Intensive Chemotherapy In Elderly Patients Research Articles

Hypomethylating Agents Versus Intensive Chemotherapy in Elderly Patients (Age ≥ 70) with Acute Myeloid Leukemia with High White Blood Cell Count

▪BackgroundAcute myeloid leukemia (AML) is primarily a disease of older adults, with 40-50% of patients ≥ 70 years old at diagnosis. Optimal frontline therapy for elderly AML patients remains controversial. Intensive chemotherapy (IC) is often favored in those AML patients who present with leukocytosis (P-AML), yet the evidence to support this practice as opposed to lower intensity therapy is scarce. We aimed to investigate the outcomes of older patients with P-AML based on treatment choice of intensive chemotherapy (IC) vs hypomethylating agents (HMA).MethodsWe retrospectively analyzed 983 elderly AML patients (age ≥ 70 years) treated at Moffitt Cancer Center between 1995 and 2016. Patients with prior exposure to HMA for non-AML diagnoses were excluded. We focused on P-AML patients, defined as baseline WBC ≥ 10x109/L, who received initial therapy with either: intensive chemotherapy (IC) (defined as daunorubicin/cytarabine or equivalent) or hypomethylating agents (HMA) (azacitidine (AZA) or decitabine (DEC)). Age, type of AML, history of antecedent hematologic disease, cytogenetics (per European LeukemiaNet (ELN) criteria), Eastern Cooperative Oncology Group (ECOG) performance status, Charlson comorbidity Index (CCI), complete blood counts and myeloblast percentage at time of diagnosis were obtained for each patient. Kaplan-Meier analysis was performed to calculate overall survival (OS) and the log-rank test was used to determine significance where a p-value of 0.05 was defined as significant. Fisher's exact t-test, hazard ratios (HR) and confidence interval (CI) were calculated using GraphPad Prism v7.03. Univariate and multivariate analysis for the baseline characteristics and type of therapy were performed using SPSS v24.0 to determine prognostic impact.ResultsWithin the entire cohort of older AML patients, we identified 156 who were treated with either HMA (n=41) or IC (n=115). Baseline characteristics of these patients are described in Figure 1A. Significant baseline differences in age, hemoglobin, WBC, ELN cytogenetic category, marrow blast %, and CCI score were observed between the HMA and IC groups. Most notably, the HMA group were older (median age 77 yrs vs 74 yrs, p=0.0037), had a higher incidence of poor-risk cytogenetics (36.6% vs 7%), and were more likely to have CCI score ≥ 3 (29.3% vs 8.7%).Median time of initial treatment was 4.3 months (range: 0.10-70.0 months) in the HMA group compared to 0.5 months (range: 0.33-1.90months) in the IC group. Median OS of the entire group was 7.85 mo. Median OS in the HMA-treated patients was superior to IC treated patients (13.7 mo vs. 5.1 mo, HR 0.63, 95% CI 0.443 - 0.886, p=0.0082) (Figure 1B). The 12 month survival rate was 55.0% in the HMA group and 31.0% in the IC group (p=0.0082). Fifty-two (33%) patients achieved CR/CRi. There was no difference in CR/CRi rates between HMA or IC treated cohorts (30.0% vs. 34.8%, p=0.6983). Rate of relapse upon achievement of CR/CRi was not statistically significant between HMA and IC cohort (41.7% vs. 62.5%, p=0.3181). The 30-day mortality rate was lower in the HMA group compared to the IC group (7.3% vs 24.4%, p=0.0217).Univariate analysis identified treatment type (p<0.0001), cytogenetic risk category (p <0.0001), and ECOG performance status (p<0.0001) as significant prognostic factors for OS. Multivariate analysis identified IC treatment (HR 2.01, 95% CI 1.24-3.26, p=0.005) and poor ECOG performance status (HR 4.30, 95% CI 1.182-15.659, p=0.027) as independent negative predictors of OS.ConclusionsElderly patients (age ≥ 70) with proliferative AML appear to achieve a survival advantage with HMA-based frontline therapy compared to IC, despite a disproportionately higher incidence of traditionally adverse prognostic features (poor-risk cytogenetics, high CCI score) in the HMA group. The reasons for this observation are unclear, but could relate to a higher early death rate with IC or biologic/molecular features that induce greater sensitivity to HMAs, which should be studied in future analyses. Although this study was limited by small size and retrospective nature, our findings cast doubt on the notion that intensive therapy should be the standard frontline approach in elderly patients proliferative/high WBC AML. [Display omitted] DisclosuresSallman:Celgene: Research Funding. Padron:Incyte: Honoraria, Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria. Lancet:Biopath, Biosight, Boehringer Ingelheim, Celator/Jazz, Celgene, Janssen, Karyopharm Therapeutics, and Novartis: Consultancy; Pfizer: Other: Institutional research funding.

Sorafenib in Combination With Intensive Chemotherapy in Elderly Patients With Acute Myeloid Leukemia: Results From a Randomized, Placebo-Controlled Trial

The prognosis of elderly patients with acute myeloid leukemia (AML) is still dismal even with intensive chemotherapy. In this trial, we compared the antileukemic activity of standard induction and consolidation therapy with or without the addition of the kinase inhibitor sorafenib in elderly patients with AML. All patients received standard cytarabine and daunorubicin induction (7+3 regimen) and up to two cycles of intermediate-dose cytarabine consolidation. Two hundred one patients were equally randomly assigned to receive either sorafenib or placebo between the chemotherapy cycles and subsequently for up to 1 year after the beginning of therapy. The primary objective was to test for an improvement in event-free survival (EFS). Overall survival (OS), complete remission (CR) rate, tolerability, and several predefined subgroup analyses were among the secondary objectives. Age, sex, CR and early death (ED) probability, and prognostic factors were balanced between both study arms. Treatment in the sorafenib arm did not result in significant improvement in EFS or OS. This was also true for subgroup analyses, including the subgroup positive for FLT3 internal tandem duplications. Results of induction therapy were worse in the sorafenib arm, with higher treatment-related mortality and lower CR rates. More adverse effects occurred during induction therapy in the sorafenib arm, and patients in this arm received less consolidation chemotherapy as a result of higher induction toxicity. In conclusion, combination of standard induction and consolidation therapy with sorafenib in the schedule investigated in our trial is not beneficial for elderly patients with AML.

5-Azacytidine (AZA) Compared to Intensive Chemotherapy in Elderly Acute Myeloid Leukemia (AML) Patients: Results of a Retrospective Single Centre Matched Analysis,

Abstract 3620AML in elderly patients is characterized by a poor prognosis, especially in those patients aged >70, and/or in frail patients with comorbidities or poor performance status (PS). Moreover, several studies already suggested that elderly AML patients with unfavorable karyotype may not benefit from intensive chemotherapy. With this background, and using a matched analysis, this report aimed to assess the outcome of a single centre series of elderly AML patients who received either non intensive therapy by hypomethylating agents, or standard induction with intensive therapy.All patients were aged over 60 and had de novo or secondary AML. For the purpose of this comparison, the cohort was divided in two distinct groups. Group A included 36 cases treated by intensive chemotherapy between 1995 and 2005 according to the GOELAMS AML-SA2002 or SA3&4 protocols (5+7 induction with idarabicine 5 mg/m2/d and cytarabine 100 mg/m2/d). In this group, patients who could achieve CR received either 3 or 6 consolidation courses delivered over 1 or 2 years (according the protocol AML-SA2002 versus SA3&4). Group B included another 36 patients who were treated between 2006 and 2010 with AZA according to the recommendations of the “compassionate use program” authorized by the French Health Agency (one cycle of AZA = 7 days of subcutaneous administration 75mg/m2 every 28 days until progression).In this group, response was assessed after 3 cycles and qualified using IWG criteria. These two groups were matched based on cytogenetic features and age.The median age for the total cohort was 72 years (range, 60–86). Groups were comparable for WBC, % marrow blasts infiltration, WHO subtypes, and cytogenetic features at diagnosis. A higher rate of secondary AML was observed in the AZA arm. CR and CR with incomplete hematological recovery (CRi) rates were significantly higher in the intensive vs. AZA arm (63% vs. 28%, p<0.0001). However, there was a trend for a higher rate of partial remission (PR) in the AZA Arm (25% vs. 5%, p=0.02). With a median follow-up of 13.3 months (range, 5–80) from diagnosis, median overall survival (OS) was comparable between the two arms: 10.4 vs. 10.3 months, p=0.3) In multivariate analysis for OS including treatment strategy, the strongest prognostic factors were an unfavorable karyotype (HR=2.05, 95%CI, 1.09–3.85; p=0.03), PS status (0 vs. 1–2; HR=2.04 95%CI, 1.16–3.58; p=0.01) and platelets number at diagnosis (analyzed as a continuous variable) (HR=1, 95%CI, 0.99–1.00; p=0.04). Of note, the treatment arm was not found to be a significant determinant for OS: (AZA vs intensive chemotherapy.; HR=1.86, 95%CI, 0.86–3.16; p=0.13).This analysis suggests that the use of AZA as an alternative to intensive chemotherapy in elderly patients with de novo or secondary AML may lead to similar OS, despite a significant difference in terms of CR and CRi rate. The different mechanism of action of AZA in comparison to conventional chemotherapy, and the higher rate of PR that can be achieved after AZA therapy might contribute to improved OS through relatively long lasting disease control. These results set the frame for a prospective controlled trial to test AZA as an ambulatory alternative to standard intensive chemotherapy in elderly AML patients, especially those patients with unfavorable karyotype or poor PS and comorbidities. Disclosures:No relevant conflicts of interest to declare.

Leukocytosis and Circulating Blasts in Older Adults With Newly Diagnosed Acute Myeloid Leukemia: Are They Valuable Factors for Therapeutic Decision-Making?

The treatment of older adults with acute myeloid leukemia (AML) is associated with unsatisfactory rates of response and overall survival. Identification of valuable factors that can facilitate therapeutic decision-making between intensive chemotherapy and investigational treatment strategies is warranted. Analysis of proliferative (white blood cell [WBC] count) and invasive (percentage of blast cells in peripheral blood) characteristics of leukemic blasts at diagnosis is presented in a population of 432 promyelocytic leukemia AML patients who are older than than 60 years and have been selected for entering onto five successive clinical trials combining an anthracycline and cytarabine. Five groups of patients were defined according to these two relevant parameters used in clinical practice. Response rates were lower for the hyperproliferative groups (47% and 46%, respectively) and the nonproliferative groups displaying circulating blasts (56% and 59%, respectively) compared with those for the nonproliferative and noninvasive group (77%) (P = .0003). Median overall survivals were shorter for the hyperproliferative groups (5.7 and 5.8 months, respectively) compared with those observed for the nonproliferative groups (8.9 and12.6 months, respectively). This combination of basic characteristics helps estimate the outcome of elderly AML patients who are usually selected for intensive chemotherapy. Although these factors remain valuable for identifying leukemia behavior, our study demonstrated that results of intensive chemotherapy in elderly patients remained poor, whatever the prognostic group. Comparison with recent data from the literature requires investigators to study results differently and to consider investigational therapy as being the most appropriate treatment even for this highly selected population.

Combination Treatment of Flag with Non-Pegylated Liposomal Doxorubicin (MYOCET™) in Elderly Patients with Acute Myeloid Leukemia: A Single Center Experience

The incidence of acute myeloid leukemia (AML) increases with age, but results of intensive chemotherapy in elderly patients are disappointing. Non-pegylated liposomal formulations of doxorubicin (Myocet™) have been developed with the aim of reducing systemic and cardiac toxicity especially in the elderly. We evaluated the efficacy and toxicity profiles of fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) regimen given in association with Myocet™ in 35 patients with AML, median age 69 years (range 61-83 years). Nineteen (54.3%) had newly-diagnosed AML, twelve (34.3%) patients had secondary AML (ten with Myelodisplastic Syndrome, two with Primary Myelofibrosis) and 4 (11.4%) patients had had a late relapse (>12 months) of AML. Complete remission (CR) and partial remission (PR) were obtained in twenty-two (63%) and 3 (8.5%) patients, respectively. Seven (20%) patients showed a resistant disease. There were 3 early deaths (8.5%). Six patients (17%) experienced severe cardiovascular toxicity. The median overall survival (OS) was 12 months (range 1-52 months) with a median disease-free survival (DFS) of 20 months (range 1-48 months). One-year and two-year DFS were 78.9% and 26.7%, respectively. This study demonstrates that in elderly patients with AML, FLAG-Myocet combination shows promising efficacy response with acceptable toxicity, enabling most patients to receive further treatments, including transplantation procedures.

Treatment of Non-APL Acute Myelogenous Leukemia with Intravenous Arsenic Trioxide Plus Ascorbic Acid.

Introduction: Arsenic trioxide (ATO) has demonstrated efficacy in acute promyelocytic leukemia (APL), inducing complete remissions (CR) in 85% of relapsed patients. On the other hand, ATO alone has no activity in non-APL AML. Although this difference could be explained by degradation of the APL specific PML/RAR fusion protein, ATO has shown to be active against APL cells by mechanisms that are independent of this gene rearrangement. ATO-induced apoptosis correlates inversely with intracellular concentrations of reduced glutathione (GSH) via generation of reactive oxygen species (ie, cells with high concentrations of GSH are more resistant to ATO). APL cells were found to have low levels of GSH compared to non-AML cells. Agents that reduce intracellular GSH, such as ascorbic acid (AA), increase ATO-induced apoptosis and can overcome resistance to ATO in non-APL AML cell lines; AA alone has no activity in these cells. Thus, the combination of ATO and AA was evaluated in patients with non-APL AML.Methods: ATO (0.25 mg/kg/d) was administrated intravenously over 1–4 hours with intravenous AA (1g/d, given 30 minutes after ATO) for five days/week (five days on/2 days off) for five weeks (25 doses=one cycle). These doses were based on a phase I/II trial of ATO + AA in patients with multiple myeloma (Behalis et al Clin Cancer Res 8:3658, 2002). Responding patients received an additional consolidation cycle of 25 doses followed by maintenance including ATO + AA two weeks of every month for 4 cycles. Patients who failed to respond after two cycles were considered treatment failures.Results: Eleven patients, aged 36–84 years (median: 66 years), were enrolled: 5 had relapsed after chemotherapy; and 6 elderly, aged 66–84, (including 5 with antecedent MDS), were previously untreated. One patient was discontinued prematurely because of QT prolongation. Major response was seen in 3 (27%) pts: CR or CRp in 2 patients and decrease in bone marrow blasts to <5% with reduced transfusion requirements in 1 patient. Three additional patients had a drop in peripheral blood blasts from 85% and 51% to <5%. All responding patients, except for 1, were previously untreated. Responses were observed after the first treatment cycle. Duration of responses were 6 months in the CR and CRp patients, and 1 week, 2 months and 4 months in the other responders. Four pts failed and had progressive disease; one patient died on study from progressive disease and infection. Grade 3/4 toxicity included infection (n=8), and QT (>500 msec), anorexia, fatigue, sensory neuropathy, elevated bilirubin (n=1 each). One responding patient developed shortness of breath with severe hypoxemia, reminiscent of the APL differentiation syndrome, which responded immediately to dexamethasone.Conclusion: ATO + AA can have anti-leukemic activity in poor risk non-APL AML with much less toxicity than chemotherapy, especially in previously untreated patients. Most relapsed patients did not respond to ATO +AA, suggesting that chemotherapy can induce resistance to this combination. Further studies are needed to explore the potential of ATO +AA as a front-line therapy instead of intensive chemotherapy in elderly patients with non-APL AML.

Treatment of Non-APL Acute Myelogenous Leukemia with Intravenous Arsenic Trioxide Plus Ascorbic Acid.

Introduction: Arsenic trioxide (ATO) is an exceptionally active drug in acute promyelocytic leukemia (APL), inducing complete remissions (CR) in 85% of relapsed patients. ATO also has clinical activity in myelodysplastic syndromes (MDS). In non-APL AML cells lines, ATO induces apoptosis in vitro; however, in a small study of 11 non-APL AML patients, ATO showed no activity (Parmer et al Leuk Res 28:090, 2004). ATO-induced apoptosis has been shown to correlate inversely with the level of intracellular reduced glutathione (GSH) via generation of reactive oxygen species; cells with high concentrations of GSH are more resistant to ATO. Ascorbic acid (AA) increases apoptosis and overcomes resistance to ATO in multiple myeloma, non-APL AML and other cell lines by reducing intracellular GSH levels. AA alone has no activity in these cells. We therefore administered ATO plus AA to patients with non-APL AML.Methods: ATO 0.25 mg/kg was administrated intravenously over 1-4 hours with 1 gram of intravenous AA given 30 minutes after ATO daily for five days a week (five days on/2 days off) for five weeks (25 doses=one cycle). These doses were based on a phase I/II trial of ATO + AA in patients with multiple myeloma (Bahlis et al Clin Cancer Res 8:3658, 2002)). Responding patients received an additional consolidation cycle of 25 doses followed by maintenance including ATO + AA two weeks of every month for 4 cycles. Patients who failed to respond after two cycles were considered treatment failures.Results: Nine patients aged 36–84 years (median: 66 years) were treated: 5 pts. had refractory AML or relapsed after chemotherapy; 4 elderly pts,. aged 66–84, with antecedent MDS were previously untreated. Activity was seen in 5 (56%) patients, including all 4 of the previously untreated pts: CR in 1 pt. (patient with an early relapse), CRp in 1 pt., decrease in bone marrow blasts to <5% with reduced transfusion requirements in 1 pt, and drop in peripheral blood blasts from 84% and 51% to <5% in 2 patients. Responses were observed after the first treatment cycle. Duration of responses were 6 months in the CR and CRp pts., and 1 week, 2 months. and 4 months in the other responders. Four pts had progressive disease; one patient died on study from progressive disease and infection. Grade 3 /4 toxicity included: infection in 8 pts., and anorexia, sensory neuropathy, elevated bilirubin in 1 pt. each. One responding patient developed shortness of breath with severe hypoxemia, reminiscent of the APL differentiation syndrome, which responded immediately to dexamethasone.Conclusions: ATO + AA has anti-leukemic activity in non-APL AML patients. Despite the high doses of ATO, higher than used in APL and MDS, toxicity was tolerable. This combination could be a less toxic alternative front-line approach to intensive chemotherapy in elderly patients with non-APL AML. Further study of ATO + AA is warranted either alone or in combination with other agents in an attempt to further improve the results.

Treatment of Acute Myelogenous Leukemia (non-APL) with Intravenous Trisenox® (Arsenic Trioxide) and Ascorbic Acid: Preliminary Results.

Introduction: Arsenic trioxide (ATO) is an exceptionally active drug in acute promyelocytic leukemia (APL), inducing complete remissions in 85% of relapsed patients. ATO also has clinical activity in myelodysplastic syndrome (MDS). In non-APL AML cells lines, ATO induces apoptosis in vitro; however, in a small study of 11 non-APL AML patients, ATO showed no activity (Parmer et al Leuk Res 28:090, 2004). In some types of cancer cells, ATO-induced apoptosis has been shown to correlate inversely with the level of intracellular reduced glutathione (GSH) via generation of reactive oxygen species; cells with high concentrations of GSH are more resistant to ATO. Ascorbic acid (AA) increases apoptosis and overcomes resistance to ATO in multiple myeloma, non-APL AML and other cell lines by reducing intracellular GSH levels. AA alone has no activity in these cells. We therefore conducted a clinical trial in patients with non-APL AML combining ATO and AA.Methods: ATO at a dose of 0.25 mg/kg is administrated intravenously over 1–3 hour with 1 gram of intravenous AA given within 30 minutes daily for five days a week (five days on/2 days off) for five weeks (25 doses - one cycle). These doses were based on a phase I/II trial of ATO+AA in patients with multiple myeloma (Behalis et al Clin Cancer Res 8:3658, 2002)). Responding patients receive an additional consolidation cycle of 25 doses followed by maintenance of two weeks of every month of ATO+ AA for 4 cycles. Patients who fail to respond after two cycles are considered treatment failures.Results: Seven patients have so far enrolled: three (aged 36,52,59) had relapsed after chemotherapy, and four aged 66–84 (median 70), never received chemotherapy. For these untreated patients ATO+AA was given as front line treatment. In three of the four previously untreated patients the number of bone marrow blasts dropped from > 40% to < 5% (2 pts. after 1 cycle; 1 pt. after 2 cycles) At the time of this report only one of the responding patients received more than one cycle and had improvement in the peripheral blood counts. The three patients, who failed chemotherapy, did not respond to ATO+AA (one patient received only one cycle). Despite the high doses of ATO, higher than used in APL and MDS, the combination was very well tolerated with grade 3 toxicity in one patient only (sensory neuropathy). One responding patient developed shortness of breath with severe hypoxemia, reminiscent of the APL differentiation syndrome, which responded immediately to dexamethasone.Conclusion: These preliminary results in patients with non-APL AML suggest that: (1) AA +ATO has anti-leukemia activity in untreated non-APL AML patients with minimal toxicity; (2) more than one cycle is probably needed to achieve a response in the peripheral blood counts; (3) in non-APL AML, ATO can cause the so called “differentiation syndrome” which should be anticipated and treated early. If confirmed in additional patients, ATO+AA might be a less toxic alternative upfront approach to intensive chemotherapy in elderly patients with non-APL AML.