Real world data with concurrent retinoic acid and arsenic trioxide for the treatment of acute promyelocytic leukemia.
Ontology highlight
ABSTRACT:
SUBMITTER: Kulkarni UP
PROVIDER: S-EPMC8803919 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
Publications
Real world data with concurrent retinoic acid and arsenic trioxide for the treatment of acute promyelocytic leukemia.
Kulkarni Uday P UP Selvarajan Sushil S Lionel Sharon S Prakash Mithun A MA Palani Hamenth Kumar HK Balasundaram Nithya N Venkataraman Arvind A Korula Anu A Devasia Anup J AJ Fouzia N A NA Janet Nancy Beryl NB Nair Sukesh Chandran SC Abraham Aby A Mani Thenmozhi T Lakshmanan Jeyaseelan J Arunachalam Arun Kumar AK Balasubramanian Poonkuzhali P George Biju B Mathews Vikram V
Blood cancer journal 20220131 1
Similar Datasets
Project description:Retinoic acid (RA) in association with chemotherapy or with arsenic trioxide (ATO) results in high cure rates of acute promyelocytic leukemia (APL). We show that RA-induced differentiation of human leukemic cell lines and primary blasts dramatically increases their sensitivity to endoplasmic reticulum (ER) stress-inducing drugs at doses that are not toxic in the absence of RA. In addition, we demonstrate that the PERK pathway, triggered in response to ER stress, has a major protective role. Moreover, low amounts of pharmacologically induced ER stress are sufficient to strongly increase ATO toxicity. Indeed, in the presence of ER stress, ATO efficiently induced apoptosis in RA-sensitive and RA-resistant APL cell lines, at doses ineffective in the absence of ER stress. Our findings identify the ER stress-related pathways as potential targets in the search for novel therapeutic strategies in AML.
| S-EPMC5808088 | biostudies-literature
Project description:Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with a unique morphological appearance, associated coagulopathy and canonical balanced translocation of genetic material between chromosomes 15 and 17. APL was first described as a distinct subtype of AML in 1957 by Dr Leif Hillestad who recognized the pattern of an acute leukemia associated with fibrinolysis, hypofibrinogenemia and catastrophic hemorrhage. In the intervening years, the characteristic morphology of APL has been described fully with both classical hypergranular and variant microgranular forms. Both are characterized by a balanced translocation between the long arms of chromosomes 15 and 17, [t(15;17)(q24;q21)], giving rise to a unique fusion gene PML-RARA and an abnormal chimeric transcription factor (PML-RARA), which disrupts normal myeloid differentiation programs. The success of current treatments for APL is in marked contrast to the vast majority of patients with non-promyelocytic AML. The overall prognosis in non-promyelocytic AML is poor, and although there has been an improvement in overall survival in patients aged <60 years, only 30%-40% of younger patients are still alive 5 years after diagnosis. APL therapy has diverged from standard AML therapy through the empirical discovery of two agents that directly target the molecular basis of the disease. The evolution of treatment over the last 4 decades to include all-trans retinoic acid and arsenic trioxide, with chemotherapy limited to patients with high-risk disease, has led to complete remission in 90%-100% of patients in trials and rates of overall survival between 86% and 97%.
| S-EPMC5359123 | biostudies-literature
Project description:BackgroundRecently, the all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) protocol has become a promising first-line therapeutic approach in patients with newly diagnosed acute promyelocytic leukemia (APL), but its benefits compared with standard ATRA plus chemotherapy regimen needs to be proven. Herein, we conducted a meta-analysis comparing the efficacy of ATRA plus ATO with ATRA plus chemotherapy for adult patients with newly diagnosed APL.MethodsWe systematically searched biomedical electronic databases and conference proceedings through February 2016. Two reviewers independently assessed all studies for relevance and validity.ResultsOverall, three studies were eligible for inclusion in this meta-analysis, which included a total of 585 patients, with 317 in ATRA plus ATO group and 268 in ATRA plus chemotherapy group. Compared with patients who received ATRA and chemotherapy, patients who received ATRA plus ATO had a significantly better event-free survival (hazard ratio [HR] = 0.38, 95% confidence interval [CI]: 0.22-0.67, p = 0.009), overall survival (HR = 0.44, 95% CI: 0.24-0.82, p = 0.009), complete remission rate (relative risk [RR] = 1.05; 95% CI: 1.01-1.10; p = 0.03). There were no significant differences in early mortality (RR = 0.48; 95% CI: 0.22-1.05; p = 0.07).ConclusionThus, this analysis indicated that ATRA plus ATO protocol may be preferred to standard ATRA plus chemotherapy protocol, particularly in low-to-intermediate risk APL patients. Further larger trials were needed to provide more evidence in high-risk APL patients.
| S-EPMC4938459 | biostudies-literature
Project description:The combination of all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of standard-risk patients with newly diagnosed acute promyelocytic leukemia (APL). A recent study demonstrated the efficacy of this regimen with added gemtuzumab ozogamicin (GO) in high-risk patients. We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without GO. For induction, all patients received ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg daily) with a dose of GO (9 mg/m2 on day 1) added to high-risk patients (white blood cell count, >10 × 109/L), as well as low-risk patients who experienced leukocytosis during induction. Once in complete remission, patients received 4 cycles of ATRA plus ATO consolidation. One hundred eighty-seven patients, including 54 with high-risk and 133 with low-risk disease, have been treated. The complete remission rate was 96% (52 of 54 in high-risk and 127 of 133 in low-risk patients). Induction mortality was 4%, with only 7 relapses. Among low-risk patients, 60 patients (45%) required either GO or idarubicin for leukocytosis. Median duration of follow-up was 47.6 months. The 5-year event-free, disease-free, and overall survival rates are 85%, 96%, and 88%, respectively. Late hematological relapses beyond 1 year occurred in 3 patients. Fourteen deaths occurred beyond 1 year; 12 were related to other causes. This study confirms the durability of responses with this regimen.
| S-EPMC5413297 | biostudies-literature
Project description:Acute promyelocytic leukemia (APL) has become curable over 95% patients under a complete chemo-free treatment with all-trans retinoic acid (ATRA) and arsenic trioxide in low-risk patients. Minimizing chemotherapy has proven feasible in high-risk patients. We evaluated oral arsenic and ATRA without chemotherapy as an outpatient consolidation therapy and no maintenance for high-risk APL. We conducted a multicenter, single-arm, phase 2 study with consolidation phases. The consolidation therapy included Realgar-Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and 4-week-off regimen for 4 cycles and ATRA (25 mg/m2 daily in an oral divided dose) in a 2-week-on and 2-week-off regimen for 7 cycles. The primary end point was the disease-free survival (DFS). Secondary end points included measurable resident disease, overall survival (OS), and safety. A total of 54 participants were enrolled at seven centers from May 2019. The median age was 40 years. At the median follow-up of 13.8 months (through April 2022), estimated 2-year DFS and OS were 94% and 100% in an intention-to-treat analysis. All the patients achieved complete molecular remission at the end of consolidation phase. Two patients relapsed after consolidation with a cumulative incidence of relapse of 6.2%. The majority of adverse events were grade 1-2, and only three grade 3 adverse events were observed. Oral arsenic plus ATRA without chemotherapy was active as a first-line consolidation therapy for high-risk APL.Trial registration: chictr.org.cn number, ChiCTR1900023309.
| S-EPMC9578225 | biostudies-literature
Project description:All-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) administration leads to granulocytic maturation and/or apoptosis of acute promyelocytic leukemia (APL) cells mainly by targeting promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα). Yet, ~10-15% of APL patients are not cured by ATRA- and ATO-based therapies, and a potential failure of ATRA and ATO in completely reversing PML/RARα-driven oncogenic alterations has not been comprehensively examined. Here we characterized the in vivo primary responses of dysregulated genes in APL cells treated with ATRA and ATO using a GFP-labeled APL model. Although induced granulocytic differentiation of APL cells was evident after ATRA or ATO administration, the expression of the majority of dysregulated genes in the c-Kit+ APL progenitors was not consistently corrected. Irf8, whose expression increased along with spontaneous differentiation of the APL progenitors in vivo, represented such a PML/RARα-dysregulated gene that was refractory to ATRA/ATO signaling. Interestingly, Irf8 induction, but not its knockdown, decreased APL leukemogenic potential through driving monocytic maturation. Thus, we reveal that certain PML/RARα-dysregulated genes that are refractory to ATRA/ATO signaling are potentially crucial regulators of the immature status and leukemogenic potential of APL cells, which can be exploited for the development of new therapeutic strategies for ATRA/ATO-resistant APL cases.
| S-EPMC5520717 | biostudies-literature
Project description:All-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combination-based therapy has benefitted newly diagnosed acute promyelocytic leukemia (APL) in short-term studies, but the long-term efficacy and safety remained unclear. From April 2001, we have followed 85 patients administrated ATRA/ATO with a median follow-up of 70 months. Eighty patients (94.1%) entered complete remission (CR). Kaplan-Meier estimates of the 5-year event-free survival (EFS) and overall survival (OS) for all patients were 89.2% +/- 3.4% and 91.7% +/- 3.0%, respectively, and the 5-year relapse-free survival (RFS) and OS for patients who achieved CR (n = 80) were 94.8% +/- 2.5% and 97.4% +/- 1.8%, respectively. Upon ATRA/ATO, prognosis was not influenced by initial white blood cell count, distinct PML-RARalpha types, or FLT3 mutations. The toxicity profile was mild and reversible. No secondary carcinoma was observed, and 24 months after the last dose of ATRA/ATO, patients had urine arsenic concentrations well below the safety limit. These results demonstrate the high efficacy and minimal toxicity of ATRA/ATO treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for de novo APL.
| S-EPMC2651325 | biostudies-literature
Project description:The objective of this study was to estimate the net cost of arsenic trioxide (ATO) added to all-trans retinoic acid (ATRA) compared to ATRA plus chemotherapy when used in first-line acute promyelocytic leukemia (APL) treatment for low to intermediate risk patients from the perspective of the overall Italian healthcare systemA Markov model was developed with 3 health states: stable disease, disease event and death. Each month, patients could move from stable to disease event or die from either state. After a disease event, patients discontinued initial treatment and switched to the other regimen as second-line therapy. Treatment regimens, efficacy and adverse events were derived from published sources and expert opinion; unit costs were collected from standard Italian sources. Clinical outcomes and costs for pre-ATO and post-ATO scenarios were combined with population and product utilization information to calculate the total budgetary impact using a 3-year time horizon; one-way sensitivity analyses were conducted. Three-year cumulative pharmacy costs for ATO+ATRA were €46,700 per-patient versus €6,500 for ATRA+chemotherapy; however, medical costs for ATO+ATRA were €12,300 per-patient versus €30,200 for ATRA+chemotherapy. The total budgetary impact was estimated to be an additional €127,300, €312,500 and €477,800 in the first, second and third years, respectively. The model was most sensitive to changes in the cost of the ATO+ATRA regimen during the consolidation phase. Budgetary impact models are valuable to payers making formulary decisions regarding the access and affordability of new medicines. The cost of treatment analysis showed that pharmacy costs for ATO+ATRA were higher than for ATRA+chemotherapy, while all other evaluated costs were lower for ATO+ATRA treated patients. The average budgetary impact was €305,900 per year overall, representing a 3.5% increase. Further research is needed to determine the cost-effectiveness of ATO+ATRA compared to the current first-line standard of care in APL.
| S-EPMC4534409 | biostudies-literature
Project description:Acquired genetic mutations can confer resistance to arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL). However, such resistance-conferring mutations are rare and do not explain most disease recurrence seen in the clinic. We have generated stable ATO-resistant promyelocytic cell lines that are less sensitive to all-trans retinoic acid (ATRA) and the combination of ATO and ATRA compared with the sensitive cell line. Characterization of these resistant cell lines that were generated in-house showed significant differences in immunophenotype, drug transporter expression, anti-apoptotic protein dependence, and promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) mutation. Gene expression profiling revealed prominent dysregulation of the cellular metabolic pathways in these ATO-resistant APL cell lines. Glycolytic inhibition by 2-deoxyglucose (2-DG) was sufficient and comparable to the standard of care (ATO) in targeting the sensitive APL cell line. 2-DG was also effective in the in vivo transplantable APL mouse model; however, it did not affect the ATO-resistant cell lines. In contrast, the resistant cell lines were significantly affected by compounds targeting mitochondrial respiration when combined with ATO, irrespective of the ATO resistance-conferring genetic mutations or the pattern of their anti-apoptotic protein dependency. Our data demonstrate that combining mitocans with ATO can overcome ATO resistance. We also show that this combination has potential for treating non-M3 acute myeloid leukemia (AML) and relapsed APL. The translation of this approach in the clinic needs to be explored further.
| S-EPMC8791572 | biostudies-literature
Project description:BackgroundAll-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have revolutionized the treatment of acute promyelocytic leukemia (APL). However, the management of high-risk APL has not been conclusively established. The optimal dosage of anthracycline in the induction has long been debated when ATO is added.ObjectivesTo explore the management of high-risk APL regarding the optimal dosage of anthracycline in the induction and the predicators of prognosis.DesignThis was a retrospective study in the real-world setting.MethodsHigh-risk APL patients defined as white blood cell (WBC) greater than 10 × 109/L who received ATO-based induction regimens were included. Data on clinical characteristics, treatment regimens, and prognosis including early death (ED) and overall survival (OS) were collected from medical records. Risk factors of ED and OS were analyzed.ResultsThis research included a total of 130 participants. Fifty (38.5%) patients received ATO+ATRA dual induction plus standard-dose anthracycline (ATO + ATRA + stDNR). Fifty-nine (45.4%) patients received ATO + ATRA with consecutive low-dose anthracycline (ATO + ATRA + ldDNR). Twenty-one (16.2%) patients were treated with ATO and various chemotherapies (ATO + others). Compared with the other two groups, the ATO + ATRA + stDNR group had the lowest ED rate of 4.0% (10.2% and 52.4%, respectively; p < 0.001). Multivariate analysis revealed that age ⩾60 years (odds ratio (OR) = 8.888, 95% confidence interval (CI): 1.126-70.129), prothrombin time (PT) ⩾18 s (OR = 4.749, 95% CI: 1.252-18.007) and WBC ⩾100 × 109/L (OR = 10.591, 95% CI: 1.995-56.232) were independent risk factors for ED. The 5-year OS rates of the three induction groups were 96%, 80%, and 31%, respectively. None of the 48 patients who underwent ATO + ATRA + stDNR induction relapsed, whereas 9.4% (5/53) patients in ATO + ATRA + ldDNR group relapsed, and the relapse rate was 30.0% (3/10) in ATO + others group (p = 0.003). The survival advantage of ATO + ATRA + stDNR was demonstrated by a Cox regression (hazard ratio (HR) = 5.079, 95% CI: 1.071-24.079). WBC ⩾100 × 109/L was correlated with an inferior OS (HR = 3.402, 95% CI: 1.359-8.518).ConclusionCompared with low-dose anthracycline, standard-dose anthracycline combined with ATO and ATRA dual induction resulted in excellent outcome for high-risk APL patients.
| S-EPMC11577467 | biostudies-literature