Achievement of Complete Hematological Remission and Reversal of High HTLV-1 Viral Loads with Anti CCR-4 Monoclonal Antibody Administration in Afro Caribbean Patients with Relapsed Chronic Adult T Cell Leukaemia (ATLL)

Introduction

The management of heavily pre-treated patients with relapsed ATLL is challenging. These patients display chemo-refractory disease with limited therapeutic options. The Kyowa Hakko Kirin protocol 0761-009 is a randomized controlled trial of anti-CCR4 monoclonal antibody therapy (mogamulizumab) compared with physician choice of salvage chemotherapy in relapsed ATLL. ATLL arises in HTLV-1 infected patients with high pre-morbid HTLV-1 proviral loads (>4–10 HTLV-1 DNA copies/ml)¹.

Methods

Three patients, female, age 38 - 72 years and of Afro Caribbean origin, with relapsed chronic ATLL, have been recruited to 0761-009 in London. All patients had received two or more lines of therapy: #1 zidovudine (ZDV)/Interferon-a (IFN), anti-CD25/bortezomib; #2 ZDV/INF, anti-CD25/bortezomib, etoposide, Gemcitabine/Oxaloplatin; #3 sodium valproate, ZDV/IFN, etoposide. Lymphocyte counts at study entry were 7.8 - 33.5 x 10⁹/L with high HTLV-1 proviral loads (range 25.4 - 122.4 HTLV-1 DNA copies/100 PBMC). Anti-CCR4 mAb was administered at a dose of 1mg/kg over 1 hour, weekly for 4 weeks and every 2 weeks thereafter. Data were censored 17/06/2014.

Results

All three patients achieved complete hematological remission (CR) after 1 – 2 infusions. Patient #1 remains on treatment and in CR day 397. Patient #2 received 3 treatment cycles with normalization of lymphocyte count and complete resolution of extensive cutaneous lesions (baseline SWAT= 93.6) but treatment was discontinued after 3 cycles due to, now resolved, drug toxicity. Patient #3 remains on treatment and in CR at day 139. In each case HTLV proviral load fell to 0.02% < 0.7% and have remained <1% for the duration of therapy.

Conclusions

Although a small case series these data illustrate the efficacy of anti-CCR4 mAb in ATLL, particularly in the chronic form, despite prior treatment failure and support the data observed in the Japanese cohort where CR was achieved in patients with blood compartmental disease, particularly chronic ATLL². However, the extent of reduction in HTLV-1 proviral load with anti-CCR4 was not observed previously in these patients (or others who achieved CR with zidovudine/interferon the first line treatment of chronic ATLL). The reduction in HTLV-1 proviral burden to <1% suggests not only clearance of circulating HTLV-1 infected malignant clones but additional depletion of HTLV-1 infected non-malignant clones. This will be confirmed by unique integration site analysis.

Reference List

(1) Hodson A, Laydon D, Bain BJ, Fields P, Taylor GP. Pre-morbid HTLV-1 proviral load, rather than percentage of abnormal lymphocytes, is associated with an increased risk of aggressive ATLL. Haematologica2013; 98(3):385-388.

(2) Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol 2012; 30(8):837-842.