scholarly journals Enasidenib, an Oral Therapy in Mutant IDH2 Relapsed/Refractory Acute Myeloid Leukemia: A Real-Life Single Center Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-21
Author(s):  
Marta Riva ◽  
Lorenzo Rizzo ◽  
Valentina Mancini ◽  
Rosa Greco ◽  
Giambattista Bertani ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Target Therapy ◽  
Real Life ◽  
Median Number ◽  
Intensive Chemotherapy ◽  
Unfit Patients ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Background: The treatment for relapsed or refractory acute myeloid leukemia (R/R AML) has minimal chances and a low impact on improving survival. One of the most important goal is to treat unfit patients who are often intolerant to intensive chemotherapy and are not eligible for allogeneic stem cell transplantation. Most patients with AML, including nearly all patients older than 60 years, present multiple, sequentially acquired, somatic mutations. Isocitrate dehydrogenase 2 (IDH2) mutations are present in approximately 8-19% of cases (Buege MJ, Cancers 2018). IDH2 mutations occur early in the leukemogenesis and accumulate an oncogenic product (R-2-hydroxyglutarate) that arrests the histone demethylation pathway, thereby stopping haematopoietic differentiation (Rakheja D, Hum Pathol. 2012). Enasidenib (ENA) is a selective, powerful oral inhibitor of the oncogenic activity of the IDH2 mutant enzyme, that decreases R-2-hydroxyglutarate levels in vitro and in vivo. Interestingly, phase I/II trials showed an overall response rate (ORR) of 40.3% in R/R disease, with 19.3% of complete remission (CR) and with 6.8 % of CR with incomplete haematological recovery (CRi). Moreover, the reported median overall survival was 9.3 months, with 19.7 months (mo) for patients who achieved CR (Stein E, Blood 2017). Aims: To study retrospectively the efficacy and safety of ENA, as single agent, in improving overall survival (OS) and progression-free survival (PFS) in IDH2 mutated R/R AML patients (pts), unfit for intensive chemotherapy. Furthermore, to compare outcomes with a cohort of patients with R/R AML IDH2 wild-type (wt). Methods: Since 2018 we have retrospectively collected and analyzed data of unfit IDH2 mutated R/R AML patients, treated with ENA, thanks to the expanded access program of this drug. The dose was 100 mg/day for all pts. PFS and OS were estimated using the Kaplan-Meier product limit method. Therefore, we considered, as historical comparison, a sample of 28 pts with R/R IDH2 wt AML, treated with the best available therapy at our Institution in the same time frame and matched for clinical features. OS and PFS were compared using the log-rank test. Results: Nine IDH2 mutated pts were considered for analysis: 4 (44%) cases were de novo AML, while 5 (56%) were secondary (1 myelodysplasia and 4 myeloproliferative neoplasms). Median age at relapse was 71 years (range 47-79). Median number of previous therapies was 2 (range 1-3). All pts completed at least one cycle of ENA with a median number of 5 cycles (range 1-16). Median OS from AML diagnosis and from the beginning of ENA was 28 mo (range 3-65), and 15 mo (range 1-27) respectively; median PFS was 13 mo (range 1-14). Among the 28 patients of the control group, with a median age at relapse of 74 years (range 65-86) we recorded a median OS of 14 mo (range 7-62) and an OS from the last relapse of 2 mo (range 0,5-26). The ENA pts group showed a significantly better OS than the control population (p = 0,0419) (Figure 1). The most prominent toxicities were hyperbilirubinemia in 2 pts (22,2%) and IDH-differentiation syndrome (IDH-DS) in 3 (33,3%); though the drug was generally well tolerated. Therefore, patients were treated as outpatients in most cases. Conclusions: In the era of precision medicine, molecular target therapy is the most promising strategy to increase the probability of treatment success with limited side effects. Our experience confirms the efficacy of the IDH2 inhibitor ENA to treat unfit patients with R/R AML in the real life, showing significantly better outcome in terms of survival for the pts treated with target therapy, compared to pts treated with standard therapy. Disclosures Veronese: Janssen Cilag:Honoraria;Bayer:Honoraria;Novartis:Other: Travel Expenses;AstraZeneca:Other: Travel Expenses.

5-Azacitidine In Patients with Myelodysplasia and Acute Myeloid Leukemia: a Single Centre Experience

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4969-4969 ◽  
Author(s):  
Capodanno Isabella ◽  
Paolo Avanzini ◽  
Francesco Merli
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Progression Free Survival ◽  
Median Number ◽  
Study Population ◽  
Blast Count ◽  
Acute Myeloid

Abstract Abstract 4969 Introduction Hypomethylating agents have recently been shown to prolong overall survival and improve quality of life in patients with INT-2 and high IPSS risk myelodysplasia (MDS) and low bone marrow blast count acute myeloid leukemia (AML). Patients and Methods Since September 2008 we have been treating 26 patients affected by acute myeloid leukemia (13 patients), MDS (11 patients) or chronic myelomonocytic leukemia (2 patients) with 5-azacitidine. According to recent guidelines, most of myelodysplastic patients eligible for treatment belonged to the IPSS INT-2 or high risk groups. Patients with acute myeloid leukemia had a medullary blast count of 20–30%, except for four cases. Patients with chronic myelomonocytic leukemia had a medullary blast count > 10% and < 20%. The median age of patients when treatment was started was 69,5 years (range: 51–82). Azacitidine was administered subcutaneously (75 mg/m2/d) for 7 days of every 28-day cycle until loss of response or disease progression. Patients received a median number of 5,5 cycles of therapy (range 1–24). We evaluated overall improvement (CR + PR+ HI), the best response obtained and adverse events in the overall study population, according to International Working Group MDS and LMA criteria. In the subgroup of patients who received at least 6 cycles of therapy (10 patients) we also evaluated overall survival (OS) and progression free survival (PFS). Results The results of 5-azacitidine therapy in our cohort of patients are described in Table 1. In the AML cohort, after a median number of 4 cycles (range 1–10), we observed a hematological improvement (HI) in 15% of the patients, a stable disease (SD) in 31% of patients and a lack of response in 38% of patients. In the MDS cohort, after a median number of 7 cycles (range 2–24), we observed a complete response (CR) (including a cytogenetic response) in 36.5% of patients, a partial response (PR) in 9% of patients, a hematological improvement in 45.5% of patients and a stable disease in 18% of patients. The overall improvement (CR + PR + HI) was 15% in the AML cohort and 91% in the MDS cohort. In the LMMC cohort, after a median number of 2.5 cycles (range 1–4), we observed a hematological improvement in 50% of the patients. In the subgroup of patients who received at least six cycles of therapy, the overall survival was 11.5 months and the progression free survival was 9 months. In the overall study population, two patients (8%) discontinued treatment as a result of adverse events. In four non-responder patients (15%) death was due to a rapid progression of disease. Discussion In this analysis we have reported good response rates in MDS patients, with 36.5% of complete response (including a complete cytogenetic response). No CR or PR were observed in AML patients; however, in this subgroup of patients the median follow-up was short (median number of cycles of therapy: four). Furthermore, in these patients even a stable disease with no need of hospitalization and a good quality of life can be considered an important result. Due to the short period of follow-up, 57.5% of our patients received fewer than 6 cycles of 5-azacitidine and their therapy is still ongoing. Conclusions The limited number of cases and the short period of follow-up did not allow us to evaluate overall survival and progression free survival in the overall study population. We will update these data as time progresses. We reported these data in the subgroup of patients who received at least six cycles of therapy. According to current evidence, we observed that 5-azacitidine plays an important role in the treatment of patients with MDS (both with high- and low-IPSS risk) and low bone marrow blast counts AML. In these subgroups of patients, 5-azacitidine prolongs survival and is well tolerated. In our limited experience, this drug had no efficacy when a higher degree of bone marrow blasts (> 30%) was present. Further trials should assess the number of cycles required for treatment, the role of hypometilating agents in low-risk MDS and in patients with AML and a bone marrow blasts counts > 30%. Disclosures: No relevant conflict of interest to declare. Disclosures: No relevant conflicts of interest to declare.

Use of Clofarabine in the Treatment of Relapsed or Refractory Acute Myeloid Leukemia in Adults: The French Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2623-2623
Author(s):  
David Sibon ◽  
Ana Berceanu ◽  
David Ghez ◽  
Frantz Foissac ◽  
Leila Kammoun ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Univariate Analysis ◽  
Median Number ◽  
Npm1 Mutation ◽  
Secondary Aml ◽  
Refractory Acute Myeloid Leukemia ◽  
First Relapse ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract Abstract 2623 Introduction. Relapsed or refractory acute myeloid leukemia (AML) patients (pts) have a dismal outcome and conventional chemotherapy offers almost no chance of cure. Consequently, allogeneic transplantation (alloSCT) has been widely used for these patients, but outcome is limited by a high relapse rate. There is no generally established standard for reinduction of remission. Clofarabine is a second-generation purine nucleoside analogue mainly evaluated in older adults with untreated AML, but there are limited data in relapsed/refractory AML. The aim of the present study was to establish the role of clofarabine in a large series of adults with relapsed/refractory AML. Methods. Eighteen French centers participated in this retrospective study. Eligibility criteria were as follows: confirmed diagnosis of AML, pts >18 years (yrs) old at clofarabine treatment, and clofarabine used outside of a clinical trial. Relapses after alloSCT were included, but use of clofarabine as part of the conditioning regimen of alloSCT was not included. Data were collected regarding patient demographics, leukemia characteristics, previous treatments and the use of clofarabine including the regimen used and the outcome following treatment. Results. Between January 2007 and June 2011, 100 pts were treated with clofarabine for relapsed/refractory AML. At first diagnosis of AML, median age was 58 yrs, male:female ratio was 60:40, 86% of pts had performance status 0–1, 57% had white blood cells < 10000/mm3, 37% had secondary AML (prior myelodysplastic syndrome 54%), 39% had unfavorable cytogenetics, 58% had intermediate cytogenetics and 3% had favorable cytogenetics, 14/55 had NPM1 mutation, 19/69 had FLT3 internal tandem duplication. At clofarabine treatment, median age was 59 yrs (range 18–77), 42 pts were in first relapse, 35 in relapse >1, and 23 had primary refractory AML. Anthracycline was previously used in 92 pts. Twenty three relapses occurred after alloSCT. Clofarabine was used as single agent (n=22) or in combination with low-dose cytarabine (LDAC, 20–40 mg/m2/d for 4–14 days, n=18) or intermediate-dose cytarabine (IDAC, 1000–2000 mg/m2/d for 3–5 days, n=56) or other drugs (n=4). The dose of clofarabine at cycle 1 was 20 mg/m2/d (n=26), 30 mg/m2/d (n=32), 40 mg/m2/d (n=40) or other (n=2) for a median number of 5 days (mean 4.9, range 3–5). Among all pts, 30 achieved complete remission (CR), and 9 achieved CR with incomplete recovery (CRi), for an overall response rate of 39%. Six pts died during cycle 1, all of infection. Responding pts received a median number of 2 cycles (mean 2.1, range 1–6). Thirteen pts underwent subsequent alloSCT and four pts proceeded to donor lymphocyte infusion. No predictive factor of response was found in univariate analysis among age (cut-off at 60 yrs), sex, de novo vs secondary AML, cytogenetics (unfavorable vs intermediate), molecular genetics, line of treatment (first relapse vs relapse>1 vs refractory AML), relapse after alloSCT vs other relapse (for patients < 65 yrs with equally distributed cytogenetics), regimen (monotherapy vs LDAC vs IDAC) or dose of clofarabine (20 vs 30 vs 40 mg/m2/d). The median disease-free survival (DFS) was 17 months (mo). No factor significantly influenced DFS in univariate analysis, even though DFS tended to be better in relapse after alloSCT than in other relapse (for patients < 65 yrs with equally distributed cytogenetics) with 1-yr DFS being 100% vs 60% (p=0.1). Median overall survival (OS) was 19 mo for responding pts (CR+CRi) vs 3 mo in treatment failure (p<0.0001). In univariate analysis, median OS was better in male than in female (6.8 mo vs 4.1 mo, p=0.03), and in intermediate vs unfavorable cytogenetics (5.4 mo vs 4.1 mo, p=0.04); median OS tended to be better in relapse after alloSCT than in other relapse (for patients < 65 yrs with equally distributed cytogenetics) with median OS being 21 mo vs 4 mo (p=0.09). In multivariate analysis, cytogenetics was the only prognostic factor for OS (p=0.02). Conclusion. This study suggests that clofarabine-based salvage regimen is safe and can be effective in the treatment of relapsed/refractory AML. Durable remissions were achieved, especially in AML relapsed after alloSCT, allowing pts the option of (second) transplantation with the potential of long term cure. Disclosures: Off Label Use: clofarabine is approved for relapsed ALL in children.

Assessment of Patients Fitness at Diagnosis in Elderly Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4012-4012
Author(s):  
Semra Aydin ◽  
Ernesta Audisio ◽  
Stefano D'Ardia ◽  
Bernardino Allione ◽  
Barbara Nicolino ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Intensive Chemotherapy ◽  
Advisory Committees ◽  
Perfect Agreement ◽  
Medical Board ◽  
Acute Myeloid

Abstract Background:Acute myeloid leukemia (AML) is a disease which predominantly affects patients with a median age at diagnosis over 65 years. The elderly population is highly heterogeneous and assessment strategies are needed to define the frailty profile. To date, evaluation of disease-related and patients specific factors in the context of clinic decision making has been largely subjective. Concerning AML therapy, several studies demonstrated improved survival for older patients receiving intensive induction chemotherapy compared to those receiving supportive care alone. Defining this subset of patients who are eligible or "fit" for intensive chemotherapy involves a great deal of subjectivity. Criteria yet have to be standardized across or within institutions. Aim:Aim of this study was to investigate the validity of four scores for assessment of patient fitness at diagnosis in parallel to physician evaluation. Further patient outcome according the respective evaluation was compared. Methods: In a single hematology center a total of 85 clinically and molecularly well characterized consecutive elderly (>60 years) patients with newly diagnosed AML were treated from 2012 to 2015 according to age, performance status and co-morbidities. Therapy response was defined according to ELN criteria. Therapy intensity decision was based on an initial haematologist evaluation followed by discussion of the patient case in an interdisciplinary board. Independently from the medical board, in parallel the local geriatric G8 screening tool, consisting of seven items from the Mini Nutritional Assessment (MNA) questionnaire and age, the HCT-CI comorbidity score as well as the AML scores proposed by the German Acute Myeloid Leukemia Cooperative Group, predicting probability of complete remission (CR) and early death (ED) were performed. Overall survival from diagnosis was compared between groups using the Cox model. Results:A total of 42 (49,4%) patients were evaluated "fit" by the medical board and treated by intensive chemotherapy ("7+3" regimen), whereas 4 patients (4,7%) underwent semi-intensive with hypomethylating agents and 39 patients (45,8%) received palliative therapy (low dose Cytarabine or Hydroxyurea). Twenty-six patients (30,6%) achieved a complete remission after induction chemotherapy, could follow consolidation chemotherapy and six of them underwent allogeneic hematopoietic stem cell transplantation. Fourty-four (51,8%) were non responders and 15 patients (17,6%) died during the first cycle. Overall, the median survival time was 6,7 months (95% CI 3,7-9,5). Primary physician care evaluation was able to define in a statistically significant manner a "fit" from an "unfit" patient. Median survival time from the "fit" patients was 10 moths (95%CI 5-not reached) compared to the "unfit" evaluated patients with 3,4 months (95%CI 1,4-5), p<0.001 with a HR (95%CI) of 3,18 (1,81 to 5,59). Parallel evaluation of patients unfitness according the proposed cut-point of the G8 (≤14), AML for CR (<40) and AML for ED (≥30) scores discriminated significantly patients survival with HRs equal to 3.03 (p<0,001), 2.11 (p=0,007) and 2.83 (p<0.001), respectively. The agreement between the frailty scores and physician evaluation on the prediction of fitness classification was analyzed by calculating the Cohens' Kappa. In this approach a Kappa level of 1,0 denotes perfect agreement. The agreement of was moderate for HCT-CI score and AML score for CR (0.47 and 0.46, respectively). The agreement was fair for G8 and AML score for ED (0.27 and 0.33, respectively). Summary/Conclusion: In conclusion, in the present AML cohort the applied frailty scores at diagnosis correlated significantly with the median overall survival. Since no perfect agreement was found respect to physician for fitness classification, frailty scores can help to improve the prognosis prediction. These results may encourage a following multi-centre analysis in order to increase the statistic power of the performed analysis. Disclosures Vitolo: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Gilead: Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures.

Treatment Acute Myeloid Leukemia Using Cytoreductive Chemotherapy Cytarabine (Ara-C) Followed Azacitidine (AZA) Maintenance: A Real Life Single Center Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5204-5204
Author(s):  
Rosa Greco ◽  
Annamaria Petrungaro ◽  
Anna Grazia Recchia ◽  
Laura De Stefano ◽  
Sabrina Bossio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Real Life ◽  
Response To Therapy ◽  
Significant Activity ◽  
Intensive Chemotherapy ◽  
Acute Myeloid

Abstract Background: Older patients (pts) with acute myeloid leukemia (AML) have a particularly dismal outcome, because of adverse features of AML in the elderly and frailty. The median duration of complete remission (CR) last less than 1 year. The optimal management of older AML pts in daily clinical practice has not been determined. Regular treatment options include best support care, low dose cytarabine (Ara-c) and intensive chemotherapy (anthracycline combined with ara-c). Recently, the DNA methyltransferase inhibitor Azacitidine (AZA) has demonstrated significant activity and favorable tolerability in AML pts also showing a survival advantage. Materials and Methods: Between May 2013 and July 2016, at our institution, 19 pts with a diagnosis of AML (13 males and 7 females) were judged to be ineligible for intensive chemotherapy due to age or comorbidities. They received a 5-day regimen of cytoreductive chemotherapy with ara-c at a dosage of 100 mg\mq\day i.v. continuous infusion. On the sixth day, on termination of Ara-c infusion, all pts had ≤30% bone marrow blasts. Therefore, AZA was administered at a dosage of 75 mg\mq\day subcutaneously for 7 days, continuing the therapy every 28 days. The median age of pts was 75 years (range, 49 to 79 years), with 17 pts (89%) aged over 65 years. Six pts (32%) had poor molecular and cytogenetic risks markers, and six other pts (32%) had either antecedent myelodisplastic/myeloproliferative diseases or therapy related AML. The response to therapy according to the AML IWG criteria was assessed by bone marrow aspiration immediately after Ara-c infusion, after one AZA cycle and every 6 months thereafter. Baseline pts characteristics are summarized in Table 1. Results: The median number of administered AZA cycles was 6 (range, 1-25 cycles). Fifty eight percent (11/19) of pts received ≥6 AZA clycles. The median overall survival was 6 months (range, 1-26 months). According to AML IWG criteria, 8 pts (42%) achieved CR after Ara-c and a single AZA cycle. Of these, 5 pts (62%) are currently alive in CR, with median duration of response of 7 months (range: 5-12 months), while 3 pts (38%) died after 4, 12, and 22 months after diagnosis. One pt (5%) achieved a partial response (PR) after one AZA cycle, maintaining at present the same response after 3 months of therapy. Other 8 pts (42%) obtained stable disease (SD). Of these, 3 pts (37%) are currently in SD after 2, 8 and 10 months of therapy, while 5 pts (64%) died within a median of 5 months (range: 2 - 18 months) after AML diagnosis. Finally 1 pt (5%) was refractory dying after 2 months of diagnosis, and another pt (5%) died after first AZA cycle for sepsis. Fever and infections were the most common non-hematologic toxic events after Ara-c chemotherapy and first AZA cycle (17/19 pts, 90%). While subsequent AZA cycles were well tolerated. Conclusion: We suggest that the use of Ara-c-AZA combination is feasible in elderly AML pts. However, the relatively small number of pts studied and short follow up preclude definitive conclusion. The study is still accruing patients. Disclosures No relevant conflicts of interest to declare.

Gemtuzumab ozogamicin in combination with intensive chemotherapy in relapsed or refractory acute myeloid leukemia

2015 ◽  
Vol 56 (8) ◽  
pp. 2326-2330 ◽  
Author(s):  
Sylvain P. Chantepie ◽  
Emilie Reboursiere ◽  
Jean-Baptiste Mear ◽  
Anne-Claire Gac ◽  
Veronique Salaun ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Intensive Chemotherapy ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

scholarly journals Randomised evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients

2021 ◽  
Author(s):  
Mike Dennis ◽  
Ian Thomas ◽  
Cono Ariti ◽  
Laura Upton ◽  
Alan K Burnett ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Intensive Chemotherapy ◽  
Wild Type ◽  
Flt3 Inhibitor ◽  
Acute Myeloid

Survival for older patients with acute myeloid leukaemia (AML) unsuitable for intensive chemotherapy is unsatisfactory. Standard non intensive therapies have low response rates and only extend life by a few months. Quizartinib is an oral Fms-like tyrosine kinase 3 (FLT3) inhibitor with reported activity in wild type patients. As part of the AML LI trial we undertook a randomised evaluation of low dose ara-C (LDAC) with or without quizartinib in patients not fit for intensive chemotherapy. Overall, survival was not improved (202 patients), but in the 27 FLT3-ITD patients the addition of quizartinib to LDAC improved response (p=0.05) with CR/CRi for quizartinib + LDAC in 5/13 (38%) v 0/14 (0%) in patients receiving LDAC alone. Overall survival (OS) in these FLT3-ITD positive patients was also significantly improved at 2 years for quizartinib + LDAC; hazard ratio 0.36 (95% confidence intervals 0.16, 0.85), (p=0.04). Median OS was 13.7 months compared to 4.2 months with LDAC alone. This is the first report of a FLT3 targeted therapy added to standard non-intensive chemotherapy that has improved survival in this population. Quizartinib merits consideration for future triplet based treatment approaches. (Clinical trial numbers: ISRCTN No: ISRCTN40571019 EUDRACT Number: 2011-000749-19).

scholarly journals Long-term survival after intensive chemotherapy or hypomethylating agents in AML patients aged 70 years and older: a large patient data set study from European registries

Leukemia ◽  
2021 ◽  
Author(s):  
Christian Récher ◽  
Christoph Röllig ◽  
Emilie Bérard ◽  
Sarah Bertoli ◽  
Pierre-Yves Dumas ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Intensive Chemotherapy ◽  
Hypomethylating Agents ◽  
Term Survival ◽  
Acute Myeloid

AbstractThe outcome of acute myeloid leukemia patients aged 70 years or older is poor. Defining the best treatment option remains controversial especially when choosing between intensive chemotherapy and hypomethylating agents. We set up a multicentric European database collecting data of 3 700 newly diagnosed acute myeloid leukemia patients ≥70 years. The primary objective was to compare overall survival in patients selected for intensive chemotherapy (n = 1199) or hypomethylating agents (n = 1073). With a median follow-up of 49.5 months, the median overall survival was 10.9 (95% CI: 9.7–11.6) and 9.2 months (95% CI: 8.3–10.2) with chemotherapy and hypomethylating agents, respectively. Complete remission or complete remission with incomplete hematologic recovery was 56.1% and 19.7% with chemotherapy and hypomethylating agents, respectively (P < 0.0001). Treatment effect on overall survival was time-dependent. The Royston and Parmar model showed that patients treated with hypomethylating agents had a significantly lower risk of death before 1.5 months of follow-up; no significant difference between 1.5 and 4.0 months, whereas patients treated with intensive chemotherapy had a significantly better overall survival from four months after start of therapy. This study shows that intensive chemotherapy remains a valuable option associated with a better long-term survival in older AML patients.

Response Rate, Event-Free Survival, and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia: US Food and Drug Administration Trial-Level and Patient-Level Analyses

2021 ◽  
Author(s):  
Kelly J. Norsworthy ◽  
Xin Gao ◽  
Chia-Wen Ko ◽  
E. Dianne Pulte ◽  
Jiaxi Zhou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Strong Association ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
Patient Level ◽  
Acute Myeloid

PURPOSE To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy. METHODS We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models. We performed patient-level responder analyses to compare OS by response using pooled data from all studies. RESULTS In trial-level analyses, association between HR for OS and OR for CR was moderate (R2 = 0.49; 95% CI, 0.05 to 0.86), as was the association with OR for CR + CRi or CRp (R2 = 0.48; 95% CI, 0.05 to 0.99). For OS versus EFS, a strong association was observed (R2 = 0.87; 95% CI, 0.47 to 0.98) when EFS definitions were harmonized across trials using raw data. In the patient-level responder analyses, patients who achieved CR had better OS compared with CRi or CRp responders (0.73; 95% CI, 0.64 to 0.84) and nonresponders (HR, 0.33; 95% CI, 0.31 to 0.37). CONCLUSION On a trial level, there is a moderate association between OS and CR rate. A strong association between EFS and OS was observed. However, CIs were wide, and results became moderate using alternative definitions for EFS. Patient-level analyses showed CR responders have better OS compared with CRi or CRp responders and nonresponders. A therapy in newly diagnosed AML with benefit in EFS or substantial benefit in CR rate would be likely to have an OS effect.

Gilteritinib: An FMS-like tyrosine kinase 3/AXL tyrosine kinase inhibitor for the treatment of relapsed or refractory acute myeloid leukemia patients

2020 ◽  
Vol 26 (5) ◽  
pp. 1200-1212
Author(s):  
Daniel R Reed ◽  
Jeremy M Sen ◽  
Eric J Pierce ◽  
Ramey Z Elsarrag ◽  
Michael K Keng
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Intracellular Signaling ◽  
Myeloid Leukemia ◽  
Phase Iii ◽  
Driver Mutations ◽  
Tyrosine Kinase Domain ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Acute myeloid leukemia has recently undergone a significant transition into identifying and successfully inhibiting driver mutations leading to disease. One of the most common mutations in acute myeloid leukemia involves the protein FMS-like tyrosine kinase 3 (FLT3), which leads to ligand-independent activation of intracellular signaling cascades leading to the survival and proliferation of the acute leukemia blast cell. Preclinical studies have demonstrated the presence of two dominant types of mutations of this protein: internal tandem duplication and tyrosine kinase domain mutations. Successful inhibition of this protein has proven to be challenging. While FLT3 has been shown to be successfully inhibited and shown to improve overall survival in the frontline therapy of acute myeloid leukemia in combination with cytarabine and anthracycline, relapsed and refractory (R/R) patients have not been shown to be a successful population until recently. A phase III trial (ADMIRAL trial) demonstrated significant overall survival benefit in patients receiving gilteritinib compared to patients receiving salvage chemotherapy. This review will provide an overview of the preclinical, clinical, and practical use of gilteritinib in the treatment of patients with relapsed and refractory acute myeloid leukemia with FLT3 mutation.

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