An 80-year-old woman with myelofibrosis sought evaluation for progressive dyspnea and hypoxemia. Her past medical history included essential thrombocytosis (BCR-ABL negative) diagnosed in 2011, which transformed to myelofibrosis diagnosed in 2013, JAK-2 negative, del (13q) in 69% of cells, diabetes mellitus type-2, and hypertension. Treatment of essential thrombocytosis and myelofibrosis included hydroxyurea (2012), anagrelide (2012-2013), ruxolitinib (2016), and fedratinib (01/2020 to time of evaluation).
She reported worsening dyspnea with exertion and prolonged speech, despite consistent use of supplemental oxygen at 2 L per minute (LPM)She also endorsed fatigue that was historically associated with anemia for which she received periodic transfusions. She denied cough, hemoptysis, recent weight change, easy bruising, fever, chills, night sweats, chest pain, palpitations, orthopnea, or lower extremity edema. She was a former smoker with a 5 pack-year history and quit over 50 years ago. She denied any environmental or occupational exposures or international travel.
She was afebrile, had a regular heart rate of 79 beats per minute, a blood pressure 170/73 mmHg, a respiratory rate of 16 breaths per minute, and was saturating 86% on room air and 100% on 2 LPM. She was in no apparent distress and was able to converse without difficulty. Cardiac examination revealed normal S1 and S2, without 3rd or 4th heart sounds, murmurs, rubs, and jugular venous distension. Lung auscultation demonstrated bibasilar crackles without wheezing. There was no evidence of pedal edema, clubbing, cyanosis, ecchymosis, lymphadenopathy, hepatomegaly, or splenomegaly.
Complete blood count revealed a hemoglobin of 9.2g/dl, a white blood cell count of 10.8x10e3/muL with a differential of 55% neutrophils, 12% lymphocytes, 9% monocytes, 3% eosinophils, 1% basophils, 5% bands, 5% metamyelocytes, 9% myelocytes, and 1% promyelocyte, and a platelet count of 139x10e3/muL. Peripheral blood smear showed 2+ polychromasia, 1+ basophilic stippling, 2+ tear drop cells, 1+ microcytes, 1+ ovalocytes, 2+ anisocytosis, and 1 nucleated red blood cell. Chest x-ray was performed showing nonspecific interstitial markings. Inspiratory and expiratory computed tomography (CT) chest showed diffuse mosaic attenuation, enlarged mediastinal and hilar lymphadenopathy (Fig. 1A and B& C), enlarged pulmonary trunk (3.4 cm), and enlarged central pulmonary arteries. Pulmonary function testing (PFT) revealed a forced vital capacity (FVC) of 1.88 L (80% predicted), forced expiratory volume in 1 second (FEV1) of 1.5 L (87% predicted),FVC/FEV1 of 80%, total lung capacity (TLC) of 3.71 L (86% predicted), and diffusion capacity (DLCO) of 55% predicted. Transthoracic echocardiogram showed normal left ventricle size with normal systolic (EF of 62%) and diastolic function. There was normal right ventricle size and systolic function. Estimated pulmonary artery systolic pressure was 39 mm Hg.
Given her dyspnea, PFT results, and new imaging findings, the differential diagnosis remained broad. The patient noticed mild improvement in dyspnea with prednisone and doxycycline but got worse when they were discontinued. The potential etiologies were atypical infection, small airway disease, central thromboembolic pulmonary hypertension, drug induced lung disease secondary to fedratinib, hypersensitivity pneumonitis, extramedullary hematopoiesis, and vasculitis. To narrow down the diagnosis, bronchoscopy with bronchoalveolar lavage (BAL), transbronchial lung cryobiopsy (TBLC) of the right lower lobe, and endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) of a right paratracheal lymph node was performed. Bacterial, fungal, and mycobacterial cultures were negative. Transbronchial lung cryobiopsy revealed expansile, vaguely nodular deposits of extramedullary hematopoiesis in a background of diffuse, homogeneous interstitial thickening (nonspecific interstitial pneumonia (NSIP) pattern) (Fig. 2A) and medium sized blood vessels with moderate to severe vascular medial and intimal thickening with disrupted/reduplicated elastica (Fig. 2B). Immunohistochemistry showed trilinear hematopoiesis with cluster of differentiation 61 (CD61) positive megakaryocytes, focal aggregates of glycophorin A positive erythroid precursors, and rare myeloperoxidase (MPO) positive myeloid precursors (Fig. 2C). Mediastinal lymph node transbronchial needle aspiration showed numerous atypical polylobated megakaryocytes, highlighted by CD61 immunostain, and erythroid and myeloid precursors at various stages of maturation, highlighted by E-cadherin and MPO, respectively, without any blasts in the background of small lymphocytes consistent with pulmonary extramedullary hematopoiesis (PEMH).
Because our patient demonstrated progression of her myelofibrosis with evidence of PEMH, she elected to proceed with enrollment in a clinical trial utilizing CPI-0610 for potential treatment. Since initiation of therapy, she has reported stable symptoms of dyspnea and has required 2 L of supplemental oxygen while resting and 4 L while ambulating. Right heart catheterization revealed mean pulmonary artery pressure of 28 mm Hg, pulmonary artery wedge pressure of 4 mm Hg, and pulmonary vascular resistance of PVR 4.3-4.6 wood units suggestive of pulmonary artery hypertension. Ventilation perfusion scan ruled out chronic thromboembolic PH. She is scheduled for pulmonary vasodilatory therapy.