Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy.

In this open-label, intra-patient phase I/II trial, bortezomib was replaced with carfilzomib (escalated from 20 to 45 mg/m(2) on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle) for multiple myeloma (MM) patients who progressed while on or within 12 weeks of receiving a bortezomib-containing combination regimen. Study objectives included determination of the maximum tolerated dose (MTD), overall response rate (ORR), clinical benefit rate (CBR), time to progression, time to response, duration of response, progression-free survival and overall survival (OS). Of 38 registered patients, 37 were treated and evaluable for efficacy and safety. Thirty-one carfilzomib-based regimens using 14 different drug combinations were tested. One regimen (carfilzomib (45 mg/m(2)), ascorbic acid (1000 mg) and cyclophosphamide (2.2 mg/kg)) reached MTD. ORR and CBR were 43.2 and 62.2%, respectively. Median progression-free survival, time to progression and OS were 8.3, 9.9 and 15.8 months, respectively. Hematologic adverse events (AEs; ⩾grade 3) included lymphopenia (35.1%), thrombocytopenia (24.3%), anemia (10.8%) and neutropenia (10.8%). Nonhematologic AEs (⩾grade 3) included fever (5.4%) and hypokalemia (5.4%). These results demonstrate that replacing bortezomib with carfilzomib is safe and can be effective for MM patients failing bortezomib-containing combination regimens. This trial was registered at http://www.clinicaltrials.gov (#NCT01365559).

Tricyclic antidepressant agranulocytosis.

Severe neutropenia is an unusual complication of antidepressant therapy. We report a case of agranulocytosis due to clomipramine, and discuss principles of management.

Alternating combination chemotherapy using cisplatin-bleomycin with sequential methotrexate-5-FU plus leucovorin rescue in patients with head and neck cancer.

Thirty-two patients (only two had previously untreated disease) with squamous cell carcinoma of the head and neck were treated with alternating combination chemotherapy. The regimen consisted of cisplatin (50 mg/m2) and bleomycin (30 units) given iv on Days 1 and 2, alternated with 1 hour of sequential methotrexate (200 mg/m2) and 5-FU (600 mg/m2) given iv, plus oral leucovorin rescue on Day 22. The entire cycle was repeated every 5 weeks (less than or equal to five cycles). Objective tumor regression was obtained in 33% of the 30 evaluable patients, with 13% complete regression. The median duration of response was only 3 months. Evidence of response occurred within one cycle, and was maximal after two cycles. Toxicity was very mild. Alternating combination chemotherapy is not more effective than either combination chemotherapy alone.