No approved-drug candidate for adult t-cell leukemia/lymphoma is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
RCSB Protein Data Bank · entry 5C4M · 1.3 Å · ligand GUANOSINE-5'-DIPHOSPHATE (GDP). Experimental structure, not a prediction.
In a prospective observational study of 113 patients aged 70 or younger with newly diagnosed aggressive adult T-cell leukemia/lymphoma (ATL) enrolled between 2015 and 2018, the 2-year overall survival was 45%, compared with 29% in a retrospective cohort of 1792 patients diagnosed between 2000 and 2013. The proportion receiving allogeneic hematopoietic cell transplantation (allo-HCT) rose from 34% to 80%, and the median interval from diagnosis to transplant fell from 170 to 128 days. Among the 90 transplanted patients, 2-year overall survival was 44%, non-relapse mortality 23%, and disease progression 46%; outcomes did not differ statistically by donor type, including cord blood and HLA-haploidentical donors.
A separate 2015 study examined telmisartan, an angiotensin II receptor blocker that activates PPARγ, in ex vivo cells from ATL patients and in leukemia cell lines. Telmisartan reduced cell viability and increased apoptosis in peripheral blood monocytes from acute-type ATL patients, and induced apoptosis in cells from chronic-type ATL patients and asymptomatic HTLV-1 carriers significantly more than in cells from healthy donors. In cell lines, telmisartan caused growth inhibition, loss of mitochondrial transmembrane potential, generation of reactive oxygen species, caspase activation (caspase-3, 8, and 9), and accumulation of the autophagy marker LC3-II. Other angiotensin II receptor blockers, irbesartan and valsartan, did not induce cell death. A caspase inhibitor did not block telmisartan-induced cell death, indicating both caspase-dependent and -independent mechanisms.
A 2015 analysis of 41 patients with relapsed T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) after first complete remission reported a median survival after relapse of 8.2 months. 61% achieved a second complete remission, but 48% of those relapsed again, with a median time to second relapse of 7.6 months. 18 patients proceeded to stem cell transplant after second remission, and half of those relapsed. Only bone marrow involvement at relapse was a significant predictor of worse post-relapse survival (hazard ratio 2.4). Nelarabine therapy, achieving second remission, and transplant were not independent predictors of survival in this small cohort.
A 1989 study of T-cell receptor delta gene rearrangements in 21 T-cell leukemias found structural modifications in all T-cell disorders, with germ-line configuration in all controls and all but one non-T-cell leukemia. In two cases of pre-T-acute lymphoblastic leukemia, only the delta gene was rearranged among the three T-cell receptor genes tested. What remains missing for ATL is a prospective trial testing telmisartan in patients, particularly those with indolent disease or carriers, to see whether the ex vivo effects translate into delayed progression or improved survival; adequate funding and a stratified design accounting for ATL subtype and HTLV-1 carrier status are needed.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Blood Advances · 2021 · 28 citations · open access
Improved survival of patients with aggressive ATL by increased use of allo-HCT: a prospective observational study
AbstractAggressive adult T-cell leukemia/lymphoma (ATL) is a hematological malignancy that is difficult to treat with chemotherapy alone, and allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy. We conducted a multicenter, prospective, observational study to clarify the treatment outcomes of aggressive ATL in the current era. Between 2015 and 2018, 113 patients aged 70 years or younger with newly diagnosed aggressive ATL were enrolled. The median age at diagnosis was 61 years. Treatment outcomes were compared with those of 1792 ATL patients diagnosed between 2000 and 2013 in our previous retrospective study. The inclusion criteria were the same in both studies. The prospective cohort demonstrated better overall survival (OS) than the retrospective cohort (2-year OS, 45% vs 29%, respectively; P < .001), with a much higher proportion of patients receiving allo-HCT (80% vs 34%, respectively; P < .001) and a shorter interval from diagnosis to allo-HCT (median, 128 vs 170 days, respectively; P < .001). Among the 90 patients who received allo-HCT (cord blood, n = 30; HLA-haploidentical related donors, n = 20; other related donors, n = 14; other unrelated donors, n = 26), the 2-year probabilities of OS, non-relapse mortality (NRM), and disease progression were 44%, 23%, and 46%, respectively. OS and NRM did not differ statistically according to donor type. Our results suggest that increased application of allo-HCT improved the survival of patients with aggressive ATL. The use of cord blood or HLA-haploidentical donors may be feasible for aggressive ATL when HLA-matched related donors are unavailable. This study was registered at the UMIN Clinical Trials Registry as #000017672.
https://doi.org/10.1182/bloodadvances.2021004932Cancers · 2015 · 22 citations · open access
Optimizing Management of Patients with Adult T Cell Leukemia-Lymphoma
AbstractAdult T cell leukemia-lymphoma is a rare disease with a high mortality rate, and is challenging for the clinician. Early allogeneic stem cell transplant can confer durable remission. As novel therapeutic agents become available to treat T cell malignancies, it is increasingly important that medical oncologists, hematologists, and hematopathologists recognize and accurately diagnose adult T cell leukemia-lymphoma. There is no uniform standard of treatment of adult T cell leukemia-lymphoma, and clinical trials remain critical to improving outcomes. Here we present one management approach based on the recent advances in treatment for adult T cell leukemia-lymphoma patients.
https://doi.org/10.3390/cancers7040893American Journal of Therapeutics · 2013 · 3 citations
PTCL Therapies
AbstractPeripheral T-cell lymphomas (PTCLs) are relatively uncommon lymphomas, compared with B-cell malignancies, and given short-lived responses to therapies and an aggressive clinical course provide a therapeutic challenge for the clinician. Although anthracycline-based regimens have been a mainstay of therapy, inferior outcomes with these regimens have called attention to the need for the development of novel agents and effective combination therapies. Recently, new agents with activity in PTCL have emerged with evidence of improved efficacy. This review summarizes novel, investigational, and standard treatment options in the management of treatment naive and relapsed refractory PTCL.
https://doi.org/10.1097/mjt.0b013e31828232a3Targets · 2024 · 1 citations · open access
Unveiling the Role of New Molecules in Acute Myeloid Leukemia: Insights into Disease Pathogenesis and Therapeutic Potential
AbstractThis review article explores the current landscape of acute myeloid leukemia treatment, including novel target molecules and recent advancements in cell therapy and immunotherapy focused on T cell activity. Advances in treatment have been promising in recent years, driven by the development of therapies targeting new molecular and genetic therapeutic targets. These findings allowed for the approval of several target therapies by the European and American drug agencies in the last 5 years. However, mortality remains very high, particularly in relapsed or refractory (R/R) patients. In recent years, the development of immunotherapy has expanded this field, leading to the introduction of new drugs and treatments.
https://doi.org/10.3390/targets2040023Blood · 2015 · 0 citations
Prognostic Correlates and Outcomes of Relapsed T-Cell Acute Lymphoblastic Leukemia/Lymphoma: An Analysis of 41 Consecutive Patients
AbstractAbstract Background: Acute T-cell lymphoblastic leukemia (T-ALL)/ lymphoma (T-LBL) are immature T-cell malignancies with very poor outcomes. In patients with relapsed disease, survival is often < 12 months (Marks et al, Blood, 2009). Prognostic correlates and treatment outcomes after relapse remain largely unknown. Aims: To evaluate prognostic correlates and treatment outcomes in patients with relapsed T-ALL/LBL. Methods: After IRB approval, 92 consecutive patients with T-cell ALL/LBL were identified. 41 patients with relapsed disease after achieving a first complete remission (CR1) were included in the study group. Features at the time of relapse were retrospectively abstracted and analyzed. Survival time after relapse was calculated from the time of relapse until death or last follow-up. Conventional methods were used for statistical analysis. Results: A. Baseline characteristics of all patients 92 patients were identified [41 LBL, 51 ALL]. Median age was 33 years (range; 18-88) and 66 (72%) were males. Median follow-up was 25 months (range 0.9-260). 13(14%) received palliative care or were lost to follow-up before treatment initiation. At last follow-up, there were 41 (52%, n = 79) relapses and 42 (46%, n = 92) deaths. Of 79 patients, 71 (90%) achieved a CR1 and 8 (10%) had primary refractory disease. Comparisons between ALL and LBL revealed expected differences in presenting features such as frequency of primary mediastinal mass at presentation in LBL and high leukocyte count in ALL. Significant differences in treatment were seen. Asparaginase-based and ALL-directed therapy were more common in the ALL group (71% vs. 45%, p = 0.009; 88% vs. 71%, p = 0.04). 13 (81%) LBL and 14 (27%) ALL underwent allogeneic SCT. The remaining three in each group underwent autologous SCT in CR1. B. Characteristics of relapsed patients 41 relapsed after achieving CR1 [23 LBL, 18 ALL]. Median time to relapse was 8.0 months (range 2.3-130), with no difference between ALL and LBL groups. Median age was 34 years (range 19-71) and 29 (71%) were males. Median follow-up after relapse was 7.2 months (range 0.3-207). At time of last follow-up, there were 30 (73%) deaths, 25 (61%) achieved a second complete remission (CR2) and 14 (34%) had persistent disease. 12 (48%) had relapse following CR2. 34 (83%) relapsed following CR1 after induction chemotherapy alone. 6 (15%) and 1 (2%) relapsed following allogeneic and autologous SCT respectively. 27 (66%) had BM involvement, 5 (12%) had CNS involvement, 13 (32%) had mediastinal involvement, and 3 (7%) had isolated extramedullary relapse. Ten (43%) patients with LBL relapsed with ALL. Of 27 patients with available data, 9 (33%) had high-risk cytogenetics at relapse, defined as ≥ 5 chromosomal abnormalities and/or markers known to confer an unfavorable prognosis. 16 of these 27 patients had follow-up cytogenetic studies performed, of which 8 (50%) had evidence of clonal evolution. Patients were treated with up to five regimens. 12 (31%) received asparaginase-based therapy and 13 (33%) received nelarabine with CR2 rates of 75% and 25% respectively. Median number of regimens needed to achieve CR2 was one. 18 (46%) went onto SCT following CR2: 14 (allogeneic), 3 (autologous), and 1 (donor lymphocyte infusion). The majority received myeloablative conditioning (92%). C. Outcomes and prognostic correlates for survival after relapse Median survival following relapse was 8.2 months (IQR 4.1-21.3) and did not differ between LBL and ALL. Nine (36%) who achieved CR2 are alive at time of last follow-up. 25 (61%) achieved CR2, but 12 (48%) relapsed following CR2, with median time to second relapse of 7.6 months (IQR 4.7-14). Nine of 18 who underwent SCT following CR2 had disease relapse (8 allogeneic, 1 autologous). Only BM involvement at relapse significantly correlated with post-relapse survival (HR 2.4 [1.1, 5.1], p = 0.03). Clonal evolution, high-risk cytogenetics, nelarabine therapy, achieving CR2, and SCT were not independent predictors of survival in our small subset of patients. Conclusion: Patients with relapsed T-ALL/LBL have dismal outcomes, in spite of advances in therapy with newer agents such as nelarabine and the use of allogeneic SCT. Regardless of T-ALL/LBL subtype, BM involvement at relapse appears to be a significant factor negatively impacting post-relapse survival. Further studies are needed to validate these findings. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding.
https://doi.org/10.1182/blood.v126.23.3730.3730Blood · 2015 · 0 citations
Telmisartan, Angiotensin II Receptor Blocker, Induces Apoptosis and Autophagy in Adult T-Cell Leukemia Cells from Patients and Leukemia Cell Lines
AbstractAbstract Introduction: Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1). Despite the recent advances in chemotherapy, allogeneic hematopoietic stem cell transplantation, and supportive care, the prognosis for patients with acute, lymphoma, or unfavorable chronic subtypes (aggressive ATL) is one of the poorest among hematological malignancies; overall survival at 3 years is only 24 % in the more aggressive subtypes of ATL. In case of favourable chronic or smoldering ATL (indolent ATL), watchful waiting until disease progression has been recommended. Some patients with indolent ATL develop infections during this period. Therefore, urgent need for therapy and prophylaxis of ATL are still required. Recently, drug repositioning offers the possibility of reduced time and risk as several stages common to novel drug discovery and development can be bypassed because repositioning candidates have frequently been through several phases of development for their original indication. With the successful clinical introduction of a number of non-cancer drugs for cancer treatment, drug repositioning now became a potent alternative strategy to discover and develop novel anticancer drug candidates from the existing drug space. On the other hand, the transcription factor PPARγ plays various roles in lipid metabolism, immune response, cellular differentiation and apoptosis. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate PPARγ. Here, we assessed how telmisartan affects ATL cells from patients and leukemia cell lines. Methods and Results: Methods used in this study were carried out in accordance with the approved guidelines by the Committees for Ethical Review of Research involving Human Subjects at Kagoshima University. The subjects were examined by standard serological testing for the presence of HTLV-1 and by haematological/Southern blotting analysis for diagnosis of ATL. The classification of ATL was performed according to the criteria of Shimoyama. Telmisartan reduced cell viability and enhanced apoptotic cells in ex vivo peripheral blood monocytes of acute-type ATL, which has a poor prognosis. Telmisartan-induced apoptosis in cells from ATL patients (acute and chronic-type) and asymptomatic HTLV-1 carriers was significantly increased compared with those from healthy donors. Telmisartan also induced significant growth inhibition and apoptosis (Annexin V+ cells and TUNEL) in leukemia cell lines (HTLV-1-related cell lines: S1T, MT-2; Jurkat and HL60), while other angiotensin II receptor blockers, irbesartan and valsartan, did not induce cell death. In apoptosis, several key events occur in mitochondria, including the release of caspase activators, such as apoptosis-induced factor, and loss of mitochondrial transmembrane potential. Telmisartan induced loss of mitochondrial transmembrane potential and generation of reactive oxygen species, although apoptosis-inducing factor level was stable. Telmisartan also inhibited cell growth via caspase activation (caspase-3, 8 and 9) in the leukemia cells. However, treatment with a caspase inhibitor did not inhibit telmisartan-induced cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation as well as autophagy. Thus, Telmisartan simultaneously caused caspase activation and autophagy. Conclusion: A hypertension medication that has an anti-proliferation effect on leukemia cells is intriguing. These results suggest that telmisartan is highly effective against HTLV-1-infected cells and ATL cells in a caspase-dependent and -independent manner, and its clinical use may suppress the progression from indolent ATL or carrier status to aggressive ATL, and thus improve the prognosis of patients with this fatal disease. Disclosures No relevant conflicts of interest to declare.
https://doi.org/10.1182/blood.v126.23.2055.2055Blood · 1989 · 0 citations · open access
Rearrangement of the T-cell receptor delta genes in human T-cell leukemias
AbstractTwo distinct types of T-cell receptors (TCR), designated alpha beta and gamma delta, have been identified on the surface of T cells. In the adult, T cells bearing the gamma delta TCR are a minority and they have the phenotype CD3+, CD4-, CD8-/+. By using appropriate probes, rearrangements of the TCR alpha, beta, and gamma genes have been extensively investigated in a variety of lymphoproliferative disorders. Because the TCR delta gene has been cloned only recently, no comparable information exists with respect to this in human leukemias. We report the analysis of the TCR delta gene configuration in 21 T-cell acute and chronic leukemias, 40 B-cell leukemias, 4 acute myeloid leukemias of difficult classification, and 12 normal controls. The TCR delta genes were structurally modified in all T-cell disorders and in germ-line configuration in all controls and all but one case of non-T-cell leukemias tested. In one case of T-chronic lymphocytic leukemia (CD3+, CD4-, CD8+) we found rearrangement and expression of TCR gamma and delta (but not alpha and beta), suggesting that leukemic transformation took place in a cell bearing a TCR gamma delta rather than a TCR alpha beta. In two cases of pre-T-acute lymphoblastic leukemia, only delta was rearranged out of the three TCR genes tested. This finding is in keeping with the suggestion that the TCR delta gene might be the first to rearrange in T cell ontogeny, and that its mode of rearrangement may play a role in the subsequent choice of the cell between production of a TCR alpha beta or gamma delta. Thus, TCR delta chain gene analysis can provide novel information of the clonal nature of T-cell disorders, particularly if the analysis of the beta and gamma genes has not been helpful.
https://doi.org/10.1182/blood.v73.2.559.bloodjournal732559Blood · 2015 · 0 citations
Treatment Outcomes in Relapsed/Refractory Adult T-Cell Lymphoma/Leukemia and Role of CNS Prophylaxis: A New York City Hospital Experience
AbstractAbstract Background: Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive peripheral T-cell neoplasm characterized by clonal human T-cell lymphotropic virus type-1 (HTLV-1) proviral DNA integration with host T lymphocytes.It presents as aggressive (acute/lymphomatous) or indolent (chronic/smouldering) subtypes. The aggressive subtypes have median survival of 6-13 months despite aggressive chemotherapy regimens. Presently, there is no established therapy for patients with relapsed/refractory disease. The data on efficacy of traditional chemotherapy agents in this setting is scant. In the last 6 years, 4 new drugs have been approved by US Food and Drug Administration for patients with relapsed/refractory peripheral T cell lymphoma (PTCL): pralatrexate and 3 histone deacetylase (HDAC) inhibitors (romidepsin, belinostat, vorinostat). Treatment approaches for PTCL are often applied to ATLL, as there is little data available for this subtype. However, none of the HDAC inhibitor trials included ATLL patients and there was only one patient in the pivotal PROPEL study for pralatrexate. The prevalence of CNS disease in the aggressive subtypes varies from 3 to 50 % and the efficacy of intrathecal chemotherapy is not known. Methods: To investigate the therapeutic benefit of second-line therapy and prophylactic intrathecal therapy, we reviewed all patients with ATLL at King's County Hospital between 2006 and 2014. Individual chart review was performed to report clinicopathologic features and treatment outcomes. SPSS was used for statistical analysis. Results: Fifty five patients were identified between January 2006 and December 2013 including 33 (60%) females and 22 (40.0%) males with a median age of 54 years (range, 31-78 years). All patients had immigrated to the United States from the Caribbean or South America. Median follow-up period was 6.6 months (0.4-124). Forty four patients were dead, 5 were alive and 6 were lost to follow-up at the time of analysis. Stage distribution was 26%, 51%, 16%, 6% for stage I, II, III and IV respectively. Forty three patients (78.2%) received etoposide/prednisone/vincristine/cisplatin/adriamycin (EPOCH) for first-line therapy. Twenty nine patients received second-line chemotherapy: gemcitabine/oxaliplatin, iphosphamide/cisplatin/etoposide (ICE), romidepsin, pralatrexate and high dose methotrexate. Median progression free survival was 6.8 weeks (range 1.6-72). No complete responses were seen. Partial response was seen in 9 (n=29) patients (31%). Median duration of response was 20.8 weeks (range 9.1-40). Three (5%) patients had CNS involvement at presentation. Prophylactic intrathecal therapy with methotrexate (IT MTx) 12 mg Q14 days was given to 21 patients (40.3%). CNS relapse was seen in 3 (14.2%) patients who received IT MTx and 6 (19.4%) patients who did not receive intrathecal chemotherapy. All patients with CNS relapse also had peripheral relapse. Conclusion: ATLL is a rare and difficult disease to manage. In our experience of relapsed/refractory ATLL, patients appear to have modest response rate to a second-line chemotherapy and these responses are not long lasting. In our patient population, risk of CNS disease at presentation was low (5%) but the incidence approaches 17.3% at the time of relapse. Administration of prophylactic intrathecal methotrexate showed a trend towards reducing the incidence of CNS disease although the results were not statistically significant. Disclosures No relevant conflicts of interest to declare.
https://doi.org/10.1182/blood.v126.23.5101.5101Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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