ATLL is an aggressive malignancy caused by HTLV-1. ATLL cannot be cured by conventional
chemotherapy thus urging the development of new therapeutic strategies. HDAC inhibitors are
broadly active anti-neoplastic agents that can be exploited for the treatment of ATLL as it
has been demonstrated that pharmacologic inhibition of HDACs promotes acetylation of
nucleosomes and chromatin unwinding at the HTLV-1 5' LTR, which results in transcription of
the viral genome.
Belinostat, a potent pan HDAC inhibitor, causes H3 subunit acetylation and induces HTLV-1
Tax expression in cultured ATLL cells resulting in dose-dependent apoptosis. Further,
Belinostat blocks constitutive expression of NF-κB, and increases apoptosis in the presence
of AZT.
Inclusion Criteria:
1. Histologically or cytologically documented adult T-cell leukemia/lymphoma (ATLL) with
the following characteristics:
- any stage of disease,
- aggressive leukemic types (unfavorable chronic or acute)
- initial absolute lymphocytosis ≥ 4.0 cells/mm3 upon initial disease
presentation, and
- documented presence of ATLL cells in peripheral blood by either morphology,
histology, flow cytometry or gene rearrangement studies
2. One of the following: Received prior zidovudine/interferon -alfa therapy (AZT/IFNα)
therapy for ≥2 weeks and achieved at least partial hematological response defined as
> 50% reduction in absolute lymphocyte count) without evidence of new disease lesions
or disease progression (defined as 50% increase in measurable disease from nadir as
in section 14.5 if imaging is performed) at the time of enrollment OR, received
chemotherapy for ≥ 2 weeks duration, followed by at least a partial hematologic
response ((defined as > 50% reduction in absolute lymphocyte count), and without
evidence of new disease lesions or disease progression (defined as 50% increase in
absolute lymphocyte count or measurable disease from nadir as specified in section
14.5 if imaging is performed) at the time of enrollment.
3. Presence of residual ATLL based on T-cell clonality in peripheral blood at the time
of enrollment
4. Documented Human T-cell lymphotropic virus type 1 (HTLV-1) infection: Documentation
may be serologic assay (ELISA) confirmed by Western blot or polymerase chain reaction
(PCR).
5. Measurable or evaluable disease.
6. 18 years of age or older.
7. Karnofsky performance status (KPS) ≥ 50% or Eastern Cooperative Oncology Group (ECOG)
performance status ≤ 2
8. Patients must have adequate end organ and bone marrow function as defined below:
- absolute neutrophil count (ANC)≥ 1,000 cells/mm3 [Exception: Unless cytopenias
are secondary to ATLL]
- platelets (PLT) ≥ 50,000 cells/mm3 [Exception: Unless cytopenias are secondary
to ATLL]
- Adequate hepatic function:
- transaminase ≤ 2.5 the institutional upper limit of normal (ULN),
- total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN),
[Exception: Unless secondary to hepatic infiltration with lymphoma. If the
elevated bilirubin is felt to be secondary to Indinavir or Atazavinir
therapy (or anti-HIV medications), patients will be allowed to enroll.]
- Creatinine clearance (CrCl) ≥ 40 mL/min, [Exception: Unless secondary to renal
involvement by lymphoma.]
9. Patients who are human immunodeficiency virus positive (HIV+) are also eligible.
10. Females of childbearing potential (CBP) must have a negative serum pregnancy test
within one week of enrollment. Women should avoid pregnancy while receiving study
treatment. Males and females must agree to use adequate birth control during
participation in this trial and for 3 months after completing therapy.
11. Patients receiving erythropoietin or Granulocyte-colony stimulating factor (G-CSF)
from baseline are eligible.
12. Ability to understand and willingness to sign a written informed consent document.
Exclusion Criteria:
1. Patients with progressive disease (after previous chemotherapy or AZT/IFNα) at the
time of enrollment.
2. Patients with lymphomatous, chronic leukemia with favorable features, or smoldering
type ATLL (for definition of ATLL subtypes see Appendix H).
3. Patients receiving any other investigational agents within 14 days prior to
initiation of study therapy. (Exception: Patients actively receiving IFN-alfa-2b or
PEG-IFN-alfa-2b are permitted).
4. Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure (CHF), unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that are likely in the
judgment of the Investigator(s) to interfere or limit compliance with study
requirements/treatment.
5. Pregnant or breast-feeding women.
6. Known hypersensitivity to histone deacetylases (HDACs), zidovudine, belinostat or any
component of the formulation(s).
7. Autoimmune or viral hepatitis or decompensated liver disease unless due to lymphoma.
8. Concurrent active malignancies, with the exception of in situ carcinoma of the
cervix, non-metastatic, non-melanomatous skin cancer, or Kaposi's sarcoma not
requiring systemic chemotherapy.
9. New York Heart Association (NYHA) Class 3 or 4 heart disease as per Appendix D.
10. Ejection fraction < 50%
11. Psychological, familial, sociological or geographical conditions likely in the
judgment of the Investigator(s) to interfere or limit compliance with study
requirements/treatment.
