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- What is myelofibrosis?
- How is the diagnosis made?
- Should I get a second opinion?
- What is the value of the bone marrow biopsy?
- What are the stages of the disease?
- What are the symptoms?
- What is the prognosis?
- What are the treatment options?
- Drug therapy for symptomatic myeloproliferation
- Drug therapy of leukemic transformation in MMM
- Current Clinical Trials for MMM
- The Role of Transplantation in MMM
What is myelofibrosis? Myelofibrosis with myeloid metaplasia (MMM) includes agnogenic myeloid metaplasia (AMM), idiopathic myelofibrosis (IMF) and the advanced phases of essential thrombocythemia (post thrombocythemic myeloid metaplasia with myelofibrosis or PTMMM) and polycythemia vera (post polycythemic myeloid metaplasia with myelofibrosis or PPMMM). MF is shorthand for myelofibrosis, the“scarring” that develops in the marrow and interferes with blood cell production .Myeloid metaplasia refers to blood cell production outside of the bone marrow(more on that later). In MMM, there is clonal myeloproliferation (the master stem cell which produces red cells, white cells and platelets becomes damaged and reproduction or cloning of the damaged stem cells is more aggressive than normal cells. These cells lose their ability to produce blood cell lines in their normal proportions. This can lead to significant changes in blood counts (i.e. anemia, low platelet counts, fatigue, constitutional symptoms, big spleen, and a risk for changing to acute leukemia. Initially, platelet counts may be too high and white counts may fall either too low or be too high.
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How is the diagnosis made? If the patient does not have a prior history of polycythemia vera (PV) or essential thrombocythemia (ET), usually a physician will notice low red cell counts and/or high or low white cell or platelet counts during a routine examination to determine the cause of a patient’s complaints of fatigue or that their abdomen is tender and enlarged or bloated (this could be from an enlarged spleen), bruising, etc. An alert doctor will order a full blood count (CBC with differential), blood chemistries and finding that some of the elements of blood counts are abnormal, may follow with an abdominal ultrasound or other scans before sending the patient to a hematologist.To be sure of the diagnosis, a bone marrow biopsy is required and special stains are employed to determine the presence, nature and extent of fibrosis in the marrow.The findings of a bone marrow biopsy are very important in reaching a diagnosis.If the patient has a prior history of PV or ET, spleen enlargement and/or the presence of fibrosis observed in a bone marrow biopsy. If falling counts are observed, MMM should be suspected and confirmed with a bone marrow biopsy and other diagnostic tests. This is more responsive to treatment if caught early,hence periodic bone marrow biopsies should be scheduled.
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Should I get a second opinion? Some hematologists have more expertise than others with MF and the myeloproliferative disorders in general. This is a serious diagnosis and it is important to have the input of an expert both as to your disease and treatment options which will vary depending upon the severity at diagnosis. Larry Milnes, our emeritus list owner of the mpd-net online support group, maintains a list of experts and their contact information as well as doctors recommended by other patients on MPD-Net in various geographic locations. You can contact Larry at LarryMilnes@comcast.net.
This is a serious diagnosis and the important question of how long do I have to live is best answered by one of the experts.
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What is the value of the bone marrow biopsy? A bone marrow biopsy is important as it provides a benchmark for measuring what is going on in the marrow directly both for the initial diagnosis and for assessing disease progression and impact of treatment. Some doctors feel they can tell all they need to know by blood tests alone but as our senior expert, Dr. Richard Silver,says, “if you don’t look, you can’t see”. It is impossible to determine the extent of this disease without this valuable diagnostic tool. In the case of myelofibrosis that develops secondary to ET or PV, catching early development means the difference of possibly responding to interferon to turn back the clock or needing more aggressive treatment if this isn’t discovered until blood counts drop.Bone marrow biopsies are done using a local anesthetic. Many find this procedure more comfortable with conscious sedation in addition to a local anesthesia. If your doctor refuses to use conscious sedation, some find taking an oral sedative such as Ativan before the procedure helps. Conscious sedation varies and depends on the personal preference of your doctor. Ativan plus demerol is one choice.
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What are the stages of the disease? The Europeans follow various staging criteria using a combination of findings in a bone marrow biopsy, degree of spleen enlargement, Hgb, platelet and WBC levels as well as other factors. MF generally isn’t staged in the United States but the nature and extend of fibrosis (reticulin 1-4+, collagen or osteosclerosis).Early on, aside from early reticulin fibrosis in the marrow, patients may be overproducing some or all blood cell lines. As the disease progresses, red counts in particular start falling and in PV patients, may seem normal for a while before progressing to anemia. Spleen enlargement is one of the early signs other than abnormalities in the marrow. Symptoms are explained below.
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What are the symptoms? Patients presenting with MMM ranged from asymptomatic patients (discovered on investigation for causes of elevated white count, anemia, spleen enlargement,elevated platelet counts) to being severely debilitated. Symptoms are broken down into three broad categories:Myeloproliferation: Myeloproliferation can clinically lead to a broad range of problems ranging from an asymptomatic mild white count and/or platelet elevation to severe organ damage. Clinical consequences of myeloproliferation can lead to illness or death from either a direct effect from increases in circulating cells or indirectly from organ damage from sequestration of immature cells known as extramedullary hematopoiesis (EMH). This results most commonly in marked enlargement of the spleen and/or liver which may lead to pain, early filling,sequestration of red cells and platelets and portal hypertension. In addition, EMH may cause problems in various other organs including lungs (respiratory distress and pulmonary hypertension), peritoneum (acsites), spine (paralysis) and percardium(tamponade). Increases in white cell count are usually asymptomatic but as this becomes extreme (WBC 100,000 or greater), symptoms of leukostatis may develop.This is not common in MMM and when it occurs is more likely to be in the setting of leukemic transformation. High platelet counts are more common and may lead to bleeding or thrombotic complications. Cytopenias: Cytopenias (low blood cell counts) are also characteristic of MMM. Anemia is the most common cytopenia. It can arise from ineffective blood cell production, decreased marrow reserve as a result of collagen fibrosis and osteosclerosis, spenic sequestration, myelosuppression from cytoreductive therapy,hemolysis, bleeding from the gastrointestinal tract including variceal bleeding and occasionally co-existing deficiencies in iron, vitamin B12 or folates. Thrombocytopenia (low platelets) may be related ineffective blood cell production,splenic sequestration or disseminated intravascular coagulation (DIC). Leukopenia(low white cell counts) is less frequent than elevated white cell counts .Constitutional symptoms: Constitutional symptoms can be debilitating in MMM. These include fatigue, early filling (can’t each much at a time because of large spleen), weight loss, night sweats, fever and pruritis (itching). These problems frequently do not respond to most medical interventions currently being employed.
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What is the prognosis? MMM is the most serious of the Philadelphia chromosome negative (non-CML)MPDs. Life expectancy is quite variable and the medical literature gives figures of2-10 or 15 years. Despite life expectancy figures in the literature, we have patients on mpd-net who have been dealing with MF for over 18 years and one who has been living with this for 30 years. Others have died from complications of their disease or from various cancers or complications following transplant within the literature range No one can accurately predict how long a given patient may live.Poor prognostic factors include• Hemoglobin less than 10 g/dL• WBC less than 4 or greater than 30(x10 /L) 9• Platelets less than 100(x10 /L) 9• Blasts in peripheral blood• Immature Myeloid cells greater than 10%According to the literature, survival with one or more of the above factors based on160 AMM patients <60 years of age ranges from 21 to 155 months.One of our mpd-net members was initially told she had 1-3 years to live. She and her husband sold their house, closed his dental practice, bought a boat and spent the next 3 years in Mexico enjoying life. When it was clear she wasn’t going to die anytime soon, they returned home and he reopened his practice. She did well without any treatment for 18 years when her counts started to drop and she experienced asplenic infarct. By this time her spleen was very large. She had a splenectomy followed by an autologous stem cell transplant and did well for several years before becoming transfusion dependent again. Before treatment could be initiated for her MMM, she was diagnosed with ovarian cancer. Treatment for that reversed her MF. Unfortunately she relapsed, was again treated and then was diagnosed with aglioblastoma (primary brain tumor) which ultimately was the cause of death about25 years after her original diagnosis.The president of CMPD Education Foundation was originally diagnosed with ET in1988. Secondary MF was found 18 months later in a BMB required by a clinical trial she was participating in. She responded to interferon-alpha and enjoyed a 3year remission. When the MF returned, she again was treated with interferon-alpha.Her MF has returned after a period on other treatment options and regressed again with another course of interferon. After a 50 month course ending in September2004, her last bone marrow biopsy in June 2006 showed no signs of fibrosis.
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What are the treatment options? Initial management of MMM Initial treatment depends on presenting symptoms. Patients who have overt thrombosis (clotting episodes such as heart attack, stroke, deep vein or superficial thrombosis, pulmonary embolism, etc) or hemorrhage need to be stabilized. This includes therapeutic anti-coagulation in those with venous or arterial thrombosis;direct intervention with arterial thrombosis such as using an anti-clot agent which breaks up the clot or thrombectomy); correction of any overt coagulopathy;correction of anemia; rapid correction of high platelets to the normal range. MMM patients may also have had gastrointestinal bleeding from varices, polyps,genitourinary sources or thrombotic events . These need to be dealt with and the source identified. Treatment plans The only potential cure for MMM is an allogeneic (someone else’s cells)hematopoeitic stem cell transplant (AHSCT). Often bone marrow transplant (BMT)is used but AHSCT is the correct term. This procedure is associated with a relatively high risk of mortality as well as morbidity (complications) that undermine its broad application. Currently both fully myeloablative procedures where the patient’s bone marrow is destroyed before infusion the donor stem cells and non myeloblative or “mini” transplants where the patients marrow is suppressed but not wiped out are in used. Patient selection, choice of conditioning regimen and full or mini-transplant issues are complex and evolving. The prognosis of MMM patient's is quite variable with various prognostic features that are helpful to stratify expected outcome. (See prognosis above)Medical, surgical, radiation, transplant and therapeutic options all are considered and organized into short term and long term treatment strategies. The following focus on current and potential medical therapies.
Currently Commercially Available Therapies for MMM
Cytopenias: Erythropoeitin: In a meta-analysis of published data on the use of erythropoeitin (EPO) Rodriguez et al reported a response rate of 33% with drug doses up to 600 units/kg/week. Rodriquez et al, rHuEpo for the treatment of anemia in myelofibrosis with myeloid metaplasia. Experience in 6 patients and meta-analytical approach. Hematological. 1998;83:616-621. Patients with serum EPO levels < 125 mi/ml had the highest likelihood of response. Thus Epo treatment should be restricted to patients with anemia and inadequate Epo levels.Both short acting and long acting dosage forms are available.
Androgen Preparations Various androgen or androgen-like formulations have been used in MMM. These include both fluoxymesterone and danazol. In one study, danazol doses of 600-800 mg/day led to responses in 4/7 patients treated from 3 to 6 months. This was recently updated with 30 MMM patients treated with starting dose of 600 mg/day. Responses were seen in 37% with a median time to response of 5 months. Danazol is most effective in those not already transfusion dependent. This therapy is generally well tolerated but the recommendations are for prostate cancer screening in males before starting androgen therapy and discussion of other side effects with all patients.
Thalidomide: Initial clinical studies of thalidomide were dose-escalating starting with 100 mg/day. Improvement in anemia and spleen enlargement was seen in approximately 20% of patients and increase in platelet counts in a higher proportion. However, the adverse effects drop out rate because of drug side effects was unacceptably high at those doses. Later trials demonstrated that lower doses of thalidomide (50 mg/day), compared to higher doses were better tolerated and retained an equivalent degree of therapeutic activity. The addition of prednisone tolow-dose thalidomide appeared to be both more effective and better tolerated thanthalidomide alone. Recent additions of either etaneracept or erythropoeitin toTHAL-PRED have been well tolerated, but appear to be only slightly additive.
Etanercept: TNF-á is implicated in the pathogenesis of MMM-associated cytopenias (low blood cell counts) as well as constitutional symptoms. Etanercept(Embrel) is a TNF-á antagonist that has been shown to be helpful in abrogating TNF-á associated disease features in rheumatoid arthritis. In a pilot study involving22 MMM patient, etanercept (25 mg twice weekly subcutaneous injections)treatment for up to 24 weeks was well tolerated and produced 60% response in constitutional symptoms. However, only modest benefit was seen in either improving anemia or reducing spleen enlargement (20%).
Interferon: Interferon works best in early MF seen in PV and ET patients.Some on MPD-NET have seen reduction, stabilization or even reversal of their secondary MF with interferon therapy. The founder of MPD-NET, Joyce Niblack,was diagnosed with ET in 1988. Secondary MF first showed up about 18 months later. This was reversed with an initial course of interferon (5MU daily). Over the years, she has seen her MF come and go depending upon whether she is on or off interferon. Her last bone marrow biopsy in June, 2006, showed no fibrosis. Others have reported similar benefit. Interferon does not work in everyone and about 20-30% of patients can not tolerate it. It has not been shown to work well in primary MMM and in advanced disease. There are a few patients with 3+ reticulin fibrosis,large spleen and transfusion dependency who did respond but according to the literature, this is less than 3%.
Drug therapy for symptomatic myeloproliferation
Hydroxyurea: Hydroxyurea is an oral, well-tolerated, non-specific myelosuppressive agent which can reliably control elevated white counts as well as platelets associated with MMM. Treatment of high white counts is clinically useful only if it is extreme and symptomatic. Control of elevated platelet counts in the presence of high risk factors for thrombosis is advised. Spleen enlargement is not as responsive to hydroxyurea and might require a higher dose (2-3 grams/day). This may worsen anemia or low platelet counts or drive the white count too low. Hydroxurea anemia might be countered by the used of Epo therapy.
Melphalan: Alkylating agents have activity in MMM by causing a direct, nonspecific myelosuppression and therefore may potentially palliate symptoms associated with myeloproliferation's. A clinical trial was recently reported in MMM using low doses of melphalan. Over a 7 year period, 104 MMM patients were treated with 2.5 mg of oral melphalan three times a week. The agent was active in66% of patients who achieved a response after a median of 7 months therapy. However, blast transformation (conversion to acute leukemia) occurred in 26% of the study cohort.
2-Chlorodeoxyadenosine: Therapeutic splenectomy in MMM patients may result in excessive elevations in platelet counts, white counts and accelerated liver enlargement. Palliative benefits from this drug (2-CdA) has been reported to provide cytoreduction in such instances. The drug has been successfully used in MMM on one of two schedules in 4 to 6 month treatment cycles with either 0.1mg/kg/day intravenously by continuous infusion for 7 days or 5 mg/m over 2 hours 2for 5 consecutive days. Responses were observed in 55%, 50%, 55% and 40% of patients for hepatomegaly, thrombocytosis, leukocytosis and anemia respectively. Responses were frequently durable and lasted for a median of 6 months after discontinuation of therapy.
Interferon-alpha: Therapy with IFN-á has been used in MMM patients based on its cytoreductive properties. It suppresses proliferation of megakaryocytes(platelet precursors) and fibroblasts and has shown significant inhibition of collagen production in experimental models of MF. Moreover IFN-á inhibits in vitro and invivo fibrogenic cytokine's such as transforming growth factor bets (TGF-â) and platelet-derived growth factor (PDGF) and in vitro has shown an anti-proliferative effect on progenitor stem cells. Interferon-alpha does control white cell and platelet elevations and there have been anecdotal incidences of bone marrow fibrosis regression as well as improvement in cellularity, shrinking of spleen, improvement of constitutional symptoms. This drug seems to work best in PV and ET patients with secondary MF who are still in the proliferative stage (overproducing blood celllines). Clinical trials of interferon-alpha in MMM have been disappointing. This may be because it was tested in small numbers for a short period of time. It takes years not months to see an effect. Although counts may normalize in a few months,it takes much longer and generally a higher dose than employed in clinical trials to see an effect on the spleen and marrow. Results have also been disappointing with interferon gamma and pegylated interferon-alpha due to lack of tolerance and negligible response rates.
Drug therapy of leukemic transformation in MMM
Approximately 10-15% of MMM patients will develop leukemic transformation. A recent study of 91 MMM patients who had transformed to acute leukemia, this was preceded by spleen and/or liver enlargement, worsening constitutional symptoms,anemia, low platelet counts and elevated white cell counts. The acute leukemia was fatal in 98% of patients after a median of 2.6 months (range 0-24.2) Survival in this group of patients was poor regardless of whether patients received supportive care long, low intensity chemotherapy or induction therapy. 24 of the 91 patients received AML (acute myelogenous leukemia) induction therapy such as cytarabineidarubicyn;mitoxantrone-etoposide, high dose cytarbine), 42% had a brief return to chronic phase and had a 33% treatment related mortality. No complete remissions were seen. Transplant in MMM should be considered well in advance of leukemic transformation to improve chance of survival. It is also a good idea to find a match as soon as possible if you are considering this option. Finding a match can take time and if this is put off until crisis point, there simply may not be time. We do have several mpd-net members who had induction therapy followed by a successful transplant after their leukemic conversion. But not all who do convert are eligible for transplant. Patients who do convert to acute leukemia from MMM should be considered for clinical acute leukemia trials for high risk patients, followed if appropriate by transplant. Otherwise, supportive care alone should be considered.
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Current Clinical Trials for MMM For clinical trial information:
http://www.cancer.gov/cancertopics/types/myeloproliferative
http://www.nci.nih.gov/cancertopics/myeloproliferative/patient/page10
http://www.clinicaltrials.gov/ct/gui/action/SearchAction?term=Bone+Marrow+Diseases
For information about treatment and clinical trials at MD Anderson Cancer Center in Houston, Texas, visit their website at
http://www.mdanderson.org/diseases/mpd
or contact Dr. Srdan Verstovsek at (713) 745-3429 or
email sverstov@mdanderson.org
For referrals call 713-563-2000 or 1-800-392-1611 (Option 1)
For information about treatment and clinical trials at the Mayo Clinic Comprehensive Cancer Center, visit
http://www.mayo-clinic.org/myelofibrosis/index.html or call
Dr. Ruben Mesa at(507) 284-2511, email mesa.ruben@mayo.edu
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The Role of Transplantation in MMM Because of the high risk, expensive nature of transplantation, this procedure is usually reserved for late stage patients who have exhausted other treatment options.
At one time, the extensive marrow fibrosis associated with MMM was considered a contra-indication for transplantation. “Creation of space” was thought essential for engraftment of donor cells. But multiple reports have demonstrated that engraftment can be obtained consistently, and that extensive fibrosis is reversible with successful allogeneic hematopoeic cell transplant (HCT)A review of the literature as of 1998 by Przepiorka et al identified 40 cases of myelofibrosis reported by 20 different transplant groups. Most had received HCT from HLA-identical sibling donors. With a median follow up of 21 (range 4-158months, survival was 53% with an apparent plateau at 22 months. Ten patients died of treatment-related complications and 4 of disease recurrence.
Guardioloa et al published on a retrospective analysis of 55 patients from multiple institutions. Blood 1999;93;2831-2838, Most patients had AMM (eight patients had MF after ET and were transplanted from HLA-identical siblings. 35 were conditioned with total-body radiation (TBI)-containing regimens, and the remaining patients with busulfan plus cyclophosphamide (BU/CY). The 5-year overall survival rate was 47% and non-relapse mortality at 1 year was 27%. Low hemoglobin values and the presence of osteomyelosclerosis identified high risk patients.
A report by the Seattle group included 56 patients 10-66 years of age who underwent transplant from related (36) or unrelated (20) donors. 35 had classic AMM, 10 had end-stage ET, 5 had end-stage PV, 5 had MF with increased blasts,1 had evolved to CML and 2 had a synchronous lymphoma. 44 were prepared with busulfan plus cyclophosphamide and 12 with total body radiation plus chemotherapy. All but 3 patients engrafted (donor cells “took” and started producing blood cells. Two died from relapse/progressive disease and 18 from other causes. At the time of the report, 36 patients were surviving at 0.5-11.6(median 2.8) years for an estimate of a58% survival. Dupriez score, clonal cytogenic abnormalities and degree of marrow fibrosis were the most significant risk factors for post-transplant mortality. Patients conditioned with busulfan regimen had a higher probability of survival (76%).
Another recent report from Seattle gave results for 25 patients with PV or ET who received either marrow or peripheral blood precursor cells from related or unrelated donors. Patients were transplanted either because of MF with spleen enlargement and peripheral blood cytopenias (low counts) or because of the development of MDS/AML. At a median follow-up of 41 months, survival was 64% for all patients and 82% for patients prepared with targeted BU/CY. Patients transplanted before they showed an excess of blasts fared better than patients with more than 5% blasts.
According to Dr. Joachim Deeg (Fred Hutchinson Cancer Center in Seattle,Washington) at the Mayo/CMPD education foundation 2005 MPD Conference,patients transplanted early in their course have an excellent outcome with as many as 80% surviving. Patients with extensive fibrosis or those with an elevated Dupriez score have an inferior prognosis. Other unfavorable prognostic factors were increasing patient age and abnormal karotype. The use of unrelated donors did not seem to negatively affect outcome.
Complications related to conditioning-associated toxicity, infections or GVHD were the most common causes of failure. Relapse accounted for a minority of deaths. Dr Deeg feels allogeneic HCT is particularly successful in younger patients and patients with early-stage disease. However, this procedure is generally reserved for advanced disease
.Reduced-intensity/non-myeloablative (or “mini”) transplants are being used inpatients with myelofibrosis. There is limited data but at one institution, four patients undergoing a mini-transplant remain alive and in remission with a follow-up of 4years despite older age and advanced disease. In another study, 20 patients conditioned with slight variations of fludarbine plus melphalan and transplanted in various institutions were followed up to 18 months. 90% remained alive. The data indicate the possibility of inducing durable remissions with reduced-intensity conditioning and HCT. This procedure can be used in patients considered too old to withstand a full, more rigorous transplant procedure.
If your doctor has recommended transplantation to you, you want to gather as much information as possible so you can make informed decisions about whether or not to undergo this procedure and if so where. You’ll want to ask the transplant facilities you are considering about their experience with MMM transplants-how many,survival rates, etc. There is good information on the Blood and Marrow Transplant Information website http://www.bmtinfonet.org
You’ll also want to join the ACOR bmt-talk online support group. To join, emailbmt-talk-request@listserv.acor.org. Include your first and last name and a list owner will add you to the list. Once you are a member, you can post to the list with your questions and search their archives.
We also have members of mpd-net who have been through transplants and are willing to share their experiences with you. To join, write to mpd-netrequest@listserv.acor.org Include your first and last name and a list owner will add you to the list.
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