Masafumi Taniwaki

BACKGROUND: Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival. RESULTS: Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients. CONCLUSIONS: Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797.).

PURPOSE: CC chemokine receptor 4 (CCR4) is expressed by peripheral T-cell lymphomas (PTCLs) and is associated with poor outcomes. Mogamulizumab (KW-0761) is a defucosylated humanized anti-CCR4 antibody engineered to exert potent antibody-dependent cellular cytotoxicity. This multicenter phase II study evaluated the efficacy and safety of mogamulizumab in patients with relapsed PTCL and cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: Mogamulizumab (1.0 mg/kg) was administered intravenously once per week for 8 weeks to patients with relapsed CCR4-positive PTCL or CTCL. The primary end point was the overall response rate, and the secondary end points included safety, progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 38 patients were enrolled, and 37 patients received mogamulizumab. Objective responses were noted for 13 of 37 patients (35%; 95% CI, 20% to 53%), including five patients (14%) with complete response. The median PFS was 3.0 months (95% CI, 1.6 to 4.9 months), and the median OS was not calculated. The mean maximum and trough mogamulizumab concentrations (± standard deviation) after the eighth infusion were 45.9 ± 9.3 and 29.0 ± 13.3 μg/mL, respectively. The most common adverse events were hematologic events, pyrexia, and skin disorders, all of which were reversible and manageable. CONCLUSION: Mogamulizumab exhibited clinically meaningful antitumor activity in patients with relapsed PTCL and CTCL, with an acceptable toxicity profile. Further investigation of mogamulizumab for treatment of T-cell lymphoma is warranted.

There are a limited number of reports of acute myeloid leukemia (AML) with t(10;11)(q22;q23). We showed that the MLL gene on 11q23 was fused to the LCX (leukemia-associated protein with a CXXC domain) gene on 10q22 in a de novoadult AML-M2 with trilineage dysplasia having t(10;11)(q22;q23). LCX consisted of at least 12 exons and was predicted to encode a 2136-amino-acid protein with an estimated molecular mass of 235.3 kDa. The LCX protein had a zinc-binding CXXC domain that MLL also contains within a methyltransferase domain, three nuclear localization signals, an alpha-helical coiled-coil region, and two homologous regions to CG2083 proteins of Drosophila melanogaster. We found approximately 12-, 9.5-, and 7.5-kb transcripts of LCX. Expression of the 7.5-kb transcript was detected in fetal heart, lung, and brain, and in adult skeletal muscle, thymus, and ovary. Expression of the 9.5-kb transcript was detected in fetal lung and brain and in adult ovary. Expression of the 12-kb transcript was detected in fetal heart and brain and in adult thymus and ovary. LCX was expressed in 8 of 22 leukemic cell lines, but not in EBV-induced normal B-cell lines. The MLL-LCX fusion protein lacked a CXXC domain of LCX, but retained an alpha-helical coiled-coil region at the COOH terminus, similar to MLL-SEPTING, MLL-CDCREL1, MLL-AF1p/Eps15, and MLL-AF6, which suggests that these fusion proteins are involved in the pathogenesis of 11q23-associated leukemia through similar mechanisms.