Human T cell leukemia virus reactivation with progression of adult T-cell leukemia-lymphoma

Abstract

Background: Human T-cell leukemia virus-associated adult T-cell leukemia-lymphoma (ATLL) has a very poor prognosis, despite trials of a variety of different treatment regimens. Virus expression has been reported to be limited or absent when ATLL is diagnosed, and this has suggested that secondary genetic or epigenetic changes are important in disease pathogenesis.

Methods and findings: We prospectively investigated combination chemotherapy followed by antiretroviral therapy for this disorder. Nineteen patients were prospectively enrolled between 2002 and 2006 at five medical centers in a phase II clinical trial of infusional chemotherapy with etoposide, doxorubicin, and vincristine, daily prednisone, and bolus cyclophosphamide (EPOCH) given for two to six cycles until maximal clinical response, and followed by antiviral therapy with daily zidovudine, lamivudine, and alpha interferon-2a for up to one year. Seven patients were on study for less than one month due to progressive disease or chemotherapy toxicity. Eleven patients achieved an objective response with median duration of response of thirteen months, and two complete remissions. During chemotherapy induction, viral RNA expression increased (median 190-fold), and virus replication occurred, coincident with development of disease progression.

Conclusions: EPOCH chemotherapy followed by antiretroviral therapy is an active therapeutic regimen for adult T-cell leukemia-lymphoma, but viral reactivation during induction chemotherapy may contribute to treatment failure. Alternative therapies are sorely needed in this disease that simultaneously prevent virus expression, and are cytocidal for malignant cells.

Trial registration: ClinicalTrials.gov NCT00041327.

Figure 1. Treatment Schema.

Subjects were treated with EPOCH chemotherapy for cycles 1 and 2 and then responses assessed. Patients with complete remissions (CR) or partial remissions (PR), received cycles 3 and 4, whereas patients with stable disease received antiviral therapy. Similar treatment assignments were applicable after cycles 3 and 4, with patients in CR or PR receiving cycles 5 and 6 EPOCH therapy, except for one patient who was in CR after cycles and 1 and 2, and remained in CR after cycles 3 and 4, and one patient in PR after cycles 1 and 2 and achieved “best response”, i.e. PR after cycles 3 and 4, who then received antiviral therapy. Subjects with stable disease, PR, or CR after 6 cycles of therapy then received antiviral therapy. Subjects with disease progression or toxicity during any stage of treatment, were taken off the treatment protocol, and were eligible to receive non-protocol therapies.

Figure 2. Viral RNA Changes with Polymerase Changes.

The figure shows initial viral RNA and DNA values for subjects (8, 9, 12, and 15) and subsequent values for each subject on the same line (at respective times 166, 191, 284 and 47 d from treatment initiation), obtained at the time that a change in the polymerase coding capacity was detected (see Supplementary Table S1). For two additional subjects (13 and 14), viral RNA values are available at the initial and subsequent time points, but no changes in polymerase coding capacity were detected. The logarithmic mean, 95% confidence intervals, and results of a two-tailed paired sample t test are presented for comparisons of the values at these time points. All of the viral RNA and DNA values and polymerase changes are provided in Supplementary Table S1.

Figure 3. Duration of response and disease-free survival of all patients on the study.