In PMF trials, JAK2 inhibitors have been shown to produce rapid reductions in spleen size and marked improvements in constitutional symptoms and quality of life.
In conclusion, a simple model which includes: age, JAK2V617F-status and constitutional symptoms can clearly separate distinct risk groups and can be used in addition to the Lille model to predict OS after RIC-ASCT for myelofibrosis.
The JAK2(V617F) mutation load in hetero-/homozygous PV and EMGM is clearly related to MPN disease burden in terms of splenomegaly, constitutional symptoms and fibrosis.
In fact, clinical trials of these compounds have demonstrated improvements in constitutional symptoms and splenomegaly in patients with both mutated and wild-type JAK2 MF.
Activation of Janus kinase 2 (JAK2), frequently as a result of the JAK2(V617F) mutation, is a characteristic feature of the classical myeloproliferative neoplasms (MPNs) polycythemia vera, essential thrombocythemia, and myelofibrosis, and it is thought to be responsible for the constitutional symptoms associated with these diseases.
Regarding therapy, reduced intensity conditioning regimens have allowed the possibility of performing allogeneic stem cell transplantation in older PMF patients, whereas the first clinical trials with JAK2 inhibitors have shown their efficacy in splenomegaly and constitutional symptoms.
The JAK inhibitors are effective in both JAK2-positive and JAK2-negative MF; one of them, ruxolitinib, is the current best available therapy for MF splenomegaly and constitutional symptoms.
JAK2 ATP competitive inhibitors (ruxolitinib, lestaurtinib, SAR302503, SB1518 and CYT387) or drugs that indirectly inhibit the JAK-STAT pathway (everolimus) have documented major effects on splenomegaly and its constitutional symptoms.
Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented.
Ruxolitinib (Rux), a Jak1/2 inhibitor, results in reduced spleen size and improvement in constitutional symptoms in the majority of patients with myelofibrosis (MF).
In a CMML patient with splenomegaly, who was treated with the JAK1/2 inhibitor ruxolitinib off label, we can demonstrate a spleen response and the disappearance of constitutional symptoms which was associated with a decrease in autonomous CFU-GM formation ex vivo.
At age 6 months we started treatment with the recombinant interleukin-1 receptor antagonist anakinra with efficacy both on constitutional symptoms and skin involvement.
Other cytokine-phenotype associations included increased IL-8 and constitutional symptoms; IL-2R, IL-12, and transfusion need; IL-2R, IL-8, and leukocytosis; IP-10 and thrombocytopenia; HGF, MIG, IL-1RA, and marked splenomegaly; and IL-1RA, IL-2R, IP-10, MIP-1β, and JAK2V617F.
Other cytokine-phenotype associations included increased IL-8 and constitutional symptoms; IL-2R, IL-12, and transfusion need; IL-2R, IL-8, and leukocytosis; IP-10 and thrombocytopenia; HGF, MIG, IL-1RA, and marked splenomegaly; and IL-1RA, IL-2R, IP-10, MIP-1β, and JAK2V617F.
Among the strongest correlations were those between IL-8 level and the two index-scores, as well as HRQoL aspects that represent constitutional symptoms.
Marked elevations in CSF protein, ongoing deterioration despite administration of IVIg, and constitutional symptoms with elevated inflammatory markers may be clues to possible HL-induced GBS.Muscle Nerve 55: 601-604, 2017.
At the time of presentation, AA patients had lower median hemoglobin levels (12.9 g/dL vs 13.7 g/dL), higher β2 microglobulin levels (2.7 mg/dL vs 2.4 mg/dL), greater frequency of constitutional symptoms (27% vs 10%), unmutated immunoglobulin heavy-chain variable region (IGHV) mutation status (65% vs 47%), ζ-chain-associated protein kinase 70 (ZAP70) expression (58% vs 32%), and deletion of chromosome 17p or chromosome 11q (28% vs 17%; P ≤ 02 for each comparison).
The traditional concept of GCA has focused on cranial symptoms such as headache and visual disturbance, but extra-cranial manifestations such as constitutional symptoms, polymyalgia and limb claudication have also long been recognized.
Other cytokine-phenotype associations included increased IL-8 and constitutional symptoms; IL-2R, IL-12, and transfusion need; IL-2R, IL-8, and leukocytosis; IP-10 and thrombocytopenia; HGF, MIG, IL-1RA, and marked splenomegaly; and IL-1RA, IL-2R, IP-10, MIP-1β, and JAK2V617F.
At the time of presentation, AA patients had lower median hemoglobin levels (12.9 g/dL vs 13.7 g/dL), higher β2 microglobulin levels (2.7 mg/dL vs 2.4 mg/dL), greater frequency of constitutional symptoms (27% vs 10%), unmutated immunoglobulin heavy-chain variable region (IGHV) mutation status (65% vs 47%), ζ-chain-associated protein kinase 70 (ZAP70) expression (58% vs 32%), and deletion of chromosome 17p or chromosome 11q (28% vs 17%; P ≤ 02 for each comparison).
Constitutional symptoms (fever, malaise, and fatigue) and asymptomatic hyperbilirubinemia were the chief dose-limiting toxic effects of interleukin-2 therapy.