Adult T-cell leukemia (ATL) is and aggressive characterized by the presence of
CD4/CD25-expressing T cells (interleukin-2 [IL-2]R expressing) in the peripheral blood and
in lymphoid and other tissues. Denileukin diftitox (Ontak(Registered Trademark)) is a
genetically engineered fusion protein that targets IL-2-expressing malignancies. Denileukin
diftitox interacts with the IL-2R on the cell surface, is internalized via endocytosis, and
inhibits cellular protein synthesis, resulting in cell death within hours to days. The
objectives of this study are to determine the clinical response to Denileukin deftitox of
patients with ATL and the safety of Denileukin deftitox in those patients.
Eligible participants must be 18 years of age or older with chronic, lymphomatous and acute
forms of ATL, and must be infected with human T-cell lymphotropic virus type I (HTLV1).
Patients will be treated with 9 mcg/kg/d of Denileukin difitox intravenously for 5 days
every 2 weeks. Tumor response will be evaluated after two cycles of treatment. Stable or
responding patients will continue treatment for a total of 12 months, with evaluations every
four cycles of treatment. Patients will be treated for two cycles beyond a complete
remission. The trial uses an optimal two-stage design targeting for a true response
proportion of more than 30 percent. Nine patients will be treated initially, with expansion
to 29 patients if a response is seen in 1 of the initial 9 patients treated. Treatment will
be discontinued if a patient experiences serious side effects.
A potential benefit is that a patient may undergo partial or complete remission. The
research may not directly benefit participants, but the results may aid in the treatment of
Adult T-Cell Leukemia is a lymphoproliferative disorder characterized by the presence of
CD4/CD25 expressing T cells (IL-2R expressing) in the peripheral blood, in lymphoid and
Denileukin diftitox is a genetically engineered fusion protein combining the enzymatically
active domains of diphtheria toxin (DT) and the full length sequence of interleukin-2 (IL-2)
that targets IL-2 expressing malignancies.
Denileukin diftitox interacts with the IL-2 R on the cell surface, is internalized via
endocytosis, and inhibits cellular protein synthesis resulting in cell death within hours to
Determine the clinical response to Denileukin diftitox (Ontak) of patients with ATL.
Define the safety of Denileukin diftitox in patients who have ATL.
Patients with chronic, lymphomatous and acute forms of ATL.
Patients must be HTLV1 positive.
Patients will be treated with 9mcg/kg/d of Denileukin diftitox for five days, on an every
two week schedule.
Tumor response will be evaluated after two cycles of treatment. Stable or responding
patients will continue treatment with evaluations every four cycles of treatment. Patients
will be treated for two cycles beyond a complete remission.
The trial uses an optimal 2 stage design targeting for a true response proportion greater
than 30%. Nine patients will be treated initially with expansion to 29 patients if a
response is seen in one of the initial nine patients treated. If no response is seen at the
9 mcg/kg/d dose an additional 9 patients will be treated at a dose of 18 mcg/kg/d with
expansion to 29 patients at this dose level if a response is seen. A stopping rule for
excessive toxicity will be incorporated.
- INCLUSION CRITERIA:
Patients must have serum antibodies directed to HTLV-I.
All patients must have a histologically confirmed diagnosis of adult T-cell
leukemia/lymphoma and more than 10% of the malignant cells must express CD25.
All stages of Tac-expressing adult T cell leukemia except smoldering are eligible:
patients with chronic, lymphomatous or acute ATL are eligible. (See appendix 2 for
characteristics of patients with the various stages of ATL)
Patients must have measurable disease. All patients with greater than 10% abnormal (i.e.
TAC homogenous strongly expressing) PBMC in the peripheral blood will be deemed to have
The patient must have a granulocyte count of at least 1000/mm(3) and a platelet count of
greater than or equal to 50,000/mm(3).
Patients must have a creatinine of less than 2.0 mg/dl.
Omission of cytotoxic chemotherapy for ATL for 3 weeks prior to entry into the trial is
required. However, patients receiving corticosteroids will be eligible.
Patients must have a life expectancy of greater than 2 months.
Eligible patients must be greater than or equal to 18 years old. There is no upper age
Patients must have SGOT and SGPT value less than or equal to 2.5 times the upper limit of
normal and bilirubin less than or equal to 3.0/dl. If a liver function test is judged to
be elevated due to the underlying ATL, this parameter will be considered an unevaluable
parameter for toxicity determinations.
Patients must have a serum albumin greater than or equal to 2.5 g/dl
Patients must be able to understand and sign an Informed Consent form.
All patients must use adequate contraception during participation in this trial and for
three months after completing therapy.
Patients with symptomatic leukemic meningitis will be excluded. However, patients that
have both ATL and another HTLV-I-associated disease, tropical spastic paraparesis (TSP),
will be included.
Pregnant and nursing patients are not eligible for the study.
HIV positive patients are excluded from the study. Denileukin diftitox may produce a
different pattern of toxicities in immunocompromised individuals.
Patients with Smoldering ATL are excluded.
Patients with serious intercurrent illnesses, past history of a myocardial infarction
within 6 months or severe coronary artery disease
Patients who previously received Denileukin diftitox are ineligible.