SARS-CoV-2 infection can impact survival of patients with acute myeloid leukemia (AML). International experts recommend considering delaying or stopping AML treatment, test patients who need intensive induction and s prioritizing outpatient treatment. However there is little published evidence in AML. Objective To analyze the clinical futures and outcome of SARS-CoV-2 infection in AML patients. Methods and patients Observational multicenter study between March and May 2020; 117 patients reported from 47 Spanish centers, but 13 had no PCR or antibody test documented, finally including 104 patients from 45 hospitals. Results The median age was 68 years, men (56.7% vs 43.3%), and the median time from AML diagnosis to SARS-CoV-2 was 4 months. The mean of comorbidities was 1.2, high blood pressure (40.4%), heart disease (17.3%), diabetes (13.5%), smoking (8.8%), chronic obstructive pulmonary disease or emphysema (7.7%), renal failure (6.7%) and liver dysfunction (1.9%). Cytogenetic risk was low in 16.9%, intermediate in 57.1% and high in 26.0%; 55.7% had active disease, 39.2% complete remission and 5.1% partial response. 29.4% were off-therapy and 70.6% under antileukemic treatment at the time of SARS-CoV-2: induction chemotherapy (25.3%), hypomethylating (19.3%), clinical trial (17.0%), consolidation chemotherapy (14.8%), venetoclax (3.4%), FLT3 inhibitors (3.4%) and/or maintenance (1.1%). Overall 3.7% were newly diagnosed (no prior therapy), 77.8% had received one line of treatment, 14.8% two and 3.7% four. 15.4% had prior allogeneic transplantation. Only 4.0% of the patients were asymptomatic, while the main signs and symptoms were fever (77.8%), pneumonia (75.0%), cough (65.3%), dyspnea (52.0%), diarrhea (20.4%), nausea and/or vomiting (12.2%), rhinorrhea (10.2%) and headache (7.4%). Analytical parameters were: neutrophils 3112 cells/µL (1900-7300), lymphocytes 1090 cells/µL (1000-3000), interleukin 6 118 pg/mL (0-100), ferritin 4505 ng/mL (15-150) and D-dimer 2823 ng/mL (20-500), with liver enzymes altered in 23.9% of cases. 84.2% received specific treatment for coronavirus infection: chloroquine or hydroxychloroquine (82.2%), lopinavir/ritonavir (54.0%), corticosteroids (39.6%), azithromycin (33.0%), tocilizumab (15.8%), plasma convalescent (3.0%), clinical trial medication (3.0%), remdesivir (2.0%) and/or anakinra (1.0%). The course was mild in 14.7% (no hospitalization), moderate in 32.0% and severe in 53.3%. The implementation of intensive measures was assessed in 48.2%(14.9% admitted to the ICU and the remaining 33.3% rejected). The mean time to negativization was 20.5 days, duration of symptoms 17.6 days and the hospital stay 11.1 days. In 48.1% of the cases treatment for AML was maintained, in 26.6% delayed and in 25.3% modified due to coronavirus disease.47.5% died, establishing an association between mortality and age over 60 years (58.3% vs 36.4%, p=0.043), ≥2 lines of treatment (72.7% vs 44.3%, p=0.020), active disease (62.5% vs 29.4%, p=0.002) and pneumonia (61.2% versus 22.7%, p=0.002). Overall 47.5% overcame the infection, and in 5.0% SARS-CoV-2 genetic material was still detected at the time of analysis. A non-significant lower mortality rate was observed among: previous transplantation (45.7% vs 64.3%, p=0.19), neutrophil >1900 cells/µL (41.1% vs 60.0%, p=0.09), lymphocyte >1000 cells/µL (42.9% vs 63.6%, p = 0.09) and hydroxychloroquine/chloroquine plus azithromycin (35.3% vs 60.0%, p=0.10). Conclusions SARS-CoV-2 infection produces high mortality among AML patients. Mortality was correlated with age, active disease and pneumonia. Disclosures Martinez-Lopez: Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Research Funding.
Introduction The comprehensive geriatric assessment (CGA) in older patients with cancer is the gold standard to identify robust, frail or poor prognosis patients according Balducci classification. In Spain, a new proposal of a specific Geriatric Assessment in Hematology (GAH) scale has been designed and validated in patients with hematologic malignancies such as MDS/AML, multiple myeloma and CLL. The GAH scale has not been explored in patients with lymphoma. In this study, we have analyzed the utility of using the GAH scales in patients with hematologic malignancies, mostly lymphoma patients. Patients and methods. From March 2016 and September 2017, patients with hematologic malignancies were prospectively referred to the Geriatric Oncology clinic after a frailty screening test using G8 scale and with score <14 points. All patients were assessed with CIRS-G and GAH scales performed by the oncology nurses and a comprehensive geriatric assessment performed by the geriatrician. Results Of the 96 patients referred aged 70 years or over, 41 were males (42.7%) and 55 females (57.3%), the median age was 79 years (range, 70-89), and with the diagnosis of lymphoma in 53 patients (55.2%), multiple myeloma in 23 patients (24.0%), CLL in 13 patients (13.6%), MDS/AML in 5 patients (5.2%) and CML in 2 patients (2.0%). Seventy-five patients (78.1%) had good performance status with ECOG score 0-1. Regarding frailty, 20 patients (20.8%) had a score of 15 points or over at G8 scale and 76 patients (79.2%) were identified as frail because of a score of 14 points or below. Regarding comorbidities, the median CIRS-G score was 9 (range, 4-20). After the GAH scale assessment, the median number of domains affected in robust patients was 2 (1-4) and in frail patients was 4 (3-5) (p=0.0001). In the ROC curve, with an AUC of 0.7595 and a likelyhood ratio of 9, the cut-off in this series was 2 domains with impairment, with a sentivity of 13.79% and a specificity of 92.5% (p= 0.0003). Using a correlation factor for each domain, the mean score at GAH scale in robust patients was 26 points and in frail patients was 42.5 points (p=0.0038). In the ROC curve, with an area under the curve of 0.7026 and a likelihood ratio of 2.04, the cut-off value to identify robust vs frail patients was 33 points in the GAH scale, with a sensitivity of 77.5% and a specificity of 62.07% (p=0.0043). Analyzing the eight domains explored in the GAH scale, robust patients according CGA had less risk of polypharmacy of 31.25% vs 81.48% in frail patients (OR 0.1033, 95% CI 0.0472-0.2541) (p<0.0001), less gate speed/FAC impairment of 16.66% vs 81.48% (OR 0.04545, 95% CI 0.0183-0.1313) (p<0.0001), less ADL impairment 37.5% vs 85.19% (OR 0.1043, 95% CI 0.0398-0.2684) (p<0.0001), less mood impairment in 4.17% vs 40.74% in frail patients (OR 0.06324, 95% CI 0.01421-0.2498) (p<0.0001), less mental health impairments in 2.08% vs 22.22% in frail patients (OR 0.0744, 95% CI 0.0068-0.4531) (p=0.0023), less comorbidities in 2.08% vs 42.59% (OR 0.0286, 95% CI 0.0027-0.1817) (p<0.0001), less malnutrition in 10.42% vs 37.04% (OR 0.1977, 95% CI 0.0759-0.5495) (p=0.0024), and less poor self-reported well-being in 6.25% vs 66.67% (OR 0.0333, 95% CI 0.0101-0.1187) (p<0.0001). The median overall survival for patients with 3 or less domains impaired was not reached vs 90.77 months in those patients with 4-8 domains impaired (Log-rank test, p=0.0003), with HR (Log-rank) of 0.11 (95% CI, 0.04474-0.2846). Mean G8 score were similar between robust (11.68) and frail (11.04) patients (p=n.s.) among all patients with score below 14 points. Robust patients had less comorbidities according to CIRS-G scale, with a median of 9 vs 11 points (p=0.0001). There was correlation between CIRS-G and ECOG with G8 score, not found in previous studies. There is a correlation between the brief comorbidity assessment in the GAH scale with CIRS-G score. Among patients identified as not having comorbidities, the median CIRS-G score was 9 vs 13.5 among patients with comorbidities according the GAH scale (p<0.0001). Conclusions. The GAH scale is a valid tool for patients with hematologic malignancies, including patients with lymphoma, in order to classify patients according frailty phenotype. All domains explored in GAH scale were impaired with higher frequency in frail patients. Robust patients had less comorbidities and better performance status. The brief comorbidities assessment in the GAH scale correlates well with the CIRS-G. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
COVID-19 is a severe infectious complication in patients with underlying medical conditions such as having undergone hematopoietic stem cell transplantation (HCT). This prospective survey reports outcome on 272 COVID-19 patients from 19 countries having undergone allogeneic (n = 175) or autologous (n = 97) HCT reported to the EBMT registry or to the GETH. All patients had the diagnosis of SARS-CoV-2 documented by PCR. Patients were included in this analysis if COVID-19 diagnosis was before April 10, 2020. The overall survival was estimate by using the Kaplan Meier methods, considering the death due to any cause as an event and the time from COVID-19 infection to the latest follow-up as survival time; difference between groups were tested by the log-rank test. Univariate and multivariate risk factor analysis for overall survival were performed with the Cox regression model. The median age was 54.4 years (1.0 - 80.3) for allogeneic and 60.9 years (7.7 - 73.4) for autologous HCT patients. 20 patients were children (< 18 years of age; median age 11.3 (1.0 - 16.9)). The median time from HCT to diagnosis of COVID-19 was 13.7 months (0.2 - 254.3) in allogeneic and 25.0 months (-0.9 - 350.3) in autologous recipients. Lower respiratory tract disease (LRTD) developed in 84.8% and 21.5% were admitted to an intensive care unit (ICU). At the time of analysis, 68/238 (28.6%) patients had died (47/155 allogeneic patients; 21/83 autologous patients). No follow-up had been received on 34 patients. The median time from infection to death was 19 days (0-102). Five patients were reported to have other primary causes of death than COVID-19. Of the patients reported to be alive, the median follow-up was 44 days. 144 (84.7%) patients (93 allogeneic; 51 autologous) had virologic resolution of the COVID-19 infection having at least one negative PCR. 26 patients were alive and known to be still COVID-19 positive (15 allogeneic; 11 autologous). For 34 patients the resolution status was unknown. Factors influencing the likelihood of resolution in multivariate analysis were underlying diagnosis (p=.01) and longer time from transplant to diagnosis of COVID-19 (p=.035). Overall survival at 6 weeks from COVID-19 diagnosis was 76.8% and 83.8% in allogeneic and autologous HCT recipients (p =ns), respectively (figure 1). Children (n=20) tended to do better with a 6-week survival of 95.0% although the difference was not significantly different (p =.12). In multivariate analysis of the total population older age (HR 1.26; 95% CI 1.05 - 1.51; p = .01) increased the risk and better performance status decreased the risk for fatal outcome (HR 0.79; 95% CI 0.69 - 0.90; p = .0003). The same factors had significant impact on overall survival in allogeneic HCT recipients (age HR 1.28; 95% CI 1.05 - 1.55; p=.01; performance status HR 0.79; 95% CI 0.68 - 0.92); p=.002) while only age impacted survival among autologous HCT patients (data not shown). Other transplant factors such as underlying diagnosis, time from HCT to diagnosis of COVID-19, graft-vs-host disease, or ongoing immunosuppression did not have a significant impact on overall survival. We conclude that HCT patients are at an increased risk compared to the general population to develop LRTD, require admission to ICU, and have increased mortality in COVID-19. Figure 1 Disclosures Duarte: Incyte Corporation: Other: Has received speaker and advisor fees. Kwon:Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Mielke:Novartis: Honoraria, Other: received via my institution, Speakers Bureau; Celgene/BMS: Honoraria, Other: received via my institution , Speakers Bureau; Bellicum: Honoraria, Other: received via my institution, Speakers Bureau; Kite/Gilead: Honoraria, Other: received via my institution , Speakers Bureau; Miltenyi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: received via my institution , Speakers Bureau; KIADIS Pharma: Honoraria, Other: received via my institution , Speakers Bureau; DNA Prime: Honoraria, Other: received via my institution , Speakers Bureau. López Jiménez:MSD: Speakers Bureau; Roche: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Abbvie: Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau.
Background: Incidence of AML is highest among the elderly and the general outcome is poor as compared to young patients, even those who tolerate intensive induction chemotherapy and achieve morphological CR. However, the role of MRD in redefining CR in elderly AML remains poorly investigated due to the reluctance to treat them with intensive chemotherapy, the renewed interest in low-intensity therapy such as hypomethylating agents (HMA), and the lack of molecular MRD markers in most patients. Aim: To help defining the role of MRD assessment by multidimensional flow cytometry (MFC) and therapeutic decision making in older AML patients treated with semi-intensive chemotherapy vs HMA. Methods: A total of 285 AML patients (excluding APL) with a median age of 75 were included in the phase III PETHEMA-FLUGAZA clinical trial and were randomized to receive 3 induction cycles with fludarabine and cytarabine (FLUGA) followed by 6 consolidation cycles with reduced intensity FLUGA, vs 3 induction cycles with 5-azacitidine (AZA) followed by 6 consolidation cycles with AZA. After consolidation, patients continued with the same treatment if MRD ≥0.01% or stopped if MRD <0.01%. MRD was prospectively assessed after induction and consolidation among patients in CR with or without incomplete blood count recovery, in a central laboratory blinded for clinical outcomes. At diagnosis, the EuroFlow panel for MDS/AML (first-five 8-color combinations) was used to identify leukemia-associated immunophenotypes (LAIP). Patients without a LAIP (6%) were excluded from this analysis. At CR, bone marrow samples were immunophenotyped with ≥2 8-color combinations based on previously identified maturation arrest, lineage commitment and LAIPs, maintaining markers' position from diagnosis to MRD to provide a digital fingerprint of leukemic blasts at diagnosis during MRD assessment. Over 1 million events per tube were measured for assessing MRD with an estimated sensitivity of 0.01%. The cumulative incidence of relapse (CIR) was calculated from the date of CR to the date of relapse, considering death without relapse as a competing event. Results: On intention-to-treat, 38/141 (27%) patients achieved CR after 3 cycles of FLUGA, and 31/144 (21.5%) after 3 cycles of AZA (P =.33). Among patients in CR with previously identified LAIP, 14/69 (20%) achieved a negative MRD status whereas the remaining 55 (80%) had persisting MRD: 56% with ≥0.1% MRD and 24% with 0.01%-0.09% MRD. Of note, negative MRD rates were particularly lower among AML patients with myelodysplasia-related changes as compared to other subtypes (11% vs 27%, respectively; P=.09). Regarding the effect of semi-intensive chemotherapy vs HMA on depth of response, we observed a non-significant trend toward higher MRD-negative rates among patients in CR after FLUGA vs those treated with AZA (26% vs 15%, respectively; P=.28). The 2-year CIR rates for MRD-positive and MRD-negative patients were 88% and 47%, respectively (HR, 3.3; P =.001). Of note, the CIR of patients in CR but with persistent MRD were similarly poor as compared to those in partial remission (HR, 0.82; P =.48). Furthermore, MRD-positive patients with adverse cytogenetics displayed the poorest outcome with significantly higher 2-year CIR rates than MRD-positive cases with intermediate/favorable cytogenetics (HR, 2.1; P =.008). Interestingly, among patients in CR and persistent MRD, 2-year CIR rates showed a non-significant trend towards slightly more frequent relapses in those treated with FLUGA vs AZA (91% vs 77%, respectively; HR, 1.7; P =.09). On multivariable analysis for CIR including MFC-MRD and cytogenetics, MFC-MRD (HR, 3.6; P =.001) and cytogenetics (HR, 2.0; P =.007) retained significant prognostic value. The median overall survival (OS) for MRD-positive and MRD-negative patients was 17 and 29 months, respectively (P =.04). On multivariable analyses for OS including age, WBC count, cytogenetic grouping and secondary disease, persistent MRD showed a trend for independent prognostic value (HR, 2.4; P =.07). Conclusions: This study reveals that sensitive MFC-MRD assessment supersedes CR and is an independent prognostic factor in older patients with AML, treated with semi-intensive chemotherapy or HMA. Nevertheless, the risk of relapse among the few patients with no MRD (5%) remains high after stopping treatment, and warrants innovative approaches aimed at maintaining an MRD-negative CR status. Disclosures San-Miguel: Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Roche: Honoraria. Montesinos:Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau.
Background: AML is the most common acute leukemia in adults and its prevalence significantly increases in the elderly. The 5-year survival rate for adults younger than 60 is around 40% and decreases to 10% in patients above this age. Even those patients who tolerate intensive induction chemotherapy and achieve complete remission (CR) have poor outcome. Detection of MRD in younger AML refines outcome prediction of patients in CR after intensive chemotherapy. However the value of MRD in elderly patients is inconsistent between those treated with intensive vs hypomethylating drugs, and unknown after semi-intensive therapy. Aim: Define the role of MRD assessment by multidimensional flow cytometry (MFC) for therapeutic decision making in elderly AML patients treated with semi-intensive chemotherapy vs hypomethylating agents (HMA). Methods: Two-hundred eighty-three elderly AML patients were included in the PETHEMA phase III FLUGAZA clinical trial and randomized to receive three induction cycles with fludarabine and cytarabine (FLUGA) followed by six consolidation cycles with reduced intensity FLUGA, or three induction cycles with 5-azacitidine (AZA) followed by 6 consolidation cycles with AZA. After consolidation, patients continued with the same treatment if MRD ≥0.01% or stopped if MRD <0.01%. MRD was prospectively assessed using MFC after induction and consolidation. Patient-specific aberrant phenotypes were used for highly-purified FACSorting of leukemic cells at diagnosis and after treatment in MRD positive patients, or CD34 progenitors in MRD negative cases. Results: Patients in CR/CRi with undetectable MRD (N = 13/72) had significantly improved 1-year cumulative incidence of relapse (CIR, 38% vs 81%; HR: 0.43, P =.030) and relapse free survival (RFS, median of 13 vs 5 months; HR: 0.40, P = .012) as compared to cases with persistent MRD (N = 59/72), though not overall survival (median of 19 vs 11 months; HR: 0.56, P =.097). Achieving undetectable MRD significantly improved RFS of patients with adverse genetics (HR: 0.32, P =.013). On multivariate analysis including genetic risk and treatment arm, MRD status in patients achieving CR was the only independent prognostic factor for CIR (HR: 2.95; P =.002) and RFS (HR: 3.45; P =.002). Eleven of the 13 patients with detectable MRD did relapse or died after the last update of the follow-up, notwithstanding these patients showed a trend for longer overall survival. To better understand the limitations of MFC-based MRD assessment in identifying patients with long-term survival and driven by the paucity of data about immunophenotyping in elderly AML, we investigated the level of phenotypic divergence/overlap between leukemic cells vs their normal maturation-stage counterpart in healthy adults (N=10). Using an unbiased scoring approach based on principal component analysis of merged data, we found that only 7/265 (3%) patients harbored leukemic cells showing phenotypic profiles fully overlapping with their normal maturation-stage counterpart. We thus hypothesized that in patients with undetectable MRD, phenotypically normal CD34 progenitors would contain cells with leukemic-initiating-potential that could be identified on genetic grounds. Using whole exome sequencing, we systematically identified mutations and copy-number abnormalities (CNA) consistent with genetic MRD (gMRD). These findings were similar to that observed when the genomic landscape of leukemic cells at diagnosis were compared to persistent MRD cells, underpinning the extent of gMRD in patients achieving CRMRD by MFC. Interestingly, there was a significant increase in the number of genetic alterations from diagnosis to MRD stages in patients treated with FLUGA vs AZA (1.9-fold vs 1.1-fold, P =.002), which could be related to the mutagenic potential of antimetabolites. Conclusions: Our results show that older AML patients achieving undetectable MRD after semi-intensive therapy or HMA have lower risk of relapse and a trend for longer survival. However, this study unveiled that phenotypically normal CD34 progenitors possess substantial genetic abnormalities in cases with negative MRD. Thus, improved sensitivity of MRD testing by MFC and possibly the combined use of this method with NGS, might be warranted to identify elderly AML patients in CRMRD that may experience long-term survival and could benefit from treatment individualization based on MRD status. Disclosures Paiva: SkylineDx: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Adaptive: Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding. Tormo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Ramos:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel and research grants; Novartis: Consultancy, Other: travel grant; Amgen: Consultancy, Other: travel grant; Abbvie: Consultancy, Other: travel grant; Jannsen: Other: travel grant; Roche: Other: travel grant; Rovi: Other: travel grant; Merck-Sahrp & Dohme: Other: travel grant; Daiichi-Sankyo: Other: travel grant; Takeda: Consultancy, Other: travel grant . Vidriales:Janssen, BMS, Novartis, Roche, Astellas Pharma, and Jazz Pharmaceuticals.: Honoraria, Other: Advisory boards. Martinez-Lopez:Novartis: Consultancy; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Incyte: Consultancy, Research Funding. San-Miguel:Bristol-Myers Squibb, Celgene, Novartis, Takeda, Amgen, MSD, Janssen, and Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche, AbbVie, GlaxoSmithKline, and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sanz:Teva, Daiichi-Sankyo, Orsenix, AbbVie, Novartis, and Pfizer: Other: Consulting or Advisory Role.
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