High dose cyclophosphamide for cytoreduction in patients with acute myeloid leukemia with hyperleukocytosis or leukostasis.

Hyperleukocytosis may lead to multiple medical emergencies. Hydroxyurea, intensive chemotherapy, and leukapheresis are used for cytoreduction. However, there is little data regarding the best approach. Here, we report on the efficacy and safety of high dose cyclophosphamide (HDCy; 60 mg/kg). 27 patients with acute myeloid leukemia or blast phase chronic myeloid leukemia who presented with white blood cell count (WBC) of ≥50x109/L or symptoms of leukostasis were treated with HDCy. Primary endpoint was early mortality (death within seven days of admission). Median WBC was 107 × 109/L at time of HDCy; 74% had leukostasis symptoms at presentation. Eight (29.6%) patients died within seven days of admission. Sustained WBC reduction was achieved in 18/24 (75%) evaluable patients with median nadir of 0.25 × 109/L. Adverse effects attributed to HDCy included tumor lysis syndrome (n = 7; 25.9%), disseminated intravascular coagulopathy (n = 5; 18.5%), and hemorrhagic cystitis (n = 1; 3.7%). HDCy was effective for cytoreduction and adverse effects were acceptable.

Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal proliferation of differentiated myeloid cells leading to bone marrow fibrosis, cytopenias and extramedullary hematopoiesis. In late 2019, the FDA approved the highly selective JAK2 inhibitor, fedratinib, for intermediate-2 or high-risk primary or secondary MF, making it the second drug approved for MF after ruxolitinib, a JAK1/2 inhibitor, which was approved for MF in 2011. The approval of fedratinib was based on phase II trials and the phase III JAKARTA trial, in which the drug significantly reduced splenomegaly and symptom burden compared to placebo, including some patients previously treated with ruxolitinib. The main side effects of fedratinib include anemia, gastrointestinal symptoms, and elevations in liver transaminases. Fedratinib also has ablack box warning for encephalopathy, although this occurred only in about 1% of the treated patients, most of which were ultimately felt not to represent Wernicke's encephalopathy. Nonetheless, monitoring of thiamine levels and supplementation are recommended especially in high-risk patients. This concern has led to a prolonged clinical hold and delayed the drug approval by several years during which the drug exchanged manufacturers, highlighting the need for meticulous investigation and adjudication of serious, but rare, adverse events in drug development that could end up preventing drugs with favorable risk/benefit ratio from being approved. In this review, we discuss the pharmacokinetic data and efficacy, as well as the toxicity results of clinical trials of fedratinib. We also review ongoing trials of JAK inhibitors in MF and explore future treatment options for MF patients who are refractory to ruxolitinib.