Myeloproliferative disease

Question 1

Multiple myeloma

Answer 1

Pathophys:

• Over production of BJP (kapp and lambda light chains) exceeds the nephrons capacity for re-absorption so it is excreted in the urine

Question 2

Primary myelofibrosis

Answer 2

Description:

• Primary myelofibrosis (PMF) is one of the BCR-ABL negative myeloproliferative neoplasms.
• characterized by clonal proliferation of myeloid cells with variable morphologic maturity and hematopoietic efficiency.
• leads to splenomegaly and constitutional (B) symptoms

Epi:

• PMF occurs mainly in middle aged and older adults. The median age at presentation is 67 years

Pathogen:

• Genetic mutations: mutually exclusive mutations in JAK2 (60-65% cases), CALR (20-25%), MPL (5%), or triple negative (none of these mutations, seen in 8-10% cases)
• extramedullary hematopoiesis associated with PMF occurs mainly in the liver and spleen (leads to hepatosplenomegaly). Also in the vertebral (thoracic) column, LN, retroperitoneum, small % elsewhere.
• splenomegaly is one of the major clinical manifestations of MF and is directly linked to splenic extramedullary hematopoiesis. Alteration of CXCL12/CXCR4 pathway could also lead to splenic EMH. JAK2 V617F homozygous mutation was associated with a larger spleen size. Crosstalk between oncogenic JAK2 activation and CXCL12/CXCR4 signaling increased CXCL12-dependent migration and the downstream activation of the STAT, PI3K/AKT, and RAS/MAPK pathways. Thus, oncogenic JAK2 activation spontaneously activates the CXCL12/CXCR4 pathway and encourages EMH, resulting in progressive splenomegaly. PMF patients with the JAK2 V617F homozygous mutation have larger spleen size.

Clinical features:

• most common presenting complaint in PMF is that of severe fatigue, occurring in 50 to 70 percent of patients
• splenomegaly seen in 25-50% patients, often the hallmark of PMF. Can extend below the pelvic brim and across the abdo midline.
• hepatomegaly present in 40-70% cases. Portal HTN, ascites, varices, encephalopathy may be present.
• Constitutional (B) symptoms in 5-20% of wt loss, night sweats, fever, bone pain
• Pulmonary hypertension has been detected in patients with PMF; it has been associated with reduced overall survival
• Pruritus was documented in 16% pts
• thrombotic events (e.g. splenic infarcts, portal vein thrombus, VTE)
• skin involvement: erythematous plaques, nodules, ulcers, bullae
• Bone/joint involvement: osteosclerosis, periostitis (leading to bone pain), secondary gout (from cell turnover), myeloid sarcoma

Labs:

• Anaemia due to marrow failure, splenic sequestration, bleeding, autoimm haemolysis
• peripheral smear showing anisocytosis (RBCs varying in size), poikilocytosis (varying in shape), teardrop-shaped RBCs (dacrocytes), nucleated RBCs, and variable degrees of polychromasia
• high WCC (>30), high plt count (>500)
• increase in circulating CD34+ cells
• signs of tumor lysis (high urate, phosphate, potassium, LDH, B12, ALP)
• BM aspirate: usu dry tap. Not diagnostic. The most common findings are neutrophilic and megakaryocytic hyperplasia.
• Bone marrow biopsy is necessary to demonstrate fibrosis

Management:

• Ruxolitinib is the first FDA-approved selective JAK1/JAK2 inhibitor. COMFORT-I and -II trials demonstrated a significant reduction in splenomegaly in the ruxolitinib group. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877759/