Primary myelofibrosis/agnogenic primary myeloid metaplasia

What every physician needs to know:

Primary myelofibrosis (PMF) is a chronic malignant hematologic disorder that belongs to the family of Philadelphia chromosome negative myeloproliferative neoplasms.

It is characterized by: splenomegaly, a leukoerythroblastic picture on peripheral smear, bone marrow fibrosis, cytopenias, and systemic symptoms.

Approximately 60% of patients carry the Jak2 V617F gene mutation; 8% have an activating mutation of the thrombopoietin gene, MPL; 20% have either calreticulin exon 9 (CALR) insertions or deletions; and the remaining 10% of patients lack each of these mutations and their disease is referred to as being triple negative.

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Are you sure your patient has primary myelofibrosis? What should you expect to find?

The diagnosis of PMF is made based on a number of clinical and laboratory features, but the clinical presentation can have a great deal of variability.

The most common presenting complaint is fatigue. While often found to be the result of anemia, fatigue can be a significant burden even in patients who are not anemic. The majority of patients also present with splenomegaly. If significant, splenomegaly can result in left upper quadrant abdominal discomfort, left shoulder pain, early satiety, and diarrhea, which are often found to be the presenting complaints. Patients with more advanced disease often have systemic symptoms such as weight loss, bone pains, night sweats, and fevers.

Patients can also present with varying degrees of anemia. The presenting platelet and white blood cell counts show variability as well, with patients presenting with both thrombocytosis and thrombocytopenia, as well as leukocytosis and leukopenia. Immature cells from the neutrophilic series are always seen in peripheral blood, and this can include myeloblasts. The patients are also at an increased risk of having thrombotic or haemorrhagic events.

Thrombocytopenia is usually associated with later stages of this disorder.

Currently, the World Health Organization (WHO) has proposed the following criteria for the diagnosis of PMF.

Major criteria:

  • Presence of megakaryocyte proliferation and atypia, usually accompanied by either reticulin and/or collagen fibrosis

  • Not meeting WHO criteria for polycythemia vera (PV), chronic myelogenous leukemia (CML), myelodysplastic syndromes (MDS) or other myeloid neoplasm

  • Demonstration of Jak2 V617F mutation, or other clonal marker such as MPL515W->L/K or a CALR mutation in the absence of a clonal marker, no evidence of bone marrow fibrosis due to underlying inflammatory or other neoplastic diseases

Minor criteria:

  • Leukoerythroblastosis

  • Increase in serum lactate dehydrogenase level

  • Anemia

  • Palpable splenomegaly

Diagnosis requires meeting all 3 major and at least 2 minor criteria.

Beware of other conditions that can mimic primary myelofibrosis:

PMF must be distinguished from other chronic myeloproliferative neoplasms. Myelodysplastic syndrome, CML, mast cell disorders, and hairy cell leukemia may be accompanied by bone marrow fibrosis and should be ruled out, prior to entertaining a diagnosis of PMF.

Acute myelofibrosis is a syndrome characterized by acute presentation of bone marrow fibrosis, fevers, pancytopenia and minimal teardrop poikilocytosis, and absence of splenomegaly. The bone marrow is characterized by the appearance of immature myeloid cells and blast cells that often express megakaryocytic markers. The distinction between acute myelofibrosis and PMF is essential, as acute myelofibrosis is treated with aggressive chemotherapyfollowed immediately by stem cell transplantation and carries a dismal prognosis.

Many other disorders can cause bone marrow fibrosis and mimic the clinical presentation of PMF. These include nonmalignant conditions such as tuberculosis, hypoparathyroidism, systemic lupus erythematosus (SLE), scleroderma, Gaucher disease, and primary autoimmune myelofibrosis, as well as other malignant conditions such as acute myelogenous leukemia, multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphoma, and hairy cell leukemia. Secondary myelofibrosis can also occur in patients with metastatic carcinoma to the bone marrow.

Patients with another myeloproliferative neoplasm, essential thrombocythemia, can be confused at times with early stages of PMF, since both conditions are associated with thrombocytosis. Careful histopathological examination of the marrow biopsy is thought by some, but not by all, to be effective in discriminating these two diseases. The prefibrotic form of myelofibrosis not infrequently evolves to more advanced stages of the disease. Interferon alpha has been suggested as a treatment for the early phase of PMF, but has not been evaluated in rigorous randomized clinical trials.

Which individuals are most at risk for developing primary myelofibrosis:

PMF is a rare disorder and is mostly a disease of the elderly. The average age at diagnosis of PMF is approximately 65 years and most patients are diagnosed between the ages of 50 and 69. Approximately 5% of patients are diagnosed before the age of 40. Rarely the condition has been reported in the pediatric age group. While this disorder is rare, a higher incidence has been reported in Ashkenazi Jews.

The annual incidence is believed to range from 0.4 to 1.3 cases per 100,000 persons. The incidence of myelofibrosis among survivors of atomic bomb explosion in Hiroshima was 18 times the incidence reported for the rest of Japan, which provides evidence of a link between excessive radiation exposure and development of myelofibrosis. Chronic exposure to several industrial solvents such as benzene and toluene has also been associated with the development of PMF. However, most patients diagnosed with this disorder have no identifiable environmental exposures.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

The following laboratory studies are indicated for the diagnosis and prognostication of PMF:

  • Routine blood tests: complete blood count, electrolytes, liver and kidney function tests, lactate dehydrogenase, uric acid, iron studies, B12 and folate, reticulocyte count, erythropoietin level, thyroid stimulating hormone

  • Specialized blood tests: polymerase chain reaction (PCR) for Jak2V617F, mutations of the thrombopoietin receptor (MPL W515L/K), BCR-Abl, mutational analyses of CALR, and cytogenetic analyses using peripheral blood looking for clonal cytogenetic abnormalities

  • Invasive procedures: bone marrow biopsy and aspiration

  • Careful examination of peripheral blood smear and bone marrow are essential for the diagnosis of PMF. Leukoerythroblastosis with teardrop red cells strongly suggests this diagnosis. The leukoerythroblastic condition is characterized by the presence of nucleated red blood cells and immature myeloid elements in 96% of cases.

Anemia with hemoglobin less than 10g/dl develops in approximately 60% of patients. Anemia is often multifactorial in origin. Leukopenia can occur in 13% to 25% of patients, and leukocytosis is seen in one third. Thrombocytopenia becomes more common with disease progression. Platelets may be abnormally large and fragmented megakaryocytes can often be seen on the peripheral smear.

Presence of Jak2V617F mutation, MPL W515L/K, or mutations of CALR are clonal markers that help confirm the presence of a myeloproliferative neoplasm. One of these mutations is present in approximately 90% of patients with PMF. Additional laboratory abnormalities are also common, such as elevation of uric acid level, bilirubin, lactate dehydrogenase, and alkaline phosphatase. B12 levels are often elevated, and folate levels may be low due to rapid cell turnover.

Successful bone marrow aspiration is unusual, with a dry tap occurring in 80% of cases. A bone marrow biopsy is necessary in all cases, and the amount of residual hematopoietic activity and bone marrow fibrosis should be assessed. The fibrosis is generally associated with atypical megakaryocyte hyperplasia and osteosclerosis. Bone marrow or peripheral blood cytogenetics is an important part of the work-up. Patients with cytogenetic abnormalities have a poorer prognosis.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of primary myelofibrosis?

Ultrasonography or CT scan can be useful in documenting the degree of splemomegaly in those patients in whom physical examination is difficult.

If you decide the patient has primary myelofibrosis, what therapies should you initiate immediately?

In most cases of PMF, emergency PMF-directed treatment is not required as it is a chronic slow-progressing disease. In the presence of an acute thrombotic event, bleeding, or other complications of the disease, specific treatment may be required for the complication.

More definitive therapies?

The optimal treatment for PMF has not yet been defined.

A conservative approach to treatment is generally accepted with careful observation and treatment of symptomatic patients. Active therapy is generally indicated for the following conditions: symptomatic anemia, symptomatic splenomegaly, portal hypertension, significant thrombocytopenia, systemic symptoms such as bone pain, fevers, night sweats, and weight loss.

Allogeneic stem cell transplantation is the only curative option at this time, but it is suggested in patients younger than 70 years with an appropriate matched sibling donor (70% positive outcome). Successful outcomes with matched unrelated donors are less common (30%). The use of cord blood or haploidentical donors remain highly experimental. Successful transplantation results in eventual resolution of marrow fibrosis and normalization of hematopoieisis.

Since the establishment in 2005 of the role of JAK2V617F in pathogenesis of Philadelphia chromosome negative myeloproliferative neoplasms, a number of JAK2 inhibitors have been developed and evaluated in clinical trials. Many of these trials are still ongoing. The first of these medications has been approved by the Food and Drug Administration (FDA) for the treatment of patients with myelofibrosis. Ruxolitinib (Jakafi) is indicated for patient with intermediate or high risk myelofibrosis and is an excellent palliative agent which is not able to induce clinico-pathologic remission. Ruxolitinb has been shown to result in reduction of the degree of splenomegaly, improvement in systemic symptoms, and improved quality of life in these patients. However, it does not reverse the progression of marrow fibrosis, reduce the JAK2V617F allele burden or prevent the clonal evolution to acute myeloid leukemia. The use of ruxolitinib can be limited due to treatment related anaemia and thrombocytopenia

All other therapeutic modalities are similarly palliative in nature and include androgen preparations and combinations of thalidomide or lenalidomide and prednisone for anemia, and hydroxyurea for reduction of splenomegaly and systemic symptoms. Melphalan and busulfan have been used in patients with a hyperproliferative phase of the disease and can result in stabilization of the degree of leukocytosis and reduction of splenomegaly.

Splenectomy is a potential treatment modality of choice for patients with massive splenomegaly unresponsive or intolerant to medical treatments, or in patients with severe life-threatening thrombocytopenia and anemia. It should be considered in those patients who develop dose-limiting thrombocytopenia following ruxolitinib therapy or who are not candidates for ruxolitinib due to baseline severe cytopenias. At experienced centers, mortality from this procedure is less than 10% and response rates are greater than 90% for relief of abdominal symptoms due to massive splenomegaly, and approximately 60% for improvements in thrombocytopenia and anemia.

Due to the chronic and progressive nature of this hematopoietic stem cell malignancy and the lack of FDA-approved disease course modifying therapies, it is highly suggested that patients with PMF should be referred whenever possible to tertiary centers with MPN programs and considered for clinical trial enrollment.

What other therapies are helpful for reducing complications?

Patients can be treated with supportive care, receiving platelet and packed red blood cell transfusions as needed. For patients with anemia as a sole abnormality and a low endogenous erythropoietin level, erythropoiesis stimulating agents can be helpful for a short period of time.

Patients with PMF often require long-term transfusion therapy and as a result may develop syndrome of iron overload. Iron chelating agents may be considered in this situation but is rarely used due to the limited survival of patients with advanced forms of PMF.

What should you tell the patient and the family about prognosis?

PMF is a disease with high variability in outcome based upon how advanced the disease is. The patient and their family should be informed that PMF is a hematological malignancy. Clinical course at diagnosis is sometimes difficult to predict. Patients may have stable disease for many years without developing any complications, or can rapidly decompensate due to the development of systemic symptoms, progression to acute myeloid leukemia (AML), or development of thrombotic or hemorrhagic complications. Median overall survival period from the time of diagnosis is approximately 6-7 years. The incidence of acute leukemia as the terminal event ranges from 5 to 22%. Survival after blast transformation is limited. In a series of 91 patients with PMF, the median survival after leukemic transformation was 2.6 months. Standard remission induction therapy is rarely successful in this group of patients.

A number of prognostic models are available for assessing prognosis in PMF. One of the most recently developed and commonly used is the dynamic prognostic scoring system (DIPSS plus) developed by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT).

The following adverse prognostic factors were noted following a multivariate analysis:

  • Presence of constitutional symptoms

  • Hemoglobin less than 10g/dl

  • Age greater than 65 years

  • Leukocyte count greater than 25,000/ul

  • Greater than 1% blast cells in the peripheral blood

  • Platelet count less than 100,000/ul

  • An unfavorable karyotype (complex karyotype or the presence of +8, 7-/7q-, multiple copies of 1q, -5/5q-

  • The need for repeated red cell transfusions

Patients with 0, 1, 2, or 3, 4 or more of these 8 factors at any time during the patient’s clinical course have a predicted median survival of 15.4, 6.5, 2.9 and 1.3 years respectively.

Patients with PMF who lack Jak2V617F, MPL W515L/K and CALR exon 9 mutations (triple negative) have a higher rate of leukemic transformation and a shorter overall survival. Similarly patients with an ASXL1 mutation also have a shortened survival.

By contrast, patients with the CALR mutation appear to have a more indolent clinical course than patients with JAK2 V617F. The calreticulin mutation is associated a lower risk of thrombosis and longer overall survival.

"What if" scenarios.

What is the best treatment plan if patient is eligible for stem cell transplantation?

Allogeneic stem cell transplantation is the only treatment for this disease that has potential for cure. All patients and their siblings should be human leukocyte antigen (HLA) typed at diagnosis to determine if there is a potential match.

Patients under the age of 70, with reasonable performance status and available donor, should be encouraged to undergo evaluation for stem cell transplantation. While it is still a procedure with high mortality and morbidity, patients who receive hematopoietic stem cell transplants from a fully matched related donor have a good chance of doing well, with 2-year survival rates of about 75%. By contrast, those patients who receive a graft from a matched unrelated donor has a 2-year survival of 32%. The difference in outcomes in these two groups appears to be related, in part, to increased primary and secondary graft failure in the unrelated group.

Patients with high risk or intermediate-2 risk disease with available donors should be encouraged to undergo transplantation prior to developing debilitating symptoms and worsening of their performance status. Patients with low-risk or intermediate-1 disease should be monitored closely without intervention, but should be considered for transplant if disease progresses.

How should patients with thrombocytopenia be treated?

Patients with severe thrombocytopenia present a serious challenge with minimal treatment choices. Most of the standard treatments utilized for PMF, such as ruxolitinib and hydroxyurea, result in further myelosuppression and cannot be used.

Patients with platelet counts between 50,000 and 75,000 may be eligible for participation in a few clinical trials, such as some of the JAK2 inhibitor trials. The newly approved JAK2 inhibitor ruxolitinib can also be attempted in low doses if the platelet count is above 50,000. The goal of this treatment would be reduction in spleen size, resulting in improvement in platelet count.

For patients with platelet counts of less than 20,000, the treatment choices are truly limited. Supportive therapy with platelet transfusions is a possibility, though likely not sustainable long term. About 30-50% of patients with severe thrombocytopenia will have significant improvement in platelet counts following a splenectomy. However, splenectomy in patients with PMF is associated with post-operative morbidity rate of 15-30% and mortality rate of close to 10%. These numbers, however, are highly dependent on the institutional experience and the operating surgeon.

Pathophysiology

The exact pathogenesis of PMF is unknown. It is believed to arise from a somatic mutation in a pluripotent hematopoietic stem cell, resulting in clonal proliferation and an inflammatory cytokine milieu. Driver mutations in the JAK2 receptor tyrosine kinase (JAK2V617F) thrombopoietin receptor (MPL W 515L/L) or calreticulin have been identified in patients with myeloproliferative neoplasms. The calreticulin mutations are mutually exclusive with JAK2V617F and MPL W 515L/L.

An F to T nucleotide switch in exon 14 of the JAK2 pseudokinase domain produces a constitutively active tyrosine kinase. This leads to cytokine independent activation of the JAK/STAT pathway. Constitutive activation of JAK/STAT signalling appears to be an important pathogenetic event in the development of PMF and other myeloproliferative neoplasms.

All of the calreticulin mutations result in a novel C-terminal peptide which has a minimum of 36 amino acids and replaces the 27 amino acids that are lost from the normal sequence. Calreticulin is a multifunctional protein that is best known as calcium binding chaperone in the endoplasmic reticulum. The manner in which mutations in calreticulin might lead to the development of a myeloproliferative neoplasm remains poorly defined. Surprisingly, the JAK2 inhibitors are effective therapies in PMF patients with a calreticulin mutation.

Patients with PMF have been found to harbor a large number of other mutations in genes such as TET2, EZH2, IDH1 and IDH2, and ASXL1. However, none of these are specific to PMF nor do they display mutual exclusivity. It is clear that the molecular genetics of PMF are very complex, and while the driver mutations (JAK2V617F, MPL W515L/K or CALR) can influence the disease phenotype, they are likely not the initiating genetic event.

Bone marrow fibrosis is believed to be a secondary process that is a result of abnormal deposition of collagen derived from normal fibroblasts. Fibroblasts in PMF are induced to proliferate and produce excessive collagen by growth factors and cytokines secreted by megakaryocytes. The major megakaryocyte-derived growth factor is transforming growth factor beta (TGF-beta). Other growth factors also likely contribute to the fibrotic reaction include: platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF). Bone marrow fibrosis is not an irreversible process in PMF, and morphologic evidence of reversal can be seen after 12 months, following successful hematopoietic stem cell transplantation.

Another key characteristic of PMF is constitutive mobilization of CD34+ cells and endothelial progenitor cells into the peripheral blood. This dysregulation of stem cell trafficking tends to ultimately lead to the seeding of extramedullary sites with primitive hematopoietic and endothelial cells, which results in extramedullary hematopoiesis within the liver and spleen, as well as other organs.

What other clinical manifestations may help me to diagnose primary myelofibrosis?

Important or unusual questions/symptoms to ask on history

A variety of immunologic abnormalities has been reported to be associated with PMF, including direct Coomb’s test positivity, high antinuclear antibody titers, positive rheumatoid factor, presence of lupus anticoagulant activity, and hypocomplementemia. A high incidence of monoclonal gammopathies has been reported as well, with up to 10% reported in some series.

One of the hallmark findings of PMF is extramedullary hematopoiesis (EMH). Foci of EMH can develop in any organ, which can present as:

  • Splenomegaly

  • Hepatomegaly

  • Lymphadenopathy

  • Pericardial or pleural effusion

  • Direct involvement of the lungs, gastrointestinal tract or nerve tissue.

Important or unusual signs or findings on physical exam

Rarely, the development of PMF can be preceded by or associated with Sweet’s syndrome, which is characterized by multiple cutaneous plaques and nodules. This cutaneous process, however, can be associated with other hematologic malignancies.

What other additional laboratory studies may be ordered?

The number of circulating CD34 positive stem cells in patients with PMF has been reported to be 300 times higher compared to normal controls. However, this is not routinely used as a diagnostic marker, as up to 15% of patients with PMF can have normal numbers of CD34+ stem cells in the peripheral blood. CD34+ cell numbers may be used for monitoring the disease course and response to therapy. Increasing number of CD34+ cells indicates acceleration of the disease course.

What’s the evidence?

Kralovics, R, Passamonti, F, Buser, AS. “A gain-of-function mutation of Jak2 in myeloproliferative disorders”. N Engl J Med. vol. 352. 2005. pp. 1779-1790. [This publication discusses the identification of a novel unifying mutation in myeloproliferative disorders (JAK2 V617F). Three other studies were published around the same time confirming this finding.]

Pikman, Y, Lee, BH, Mercher, T. “MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia”. . vol. 3. 2006. pp. e2708[Report of MPLW515L mutation in a subset of JAK2V617F-negative myelofibrosis patients.]

Mesa, RA, Nagorney, DS, Schwager, S, Allred, J, Tefferi, A. “Palliative goals, patient selection, and perioperative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic”. Cancer. vol. 107. 2006. pp. 361-370. [This publication discusses the indications and outcomes for patients undergoing splenectomy.]

Guglielmelli, P, Bartalucci, N, Rotunno, G, Vannucchi, AM. “Calreticulin: a new horizon for the testing and treatment of myeloproliferative neoplasms”. Expert Rev Hematol. vol. 7. 2014. pp. 423-425. [This publication summarizes, in a succinct manner, our present understanding of the role pf calreticulin mutations in patients with ET and PMF.]

Rondelli, D, Goldberg, JD, Isola, L. “MPD-RC 101 prospective study of reduced intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis”. Blood. vol. 124. 2014. pp. 1183-1191. [This study demonstrates the value of reduced intensity conditioning in patients with advanced forms of myelofibrosis who are fortunate to have an appropriate stem cell donor.]

Cervantes, F, Alvarez-Larran, A, Domingo, A. “Efficacy and tolerability of danazol as a treatment for the anemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients”. . vol. 129. 2005. pp. 771-775. [Study demonstrating that danazol is well-tolerated and induces good responses in some patients with myelofibrosis and anemia.]

Verstovsek, S, Mesa, RA, Gotlib, J. “A double blind placebo-controlled trial of ruxolitinib for myelofibrosis”. N Engl J Med. vol. 366. 2012. pp. 799-807. [This combined JAK1/JAK2 inhibitor is the only JAK2 inhibitor currently FDA approved for the treatment of PMF.]

Zhou, A, Oh, ST. “Prognostication in MF: from CBC to cytogenetics to molecular markers”. Best Pract Res Clin Haematol. vol. 27. 2014. pp. 155-164. [Superb review of the use of a variety of clinical and laboratory tools to determine the prognosis of myelofibrosis patients.]

Tefferi, A, Lasho, TL, Finke, CM. “CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons”. Leukemia. vol. 28. 2014. pp. 1472-1477. [Retrospective study correlating molecular features and clinical phenotypes as well as prognosis.]

Klampfl, T, Gissinger, H, Harulyunyan, AS. “Somatic mutations of calreticulin in myeloproliferative neoplasms”. N Engl J Med. vol. 369. 2013. pp. 2379-2390. [One of the two first papers to describe the finding of calreticulin gene mutation in patients lacking the JAk2V617F or MPL mutations.]

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