Phase I study of alternate-week administration of tipifarnib in patients with myelodysplastic syndrome.

PURPOSE: To determine the safety and describe the antitumor activity of tipifarnib in patients with myelodysplastic syndrome (MDS) using an alternate-week schedule. EXPERIMENTAL DESIGN: Patients with MDS were given tipifarnib, escalating from 100 mg orally twice daily until the maximum tolerated dose for 8 weeks followed by maintenance therapy (same dose/schedule) for patients with stable disease or better. RESULTS: Sixty-three patients were treated. The most common toxicity was myelosuppression (60% of patients). Twenty percent of patients had no side effects. Nonhematologic toxicities included fatigue (20%), skin rash (9%), diarrhea (16%), increase in liver transaminases (14%) and bilirubin (11%), and nausea (11%). Dose-limiting toxicities of ataxia (n = 1), fatigue (n = 1), nausea (n = 1), and neutropenic fever (n = 2) occurred at tipifarnib doses above 1,200 mg/d. Sixteen of 61 (26%) evaluable patients responded (3 complete remissions and 13 hematologic improvements) with major platelet responses being most common (11 of 16 responders). There was no obvious dose-response relationship. Four of the 16 responders (25%; including a complete responder) were treated at the lowest dose level (100 mg twice daily). Only one responder had a Ras mutation. Giving tipifarnib resulted in potent inhibition of farnesyl transferase (usually more than 75%) in peripheral blood mononuclear cells regardless of dose. Partial farnesyl transferase inhibition persisted during the week off. CONCLUSIONS: Alternate-week tipifarnib is active and well tolerated in patients with MDS at doses up to and including 600 mg orally twice daily. The biological activity of tipifarnib is not dependent on dose.

JAK1 Genomic Alteration Associated With Exceptional Response to Siltuximab in Cutaneous Castleman Disease.

Importance: Castleman disease (CD) is an ultrarare, interleukin-6 (IL-6)-driven lymphoproliferative disorder whose underlying molecular alterations are unknown. Siltuximab (anti-IL-6 antibody) is approved for treatment of this disease. To our knowledge, genomic sequencing of CD has not been reported. Objective: To investigate and identify molecular aberration(s) that help explain the exceptional response to siltuximab in a patient with cutaneous CD. Design, Setting, and Participants: This case study examines data from comprehensive genomic profiling (using targeted next-generation sequencing) of tissue from a patient with cutaneous CD who demonstrated an exceptional response to siltuximab treated at a National Cancer Institute-designated Comprehensive Cancer Center. Interventions: Intravenous siltuximab 12 mg/kg every 3 weeks. Tissue from the patient was interrogated by next-generation sequencing (405 genes). Serum was evaluated for IL-6 levels by enzyme-linked immunoassay. Main Outcomes and Measures: Identification of pretreatment serum IL-6 levels and somatic variants that may explain the exceptional response to siltuximab in this patient with cutaneous CD. Results: Patient pretreatment serum IL-6 levels were normal. Treatment with siltuximab resulted in a complete response lasting 7 years. Next-generation sequencing demonstrated a JAK1V310I missense mutation. Janus Kinase 1 (JAK1) is a crucial signaling component of the IL-6/IL-6 receptor/gp130 machinery. JAK1V310I may induce a conformation change with functional activation effect leading to enhanced sensitivity to the IL-6 ligand. Conclusions and Relevance: Our observations suggest that a JAK1 alteration may explain the underlying biology of a patient's cutaneous CD, as well as the patient's exceptional response to siltuximab.

Sequential interleukin 3 and granulocyte-macrophage-colony stimulating factor therapy in patients with bone marrow failure with long-term follow-up of responses.

BACKGROUND: Interleukin-3 (IL-3) and granulocyte-macrophage-colony stimulating factor (GM-CSF) have synergistic, hematopoietic growth-promoting activity in preclinical studies. Because of the paucity of effective therapies for patients with chronic bone marrow failure states, the authors studied the biologic activity of sequential IL-3/GM-CSF in such patients. METHODS: IL-3 was given subcutaneously for 5 days (at escalating doses of 0.15 microg/kg, 0.3 microg/kg, 0.6 microg/kg, 1.2 microg/kg, 2.5 microg/kg, 5.0 microg/kg, 10.0 microg/kg, or 15.0 microg/kg per day), and GM-CSF for was given subcutaneously for 9 days (at a dose of 5 microg/kg per day; Phase I 3 + 3 design) followed by 14 days of rest (total, 2 courses), then maintenance therapy. RESULTS: The majority of 38 evaluable patients had aplastic anemia or myelodysplastic syndrome. Most patients (79%) had neutrophil responses. Ten patients (26%), all of whom were treated with IL-3 doses >/= 1.2 microg/kg per day, had platelet responses, with a median increase of 132 x 10(9)/L (range, 41-180 x 10(9)/L) over baseline in responders. Six patients (16%) had trilineage recovery, which could be durable (the longest ongoing at 6.5 years after therapy completion). The most common toxicities were low-grade fever, headache, and fatigue. The maximum tolerated doses were IL-3 at 10 microg/kg per day and GM-CSF at 5 microg/kg per day. CONCLUSIONS: Sequential IL-3/GM-CSF effectively raised blood counts in some patients with bone marrow failure at doses that were tolerated well. These results indicate that early-acting growth factors can induce durable, multilineage responses in a subset of individuals with bone marrow failure.