Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study

Abstract

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

Keywords: CCR4; adult T-cell leukaemia-lymphoma; antibody therapy; mogamulizumab; randomized phase II study.

Figure 1

Treatment protocol. The mLSG15 protocol consists of three chemotherapeutic regimens, namely VCAP, AMP and VECP. Subjects assigned to the mLSG15‐plus‐mogamulizumab arm received up to eight infusions of mogamulizumab during four cycles of mLSG15. Cytarabine, methotrexate and prednisolone were intrathecally injected before initiation of VCAP administration in cycles 2 and 4. VCAP: vincristine, cyclophosphamide, doxorubicin, and prednisolone; AMP: doxorubicin, ranimustine, and prednisolone; VECP: vindesine, etoposide, carboplatin, and prednisolone; IV, intravenous; PO, per os (oral administration); IT, intrathecal; VCR, vincristine; CPA, cyclophosphamide; ADM, doxorubicin; PSL, prednisolone; MCNU, ranimustine; VDS, vindesine; ETP, etoposide; CBDCA, carboplatin; Ara‐C, cytarabine; MTX, methotrexate. *Before cycles 2 and 4 (Days −2 to −1). ^†After VCAP in Cycle 1 (Days 2 to 5). ^‡Preceding VECP in Cycles 1–4 (Days 12 to 14). ^§Preceding VCAP in Cycles 2–4 (Days −3 to −1).

Figure 2

CONSORT diagram. Patients with newly diagnosed CC chemokine receptor 4 ‐positive aggressive adult T‐cell leukaemia‐lymphoma were assigned in a 1:1 ratio to receive treatment with mLSG15 plus mogamulizumab or mLSG15 alone. One patient assigned to the mLSG15 arm was withdrawn from the study, owing to the patient's treatment having to be deferred due to abnormal laboratory values that met the protocol criteria, and the patient was unable to wait for the protocol treatment due to deterioration of their general condition.

Figure 3

Progression‐free survival and overall survival. (A) Kaplan–Meier curve of estimated progression‐free survival (median, 8∙5 months and 6∙3 months in the mLSG15‐plus‐mogamulizumab and mLSG15 arms, respectively). (B) Kaplan–Meier curve of estimated overall survival (median, not achieved in either arm). The median follow‐up periods in the mLSG15‐plus‐mogamulizumab and mLSG15 arms were 413 days (range, 63–764 days) and 502 days (range, 62–794 days), respectively.

Figure 4

T‐cell subset analysis. Blood samples were taken (i) immediately before the initiation of treatment, (ii) immediately before VCAP therapy for cycle three, and (iii) 28 days after VECP therapy for cycle four. The numbers of CD4/CD25/CC chemokine receptor 4 (CCR4)‐positive cells (A) and CD4/CD25/FOXP3‐positive cells (B) are shown as box and whisker plots indicating the minimum, lower, median, upper quartile, and maximum values. The number of samples used for analysis at each point is indicated below the graph. The differences of each point [(ii) & (iii)] between the mLSG15‐plus‐mogamulizumab and mLSG15 arms are indicated as p‐values (Wilcoxon signed‐rank test) below the graphs. CCR4 was detected by using a monoclonal antibody (clone 1G1), with its binding to CCR4 being unaffected by the presence of mogamulizumab. VCAP: vincristine, cyclophosphamide, doxorubicin, and prednisolone; VECP: vindesine, etoposide, carboplatin, and prednisolone.