The National Organization for Rare Disorders NORD Guides for Physicians The Physician’s Guide to Myelofibrosis Visit website at: nordphysicianguides.org/myelofibrosis/ For more information about NORD’s programs and services, contact: National Organization for Rare Disorders (NORD) PO Box 1968 Danbury, CT 06813-1968 Phone: (203) 744-0100 Toll free: (800) 999-NORD Fax: (203) 798-2291 Website: www.rarediseases.org Email: orphan@rarediseases.org NORD’s Rare Disease Database and Organizational Database may be accessed at www.rarediseases.org. Contents ©2012 National Organization for Rare Disorders® What is Myelofibrosis? Myelofibrosis (MF) is classified as a chronic myeloproliferative neoplasm (MPN). These are a group of heterogeneous hematopoietic stem cell malignancies that include chronic myelogenous leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). CML is categorized as a Philadelphia chromosome-positive MPN due to the presence of the BCR-ABL1 proto-oncogene. ET, PV and PMF comprise the Philadelphia chromosome-negative MPNs. ET and PV can evolve into MF, termed post-ET/PV MF. These cases, together with PMF, are collectively referred to as MF. In 2008, the World Health Organization (WHO) modified the terminology of myeloproliferative disorders (MPDs) to MPNs to correctly reflect the malignant nature of these related hematologic cancers. Cytogenetic and molecular studies indicate that MF is a clonal hematologic malignancy originating in primitive hematopoietic cells capable of producing lymphoid and myeloid cells. The accumulation of bone marrow reticulin and collagen fibrosis that typifies this cancer represents a secondary reaction of non-clonal bone marrow fibroblasts. MF can have a hypercellular pre-fibrotic phase and then later in the course develop severe cytopenias, progressive symptomatic splenomegaly, and worsening bone marrow fibrosis. Recent advances in the understanding of the pathobiology of MF have highlighted the presence of genetic mutations, epigenetic alterations, hyperactive signalling pathways, and a heightened inflammatory state. Symptoms & Signs MF is characterized by constitutional symptoms (fevers, night sweats, weight loss), bone marrow myeloproliferation and fibrosis, worsening cytopenias, leukoerythroblastosis (presence of peripheral blood nucleated erythrocytes and early myeloid forms), and progressive symptomatic splenomegaly. Extra-medullary hematopoiesis (EMH) is the result of 1 abnormal trafficking of hematopoietic stem cells (HSC) from the bone marrow to organs such as the spleen, liver, and lung causing organomegaly and sometimes organ dysfunction. Common MF symptoms include bone pain, debilitating fatigue, pruritus, and bowel irregularity (see Table 2) Dyspnea can be due to anemia, pulmonary emboli, congestive heart failure, and/or the development of pulmonary artery hypertension secondary to EMH. Splenomegaly can result in early satiety that further adds to weight loss, abdominal bloating, and severe left upper quadrant abdominal pain from splenic infarcts. Figure 1 depicts the classic body habitus of a cachectic MF patient with massive hepatosplenomagly that is outlined with marker on the patient’s abdominal wall. Portal hypertension is common in patients with MF and can result from massive splenomegaly (Banti’s syndrome) or contribute to the development of splenomegaly in some patients. Portal vein thrombosis is also associated with portal hypertension in some patients with MF. An increased rate of thrombotic complications is associated with MF and can occur in the venous circulation (cerebral venous sinus thrombosis, splanchnic vein thrombosis, deep vein thrombosis, pulmonary thromboembolism) or arterial circulation (stroke, transient ischemic attacks, retinal artery occlusion, myocardial infarction, and peripheral arterial disease). Conversely, bleeding episodes can also complicate the clinical course of MF patients and can be attributed to either thrombocytopenia or qualitative platelet dysfunction. Peripheral blood count abnormalities 2 are often noted at time of diagnosis and can include leukocytosis or leukopenia, anemia and thrombocytosis or thrombocytopenia. Figure 1 Many patients develop clinically relevant anemia through the course of their disease and require red blood cell transfusion support. Patients with thrombocytopenia are at an increased risk of bleeding and ecchymosis and gastrointestinal bleeding is not uncommon. Some patients develop profound transfusion dependent thrombocytopenia and in some cases become refractory to platelet transfusions. Causes The true incidence of MF is not known but estimated to be approximately 1-1.5/100,000 people and is likely higher due to underdiagnosing and underreporting. The median age at diagnosis is approximately 65, but MF can be diagnosed in patients of all ages. The disorder is rare in children. The cause of MF is as yet unknown, however, chronic exposure to several industrial solvents, including benzene and toluene, has been associated with development of MF. Additionally, Japanese people exposed to radiation from the atomic bomb at Hiroshima were found to be at a significantly increased risk of developing MF as well as other hematologic malignancies. MF has been reported in every ethnic background. There appears to be a higher risk of developing MF in Ashkenazi Jewish populations even when controlling for environment. 3 In 2005, separate laboratories reported the finding of a gain of function point mutation in the Janus kinase 2 gene (JAK2). The JAK2V617F mutation is located in exon 14 at position 617 of the JAK2 gene and affects the pseudokinase domain (JH2) of this non-receptor tyrosine kinase rendering the enzyme constitutively active. JAK2 is associated with thrombopoietin and erythropoietin receptor signaling and phosphorylated JAK2 activates signal transducers and activators of transcription (STATs) which then in turn dimerize and translocate to the nucleus. STATs act as transcription factors (TFs) regulating the expression of cytokine inducible genes that are pivotal in cell differentiation, proliferation, and survival. JAK2V617F can be found in approximately 96%, 50%, and 50% of patients with PV, ET, and MF. More recently it has been appreciated that even in those MPN patients that lack JAK2V617F, hyperactive JAK-STAT signaling is present and can be attributed to other identified mutations (JAK2 exon 12, MPL515L/K, LNK) or yet unrecognized lesions. In the last several years a growing appreciation of the complex pathobiologic mechanisms underlying MF has developed based on a deeper understanding of genetic determinants of normal hematopoiesis and acquired mutations detected in the hematopoietic compartment of MF patients. Mutations in genes that activate the JAK-STAT pathway (JAK2, MPL, LNK) and alter epigenetic regulation (TET2, DNMT3a, EZH2, IDH 1/2, SUZ12) have been implicated in MF pathogenesis. Given the low frequency in which the non-JAK2V617F mutations occur in patients with MF, the true relevance of each of these genetic and epigenetic lesions remains unclear and is subject of much laboratory and translational research. The order in which these events are acquired and their co-existence can affect MF phenotype, and may in part, explain the heterogeneity in clinical course. Current and future therapeutic trials in MF will test novel agents that exploit these targets as well as evaluate these biomarkers in terms of their prognostic power and their ability to predict response to different therapies. Prognosis Patients with MF have a median survival of 5-6 years from time of diagnosis. MF patients are at an increased risk of arterial and venous thrombosis with a predilection for the splanchnic vasculature which contributes to significant morbidity and mortality in this disease. There is an approximate 10-20% risk of transformation to acute leukemia over the first decade from time of MF diagnosis. Leukemic transformation of MF is termed MF-BP (blast phase) and is associated with a dismal prognosis with a median survival of approximately 3-5 months even with anthracycline-based induction chemotherapy. 4 The clinical course of MF can be variable and often patients should be risk stratified for survival at time of diagnosis in order to best select the appropriate treatment approach for a given patient. The Lille classification was the first such widely used prognostic scoring system based on white blood cell count and hemoglobin at time of PMF diagnosis. A white blood cell count (WBC) of either >30 x 109/L or <4 x 109/L earns a point and hemoglobin <10g/dL earns a point. Low (0 points), intermediate (1 point), or high risk (2 points) disease is associated with median survivals of 93, 26, and 13 months, respectively (Table 3). More recently, newer scoring systems based on a composite of multiple prognostic variables have been created and validated for use in clinical practice. The International Prognostic Scoring System (IPSS) was developed by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) and incorporates five statistically significant MF clinical features derived from multivariate analysis. Age > 65 years, leukocyte count >25×109/L, hemoglobin <10g/dL, peripheral blood blast percentage ≥1%, and the presence of constitutional symptoms are each assigned a point. Four risk groups with independent median survivals of 135, 95, 48, 27 months, can be calculated for low risk (0 points), intermediate-1 (1 point), intermediate-2 (2 points), and high risk MF patients (≥3 points), respectively. The IPSS score was designed to be calculated at time of diagnosis and the newer dynamic IPSS (DIPSS) can be used to calculate an individual MF patient’s risk group status at any point in their clinical course. The prognostic significance of JAK2V617F remains unclear. The presence of JAK2V617F does not appear to influence thrombosis risk, risk for leukemic transformation, or survival in several large retrospective studies. JAK2V617F appears to be associated with a higher hemoglobin and less need for transfusion in MF patients, as well as older age, thrombocytopenia and increased peripheral blood blasts. Interestingly, the presence of low JAK2V617F allele burden (when compared to high allele burden or the absence of the mutation) may have prognostic significance as it has been 5 shown to predict for shorter overall and leukemia-free survival. Karyotypic abnormalities are present in approximately 30-50% of MF patients and unfavourable chromosomal (complex abnormalities or sole or two abnormalities that include +8, -7/7q-, i7/7q-, i(17q), -5/5q-, 12p-, inv(3) or 11q23 rearrangements) have been incorporated in the DIPSS plus as a negative prognostic indicator. Diagnosis Patients with MF often, but not always, present to their physician with vague complaints that can range from profound fatigue, dyspnea, bone pain or abdominal discomfort. On occasion, patients are discovered to have asymptomatic MF on routine blood work by abnormal blood counts alone and this may motivate further evaluation. It is not unusual for patients to undergo sometimes extensive testing before referral to a hematologist. Figure 2 A complete blood count (CBC) and differential is a necessary and often the first step in establishing the diagnosis of MF. Manual review of the peripheral blood to assess for the presence of leukoerythroblastosis and other morphologic changes in myeloid and erythroid cells is important (Figure 2). A complete comprehensive metabolic panel, coagulation profile, iron studies, B12, folate, reticulocyte count, and should also be obtained. Further laboratory evaluation is often needed and is dictated by competing co-morbidities and complaints. Presently, mutational analyses for the presence of JAK2V617F, JAK2 exon 12, JAK2 exon 13, MPL515L/K, and in some commercial labs, TET2 are available for testing. Although the detection of molecular markers can help establish clonality, which is a hallmark of malignancy, they are not 6 able to adequately predict prognosis or determine therapy in MF. A bone marrow biopsy and aspiration is an integral part of the evaluation of a patient with MF. Often bone marrow aspiration is unobtainable due to extensive marrow fibrosis or excessive marrow cellularity. Flow cytometry and cytogenetic analysis are preferably performed on the aspirate specimen, but in cases where an aspirate is not available, it can be informative when performed on the peripheral blood. Additionally, the bone marrow biopsy should be submitted for iron, reticulin, and collagen stains and is best read by an experienced hematopathologist. Overall marrow cellularity, megakaryocyte atypia, myeloid to erythroid ratio, reticulin and collagen fibrosis, and percentage of myeloblasts should be reported and are important in establishing the diagnosis of MF. Bone marrow fibrosis grading systems exist and scores should be reported as well. The marrow cellularity can be variable, and can range from hypo- to hyper-cellular with characteristic atypical hyperlobated megakaryocytes that can be found singly and in clusters (Figure 3A). The development of bone marrow reticulin and collagen fibrosis can replace hematopoiesis and profoundly alter the hematopoietic niche (Figure 3B).The presence of ≥ 20% myeloblasts in the aspirate or peripheral blood is by definition MF-BP and these patients should pursue clinical trial or HSCT immediately. Figure 3A Figure 3B 7 The physical exam is also important in establishing the diagnosis of MF with special attention to palpable hepatosplenomegaly. Although not necessary, imaging of the abdomen with ultrasound, CT scan, or MRI can document and confirm organomegaly. Imaging of the chest or echocardiography is sometimes necessary to assess for heart dysfunction, pulmonary hypertension, and the presence of pulmonary EMH or thromboembolic disease. The WHO and the International Working Group for the Treatment of Myelofibrosis (IWG-MRT) has developed major and minor criteria for the diagnosis of PMF and post-PV/ET MF, respectively (Table 1 A and Table 1 B). These criteria are very helpful in establishing a diagnosis and can easily be used by hematologists/oncologists in the community. It is important to note that the finding of bone marrow fibrosis is not specific to MF and can be seen in many other conditions such as myelodysplastic syndrome, hairy cell leukemia, tuberculosis, metastatic carcinomas (e.g. prostate, lung, breast), lymphoma, and non-malignant conditions such as autoimmune disorders and infectious causes like tuberculosis. 8 Treatment MF is a chronic progressive disease that does not spontaneously remit. The only therapeutic modality that currently offers the potential for cure is hematopoietic stem cell transplantation (HSCT). Medical management with oral agents has mostly been palliative and until recently no single agent was FDA-approved for the treatment of patients with MF. Ruxolitinib (Jakafi) is 9 the only FDA-approved agent for the treatment of MF patients regardless of their JAK2 mutational status. Ruxolitinib is a first in class, oral agent, taken twice daily on a continuous basis, and has been shown to inhibit the hyperactive JAK-STAT pathway in MF hematopoietic cells. In the COMFORT-1 and COMFORT-2 (COntrolled MyeloFibrosis study with Oral JAK inhibitor Treatment) studies, ruxolitinib was shown to be superior when compared to placebo and best available therapy, respectively, in achieving the primary endpoint of proportion of treated patients achieving a spleen volume reduction of at least 35% by 24 weeks or at 48 weeks, respectively. In a crossover design, with intention to treat analysis, patients with intermediate-2/ high risk MF by IPSS were randomized in a double-blinded fashion to receive ruxolitinib or placebo. In both trials, ruxolitinib therapy achieved the primary endpoint of spleen volume reduction and also demonstrated superiority in symptom improvement as assessed by the myeloproliferative neoplasm symptom assessment form (MPN-SAF) in COMFORT-1. Ruxolitinib has a favorable clinical side effect profile and grade 1/2 headache, dizziness, and bruising were the most common adverse events noted in COMFORT-1 and almost all were grade 1/2. Reversible thrombocytopenia is the dose limiting toxicity of this agent and patients should be aware of the potential for worsening anemia, which is most pronounced during the first three months of therapy. Dosing of ruxolitinib is based on the platelet count and careful monitoring of blood counts with dose adjustments for treatment emergent thrombocytopenia is important to ensure patient safety. In ad hoc analysis, ruxolitinib demonstrated a modest statistically significant survival advantage over placebo in the COMFORT-1 study. Reversal of markedly elevated inflammatory cytokines with ruxolitinib therapy has been postulated to drive improvement in many of the MF related symptoms. The improvement in performance status of MF patients with ruxolitinib treatment may in part explain the survival advantage seen in this phase III trial. See Table 4 for a list of therapies used in the treatment of MF and which aspects of the disease are addressed. Therapeutic approaches to address the myeloproliferation (leukocytosis, thrombocytosis) and organomegaly (splenomegaly and hepatomegaly) associated with MF include chemotherapeutic agents such as hydroxyurea, melphalan, busulfan, and cladribine. Hydroxyurea is an oral agent that inhibits ribonucleotide reductase, thereby reducing the production of deoxyribonucleotides. Hydroxyurea is one of the most commonly used initial agents in patients 10 with MF and can be very effective in controlling elevated leukocytes and platelets, ameliorating spleen discomfort and at times improving anemia if driven by splenic sequestration. Worsening cytopenias, mucositis, malleolus ulcers, rash and gastrointestinal toxicities are potential side effects that require monitoring by the treating physician. Symptomatic splenomegaly (and/or hepatomegaly) can be controlled with chemotherapy as well and the same agents used to control leukocytosis/ thrombocytosis are also given to address extramedullary hematopoiesis of the spleen/liver/lung/skin or other organs that cause symptoms. Radiotherapy can be employed to address symptomatic splenomegaly refractory to medical management or in cases of EMH affecting the lung, peritoneum, or impinging on nerves. Anemia is common in MF patients and can be multifactorial in origin (iron deficiency, B12 deficiency, folate deficiency, ineffective erythropoiesis, splenic sequestration, and hemolysis) and has been demonstrated to be a definitive negative prognostic indicator. Many patients develop red blood cell transfusion dependence and long term transfusion therapy can lead to the development of iron overload. The role of iron chelation therapy has not yet been adequately defined in this disease. Multiple approaches to alleviate anemia have been evaluated over the last several decades. Erythropoiesis stimulating agents (ESA) have also been used to improve anemia in MF patients that have not already been heavily transfused and do not have elevated endogenous erythropoietin levels. Immunomodulatory 11 agents such as thalidomide and lenalidomide alone or in combination with prednisone have been reported to have anemia response rates of 20-50% depending on the clinical trial. Danazol is a synthetic attenuated androgen that can be a reasonable approach in some patients with anemia and should be avoided in young women, men with active prostate conditions, and in patients with significant liver dysfunction. Occasionally corticosteroids given for short periods of time can be effective if the anemia is due to an autoimmune hemolytic process. HSCT is the only treatment modality that offers the potential of cure at the risk of transplant related complications and graft versus host disease (GVHD). HSCT with myeloablative conditioning is associated with transplant-related mortality and morbidity that requires careful consideration for appropriate patient candidates. Reduced intensity conditioning (RIC) is associated with less transplant related morbidity but a potentially higher rate of engraftment failure. Patients with low/intermediate-1 risk MF by IPSS should either be followed closely for signs of disease progression or treated with conventional agents (thalidomide, lenalidomide, danazol, hydroxyurea) or ruxolitinib to address disease features listed in Table 4. Patients that have intermediate-2/high risk disease should be considered for treatment with ruxolitinib or experimental therapy and those less than 65 years of age with preferably a matched sibling donor or matched unrelated donor should be considered for stem cell transplant. HSCT clinical trials are currently evaluating RIC approaches as well as pre-conditioning with ruxolitinib therapy. Transplant approaches utilizing alternative graft sources such as cord blood and haploidentical donors will also be explored in the near future. Patients with MF should preferably be transplanted at centers with significant experience with this particular patient population. Investigational Therapies Experimental therapies remain a very important treatment option for many patients with MF. Since MF originates at the level of the hematopoietic stem cell (HSC), the identification of novel drugs that target the MF HSC is likely the most effective path to potentially curative pharmacological strategies. Table 5 lists a number of experimental agents that are being evaluated in phase I, II, and III studies. Centers that offer these trials can be found at www.clinicaltrials.gov. Signaling pathways that remain essential to HSC function, proliferation and survival are potential drug targets. Modifying the chromatin structure in MF 12 HSCs is also an attractive therapeutic approach based on scientific rationale and supported by preclinical studies. Histone deacetylase inhibitors (HDACi) such as panobinostat, givinostat, and pracinostat are being tested in phase II studies and have already proven to be effective in reducing splenomegaly and in small numbers of patients after long term administration at low doses have demonstrated the ability to improve bone marrow morphology and reduce bone marrow fibrosis. Further studies with these agents are ongoing. 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Resources The following organizations are members of the MPN Coalition, a group of organizations providing a broad range of services for patients affected by these diseases, their families and medical professionals providing their care. Visit their websites to learn about the specific services they provide. A Myelofibrosis Resource Guide for Patients and Families may be downloaded at www.rarediseases.org/rare-disease-information/resources-tools. 17 Printed copies of the Resource Guide are available free from NORD or from other members of the MPN Coalition. MPN-Specific Organizations: MPN Education Foundation www.mpninfo.org MPN Research Foundation www.mpnresearchfoundation.org Serving the Cancer Community: CancerCare www.cancercare.org Cancer Support Community www.cancersupportcommunity.org The Leukemia & Lymphoma Society www.LLS.org Serving the Rare Disease Community: National Organization for Rare Disorders (NORD) www.rarediseases.org Clinical Centers & Medical Experts MPN Education Foundation Scientific Advisory Board www.mpdinfo.org/CMPD_foundation.html MPN Research Foundation Scientific Advisory Board www.mpnresearchfoundation.org/MPNRF-Scientific-Advisory-Board Myeloproliferative Disorders Research Consortium www.mpd-rc.org/home.php Mount Sinai School of Medicine Myeloid Malignancies Program http://www.mssm.edu/research/institutes/tisch-cancer-institute/cancerresearch/research-programs/myeloid-malignancies 18 Acknowledgements NORD is grateful to the following medical expert for serving as author of this physician guide: John Mascarenhas, MD Myeloproliferative Disorders Program Tisch Cancer Institute, Division of Hematology/Oncology Mount Sinai School of Medicine New York, NY NORD also grateful acknowledges the members of the MPN Coalition for their help in the creation of this guide and for the many wonderful services they provide for patients and families affected by MPNs. This guide was made possible by an educational grant from Incyte. 19 Patient Support and Resources National Organization for Rare Disorders (NORD) 55 Kenosia Avenue PO Box 1968 Danbury, CT 06813-1968 Phone: (203) 744-0100 Toll free: (800) 999-NORD Fax: (203) 798-2291 www.rarediseases.org orphan@rarediseases.org NORD gratefully acknowledges the assistance of the following medical expert in the preparation of this physician guide: John Mascarenhas, MD Myeloproliferative Disorders Program Tisch Cancer Institute, Division of Hematology/Oncology Mount Sinai School of Medicine New York, NY NORD also gratefully acknowledges the members of the MPN Coalition for their help in the creation of this guide and for the many wonderful services they provide for patients and families affected by MPNs. This guide was made possible by an educational grant from Incyte. 20 NORD Guides for Physicians For information on rare disorders and the voluntary health organizations that help people affected by them, visit NORD’s web site at www.rarediseases.org or call (800) 999-NORD or (203) 744-0100. #1 The Pediatrician’s Guide to Tyrosinemia Type 1 #2 The Pediatrician’s Guide to Ornithine Transcarbamylase Deficiency...and other Urea Cycle Disorders #3 The Physician’s Guide to Primary Lateral Sclerosis #4 The Physician’s Guide to Pompe Disease NORD helps patients and families affected by rare disorders by providing: #5 The Physician’s Guide to Multiple System Atrophy • Physician-reviewed information in understandable language #6 The Physician’s Guide to Hereditary Ataxia #7 The Physician’s Guide to Giant Hypertrophic Gastritis and Menetrier’s Disease #8 The Physician’s Guide to Amyloidosis #9 The Physician’s Guide to Medullary Thyroid Cancer #10 The Physician’s Guide to Hereditary Angioedema (HAE) #11 The Physician’s Guide to The Homocystinurias #12 The Physician’s Guide to Treacher Collins Syndrome #13 The Physician’s Guide to Urea Cycle Disorders #14 The Physician’s Guide to Myelofibrosis These booklets are available free of charge. To obtain copies, call or write to NORD or download the text from www.NORDPhysicianGuides.org. • Referrals to support groups and other sources of help • Networking with other patients and families • Medication assistance programs • Grants and fellowships to encourage research on rare diseases • Advocacy for health-related causes that affect the rare disease community • Publications for physicians and other medical professionals Contact NORD at orphan@rarediseases.org. National Organization for Rare Disorders (NORD) PO Box 1968 Danbury, CT 06813-1968 Phone: (203) 744-0100 Toll free: (800) 999-NORD Fax: (203) 798-2291 This booklet was made possible through an educational grant from Incyte.