The Combination of AZT/Interferon-α Therapy with the HDAC Inhibitor Valproic Acid for the Treatment of Adult T-Cell Leukemia/Lymphoma

Abstract Abstract 4877 Adult T-cell leukemia/lymphoma (ATLL) carries a dismal long-term prognosis and is generally chemotherapy resistant. We and other groups have demonstrated that the combination of AZT and interferon (IFN) alpha can effectively suppress ATLL long-term; however, these drugs fail to eradicate malignant ATLL clones as patients ultimately progress. We recently tested our hypothesis that histone deacelytase (HDAC) inhibitors would re-activate latent HTLV-I in ATLL cells harboring intact provirus thus helping to eliminate residual disease after cytoreductive treatment. Histone acetylation can result in HTLV-I promoter activation and viral transcription. We found that HDAC inhibitors, including the inexpensive drug valproic acid (VPA), reactivated HTLV-I expression in ATLL cells and caused apoptosis. Based on these concepts, we recently completed a pilot trial for ATLL using AZT/IFN and adding VPA during the maintenance treatment phase. Thirteen subjects with aggressive acute-type ATLL were enrolled in the study, including 11 treatment-naïve patients. The estimated 12-month overall survival rate was 46%. In 12 evaluable subjects (10 naïve) the complete response (CR) rate was 33% and overall response 42% (5 patients). A total of eight subjects (66%) had a hematologic response, including 5 complete hematologic responses (38%). VPA was added at the beginning of month 3 during AZT/IFN maintenance in 3 subjects. One subject achieved a molecular remission and clearance of ATLL after adding VPA as measured by serial multiplex PCR studies. This subject remains disease-free 2.5 years later. Our findings were surprising, as previous studies performed on long-term responders treated with AZT/IFN alone had not demonstrated any molecular remissions. Our data suggest that VPA could potentially eradicate ATLL clones in vivo. The dual anti-neoplastic and viral inducing roles of HDAC inhibitors can be exploited in the treatment of ATLL. This exciting approach may help advance the cure for this disease. We will present our updated interim clinical trial results at the conference. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

The Combination of Belinostat with Zidovudine for Treatment of HTLV-I Related Adult T-Cell Leukemia-Lymphoma

Blood ◽

10.1182/blood.v126.23.1562.1562 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1562-1562

Author(s):

Ngoc Toomey ◽

Juan Carlos Ramos

Keyword(s):

T Cell ◽

Protein Expression ◽

Conflicts Of Interest ◽

Hdac Inhibitors ◽

Constitutive Expression ◽

Viral Gene ◽

Acute Type ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia

Abstract Adult T-cell leukemia-lymphoma (ATLL) is an aggressive malignancy with poor prognosis that is incurable by conventional drugs. Histone deacetylase (HDAC) inhibitors (HDIs) are broadly active anti-neoplastic agents that can be cautiously exploited in the treatment of ATLL. The HTLV-I provirus is clonally integrated in virtually all ATLL cells. The HTLV-I 5'LTR promoter is trans -activated by the viral protein Tax through binding of CREB and p300/CBP. Tax binding enhances p300/CBP histone acetyl transferase (HAT) activity resulting in histone acetylation, chromatin unwinding, and transcription of the viral genome. HAT activity is countered by HDACs, and also by the viral-encoded protein HTLV-I bZip factor (HBZ), which is transcribed from the negative proviral strand at the 3' end. The 5' LTR is often mutated or deleted in ATLL cells thus HBZ is the only viral gene consistently expressed in ATLL. We hypothesized that HDAC inhibitors, which can be potent anti-neoplastic drugs, would reactivate HTLV-I in ATLL tumors containing intact provirus, thus killing virus-infected cells and provoking an immune response in vivo. Supporting this notion, adding the old generation HDI valproic acid (VPA) to AZT/IFNa in one subject suffering from aggressive acute-type ATLL resulted in HTLV-I proviral load reduction, followed by a complete molecular and prolonged clinical remission that lasted several years. We recently tested other more potent HDIs on primary ATLL cells and low-passage cell lines, which are rare and difficult to establish. In general, HDIs induced dose-dependent Tax expression and apoptosis in ATLL cells. Belinostat, a pan HDI, caused H3 acetylation, blocked HBZ protein expression, and induced Tax protein expression in ATLL cells resulting in concomitant apoptosis. ATLL cells exhibit high constitutive expression of nuclear factor kappa B (NF-kB), which is known to be activated by Tax and to play a major role in HTLV-I mediated T-cell transformation and ATLL development. Paradoxically, while belinostat induced Tax, it also inhibited NF-kB nuclear activity resulting in apoptosis. Further, adding AZT to belinostat augmented ATLL cell death. By contrast, IFNα diminished apoptosis induced by belinostat in freshly isolated ATLL cells from some of our patients. Based on these preclinical data, we have developed a clinical trial using belinostat in combination with AZT as consolidation therapy for ATLL. Our primary goal using this approach is to eradicate residual ATLL cells and HTLV-I infected reservoirs that normally persist regardless of treatment. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Using HDAC Inhibitors to Eradicate Adult T-Cell Leukemia-Lymphoma

Blood ◽

10.1182/blood.v124.21.5492.5492 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5492-5492

Author(s):

Agustin Pimentel ◽

Isildinha Reis ◽

Ngoc Toomey ◽

Luis Diaz ◽

Phillip Ruiz ◽

...

Keyword(s):

Clinical Trial ◽

T Cell ◽

Pilot Trial ◽

Hdac Inhibitors ◽

Cytotoxic T Cell ◽

Molecular Response ◽

Dependent Manner ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia

Abstract Adult T-cell leukemia-lymphoma (ATLL) is an aggressive malignancy with a poor prognosis caused by HTLV-I, which is endemic in Japan, the Caribbean, and South America. ATLL cannot be cured with conventional chemotherapy thus urging the development of new therapeutic strategies. Histone deacetyalse (HDAC) inhibitors are broadly active anti-neoplastic agents, which have shown efficacy in T-cell lymphomas. At our institution we encounter a relatively high number of ATLL cases as compared to other regions in the U.S. We have conducted a pilot trial using AZT/interferon-α(IFNα) plus the HDAC inhibitor valproic acid (VPA) during maintenance therapy in acute (leukemia-type) ATLL. We hypothesized that VPA would reactivate HTLV-I leading to a cytotoxic T-cell immune response followed by reduction of residual blood circulating ATLL clones that normally persist during AZT/IFNα therapy despite its suppressive effects. Supporting this notion, the addition of VPA to AZT/IFNα resulted in reduction of HTLV-I proviral loads in treated patients and a sustained molecular response in one subject who is still alive >4.5 years later. More recently, we have tested newly available and more potent HDAC inhibitors using fresh primary leukemic ATLL cells and low-passage cell lines. Through HDAC inhibition, these agents reactivated HTLV-I Tax gene expression and induced apoptosis in a dose-dependent manner. Belinostat, which is currently FDA-approved for the treatment of relapsed or refractory peripheral T-cell lymphoma, augmented ATLL cell death when added to AZT/IFNα at nanomolar concentrations. Therefore, we have proposed a new pilot clinical trial using belinostat for the treatment of ATLL during post-induction therapy. The role of HDAC inhibitors in ATLL, pre-clinical laboratory studies involving these agents, and clinical trial design will be discussed at the meeting Disclosures Off Label Use: The use of HDAC inhibitors in adult T-cell Leukemia-lymphoma.

Download Full-text

The Combination of Arsenic Trioxide and Interferon-Alpha Eradicates Leukemia Initiating Cells in TAX-Driven Murine Adult T Cell Leukemia/Lymphoma.

Blood ◽

10.1182/blood.v114.22.2714.2714 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2714-2714

Author(s):

Ali Bazarbachi ◽

Hiba El Hajj ◽

Marwan El-Sabban ◽

Hideki Hasegawa ◽

Ghazi Zaatari ◽

...

Keyword(s):

T Cell ◽

Conflicts Of Interest ◽

Critical Role ◽

Proteasome Inhibition ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Term Outcome ◽

Long Term Outcome ◽

Adult T Cell Leukemia

Abstract Abstract 2714 Poster Board II-690 Adult T cell leukemia (ATL) is one of the rare human cancers initiated by a transforming retrovirus, HTLV-I. After many years of controversy, it is now accepted that the viral transactivator protein Tax plays a critical role in initiating the leukemic process, because Tax transgenics develop a disease with striking ATL features. Long-term prognosis of ATL patients remains extremely poor, but we recently reported that the combination of As2O3, interferon-a (IFN), and zidovudine yielded unprecedented response rates. Indeed, in 10 chronic ATL patients, a 100% response rate was observed, including 7 complete remissions (CR), 2 CR but with more than 5% circulating atypical lymphocytes, and one partial response. We demonstrate that the As2O3/IFN combination, previously shown to degrade Tax, cures Tax-driven murine ATLs. Unexpectedly, this combination immediately abrogates leukemia transplantation into secondary recipients, while the primary tumor continues to grow and only exhausts much later. Leukemia initiating cell (LIC) clearance is reversed by proteasome inhibition, demonstrating that LICs are addicted to continuous Tax expression. Most anticancer treatments fail to target LIC. These results establish that As2O3/IFN/zidovudine acts through Tax targeting and predict a favorable long-term outcome for responsive patients. Thus, oncogene degradation can selectively target LICs, explaining this very recent success of a similar regimen in patients. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

CD30 Expression Is Associated With Decreased Survival In Patients With Acute and Unfavorable Chronic Types Of Adult T-Cell Leukemia-Lymphoma

Blood ◽

10.1182/blood.v122.21.4312.4312 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4312-4312 ◽

Cited By ~ 2

Author(s):

German Campuzano-Zuluaga ◽

Agustin Pimentel ◽

Luis A Diaz ◽

Jennifer Rose Chapman-Fredricks ◽

Juan Carlos Ramos

Keyword(s):

T Cell ◽

Median Survival ◽

Conflicts Of Interest ◽

Statistical Tests ◽

Acute Type ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Risk Of Death ◽

Significant Difference

Abstract Background Adult T-cell leukemia-lymphoma (ATLL) is a rare malignancy caused by the human T-lymphotropic virus type-1 (HTLV-I) which has a dismal prognosis, urging development of new therapeutic strategies. ATLL is commonly encountered in Miami due to its proximity to the Caribbean, where HTLV-I is endemic. CD30, a well-known marker of activated T-cells that participates in regulating memory cells, has been reported to be positively expressed at variable frequencies in ATLL cells, with positive expression rates ranging from 21- 50% of cases. The variation in reported CD30 expression rates is likely due to the heterogeneous nature of this neoplasm and inclusion of different ATLL subtypes within previous study populations. We hypothesized that the CD30 expression in ATLL was likely to differ based on the subtype of ATLL. Additionally, because CD30 is a molecule involved in multiple cell regulation and activation functions, predominantly through the NFKB signaling pathway, we predicted that CD30 could be a potential marker for prognosis and disease behavior in ATLL. We have conducted this study to evaluate the association that CD30 expression may have with ATLL disease subtype and survival in our population. The availability of targeted therapy (anti-CD30-monomethyl-auristatin-E conjugate brentuximab vedotin) makes identification of the role of CD30 expression in ATLL an important one, particularly as clinical trials using these therapies are currently underway. Design We conducted a historic cohort study of CD30 expression in cases of ATLL including patients of any age and at initial diagnosis. Cases were retrieved from our clinical and pathology information systems (UM/JMH). CD30 expression was evaluated by either immunohistochemistry (IHC) using antihuman CD30 monoclonal mouse antibody, clone Ber-H2, (Dako, Carpinteria, CA; IR602, Dilution: 1:30) performed on formalin-fixed paraffin-embedded tissue sections or on cytospins prepared from CD4+-enriched peripheral blood leukemic specimens, using 30% expression as a cut-off positive value. We analyzed overall CD30 expression, CD30 expression by sub-type and survival outcome according to CD30 expression. Kaplan-Meier survival curves, log-rank test and Cox proportional hazards regression where used for survival analysis. An alpha value of 0.1 was used for all statistical tests. Results Sixty-eight ATLL cases (lymphomatous n= 31, acute n=33, unfavorable chronic n=3, smoldering n=1) met inclusion criteria, and had CD30 status and complete clinical data available. The overall proportion of CD30+ ATLLs was 22.1% (95% CI 13.8% – 30.3%). The frequency of CD30 expression for each group is as follows: lymphomatous: 25.8%, acute: 21.2%, unfavorable chronic: 0%, smoldering: 0%. There was no significant difference for CD30 expression between the combined acute/unfavorable chronic (A/UC) subgroup and the lymphomatous subgroup (proportion difference 6.4%; CI 90% -10.52% – 23.24%). Within the A/UC subgroup the median survival for CD30+ patients was 10.1 weeks compared to 33.7 weeks for CD30- patients (P=0.071). CD30 expression was associated with a higher risk of death in patients within the A/UC subgroup (hazard ratio [HR]: 2.6, 90% CI: 1.1 – 6.2) (Figure 1A). Within the lymphomatous subgroup the median survival for CD30+ patients was 63.1 weeks compared to 60.3 weeks for CD30- patients (P=0.260) and there no association of CD30 status with the risk of death in the lymphomatous subgroup (HR: 0.6, 90% CI: 0.2 – 1.3) (Figure 1B). Conclusions Our data show that 22.1% of ATLL is CD30+ and that expression is similar amongst aggressive ATLL subtypes. CD30 could be a marker of prognosis in cases of acute or unfavorable chronic ATLL. CD30+ cases of any subtype are potentially amenable to anti-CD30 therapy. Targeted anti-CD30 therapy may be especially useful in CD30+ acute type ATLL, which carry the worst prognosis. Given the sample size, these results must be validated in a larger cohort. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

THE EFFECT OF LONG-TERM MAINTENANCE CHEMOTHERAPY FOR AGGRESSIVE ADULT T CELL LEUKEMIA/LYMPHOMA

Hematological Oncology ◽

10.1002/hon.2439_163 ◽

2017 ◽

Vol 35 ◽

pp. 394-395

Author(s):

M. Tsukaguchi

Keyword(s):

T Cell ◽

T Cell Leukemia ◽

Maintenance Chemotherapy ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Term Maintenance

Download Full-text

Long-term study of indolent adult T-cell leukemia-lymphoma

Blood ◽

10.1182/blood-2009-09-242347 ◽

2010 ◽

Vol 115 (22) ◽

pp. 4337-4343 ◽

Cited By ~ 102

Author(s):

Yumi Takasaki ◽

Masako Iwanaga ◽

Yoshitaka Imaizumi ◽

Masayuki Tawara ◽

Tatsuro Joh ◽

...

Keyword(s):

T Cell ◽

Survival Curve ◽

Performance Status ◽

Survival Rates ◽

T Cell Leukemia ◽

Cell Leukemia ◽

High Concentration ◽

Adult T Cell Leukemia ◽

Long Term Study

Abstract The long-term prognosis of indolent adult T-cell leukemia-lymphoma (ATL) is not clearly elucidated. From 1974 to 2003, newly diagnosed indolent ATL in 90 patients (65 chronic type and 25 smoldering type) was analyzed. The median survival time was 4.1 years; 12 patients remained alive for more than 10 years, 44 progressed to acute ATL, and 63 patients died. The estimated 5-, 10-, and 15-year survival rates were 47.2%, 25.4%, and 14.1%, respectively, with no plateau in the survival curve. Although most patients were treated with watchful waiting, 12 patients were treated with chemotherapy. Kaplan-Meier analyses showed that advanced performance status (PS), neutrophilia, high concentration of lactate dehydrogenase, more than 3 extranodal lesions, more than 4 total involved lesions, and receiving chemotherapy were unfavorable prognostic factors for survival. Multivariate Cox analysis showed that advanced PS was a borderline significant independent factor in poor survival (hazard ratio, 2.1, 95% confidence interval, 1.0-4.6; P = .06), but it was not a factor when analysis was limited to patients who had not received chemotherapy. The prognosis of indolent ATL in this study was poorer than expected. These findings suggest that even patients with indolent ATL should be carefully observed in clinical practice. Further studies are required to develop treatments for indolent ATL.

Download Full-text

Pathologically Proven Intraocular Infiltration With Adult T-Cell Leukemia/Lymphoma: Two New Cases With Either Vitreous Opacity or Aqueous Hypopyon and Literature Review of 16 Cases

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/2324709620966843 ◽

2020 ◽

Vol 8 ◽

pp. 232470962096684

Author(s):

Toshihiko Matsuo ◽

Takehiro Shimizu ◽

Takehiro Tanaka ◽

Akira Yamamoto ◽

Hiroki Takasuka

Keyword(s):

T Cell ◽

Kidney Injury ◽

Central Nervous System Relapse ◽

Acute Type ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Hematopoietic Stem ◽

Adult T Cell Leukemia ◽

First Case ◽

Vitreous Opacity

This study reported 2 new patients and 16 historical cases with pathologically proven intraocular infiltration with adult T-cell leukemia and lymphoma (ATLL) to know the timing of intraocular infiltration in the disease course. The first case was a 67-year-old woman who developed bilateral vitreous opacity about half a year after the onset of acute type of ATLL that had been unresponsive to chemotherapy. She underwent vitrectomy combined with cataract surgery in both eyes. She had bilateral optic disc atrophy and localized retinal white infiltrates in both eyes. Cytological examination of vitreous aspirates demonstrated medium-sized cells with aberrant flower-like convoluted nuclei, positive for CD3, and thus indicative of T-cells. The second case was a 38-year-old man who was diagnosed acute type of ATLL at the presentation of acute kidney injury. About half a year after initial chemotherapy and allogeneic hematopoietic stem cell transplantation, he developed aqueous hypopyon in the right eye, concurrent with cutaneous and central nervous system relapse. Aqueous tap disclosed class V abnormal cells. The aqueous “pseudohypopyon” resolved in response to another round of chemotherapy with mogamulizumab. In review of 18 patients, intraocular infiltration with ATLL was diagnosed by vitrectomy in 9, aqueous tap in 3, chorioretinal biopsy in 3, and autopsy in 3. The intraocular infiltration developed concurrently with systemic diagnosis of ATLL in 5 patients, but developed later after chemotherapy in 13. In conclusion, intraocular infiltration with ATLL appears rare, and pathological diagnosis by vitrectomy and aqueous tap would help determine therapeutic plan in relapse after chemotherapy.

Download Full-text

Association of High Proliferation in Adult T-cell Leukemia Cells With Apoptosis, and Expression of p53 Protein in Acute Type ATL

Journal of Clinical and Experimental Hematopathology ◽

10.3960/jslrt.48.1 ◽

2008 ◽

Vol 48 (1) ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Jia Wang ◽

Kazuhisa Hasui ◽

Atae Utsunomiya ◽

Xinshan Jia ◽

Takami Matsuyama ◽

...

Keyword(s):

T Cell ◽

P53 Protein ◽

Leukemia Cells ◽

Acute Type ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia

Download Full-text

Therapy-induced selective loss of leukemia-initiating activity in murine adult T cell leukemia

Journal of Experimental Medicine ◽

10.1084/jem.20101095 ◽

2010 ◽

Vol 207 (13) ◽

pp. 2785-2792 ◽

Cited By ~ 59

Author(s):

Hiba El Hajj ◽

Marwan El-Sabban ◽

Hideki Hasegawa ◽

Ghazi Zaatari ◽

Julien Ablain ◽

...

Keyword(s):

T Cell ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Short Term ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

Long Term Prognosis ◽

Cell Immortality

Chronic HTLV-I (human T cell lymphotropic virus type I) infection may cause adult T cell leukemia/lymphoma (ATL), a disease with dismal long-term prognosis. The HTLV-I transactivator, Tax, initiates ATL in transgenic mice. In this study, we demonstrate that an As2O3 and IFN-α combination, known to trigger Tax proteolysis, cures Tax-driven ATL in mice. Unexpectedly, this combination therapy abrogated initial leukemia engraftment into secondary recipients, whereas the primary tumor bulk still grew in the primary hosts, only to ultimately abate later on. This loss of initial transplantability required proteasome function. A similar regimen recently yielded unprecedented disease control in human ATL. Our demonstration that this drug combination targeting Tax stability abrogates tumor cell immortality but not short-term growth may foretell a favorable long-term efficiency of this regimen in patients.

Download Full-text