Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study

Hishizawa, Masakatsu; Kanda, Junya; Utsunomiya, Atae; Taniguchi, Satoshi; Eto, Tetsuya; Moriuchi, Yukiyoshi; Tanosaki, Ryuji; Kawano, Fumio; Miyazaki, Yasushi; Masuda, Masato; Nagafuji, Koji; Hara, Masamichi; Takanashi, Minoko; Kai, Shunro; Atsuta, Yoshiko; Suzuki, Ritsuro; Kawase, Takakazu; Matsuo, Keitaro; Nagamura‐Inoue, Tokiko; Kato, Shingo; Sakamaki, Hisashi; Morishima, Yasuo; Okamura, Jun; Ichinohe, Tatsuo; Uchiyama, Takashi

doi:10.1182/blood-2009-10-247510

Cited by 252 publications

(235 citation statements)

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“…Antibody-based approaches including use of daclizumab, alemtuzumab, and anti-CCR4 showed value but are not curative (31)(32)(33)(34). Allogeneic bone marrow transplantation is an aggressive approach that is curative in select patients (35). Due to these limited options, there is a clear need for new treatment strategies for ATL.…”

Section: Discussionmentioning

confidence: 99%

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

Zhang

Griner

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Adult T-cell leukemia (ATL) develops in individuals infected with human T-cell lymphotropic virus-1 (HTLV-1). Presently there is no curative therapy for ATL. HTLV-1-encoded protein Tax (transactivator from the X-gene region) up-regulates Bcl-xL (B-cell lymphoma-extra large) expression and activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems, resulting in amplified JAK/STAT signaling. Inhibition of JAK signaling reduces cytokinedependent ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients in smoldering/chronic stages. Currently, two JAK inhibitors are approved for human use. In this study, we examined activity of multiple JAK inhibitors in ATL cell lines. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. This combination strongly blocked ex vivo proliferation of five ATL patients' PBMCs. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL.adult T-cell leukemia | Janus kinase | ruxolitinib | navitoclax T -cell leukemia/lymphoma represents ∼10% of lymphoid malignancies. Genetic alterations affecting members of the Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) were discovered in a variety of T-cell malignancies (1, 2). Furthermore, increases in the common γc cytokine concentrations that signal through the JAK1/3, STAT3/5 pathway have been demonstrated in angioimmunoblastic T-cell lymphoma, gamma delta T-cell lymphoma, and adult T-cell leukemia (ATL), thereby identifying effective therapeutic targets.ATL is an aggressive T-cell malignancy characterized by the clonal expansion of CD4 + CD25 + T lymphocytes that develops in a small proportion of individuals infected with human T-cell lymphotrophic virus-1 (HTLV-1) (3-5). Clinically, ATL is subclassified into four subtypes: smoldering, chronic, lymphomatous, and acute (4, 5). Presently, there is no curative therapy for ATL (4, 5). In search of effective therapies, we examined key signaling pathways that confer a proliferation and viability advantage to ATL cells. It was noted that the HTLV-1-encoded Tax (transactivator from the X-gene region) is associated with increased Bcl-xL (B-cell lymphoma-extra large) expression in ATL cells (6). Furthermore, we reported two autocrine loops (IL-2/IL-2Rα, IL-15/IL-15Rα) and one paracrine loop that in...

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Section: Discussionmentioning

confidence: 99%

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

Zhang

Griner

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Importantly, a large retrospective study was reported in 2010 and included 386 patients allografted between 1995 and 2005 using either standard or reduced-intensity conditioning regimens. 18 After a median follow-up of 41 months, the 3-year OS was 33%. Interestingly, donor HTLV-I seropositivity adversely affected the disease-associated mortality, specifically for patients who received transplants from related donors.…”

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confidence: 97%

Outcome of patients with HTLV-1-associated adult T-cell leukemia/lymphoma after SCT: a retrospective study by the EBMT LWP

Bazarbachi

Cwynarski

Boumendil

et al. 2014

Bone Marrow Transplant

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Adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis. Experience with allo-SCT for ATL appears encouraging but is limited to Japanese series. This retrospective analysis of the EBMT registry revealed 21 HTLV-I seropositive ATL including 7 acute and 12 lymphoma subtypes. Four patients received auto-SCT and rapidly died from ATL. Out of 17 allo-SCT (4 myeloablative, 13 reduced intensity), 6 are still alive (4 were in CR1 at SCT). Eleven patients died within 2 years, eight from relapse/progression and three from transplant toxicity. Six of seven informative patients who lived 412 months had chronic GVHD. Overall these results indicate that allo-SCT but not auto-SCT may salvage a subset of ATL patients, supporting the existence of graft vs ATL effect also in non-Japanese patients.

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“…This may be due to poorer outcome of CBT than BMT/PBSCT in ATL patients than other diseases. 19 Alternately, it may be associated with a small size of the subgroup. Therefore, these observations should be confirmed in a prospective analysis of larger numbers of patients.…”

Section: Discussionmentioning

confidence: 99%

Validation of pretransplantation assessment of mortality risk score in the outcome of hematopoietic SCT in non-Caucasians

Mori

Teshima

Kamezaki³

et al. 2011

Bone Marrow Transplant

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The Pretransplantation Assessment of Mortality (PAM) score is a risk score for mortality after allogeneic hematopoietic SCT (HSCT). Ethnicity is a genetically determined factor that correlated with immune-mediated outcomes of allogeneic HSCT. We evaluated the predictive value of the PAM score for transplant outcome in 276 Japanese populations in which transplantrelated complications occur less frequently than Caucasians. The PAM score effectively risk-stratified these patients for survival; overall survival (OS) at 2 years was 100%, 80.2%, 49.4%, and 13.9% in the categories 1, 2, 3, and 4, respectively, showing a clear distinction of OS by categories (Po0.001). In addition, the PAM score is useful for the prediction of transplant outcomes both in patients with standard-risk underlying diseases and those with high-risk diseases. The PAM score developed in Caucasian populations is thus useful in non-Caucasian populations.

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Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study

Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used as a curative option for adult T-cell leukemia (ATL), an intractable mature T-cell neoplasm causally linked with human T-cell leukemia virus type I (HTLV-I). We com-

Cited by 252 publications

References 42 publications

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

Outcome of patients with HTLV-1-associated adult T-cell leukemia/lymphoma after SCT: a retrospective study by the EBMT LWP

Validation of pretransplantation assessment of mortality risk score in the outcome of hematopoietic SCT in non-Caucasians

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