Dose-adjusted EPOCH chemotherapy with bortezomib and raltegravir for human T-cell leukemia virus-associated adult T-cell leukemia lymphoma
Authors: L Ratner, D Rauch, H Abel, B Caruso, A Noy, S K Barta, S Parekh, J C Ramos, R Ambinder, A Phillips, J Harding, H H Baydoun, X Cheng, S Jacobson
Journal: Blood Cancer Journal (2016)

Acute' and 'lymphoma' subtypes are the most common forms of human T-cell leukemia virus (HTLV)-associated adult T-cell leukemia lymphoma (ATLL), with median survivals of only 8-12 months. 1 Treatment with interferon, zidovudine, arsenic, mogamulizumab, multiagent chemotherapy and allogeneic stem cell transplants yielded positive results, but most individuals with ATLL succumb to their disease.In our previous multicenter trial of 19 subjects, using dose-adjusted infusional chemotherapy (DA-EPOCH) followed by maintenance interferon and zidovudine, there were two complete remissions, four subjects with early severe toxicity and an overall response rate of 58%. 2 Half of the evaluable subjects manifested significantly increased viral gene expression with disease progression and new integration sites were identified in most subjects.The current study was designed to test the tolerability and efficacy of a regimen with: (1) decreased dose intensity during the initial cycles of therapy, (2) addition of bortezomib to block NFκB activation and (3) incorporate the antiviral raltegravir (previously shown to block HTLV-1 replication) (Supplementary Protocol File). 3 In addition, we assessed viral and cellular parameters of response.Our phase 1/2 trial enrolled consenting subjects with untreated (n = 14) or previously treated (n = 4) acute (n = 6) or lymphoma ATLL (n = 12), adequate hematologic, renal and hepatic function, and Karnofsky performance score 450 (Figure 1a).Subjects were enrolled at six centers from 2011 to 2013 and were treated with DA-EPOCH with intravenous bortezomib (d1 and 4, 1.0 mg/m 2 ), and daily raltegravir (400 mg bid) was initiated with cycle 2 therapy.Patients received up to six 21-day cycles of treatment unless they had evidence of disease progression or dose-limiting toxicity.Disease staging and viral studies were performed at baseline, just before cycles 3 and 5, and after completion of treatment.Viral DNA load, tax and hbz RNA levels were quantified by digital droplet polymerase chain reaction. 4Viral sequences were determined by Illumina HiSeq-2500 (San Diego, CA, USA).The sample size was based on a two-stage Simon's design for a response rate of at least 30%, with a significance level of 10% and a power of 80%.The Kaplan-Meier method was used to determine duration of response and survival.Correlations of viral parameters with response were assessed by two-sided Student's t-tests (see Supplementary Methods).The mean age of subjects was 52 years and all but three US subjects were born in the Caribbean (Figure 1a).At baseline, all but one subject had stage IV disease, nine had hypercalcemia, 16 had elevated lactate dehydrogenase levels, one had thrombocytopenia and six patients had hypoalbuminemia.The mean absolute lymphocyte count was 38 900/mm 3 for acute ATLL patients and 1610/mm 3 for those with lymphoma.Patients received on average, 4.5 cycles of DA-EPOCH-bortezomib, with raltegravir.Complications of therapy were similar to