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Blood ◽  
2022 ◽  
Author(s):  
Gi-June Min ◽  
Byung-Sik Cho ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
Young-Woo Jeon ◽  
...  

Given a few prospective studies with conflicting results, we investigated the prognostic value of multi-parameter geriatric assessment (GA) domains on tolerance and outcomes after intensive chemotherapy in older adults with acute myeloid leukemia (AML). Newly diagnosed AML aged over 60 years who received intensive chemotherapy consisting of cytarabine and idarubicin (n=105) were enrolled prospectively. Pretreatment GA included evaluations for social and nutritional support, cognition, depression, distress, and physical function. The median age was 64 years (range, 60-75), and 93% had an Eastern Cooperative Oncology Group score <2. Between 32.4% and 69.5% of patients met the criteria for impairment for each domain of GA. Physical impairment by the Short Physical Performance Battery (SPPB) and cognitive dysfunction by the Mini-Mental State Examination in the Korean version of the CERAD Assessment Packet (MMSE-KC) were significantly associated with non-fatal toxicities, including grade III-IV infections (SPPB, P=0.024; MMSE-KC, P=0.044), acute renal failure (SPPB, P=0.013), and/or prolonged hospitalization (³40 days) during induction chemotherapy (MMSE-KC, P=0.005). Reduced physical function by SPPB and depressive symptoms by the Korean version of the short form of geriatric depression scales (SGDS-K) were significantly associated with inferior survival (SPPB, P=0.027; SGDS-K, P=0.048). Gait speed or sit-and-stand speed was the single powerful tool to predict survival outcomes. Notably, the addition of SPPB and SGDS-K, gait speed and SGDS-K, or sit-and-stand speed and SGDS-K significantly improved the power of existing survival prediction models. In conclusion, GA improved risk stratification for treatment decisions and may inform interventions to improve outcomes for older adults with AML. This study was registered at the Clinical Research Information Service (KCT0002172).


Blood ◽  
2022 ◽  
Author(s):  
Gail J. Roboz ◽  
Farhad Ravandi ◽  
Andrew H. Wei ◽  
Hervé Dombret ◽  
Felicitas Thol ◽  
...  

Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor survival. Post-remission maintenance therapy that prolongs MRD negativity or converts MRD positive (MRD+) patients to MRD negative (MRD-) status may delay or prevent relapse and improve overall survival (OS). In the phase 3 QUAZAR AML-001 trial, oral azacitidine (Oral-AZA; formerly CC-486), a hypomethylating agent, significantly prolonged OS and relapse-free survival (RFS) compared with placebo in patients aged ≥55 years with AML in first remission after intensive chemotherapy who were not candidates for hematopoietic stem cell transplantation. In this trial, MRD (≥0.1% leukemic cells in bone marrow) was assessed by multiparameter flow cytometry in serial samples collected at baseline and on day 1 of every 3 cycles. As expected, baseline MRD status was significantly associated with both OS and RFS. Multivariate analyses showed Oral-AZA significantly improved OS and RFS vs. placebo independent of baseline MRD status. Oral-AZA treatment also extended the duration of MRD negativity by 6 months vs. placebo, and resulted in a higher rate of conversion from MRD+ at baseline to MRD- during treatment: 37% vs. 19%, respectively. In the Oral-AZA arm, 24% of MRD responders achieved MRD negativity >6 months after treatment initiation. While presence or absence of MRD was a strong prognostic indicator of OS and RFS, there were added survival benefits with Oral-AZA maintenance therapy compared with placebo, independent of patients' MRD status at baseline. NCT01757535 Clinicaltrials.gov


Author(s):  
Kelly J. Norsworthy ◽  
Xin Gao ◽  
Chia-Wen Ko ◽  
E. Dianne Pulte ◽  
Jiaxi Zhou ◽  
...  

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.


Author(s):  
David Martínez-Cuadrón ◽  
Juan Eduardo Megías-Vericat ◽  
Josefina Serrano ◽  
Pilar Martínez-Sánchez ◽  
Eduardo Rodríguez-Arbolí ◽  
...  

Secondary acute myeloid leukemia (sAML) comprises a heterogeneous group of patients, and is associated with poor overall survival (OS). We analyze the characteristics, treatment patterns and outcomes of sAML adult patients of the Programa Español de Tratamientos en Hematología (PETHEMA) registry. Overall, 6211 (72.9%) were de novo and 2310 (27.1%) sAML, divided into myelodysplastic syndrome (MDS-AML, 44%), MDS/myeloproliferative (MDS/MPN-AML, 10%), MPN-AML (11%), therapy-related (t-AML, 25%), and antecedent neoplasia without prior chemotherapy/radiotherapy (neo-AML, 9%). Compared to de novo, sAML were older (median age 69 years old), had more ECOG ≥2 (35%) or high-risk cytogenetics (40%), less FLT3-ITD (11%) and NPM1 mutations (21%), and received less intensive chemotherapy regimens (38%) (all P<0.001). Median OS was higher in de novo than in sAML (10.9 vs 5.6 months, P<0.001); and shorter in sAML after hematologic disorder (MDS, MDS/MPN or MPN) as compared to t-AML and neo-AML (5.3 vs 6.1 vs 5.7 months, respectively, P=0.04). After intensive chemotherapy, median OS was better among de novo and neo-AML patients (17.2 and 14.6 months). No OS differences were observed after hypomethylating agents according to type of AML. sAML was as an independent adverse prognostic factor for OS. We confirm high prevalence and adverse features of sAML and we establish its independent adverse prognostic value. This study was registered at www.clinicaltrials.gov as #NCT02607059.


Leukemia ◽  
2021 ◽  
Author(s):  
Christian Récher ◽  
Christoph Röllig ◽  
Emilie Bérard ◽  
Sarah Bertoli ◽  
Pierre-Yves Dumas ◽  
...  

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.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3962-3962
Author(s):  
Oren Pasvolsky ◽  
Shai Shimony ◽  
Ron Ram ◽  
Avichai Shimoni ◽  
Liat Shargian-Alon ◽  
...  

Abstract The therapeutic landscape for acute myeloid leukemia (AML) has evolved in recent years with the introduction of hypomethylating agents (HMA) and venetoclax in patients previously deemed unfit for curative - intent treatment. Some of these patients undergo allogeneic hematopoietic cell transplant (alloHCT), yet there are scarce data regarding transplantation outcomes. We conducted a multicenter nationwide retrospective cohort study to evaluate outcomes of patients with AML who underwent alloHCT in first CR (CR1) after frontline treatment with 5-azacitidine plus venetoclax (aza-ven group). In addition, we collected a historical control group of patients who achieved CR1 following first line intensive chemotherapy followed by alloHCT (intensive group). 24 patients in the aza-ven group were transplanted between 2019 and 2021. Compared to the intensive group, patients in the aza-ven group were older (median age 71.7 vs. 58.4 years, p &lt;0.001), had higher incidence of therapy related AML and AML with antecedent hematologic disorder (p &lt;0.001) and had more often adverse cytogenetics (p=0.022). They had a higher percentage of allografts from matched unrelated donors, and reduced intensity conditioning was more commonly used (Table 1). Median follow up was 8 (range, 0 to 25) months in the aza-ven group and 23 (range, 4 to 56) months in the intensive group. Estimated 12 months non relapse mortality was 19.1% in the aza-ven group and 11.8% in the intensive group (p=0.492). The estimated median relapse free survival (RFS) was not reached in the aza-ven group and was 19.3 months (CI 95% 1-38) in the intensive group. There was no difference between the two groups in 12 months RFS (58% and 54% in the aza-ven group and intensive group, respectively, p = 0.892). The estimated median survival of the aza-ven group was not reached and the 12 months overall survival (OS) rate was 63.2%. The estimated median survival of the intensive group was 50 months (CI 95% 5 - 96) and the 12 months OS rate was 70.8%. There was no statistical differences between the two groups regarding OS (p = 0.58). In a subgroup Cox regression analysis of the aza-ven group, adverse ELN 2017 risk category and HCT-CI score ≥3 were predictive of decreased RFS, both in univariate analysis (UVA) and in multivariate analysis (MVA) (HR 10.56, CI 95%1.64-68.1, p=0.013 and HR 6.43, CR 95% 1.34-30.75, p=0,02, respectively). Graft source (alternative vs. matched donor) and HCT-CI score ≥3 were predictive of decreased OS in UVA (HR 19.45, CI 95% 1.66-228.13, p= 0.018 and HR 5.93, CI 95% 1.13-31.05, p=0.03], yet in MVA neither of these factors retained their predictive value. The cumulative incidence of acute GVHD at 6 months was similar between groups: 58% in the aza-ven group vs. 62% in the intensive group (p=0.39). Likewise, there was no difference in the cumulative incidence of chronic GVHD at 12 months: 40% vs 42%, respectively (p=0.747) In conclusion, our data suggests that alloHCT for AML patients achieving first CR with aza-ven appears feasible, with short term post-transplant outcomes comparable to those expected after traditional intensive chemotherapy. Our results were collected in the real world setting, and patients in the aza-ven group were older and had inherently worse leukemia characteristics, including more secondary AML and more adverse cytogenetic features. Future research is warranted to decipher the true spectrum of AML patients who could benefit from remission induction with this less intensive regimen prior to alloHCT. Figure 1 Figure 1. Disclosures Ram: Gilead: Honoraria; Novartis: Honoraria. Wolach: Janssen: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; Amgen: Research Funding; Novartis: Consultancy; Neopharm: Consultancy. Yeshurun: Astellas: Consultancy; Janssen: Consultancy.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4047-4047
Author(s):  
Mo Zhou ◽  
Hongbo Yang ◽  
Yan Song ◽  
Deborah A. Marshall ◽  
James D. Griffin ◽  
...  

Abstract Background The number of targeted antileukemic therapies for the treatment of AML has increased over the past decade. However, for patients who are not candidates for high intensive chemotherapy (HIC), a better understanding is needed of what treatment attributes patients and physicians value and how their preferences differ to potentially improve treatment satisfaction. Objective To understand the impact of treatment attributes on treatment selection, we quantified the preferences of: a) patients newly diagnosed with AML who are not candidates for HIC; and, b) the physicians who treat them. Methods A discrete choice experiment (DCE) was performed to quantify the extent to which treatment attributes impact patients' and physicians' treatment decisions in various scenarios. A literature review was conducted to identify treatment attributes important to patients with AML. Following the review, one-on-one phone interviews were conducted with patients (United States [US], n=3; United Kingdom [UK], n=3) and physicians (US, n=2; UK, n=2) to finalize the attributes and levels included in the DCE. Patients who were eligible to participate in the online survey were adults with a self-confirmed AML diagnosis, who had not relapsed or been refractory to treatment, had not received a stem cell transplant, and had not received HIC or met one of the following criteria: aged ≥75 years, diagnosis of congestive heart failure, chronic kidney disease, or other types of cancer, or ECOG score of 3 or 4. Physicians included hematologists/ oncologists treating &gt;5 patients with AML over the past year. The web-based DCE included choice cards showing 2 hypothetical treatment profiles with 6 attributes (chance of 2-year overall survival [OS], average quality of life [QoL], risk of serious infections, risk of grade 3/4 nausea, chance of achieving transfusion independence, and duration of hospitalization per year) at varying levels. Participants chose a preferred treatment for each choice card. Conditional logit regression models were used to estimate preference weights and to analyze the impact of treatment attributes on participants' choices. Results The DCE was completed by 77 patients newly diagnosed with AML who had not received HIC (US, n=47; UK, n=30) and 145 physicians (US, n=48; UK, n=52; Canada, n=29; Australia, n=16). Mean patient age was 71.4 years; 51.9% were female. Mean (SD) time since AML diagnosis was 8.3 (8.2) months. Most physicians were hematologists (81.4%) and saw a median of 30 AML patients yearly. For patients, duration of hospitalization (decrease from 6 to 2 weeks/year) was the most important attribute followed by average QoL (increase from 50 to 85 on a 100-point QoL scale) and chance of 2-year OS (increase from 15% to 40%; Figure). Based on these findings, we estimated that patients were willing to accept a decrease in 2-year OS (from 40% to 15%) or an increase in risk of serious infections (from 5% to 20%) to decrease time spent hospitalized (from 6 to 2 weeks per year). For physicians, chance of 2-year OS (from 15% to 40%) was the most important attribute followed by average QoL (increase from 50 to 85 on a 100-point scale), risk of serious infections (from 20% to 5%), and risk of grade 3/4 nausea and vomiting (from 20% to 1%; Figure). Based on these findings, we estimated that physicians were willing to accept an increased risk of grade 3/4 nausea and vomiting (from 10% to 20%) in exchange for decreased time in hospital (from 6 to 2 weeks per year) and increased chance of achieving transfusion independence (from 35% to 55%) when other treatment attributes remained stable. Conclusion Significant differences in treatment attribute importance for patients with newly diagnosed AML who had not received HIC were observed between patients and physicians. Patients most valued treatments that reduced hospitalization duration while physicians most valued treatments that improved chance of 2-year OS. These differences highlight the importance of a shared decision-making process when choosing treatments for patients with AML ineligible for HIC. However, given the variability among individual patients, it may be particularly worthwhile for physicians to initiate a discussion with patients prior to treatment selection to determine what treatment attributes each patient values most. Treatment selection could then be tailored based on attributes most valued by the patient and likely lead to improved treatment satisfaction. Figure 1 Figure 1. Disclosures Zhou: Astellas Pharma, Inc.: Consultancy. Yang: Astellas Pharma, Inc.: Consultancy. Song: Astellas Pharma, Inc.: Consultancy. Marshall: Astellas Pharma, Inc.: Consultancy; Arthur JE Child Chair: Other: Indirectly related salary support. Griffin: Novartis: Patents & Royalties: Post marketing royalties from midostaurin; Astellas Pharma, Inc.: Consultancy. Saini: Astellas Pharma, Inc.: Consultancy, Honoraria. Shah: Astellas Pharma, Inc.: Current Employment; University of Michigan School of Public Health Department of Health Management and Policy Alumni Board: Other: Chair-Elect.


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