Maintained By: Joyce Niblack JNiblack@Aol.com Fax (602)-443-1154
This FAQ was last updated February 3, 1999
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Copyright 1999 by Joyce Niblack for the MPD Research Center, Inc., New York, New York. No part of this document may be used or reproduced in any form or by any means, or stored in a data base or retrieval system, without prior written permission of the copyright owner. You may however, print out a copy for your own personal use or that of your physician.
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.
INDEX
It is a disease of the bone marrow in which the bone marrow becomes fibrotic. This fibrotic scar tissue inside the marrow cavity eventually takes over leading to increasingly inefficient blood cell production and ultimately may result in bone marrow failure. It may be called by several names including primary or ideopathic myelofibrosis (more common in the British health system) or agnogenic myeloid metaplasia (usually used in the USA). These names describe a situation where myelofibrosis is the first disease diagnosed. It is also possible to have myelofibrosis as a consequence of another myeloproliferative diseases such as polycythemia vera (PV), essential thrombocythemia (ET), or chronic myelogenous leukemia.
In the setting of a myeloproliferative disorder, myelofibrosis is accompanied by varying degrees of myeloid metaplasia (often seen as enlargement of spleen and/or liver), due to reactivation of fetal hematopoietic sites than are normally dormant in adult life. It is this combination that distinguishes myeloproliferative disease-related myelofibrosis from the secondary or interactive myelofibrosis that occurs in the setting of malignancy, chemical or physical injury, infection or infarction. The increase of fibrous tissue in the bone marrow, the extramedullary hematopoeisis that presents itself primarily as progressive enlargement of the spleen (splenomegaly), and the leuko-erythroblastosis in the peripheral blood form the basis of the myriad clinical presentations of myelofibrosis. Clinical and laboratory findings, the course and complications and the ultimate outcome are determined by the degree of preservation of normal hematopoeitic tissue, the extent of hematic dysplasia, and the balance between cell proliferation and cell destruction. Departures from "classical" clinical presentations are common.
Usually by a physician noticing low red cell counts and perhaps other abnormal blood counts such as elevated white cell and/or platelet count during a routine exam or as a result of an examintion to determine the cause of a patient's complaints of feeling more tired than usual or that their abdomen in tender and enlarged or bloated (this comes from the enlarged spleen), bruising, etc. An alert doctor will request a full blood screen which will identify that some elements of the blood counts are abnormal and may follow up with an abdominal ultrasound or other scan before sending a patient to a hematologist for further work-up.
To be sure of the diagnosis a bone marrow biopsy is required to test the state of the marrow itself and provide conclusive evidence of the disorder. At the Rotterdam MPD-Workshop held March 13-14, 1998, there was discussion of the criteria of this disorder proposed by the Cologne Clinicopathological MPD Study Group and the Thrombocythemia Vera Study Group reported in the literature at: Thiele J. et al, Idiopathic primary osteo-myelofibrosis: a clinico-pathological study on 208 patients with special emphasis on evolution of disease features, differentiation from essential thrombocythemia and variables of prognostic impact. Leukemia Lymphoma 1996; 22:303-317; Thiele J. et al., Clinicopathological diagnosis and differential criteria of thrombocythemia in various myeloproliferative disorders by histopatholgy, histochemistry and immunostaining from bone marrow biopsies. Leuekmia Lymphoma 1998.
The proposed criteria include clinical and hematological features and diagnostic criteria.
Clinical and hematologic features: A) No preceding or allied other subtype of myeloproliferative disorders or MDS; B) Splenomegaly on palpation or >11 cm or ultrasound scan or CT; C) Thrombocythemia, platelets of >400,000; D) Anemia, hemoglobin <12 g/dl; E) Definitive leuko-erythroblastic blood picture and/or tear drop shaped erythrocytes.
Diagnostic features: F) Histopathology: megakaryocytic plus granulocytic myeloproliferation. Abnormal clustering and increase of atypical giant to large megakarocytes displaying defects of multilobulated nuclei and definitive maturation defects of cytoplasm and nuclei; F1) no reticulin fibrosis; F2) slight reticulin fibrosis; F3) marked increase (density) in reticulin or collagen fibrosis; F4) Osteosclerosis, endophytic bone formation.
Clinicopathological Staging
Stage 1 A+B+C+F1 is consistent with a hypercellular prefibrotic stage of AMM(IMF) simulating clinically ET
Stage 2 A+B+C+D+F2 is consistent with early AMM (IMF)
Stage 3 A+B+D+F3 is consistent with manifest AMM (IMF)
Stage 4 A+B+D+E+F3+4 is consistent with advanced MF complicated by osteosclerosis, osteomyelosclerosis
Some hematologists will have had more experience at dealing with the disease; others use a wide range of tools and others will provide a positive framework for your questions. So don't necessarily accept the first opinion as being the best.
It is important as it provides a bench mark for measuring the progress of the bone marrow directly. The blood reports show the consequences of the state of the bone marrow. Nothing beats firsthand information. Some doctors claim they can tell by peripheral blood counts and do not rely on bone marrow biopsies. As you can see from the above criteria, it is virtually impossible to stage the disease without this tool. And staging provides a guide to the most appropriate treatment option.
However the procedure may be difficult as local anesthetics cannot reach the bone marrow itself. You may find that if you prepare with a relaxant (mild tranquilizer) about an hour ahead that the procedure (which takes 3 - 30 minutes depending on skill and bone density) can be coped with. A skilled technician or nurse who does the procedure on a regular basis may be preferable to a doctor who does it rarely. For example, nurses perform these procedures at centers such as MD Anderson and Mayo Clinic. Some physician's will order intravenous medication such as a combination of demerol and versed or morphine and valium. If you choose this option, you will generally have to stick around for several hours while you are monitored and sleep off the effects of the drugs. Other doctors require a general anesthetic (which has its own risks and takes longer to recover from). We do not recommend going through this procedure without at least a mild tranquilizer. Beyond that is a matter of personal choice. If you find it difficult, insist on pain relief. The frequency of bone marrow procedures will depend upon your physician, your condition, the treatment you are receiving, etc.
The staging criteria defined above is one means of determining disease state/progression.
Dr. Harriet S. Gilbert, a noted specialist in the myeloproliferative disorders and founder of the MPD Research Center, classified MF syndromes as follows in Myelofibrosis Revisited: Characterization and Classification of Myelofibrosis in the Setting of Myeloproliferative Disease, pp 3-17, Myelofibrosis and the Biology of Connective Tissue, 1984, Alan R. Liss, Inc., 150 Fifth Avenue, New York, NY 10011.
1) Reactive Myelofibrosis With Bone Marrow Hyperplasia
In this
syndrome bone marrow is still functioning and in fact overproducing
platelets, white cells and/or red cells. (You have ) bone marrow
fibrosis of varying degree with an excess of megakarocytes,
overproduction (hyperplasia) of one or more cell types, and
maintenance of normal differentiation and maturation of the blood
cells; b) centrifugal expansion of the bone marrow, with or without
axial fibrosis; and c) progressive myeloid metaplasia.
In this stage, proliferative blood cell production is prominent. It can arise de novo or appear as an evolutionary stage of a preexisting myeloproliferative disease, such as polycythemia vera, essential thrombocythemia or chronic myeloid leukemia. Patients may be overproducing red cells, platelets or white cells and may require treatment to reduce high counts. Panmyelosis is generally present and bone marrow collagen fibrosis is minimal or absent. The inability to aspirate marrow is due more to a disrupted architecture with a mixture of densely packed blood cells, reticulin and fibrous tissue than to an empty or densely fibrotic marrow. Platelets, white cells and red cells are present in abundance. The cell production is generally orderly and the normal morphology is preserved. Megakarocytosis is generally present in the marrow. Regardless of the degree of central marrow fibrosis, there is generally centrifugal marrow expansion. Also myeloid metaplasia is usually present as part of this syndrome. The spleen is often enlarged to the umbiblicus at time of diagnosis. Lesser degrees of splenomegaly occur, but progressive enlargement at the rate of one to two centimeters per year can be anticipated. Hepatomegaly (enlarged liver) is also present but this lags behind the spleen.
The peripheral blood picture is extremely variable. Anemia may initially be absent or very slight. Erythrocytes are usually normochromic and normocytic , but hypochromia and microcytosis are common in post-poycythemic reactive myelofibrosis when previous phlebotomy or spontaneous bleeding has rendered the patient iron-deficient. Some patients may display signs of folic acid deficiencies. Tear drop erythrocytes and ovalocytes, while considered a characteristic, may be relatively infrequent. The prevalence of these abnormal red cell forms is said to vary directly with the degree of spleen enlargement. The erythrocytes may display metabolic abnormalities, such as increased susceptibility to lipid peroxidation. Stigmata of low-grade hemolysis may appear, including elevated LDH, indirect hyperbilirubinemia and reduced haptoglobin levels. Normoblasts are usually present in small numbers in the peripheral blood, but less mature erythroid precursors are absent. A modest reticulocytosis is usual. Anemia at this stage of the disease results from hemodilution resulting from the hydremia that accompanies splenomegaly, splenic pooling of erythrocytes, decreased functioning erythropoietic tissue, increased ineffective erythropoeisis and shorted erythrocyte survival. Detailed assessment by direct, quantitation of red cell mass and plasma volume, bone marrow scanning, ferrokinetics, and erythrocyte survival studies is required to identify the contribution of these various factors and to provide valuable therapeutic and prognostic guidelines.
Leukocytosis (elevated white cell counts) is common in myelofibrosis with bone marrow hyperplasia. There is a shift of the myeloid population to the left, but few myeloblasts are seen in the peripheral blood. Basophil hyperplasia is common and leads to histaminemia and histaminuria. The neutrophils are morphologically normal but display metabolic abnormalities which indicate the activated state. These include increased adherence, increased hexose-monophosphate shunt activity, increased leukocyte alkaline phosphatase (LAP) activity, increased Fc-receptor activity, and increased spontaneous release of specific granule contents which accounts for elevated plasma levels of transcobalamin III, detected as an increased B12 binding complex.
Platelets are often increased at this stage, particularly if the myelofibrosis has evolved from preexisting essential thrombocythemia, polycythemia vera or chronic myelogenous leukemia. However, there may also be marked thrombocytopenia (low platelet counts) due to significant sequestration in the spleen. There may be evidence of in vivo aggregation including the presence of circulatiing platelet aggregates and increased plasma levels of products of the platelet release reaction.
Reduced plasma total cholesterol levels are prevalent. This is due to significant reductions in low density lipoproteins (LDL) and high density lipoprotein (HDL) in cholesterol. Among the features of myeloproliferative disease, spleen size has the greatest influence on cholesterol levels. Splenectomy or control of proliferation with cytotoxic therapy corrects the low cholesterol levels. LDL cholesterol levels show an inverse relation to disease activity.
Chronic reactive myelofibrosis in the proliferative phase of myeloproliferative disease is an indolent process. Complications arise from splenic infarction, thrombosis, hemorrhage, circulatory overload from hydremia, and hypermetabolism with inanition. Abnormal portal circulation and the hypercoagulable state present an increased risk of portal or hepatic vein thrombosis. If the proliferative phase persists, prolonged survival is possible and the literature gives ranges from 5 to 15 years with a median of 8 years. However, we have MF patients in our MPD-NET discussion group who have been living with MF for 20 years or longer.
The proliferative phase of myeloproliferative disease with chronic reactive myelofibrosis is the variant that responds best to therapy. Preservation of the blood producing function and marrow reserve permits the administration of myelosuppressive therapy to reduce the spleen size and control thrombocythemia. Platelet deaggregating therapy may inhibit in vivo platelet aggregation and reduce the risk of thrombosis. Splenectomy may be indicated for repeated infarcts, severe mechanical embarrassment, hypersplenism or marked hydremia. It is contraindicated in the presence of megakarocytosis and thrombocythemia because an uncontrolled and life-threatening postoperative increase in platelet count occur. When surgery is required, the megakaryocyte population should be reduced with myelosuppresive therapy. Splenic irradiation has been employed to reduce the spleen size and correct hypersplenism. It has met with short-lived success compared with splenectomy, but may be of value in patients who are poor operative risks. Unfortunately, radiation-induced cytopenias often limit delivery of effective dosage to the spleen. Anemia should be evaluated to determine the cause. Hydremia may be reduced with diuretic therapy and hypersplenism eliminated by splenectomy if the spleen fails to respond to myelosuppresive therapy. Interferon-alpha has been found to be effective in a number of patients. Administration of hematiminics may improve red cell formation by correcting iron or folic acid deficiency.
2) Reactive Myelofibrosis With Bone Marrow Dysplasia
In this
form, there is a) bone marrow fibrosis with an excess of
megakarocytes, normal or increased proliferation of one or more cell
lines and abnormal differentiation and maturation which shows up as
ineffective hematopoeisis with intramedullary cell death and varying
degrees of anemia and peripheral cytopenia;
b) centrifugal expansion of bone marrow with axial marrow fibrosis;
c) myeloid metaplasia with hypersplenism.
In this stage, the central bone marrow may be diffusely fibrotic, but it is not uncommon for fibrosis to be patchy in distribution and interspersed with areas of proliferating cells of the hematic trilineage (red cells, white cells and platelets) . Osteosclerosis is present in about one-third of patients and the increased deposits of new bone is seen on x-ray as a patchy increase in density of the bone marrow cavity with retained cortex. The total mass of hematic cells is reduced. But megakarocytes are preserved out of proportion to the other populations. Megakaryocyte morphology is often atypical. The bone marrow usually shows some features of dysplasia. There may be erythroid hyperplasia with sideroblastic proliferation and refractory anemia. An abnormal clone with the characteristics of par hemoxysmal nocturnal hemoglobinuria may result in peripheral pancytopenia in the presence of active bone marrow proliferation. Reversal to fetal erythropoeisis may be seen increased fetal hemoglobin.
Reactivation of fetal hematopoeisis is also seen as centrifugal redistribution of the marrow, as for example, expansion into the long bones and significant myeloid metaplasia. The spleen is usually enlarged at diagnosis and continued growth leads to massive splenomegaly. Compromised bone marrow function, through decreased marrow mass, dysplastic growth, and myeloid metaplasia results in a grossly abnormal hemgram. Anemia is common. Erythrocyte morphology is abnormal with macrocytosis and an abundance of tear drop forms and ovalocytes. Circulating erythroid precursors of all degrees of immaturity are present and normoblastosis is striking. Reticulocytosis is present and usually is accompanied by stigmata of ineffective erythropoeisis, such as elevated serum LDH, increased indirect bilirubin, and decreased serum haptoglobin. Neutropenia and left shift in the myeloid population are common. Basophils may be increased. Modest thrombocytopenia is typical. Platelet morphology is abnormal. In addition, circulating megakarocyte fragments are present and nucleated megakarocytes may also appear. Platelet clumps are noted and in vivo platelet aggregation is usually seen. Abnormalities in platelet function are similar to those of reactive myelofibrosis with bone marrow hyperplasia.
Patients with chronic reactive myelofibrosis accompanying this dysplastic form of myeloproliferative disease have serious hematologic compromise. As a result, the disease course is approximately 3 years with a range of one to five years. Bone marrow transplants offer the only hope of a cure or extended life expectancy. Anemia and the complications of a chronic transfusion requirement pose major problems. Bleeding, infection, splenic infarction, circulatory overload with congestive heart failure, hyperuricemia, debilitation and leukemia transformation all contribute to the short and often stormy course of these patients.
The shrinking or dysplastic erythropoeitic marrow may be stimulated by androgens or structurally related non-androgenic testosterone metabolites. The response is variable. While some have reported a 30-50% response rate to oxymetholone, a prospective, randomized, double-blind study showed no difference in response to nandrolone and placebo. The occurrence of spontaneous remissions confounds evaluation of these agents.
Splenectomy may correct anemia and cytopenias in some patients, permitting longer cell survival and eliminating the splenic pool. However, dyshematopoiesis is unaffected by this procedure and the extent to which anemia and cytopenia occur will limit the benefits of splenectomy. Curettage of the bone marrow has been attempted to alter the presumably deranged hematopoeisis-inducing microenvironment. Several reports of regrowth of functional bone marrow at the sites of curettage have been published. The success rate in a non-randomized study was low and in one study, the effect was found to be transient.
The genetically engineered human growth factors are offering hope for stimulating blood cell production so that the underlying condition can then be treated. These include the erythropoeitin factors which stimulate red cell production (Procrit and Epogen), colony stimulating factor which stimulates white cell growth (Neupogen) and the experimental thrombopoeitin factor currently in clinical trials (Genentech has information about this on their web page at http://www.gene.com
Fred Hutchinson Cancer Center in Seattle Washington is treating MF patients with bone marrow transplants. One of our mpd-netters received a bone marrow transplant at the Hutch about 3 weeks ago. We have another woman in our MPD-NET group who is "too old" for a bone marrow transplant but will be treated with a transplant of her own stem cells. She will be the second MF patient to receive this treatment and the first woman in the world to have it.
Because of poor marrow function and reserve, there is reluctance to use myelosuppression. Its judicious use may decrease splenomegaly. A platelet sparing regimen of vincristine and prednisone may be helpful in some patients. More modern, encouraging results have been achieved by combining interferon-alpha with erythropoetin and colony stimulating factor as noted above. The variable and sometimes lengthy survival of patients with chronic reactive myelofibrosis has led to a conservative approach to management.
3) Reactive Myelofibrosis with Aplastic or Hypoproliferative Bone
Marrow
This is the most serious of the syndromes. There is:
a) generalized fibrosis of the bone marrow, retention of clusters of
atypical megakarocytes, hyperplasia and immaturity of all three cell
lines, and marked decrease or absence of normal hematopoeisis;
b)
absence of centrifugal expansion of intramedullary hematopoeisis; and
c) absent or minimal myeloid metaplasia.
Bone marrow failure results in profound anemia and cytopenias. The number of tear drop erythrocytes and degree of leukoerythroblastosis is less than in the previously described forms. There is usually reticulocytopenia. Thrombocytopenia is common and the platelet abnormalities seen in other variants is present. Neutropenia may be severe. Circulating granulocyte precursors are present, but blast forms comprise less than 10% of the leukocytes. Hyperuricemia is not a prominent feature. An elevated erythrocyte sedimentation rate and hyperglobulinemia are prevalent.
This form runs an acute course and is also known as "acute" or "malignant" myelofibrosis or "malignant myelosclerosis and is now considered a form of leukemia. It is a fulminate disease with a median survival of less than one year. Complications of severe bone marrow failure lead to life-threatening bleeding and infection. The patient may tend to run a fever without any demonstratable infection. Bone pain, arthritis, and generalized wasting are frequent. The spleen may remain small or may show some enlargement but never reaches the size seen in the other variants. But there is macrophage hyperfunction evidenced by markedly shortened survival of autologous and transfused cells. Death usually occurs from infection or hemorrhage. Bone marrow transplant offers the best hope of treatment for this patient group.
Many doctors will give quite a negative prognosis, for example: "you have years rather than decades to live"; "don't make any long term plans"; "average life span after diagnosis is four years" and so on. This is based on existing text books which usually are describing figures from some years ago.
We feel that while this may have been appropriate in the past that new treatments and new approaches as well as earlier diagnosis offer new possibilities. Each of us is an individual and should take the most positive approach to maximizing the possibilities of our lives.
If you would like another example, consider the following extract from Blood Reviews, June 1991:
"In general, the survival of patients with idiopathic
myelofibrosis seems to a large extent programmed by their presenting
findings and is not very much altered by therapy. Approximately 60% of
patients with idiopathic myelofibrosis live 5 years. There is a
significant cohort of patients who live 10 years or more. Patients
with idiopathic myelofibrosis who tend to do very well include those
whose presenting hemoglobin levels are greater than 10 gm/dl, platelet
counts greater than 100x3/ul and only modest enlargement of the
liver. Spleen size and sex seem to have no prognostic
significance"
- Haematological Oncology, Idiopathic Myelofibrosis: Historical Review, Diagnosis and Management, written by I.M. Weinstein, M.D.
We have patients in the mpd-net group who have done well for 18 or more years before requiring aggressive treatment (bone marrow or stem cell transplant) and we have had patients with the acute form. Since interferon has, in some, turned back the clock and reversed early stage MF, and new therapies are being evaluated, the picture can be expected to change as the "watch and wait" until disaster strikes falls out of favor.
As discussed above, if you were previously diagnosed with a myeloproliferative disorder such as essential thrombocythemia, polycythemia vera or chronic myelogenous leukemia, your myelofibrosis is reactive and secondary to the pre-existing MPD. If it arose de novo with no prior history of another MPD, no one knows for sure. You might have had a prior undiagnosed myeloproliferative disorder, discovered only after you developed myelofibrosis. It might be likely to be a specific gene abnormality which develops over a period of years. It may be triggered by exposure to harmful chemicals such as benzene or radiation; but then from a group of firemen who were all exposed to benzene some got it and others didn't. Some of us cannot identify any particular exposure. Some of us have found connections within families, but this is an extremely rare condition so not everyone gets it.
Treatment options are a function of your condition, your doctor's knowledge, experience and preference, whether you live in the United States or a country with a national health care system, etc. The following options are not in any preference order.
Watchful Waiting
This involves taking no medication and monitoring blood counts on a regular basis, which
may initially be monthly, followed by bi-monthly or quarterly if results are stable. This
seems to be mentioned more frequently by patients living in countries with national health
care systems.
Advantage:
No chemicals are entering your system and causing effects that may be difficult to deal
with. You may then in better shape if you decide later to have a bone marrow transplant.
Also, with time come new treatment options.
Disadvantage:
You may be anxious and feel frustrated about the lack of action. Your disease may progress
whereas it may have been possible to reverse or retard its progression. This should be
discussed carefully with your doctor. If you are in a hyperproliferative stage, that is
your platelets, red cells and/or white cells are elevated, you may require treatment to
avoid complications. Since interferon works best in the early stages of the disease and
also regulates blood counts, "watchful waiting" may be robbing you of an
opportunity to gain control and slow down progression or turn back the clock by reversing
the presence of MF in your marrow. Waiting risks progression which can lead to
becoming transfusion dependent and requiring a bone marrow or stem cell transplant to
survive.
Treatment for Anemia
Anemia is common in this disorder. According to the Mayo Clinic, only 20% of patients respond to treatment for anemia. Mayo uses an androgen preparation, usually 10 mg twice a day of Halotesting (fluoxymesterone) plus 0.5 mg/kg/day of prednisone. The remaining 80% become candidates for splenectomy (spleen removal), a procedure that carries some post-operative complications and about an 8% mortality rate. Only 50% of patients benefit for their low blood counts following spleen removal.
Patients who do not respond to androgen therapy may benefit from erythropoeitin (Epogen or Procrit).
Patients with severe anemia may require blood transfusions if the red blood cells fall too
low. This is usually done in the hospital setting. If you are feeling really tired from
the anemia this may give you a boost to your energy levels and also reduce the risk of
cardiovascular or other complications which can develop. However, you may pick up someone
else's antibodies or be exposed to hepatitis or the AIDS virus. While blood is screened
for these diseases, there have been instances where contaminated blood did find its way to
various hospitals, in several cases, with the knowledge of the government. However, you
may have little choice. Transfusions are not a "forever" treatment. They
do not stop disease progression and eventually become ineffective.
Myelosuppresive Treatment
If you are overproducing blood cells, to minimize risk of complications, some doctors will
suggest trying chemotherapy such as Hydrea to control platelets and white cell counts in
patients whose marrow is overactive. Other doctors believe that interferon is a better
first line of treatment. The problem with Hydrea is that it can depress the marrow and
also increase the risk of leukemia. However, its risks are lower than those associated
with older agents-i.e. alkylating agents such as chlorambucil or radioactive phosphorus.
Anagrelide is a drug that lowers platelet counts. If high platelets are the chief concern, this drug may be prescribed. It may be combined with other drugs. Several ET patients in our mpd-net group have developed secondary myelofibrosis while taking this drug. This is not considered chemotherapy since anagrelide is not cytotoxic.
Interferon is a biological response modifier which has positive effects on the immune system and has the ability to improve the cellularity and morphology of the bone marrow. It also seems to have an impact on the communication process within and between cells in ways that more traditional chemotherapy doesn't. It also acts to reduce the size of the spleen and in some patients with early stage MF, has actually reversed the fibrosis or stopped its progression. It has extended the life expectancy of CML patients, in some cases actually eliminating the market Philadelphia chromosome.
There is a recent literature report of using interferon combined with recombinant human erythropoietin and granulocyte-macrophage colony stimulating factor (Acta Haematology 1996; 96 (2): 79 - 82 authors: KL Bourantas et al. Treatment of r-hu-Epo plus IFN plus GM-CSF was provided to seven patients in Greece aged 48 - 72 with ideopathic myelofibrosis with beneficial results for all patients. However all showed different benefits ( reduced anemia, improved spleen, reduced marrow fibrosis (only for 2), increased white blood cells and six of the seven showed mild side effects with one showing severe side effects from the IFN.
Interferon is taken by way of injection. The dose varies depending upon a patient's stage of the disease. For example, we have one woman in mpd-net with secondary MF. Her spleen was enlarged to 24 cm at the time of diagnosis of grade 1(+ fibrosis). She is being treated with 8MU daily. Her marrow is still in the hyperproliferative stage so she tolerates this dose without undue suppression of all counts. But for someone with very low counts to begin with, a much lower dose is used.
Interferon initially produces flu like symptoms. People have found it best to take it at night with Tylenol to reduce impact of side effects. Initially, patients experience flu like symptoms which are generally well controlled with Tylenol. As the body adjusts, these symptoms gradually diminish. Some patients report adjusting in a week or two. Others feel wretched all the time they are on it (flu like symptoms: fever, chills, fatigue, muscle aches, head ache, loss of appetite, diarrhea, dizziness, dry skin, dry mouth, slight confusion and weight loss - unfortunately you don't get to pick which symptoms you will have). Generally increased fatigue is the most common persistent side effect.
If you decide to take it try to get the smallest gauge needle possible ( for example a 30 gauge insulin type needle); or if you require a syringe larger than 1cc, replace the coarse tip (25 gauge) with a 30 gauge tip.
Interferon replicates the body's own natural healing process. If you do respond, in some patients, it can keep your system stable for long periods. Constant administration may not be necessary. We have one ET patient in our mpd-net group whose early stage MF was not only reversed, she was able to go without further treatment of any kind for three years, then only needed anagrelide for several more years. She went back on interferon because of the return of early stage myelofibrosis which was again reversed after 26 months of treatment. We also have a CML patient in mpd-net whose myelofibrosis was reversed on interferon. Because of his CML, he remains on interferon.
The disadvantages of this treatment option include cost, need to inject oneself, side effects, it might not work. It is not a cure and repeated courses or perpetual maintainance are necessary. It does not reduce spleen size in all patients.
For more information about side effects of drug treatments check the Physicians Desk Reference or do a net search on the name of the drug and see specific references to many pieces of research.
Bone marrow transplant
This involves the destruction of your
own marrow and immune system by chemotherapy often combined with total
body radiation and the subsequent replacement with a matched related
or unrelated donor transplant or your own marrow. It is a
complicated and hugely expensive operation with a high risk
factor. However, this is the only treatment which offers the
possibility of a cure. Fred Hutchinson
Cancer Center in Seattle, Washington is one major center who is
doing bone marrow transplants on MPD patients, including MF
patients.
There are age limitations on matched unrelated donor (MUD) transplants and some centers such as Johns Hopkins will not do them.
There are three types of bone marrow transplants. 1) Autologous where a patients marrow is harvested when the patient is in remission or in an early stage (this is not curative but may prolong life). 2) Matched Related Donor (sibling, parent, child) which is preferred. 3) Matched Unrelated Donor (MUD).
The What's New Issue of MPD VOICE discusses these options.
Fred Hutchinson Cancer Center
(Hutch) in Seattle, Washington, USA, published its early
experiences with bone marrow transplants in the myeloproliferative
disorders in Br J Haematol 1997 Sept; 98(4):1010-1016, Anderson
J.E. et al. This article discusses the experience with 13
patients between 1980 and 1996. Of the 13, 8 had primary
myelofibrosis, 3 had myelofibrosis secondary to essential
thrombocythemia and 2 had myelofibrosis secondary to polythemia
vera. The median age at transplant was 40 (range 18-49).
Patients were transplanted at a mediam of 39 months from diagnosis
(range 5-192). Three patients received total body radiation and
10 received busulfan-cyclophosphamide in preparation for their
transplants. Nine received marrow from HLA-matched related
donors, one from an antigen mismatched related donor and three
from HLA-matched unrelated donors.
The median time for granulocyte and platelet engraftment was 21
days. 9 patients survive at time of publication for between 1.2
and 7.1 years following their transplants. 2 of the 9 relapsed but
were living in chronic stage disease. 4 died of
transplant-related complications. At one year post transplant,
the majority of survivors had normal peripheral blood counts and
none-to-minimal marrow fibrosis.
According to a letter from a Hutch doctor recently posted on
MPD-Net, Hutch has now done 22 transplants for MF. 17
patients survive, with one or more 8+ years post-transplant and
because of these positive results, they are recommending bone
marrow transplantation early in the disease.
MD Anderson reported its
experience with allogenic bone marrow transplant in 6 patients in
Hematol 1998 Jan:57(1):24-28. Of 6 patients, 3
survived.
The French Society of Bone Marrow Transplantation reported a
retrospective study of 12 patients allografted for AMM.
Br. J. Haematol 1997 Sept; 98(4):1004-1009. Ten
patients had splenectomies prior to transplant. Eight were
transfusion dependent. Donors in all but 1 case were HLA-matched
siblings. Total body radiation and cyclophosphamide were used prior
to transplant in 8. 11 of the 12 engrafted, graft failure
occurred in 1. 10 developed grade II-IV acute graft v host
disease. One patient relapsed 14 months after transplant,
was retreated and well 14 months later. 3 died from the
proceudre. Follow-up at 25 months and 4 years showed overall and
event-free survivals at 71% and 59% respectively.
Stem Cell Transplant for MF
For those who are "too old" for bone marrow transplants,
there is Dr. Jeanne Anderson's autologous stem cell transplant for MF.
Bonnie McDonald was the second patient to undergo this
procedure and the first woman in the world to have it. Bonnie
had her procedure at Fred Hutchinson
Cancer Center in Seattle, Washington and was particularly
fond of Dr. Anderson and Dr. Holmberg. Those interested in
information can reach Dr. Holmberg at 206-667-4762 and Dr. Anderson,
who is now at the University of Texas Health Science Center. Her
phone and fax numbers are (210)-567-4848, fax (210)-567-1956.
Patients who have some evidence of advanced disease (such as
hemoglobin less than 10; white blood cell count less than 4,000;
platelet counts less than 100,000; markedly enlarged spleen) who
are unable to or elect not to undergo allogeneic tranplantion, and are
75 years or younger, are candidates for this procedure.
The patient receives a drug called G-CSF (granulocyte colony
stimulating factor) which helps stem cells circulate in the blood and
then undergo apheresis, a procedure by which stem cells are
collected from the blood. The patient then receives
busulfan, a chemotherapeutic agent in pill form, which is
designed to clear out the marrow. Finally, the collected stem
cells are reinfused. Patients will have a period of days to
weeks where bone marrow function is impaired, blood and platelet
transfusions are needed, and there is a risk of infectiond ue to low
white blood cell count.
This is an exciting option for older MF patients. It is
experimental but Dr. Ayalew Tefferi stated at the San Diego MPD
Conference he intends to work closely with Dr. Anderson and the first
woman to have this procedure has reported Dr. Tefferi will start
doing this procedure at Mayo Rochester beginning in March of this
year.
Bone Marrow Curretage
The What's New issue of MPD VOICE newsletter also mentioned Dr. Richard Silver's (New York Hospital/Cornell University)'s curretage or "rangeur" procedure. This procedure does not involve prior chemotherapy or total body radiation. The patient's stem cells are collected from peripheral blood, areas of fibrosis are surgically removed from the patient's marrow and the stem cells are reinfused following the surgery. Dr. Silver discussed this procedure at the October, 1998 MPD Conference in San Diego, California. The theory is that scraping of the endosteal surface of the marrow cavity may be one way of altering the micro-environment for facilitating stem cell transplantation and regeneration. Dr. Silver reported that his oldest patient is 78. He was transfusion dependent prior to the procedure and as of last October, no longer needed transfusions. Silver reported having done 5 of these as of last fall. He showed slides of a patient undergoing the procedure. The patient's legs and arms were wrapped and a surgeon was drilling into the thigh bone. Some of the marrow in the hip area is also removed so the patient can be followed by bone marrow biopsy. Dr. Silver's office telephone number is (212)-288-5040. He will see patients only if they are first referred by their own hematologist.
Cord Blood Transplants
Cord blood transplantation at present, is more suitable for
children because of the limited number of cells harvested in this
fashion. Placental and umbilical cord blood contains stem cells which
are the master cells that generate red cells, white cells and
platelets. If the cord blood is given in a transfusion it can generate
renewed growth of cells. Cord cell transfusions are seen as
offering the potential for potentially less risky and less expensive
treatments than bone marrow transplants. But at the present time, its
use is primarily in small children because of the limited quantities
available. There was a recent report on a large number of these
transplants in various conditions. The risks in adults did not
seem all that different that conventional bone marrow and stem cell
transplants.
You will find a lot of discussion on the archives about the pros and
cons of bmts as people wrestle with this most difficult decision. For
patients with advanced myelofibrosis, this may be their only treatment
option. We suggest that you sign on to BMT-TALK for more
information. There is a direct link to this group on our web page.
Why is a particular treatment recommended? How important are social
and psychological factors in choosing a treatment option? As you can
see from the above discussion, there isn't a single myelofibrosis with
a given set of symptoms and conditions which respond to a specific
treatment. If a patient's marrow is still overproducing platelets, red
cells and white cells, their treatment needs are completely different
from a patient whose marrow is barely functioning.
Each patient needs to work with his or her doctor in deciding on the
best treatment option. Only your doctor has reviewed your records and
test results and can recommend a specific course of action that has
the best chance of dealing with your condition. The important thing
from the patient standpoint is to understand what treatment options
are available and discuss what is best for you with your
hematologist.
Coming to the understanding that these are chronic, incurable (without
a successful bone marrow transplant) conditions that require medical
monitoring and treatment for the remainder of one's life can be
difficult and we all cope in different ways. Some patients feel that
quality of life issues are the most important consideration. There are
several women in our group who were quite upset by hair loss, fatigue
and lack of response in shrinking their spleen and opted for
splenectomy so they could stop the interferon. Some do not have
insurance that covers the cost of a particularly treatment. In
countries with a national health care system, for example, interferon
may not be available as a treatment option unless the patient pays for
it personally. In the United States, Medicare patients face difficult
economic issues if interferon is the drug of choice.
Living with a potentially life-threatening chronic disease is
difficult. You will need to learn how to chill out so to speak. This
is not like a broken leg or similar physical injury. It is a chronic
disease which will require you to make certain changes in your life
from now on; for ever more. Unless you have a successful bmt; and
there are not many of those around; you will live with this for the
rest of your life. And your life will be different.
Those of us who have always been healthy find this very difficult. It
is helpful to be able to talk it out if you are a talker and have an
audience - otherwise join us on the net and share your thoughts and
feelings.
As mentioned above, The Hutch is recommending transplant early
on in the disease. This also is the present thinking in chronic
myelogenous leukemia, another myeloproliferative disorder.
It is not known for sure but it seems highly possible that the choice
you make about treatment may influence your system's capacity to deal
with subsequent choices. Prolonged chemotherapy damages organs and
patients may be less able to weather the severe chemotherapy required
prior to a bmt. Johns Hopkins
Medical Center has a cut off of one year for prior chemotherapy
for this reason.
Some German researchers have claimed that CML patients treated with
interferon first have not done so well with a bmt but other doctors do
not accept their results. The Hutch followed by a warning about
undergoing transplantion for CML for those on interferon more than one
year.
However, since some do well for a period of years with no
treatment and some have seen improvement or reversal on
interferon, this presents difficult choices if one is young
enough for a transplant and has a matched related donor.
Are there any new treatment options coming along?
The answer is maybe. Mayo Clinic has investigated a number of agents which were unsuccessful including oral interferon. There is a new trial just starting with a new agent that has shown anti-fibrotic activity in test animals and in humans with lung and kidney fibrosis. The first phase is limited to 30 patients and those slots are already full. It will be at least 3 months before any information is available. A second drug which has shown success is multiple myeloma will also be tested. When information is available as to patient response, we will update this FAQ, make an announcement on mpd-net and include it in the coming Myelofibrosis issue of MPD VOICE newsletter.
Different doctors will have different expectations - but you should expect monthly checks in the early stages while the doctor or team determines whether you are in a stable or deteriorating state; followed by two or three monthly checks if you are early and stable.
The myeloproliferative disorders are hematological malignancies but
there are no cancerous cells that divide and invade
(metasticize). There is an excellent explanation of this on the
MPD page web page under Writings of Dr. Gilbert. This is accessed at
http://www.acor.org/mpd and in
the What's New issue of MPD VOICE newsletter.
You may like to say to people that it is a rare bone marrow
disease.
There is a huge amount of material available on the Internet about
treatments and case reports and so on. As a rare disease there is not
much research specifically on myelofibrosis.
Use the web page for suggestions of how and where to search; or just
ask a question of the MPD-NET group. You might also want to search the
mpd-net discussion group archives which are located at http://www.acor.org or http://listserv.acor.org.
You must be a member of mpd-net to search the
listserv.acor.org archives.
Of course it depends on what kind of work you do and how well you feel; but in general if you pace yourself for any extra fatigue you should be able to continue in your current work. However, at some point you may wish to reassess the role of work in your life and consider undertaking work that is not as stressful (if you find your current work stressful that is). If you are considering changing employment you will need to take into account how much you disclose to a new employer and it is important to consider insurance issues on any employment change. If you plan a bone marrow transplant you will need six to twelve months sick leave from your work.
When you are newly diagnosed your emotional responses may be stronger
and more erratic than you are used to. It is hard to deal with other
people's reactions when you are feeling a bit wobbly yourself. If
there is no impact on your work consider not disclosing for at least
three months after diagnosis and then only to those who need to
know. Once you have a label in people's minds it cannot be
erased.
Those of us who have tried to obtain insurance after diagnosis have met with generally negative responses including a flat refusal to provide life insurance. In this particular case much research information was provided to the underwriter but it had no effect.
On the other hand the same person took up new health insurance with a full disclosure and did not receive any limitations. This may be because the decision is made at a lower level where there is a list of exclusions that does not include this unusual disease. If you are thinking of changing jobs, you should look into the pre-existing exclusions in the new plan.
The only answer is that no one knows for sure. It may be as little as three years (less with the acute form) but it may be 10 - 15 years - or who knows it may be the full span if you have a successful bmt. What you do know for sure is that you do not have an unlimited life span and it is sensible to consider the implications on your life. In a way we are lucky that we have time to prepare - a car accident or other tragedy leaves no planning time at all.
One well known speaker who advocates "healing" (in the sense of coming to terms with one's disease) claims patients who do well have certain traits in common.
- They do not meekly accept a bleak diagnosis. When given an ominous prognosis, they obtain other opinions and assess their situation. They do not sit around.
- They accumulate information and learn about the condition through library research, speaking with others, asking questions, etc.
- They seek out others with the same problem, learn about their experiences and get support. This serves to counterbalance and help deal with negative input.
- They form a partnership with a competent health care provider who will support them, monitor them and work with them to structure a treatment regimen, including integration of standard and alternative medicine if that is the patient's wish.
- They make radical changes in lifestyle as needed. They change their diet, daily routines, jobs, attitudes or whatever it takes to improve their well being.
- They look on their illness as a gift that can lead to reassessment and improvement of their lives.
- While conventional wisdom at least in the United States is to fight the condition, patients who heal accept the problem rather than refusing to recognize or adjust to it.
Several in the MPD-NET group have tried a pretty wide range of
alternatives to conventional medicine including the following:
- vitamins and minerals especially those focusing on the liver -
Kombucha tea - Chinese herbs - Qi Gong massage - Tai Chi and Qi Gong
exercises - somatic therapy - meditation - carrot, beetroot and other
vegetable juice - liver cleansing diet However, there is no evidence
that any of the so called alternative medicines improve MF. It is
best to discuss this issue with your doctor and ask him to outline a
regimen of vitamins which may improve your sense of
well-being. Meditation, visualization and other techniques may be of
help in your mental outlook and ability to cope.
There is clearly a connection between one's mind and their body. So
if doing these things helps to improve how you feel about yourself
then it is worth doing them. Just don't expect miracle cures from
them.
This is an issue you need to discuss with your doctor. But if you have a bmt expect instant menopause. One woman in our mpd-net group was thrown into menopause by Hydrea.
When one is faced with a diagnosis of a life threatening disease this
has a real impact on both the individual and the relationship they are
in. Our sense of ourselves as a whole healthy person is challenged and
we are forced to face mortality. Over time our body does not work as
well as before and we may become very focused on the disease as it
assumes a greater portion of our lives. The increased anxiety as well
as effects of medication all impact on one's sexuality.
The reality is that things are not going to be what they were
before. The challenge is to find positive ways to maintain and enhance
the physical and emotional benefits that accrue from the expression of
our sexuality.
The nature of the disease is complex, uncertain and frustrating to
deal with. Gather all the information you can. Don't expect to
understand it all at once. This is hard stuff. Doctors had to study
for years to learn about all this. There are difficult decisions to be
made. Emotional challenges. Some days you will feel depressed and will
need to grieve for your loss of good health. Your awareness of the
suffering of others is likely to increase - you will be attending
hospitals and discussing mortality rates on a regular basis. Sometimes
it can all be too much and you wish you could wake up one morning and
find it gone.
But there are lots of positive things you can do. Three things are
even more essential now than ever before:
Your immune system has been disturbed - anything you can do to redress
that will be helpful. Review your time frames to ensure that you are
living in the moment. Knowledge and action are good antidotes to down
days. It may also be helpful to join a support group of people with
life threatening diseases. The Internet is a great place to meet
people who share your concerns. The outcome we are seeking looks a bit
like this: "I wouldn't have chosen to join this group, but now
that I'm here I'm glad I've had the opportunity to learn so much about
life."
This FAQ is a resource of MPD Research Center, Inc.
It is part of a family of resources which include:
MPD-NET Internet discussion/support
group
To join this discussion group, Address an email to: listserv@listserv.acor.org
and in the body, put the words SUBSCRIBE and your first and last
name.
MPD WEB PAGE
Our group's webpage is a complete source of information regarding the myeloproliferative disorders. The page provides links to a wealth of pertinent resources, as well as to articles and places of interest and includes original writings of Harriet S. Gilbert, MD, director of the MPD Research Center. Be sure to check out the biographies of our patient members as well
The MPD Voice is an "offline" newsletter published and printed by the MPD Research Center. Center members (annual fee $25) receive this periodical. If you would like to become a member of the center, send your check, payable to MPD Research Center, 115 E. 72nd St., New York, NY 10021. For a complimentary copy of the newsletter,send your name and mailing address to:
Additional FAQS on other topics are available at this website (essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera . For information on future subjects, contact Joyce Niblack JNiblack@Aol.com
This is a hot line maintained by MPD Research Center, Inc.
