Association of Deferasirox and Vitamin D Promotes Cell Differentiation and Improves Overall Survival in Acute Myeloid Leukemia (AML) Elderly Patients After Demethylating Agents Failure: A Retrospective Case Control Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3622-3622
Author(s):  
Etienne Paubelle ◽  
Felipe Suarez ◽  
Florence Zylbersztejn ◽  
Celine Callens ◽  
Michael Dussiot ◽  
...  

Abstract Abstract 3622 Background: AML is a group of heterogeneous malignant diseases characterized by uncontrolled cell growth and differentiation arrest. Following the success of differentiating therapies in APL, great hopes were placed in Vitamin D (VD) and its ability to promote differentiation of non-APL AML cells. However, results of clinical studies were disappointing and trials were interrupted due to the occurrence of life-threatening hypercalcemia. Our group has shown that iron chelators such as deferasirox (DFX) are able to promote monocytes differentiation in both normal hematopoietic progenitors and AML cells (Callens et al Jexp Med 2010). Moreover, iron deprivation synergized with VD to promote cell differentiation on leukemic cells. Most elderly patients diagnosed with AML suffer from secondary iron overload because of in some cases ineffective erythropoiesis and iterative red blood cell transfusions. Furthermore, in myelodysplastic syndromes, retrospective studies have suggested that iron chelators may increase life expectancy and decrease the risk of transformation into AML. In AML of the elderly, the use of demethylating agents such as 5-azacytidine or decitabine may induce hematological response and increase life expectancy. However, response is often of short duration. Since VD deficiency and iron overload prevalence is high in the elderly, the association of VD and DFX was given to a subgroup of patients following demethylating agents failure. Methods: A retrospective chart review of 17 elderly AML patients after demethylating agents failure was performed in three French centers. Patients treated by the combination of DFX/VD were matched to patients treated with best supportive care (BSC). Based on ferritin, and creatinin levels the dose of DFX was adapted in each case. DFX dose was up to 2000 mg a day and VD was used at 100,000 units orally weekly. The tolerance and the overall survival (OS) were analyzed. Pre-clinical studies were conducted in vitro on cell lines (HL60, U937, OCI-AML3, THP-1, MOLM 13) to evaluate cell differentiation induced by DFX and a new VDR agonist (Inecalcitol) by cell morphology and flow cytometry (expression of CD11b and CD14 markers). VDR activity and expression were evaluated by flow cytometry, immunoblotting, luciferase reporter assays and qPCR to detect VDR-targeted genes. Results: Median age of DFX/VD patients and BSC control group were 76 (range 63–84) and 71 (58–85) respectively. Most patients were diagnosed with AML with multilineage dysplasia (cases 70%, controls 76%). Prognosis groups were distributed homogeneously between the treated patients and controls. There were no significant differences in blast infiltration, leukocytosis, neutropenia, systemic iron and phosphocalcium parameters. All patients received 5-azacytidine (median of 8 courses for the cases and 7 for the controls).No renal insufficiency, hepatotoxicity or hypercalcemia were observed in DFX/VD patients. At 3 months, 4 treated patients (23.5%) had significant monocyte level increase an evidence of the enhanced monocyte differentiation efficacy. The treatment did not decrease the need of transfusion. Most interestingly median survival of treated patients was significantly increased (10.4 m vs 4 m, p=0.002). In vitro studies were conducted in parallel aiming to characterize new potential alternative therapeutic associations, which could improve patients' response. We show that the use of a new highly potent VDR agonist (Inecalcitol) potentiated the effect of DFX in promoting terminal monocyte differentiation of leukemic cell lines. It also increased VDR activity evaluated by VDR expression and phosphorylation and expression of VDR-targeted genes. In vivo studies in mice model of AML using combined DFX/inecalcitol therapy will be presented. Conclusions: The prognosis of elderly patients diagnosed with AML after demethylating agents remains poor. Here we show that the differentiating therapy by the association of Deferasirox and Vitamin D was able to improve overall survival with low toxicity. New generation of highly-potent VDR agonists (which are devoided of hypercalcemic properties) significantly enhanced VDR activation and terminal monocyte differentiation of AML cells and represent potential therapeutic alternatives in the near future. These encouraging results should be verified in a large randomized prospective multicenter study. Disclosures: No relevant conflicts of interest to declare.

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e65998 ◽  
Author(s):  
Etienne Paubelle ◽  
Florence Zylbersztejn ◽  
Sawsaneh Alkhaeir ◽  
Felipe Suarez ◽  
Céline Callens ◽  
...  

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yongfei He ◽  
Tianyi Liang ◽  
Shutian Mo ◽  
Zijun Chen ◽  
Shuqi Zhao ◽  
...  

Abstract Background The effect of time delay from diagnosis to surgery on the prognosis of elderly patients with liver cancer is not well known. We investigated the effect of surgical timing on the prognosis of elderly hepatocellular carcinoma patients undergoing surgical resection and constructed a Nomogram model to predict the overall survival of patients. Methods A retrospective analysis was performed on elderly patients with primary liver cancer after hepatectomy from 2012 to 2018. The effect of surgical timing on the prognosis of elderly patients with liver cancer was analyzed using the cut-off times of 18 days, 30 days, and 60 days. Cox was used to analyze the independent influencing factors of overall survival in patients, and a prognostic model was constructed. Results A total of 232 elderly hepatocellular carcinoma patients who underwent hepatectomy were enrolled in this study. The cut-off times of 18, 30, and 60 days were used. The duration of surgery had no significant effect on overall survival. Body Mass Index, Child-Pugh classification, Tumor size Max, and Length of stay were independent influencing factors for overall survival in the elderly Liver cancer patients after surgery. These factors combined with Liver cirrhosis and Venous tumor emboli were incorporated into a Nomogram. The nomogram was validated using the clinical data of the study patients, and exhibited better prediction for 1-year, 3-year, and 5-year overall survival. Conclusions We demonstrated that the operative time has no significant effect on delayed operation in the elderly patients with hepatocellular carcinoma, and a moderate delay may benefit some patients. The constructed Nomogram model is a good predictor of overall survival in elderly patients with hepatectomy.


2020 ◽  
Vol 10 (6) ◽  
pp. 315-324
Author(s):  
Fahmi Radityamurti ◽  
Fauzan Herdian ◽  
Tiara Bunga Mayang Permata ◽  
Handoko Handoko ◽  
Henry Kodrat ◽  
...  

Introduction: Vitamin D has been shown to have anti-cancer properties such as antioxidants, anti-proliferative, and cell differentiation. The property of vitamin D as an anticancer agent triggers researchers to find out whether vitamin D is useful as a radiosensitizer. Multiple studies have been carried out on cell lines in various types of cancer, but the benefits of vitamin D as a radiosensitizer still controversial. This paperwork aims to investigate the utilization of Vitamin D3 (Calcitriol) as radiosensitizer in various cell line through literature review.Methods: A systematic search of available medical literature databases was performed on in-vitro studies with Vitamin D as a radiosensitizer in all types of cell lines. A total of 11 in-vitro studies were evaluated.Results: Nine studies in this review showed a significant effect of Vitamin D as a radiosensitizer agent by promoting cytotoxic autophagy, increasing apoptosis, inhibiting of cell survival and proliferation, promoting gene in ReIB inhibition, inducing senescene and necrosis. The two remaining studies showed no significant effect in the radiosensitizing mechanism of Vitamin D due to lack of evidence in-vitro settings.Conclusion: Vitamin D have anticancer property and can be used as a radiosensitizer by imploring various mechanism pathways in various cell lines. Further research especially in-vivo settings need to be evaluated.


Author(s):  
Josiah Ng ◽  
Yoshio Masuda ◽  
Jun Jie Ng ◽  
Lowell Leow ◽  
Andrew M. T. L. Choong ◽  
...  

Abstract Objectives We performed a systematic review and meta-analysis of outcomes of lobectomy versus sublobar resection in elderly patients (≥65) with stage 1 nonsmall cell lung carcinoma (NSCLC). Methods We searched for relevant articles using a set of inclusion and exclusion criteria. Meta-analytic techniques were applied. Results Twelve studies (n = 5834) were chosen. Our results indicate that in the elderly, lobectomy for stage 1 NSCLC confers a survival advantage over sublobar resection. Lobectomy patients had a lower risk of death within 5 years and lower odds of local cancer recurrence. Our results show that lobectomy had a better 5-year cancer-specific survival and 5-year disease-free survival that trended toward significance. The sublobar resection group showed better 30-day operative mortality that trended toward significance. Subgroup analysis of stage 1A cancer demonstrated no difference in 5-year overall survival rates. However, for stage 1B tumors 5-year overall survival favored lobectomy. Conclusion Lobectomy for stage 1 NSCLC in elderly patients is superior to sublobar resection in terms of survival and cancer recurrence and should be afforded where possible. For stage 1A tumors, sublobar resection is noninferior and may be considered. Further randomized controlled trials in this topic is required.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1305-1305
Author(s):  
Andreas Engert ◽  
Heinz Haverkamp ◽  
Hans T. Eich ◽  
Andreas Josting ◽  
Beate Pfistner ◽  
...  

Abstract Purpose: The HD8 study of the German Hodgkin Study Group (GHSG) demonstrated that involved field (IF) radiotherapy is equally effective when compared with EF radiotherapy after four cycles of chemotherapy (2 x COPP/ABVD). Since there are indications that elderly patients with HD might fare worse depending on the type of treatment applied, we revisited the HD8 data for possible differences between younger and older patients. Methods and results: A total of 1204 patients were randomised to receive two double cycles of COPP/ABVD and either 30 Gy EF + 10 Gy bulk or 30 Gy IF + 10 Gy bulk. Of these, 98 evaluable patients were older than 60 years and 1038 patients were younger than 60 years. In general, there were more risk factors such as B-symptoms, elevated ESR, and poorer Karnofski index in the elderly group. On the other hand, there were fewer bulky tumours, large mediastinal tumours and a lower number of lymph node areas involved in elderly patients. The toxicity of treatment was more pronounced in elderly patients with 76 of 96 patients experiencing chemotoxicity Grade III or IV (79%) compared with 699 of 1018 (69%) in those younger than 60 years. After a median follow up of 52 months, the 5-year-FFTF was 85% in younger patients and 63% in patients older than 60 years (p <0.001). The 5-year-overall survival was 94% for patients younger than 60 years and 66% for patients older than 60 years (p < 0.001). In addition, patients older than 60 years treated with EF had a trend for worse FFTF and overall survival compared to those receiving IF radiotherapy. Conclusion: Event-free and overall survival of patients older than 60 years old are worse compared with younger patients. In particular, patients older than 60 years receiving EF radiotherapy had a poorer prognosis.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1512-1512
Author(s):  
Enrique M Ocio ◽  
Pilar Herrera ◽  
Teresa Olave ◽  
Salut Brunet ◽  
Albert Oriol ◽  
...  

Abstract Abstract 1512 Introduction: Acute Myeloblastic Leukemia (AML) in elderly patients remains an unmet medical need with a long term survival rate inferior to 10% despite the use of novel drugs. Therefore, there is a need for new agents that could induce higher CR rates and, most importantly, that could prolong the relapse free survival (RFS) and the overall survival (OS) of these poor-prognosis patients. Agents targeting epigenetics such as the hypomethylating drug 5-Azacitidine, have emerged as a promising strategy for elderly patients with AML or MDS. A second group of drugs targeting the epigenome are deacetylase inhibitors. Panobinostat is a pan-deacetylase inhibitor, with clear in vitro activity in AML and which is synergistic with anthracyclines (Maiso et al. Leukemia 2009). Based on these data we designed a phase I/II trial of panobinostat in combination with idarubicine and cytarabine followed by panobinostat maintenance in newly diagnosed AML patients older than 65 years. Methods: The initial schema included one or two induction cycles with idarubicine (8 mg/m2 days 1–3) + cytarabine (100 mg/m2 days 1–7) followed by escalating doses of panobinostat three days per week, per 3 weeks starting at 20 mg. Patients achieving CR/CRi received a consolidation cycle with the same schema. Those patients remaining in CR/CRi started a maintenance phase with 40 mg oral panobinostat in monotherapy three days per week, for 3 weeks in 28-days cycles. This schedule was amended after the six first patients, to reduce the weeks of administration of panobinostat to two weeks in the cycles in combination and to every other week in the maintenance phase. Initially a dose-escalating phase I with the classical 3+3 schema was carried out to define the maximum tolerated dose (MTD) of panobinostat in this combination; and then a phase 2 expansion phase was started to determine the efficacy of this combination in terms of CR rate and RFS. Results: 21 patients have been included after the amendment. Median age was 71 (range 66–83). Median % blasts was 40 (20–93). 35% of patients had AML with dysplastic features while adverse cytogenetics were present in 24%. Two out of 6 evaluable patients in the first cohort developed DLTs with panobinostat 20 mg (G3 hyperbilirrubinaemia in both, and one of them also G3 oedema), accordingly the dose of panobinostat was reduced to 10 mg. No DLTs were observed at this dose level, so 10 mg panobinostat was defined as the MTD in this combination. Treatment was well tolerated in the intensive cycles with the toxicity proper of standard induction chemotherapy. The most common non-hematologic toxicities (occurring in ≥20% of patients) included: fever (90%), infections (62%), mucositis (52%), diarrhoea (62%), constipation (43%), vomiting (57%), skin rash (38%), hepatotoxicity (38%) and hypokalaemia (24%). Grade 3/4 AEs were fever, infection, diarrhoea and hepatotoxicity in 2 patients each (10%) and hypokalaemia in 5 (24%). The median duration of the aplasia was 32 days (range 26–51). Regarding the maintenance phase with panobinostat monotherapy, the most frequent AEs were gastrointestinal: diarrhoea (62%), vomiting (62%) or abdominal pain (25%); as well as asthenia (50%. One of them being G3) and hyporexia (25%). In terms of efficacy, 11 patients (52%) achieved CR plus 2 more (10%) achieving CR with incomplete blood recovery (CRi) (overall 62%). There were 2 deaths in induction (10%), one due to a tumoral lysis syndrome before starting panobinostat and the other secondary to a respiratory infection. From the remaining 6 patients, 2 achieved partial response (10%) and 4 showed refractory disease (19%). With a median follow up of 6 months (range 2–14), among the 11 patients that achieved CR, 10 of them remain in CR and only 1 has progressed (in the 9th maintenance cycle). Both patients that achieved CRi have progressed in the 2nd and 6thmaintenance cycles. The median overall survival for the whole population is 13 months (2.3–23.6), and has not been reached for patients achieving CR. Conclusion: To the best of our knowledge, this is the first report of the use of a histone deacetylase inhibitor with chemotherapy in elderly AML patients. This combination was shown to be safe at the MTD. Although preliminary results are encouraging, particularly for the potential benefit of the maintenance phase, longer follow up is needed to evaluate if panobinostat maintenance is able to prolong RFS and subsequently OS in this poor prognostic population. Disclosures: Ocio: Novartis: Consultancy, Research Funding. Off Label Use: Panobinostat in newly diagnosed AML. Aliseda:Novartis: Employment. Winiger:Novartis: Employment. Hardikar:Novartis: Employment. Mateos:Novartis: Consultancy. San-Miguel:Novartis: Consultancy, Research Funding.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2072-2072 ◽  
Author(s):  
Eden Hailemichael ◽  
Jonathan L. Kaufman ◽  
Christopher R. Flowers ◽  
Edmund K. Waller ◽  
Mary Jo Lechowicz ◽  
...  

Abstract Abstract 2072 Introduction: Many randomized control trials demonstrated that HDT-ASCT is superior to conventional therapies in myeloma patients and prolongs progression free survival (PFS) and overall survival (OS) (Attal M, 1996, Childs JA, 2003). However, in treating a malignancy with a median age of diagnosis of 69 years, the majority of the patients will not be eligible for this beneficial approach if a nominal numerical age cut-off (<65 years) is followed based on the assumption that elderly patients cannot tolerate HDT-ASCT; nor will they be eligible for clinical trials involving HDT-ASCT if stringent age-restricted inclusion criteria are incorporated. Therefore, we have evaluated if the elderly patients benefit from HDT-ASCT. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) 18 registry data (www.seer.cancer.gov) as our comparator (reflects 28% of the US population);to provide information on incidence, prevalence and survival from 1973–2009. The data from an institutional cohort (IC) is obtained from the records of patients that underwent HDT-ASCT from January 2000 to January 2012. We used IBM SPSS version 20 to generate the Kaplan-Meier survival curves. Results: Of the 6,571,117 malignant cases listed in SEER registry, a total of 74,826 cases (1.1%) of multiple myeloma (ICD-03 code 9732) were identified (39735 males and 35091 females). Median age of the patients is 70 years. Among these patients 48,988 patients (65%) are over the age of 65. A total of 901 myeloma patients underwent HDT-ASCT from IC during the evaluable period and 167 patients (19%) were over the age of 65. The median survival for each subset is listed in Table 1. Both male and female WCI-ASCT myeloma patientshad prolonged OS compared to the SEER myeloma patients, despite the difference in magnitude of advantage in IC-ASCT male patients vs. female patients. Both white and black patients, as well as patients undergoing HDT-ASCT across all age subgroups had a significant survival advantage. Conclusions: In each subgroup, by the decade of diagnosis, gender, race, age subsets we have consistently demonstrated a significant survival benefit for IC transplant patients ≥age 65 compared to SEER myeloma patients ≥age 65 if offered HDT-ASCT. Selection-bias prevails in the groups showing improved overall survival. Hence, a careful selection process considering physiologic age as a determinant for transplant eligibility would result in better outcomes, and not preclude the elderly from the survival benefits of HDT-ASCT. Disclosures: Kaufman: Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Flowers:Celgene: Consultancy; Prescription Solutions: Consultancy; Seattle Genetics: Consultancy; Millennium: Research Funding, Unpaid consultancy, Unpaid consultancy Other; Genentech: Unpaid consultancy, Unpaid consultancy Other; Gilead: Research Funding; Spectrum: Research Funding; Janssen lymphoma research foundation: Membership on an entity's Board of Directors or advisory committees. Waller:Outsuka: Research Funding.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15647-e15647 ◽  
Author(s):  
Elinor Tan ◽  
Charbel Sandroussi

e15647 Background: Liver surgery in the elderly remains controversial amidst growing incidence in developed countries. This study compares perioperative outcomes of elderly with non-elderly patients undergoing curative hepatectomy for primary liver malignancies. Methods: 310 patients underwent liver resection for primary tumours between 2000 and 2018. There were 71 elderly (≥70 years) and 239 non-elderly patients ( < 70 years). Survival analyses, stratified according to pathology (Hepatocellular carcinoma (HCC), n = 262 and Cholangiocarcinoma (CC) n = 48), were compared between the elderly and non-elderly group. Multiple regression analyses were performed to evaluate independent predictors of major complications and overall survival. Results: Elderly patients had higher frailty score (modified Frailty Index, mean, 1.14 v 0.51, p < 0.001), more comorbidities (Comorbidities ≥4: 28% v 14%, p = 0.005), had non viral-induced primary liver cancers (Non-Hep B Non-Hep C: 65% v 19%, p < 0.001) with lower AST (p = 0.014) and ALT (p = 0.004) levels. 46% of patients underwent major hepatectomy and were similar between both groups (p = 0.502). The overall complication rate and duration of stay were comparable (p > 0.05). Post-Hepatectomy Liver Failure occurred in 10 (3%) patients with no difference between both groups (p > 0.05). There were 11 (4%) postoperative deaths with higher mortality in the elderly group (8% v 2%, p = 0.011). Multiple logistic regression revealed that MELD ≥11 (OR 2.415, p = 0.480) and a positive surgical margin (OR 2.549, p = 0.024) were independent predictors for major complications. The overall survival (OS) and disease free survival (DFS) for both HCC and CC were similar between elderly and non-elderly group respectively (HCC: 5-yr OS, 62% v 68.5%, p = 0.712; 5-yr DFS, 30.4% v 38.8%, p = 0.323; CC: 5-yr OS, 62.2% v 48.3%, p = 0.919; 5-yr DFS, 43.6% v 28.2%, p = 0.618). Multiple Cox regression revealed that albumin < 40g/L (HR 2.533, p = 0.002) and the presence of vascular invasion (HR 2.417, p = 0.004) were independent predictors of poor survival. Conclusions: Long-term survivals were comparable between the elderly and non-elderly patients following surgical treatment for primary liver cancers. Low albumin and vascular invasion predicted poor survival. Age alone should not be a contraindication to liver surgery. Major complications may be minimised by carefully selecting patient and paying particular attention to the MELD score in elderly patients with primary liver disease. Further prospective studies are required to confirm the findings here.


Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Nicholas M Orme ◽  
Ryan J Lennon ◽  
Bradley R Lewis ◽  
Rajiv Gulati ◽  
Gurpreet Sandhu ◽  
...  

Background: The presence of frailty increases the risk of long-term mortality for a myriad of reasons, but its association with cardiac-specific mortality among the elderly undergoing percutaneous coronary intervention (PCI) is unknown. We sought to determine the relationship between frailty and cause-specific (cardiac versus non-cardiac) mortality among elderly patients undergoing PCI. Methods: A prospective cohort of elderly (>65 years) patients undergoing PCI at Mayo Clinic between October 2005 and September 2008 were tested for frailty using the Fried criteria. Vital status was prospectively monitored including evaluation of death certificates, telephone interviews and review of autopsy/medical records. Results: Frailty data was obtained in 428 (84%) of 508 elderly patients (median age 74.2 years [SD 6.4, range 65-100]; 59% male). Of these, 92 (21%) patients were frail while 231 (54%) had intermediate frailty and 105(25%) were not frail. Frail patients were older than intermediate and non-frail patients (77.6 vs 74.3 vs 71.0 years; p<0.001) and had more comorbidities (mean Charlson index 4.6 vs 3.9 vs 2.8; p<0.001). There were 113 deaths (26% of cohort) during 5.1 median years of follow-up, of which 77 (68%) were classified as non-cardiac and 36 (32%) which were classified as cardiac. Frailty at baseline was associated with poor overall survival compared to non-frail patients (HR 6.1, 95% CI 3.2, 11.6; p<0.001). The estimated effect of frailty was nearly 3 times greater for cardiac mortality (HR 13.1, 95% CI 3.0, 57.0; p=0.001) than non-cardiac mortality (HR 4.6, 95% CI 2.2, 9.7; p<0.001). These findings remained significant following multivariable adjustment. Conclusions: Frailty is common among elderly patients undergoing PCI and is associated with poor overall survival and both cardiac and non-cardiac causes of death.


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