Impact of Non Professional Physicians' Characteristics on Medical Decision Making in Older Patients with Acute Myeloid Leukemia

Abstract Frontline therapy for newly diagnosed AML in older adults can be classified as "more" or "less" intensive. Assignment of patients (pts) to intensive chemotherapy (ICT) or low-intensity therapy (LIT) such as hypomethylating agents (HMA), low-dose aracytine (LDAC) or best supportive care (BSC), should be based on patient- and disease-related prognosis factors. Although scoring systems have been proposed to rationalize this clinical decision-making, there is a strong heterogeneity in clinical practice. Cancer management study mainly focused on patients' determinants of care but very few have assessed the influence of physicians' characteristics and none in AML. In behavioral sciences, attitudes towards risk and ambiguity are psychological traits that may explain medical choices. These traits are connected with theoretical models of decision under uncertainty that can be divided in Expected Utility (EU) and Non-Expected Utility (Non-EU) models where the former is often considered as a benchmark of "economic rationality". Choice patterns in decision task known as Allais paradox allow classifying individuals in these two classes of models. In addition, behavioral consequences when the probabilities of uncertain events are unknown are defined as ambiguity attitudes. Our study investigated the impact of physician's characteristics on their medical decisions regarding 6 clinical vignettes of older AML pts that highlight distinct and difficult situations derived from clinical practice. Physicians' demographical and occupational characteristics were collected through a national cross-sectional web survey among French hematologists. We categorized physicians as EU or non-EU using their responses to the binary lottery choice questions of the Allais paradox (Kahneman &amp; Tversky, 1979). A last question elicited a certainty equivalent (sure gain between 0 and 500 euros) of an ambiguous lottery (Abdellaoui &amp; al, 2011) as a proxy of physicians' ambiguity tolerance. Physicians were asked to decide how to treat (ICT, LIT or BSC) elderly AML pts presented in 6 vignettes (table1). Assessable respondents included those who answered all cases. We used k-means clustering method in order to define clinician's groups with homogeneous pattern of responses to the clinical cases. Among the 230 physicians with assessable answers, the median age was 42 years [standard deviation (SD)± 11.2], 123 were male (54%), 160 were consultant or professor (70%), 166 worked in an academic center (72%), 197 were specialized in hematology (86%), and the mean number of older AML pts treated a year per physician was 20.7 (SD ± 17.1). Regarding the Allais paradox, EU, non-EU and undefined represented respectively 101 (43.9%), 109 (47.3%) and 20 (8.7%) respondents. Regarding ambiguity tolerance, the mean of the certainty equivalent was 241 euros (SD ±136). From the pattern of responses to the vignettes, the K-means clustering yielded two distinct groups identified as (1) clinicians who were more prone to prescribe "more" intensive therapy (ICT), and (2) clinicians who were more prone to prescribe "less" intensive therapy (LIT or BSC). We studied the factors associated with the probability of belonging to the "more intensive" category of physicians. A multivariate model (n=210) on variables identified from the bivariate analyses systematically adjusted for age and gender highlighted the following effects and trend:ambiguity tolerant physicians prescribe significantly less ICT (OR 0.87 [for each 50 euros-increase]; 95%CI, 0.77-0.99, p=0.039), physicians not conforming to expected utility ("economically irrational") recommend more ICT (OR 1.85; 95%CI, 0.92-3.73, p=0.084) and female physicians tend to prescribe less ICT (OR 0.58; 95%CI, 0.28-1.20, p=0.14). Physicians' age, hierarchical status, hospital facility or volume of older AML pts treated a year were not associated with the clusters. Final results of national cross-sectional study performed on French hematologists, show that physicians' attitudes towards risk and ambiguity, i.e. physicians' nonprofessional characteristics, may influence their medical decision making process between "more" and "less" intensive therapy for older AML patients. The extension of this study in different countries is planned to test the cross-cultural robustness of our results and increase our knowledge on psychological traits that could influence physicians' practice. Disclosures Malak: Novartis: Membership on an entity's Board of Directors or advisory committees. Recher:Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding; Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees. </jats:sec

Comparison of Short- and Long-Term Mortality in Patients with or without Cancer Admitted to the ICU for Septic Shock: A Retrospective Observational Study

Introduction: Cancer patients are at high risk of developing septic shock (SSh) and are increasingly admitted to ICU given their improved long-term prognosis. We, therefore, compared the prognosis of cancer and non-cancer patients with SSh. Methods: We conducted a monocentric, retrospective cohort study (2013–2019) on patients admitted to ICU for SSh. We compared the clinical characteristics and management and studied short- and long-term mortality with ICU and in-hospital mortality and 1-year survival according to cancer status. Results: We analyzed 239 ICU stays in 210 patients, 59.5% of whom were men (n = 125), with a median age of 66.5 (IQR 56.3–77.0). Of the 121 cancer patients (57.6% of all patients), 70 had solid tumors (33.3%), and 51 had hematological malignancies (24.3%). When comparing ICU stays of patients with versus without cancer (n = 148 vs. n = 91 stays, respectively), mortality reached 30.4% (n = 45) vs. 30.0% (n = 27) in the ICU (p = 0.95), and 41.6% (n = 59) vs. 35.6% (n = 32) in hospital (p = 0.36), respectively. ICU length of stay (LOS) was 5.0 (2.0–11.3) vs. 6.0 (3.0–15.0) days (p = 0.27), whereas in-hospital LOS was 25.5 (13.8–42.0) vs. 19.5 (10.8–41.0) days (p = 0.33). Upon multivariate analysis, renal replacement therapy (OR = 2.29, CI95%: 1.06–4.93, p = 0.03), disseminated intravascular coagulation (OR = 5.89, CI95%: 2.49–13.92, p &lt; 0.01), and mechanical ventilation (OR = 7.85, CI95%: 2.90–21.20, p &lt; 0.01) were associated with ICU mortality, whereas malignancy, hematological, or solid tumors were not (OR = 1.41, CI95%: 0.65–3.04; p = 0.38). Similarly, overall cancer status was not associated with in-hospital mortality (OR = 1.99, CI95%: 0.98–4.03, p = 0.06); however, solid cancers were associated with increased in-hospital mortality (OR = 2.52, CI95%: 1.12–5.67, p = 0.03). Lastly, mortality was not significantly different at 365-day follow-up between patients with and without cancer. Conclusions: In-hospital and ICU mortality, as well as LOS, were not different in SSh patients with and without cancer, suggesting that malignancies should no longer be considered a barrier to ICU admission.</jats:p

Comparison of Mycophenolate Mofetil and a Calcineurin Inhibitor Versus Calcineurin Inhibitor Based Graft-Versus-Host-Disease Prophylaxis for Matched Unrelated Donor Transplant for Acute Myeloid Leukemia. a Study from the ALWP of the EBMT

Cyclosporine A (CsA) alone or in combination with mycophenolate mofetil (MMF) has been used as graft-versus-host-disease (GvHD) prophylaxis since the early development of reduced intensity conditioning (RIC). The association of CsA+MMF, while commonly used after transplantation from a matched unrelated donor (MUD), has never been tested in a large randomized prospective trial. We retrospectively investigated the outcomes of adult patients with AML in complete remission (CR) undergoing a MUD transplant using CsA+MMF or CsA alone as GvHD prophylaxis, transplanted between 2007-2017 and registered with the ALWP of the EBMT. Of the 497 patients who were evaluated, 183 received CsA alone and 314 received CsA+MMF. The median age at transplant was similar, being 59 (range, 20-75) years in the CsA group and 60 (range, 21-75) years in the CsA+MMF group. All patients underwent a RIC regimen with fludarabine and busulfan and received anti-thymocyte globulin as part of the conditioning. The median follow-up was 33 (range, 18-60) months in the CsA group and 34 (range, 18-75) months in the CsA+MMF group. Disease status at transplant was first complete remission (CR1) for 81% (n=149) in CsA group and 86% (n=268) in CsA+MMF group (p=NS). Poor risk cytogenetics was reported for 19% of patients who received GvHD prophylaxis with CsA alone and for 15% of patients receiving CsA+MMF (p=NS). Peripheral blood stem cells (PBSC) was the graft source in 93% of patients receiving CsA alone and in 96% of patients who received CsA+MMF (p=0.17). Female to male mismatch was present in 13% and 15% of patients in the CsA goup and CsA+MMF group respectively, (p=NS). All but 2 patients engrafted. The 100 day cumulative incidence (CI) of grade II-IV and grade III-IV GvHD were 30% and 10%, respectively. The 2-year CI chronic GvHD was 35% and CI of extensive cGvHD was 15%. The 2-year CI of non-relapse mortality (NRM) and relapse were 19% and 25%, respectively. Of the 81 patients who died in the CsA group, disease recurrence (n=31), GvHD (n=20) and infection (n=17) were the most common causes of death. One hundred twenty seven patients died in the CsA+MMF group; cause of death was relapse for 53, GvHD for 28 and infection for 28 of them. The 2-year GVHD-free relapse-free survival (GRFS), leukemia- free survival (LFS), and overall survival (OS) were 45%, 56% and 60%, respectively. On multivariate analysis (MVA), no statistically significant differences were found among the two GvHD prophylaxis groups with respect to relapse, NRM, LFS, OS, acute and chronic GvHD. A positive cytomegalovirus serology of the donor was associated with higher NRM [HR=2.03, p&lt;0.001] and higher cGvHD [HR=1.44, p=0.03] and a lower OS [HR 1.66, p&lt;0.001], LFS [HR=1.69, p=0.001] and GRFS [HR=1.75, p&lt;0.001]. In a subgroup analysis of patients in CR1 who received PBSC, (CsA alone, n=138; CsA+MMF, n=257), no differences were detected between the two groups for relapse, NRM, LFS, OS, or aGvHD, but patients who received CsA alone tended to have a higher cGvHD (41% vs 33%, p=0.05). However, on MVA, although the risk of cGvHD was lower in the CsA+MMF group, this finding was not statistically significant [HR=0.67, p=0.08]. Adverse cytogenetics was an independent risk factor for relapse [HR=2.22, p&lt;0.001]. In this study, we observed comparable outcomes in patients with AML in CR1 who underwent MUD transplantation and RIC with CsA+MMF or CsA alone as GvHD prophylaxis. This suggests that both strategies may be considered valid approaches. Additional randomized trials are needed to further assess which patients could benefit from the addition of MMF in GvHD prophylaxis. Disclosures Blaise: Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria. Socie:Alexion: Consultancy. Chevallier:Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding. </jats:sec

Therapy related myeloid neoplasms (t-MNs) following PARP inhibitors (PARPi): Real-life experience.

7057 Background: PARPi have shown promising results in several cancers, especially breast (BC) and ovarian cancer (OC), but may be associated with an increased risk of t-MNs. A careful monitoring of hematologic toxicity to exclude this risk is necessary. Here we described, in a real-life setting, the management of these adverse effect. Methods: First,we described, in a large cancer center, the profile of t-MN patients among OC patients treated with PARPi addressed in hematological consultation for cytopenias. Secondly, we compared t-MN post OC characteristics according to previous exposition to PARPi. Lastly, we described a large national observatory of 69 t-MNs post PARPi to decipher specific characteristics of these t-MNs. Results: From 2016 to 2021, among 373 PARPi treated patients for OC, 37 (10%) were explored for cytopenia’s leading to 13 (3,5%) t-MNs diagnosis. No differences were seen in terms of age, BRCA1/2 status, type of PARPi, hemoglobin level but patients with t-MNs developed delayed cytopenias post-PARPi initiation (11 months vs to 4 months, p = 0.01), had a longer PARPi exposition (9 months vs 3 months, p = 0.01), lower platelets level (74 G/L vs 173 G/L, p = 0.0005), more cytopenias (2 vs 1, p = 0.0005). 77% of t-MNs patients had a TP53 mutated t-MNs, 33% of patients w/o t-MNs had TP53 mutated clonal hematopoiesis. In the last 20 years, 37 patients were addressed for t-MN post OC at our institute, with an increased incidence of 50% during the last 6 years. Compared to t-MN not exposed to PARPi, t-MN-PARPi patients had more BRCA1/2 predisposition (61.5% vs 0% p = 0.03), their OC tended to be non-progressive (CR/PR/SD = 62.5% vs 38.5%, p = 0.3) and tend to have more TP53 mutated t-MNs (77% vs 47%, p = 0.1). Median OS for t-MNs post PARPi was poor at 8.2 months (CI95% [2.03-18.7]) but not significantly different form other t-MNs (p = 0.8). We then studied 69 t-MNs-PARPi including 28 AML and 41 MDS in patient with history of OC (75%), BC (9%) or both (16%). Median age was 64 years, 80% received Olaparib, 72.5% had a BRCA1/2 predisposition. Median time between cancer diagnosis and initiation of PARPi was 44 months and median duration of PARPi treatment was 14 months. History of haematological toxicity secondary to PARPi was reported in 51% of patients. Karyotype was often complex (61%) associated with a high rate of TP53 mutation (70.5%). Median OS was 9.7 months (CI95%, 5.3-13.9). In multivariate analysis, a longer delay between the end of PARPi treatment and t-NM diagnosis (HR 1.046, p = 0.02), as well Olaparib treatment compared to others PARPi (HR 5.82, p = 0.003 and AML diagnosis (HR 2.485, p = 0.01) were associated with shorter OS. Conclusions: We describe in a large series a higher incidence of t-MNs post PARPi than previously reported. Unfavorable cytogenetic and molecular abnormalities associated with these t-MNS explained the poor OS. Early detection is crucial particularly in case of delayed appearance of cytopenias. </jats:p

Combining blinatumomab and donor lymphocyte infusion in B-ALL patients relapsing after allogeneic hematopoietic cell transplantation: A study of the SFGM-TC

Abstract Relapsed B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic stem cell transplantation (allo-HCT) still represents a major concern with poor outcomes. The aim of this study is to compare the efficacy and safety of blinatumomab and donor lymphocyte infusion (DLI) versus blinatumomab alone in this setting. This is a multicenter retrospective study from centers of SFGM-TC. All transplanted patients who received blinatumomab salvage therapy were included. Patients who received DLI from 1 month before to 100 days after the starting of blinatumomab were included in the blina-DLI group. Seventy-two patients were included. Medium follow-up was 38 months. Fifty received blinatumomab alone and 22 the association blinatumomab-DLI. Two-year overall survival (OS) was 31% in the blinatumomab group and 43% in the blinatumomab-DLI group (p=0.31). Studying DLI as a time dependent variable, PFS did not significantly differ between the 2 groups (HR:0.7, 95%CI:0.4-1.5). In multivariate analysis, DLI was not a prognostic factor for OS, progression-free survival and progression/relapse incidence. Adverse events and graft-versus-disease rates were comparable in the 2 groups. In conclusion, adding DLI between 1 month before and 100 days after start of blinatumomab is safe and does not seem to improve outcomes in B-ALL patients who relapsed after allo-HCT.</jats:p

Outcomes of acute myeloid leukemia patients who responded to venetoclax and azacitidine and stopped treatment

International audienceAbstract Venetoclax‐azacitidine is the standard of treatment for unfit acute myeloid leukemia patients. In the VIALE‐A study, treatment was given until progression but there are no data on its optimal duration for responding patients who do not tolerate indefinite therapy. We retrospectively analyzed the outcome of patients who discontinued venetoclax or venetoclax‐azacitidine due to poor tolerance. Sixty‐two newly diagnosed (ND) AML patients and 22 patients with morphological relapse or refractory AML were included. In the ND cohort ( n = 62), 28 patients stopped venetoclax and azacitidine and 34 patients continued azacitidine monotherapy. With a median follow‐up of 23 months (IQR, 20–32), median overall survival and treatment‐free survival were 44 (IQR, 16‐NR) and 16 (IQR, 8–27) months, respectively. Patients who stopped both treatments and those who continued azacitidine monotherapy had the same outcomes. Negative minimal residual disease was associated with a 2‐year treatment‐free survival of 80%. In the RR cohort ( n = 22), median overall survival and treatment‐free survival were 19 (IQR, 17–31) and 10 (IQR, 5‐NR) months, respectively. Prior number of venetoclax‐azacitidine cycles and IDH mutations were associated with increased overall survival. The only factor significantly impacting treatment‐free survival was the number of prior cycles. This study suggests that patients who discontinued treatment in remission have favorable outcomes supporting the rationale for prospective controlled trials

Comparison of HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia

HLA-haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) is frequently used as treatment for patients with active acute myeloid leukemia (AML). Here, we investigated whether 9/10 HLA-mismatched unrelated donor transplantation (MMUD-HCT) with post-transplant cyclophosphamide (PTCy) is an adequate alternative. Inclusion criteria in this retrospective registry study consisted of adult patients, first HCT with a Haplo donor or MMUD between 2010 and 2020 using PTCy as graft-versus-host disease (GVHD) prophylaxis, and primary refractory or relapsed disease. MMUD patients were pair-matched 1 to 2 with Haplo-recipients. A total of 73 MMUD patients met the inclusion criteria. Their data were compared to those of 146 Haplo patients in a matched-pair analysis. Median follow-up was 27 months in MMUD patients and 36 months in Haplo recipients. Two-year incidences of relapse and non-relapse mortality (NRM) were 40% and 18% in MMUD patients, respectively, versus 50% (P = 0.23) and 24% (P = 0.18) in Haplo recipients. Two-year leukemia-free survival (LFS) and overall survival (OS) was 42% and 46% in MMUD recipients, respectively, versus 26% (P = 0.1) and 28% (P = 0.061) in Haplo-patients. In conclusions, in AML patients with active disease at transplantation, MMUD-HCT results in at least comparable outcomes to Haplo-HCT when PTCy is applied. We report a paired-matched analysis of HLA-mismatched unrelated donor transplantation (MMUD, n = 73) versus HLA-haploidentical transplantation (n = 146) in AML patients with active disease at transplantation. Two-year leukemia-free survival and overall survival was 42% and 46% in MMUD recipients, respectively, versus 26% (P = 0.1) and 28% (P = 0.061) in Haplo-patients

Allogeneic Hematopoietic Cell Transplantation in Patients with Therapy-Related Myeloid Neoplasm after Breast Cancer: A Study of the Chronic Malignancies Working Party of the EBMT

Introduction: Therapy-related myeloid neoplasms (t-MNs) account for about 10 to 20% of all cases of AML and MDS. Allogenic hematopoietic cell transplantation (allo-HCT) is considered as the only curative treatment in this high-risk setting. Given the rise of long-term cancer survivors, an increasing number of patients are expected to become transplant candidates. Physicians are concerned about the frailty and the risk of recurrence of primary cancer. In this retrospective registry-based study, we focused on patients with t-MN secondary to breast cancer radio- and/or chemotherapy, and collected information about the outcomes and complications after allo-HCT. Methods and results: In the EBMT registry we identified 252 female adult patients who underwent an allo-HCT between 2006 and 2016 for t-MN secondary to breast cancer treatment. Median age at transplantation was 57 years, and the median time from the breast cancer diagnosis to t-MN diagnosis and subsequent allo-HCT were 3.7 and 4.6 years, respectively. The indication for allo-HCT was AML and MDS in 77% and 23% of cases, respectively. Sixty-seven% of patients were in complete remission (CR) of their t-MN at the time of transplant. Abnormal karyotype was recorded in 40% of cases. A reduced Karnofsky performance status (KPS&amp;lt;90) was noted in 29% of cases, and 44% of patients presented with at least one comorbidity other than the primary malignancy. Stem cell source was peripheral blood in 89% of cases. Conditioning regimens were reduced-intensity (RIC) in 61% and myeloablative (MAC) in 39% of patients, respectively, and in vivo T-cell depletion was applied in 55% of cases. TBI was used in 18%. Thirty-nine% of donors were matched related (MRD), and 30% matched unrelated (MUD). For the breast cancer, at the time of diagnosis, 5% presented with distant metastasis and 15% were triple negative; 86% received chemotherapy and 88% radiotherapy, 72% both. Of note, at the time of transplant, 93% of patients were deemed in first CR of their breast cancer, and additional 5% were in second CR or more: data on remission status were missing for 57 of patients. Median follow-up from transplant was 20 months and for the entire cohort the 2-year overall survival (OS) was 50% (95%CI 44-56%): in univariate analysis (UVA), an abnormal karyotype, being transplanted not in CR for the hematological malignancy and a worse KPS were associated with a worse prognosis [2-year OS: 41% (28-53%) for abnormal karyotype, 52% (42-62%) for normal, p=.035; 57% (49-64%) for CR, 56% (23-88%) for untreated, 34% (23-45%) for not in CR, p=.002; 55% (47-63%) for KPS≥90, 43% (31-55%) for KPS&amp;lt;90, p=.05]. The 2-year relapse-free-survival (RFS) was 45% (39-52%): as observed for the OS, a detrimental effect on RFS was observed for abnormal karyotype [2-year RFS: 34% (22-46%) for abnormal, 49% (39-59%) for normal karyotype, p=.034] and not being transplanted in remission for the t-MN [52% for CR (44-59%), 44% for untreated (12-77%), 31% (20-42%) for not in CR, p=.002]. 2-year relapse incidence and NRM were 33 (27-39%) and 22% (17-27%), respectively. An abnormal karyotype was significantly associated with a higher relapse rate compared to a normal [50 (37-62%) vs 26% (17-34%), p&amp;lt;0.001], as did an uncontrolled t-MN at the time of transplant [27% (20-34%) for CR, 33% (3-64%) for untreated, 47% (35-59%) for not in CR, p&amp;lt;.001]. Patients pre-exposed to radiotherapy for breast cancer experienced a higher relapse rate compared to those who did not [35 (28-43%) vs 17% (2-33%), p=.04], while the NRM was lower [18 (12-24%) vs 38% (19-58%), p=.02]. Acute grade II-IV GVHD occurred in 26% (22-33%) of patients, and the 2-year incidence of chronic GVHD was 41% (35-47%) including 22% (17-27%) of extensive grade. Seventeen cases of breast cancer recurrence were observed, of which 13 invasive. A curative approach was adopted in 7 cases. The most frequent cause of death in the whole cohort was relapse of t-MN (36%), followed by infection (28%) and GVHD (16%): the relapse of the primary breast cancer accounted for 10 (7%) cases of death. Conclusions: Our study shows that allo-HCT can be safely performed in patients with t-MN secondary to treatment to breast cancer. A major drawback is the relapse of the primary disease which nevertheless appeared a rare event. Tight collaboration and multidisciplinary discussion between the oncologist and the hematologist are fundamental, and an adequate follow-up for the solid malignancy is essential thereafter. Figure 1 Disclosures Ganser: Novartis: Consultancy; Celgene: Consultancy. Scheid:Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria, Research Funding; BMS: Honoraria. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. </jats:sec