Alemtuzumab and CHOP Chemotherapy for the Treatment of Aggressive Histology Peripheral T Cell Lymphomas: A Multi-Center Phase I Study

作者：Buckstein Rena^*; Fraser Graeme; Cheung Matthew; Kukreti Vishal; Kuruvilla John; Imrie Kevin; Piliotis Eugenia; Pond Gregory; Windsor Jolanta; Ghorab Zeina; Shuoprasad Kevin; Turner Ruth; Meyer Ralph M; Pritchard Kathy; Walker Scott; Levine Mark; Crump Michael

来源：Clinical Lymphoma Myeloma & Leukemia, 2016, 16(1): 18-28.

DOI：10.1016/j.clml.2015.11.008

• CD52(+)
• Immune reconstitution
• Pharmacokinetics
• Phase 1
• PTL

We conducted a phase I study of alemtuzumab combined with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) chemotherapy in peripheral T cell lymphomas. The objectives were to establish the safest dose with the highest antibody levels and evaluate the effects on the immune system. Twenty patients were enrolled across 4 dose levels. Maximally tolerated dose was not reached with alemtuzumab 60 mg subcutaneously every 3 weeks and antibody levels were highest at this dose level. The results of this study inform other investigators about possibilities for optimal dosing in T cell lymphomas when used in combination with chemotherapy and highlight the high levels of baseline and post-treatment immune suppression observed in this patient group.
Background: Alemtuzumab has single-agent activity in relapsed peripheral T cell lymphoma (PTL), but the optimal dose and/or schedule in combination with chemotherapy for first-line use is unknown. The primary objectives were to establish the maximally tolerated dose and pharmacokinetics (PK) of alemtuzumab combined in this way. Patients and Methods: Adult patients with untreated CD52-positive (CD52(+)) PTL were enrolled in a phase I trial. Alemtuzumab was given subcutaneously in escalating doses and/or schedules in combination with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) using a 3+3 design. Trough PK of alemtuzumab were measured on day 1 of each 21-day cycle and B and T cell subsets were serially measured. Results: Twenty patients were enrolled across 4 dose levels. Dose-limiting toxicities necessitated expansion at 10 mg weekly (fatal tuberculosis reactivation) and 60 mg every 3 weeks (grade 4 thrombocytopenia) dose levels. Maximally tolerated dose was not reached. Ten patients developed asymptomatic cytomegalovirus reactivations at a median of 39 days (range, 4-99 days). Two patients developed fungal pneumonias. The overall and complete response rates were 68% and 37%, respectively. Highest day 1 alemtuzumab trough levels were achieved at 60 mg (1973 ng/mL), but with significant inter- and intradose variability. Lympliopenia at baseline was common and T cell recovery was significantly delayed. Conclusion: With monitoring and prophylaxis, alemtuzumab 60 mg combined with CHOP showed activity in CD52(+) PTL and achieved the highest drug levels.

• 出版日期2016-1