A phase II study of the efficacy and toxicity of alemtuzumab for the therapy of human T cell lymphotrophic virus-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2535-2535 ◽  
Author(s):  
K. Sharma ◽  
J. Janik ◽  
D. O’Mahony ◽  
D. O’Hagan ◽  
W. W. Gao ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Phase Ii Study ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Open Label ◽  
Eligibility Criteria ◽  
Adult T Cell Leukemia ◽  
Highly Active ◽  
Human T Cell

2535 Background: HTLV-1-associated ATL is an aggressive lymphoproliferative disorder with limited effective therapy. Alemtuzumab is a humanized monoclonal antibody directed against CD52. High levels of CD52 are expressed on the surface of ATL cells. Preclinical studies in the MET-1 mouse model of ATL showed alemtuzumab to be highly active. Methods: A single institution open-label phase II study examining the response and toxicity of alemtuzumab in patients with ATL. Eligibility criteria: HTLV-1-associated ATL (chronic, acute and lymphoma type), ≥10% CD52+ malignant cells, measurable disease, age ≥18 years, AGC ≥1000/μL, platelets ≥50,000/μL, adequate physiologic status and informed consent. Results: Ten (10) patients, 6 with leukemia, 4 with lymphoma, 8 Afro-Caribbean, 1 African-American and 1 Japanese, 7 women, 3 men, median age 49 years (range, 36–62), all having received previous treatments including CHOP (7), other monoclonal antibodies (5), radioimmunotherapy (2), and radiation (1), median WBC 48,500/μL (leukemia Pts.) received alemtuzumab standard induction followed by 30 mg 3 times weekly for a minimum of 4 weeks and maximum of 12 weeks. All patients experienced infusion reactions (grade, 1–3) including hypotension, fever, rigors, chills, pruritus and urticaria; however, no patient required discontinuation of treatment. All patients developed grade 4 lymphopenia, and transient cytomegalovirus (CMV) antigenemia. Four (4) patients with leukemia responded (1 CR, 3 PR). No patient with lymphoma responded. Conclusions: Alemtuzumab has antitumor activity in HTLV-1-associated adult T cell leukemia and is well tolerated. Lymphomatous ATL appears unresponsive to alemtuzumab. The reason for this is unknown; however, antibody levels achieved in lymph nodes may be suboptimal. Accrual continues. No significant financial relationships to disclose.

Phase II Study of Cladribine (2-Chlorodeoxyadenosine) in Relapsed or Refractory Adult T-Cell Leukemia-Lymphoma

2003 ◽  
Vol 77 (5) ◽  
pp. 512-517 ◽  
Author(s):  
Kensei Tobinai ◽  
Naokuni Uike ◽  
Yoshio Saburi ◽  
Takaaki Chou ◽  
Tetsuya Etoh ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Phase Ii Study ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

scholarly journals A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T‐cell leukemia/lymphoma

2015 ◽  
Vol 106 (9) ◽  
pp. 1219-1223 ◽  
Author(s):  
Kenji Ishitsuka ◽  
Atae Utsunomiya ◽  
Hiroo Katsuya ◽  
Shogo Takeuchi ◽  
Yoshifusa Takatsuka ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Phase Ii Study ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

scholarly journals Phase II Study of Alemtuzumab (CAMPATH-1) in Patients with HTLV-1–Associated Adult T-cell Leukemia/lymphoma

2016 ◽  
Vol 23 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Kamal Sharma ◽  
John E. Janik ◽  
Deirdre O'Mahony ◽  
Donn Stewart ◽  
Stefania Pittaluga ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Phase Ii Study ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

Phase II trial of daclizumab in human T-cell lymphotropic virus type-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL).

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. 8043-8043 ◽  
Author(s):  
J. L. Berkowitz ◽  
J. E. Janik ◽  
D. M. Stewart ◽  
S. Fioravanti ◽  
E. S. Jaffe ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Human T Cell

THP-COP regimen for the treatment of peripheral T-cell lymphoma and adult T-cell leukemia/lymphoma: a multicenter phase II study

2010 ◽  
Vol 84 (5) ◽  
pp. 391-397 ◽  
Author(s):  
Yasushi Takamatsu ◽  
Junji Suzumiya ◽  
Atae Utsunomiya ◽  
Koichi Maeda ◽  
Hitoshi Matsuoka ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Peripheral T Cell Lymphoma ◽  
Adult T Cell Leukemia ◽  
Multicenter Phase

scholarly journals Chronological genome and single-cell transcriptome integration characterizes the evolutionary process of adult T cell leukemia-lymphoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Makoto Yamagishi ◽  
Miyuki Kubokawa ◽  
Yuta Kuze ◽  
Ayako Suzuki ◽  
Akari Yokomizo ◽  
...  
Keyword(s):  
T Cell ◽  
Single Cell ◽  
Disease Onset ◽  
Evolutionary Process ◽  
Proliferative Potential ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell

AbstractSubclonal genetic heterogeneity and their diverse gene expression impose serious problems in understanding the behavior of cancers and contemplating therapeutic strategies. Here we develop and utilize a capture-based sequencing panel, which covers host hotspot genes and the full-length genome of human T-cell leukemia virus type-1 (HTLV-1), to investigate the clonal architecture of adult T-cell leukemia-lymphoma (ATL). For chronologically collected specimens from patients with ATL or pre-onset individuals, we integrate deep DNA sequencing and single-cell RNA sequencing to detect the somatic mutations and virus directly and characterize the transcriptional readouts in respective subclones. Characteristic genomic and transcriptomic patterns are associated with subclonal expansion and switches during the clinical timeline. Multistep mutations in the T-cell receptor (TCR), STAT3, and NOTCH pathways establish clone-specific transcriptomic abnormalities and further accelerate their proliferative potential to develop highly malignant clones, leading to disease onset and progression. Early detection and characterization of newly expanded subclones through the integrative analytical platform will be valuable for the development of an in-depth understanding of this disease.

scholarly journals Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Marcia Bellon ◽  
Izabela Bialuk ◽  
Veronica Galli ◽  
Xue-Tao Bai ◽  
Lourdes Farre ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Spastic Paraparesis ◽  
Cellular Transformation ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Fragile Histidine Triad ◽  
Adult T Cell Leukemia ◽  
Human T Cell

Abstract Background Human T cell Leukemia virus type 1 (HTLV-I) is etiologically linked to adult T cell leukemia/lymphoma (ATL) and an inflammatory neurodegenerative disease called HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP). The exact genetic or epigenetic events and/or environmental factors that influence the development of ATL, or HAM/TSP diseases are largely unknown. The tumor suppressor gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT), is frequently lost in cancer through epigenetic modifications and/or deletion. FHIT is a tumor suppressor acting as genome caretaker by regulating cellular DNA repair. Indeed, FHIT loss leads to replicative stress and accumulation of double DNA strand breaks. Therefore, loss of FHIT expression plays a key role in cellular transformation. Methods Here, we studied over 400 samples from HTLV-I-infected individuals with ATL, TSP/HAM, or asymptomatic carriers (AC) for FHIT loss and expression. We examined the epigenetic status of FHIT through methylation specific PCR and bisulfite sequencing; and correlated these results to FHIT expression in patient samples. Results We found that epigenetic alteration of FHIT is specifically found in chronic and acute ATL but is absent in asymptomatic HTLV-I carriers and TSP/HAM patients’ samples. Furthermore, the extent of FHIT methylation in ATL patients was quantitatively comparable in virus-infected and virus non-infected cells. We also found that longitudinal HTLV-I carriers that progressed to smoldering ATL and descendants of ATL patients harbor FHIT methylation. Conclusions These results suggest that germinal epigenetic mutation of FHIT represents a preexisting mark predisposing to the development of ATL diseases. These findings have important clinical implications as patients with acute ATL are rarely cured. Our study suggests an alternative strategy to the current “wait and see approach” in that early screening of HTLV-I-infected individuals for germinal epimutation of FHIT and early treatment may offer significant clinical benefits.

scholarly journals Biochemical Characterization, Specificity and Inhibition Studies of HTLV-1, HTLV-2, and HTLV-3 Proteases

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 127
Author(s):  
Norbert Kassay ◽  
János András Mótyán ◽  
Krisztina Matúz ◽  
Mária Golda ◽  
József Tőzsér
Keyword(s):  
T Cell ◽  
Biochemical Characterization ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

The human T-lymphotropic viruses (HTLVs) are causative agents of severe diseases including adult T-cell leukemia. Similar to human immunodeficiency viruses (HIVs), the viral protease (PR) plays a crucial role in the viral life-cycle via the processing of the viral polyproteins. Thus, it is a potential target of anti-retroviral therapies. In this study, we performed in vitro comparative analysis of human T-cell leukemia virus type 1, 2, and 3 (HTLV-1, -2, and -3) proteases. Amino acid preferences of S4 to S1′ subsites were studied by using a series of synthetic oligopeptide substrates representing the natural and modified cleavage site sequences of the proteases. Biochemical characteristics of the different PRs were also determined, including catalytic efficiencies and dependence of activity on pH, temperature, and ionic strength. We investigated the effects of different HIV-1 PR inhibitors (atazanavir, darunavir, DMP-323, indinavir, ritonavir, and saquinavir) on enzyme activities, and inhibitory potentials of IB-268 and IB-269 inhibitors that were previously designed against HTLV-1 PR. Comparative biochemical analysis of HTLV-1, -2, and -3 PRs may help understand the characteristic similarities and differences between these enzymes in order to estimate the potential of the appearance of drug-resistance against specific HTLV-1 PR inhibitors.

scholarly journals Smoking is a risk factor for development of adult T-cell leukemia/lymphoma in Japanese human T-cell leukemia virus type-1 carriers

2016 ◽  
Vol 27 (9) ◽  
pp. 1059-1066 ◽  
Author(s):  
Hisayoshi Kondo ◽  
Midori Soda ◽  
Norie Sawada ◽  
Manami Inoue ◽  
Yoshitaka Imaizumi ◽  
...  
Keyword(s):  
Risk Factor ◽  
T Cell ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

scholarly journals The discovery of HTLV-1, the first pathogenic human retrovirus

2015 ◽  
Vol 112 (51) ◽  
pp. 15525-15529 ◽  
Author(s):  
John M. Coffin
Keyword(s):  
T Cell ◽  
Human Cancer ◽  
Leukemia Virus ◽  
Conclusive Evidence ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Culture Methods ◽  
Research Knowledge ◽  
Adult T Cell Leukemia ◽  
Human T Cell

After the discovery of retroviral reverse transcriptase in 1970, there was a flurry of activity, sparked by the “War on Cancer,” to identify human cancer retroviruses. After many false claims resulting from various artifacts, most scientists abandoned the search, but the Gallo laboratory carried on, developing both specific assays and new cell culture methods that enabled them to report, in the accompanying 1980 PNAS paper, identification and partial characterization of human T-cell leukemia virus (HTLV; now known as HTLV-1) produced by a T-cell line from a lymphoma patient. Follow-up studies, including collaboration with the group that first identified a cluster of adult T-cell leukemia (ATL) cases in Japan, provided conclusive evidence that HTLV was the cause of this disease. HTLV-1 is now known to infect at least 4–10 million people worldwide, about 5% of whom will develop ATL. Despite intensive research, knowledge of the viral etiology has not led to improvement in treatment or outcome of ATL. However, the technology for discovery of HTLV and acknowledgment of the existence of pathogenic human retroviruses laid the technical and intellectual foundation for the discovery of the cause of AIDS soon afterward. Without this advance, our ability to diagnose and treat HIV infection most likely would have been long delayed.

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