Definition

Myelofibrosis (MF) is a clonal proliferative disease of hematopoietic stem cells, leading to an inappropriate cytokines release, fibrosis of the bone marrow, constitutive mobilization of committed progenitor cells into the peripheral blood and extramedullary hematopoiesis. MF is the most symptomatic and has the worst prognosis among the Philadelphia-chromosome-negative chronic myeloproliferative neoplasms (MPNs).

This disease may present either as idiopathic (primary myelofibrosis, PMF) or as transformation of an antecedent polycythemia vera (PV) or essential thrombocythemia (ET). PV and ET are phenotypically overlapping with PMF and manifestations and therapeutic approaches are virtually the same in PMF and PV/ET.

Myleofibrosis is characterized by a progressive clinical course. Established prognostic factors including age, hemoglobin level, and white blood cell count have been used for risk assessment, but these characteristics do not fully explain the risk of death or major clinical events.

Morbidity and mortality of myelofibrosis are usually the result of leukemic transformation, spleno-portal hypertension, and infections, as well as thrombosis and hemorrhage.

Table 1 Poor Prognosis Factors – International Working Group-derived International Prognostic Scoring System (IPSS)

Poor Prognosis Risk Factors
1 Age > 65 yrs
2 Presence of constitutional Symptoms
3 Anemia (Hemoglobin < 10 g/dL)
4 Leukocytosis (White blood cell count > 25 x 103/mm3)
5 Circulating blast cells of 1% or greater

The presence of the factors in the table above defines risk degree of myelofibrosis:

  • No risk factors – low-risk
  • One risk factor – intermediate-1-risk
  • Two risk factors – intermediate-2-risk
  • Three or more risk factors – high-risk

What must be paied attention is that this system (IPSS) is used for risk evaluating from time of diagnosis. There is another assessment criteria called Dynamic IPSS plus (DIPSS-Plus) which can be used for risk evaluating at any time during the disease course. The DIPSS-Plus has three additional independent risk factors including red cell transfusion need, platelet count < 100 × 109/L, and unfavorable karyotype. The unfavorable karyotype includes complex karyotype or sole or 2 abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement.

Note that leukocytosis can happen in patients after splenectomy due to “myeloproliferative” reaction and it does not necessarily imply disease progression.

Figure 1 The Dynamic International Prognostic Scoring System (DIPSS) plus prognostic model for primary myelofibrosis (PMF).

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors – high

These four risk groups are with respective median survivals of 15.4, 6.5, 2.9, and 1.3 years. Leukemic transformation was predicted by the presence of unfavorable karyotype or platelet count < 100 × 109/L.

Clinical Manifestations

Symptomatic myelofibrosis can present with anemia, significant splenomegaly, aberrant production of proinflammatory cytokines (which causes constitutional symptoms such as weight loss, night sweats, fever of unknow origin), severe fatigue, cachexia, and pruritis.

These manifestations include anemia (either moderate or transfusion dependent), splenomegaly and/or hepatomegaly, the development of foci of nonhepatosplenic hematopoiesis, myeloproliferation manifesting with marked leukocytosis or thrombocytosis. and increased risk of thrombohemorrhagic complications, and a spectrum of debilitating constitutional symptoms.

Biology

JAK2V617F (Janus kinase 2 mutation V617F) mutation plays an important role in the pathogenesis of myelofibrosis. JAK2V617F has been identified in approxmiately 60% of patients with myelofibrosis (half of patients with PMF and post-ET myelofibrosis and in nearly all of those with a secondary form following a previous PV). Despite its crucial role in pathogenetic role, the clinical relevance of JAK2V617F in myelofibrosis is not completely understood. In a large retrospective survey showed that JAK2V617F mutation plays a significant and independent influence on the disease phenotype and showed that many clinical manifestations are correlated with the expansion of clonal hematopoietic cells harboring the JAK2V617F mutant allele.

Management of Myelofibrosis

The treatment of MF is guided by risk stratification and the patient’s clinical needs. As we mentioned before, the risk stratification are:

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors – high

For low- or intermediate 1-risk disease, the respective median survival of patients exceeds 15 and 6 years and even longer for patients younger than age 65 years. Therefore, the risk of allo-SCT-associated mortality and morbidity is not justified in such patients, and it is also not prudent to subject them to investigational drug therapy, considering the limited information about long-term safety of new therapeutic agents. Similarly, there is no evidence to support the value of conventional drug therapy in asymptomatic patients with low- or intermediate 1-risk diseases. For this group of patients without symptoms, “watch and wait” is preferred.

For this group of patients with symptoms, they may occasionally experience splenomegaly, nonhepatosplenic extramedullary hematopoiesis, extramedullary hematopoiesis (EMH)-associated pulmonary hypertension, fatigue, bone (extremity) pain, pruritus, or thrombocytosis with a thrombosis history. Intermediate 1-risk patients might in addition display symptomatic anemia, marked leukocytosis, or constitutional symptoms such as drenching night sweats, fever, or weight loss (cachexia). If clinical needed, it is reasonable to start with conventional drug therapy.

However, if the patient is del(5q) present, lenalidomide is the recommended first-line therapy because significant improvement.

Figure 2 Risk-adapted therapy in primary myelofibrosis.

For patients with high- or intermediate 2-risk disease can be managed by conventional drug therapy, splenectomy, radiotherapy, allo-SCT, or experimental drug therapy. With each one of these treatment modalities except allo-SCT, the primary goal is palliation of anemia, symptomatic splenomegaly, constitutional symptoms, or disease complications from EMH (extramedullary hematopoiesis).

Allogeneic SCT

The achievement of a JAK2V617F negativity after SCT is associated with complete hematologic and cytogenetic remission and results in a low incidence of relapse and is currently the only treatment option in MF that is capable of inducing complete hematologic, cytogenetic, and molecular remissions.

Reduced-intensity conditioning (RIC) regimens have been used in recent years with the dual aims of improving the high transplantation-related mortality rate of conventional-intensity conditioning (CIC) regimens and to accommodate the advanced median age of MF patients. However, no prospective study comparing RIC with CIC, or SCT with conventional therapy, has yet been completed. Analysis of the largest published series indicated that transplantation-related mortality ranged from 10% to more than 40%, overall survival at 3 years was between 30% and 50%, and grade II-IV acute GVHD occurred in 20%-60%. The incidence of extensive chronic GVHD is not well established, but in some series it affected more than two-thirds of the patients. However, a retrospective analysis of young (< 60 years), high-/intermediate-risk PMF patients who were managed with nontransplantation procedures at 3 experienced centers reported 3-year survival estimates of 55%-77%, overall comparable to the results obtained with either CIC or RIC SCT.

But transplantation-related mortality and morbidity in MF have not been favorably altered by the use of RIC transplantation when TRM (treatment-related mortality), relapse, and chronic GVHD rates remain uncomfortably high. Therefore, if allo-SCT is indicated because of high- or intermediate 2-risk disease, it is inclined to favor the use of CIC transplantation in younger patients (age < 40-50 years), considering its association with a lower risk of relapse, compared with RIC transplantation. It is reasonable to offer RIC transplantation for older patients with high- or intermediate 2-risk disease, especially if a matched related donor is available.

Variables associated with transplantation outcome are represented by HLA disparity, use of an unrelated donor, age of the recipient, and a transfusion history of > 20 red cell units. In summary, no evidence-based recommendation can be provided at this time about who should certainly undergo SCT and when. Not all patients  with high- or intermediate 2-risk disease should undergo all0-SCT. A decision to refer the patient to SCT is commonly postponed in clinical practice. But patients who acquire additional unfavorable cytogenetic aberrations (particularly of chromosome 17) and/or manifest signs of disease progression (e.g., increasing blasts and worsening of thrombocytopenia) that could imply impending transformation to acute leukemia and that predict survival at < 1 year should be subjected to SCT without further delay.

Anemia

Low-dose prednisone, erythropoiesis-stimulating agents (ESAs), androgens, danazol, and thalidomide are commonly used and often in that order.

ESAs are worth trying in patients with moderate, non-transfusion-dependent anemia and a low (< 125 U/L) serum erythropoietin level; a rapid enlargement of the spleen under treatment has occasionally been reported. Response rates vary from 20%-60% in different studies, with no clear support for darbepoetin-alpha versus conventional recombinant erythropoietin; indeed, no prospective randomized study of the value of ESAs has been published. Responses are usually short-lived (< 1 year). ESAs are not indicated in anemic subjects with established transfusion dependency.

If ESAs do not work or lose efficacy and there are no contraindications, different androgen preparations or danazol can be  used; responses may occur in ~ 20%, often after > 3 months of treatment.

Low-dose (50 mg/d) thalidomide in association with tapering prednisone has produced responses in anemia in ~ 20%-40% of patients; however, this treatment is often poorly tolerated, with peripheral neuropathies, constipation, and somnolence leading to discontinuation of the drug in most. Due to the risk of thrombosis, prophylaxis with aspirin is recommended in patients with a platelet counts > 50 × 109/L.

In patients with del(5q31)-associated anemia, lenalidomide is the recommended first-line therapy because significant improvement, with resolution of anemia and occasionally evidence of molecular remission, has been reported. However, in patients without del(5q) lenalidomide is not recommended. In a multicenter Eastern Cooperative Oncology Group phase 2 trial in PMF patients lacking the del(5q) lenalidomide in association with prednisone appeared to be of little benefit in improving anemia or reducing splenomegaly.

If the anemia is transfusion-dependent and the reason is splenomegaly, in which drug therapies fails or not tolerated, splenectomy could be considered. Improvement in anemia has been reported in 50% of patients after splenectomy, respectively.

Splenomegaly

Development of massive splenomegaly with a variety of associated problems is the most common symptom. Splenomegaly-related manifestations incude pain, early satiety, bloating, splenic infarctions, signs due to compression of abdominal organs or portal hypertension, and cytopenias.

The main approaches for the treatment of symptomatic splenomegaly are medical (with oral or IV drugs) or surgical. The first choice is hydroxyurea, which usually produces modest responses at higher doses, which are not easily tolerated because of newly developed or exacerbated cytopenias. Greater than 25% and 50% reductions in spleen size have been reported in up to 35% and 17%, respectively, of the patients treated with hydroxyurea. These responses are usually modest and transient, occur mostly in subjects with nonmassive (< 10 cm) splenomegaly, and preferentially in those who are JAK2V617F mutated.

Busulfan or melphalan are used in older subjects who do not tolerate or do not respond to hydroxyurea.

Responses in splenomegaly with low-dose (50 mg/d) thalidomide are infrequent (< 20%).

In cases of massive, refractory splenomegaly monthly IV cladribine courses produced up to 50% responses, with severe but reversible cytopenias being the main toxicity.

Splenectomy remains a valuable alternative to medical therapy when the latter is ineffective or not tolerated. Indication for splenectomy are symptomatic massive splenomegaly, symptomatic portal hypertension with esophageal varices and/or bleeding, profound cachexia, and transfusion-dependent anemia. However, isolated thrombocytopenia is not an indication for splenectomy.

Removal of the spleen produces improvements in mechanical symptoms, especially early satiety and pain, in most cases and is often followed by weigh gain in cachectic patients, but it is usually not as effective against other constitutional symptoms.

Careful assessment of potential candidates, exclusion of comorbidities or ongoing coagulopathy, and a detailed discussion with the patient of expected benefits and potential risks are all mandatory. Complications of splenectomy include bleeding, thrombosis, infections, and a “myeloproliferative” reaction, with thrombocytosis and leukocytosis that can usually be well controlled with hydroxyurea and do not necessarily imply disease progression. It is prudent to lower the platelet count to ~ 200 × 109/L in the preoperative setting and to maintain it  around this level in the postoperative period with hydroxyurea or platelet apheresis to reduce the risk of thrombosis. Prophylactic full-dose heparin should be delivered for at least 4-6 weeks. Not infrequently, thrombosis occurs in the splanchnic venis; therefore, ultrasound of the abdomen vessels should be performed 7 and 30 days after the procedure to detect this complication early and to maximize anticoagulation if necessary. Progressive hepatomegaly sometimes follows splenectomy, likely due to the migration of hematopoiesis, and a markedly enlarged liver is a contraindication to splenectomy. Current data do not convincingly support an increased rate of leukemic transformation after spleen removal.

Although radiotherapy of an enlarged spleen may potentially provide some relief of symptoms due to mechanical discomfort, this approach should only be used in very selected cases that are unresponsive to conventional treatment and cannot undergo (or refuse) splenectomy. The recommendation is made for the following reasons: (1) responses last a few months at maximum and usually do not even produce satisfactory relief of symptoms, (2) radiation can induce marked and durable cytopenias responsible for 10 10%-15% mortality, and (3) radiation causes local fibrosis with splenic adhesions to surrounding tissues that make a subsequent splenectomy technically more complicated and increase the morbidity and mortality of the procedure.

Extra-hepatosplenic hematopoiesis

Hematopoiesis in sites and organs other than the spleen and liver most often involves the peritoneum with ascites, the lungs with pulmonary hypertension and pleural effusions, the lymph nodes with lymph adenomegaly, the thoracolumbar vertebral column with pain or neurologic defects due to compression, and the lower and upper extremities with analgesic-refractory pain.

Asymptomatic localizations are left untreated;low-dose, fractionated (up to 1 Gy in 10 fractions) radiation in involved fields is the treatment of choice for symptomatic manifestations. Diffuse lung parenchymal involvement can be managed with single-fraction (100 cGy) whole-lung radiotherapy which induces prompt regression of symptoms. Surgical removal of extra-hepatosplenic foci of hematopoiesis is required only occasionally.

Risk of thrombosis

Patients with PMF suffer from an increased risk of major cardiovascular events. Fatal and nonfatal thromboses were reported in 7.2% of 707 PMF patients included in a multi-institutional series. Risk factors for thrombosis were age > 60 years and a JAK2V617F mutational status, particularly if the latter was associated with leukocytosis. Whether the risk of thrombosis could be favorably affected by hydroxyurrea is unknown;however, even if cytotoxic treatment is not otherwise required for manifestations of the underlying disease, hydroxyurea and low-dose aspirin should be prescribed in older patients and in those with a history of thrombosis.

Constitutional symptoms

Efficacy of conventional therapies against severe constitutional symptoms is modest at best.

Low-dose prednisone may sometimes produce a feeling of well-being, but the effect is usually modest and transient. However, results from the randomized COMFORT-II study indicated that none of the patients in the best-available therapy arm presented measurable improvements in symptoms, as measured by the EORTC QLQ-C30 or FACT-Lym scores.