Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial.

Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study ( NCT02561988 ) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30-400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.

Morphoproteomic expression of H-ras (p21ras) correlates with serum monoclonal immunoglobulin reduction in multiple myeloma patients following pamidronate treatment.

Bisphosphonates have been used to treat lytic lesions of multiple myeloma because of their inhibitory effects on osteoclasts. However, their effects on myeloma cells, per se, are not known to be correlated with specific markers. The goal of this study was to assess molecular concomitants of myeloma that might serve as markers for predicting the pharmacologic impact of bisphosphonates on malignant plasma cells. We tested the correlation of serum monoclonal immunoglobulin (Ig) level (IgG and IgA classes) with therapies utilizing two aminobisphosphonates, pamidronate (Aredia) and/or zoledronate (Zometa), in 19 patients with multiple myeloma. Myeloma cells from bone marrow biopsies were immunohistochemically stained for H-ras (p21 ras), N-ras, and the alpha subunit common to farnesyl and geranylgeranyl transferase (FTalpha/GGT alpha). Elevated expression level of H-ras in myeloma cells, rather than N-ras or FTalpha/GGTalpha, was significantly associated with a decrease of serum monoclonal Ig level following pamidronate treatment. The data suggest that pamidronate may have a direct inhibitory effect on the proliferation of myeloma cells, thus causing reduction in serum monoclonal Ig level. H-ras expression in myeloma cells may prove to be valuable in predicting the therapeutic effects of pamidronate.

Plasmablastic lymphoma of the cervical lymph nodes in a human immunodeficiency virus-negative patient: a case report and review of the literature.

We report a case of plasmablastic lymphoma presenting in cervical lymph nodes in an 82-year-old, human immunodeficiency virus-negative man. Cytologic and histologic examinations demonstrated a large cell lymphoma with plasmacytic differentiation. The tumor cells were positive for CD138, CD38, epithelial membrane antigen, CD30, and lysozyme, but lacked expression of leukocyte common antigen, T-cell, and B-cell markers. Abundant Epstein-Barr virus-encoded RNA transcripts were identified by in situ hybridization. A monoclonal rearrangement of kappa-light- chain gene was demonstrated. The cytologic, histologic, immunohistochemical, and molecular features of plasmablastic lymphoma are reviewed. The potential diagnostic pitfalls and differential diagnoses, especially in a fine-needle aspiration specimen, are addressed.