Primary myelofibrosis

Clonal hematopoietic stem cell disorder by progressive anemia, leukoerythroblastosis, splenomegaly, progression to acute leukemia and premature death.

Estimated 13,000 patients have myelofibrosis in the United States.

It is the most aggressive of the Philadelphia chromosome negative myeloproliferative neoplasms.

Also known as agnogenic myeloid metaplasia.

A chronic leukemia.

Referred to now as primary myelofibrosis (MF).

Characterized by clonal hematopoiesis and replacement of the bone marrow by reticulin/collagen fibrosis.

Rarest of myeloproliferative neoplasms.

MF can percent as a de novo disorder or can develop from the progression of polycythemia vera and essential thrombocytosis.

Sub categorized as primary myelofibrosis, and post polycythemia rubra vera or post essential thrombocytosis MF.

Early stage MF is characterized by an increase in atypical megakaryocytes, reduced erythropoiesis, and increased bone marrow cellularity.

Early disease, pre-fibrotic may lack bone marrow fibrosis and may be diagnosed as essential thrombocytosis.

Some patients present with myeloproliferative phenotype characterized by leukocytosis and thrombocytosis, whereas in others, a myelodepleted phenotype develops that resembles a bone marrow failure state, often with transfusion dependent anemia and thrombocytopenia, as well as neutropenia.

Incidence rate approximately 0.4-.7/100,000 person/years (Lissandre S et al).

Prevalence of myelofibrosis 4-6 per 100,000.

Characterized as the BCR/ABL negative myeloproliferative disorder.

Characterized by clonal proliferation of myeloid cells, leading to extra medullary hematopoesis,, hepatosplenomegaly constitutional symptoms and cytopenias, along with bone marrow fibrosis and an increased risk for evolution into acute myeloid leukemia.

Originates in hematopoietic stem cells leading to cytokine release, myeloid hyperproliferation, and bone marrow fibrosis.

Hyperactive signaling of the Janus kinase/signal transducer and activator of transcription proteins (JAK/STAT) pathway is implicated in the molecular pathogenesis of primary myelofibrosis, and mutations of crucial genes in this pathway are now part of the major criteria for the diagnosis of primary myelofibrosis.

There is an increases in inflammatory cytokines such as transforming growth factor beta 1 that may increase fibrosis and trabecular thickening.

Approximately 3000 cases per year are diagnosed in the United States, and includes patients with post-polycythemia and post-thrombocytosis myelofibrosis.

Patients tend to be older than patients with essential thrombocytosis and polycythemia vera as the median age at diagnosis is often in the 7th decade.

Can evolve from an antecedent polycythemia vera or essential thrombocythemia or can manifest as an initial diagnosis.

Complications include portal hypertension, thromboembolism, increased infections, and approximately 8 to 30% of patients progressed to blast phase acute myeloid leukemia.

Both lab and clinical findings are required to establish a diagnosis.

Unlike essential thrombocytosis primary myelofibrosis has a male predominance.

Median age is 66 years with a male predominance 3:2 (Tefferi A et al).

In a study of 1000 consecutive patients with primary myelofibrosis 13% of patients were younger than 50 years and 31% were younger than 60 years (Tefferi A et al).

Most cases are idiopathic, but there is a higher risk with radiation and benzene exposure.

Almost 25% of patients have a history of antecedent essential thrombocytosis or polycythemia vera.

Of all the myeloproliferative disorders has the most morbidity and poorest life expectancy.

Classic presenting manifestations include splenomegaly, teardrop red blood cells, leukoerythroblastic changes, hypercellular marrow with osteisclerosis and collagen fibrosis.

Highly heterogenous with regard to age of onset, phenotype, clinical features and prognosis.

Patients may present with constitutional symptoms including fatigue, and night sweats, bone pain, pruritus, cough and weight loss.

WHO major criteria for diagnosis require 3 of the following: atypical megakaryocytes in the setting of collagen or reticulin fibrosis, exclusion of other myeloid neoplasms such as CML or polycythemia vera, and the presence of a clonal marker such as JAK2 V617F, and exclusion of secondary causes of marrow fibrosis (Vardiman JW).

Mutations involving JAK2, MPL, TET2, ASXL1, IDH1/IDH2, CBL, Idh1,IDH2 IKZF1, LNK, DNMT3A,CUX1,SF3B1, EZH2 and calcireticulin (CALR) have been described.

Dysregulation of the JAK signaling pathway is frequently noted in patients with myelofibrosis, with or without V7617F mutation.

V7617F mutation seen in 50-60% of patients.

The absence of this mutation in 50% of all patients with primary myelofibrosis and presence of Jak2-negative leukemia transformation in patients with JAK2 primary myelofibrosis suggests this mutation is a secondary event.

JAK2, MPL myeloproliferative leukemia, and calcreticulin(CALR), driive the development of myeloproliferative neoplasms, particularly, myelofibrosis.

Patients with CALR mutation are younger and have a favorable prognosis with a median overall survival of 17.7 years.

CALR mutations are associated with a better overall survival than JAK2 or MPL mutations.

The ten-year cumulative incidence of leukemic transformation is lower for patients with CAL or mutation at 9% versus 19% for those with JAK2 and 17% for those with MPL mutations.

MPL and JAK2 mutations are associated with a similar median survivals of approximately 9 years.

Triple mutation negative disease is associated witha shortened median survival of 3.2 years.

None of the mutations are MF specific, and these mutations probably constitute secondary events.

JAK2 mutations occur in approximately 50% of patients and can directly induce JAK-STAT hyperactivation.

Aberrant activiation of the JAK signal transducer and activator of JAK-STAT transcription pathway is core to the pathogenesis of myeloproliderative diseases.

There is increased signaling via STAT, mitogen-activated protein kinase (MAPK), phosphoionositide 3-kinase (PI3K) and serine/threonine kinase (STK) and a downstream increase in gene transcription and expression.

The most common mutation in the JAK2 allele, JAK2 v16f occurs within the autoinhibitory JH2 domain of the JAH2 enzyme.

The valine (V) to phenylalanine (F) switch prevents autoinhibitory actions of that domain with activation of phosphorylation and abnormal downstream signaling.

WHO minor requirement for primary myelofibrosis require 2 of the following: Elevated LDH, leukoerythroblastocytosis,anemia and splenomegaly (Vardiman JW).

Symptoms result from elevated pro-inflammatory cytokines and progressive anemia.

Fatigue present in 85% of patients.

Night sweats, fatigue, abdominal pain, bowel disturbances,pruritus, bone pain, dacrcytosis and weight loss frequent.

Hypercatabolic symptoms include weight loss, night sweats, and fevers.

Symptoms from high blood counts, such as leukocytosis, thrombocytosis, erythrocytosis or combination, include headaches, vascular events and TIAs.

Can aggravate other disease states, and rarely can lead to ascites.

Patients may experience dyspnea secondary to anemia, pulmonary emboli, CHF pulmonary arterial hypertension secondary to extramedullary hematopoiesis.

Thrombosis, either arterial or venous can complicate 10% of cases during a 5 year follow-up (Cervantes F).

JAK2 mutation is linked with an increased propensity to thrombosis.

Splenomegaly present in almost all cases, may be massive and lead to early satiety, pain and pancytopenia.

40% develop a large liver.

Worst prognosis of all myeloproliferative neoplasms.

Leukemic transformation results in death in 15% of patients.

Longer survival associated with lack of symptoms, hemoglobin over 10g/dL, platelet count greater than 100,000x 10 to the third, and and the absence of slenomegaly.

May manifest as primary myelofibrosis, post-essential thrombocytosis myelofibrosis or post-polycythemia vera myelofibrosis.

Characterized by bone marrow fibrosis and extramedullary hematopoiesis.

Extramedullary hematopoiesis a result of abnormal trafficking of hematopoietic stem cells from the bone mineral to the spleen, liver and lung.

Extramedullary hematopoiesis may be manifested by organomegaly and organ dysfunction.

No sex differences in frequency.

Diffuse bone marrow fibrosis, splenomegaly, teardrop erythrocytes, circulating immature myeloid cells, circulating erythroblasts, clusters of megakaryocytes in bone marrow and myeloid metaplasia.

Clinical signs include progressive anemia, progressive bone marrow fibrosis and splenomegaly, and debilitating symptoms of fatigue, weakness, bone pain, weight loss and a hypermetabolic state.

Myelofibrosis associated with high levels of circulating inflammatory cytokines such as IL-6 which probably contributes to hypercatabolism, weight loss and fatigue.

Median spleen mass 2700 gm.

Splenectomy does not alter the natural history.

Splenectomy may be useful in patients with significant splenomegaly and associated anemia or thrombocytopenia refractory to therapy.

Significant morbidity and mortality is associated with splenectomy in primary myelofibrosis with mortality rates 5-10% in up to 50% of patients experiencing complications such as rebound hepatomegaly can result in renal failure and death.

Splenectomy basically reserved for patients with portal hypertension, severe splenomegaly, pain or cachexia and/or severe cytopenias not responding to nonsurgical therapy

Isolated thrombocytosis presenting process in approximately 20% of patients.

Substantially shortened 10 year survival.

Survival is related to the number of risk factors and ranges from 2-4 years among patients with 2 or more risk factors to 8-11 years among patients no risk factors one risk factor.

Median age a diagnosis 65 years at onst, although 20% younger than 55 years of when diagnosed.

Median survival ranges from less than two years to greater than 15 years (6 years).

Median survival from diagnosis for patients with intermediate-2-risk disease is four years and two years, for patients with high-risk disease.

Improvement in relative survival have occurred for women, younger patients, and low/intermediate-1-risk subgroups.

Causes of death include bone marrow failure, leukemic transformation, and complications of thrombosis or bleeding.

Transformation into AML associated with less than a 3 month median survival.

Allogeneic hematopoietic stem cell transplantation is potentially curative in a subset of young patients with MMM.

Adverse prognosis associated with advanced age, anemia, leucocytosis, and the presence of an abnormal karyotype.

Autologous stem cell transplantation lacks clear survival benefit.

Allogeneic stem cell transplantation should be offered to eligible patients with myelofibrosis whose median survival is expected to be less than five years.

Stem cell transplant for appropriate candidates can achieve a cure and is used primarily in patients with intermediate risk or high-risk myelofibrosis who are considered to be good candidates based on age, comorbidities, and the presence of a donor.

Fewer than 40% of patients have nonrandom chromosome abnormalities.

Deletions of 13q and 20q present in 24% and 23% of cases of abnormal metaphases, respectively.

Gain of function mutations JAK2V617F and MPLW5151/K occur in 45% and 5% of patients, respectively.

Presentation usually with anemia, splenomegaly, debilitation and constitutional symptoms.

Characterized by profound constitutional symptoms and cachexia.

Evaluation includes: History and physical examination for signs of palpable spleen and or liver, complete blood count, chemistry panel, review of peripheral blood smear, a bone marrow examination biopsy for reticulin and collagen staining, testing for mutations in the JAK2, CALR, and MPL, testing for BCR/ABL, testing for bone marrow histology showing hypocellularity and dysplastic megakaryocytes, EPO level, serum iron studies and HLA typing for patients with MF for consideration of allogeneic bone marrow transplant.

Once a diagnosis of a myeloproliferative syndrome is confirmed, next generation sequencing is recommended for mutational prognostication.

Bone marrow fibrosis is not enough for diagnosis because various degrees of fibrosis are seen in other myeloproliferative neoplasms.

Laboratory findings include leukoerythroblastosis, leucocytosis, leukopenia, thromobocytosis or thrombocytopenia and elevated LDH levels.

As many as 30% actually have polycythemia vera.

Is a complication of polycythemia vera and erythrocytosis.

Progression of disease to organomegaly, worsening cytopenias, cachexia, edema, portal hypertension, thrombotic or bleeding complications, extramedullary hematopoiesis and blast phase disease.

Bleeding episodes can complicate PMF and can be attributed to thrombocytopenia or a qualitative platelet dysfunction.

Bone marrow stromal reaction include collagen fibrosis, osteosclerosis and neoangiogenesis.

In some cases osteosclerosis and extramedullary hematopoieis develops.

Many patients develop anemia and require red blood cell transfusion support.

As a result of impaired hematopoiesis progressive anemia occurs in one third or more patients, and can lead to transfusion requirement.

Elevated levels of circulating inflammatory cytokines contributes to fevers, night sweats, fatigue, bone and joint pain, and pruritus.

Transfusion dependent thrombocytopenia may develop.

Thrombotic complications, bone marrow failure, transfusion dependence bleeding episodes, infection risk, trans-formation to acute leukemia all contribute to reduce survival in PMF.

Most patients die of complications or disease progression without leukemia transformation.

Approximately 80% of patients with myelofibrosis will develop a very large spleen, and 40% with develop a large liver.

Symptomatic splenomegaly can lead to fullness in the abdomen, abdominal pain and distention, and inability to bend over.

Bone marrow examination is essential for accurate diagnosis.

WHO Diagnostic criteria for PMF:

Major criteria:

Megakaryocyte proliferation and atypia accompanied by either reticulin and/or collagen fibrosis; or in the absence of reticulin fibrosis, megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis.

Not meeting WHO criteria for CML, PV, MDS or other myeloid neoplasm

Demonstration of JAK2 or other clonal marker; in the absence of clonal markers, no evidence of secondary bone marrow fibrosis

Minor criteria:

Leukoerythroblastosis

Increased serum lactate dehydrogenase

Anemia

Palpable splenomegaly

Median survival of 5 years has not been altered by conventional drug therapy.

Life expectancy varies depending upon risk factors which include: age greater than 65 years, hemoglobin level of less than 10 g/dL, white blood cell count of 25,000 millimeters3, circulating blasts of 1% of more, the presence of constitutional symptoms, a platelet count hundred thousand millimeter3 or less, transfusion dependence, and an unfavorable karyotype.

Estimated median survival times range from 11-15 years for low risk patients and approximately 2 years for high-risk patients.

TREATMENT:

Three indications for therapy include: significant anemia, significant general systemic symptoms leading to quality of life issues, and symptomatic splenomegally.

In most patients treatment goal is to decrease the burden of disease, which can include increasing survival, decreasing splenomegaly, improving cytopenias, and/or alleviating symptomatology.

Treatment is generally initiated splenomegaly and/or constitutional symptoms that have reduced the patient’s quality of life.

Historically treatments for myelofibrosis include erythropoiesis, stimulating agents, androgens, prednisone, danazol, thalidomide, lenalidomide, hydroxyurea, pegylated Alpha Interferon.

Thalidomide and lenalidomide are effective treatments of anemia and thrombocytopenia in MMM.

Anemia is common in PMF with 30 to 40% of patients presenting at the time of diagnosis, and an increasing incidence over time.

Cytokines platelet derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) contribute to fibrosis, osteosclerosis and increased angiogenesis.

Progressive angiogenesis demonstrated in 98% of patients and is associated with a poor prognosis.

Anemia is associated with an overall shorter survival, and is an independent prognostic risk factor for leukemic transformation.

Progression of angiogenesis accompanies the acceleration of essential thrombocythemia into myelofibrosis.

Therapy is suboptimal and include: erythropoietin, androgens, corticosteroids, thalidomide, lenalidomide, splenectomy, and splenic irradiation.

Present drug therapy in primary MF is not curative, and has not shown to prolong survival.

More than half the patients are symptomatically anemic and up to 38% require red cell transfusions.

The prognosis is based on the Dynamic International Prognostic Scoring System (DIPSS)-plus.

DIPSS Plus includes transfusion, dependency, karyotype, and platelet count.

DIPSS Plus high-risk category can be stratified into a very high-risk group with a 2 year mortality rate of more than 80%, by the presence of a monosomal caryotype, inv(3)/I(17q) abnormalities, or any 2 of the following 3 features: circulating blast level above 9%, leukocyte level of 40×109/L, and another unfavorable karyotype.

IPSS utility is at the time of diagnosis the median survival is impacted by: age older than 65 years, hemoglobinbelow 10 gm, WBC below 2500, and peripheral blood level of at least 1% and constitutional symptoms.

The IPSS incorporates 5 prognostic clinical variable, assigning a point each for age greater than 65 years, leukocyte count greater than 25,000, hemoglobin less than 10 g/dL, peripheral blood blast percentage of 1% or greater, and the presence of constitutional symptoms.

IPSS has four risk groups defined-low risk zero points, intermediate-1, 1point, intermediate-2, 2points and high-risk 3 or greater points with independent median survivals of 135, 95, 48, and 27 months, respectively.

IPSS score is calculated at the time of diagnosis and the dynamic IPSS (DIPSS) and the DIPSS-plus can calculate an individual patient’s risk group status any point during the illness.

DIPPS-plus incorporates thrombocytopenia, transfusion dependent anemia, cytogenetic abnormalities as adverse prognostic markers.

Prognosis is associated with cytogenetic abnormalities, thrombocytopenia, and red blood cell transfusion requirement.

Typically associated with leukoerythroblastosis and, as the disease progresses there is increasing ineffective hematopoiesis and extramedullary hematopoiesis which may lead to massive splenomegaly.

In PMF splenomegaly is common and is often symptomatic with pain under the left rib cage, early satiety and abdominal fullness, and may result in severe portal hypertension and splenic infarcts.

30% of patients have abnormal karyotype abnormalities and unfavorable chromosome abnormalities include: +8, -7/7q, i77q-, -5/5q, 12p-, inv(3), and 11q23 rearrangements.

Prognosis associated with low risk disease has a median survival of greater than 15years for all patients, and up to 20 years for younger patients, and such patients should not undergo ASCT.

High-risk patients may be best served with ASCT.

Allogeneic stem cell transplant may prolong disease remission in selected patients, but is associated with a high risk of treatment related death and morbidity.

Fewer than 20% of patients with primary MF (PMF) are eligible for allogeneic stem cell transplant.

JAKs are the frontline therapy for patients with high or intermediate risk disease or symptomatic low risk disease.

For patients with platelet counts above 50,000, ruxolitinib is a good first choice of therapy.

COMFORT I and II trials (Controlled Myelofibrosis Study With Oral JAK Inhibitor Tratment)with ruxolitinib-has significant potential to offer benefit compared to placebo-fewer symptoms and reduced spleen volume.

In 2 trials of 528 patients with resistant or refractory disease, or any eligible for bone marrow transplantation, with all patients having splenomegaly, patients receiving ruxolitinib (Jakafi) experienced greater than 35% reduction in spleen size, and a greater than 50% reduction in myelofibrosis symptoms compared with patients receiving placebo on best available care.

Treatments aim to reduce patient’s symptoms and Improve survival by reducing the risk leukemic transformation and or thrombosis

Ruxolitinib has been approved for the treatment of intermediate and high-risk myelofibrosis.

Ruxolitinib an oral Janus kinase 1(JAK) 1 and JAK 2 inhibitor, and is approved for patients with intermediate or high-risk MF.

Ruxolitinib selectively inhibits the proliferation of JAK2 V617F-driven Ba/F3 cells, and is correlated with decreased levels of phosphorylated JAK2 and of signal transducer and activator of transcription 5 (STAT 5) (Quintas-Cardama A et al).

Ruxolitinib is well tolerated with anemia and thrombocytopenia the most frequent adverse events.

Ruxolitinib in myelofibrosis associated with weight gain, reduction in spleen size and in debilitating symptoms.

Ruxolitinib controls symptoms by mediating suppression of inflammation, mirrored by a reduction in pro-inflammatory and pro angiogenic cytokines.

With Ruxolitinib reduction in cytokines is paralleled by significant shrinkage of the spleen.

Ruxolitinib response is independent of JAK2 mutational status.

Ruxolitinib can improve self splenomegaly symptoms and even prolong survival in patients with intermediate-2-risk and high risk myelofibrosis.

Ruxolitinib and fedratinib improve quality of life in approximately 40 to 45% of patients within six months.

Ruxolitinib is used in patients with symptomatic intermediate-1-risk and lower risk myeolofibrosis.

Ruxolitinib starting dose is 20 mg twice a day for patients with platelet count above 200,000, and for patients with platelets between 150-100,000 is 15 mg twice a day with those platelets between 50 and 100,000 5 mg twice a day.

Ruxolitinib requires close monitoring and titrate dose based on platelet count over the first 3-6 months.

Ruxolitinib is not recommended for patients with platelet count below 50,000.

Optimization of Ruxolitinib dose is important as the spleen response to Ruxolitinib is dose dependent and correlates with survival.

Ruxolitinib rarely induce is complete or partial omissions, with the vast majority of patients with Milo fibrosis deriving clinical improvement.

Ruxolitinib effects on bone marrow fibrosis and driver mutation allele burden are modest, questioning whether the agent is truly disease modifying.

Ruxolitinib’s duration of spleen response to Ruxolitinib is around three years and the disease eventually progresses.

Ruxolitinib can change the body metabolism and increase levels of proteins and cholesterol, which are low in patients with advanced myelofibrosis.

Ruxolitinib failure is associated with a poor prognosis, with the median survival of 13-14 months.

JAK Inhibitors include fedratinib for the treatment of myelofibrosis.

Fedratinib can be use successfully after ruxolitinib.

Pacritinib can be used after ruxolitinib and is the agent of choice for patients with low platelets.

Other therapies can be helpful in alleviating anemia and are used off label and include immunomodulatory drugs such as thalidomide, lenalidomide , androgens, erythropoietin stimulating agents.

JAK inhibitors frequently cause exacerbation of anemia rather than alleviating it.

In COMFORT-II ruxolitinib reduced fibrosis in 15%, and stability in 32%, and reduced levels proinflammatory cytokines, and a 33%reduction in death at 5 years.

JAK inhibitors are not recommended for patients with a platelet count below 50,000 and in this setting for  pacritinib a new JAK inhibitor can be used.

Median survival time on Ruxolitinib is from one and a half to three years.

Imetelstat active in patients with myelofibrosis with a 21 percent complete and partial response rate and a median duration response of 18 months.

Imetelstat resulted in bone marrow fibrosis reversal in all patients who had complete responses iand a molecular response in three of four patients treated (Tefferi A et al).