Current Management of Chronic Neutrophilic Leukemia

Opinion statement

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) characterized by oncogenic driver mutations in colony-stimulating factor 3 receptor (CSF3R). Due in large part to the rarity of the disease and dearth of clinical trials, there is currently no standard of care for CNL. Available therapies range from conventional oral chemotherapy to targeted JAK inhibitors to hematopoietic stem cell transplant (HSCT), the latter representing the only potentially curative modality. For this reason, coupled with CNL’s typically aggressive clinical course, allogeneic HSCT remains the primary recommended therapy for eligible patients. For ineligible patients, a number of nontransplant therapies have been evaluated in limited trials. These agents may additionally be considered “bridging” therapies pre-transplant in order to control myeloproliferation and alleviate symptoms. Historically, the most commonly utilized first-line agent has been hydroxyurea, though most patients ultimately require second (or subsequent)-line therapy; still hydroxyurea remains the conventional frontline option. Dasatinib has demonstrated efficacy in vitro in cases of CSF3R terminal membrane truncation mutations and may cautiously be considered upfront in such instances, though no substantive studies have validated its efficacy in vivo. Numerous other chemotherapy agents, practically re-appropriated from the pharmaceutical arsenal of MPN, have been utilized in CNL and are typically reserved for second/subsequent-line settings; these include interferon-alpha (IFN-a), hypomethylating agents, thalidomide, cladribine, and imatinib, among others. Most recently, ruxolitinib, a JAK1/2 inhibitor targeting JAK-STAT signaling downstream from CSF3R, has emerged as a potentially promising new candidate for the treatment of CNL. Increasingly robust data support the clinical efficacy, with associated variable reductions in allele burden, and tolerability of ruxolitinib in patients with CNL, particularly those carrying the CSF3RT618I mutation. Similar to conventional nontransplant strategies, however, no disease-modifying or survival benefits have been demonstrated. While responses to JAK-STAT inhibition in CNL have not been uniform, data are sufficient to recommend consideration of ruxolitinib in the therapeutic repertory of CNL. There remains a major unmet need for prospective trials with investigational therapies in CNL.