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Statements contained herein are of a general nature and should not be construed as personal advice in lieu of recommendations by your physician or other relevant professional consultant

CML is shorthand for chronic myeloid, chronic myelocytic or chronic myelogenous leukemia (also known as chronic granulocytic leukemia or cgl) CML is a form of leukemia which affects the cells which make granulocytes (the polymorphs that eat bacteria) and the platelets (the little cells which help the blood to clot). In its early stages it produces an increase in the numbers of granulocytes and platelets but these cells still function normally and the patient may have no symptoms. This situation may continue for 3 or 4 years (known as chronic phase) and the disease may be unsuspected with the diagnosis made incidentally in the course of an insurance examination or a pre-anesthetic work-up. However, eventually the nature of the disease changes and CML starts to behave like other leukemias. These changes are called transformation and are often slight to start with (accelerated phase), but within 6 months or so usually progress to the full-blown leukemic picture (blast phase). Survival from the development of blast phase is usually measured in months. CML is one of the myeloproliferative disorders.

2.WHAT ARE THE SYMPTOMS?

Patients often have nonspecific symptoms such as fatigue, weakness, loss of appetite or weight loss, or are diagnosed from blood studies done for other reasons. When patients are first seen, the spleen is usually moderately enlarged which can cause epigastric distress and a sense of fullness. Minor lymphadenopathy (minor problems with the lymph nodes) can occur but this is much less evident than in CLL. Hemostatis is rarely impaired until late, after "blastic transformation" develops or after therapy or the evolution of the disease leads to thrombocytopenia (low platelet counts). In patients who develop thrombocytosis (platelets greater than 1,000,000), homeostatic problems may be secondary to inadequate platelet function.

3. HOW IS CML DIAGNOSED?

CML is generally considered in patients with an elevation in blood granulocyte concentration if the explanations of infection and inflammation aren't likely. The differential diagnosis includes the other myeloproliferative disorders, myelofibrosis, polycythemia vera, other causes of leukocytosis (inflammation or infection). The presence of enlarged spleen, the characteristic blood picture, bone marrow aspirate, leukocyte alkaline phosphatase test and the presence of the Philadelphia (Ph) chromosome help in differentiation.

4.WHAT ARE THE LABORATORY FINDINGS IN DIAGNOSIS?

Granulocyte count of more than 30,000 (normal 4 - 8,000) with the cells maturing in an orderly fashion. Platelet count more than 400,000 (normal 150 - 350,000). The marrow is packed with large numbers of mature and maturing granulocytes. When the chromosomes of these cells are examined by cytogenetic tests, a particular type of deformed chromosome is discovered. This is known as the Philadelphia chromosome (Ph chromosome) and its presence is diagnostic of CML (although very rarely it can be found in other types of leukemia). However, a small percentage of CML patients are Ph negative. Unless the Ph chromosome or the BCR/ABL product can be detected, the correct diagnosis is not CML, and the patient has a different type of MPD.

5. WHAT IS THE PHILADELPHIA CHROMOSOME, BCR-ABL?

BCR-ABL stands for the name given to an abnormal gene that is the result of a fusion of material from 2 chromosomes (22 and 9). In fact, this has everything to do with CML and the Philadelphia chromosome. This Philadelphia (PH) chromosome is an abnormal chromosome that results from an exchange of material (DNA) between the normal chromosomes 22 and 9. It is present in over 90% of CML cases. In chromosome 9, there is a gene called c-abl (from "Abelson"). A break occurs beside this gene, and it is translocated to a place in chromosome 22, called bcr (breakpoint cluster region). What happens then is the fusion of these two pieces of DNA, that gives rise to a fusion gene (bcr-abl). This fusion gene is involved in the pathogenesis of CML and possibly other leukemias (e.g. ALL). Also, it serves as a molecular marker of PH-positive cells, and is currently screened by PCR in the post-BMT period. Very interestingly, bcr-abl might prove useful as a target for specific treatment with antibodies directed to it. That, if feasible, would permit us to attack only the leukemic cells, sparing normal tissues from the damage caused by chemotherapy (which is not selective for leukemic tissue).

6.WHAT ARE THE TREATMENT OPTIONS FOR CML?

For many years, the only treatment for CML was palliation with the drug busulfan (a drug that reduces the number of white cells and platelets as well as red cells but does not slow down progression of the disease. Hydroxyurea was also used for this purpose.

Then it was found that interferon-alpha can control CML in about 80% of patients and reduces the Philadelphia chromosome in about 40%. Interferon-alpha does not cure CML but it did extend the time to progression from about 4 years for hydroxyurea to 12 or more years. An intractable problem was the side effects experienced at the doses used to treat CML. Next came combinations of interferon-alpha and ARA-C which were found to be superior to interferon alone.

But the advent of the first targeted therapy, imatinib (Gleevec) changed the face of CML treatment. This drug binds the bcr-abl protein and turns off its abnormal activity. It is first line therapy for newly diagnosed CML patients and many achieve complete hematologic and cytogenic remission. For detailed information about Gleevec in CML, go to http://www.newcmldrug.com/

In about 25% of patients treated with Gleevec, in time, additional cytogenic abnormalities develop that are not touched by Gleevec and patients relapse. The good news is second generation targeted therapies have been developed. Dasatinib is one.

Bone marrow transplantation is the only form of treatment which is known to improve survival and possibly cure CML. This is a high-risk, expensive procedure and carries with it complications such as graft-vs-host disease which can plague patients for some years. The risks are greater in older patients and in patients with very advanced disease. “Mini” transplants which use a less rigorous preparation have made it possible for older patients to undergo transplant. In good risk patients, treatment-related mortality in the best centers is between 10-15%. The results are worse in centers with less experience. For information about transplants, visit http://www.bmtinfonet.org/ and http://www.marrow.org/

If you are considering transplantation, you should join ACOR’s bmt-talk online support group. To join, send an email to listserv.acor.org with a one line message

subscribe bmt-talk first and last name. You also should join the ACOR CML list. Address your email to cml-request@listserv.acor.org with the one line message subscribe cml first and last name

Patients who are found to be “hiding” Philadelphia chromosome cells or bcr-abl rearrangements (minimum residual disease) naturally fear a comeback of CML. In fact, some patients harbor the bcr-abl protein without ever showing signs of relapse. What seems to matter is the amount and type of cells found in the test, not simply their presence. Minimum residual disease does require following by quantitative PCR assay or other tests. done serially. If a relapse is predicted, your doctor may recommend a new stem cell infusion early (as soon as a potential problem is identified), so that the CML mass is still small and more sensitive to treatment. If new mutations are found, your doctor may want to try one of the newer targeted therapies before proceeding to transplant.

7. WHAT ABOUT HIDDEN PH+ OR BCR-ABL AFTER 100% CYTOGENIC RESPONSE?

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.

8.WHAT IS INTERFERON, HOW DOES IT WORK?

Interferon's 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).

9.WHAT SIDE EFFECTS CAN I EXPECT FROM INTERFERONL?

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.

10.WHAT IS HYDREA AND WHAT SIDE EFFECTS CAN I EXPECT?

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.

11. CAN EVERYONE HAVE A DONOR TRANSPLANT?

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.

12. WILL INSURANCE PAY FOR MY TRANSPLANT?

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 BMT's 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 BMT's using mismatched 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.

13.HOW DO I FIND A MATCHED DONOR FOR AN ALLOGENIC TRANSPLANT?

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.

14.WHAT PROBLEMS COULD BE EXPECTED DURING AND FOLLOWING AN ALLOGENIC BONE MARROW TRANSPLANT?

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.

15. WHEN IS THE BEST TIME TO PURSUE A TRANSPLANT?

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.

16. HOW DOES CML PROGRESS? WHAT IS THE PROGNOSIS?

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 ARAC 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.

17. WHAT CAUSES CML?

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).

18. IS CML HEREDITARY?

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.

19.WHAT IS REMISSION, CURE?

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 suspension 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 situation, 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.

20.HOW DO PEOPLE GET THEIR BONE MARROW TYPED?

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.

21.WHAT IS CORD BLOOD?

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.

22.WHAT IS V.O.D?

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.

23.WHAT IS THE OREGON/CIBA-GEIGY/BCR-ABL TESTING ABOUT?

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 Limited, CH-4002, Basel, Switzerland. Correspondence should be addressed to B.J.Druker. The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 98% decrease in the number of bcrabl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.

24.HOW CAN I FIND MORE INFORMATION?

MPD-NET internet support group To join this discussion group with over 720 patients from 33 countries (and growing), Address an email to mpd-net-request@listserv.acor.org and in the body, put the words subscribe mpd-net and your first and last name. MPD-NET is a member of ACOR (Association of Online Cancer Resources)

MPD-NET Web page MPD-NET page. Our group's patient created web page has a wealth of information and links to a number of sites on the internet where you can find even more information depending upon how detailed you want to get.

MPD Voice -- Newsletter The MPD VOICE newsletter is published by the CMPD Research Center. For questions or suggestions about the newsletter, contact the Editor, Joyce Niblack jniblack@mpdinfo.org.

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