Some doctors feel very comfortable with its use, some do not like to use it in younger patients who will require treatment for many years but feel comfortable using it in older patients who are unlikely to remain on it long enough to develop any secondary problems. The literature reports of secondary leukemias associated with prolonged Hydrea therapy indicate the risk is lower than older agents. There was a recent abstract in which the authors claimed to have found no statistically significant different but their figures for phlebotomy patients were higher than in other reports. This is something you need to discuss with your doctor.
Unless your doctor changes you to another treatment agent, for life. PV is a chronic condition. The rapid rebound following drug withdrawal requires continuous administration.
Because hydroxyurea has less of a suppressive effect on erythropoiesis (red cell production ) than on platelet and neutrophil production, supplementary phlebotomies may be required for the maintenance of an optimal hematocrit.
Yes, interferon has been used in the treatment of polycythemia vera and other myeloproliferative disorders since the mid-1980's. Some literature reports suggest that interferon is proving superior to phlebotomy and may become the treatment of choice for PV and related MPD disorders as it may offer the best option for improving the marrow status and delaying or preventing development of the "spent phase" in PV and Et. In Diagnosis and Treatment of Polycythemia Vera, Leukemia and Lymphoma 2000, Vol 36(3-4)pp 239-253, interferon is referred to as first line treatment for PV. But not all doctors are in agreement on this. One of the main advantage of interferon is that patients can be cycled. This agent actually improves the marrow in some patients and the improvement is lasting so they can go months to years before needing further treatment. One patient in the MPD-NET discussion group was able to go without treatment for 3 years after stopping inteferon before her platelet counts started to rise. Even then, much of the improvement in her bone marrow was still seen. After a second course, studies of Dr. Joseph Prchal showed she was polyclonal, that is there was a return of normal hematopoeitic stem cells and only a small percentage of the PV clone.
However, there is no consensus among the experts as to how long, how much and whether to stop interferon and start it again when counts rise or the spleen enlarges or whether patients should remain on a lower maintenance dose forever.
Anagrelide, an agent which lowers platelet counts, is also used in PV patients. In some cases, anagrelide is combined with hydrea.
While oral dosage forms was tested in PV, ET, and MF patients by Dr. Murray Silverstein at Mayo Clinic Rochester, and low dose "oral" interferon has been used to treat conditions such as hepatitis, at the moment, interferon for myeloproliferative disorders involves an injectable drug. Usually the patient self-administers subcutaneous shots. The dose and frequency varies depending upon the bias of your doctor. Some hem-oncs prescribe daily injections for a period of time until there is improvement, then cut back to a lower maintenance dose for a period of time. Some use a three times a week routine. There is no agreement on dose, frequency of injection, how long patients should stay on the drug, whether they should remain on for life at a lower maintenance dose or cycle. This is frustrating for patients who need to review the literature and discuss their options with their hem-onc. Results are what are important.
Initial flu like symptoms are experienced by nearly everyone. Tylenol controls these and they subside as the body adjusts to this medication. Some people experience fatigue and find they have to slow down while on interferon. Some tolerate the drug better than others and are able to carry out a fairly normal routine. Others discontinue treatment. We have a number of people on interferon in our MPD-NET discussion group who will be happy to discuss this issue with you. Your doctor should give you written information about side effects and the package literature also lists reported side effects.
Post polycythemic myeloid metaplasia (PPMM) is also referred to as the "spent phase". After years of hyperactivity, the marrow may become increasingly fibrotic (scarred), hematopoiesis (blood production) becomes ineffective and peripheral blood counts decrease. The marrow becomes hypocellular as opposed to the hypercellular state in the proliferative phase. During this phase, hematopoiesis may resemble that seen in aplastic anemia, sideroblastic anemia, refractory anemia, or paroxysmal nocturnal hemoglobinuria.
Some patients seem to have growth factors that predispose them to the development of fibrosis. Interferon has retarded or reversed this is some patients but is not effective in all. Bone marrow transplantation is being used at some centers to treat myelofibrosis, spent phase PV and ET as well as CML.
There is not much literature on this for PV patients but Dr. Jeanne Anderson, formerly of Fred Hutchinson Cancer Center in Seattle, Washington and colleagues have published on both bone marrow and stem cell transplantion for myeloproliferative disorders including PV. Transplantion is used in PV patients who have progressed to the post polycythemic myeloid metaplasia stage, have progressed to acute leukemia, or who cannot be controlled by other therapies. Stem cell harvest and storage is being recommended for PV patients in the proliferative stage who may progress to myeloid metaplasia with myelofibrosis, etc.
There is information on bone marrow transplants in the mpd-net archives and you can contact One member of mpd-net reported his son will have a bone marrow transplant with the father as the donor. Many PV patients tend to live out normal life spans so unless there is conversion to a more aggressive form of these diseases, bone marrow transplants are not presently considered as first line treatment. The CML FAQ has a lot of information about bone marrow transplants since this procedure is more commonly used in that MPD variant. To get the CML FAQ, address your message to
Listserv@listserv.acor.org andhave a 1 line message that reads get mpd-net.cml-faq.
Some PV patients are bothered by itching (pruritis). One of Dr. Gilbert's earliest research studies in PV dealt with this issue. She has written " I found that it was the result of histamine release by the basophiles. Basophils are the type of segmented white blood cells produced by the bone marrow precursor involved in PV. An increased number of basophils are produced and they do maintain their function, as do most of the cells produced in the PV marrow. Basophils produce and release histamine in response to cells and platelets and causes the spleen to shrink. However the treatment does not slow the natural progression of the disease and does not increase survival. Moreover, recent studies show that prolonged treatment with busulfan can make subsequent marrow transplantation more dangerous and can lead to secondary cancers. Over the past 10 years there has been a gradual change from busulfan to hydroxyurea (hydrea) which appears to be safer and more effective. Recent studies suggest that hydrea may delay the development of transformation and prolong survival.
The literature indicates that the substance alpha-interferon can control the high white cell and platelet counts in more than 80% of newly diagnosed patients. The exciting thing about this form of treatment is that it can reduce the number of Ph chromosomes in about 40% of patients and in about 20% it suppress them to an undetectable level. There is no doubt that this form of treatment can prolong survival. However there is not yet any evidence that it can cure CML and patients will probably need to continue treatment for life. The treatment is very expensive (probably more than $20,000 annually, although this problem can almost certainly be solved.>
>A more intractable problem is that many patients have significant side effects from this form of treatment. These range from a flu-like syndrome to more severe complications. Often these side-effects become less severe as treatment continues, but some patients find it impossible to continue interferon therapy. Despite all this, interferon therapy is a dramatic improvement over other forms of drug therapy.
There are studies investigating the combination of interferon-alpha and ARA-C. MD Anderson has been investigating this combination for some time. More recently, a controlled clinical trial to determine whether the combination of interferon and ARA-C is superior to interferon is underway. For information, contact Dr. Harriet S. Gilbert, 212-535-4200 or Dr. Richard Silver (Study Chair) 212-327-2700. The French CML study group published their findings earlier this year in the New England Journal of Medicine. These investigators believe the addition of ARA-C to interferon provides superior results to inteferon alone. The father of a 13 year old CML patient in the lists recently reported that his daughter is doing well on a regimen of high dose interferon, ARA-C and Hydrea. Details are in the hem-onc archives for December 19, 1997).
Bone marrow transplantation is the only form of treatment which is known to produce long-term disease-free survival (and possible cure) in CML. This is a dangerous form of treatment and some patients die because of treatment complications. The risks are greater in older patients and in patients with more advanced disease. In the good-risk groups, the treatment-related mortality during the first year after transplantation in the best centers is between 10% and 15%. This is about the same as mortality from CML itself in newly diagnosed patients treated with Hydrea. The results are worse in patients with more advanced disease and in centers with less experience. The Fred Hutchinson Cancer Center in Seattle, Washington recently published that results are less favorable in patients treated with interferon for more than 6 months.
Another problem is that not all patients are cured. During the first five years after transplant, the disease comes back (relapse) in about 20% of patients. Of patients transplanted in chronic phase within one year of diagnosis, about 50% will be alive without further treatment and without signs of disease at 8 years. To receive this form of treatment you must have a suitable donor. Most transplant centers will not treat you if you are older than 55 years, one center (Seattle) will accept patients up to the age of 65 years and another (M.D. Anderson) will not use transplantation as first treatment for patients older than 45 years. The best donors are tissue-matched close relatives (brothers, sisters, parents). About 30% of patients in the USA will have such potential donors. The next-best choice is a tissue-matched volunteer unrelated donor. Using the large international panels such donors can be found for about 30% of patients in the USA although it is more difficult to find such donors for members of certain ethnic groups. It takes several months to search for and arrange the use of a volunteer unrelated donor. The process is complicated and expensive (many thousands of dollars), but most insurance companies will pay for the search. Patients looking for an unrelated donor should be treated with interferon in the interim.
Patients who are found to be "hiding" Ph1+ cells or BCR-ABL rearrangements in their blood should not necessarily fear a comeback of CML. In fact, some patients harbor the BCR-ABL gene for years without ever showing signs of relapse. What seems to matter is is the amount and rate of accumulation of positive cells in the test, not simply their presence. This is what the researchers in the field of "minimal residual disease" call the "quantitative" PCR assay, which is done serially. Some centers use it as a tool for prediction of relapse, and recommend a new stem cell infusion early (as soon as a rising pattern is identified), so that CML mass is still small and more sensitive to treatment.
Interferons are substances made by cells. They act by enhancing the immune functions of lymphocytes against viruses and some tumor cells. The interferon used for treatment of CML is a synthetic alpha-interferon. There is no doubt that this agent has a powerful effect against CML tumor cells, but the mechanisms by which this takes place are unknown. Some believe that it works by enhancing an existing immune response against malignant cells, but another possibility is that it interferes with transcription (the process whereby nucleic acids make each other and proteins).
During the first few weeks, one can expect fairly strong Flu-like symptoms: feverish, achy, joint pain, fatigue and difficulty in sleeping or vivid or anxiety-filled dreams, etc. Given time your body will learn to tolerate ifn and the symptoms will diminish. The ifn shots should be taken before bedtime to diminish discomfort. Most get side-effect relief by taking Tylenol or Extended Relief Tylenol a half hour before ifn shot. An anti-anxiety sleep aid such as Ambien, taken just before retiring also helps. After several months, when the side-effects of ifn have diminished, an occasional Tylenol may be required for aches or feverish feeling. The fatigue seems to be a constant. Some complain of disorientation or inability to concentrate. Obviously, strong side-effects should be discussed with your prescribing doctor. Dosage can be adjusted.
Hydrea is the commonly used name for hydroxyurea, an antimetabolite used to treat CML. Taken by mouth, it alters blood chemistry to reduce the number of white blood cells to a normal range. Like any other medicine, it has side effects. GI upset is not uncommon It is important to be monitored by your doctor while taking hydrea. Your immune system may be more fragile, and it is wise to avoid people with contagious illnesses or getting minor injuries. It is important to discuss any other immune system illnesses (e.g., shingles) you might have with your doctor. Very often drinking more water is suggested to make taking the drug easier on the kidneys.
If you have any questions, do not hesitate to ask your doctor and/or pharmacist. The information you get here or elsewhere on the Internet in no way should replace a good relationship with medical professionals.
No. You must have a suitable donor. Most transplant centers will not treat you if you are older than 55 years, one center (Seattle) will accept patients up to the age of 65 years and another (M.D. Anderson) will not use transplantation as first treatment for patients older than 45 years. The chemo and radiation therapy required to destroy your marrow, prior to transplant of healthy marrow, and the drugs used to combat GVHD (graft vs host disease) places unusual stress on heart, lungs and liver. A candidate for successful donor transplant must have good heart, lung and liver function to withstand the treatment. Some centers will do autologous transplants on patients who are above the age limit for transplants using someone else's marrow and will also use stem cell transplants on older patients.
There's a tug-of-war going on between some insurance companies and hospitals with BMT patients caught in the middle. On the one hand, hospitals are striving to provide the most effective, state of the art health care for their patients. On the other hand, insurance companies are fighting to contain escalating health care costs. The patients are simply fighting to stay alive. There is a better chance of having insurance pay for your BMT is you participate in an approved clinical protocol at a major center. Between 1988 and 1991 more than 200 people were unable to undergo a BMT because their insurance company would not cover the cost of the procedure. Many more had their BMT delayed as they attempted to persuade insurers to pay for the BMT or tried to raise the funds on their own. The good news is that the situation is improving. The bad news is that persuading insurers to cover a BMT often involves a long, arduous fight a fight most BMT patients are unprepared to undertake alone.
A 1991 BMT Newsletter survey of transplant centers found that an autologous BMT-a BMT in which the patient is his/her own bone marrow donor-is the type of BMT most frequently resisted by insurance companies, particularly if it is for treatment of breast cancer or other solid tumors. The survey also found that, despite insurers' initial refusal to pre-approve an autologous BMT, correspondence from the patient's physician that included studies showing the effectiveness of BMTs in treating the patient's disease, second Opinions from other medical experts in the field, and evidence that other medical authorities endorse the practice was often successful in reversing the insurer's initial denial of BMT coverage. Intervention by employers and legal action have also been effective in compelling payment.
Insurance reimbursement for BMTs using mis-matched donors (donors whose bone marrow is not a perfect genetic match with the patient's) was also cited by survey respondents as a problem. The costs incurred in locating a suitable bone marrow donor, performing physical exams on the donor, and extracting the donor's bone marrow were frequently cited by respondents as expenses insurance failed to reimburse. What's the bottom line? Don't assume your insurance company will cover any or all costs associated with your BMT. Knowing your rights, understanding your insurance policy, enlisting the help of your employer and having a physician who's willing to work closely with you to persuade your insurer to cover your BMT is essential. If you're one of the many persons whose insurance company will pay for your BMT without a fight, be thankful. If not, remember: when your insurance company says "no" don't take no for an answer.
The best donors are tissue-matched close relatives (brothers, sisters, parents). About 30% of patients in the USA will have such potential donors. The next-best choice is a tissue-matched volunteer unrelated donor. Using the large international panels such donors can be found for about 30% of patients in the USA although it is more difficult to find such donors for members of certain ethnic groups. It takes several months to search for and arrange the use of a volunteer unrelated donor. The process is complicated and expensive (many thousands of dollars), but most insurance companies will pay for the search.
This is a dangerous form of treatment and some patients die because of treatment complications. The risks are greater in older patients and in patients with more advanced disease. In the good-risk groups, the treatment-related mortality during the first year after transplantation in the best centers is between 10% and 15%. This is about the same as mortality in newly diagnosed patients treated with hydrea. The results are worse in patients with more advanced disease and in centers with less experience.
Another problem is that not all patients are cured. During the first five years after transplant, the disease comes back (relapse) in about 20% of patients. Of patients transplanted in chronic phase within one year of diagnosis, about 50% will be alive without further treatment and without clinical and hematologic signs of disease at 8 years.
It is known that delay after diagnosis reduces the success rate after transplantation and there is now general agreement that young patients who have matched related donors should be transplanted as soon as possible after diagnosis. However, it is now clear that interferon treatment prolongs the survival of all patients and, in about 20% of patients, makes all signs of the disease disappear as long as the patients continues the treatment. This has produced some controversy as to the timing of transplantation for older patients, with some centers advocating delay of transplantation until patients have failed to respond to interferon (this demonstration usually takes at least one year), and others advocating early transplant for all patients.
Without interferon or a transplant the life expectancy has historically been 3 to 5 years after diagnosis. Interferon has been proven to significantly increase life expectancy and the combination of interferon and ARA-C is believed to be superior to interferon alone. Autologous marrow or stem cell transplants, likewise, if successful engraftment takes place, extend life expectancy, but since the immune system has not been replaced (as with a donor transplant) are not currently curative. While a bone marrow transplant could return you to a normal life span there is the above mentioned possible mortality from the procedure.
Leukemia strikes both sexes and all ages. Causes of most cases are unknown. Persons with Down syndrome and certain other genetic abnormalities have higher than normal incidence of leukemia. It has also been linked to excessive exposure to ionizing radiation and to certain chemicals such as benzene, a commercially used toxic liquid that is also present in lead-free gasoline. Certain forms of leukemia and Lymphoma are caused by a retrovirus, HTLV-I (human T-cell leukemia/lymphoma virus-I).
CML is chromosomal/genetic but not hereditary. This means it is not caused by a gene being passed on. During the patient's lifetime, they somehow were exposed to something which damaged their genes. This resulted in the translocation of the 9 and 22 chromosome, and led to CML. However, there are familial incidences among 2 or more family members in other myeloproliferative disorders so the answer is not clear.
There is a subtle difference between the terms "remission" and "cure". Remission is a term coined by oncologists to designate a situation in which 1) the disease is undetectable by the diagnostic methods used, or 2) the disease is still detectable, but the amount of neoplastic cells is so small as not to produce symptoms. Let us give you some examples:
In CML, we can define remissions by various criteria. The first is what we call "hematologic remission". That means, basically, that your blood counts are normal, and your bone marrow biopsy has the appearance of a normal one (normal cellularity, no abnormally looking cells, no fibrosis). If we go further and study the aspect of the chromosomes in your bone marrow cells (which we call doing a "karyotype analysis"), then we might find or not that famous abnormal chromosome called Philadelphia (PH), which is found in over 90% of CML cases and functions as a marker for the disease. If we can't find it, we say that the patient is in "cytogenetic remission". Recently, a new tool called "PCR" has emerged as the most sensitive test for abnormalities in the chromosomes of marrow cells. PCR (polymerase chain reaction) analysis can detect incredibly small quantities of abnormal genetic material in a suspen- sion of cells, including pieces of the PH chromosome. When it can't, what ensues is "molecular remission". The significance of being in molecular remission is still not completely understood, since many transplanted patients remain, several years after BMT, in hematologic remission (asymptomatic, without disease manifestations) despite the stubborn presence of small amounts of PH-positive cells in their blood.
As you may already guess, cure is a very complex issue in this situa- tion, because the possibility (at least, theoretically) of a relapse cannot be discarded. Anyway, cure is in itself a very simple concept for all of us, who know how bad having any disease is.
Bone marrow typing for the public is handled through area blood centers or the American Red Cross. To find out which in your area, you may call the National Marrow Donor Program at (800) 654-1247.
Currently it is a confusing system,with potential donors being asked to pay varying amounts of money for the right to be tested. For example, as of 8/96, it cost $175 to be typed in San Francisco, and $50 to by typed in San Jose, California. In Buffalo, NY potential donors are asked to participate in pharesis, which means several hours at the blood center having your blood filtered. (If you are Asian or African- American, the costs are waived.)
Many times, when companies or institutions find out an employee has a disease that is responsive to BMTs, drives are arranged. These are often the best ways to become a donor.
The test to be HLA-typed involves drawing a small amount of blood. If you are a match, the donation procedure is more complex and will most likely involve an overnight stay in the hospital. the donor pays nothing toward the cost of the procedure. Donors need to be between the ages of 18 and 55, and relatively healthy.
When a cancer patient is searching for bone marrow, it is the stem cells contained within that are the key to treatment. Stem cells are the building blocks of red and white blood cells, and the foundation of the human immune system. But finding a bone marrow match is a difficult process, and, in the U.S., nearly half of the patients searching will die before they do. Now, new research shows that umbilical cord blood contains the same type of stem cells as bone marrow. The largest Cord Blood Bank is in NY, NY,you can see it at: CORD BLOOD PAGE
For additional information, call the NY blood Center: 800-NY-BLOOOD or 212-570-3210.
For more information, see : The International Cord Blood Foundation : INTERNATIONAL CORD BLOOD FOUNDATION
see also: BMT
Find a match? - when a Doctor declare search at NMDP - it should go automatically also to search in Cord Blood Registry. NMDP- National Marrow Donor Program, 800-MARROW-2, MARROW DONOR
If a match is found - they will fly in on request from anywhere.
V.O.D. (a.k.a. veno-occlusive disease of the liver) is a toxic reaction which sometimes can happen after high-dose chemotherapy (not necessarily after BMT). The clinical picture is one of liver enlargement and tenderness, jaundice (yellow discoloration of the skin and mucous membranes) and weight gain (from the accumulation of fluids in body cavities - mostly the abdominal cavity - which we call ascites). The cause of the reaction is not completely understood, but is strongly related to some chemotherapeutic agents when used in high doses (e.g. Ara-C). What happens is that the small vessels that traverse the liver get clogged by thrombi, raising the pressure of the venous circulation in a retrograde fashion. In this way, every vein that drains its blood into the hepatic circulation (the portal system) becomes overloaded with blood. The rise in venous pressure causes the leakage of fluids into the abdomen and may cause enlargement of the spleen (an organ which empties its blood into the portal system too). V.O.D. can be a light, self-limited condition or, in the other extreme, a potentially life-threatening event. The treatment of VOD is controversial. It can be done with supportive measures like fluid restriction, use of diuretics and salt restriction. Or it can be actively treated with TPA, a drug that has the ability of dissolving formed thrombi. The risk of VOD is related to many factors, including the type and dose of drugs used for conditioning, the age of the patient, and mainly the state of his liver before the BMT.
This is described in Nature Medicineat: . The abstract of this article is at:
.Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Brian J. Druker, Shu Tamura, Elisabeth Buchdunger, Sayuri Ohno, Gerald M. Segal, Shane Fanning, Crg Zimmermann & Nicholas B. Lydon, Division of Hematology and Medical Oncology, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon, USA Ciba Pharmaceuticals Division, Oncology Research Department, Ciba-Geigy Limitme (RBC plus plasma) are accomplished by changes in the plasma which are controlled by the kidney, as plasma is mostly water. The blood volume is adjusted by the body to maintain an adequate blood pressure. When the blood volume falls quickly, as in bleeding, the body gets a signal to increase the amount of fluid that is circulating. That is why an early sign of blood loss is thirst.
After phlebotomy, as the blood increases its plasma content, the hematocrit falls, so the red blood cells are now diluted. The benefit of reducing the hematocrit(Hct) is to get the blood to a normal consistency (viscosity), as the heart and blood vessels are designed to pump and hold a fluid close to the viscosity of water, not oil. You can imagine what would happen if you filled your water tank and plumbing system with motor oil instead of water.
Once the blood volume is replete and the viscosity of the blood is normal, the red blood cells can fulfill their function of oxygen delivery to the tissues much better. The red blood cells have a fantastic capacity to increase their oxygen delivering ability by many adaptive mechanism so that, with the proper compensations in fluid replacement, your body should not be deprived of adequate circulation or oxygen.
At the beginning of your PV you will have an elevated Hct. As the initial salvo of phlebotomies are performed, the RBC mass and plasma volume are reduced to normal levels. After that, depending on the rate of your RBC production and how fast you build up your red blood cell mass, it should take periodic phlebotomies to maintain your Hct at a normal level unless you are receiving other therapy which controls your counts and reduces or eliminates the need for further phlebotomies. The frequency of phlebotomy after the initial series varies widely from patient to patient and within one individual, depending on the disease activity.
Most patients tolerate phlebotomies rather well. Special care must be taken in patients with cardiovascular instability. Also phlebotomy may temporarily cause an increase in platelet counts.
Yes. The immediate post-phlebotomy period symptoms of weakness, headache, etc. are due to the acute change in blood volume. Drink plenty of fluids just before and for two days after the phlebotomy. Also, do not engage in strenuous physical activity during that time. Low dose aspirin (81 mg/day) especially pre- and post-phlebotomy is suggested to keep the platelets from being too sticky. This helps in maintaining good circulation even if there is a post-phlebotomy increase in the platelet count. This should be taken only if there are no contraindications so check with your doctor before taking aspirin.
No. In many instances, phlebotomy is used to rapidly bring down the red cell mass and then myelosuppressive drugs are added to the treatment plan. Some patients will not tolerate phlebotomies or may have such active red cell production that the required frequency of phlebotomy is unacceptable. In addition, some patients have other elevated cell lines such as high platelets or high white cell counts. Some experts use phlebotomy initially but think it speeds the process toward the spent phase. For a variety of r