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Myelofibrosis-Biology, Management, and Case Report of Ocular Manifestation

MF-BIOLOGY, MANAGEMENT, AND CASE REPORT OF OCULAR MANIFESTATION

Myelofibrosis is an uncommon myeloproliferative neoplasm, a type of blood cancer where excess red blood cells, white blood cells, or platelets are produced in the bone marrow.  The rarity of this abnormality has many medical professionals struggling to understand its genetic underpinnings. This review seeks to outline the current appreciation of the pathogenesis of myelofibrosis, its complications, and modern clinical treatment strategies. 

A Brief Introduction To Myelofibrosis (MF)

The first-ever recorded case of myelofibrosis was in 1879. However, its eventual classification as a myeloproliferative disorder wasn’t until 1951. In 2005, the first glimpse into the pathogenesis of the disease emerged with the discovery of the Janus kinase 2 mutations. Following this, several genetic breakthroughs in the last decade have resulted in establishing driver mutations such as the JA2, MPL, and CALR, as well as concomitant mutations in epigenetic regulators such as the ASXL1, TET2, DNMT3A, SRSF2, EZH2, IDH ½, and U2AF1. As many as 10-13 molecular characterizations of the disease also led to several gains in personalized prognostic assessments and eventually therapeutic interventions. 

The goal of this review is to summarize genetic alterations together with the observation of the bone marrow microenvironment as contributors to disease biology. This review also includes clinical practice changes that range from nomenclature and diagnostic evaluations to novel therapeutic strategies.  

Biology of Primary Myelofibrosis (PMF)

Microscopic anatomy of primary myelofibrosis includes pre-fibrotic and fibrotic variants where a hematopoietic stem defect results in an abnormal augmentation of megakaryocytes and granulocytes, resulting in increased reticulin fibrosis progression to collagen fibrosis and osteosclerosis. Around two-thirds of patients who have this disorder harbor the gain of function JAK2V617F mutation, a quarter have CALR mutations, and 10% have the MPL mutation.

Symptoms and Complications 

Around 20 percent of people with primary myelofibrosis do not have any symptoms and most of them are only diagnosed through a routine blood test. For others, symptoms usually develop over the course of a few months. This includes unexplained tiredness, shortness of breath, and palpitations. 

Primary myelofibrosis is often suspected in patients with an enlarged spleen, anemia, and abnormal blood count. Although anemia is usually present and even increases over time. The course of the disease can vary for each individual. In some, the disease remains stable for a long period of time- enough to live a normal life with minimal interruptions from symptoms. For others, myelofibrosis progresses more quickly and people usually require regular treatment to relieve symptoms of their disease. 

Ocular Manifestations of PMF

Ocular neoplasms as a result of myelofibrosis are extremely rare.  However, myeloproliferative neoplasms can have ocular manifestations, usually presenting as retinal hemorrhages in the retina, but can involve other parts of the eye simultaneously. There are only a few published cases. The following is the first reported case of neoplastic infiltration by primary myelofibrosis into the eye presenting as bilateral acute angle-closure glaucoma, choroidal effusions, serous retinal detachments, and scleritis.

Case Report

A 57-year-old African American male was referred to us for acute bilateral angle-closure glaucoma with no other ophthalmic history, but a positive history of myelofibrosis. His chief complaint was three days of increasing eye redness and pain. The patient was initially examined by his community ophthalmologist and had visual acuity of 20/40 in both eyes, an intraocular pressure (IOP) of 40 mmHg in the right, and 60 mmHg in the left, and bilaterally closed angles on gonioscopy. Even though the patient was treated with maximum interventions to reduce his IOP along with bilateral laser peripheral iridotomies, his IOP in both eyes remained elevated.

At our first screening, visual acuity was now 20/400 with worsening to light perception. His right eye IOP was 34 mmHg and his left eye was 52 mmHg. On examination, the patient had prominent proptosis of the left eye and restricted extraocular movements with injected chemotic conjunctiva in both eyes. Anterior chambers were very shallow in both eyes and gonioscopy again confirmed bilateral angle closure. Fundus examination of the right eye revealed multiple serous retinal detachments involving the macula, scattered choroidal and retinal infiltrates, and Roth spots. Fundus viewing in the left eye was similar. Ultrasonography revealed bilateral choroidal and annular anterior ciliochoroidal effusions with anterior rotation of the ciliary body and confirmed serous retinal detachments with thickened sclera and the presence of a “T” sign. The patient had leukocytosis with thrombocytopenia. He was taken to surgery for a vitrectomy with radial sclerotomies to decompress the patient’s left eye.

Multiple radial sclerotomies were required for adequate drainage. We collected the fluid for analysis. A core vitrectomy was performed to debulk the vitreous. After surgery, the patient’s IOP was then maintained between 20 and 25 mmHg in his left eye with topical medication applied. The IOP in the right eye remained elevated, and patient’s vision in the right eye continued to deteriorate. An MRI of both orbits showed signal abnormalities and enhancement of the optic nerves and sclera with scleral thickening, suggesting the presence of an infiltrate. Cytologic analysis of choroidal fluid obtained from surgery revealed neutrophilic infiltrates including immature forms and erythroid precursors, suggesting a myeloproliferative neoplasm.

A second bone marrow biopsy was performed a month later, with the same findings as his initial biopsy. We performed a lumbar puncture and found no blasts, but we did find a few immature neutrophils and some eosinophils. These findings suggested the patient’s primary myeloproliferative neoplasm had reached the CNS. The patient was admitted briefly for corticosteroids and intrathecal methotrexate pump placement.

His clinical presentation two months later was much improved. Vision in his right eye had normalized to 20/20 with no IOP elevation (and not requiring medications). His fundus examination was normal. His left eye was at light perception, but IOP was normal.

In summary, this patient was treated with maximal medical and surgical interventions. Standard therapies for angle-closure glaucoma failed in this patient because the mechanism this patient’s acute angle closure was due to anterior rotation of his ciliary body from his ciliochoroidal effusions.  The decision for surgical intervention was based on rapidly declining vision to light perception from intractable glaucoma. Surgically obtained choroidal fluid analysis was critical for an accurate diagnosis. Surgery treated this patient successfully in two ways: reduction of the elevated IOP and prevention of permanent vision loss. If intrathecal methotrexate alone were to be used, it likely would not have reduced the infiltrative load enough to relieve the IOP and save vision in this patient. Aggressive immunomodulation should, therefore, be considered the primary treatment focus.

This case provides further insight into rare and damaging ocular manifestation that can occur with MF.  As with this patient, the first sign of systemic exacerbation of PMF may be in the eye or surrounding ocular structures, and timely recognition this etiology can result in the best outcomes for ophthalmic manifestations of primary myelofibrosis.

Management Approach 

Diagnostic Evaluation 

Primary myelofibrosis is diagnosed based on a patient’s clinical and laboratory results. Most patients are laboratory tested for full blood count and also enrolled for bone marrow examination. Symptoms range from simple fatigue, extreme weight loss, and night sweats to serious anemia, hemorrhage, thrombosis, and hepatosplenomegaly. 

In a study of clinical findings, 1,282 PMF patients with a median age of 65 years showed the following symptoms: 33% had transfusion-dependent anemia, 72% had palpable splenomegaly, and 29% had constitutional symptoms. Laboratory findings show a leukoerythroblastic smear with teardrop-shaped red cells (macrocytosis), nucleated red cells, leukocytosis with or without an increase in circulating blasts, and thrombocytosis or thrombocytopenia with circulating megakaryocytes. 

Bone marrow biopsy with cytogenetic and molecular studies is a requirement for diagnosis. Based on the revised WHO classification in 2016, PMF is differentiated into two kinds of clinical entities: profibrotic MF and overtly fibrotic MF. This distinction is important and has enabled the dissection of essential thrombocythemia (ET) from profibrotic MF. Furthermore, the presence of a driver mention (as mentioned in the early paragraphs), points toward a diagnosis of PMF within the correct clinical context, noting that these mutations are not specific to PMF but are frequently present in PV and ET, with a subset of PMF patients (10%) being triple negative.

Prognostic Assessment 

Currently available medical tools have evolved greatly over the years. Next-generation sequencing has given way to genetic-based therapies . Before this method was realized, clinical and laboratory features were utilized to formulate prognostic scores. For example, the International Prognostic Scoring System (IPSS) is based on symptoms, age, leukocyte count, and hemoglobin, peripheral blast percentage. To accurately assess prognosis, the IPSS was refined and improved by the incorporation of red cell transfusion need, degree of thrombocytopenia, and unfavorable karyotype. All assessment tools relied on laboratory parameters which are prone to fluctuations. This has been overcome already by modern prognostic scores such as the Mutation Enhanced Prognostic Scoring Systems (MIPSS 70, MIPSS 70-plus, and MIPSS 70-plus version 2.0) which all rely on genetics in addition to laboratory parameters. 

We offer a prognostic scoring tool for MF based on modern scoring systems  CLICK HERE TO ACCESS TOOL

Treatment Strategies 

Patients with PMF depict a considerably heterogeneous clinical course with a median survival ranging from over a decade to less than 2 years. Today, the management of post-exon 12 PV MF, post-PV/post-ET MF is similar to PMF. Treatment for PMF is largely supportive and aimed at preventing complications from low blood counts and enlarged spleen. For a long time, primary myelofibrosis was regarded as incurable. The drugs given all have palliative benefits that don’t change or modify the disease or cause adverse effects.  

Another therapy is the use of nonspecific JAK pathway inhibitors, which is often effective whether or not a JAK2 mutation is present. The only curative therapeutic option is allogeneic stem cell transplantation. But this method is very limited due to factors for transplant including age, medical comorbidities, and donor availability. This is also a very risky and life-threatening process. 

So given the limited effectiveness of drugs including JAK inhibitors, clinical trials are encouraged for all high-risk PMF patients. There are several mechanisms now being explored such as telomerase inhibition and aurora kinase inhibition. Targeting mutations CALR with immunological approaches is also being used as another therapeutic strategy.

Conclusion  

There are numerous significant genetic discoveries over the last decade, which have all been important to the development of management and therapy of the disease. It has also substantially enhanced prognostic assessment. However, the co-occurring mutation deserves further study. Disease-modifying therapies must be explored to target mechanisms beyond JAK_STAT, and in combination with JAK inhibitor therapy. 

 

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