cyclosporine would theoretically decrease the likelihood of an "escape clone" such as an MDS or PNH clone that is resistant to the immunologic assault, if it is effective in eliminating the autoimmune attack. However, if the drug together with

ATG were to be responsible for the long-term survival of a whole group of patients who would not have otherwise survived, then it might have the appearance of increasing the number of cases of progression to clonal disease, simply by increasing the number of patients at risk.

Other Immunosuppressive Drugs

Would there be any benefit for aplastic anemia patients on long-term cyclosporine treatment to consider adding mycophenolate mofetil (MMF) or other immunosuppressive drug?

This is an important research question for a clinical trial.

Cyclosporine and

ATG are the standard of care for severe aplastic anemia. If cyclosporine is causing significant side effects or is not producing an adequate response, then use of additional drugs MAY be beneficial. Talk to your doctor about all treatment options. Find out about immune suppressive medicines in clinical trials for aplastic anemia by visiting the Patient Clinical Trials page.

Pregnancy and Aplastic Anemia

If a woman with aplastic anemia is pregnant and needs treatment, will taking ATG and cyclosporine effect the development of the fetus? What are the options in a situation such as this?

Questions concerning the use of

ATG and

Cyclosporine during pregnancy are more complicated that just which drug therapy to use. There can be different relationships between the pregnancy and aplastic anemia that might influence the treatment decisions. For example,

pregnancy-associated aplastic anemia may resolve without treatment when the pregnancy is terminated (either normally or prematurely);
aplastic anemia that preceded the pregnancy may become more severe during the pregnancy.

The decision to treat needs to be based on the nature of this relationship and the severity of the disease.

ATG and

cyclosporine, which are standard in the treatment of aplastic anemia, are classified as pregnancy category C drugs, which means that they can be used when needed during pregnancy though their safety has not been officially proven. In other words, if a woman would be treated with these agents if she were not pregnancy, then she should be treated with these agents if she is pregnant.

There is a lot of literature on the use of cyclosporine during pregnancy - mostly in women with renal transplants - and it is all encouraging, i.e. there were no obvious adverse effects on the fetus. A number of solid organ transplant recipients have received cyclosopirne during pregnancy without significant defects except for premature deliveries. Cyclosporine is both fetolethal and teratogenic in animal studies in markedly elevated doses in comparison to the usual human doses.

There is less literature on the use of anti-thymocyte globulin (ATG) during pregnancy. As for its safety and effectiveness in aplastic anemia during pregnancy, refer to the recent paper by Tichelli et al, which is quite encouraging.

Because of the risks of bone marrow transplantation (BMT), it is clearly not considered to be safe during pregnancy. If a fairly young patient has a matched donor and severe neutropenia - for example and ANC of less than 0.1 - then BMT might actually be the preferred treatment if she were not pregnant. In this case, a very difficult decisions would have to be made about continuing the pregnancy.

Each case should be carefully evaluated to see if therapy needs to be done. The patient should be able to have open and honest discussion of all treatment options with her doctor.

ATG/Cyclosporine and fertility

Is there any data on the long-term effects of ATG and cyclosporine on fertility?

There is no conclusive data that

ATG (anti-thymocyte globulin) or

cyclosporine cause fertility problems. Data from women with renal transplants on cyclosporine are reassuring. Though cyclosporine is pregnancy category C (a type of drug that can be used when needed during pregnancy but its safety has not been officially proven), probably it is safer than this rating would suggest. The likelihood of conception is another question.

Drug Interaction with Grapefruit Juice

Does grapefruit juice interact with cyclosporine?

Grapefruit and grapefruit juice may interact negatively when used with cyclosporine and other immunosuppressants such as sirolumus and tacrolimus. This is because it contains a substance that can increase the drug concentration. Consult your physician with questions and concerns about your treatment.

Concurrent Hepatitis C and Aplastic Anemia

Would treatment for hepatitis C cause a problem for aplastic anemia patient who was treated successfully with immunosuppressive therapy?

In a patient with aplastic anemia and hepatitis C, one is concerned that immunosuppression for the AA will "reactivate" the hepatitis C, and conversely, that anti-viral therapy will result in falling blood counts. Such a patient should be seen by a Hepatologist and have a measurement of viral load and perhaps a liver biopsy to determine the degree of activity of viral infection. It may also be possible to genotype the virus to predict whether the virus is likely to respond to the therapy. If the viral load is high, the genotype is favorable, and if it appears that there is active hepatitis, then treatment may be necessary, with close monitoring of the blood counts.

Bloodless Treatment

What are the success rates of ATG therapy without blood transfusion support for aplastic anemia patients?

At the moment there is no substitute for the transfusion of blood and of certain blood products. With respect to the use of these agents in the course of

ATG (anti-thymocyte globulin) treatment, it will depend to some extent on the blood count before starting ATG. Thrombocytopenia is a serious problem which may be made transiently worse during a course of ATG: therefore platelet transfusions are given almost in every case to patients with aplastic anemia or PNH who receive ATG treatment.