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INTRODUCTION
Acute Myeloid Leukemia (AML) and high risk Myelodisplastic Syndrome (MDS) have a higher incidence in older patients. Due to their age, comorbidity and unfavorable biology of the ...disease, intensive chemotherapy offers poor results. Hypomethylating agents and other alternative regimens are being tested but the best strategy is currently not well defined.
OBJECTIVE
Updating the FLAGIDA-lite intermediate intensity chemotherapy scheme results (Am J Hematol. 2012 Jan;87(1):42-4). Rate of overall response (OR), overall survival (OS) and treatment-related mortality (TRM) were evaluated. An estimated cost approach and a review of the 5-azacytidine cost estimation was made.
PATIENTS AND METHODS
Seventy patients older than 65 years with AML or high risk MDS treated with the FLAGIDA-lite regimen in three Spanish centers between 2006 and 2016 were analyzed. Median age was 76 years (IQL 73-81) and patients´ characteristics are shown in table 1 . The regimen consisted of: Fludarabine (40mg/m2 daily, days 1-5, P.O), Citarabine (20 mg/m2 daily, days 1-5, sub-Q) and Idarrubicin (15 mg/m2 daily, days 1-3, P.O until 2014, or IV 10 mg/m2 daily, days 1-3 when oral formulation disappeared). G-CSF (300 µg/24h sub-Q, days -1 to 5) was added except when leukocytosis was greater than 100,000/µl. Treatment administration and subsequent follow-up were performed under hospitalization, home care or ambulatory regimen. We calculated the regimen costs.
RESULTS
Toxicity and Treatment Related Mortality
A total of 117 chemotherapy cycles were administered (80 as induction and 37 as consolidation).
Sixty-one (76.2%) induction and 34 (91.9%) consolidation cycles were administered under ambulatory or home care regimen; in 21 (34.4%) and 8 (21.6%) of them, respectively, hospital admission was necessary, mainly due to infectious complications.
Thirteen (18.6%) patients died after induction, 10 due to treatment-related complications and 4 due to disease progression. Early mortality at 8 weeks was 20.9%. Treatment-related mortality was higher in patients older than 80 years (30 vs 10%), as shown in figure 1.
Overall Response and Overall Survival
Sixty patients received one induction cycle and 10 received 2. OR rate was 64.9% (49.1% CR, 8.8% CRi; 7% PR) and 35.1% of patients were refractory. Median time to CR was 36 days (26-51). Twenty-six patients who had reached CR/CRi received consolidation with the same regimen (35 cycles) and 6 patients were submitted to a related allogeneic hematopoietic stem-cell transplantation.
With a median follow-up of 23.8 months (9-105) in alive patients, estimated OS at 2 years was 22.6 (±5.4%) in the whole series and 41.1% (±9.4%) in patients who reached CR/CRi, as shown in figure 2. Median OS in patients who reached CR/CRi was significantly higher than in non-responder patients (17.4 vs 2.9 months, p< 0,001).
Cost estimation
The cost of one cycle of FLAGIDA-lite, in Spain, is 1825.18 euros, as shown in table 2 . The median number of cycles administered in our study was 2, so the global cost of treatment drugs was 3650.36 euros. The estimated cost in Spain of another non-intensive regimen with not higher or similar efficacy (5-azacitidine) according to literature is 3028.14 euros each cycle and a total cost of 18,168.84 euros (median number of 6 cycles) . ( Health Econ Rev. 2013 Dec 5;3(1):28).
CONCLUSION
FLAGIDA-lite is an effective alternative regimen in elderly patients with AML and high risk MDS, with low treatment-related mortality in patients younger than 80 years (10%) and with the possibility of an ambulatory management. This treatment offers an overall response rate around 65%, and an estimated overall survival at two years around 41% in responder patients. Its cost is markedly lower than the cost of 5-azacytidine.
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No relevant conflicts of interest to declare.
Background: Endothelial Activation and Stress Index (EASIX) was developed as a simple surrogate of endothelial dysfunction and when evaluated pre-allogeneic hematopoietic cell transplantation ...(allo-HCT), is one of the strongest tools for predicting non-relapse mortality (NRM). In several datasets, we have found that high EASIX scores at days +30 and +100 post allo-HCT and at the onset of graft-versus-host disease (GVHD) are associated with higher NRM and poorer overall survival (OS) (data unpublished). These data demonstrate that EASIX analyzed as a categorical variable at specific landmarks is associated with outcomes after allo-HCT. However, the trend of EASIX scores has never been evaluated as a continuous variable over time. We hypothesized that defining the natural history of changes in EASIX post-HCT would help us identify an optimal time point at which EASIX has the highest discrimination for NRM. We also sought to determine whether changes in EASIX over time may be a more informative marker of NRM.
Methods: We evaluated 509 adult patients who received an unmodified or ex-vivo CD34+-selected allo-HCT between April 2008 and December 2016. One hundred and forty-nine patients underwent unmodified, reduced intensity or nonmyeloablative allo-HCT with uniform GVHD prophylaxis of sirolimus/tacrolimus and low-dose methotrexate. Three hundred and sixty patients underwent myeloablative allo-HCT with ex-vivo CD34+ selection (CliniMACS® CD34 Reagent System) as GVHD prophylaxis. The EASIX score (LDH*creatinine/platelet count) was calculated at continuous timepoints from baseline day -30 to day -10 until 1-year post-HCT. For each longitudinal evaluation, the concordance of EASIX was estimated for NRM events occurring in the subsequent 180 days. A log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. A one-unit increase in log2 EASIX is associated with a doubling (one-fold increase) of EASIX on the original scale. Disease relapse or death were considered competing risks for NRM.
Results: Patient and HCT characteristics are detailed in Table 1. Median age at HCT was 56 years (range 19-78) and 59% of patients were males. The majority of unmodified allo-HCT were done for non-Hodgkin lymphoma (69%), while the majority of CD34-selected allo-HCTs were done for acute leukemia (61%). Most patients had sensitive disease at time of HCT (CR=61%; PR=13%). All patients except two received peripheral blood mobilized allografts. HCT-CI was 0 in 24% of patients, 1-2 in 32% and ≥ 3 in 44%. Sixty-eight patients experienced NRM within 1-year post-HCT. Causes of death in these patients were infection (41%), GVHD (29%), toxicity/organ failure (24%) and other (6%). Among all patients, EASIX scores rise rapidly early post-HCT and peak day +8 followed by sharp decline until day +40. Thereafter, EASIX scores tend to downtrend, but remain above baseline for the duration of the first year post-HCT (Figure 1). EASIX discrimination of 180-day NRM increases from time of allo-HCT until day +180 to +210, when concordance is highest (concordance index=0.85) (Figure 2). Overall, the ability of the EASIX score to discriminate NRM event times is similar when EASIX is analyzed as a categorical variable at landmark timepoints and as change from pre-HCT baseline EASIX score. In the first days post-HCT, EASIX values rise to a similar degree in patients regardless of whether they experience NRM or relapse in the following 180 days. Later in the post allo-HCT course, patients who do not experience NRM, including patients who relapse, have consistently lower EASIX scores compared to those who experience NRM in the following 180 days (Figure 3).
Conclusions: Our data are the first to characterize the continuous trend of EASIX scores after allo-HCT, demonstrating that EASIX scores are highly dynamic and have variable concordance with NRM when analyzed longitudinally. While pre-HCT EASIX can be used to help guide allo-HCT treatment decisions prior to allo-HCT, evaluation of the dynamic changes in EASIX scores may better predict risk of NRM over time as patients acquire additional endothelial injury and toxicities after HCT. Assessment of dynamic EASIX scores may be useful in guiding novel investigative approaches to reduce the risk of toxicities and NRM along the allo-HCT journey.
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Giralt:Actinium: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Takeda: Consultancy, Research Funding; Kite: Consultancy; Miltenyi: Research Funding. Perales:Miltenyi: Research Funding; Kyte/Gilead: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy.
Various grading systems are currently used for chimeric antigen receptor (CAR) T-cell–related toxicity, cytokine release syndrome (CRS), and immune effector cell–associated neurotoxicity syndrome ...(ICANS). We compared the recently proposed American Society for Transplantation and Cellular Therapy (ASTCT) grading system to other grading scores in 2 populations of adults: patients (n = 53) with B-cell acute lymphoblastic leukemia (B-ALL) treated with 1928z CAR T-cells (clinicaltrials.gov #NCT01044069), and patients (n = 49) with diffuse large B-cell lymphoma (DLBCL) treated with axicabtagene-ciloleucel (axi-cel) or tisagenlecleucel after US Food and Drug Administration approval. According to ASTCT grading, 82% of patients had CRS, 87% in the B-ALL and 77% in the DLBCL groups (axi-cel: 86%, tisagenlecleucel: 54%), whereas 50% of patients experienced ICANS, 55% in the B-ALL and 45% in the DLBCL groups (axi-cel: 55%, tisagenlecleucel: 15%). All grading systems agreed on CRS and ICANS diagnosis in 99% and 91% of cases, respectively. However, when analyzed grade by grade, only 25% and 54% of patients had the same grade in each system for CRS and ICANS, respectively, as different systems score symptoms differently (upgrading or downgrading their severity), leading to inconsistent final grades. Investigation of possible management implications in DLBCL patients showed that different recommendations on tocilizumab and steroids across current guidelines potentially result in either overtreating or delaying treatment. Moreover, because these guidelines are based on single products and different grading systems, they cannot be universally applied. To avoid discrepancies in assessing and managing toxicities of different products, we propose that unified grading be used across clinical trials and in practice and that paired management guidelines with product-specific indications be developed.
•Use of different grading systems leads to inconsistent CAR T-cell toxicity rates, with possible implications for disease management.•A unified grading system should be used in clinical practice and trials, and related management guidelines should be developed.
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The Endothelial Activation and Stress Index (EASIX) is a prognostic tool that uses common clinical laboratory values and has been shown to predict non-relapse mortality (NRM) and overall survival ...(OS) at the onset of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We hypothesized that EASIX calculated at different time points pre- and post- HCT may predict NRM and OS, and that EASIX calculated at onset of GVHD may predict response to steroids. We evaluated the EASIX score pre- and post-HCT in 152 patients with lymphoid malignancies undergoing unmodified reduced intensity conditioning (RIC) alloHCT with uniform GVHD prophylaxis. In multivariate analysis, EASIX calculated pre-HCT was significantly associated with higher NRM (HR = 1.64, p = 0.009) and lower OS (HR = 1.33, p = 0.046). Furthermore, EASIX calculated at day 30 and at day 100 was associated with increased NRM (HR = 1.65, p < 0.001; and HR = 1.65, p < 0.001) and decreased OS (HR = 1.27, p = 0.018; and HR = 1.49, p < 0.001), independent of HCT-CI, disease and conditioning regimen. Our study shows that high EASIX scores at various time points pre- and post-HCT are significantly associated with poorer overall outcomes. EASIX provides an independent and easily accessible tool to predict outcomes that can be complementary to other measures of risk stratification for patients undergoing HCT.
Keywords
Allogeneic transplantation; endothelial damage; biomarkers.
Background
Endothelial damage is associated with severe complications and increased risk of death after allogeneic hematopoietic ...cell transplantation (AlloHCT). The recently developed Endothelial Activation and Stress Index (EASIX) is a prognostic tool that uses clinical lab values and has been shown to predict non-relapse mortality (NRM) and overall survival (OS) at onset of acute graft versus host disease (aGVHD) in reduced intensity (RIC) alloHCT (Luft, Lancet Haematol 2017). We hypothesized that EASIX may be valuable for more broadly predicting aGVHD, NRM and OS after AlloHCT, beyond time of onset of aGVHD.
Design
We evaluated 152 adult patients who received an unmodified RIC AlloHCT from a related or unrelated donor with uniform GVHD prophylaxis of sirolimus/tacrolimus and low-dose MTX for treatment of lymphoid malignancies, between April 2008 and May 2017. The EASIX formula (LDH*Creatinine/platelet counts) was calculated at multiple timepoints (pre-HCT, day 30, day 100, onset TMA and aGVHD). For all EASIX assessments post-HCT, a landmark analysis was conducted at the given timepoint A log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. A one-unit increase in log2 EASIX is associated with a doubling (one-fold increase) of EASIX on the original scale. Kaplan-Meier, cumulative incidence, and cox modeling (cause specific for NRM and aGVHD) were used to evaluate EASIX as it relates to outcomes of interest. Relapse and death or relapse were considered competing risks for NRM and aGVHD respectively.
Results
The median age at transplant was 54 years (range 23-78), 70% were males, a majority had non-Hodgkin lymphoma (68%), and most had sensitive disease at time of HCT (CR=56%; PR=33%). All patients, except two, received peripheral blood stem cells. Sixty-three patients had an HLA-identical related donor, while the remaining 89 had an unrelated donor transplant (HLA-matched in 75 patients, and HLA-mismatched in 14 patients). HCT-CI was 0 in 49 patients, 1-2 in 41 and ≥ 3 in 62 patients. With a median follow-up in surviving patients of 5.4 years (range, 0.8-10), the 1 and 3 years OS rate was 84.2% (95% CI, 77.3-89.1) and 67.9% (95% CI, 59.6-74.8), respectively. The NRM rate at 1 and 3 years was 7.9% (95% CI, 4.3-12.9) and 16.4% (95% CI, 10.9-22.8), respectively. The 1-year cumulative incidences of grades 1-4, 2-4 and 3-4 aGVHD were 56.6% (95% CI, 48.3-64.1), 42.1% (95% CI, 34.2-49.8) and 7.9% (95% CI, 4.3-12.9), respectively. Post-HCT thrombotic microangiopathy was only observed in 13 patients, representing too few events for EASIX analysis. As expected, HCT-CI was significantly associated with both OS and NRM. Pre-HCT EASIX was significantly associated with increased NRM (HR=1.60 95% CI, 1.15-2.23, p=0.005) and aGVHD grade 1-4 and 2-4 (HR=1.33 95% CI, 1.08-1.64, p=0.006 and HR=1.39 95% CI, 1.10-1.75, p=0.005; respectively), but not OS or grade 3-4 aGVHD (Table 1). EASIX at day 30 and day 100 was significantly associated with both OS and NRM (Figures 1-4). Furthermore, confirming the results of Luft, EASIX calculated at onset of any grade aGVHD was significantly associated with OS (HR=1.34 1.10-1.63, p=0.004) and NRM (HR=1.47 1.11-1.94, p=0.007). Finally, there was no correlation between HCT-CI and EASIX score.
Conclusions
We conclude that the EASIX formula, calculated at various timepoints pre and post AlloHCT, is significantly associated with NRM and OS. Pre-HCT EASIX also predicts risk of aGVHD, confirming prior results, EASIX at onset of acute GVHD is a predictor of NRM and OS in adult recipients RIC AlloHCT. EASIX provides an independent and easily accessible tool to predict important AlloHCT outcomes that can be used in addition to HCT-CI to better risk stratify patients.
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Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Perales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees; Novartis: Other: Personal fees.
Patients who develop chimeric antigen receptor (CAR) T-cell–related severe cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) exhibit hemodynamic ...instability and endothelial activation. The EASIX (Endothelial Activation and Stress Index) score (lactate dehydrogenase LDH; U/L × creatinine mg/dL/platelets PLTs; 109 cells/L) is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation. Elevated LDH and low PLTs have been associated with severe CRS and ICANS, as has C-reactive protein (CRP), while increased creatinine is seen only in a minority of advanced severe CRS cases. We hypothesized that EASIX and 2 new modified EASIX formulas (simplified EASIX, which excludes creatinine, and modified EASIX m-EASIX, which replaces creatinine with CRP mg/dL), calculated peri-CAR T-cell infusion, would be associated with development of severe (grade ≥ 3) CRS and ICANS. We included 118 adults, 53 with B-acute lymphoblastic leukemia treated with 1928z CAR T cells (NCT01044069) and 65 with diffuse large B-cell lymphoma treated with axicabtagene ciloleucel or tisagenlecleucel. The 3 formulas showed similar predictive power for severe CRS and ICANS. However, low PLTs and high CRP values were the only variables individually correlated with these toxicities. Moreover, only m-EASIX was a significant predictor of disease response. m-EASIX could discriminate patients who subsequently developed severe CRS preceding the onset of severe symptoms (area under the curve AUC at lymphodepletion, 80.4%; at day −1, 73.0%; and at day +1, 75.4%). At day +3, it also had high discriminatory ability for severe ICANS (AUC, 73%). We propose m-EASIX as a clinical tool to potentially guide individualized management of patients at higher risk for severe CAR T-cell–related toxicities.
•m-EASIX calculated before and early after CAR T-cell infusion can predict severe CRS and ICANS before the onset of severe symptoms.•m-EASIX includes laboratory parameters routinely available in CAR T-cell clinical practice and can be easily calculated at bedside.
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