The Current Landscape of Secondary Malignancies after CAR T-Cell Therapies: How Could Malignancies Be Prevented?

Chimeric antigen receptor (CAR) T-cell therapies have revolutionised the field of haematological malignancies by achieving impressive remission rates in patients with highly refractory haematological malignancies, improving overall survival. To date, six commercial anti-CD19 and anti-BCMA CAR T-cell products have been approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory B-cell haematological malignancies and multiple myeloma. The indications for CAR T-cell therapies are gradually expanding, with these therapies being investigated in a variety of diseases, including non-malignant ones. Despite the great success, there are several challenges surrounding CAR T-cell therapies, such as non-durable responses and high-grade toxicities. In addition, a new safety concern was added by the FDA on 28 November 2023 following reports of T-cell malignancies in patients previously treated with either anti-CD19 or anti-BCMA autologous CAR T-cell therapies both in clinical trials and in the real-world setting. Since then, several reports have been published presenting the incidence and analysing the risks of other secondary malignancies after CAR T-cell therapies. In this opinion article, the current landscape of secondary malignancies after CAR T-cell therapies is presented, along with a proposed strategy for future research aiming at potentially diminishing or abrogating the risk of developing secondary malignancies after CAR T-cell therapies.

A decade of CD4+ chimeric antigen receptor T-cell evolution in two chronic lymphocytic leukemia patients: were chronic lymphocytic leukemia cells present?

On Feb 2, 2022, Nature published the paper titled "Decade-long leukemia remissions with the persistence of CD4+ CAR T-cells" (Nature. 2022;602:503-9. doi: 10.1038/s41586-021-04390-6). According to the results presented, it could be argued that "chimeric antigen receptor (CAR) T-cells can actually cure patients with chronic lymphocytic leukemia (CLL)". CAR T-cells remained detectable more than ten years after infusion, and immunoglobulin heavy chain (IGH) rearrangement deep sequencing showed persistent deep molecular remission for both patients (no CLL clonotypes were detectable six months after CAR T-cell infusion and onwards). However, the existing actual disease status of both patients remained unclear, as it was unknown: (1) if CAR T-cells killed all leukemia cells during the initial anti-leukemic response phase, that is, soon after CAR T-cell infusion into both patients; (2) if few CLL cells survived, but persistent CAR T-cells had been able to destroy any leukemia cells before they reach detectable levels. In the first case, both patients could be considered definitely cured; in the second not and their decade-prolonged deep remission could be a consequence of the cytotoxic activity of the functionally active CD4+ CAR T-cells. The first version appears to be stronger and the supporting arguments have been included in a comprehensive commentary article. A new therapeutic intervention may emerge with the potential to fully improve the quality of life of both patients and in addition, ongoing research into CAR T-cells may turn in a new, more effective direction.

Anti-CD19 CAR-T cells: Digging in the dark side of the golden therapy.

The unprecedented technological advances in genetic engineering have resulted in the advent of the very promising chimeric antigen receptor (CAR)-T cell therapy. Based on the striking outcomes of clinical trials, the first two commercial CAR-T cell products, tisagenlecleucel and axicabtagene ciloleucel, have been approved in both the United States and Europe for the treatment of patients with highly aggressive CD19-positive hematological malignancies. Despite the initial remarkable responses many patients finally relapse, implying the presence of resistance mechanisms. In this review, we describe the limitations and resistance mechanisms to anti-CD19 CAR-T cells and address potential strategies to overcome CAR-T cell barriers.

Exploring the Dilemma of Allogeneic Hematopoietic Cell Transplantation after Chimeric Antigen Receptor T Cell Therapy: To Transplant or Not?

Patients with refractory or relapsed (R/R) B cell acute lymphoblastic leukemia (B-ALL) and highly aggressive B cell non-Hodgkin lymphoma (B-NHL) have a very dismal prognosis and limited treatment options. The advent of chimeric antigen receptor (CAR) T cell therapy constitutes a milestone in current cell and gene therapies, covering the unmet need of treatment of high-risk patients and bringing immunotherapies one step closer toward cancer therapeutics, including hematologic malignancies. CAR T cells targeting CD19 antigen have shown startling remission rates in heavily pretreated B-ALL and B-NHL patients, in whom CAR T cell therapy may sometimes be their last-resort treatment. However, a high proportion of these patients evade immune surveillance by CAR T cells losing their initial deep responses, which leads to disease recurrence as either CD19-positive or CD19-negative relapse. As a result, many investigators have questioned the need for consolidative allogeneic hematopoietic stem cell transplantation (allo-HCT) after CAR T cell therapy, once a patient has achieved remission. There remains much controversy regarding whether CAR T cells should be a bridge therapy to allo-HCT or a definitive treatment, owing to the paucity of strong evidence-based data. In this context, here we review the existing data regarding the necessity, safety, and outcomes of allo-HCT performed after autologous anti-CD19 CAR T cell therapy in B-ALL and B-NHL patients.

Isolated Extramedullary Relapse as a Poor Predictor of Survival after Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia.

Limited and conflicting data exist on outcomes of patients with extramedullary relapses (EMRs) after allogeneic hematopoietic cell transplantation (allo-HCT) for acute leukemias. We retrospectively reviewed charts of consecutive allo-HCT recipients who underwent transplantation in our center with the indication of acute leukemia (July 1990 to July 2018). Incidences of isolated EMR (iEMR) and bone marrow relapse (BMR) were calculated using cumulative incidence (CI) analysis, with each and treatment-related mortality considered a competing risk. We studied 554 allo-HCT recipients for 1.8 years (range, .04 to 27.75). Ten-year CI of 10.5% for iEMR was associated only with advanced disease phase at transplantation, whereas 10-year CI of 34.8% for BMR was independently associated with pretransplant disease phase, lines of treatment, and fungal infections. Most iEMR and BMR patients (75% and 81%, respectively) received systemic treatment combined with local radiation for iEMR (26%) and donor lymphocyte infusions (16% and 28%, respectively) when feasible. Extensive chronic graft-versus-host disease (GVHD) was recorded in 47% of iEMR and 48% of BMR patients. Outcomes were poor both in iEMR (10-year overall survival [OS], 18.3%) and BMR (10-year OS, 19.1%). Independent predictors of OS were disease phase, type of donor, acute and chronic GVHD, fungal infections, iEMR, and BMR. In a large population with long-term follow-up, incidence of iEMR was relatively high, developed at the late post-transplant period, and was associated only with disease phase at transplantation. Furthermore, iEMR and BMR conferred similarly poor outcomes despite systemic treatment or extensive chronic GVHD.

Effects of major adipokines and the -420 C > G resistin gene polymorphism on the long-term outcome of patients with acute ischemic stroke.

Aim: The association between adiponectin, leptin, and resistin and the long-term outcome of ischemic stroke are controversial. We aimed to evaluate this relationship. Methods: We prospectively studied 83 patients consecutively hospitalized for acute ischemic stroke (38.6% males, age 79.7 ± 6.3 years). Serum adiponectin, leptin, and resistin levels and the -420C > G polymorphism of the resistin gene were determined at admission. Stroke severity at admission was evaluated with the National Institutes of Health Stroke Scale (NIHSS). One year after discharge, functional status, incidence of cardiovascular events and all-cause mortality were recorded. Functional status was evaluated with the modified Rankin scale (mRS). Results: Patients with the G allele had lower mRS (p < .05) and patients with adverse outcome had higher serum resistin levels (p < .05). The only independent predictor of adverse outcome was mRS at discharge (risk ratio (RR) 2.78, 95% confidence interval (CI) 1.54-5.00; p < .001). Higher adiponectin levels were an independent predictor of cardiovascular morbidity (RR 1.07, 95% CI 1.01-1.14; p < .05). Patients who died had higher serum adiponectin levels than those who survived (p < .05). The only independent predictor of all-cause mortality was NIHSS at admission (RR 1.19, 95% CI 1.04-1.35; p < .01). Conclusions: In patients with acute ischemic stroke, the G allele of the -420C > G polymorphism of the resistin gene promoter is more frequent in those with a more favorable functional outcome at one year after discharge. Patients with higher serum resistin levels appear to have worse long-term functional outcome, while higher serum adiponectin levels are associated with higher incidence of cardiovascular events.

Long-term outcomes of total body irradiation plus cyclophosphamide versus busulfan plus cyclophosphamide as conditioning regimen for acute lymphoblastic leukemia: a comparative study.

The role of total body irradiation (TBI) in allogeneic hematopoietic stem cell transplantation (HCT) for adult acute lymphoblastic leukemia (ALL) remains controversial. Therefore, we investigated long-term treatment outcomes of transplanted ALL patients aiming to identify prognostic factors and the impact of conditioning. We enrolled consecutive ALL patients transplanted from 1990 to 2016, following TBI- or busulfan (Bu)-based conditioning regimen. We studied 151 ALL patients transplanted in first complete remission (CR) (60), other CR (33), or relapsed/refractory disease (58) from sibling (87), and HLA-matched (42) or mismatched (17) unrelated and alternative donors (5). High-dose fractionated TBI-based conditioning was administered in 84. No differences were observed in baseline characteristics, except for disease stage at transplant, donor type, and graft source. With a follow-up of 19.0 (0.5-170.5) in TBI and 14.5 (1.2-319.1) months in non-TBI patients, there was no difference in acute (grades II-IV) or chronic GVHD, thrombotic microangiopathy, and bacterial or fungal infections. Only viral infections were significantly increased in the non-TBI group. There was no significant difference in the cumulative incidence (CI) of treatment-related or relapse mortality and disease-free or overall survival (OS). In the multivariate analysis, unfavorable pre-transplant predictors of OS were age (p = 0.024), advanced disease stage (p = 0.007), and female-to-male donor (p = 0.006). Interestingly, TBI patients younger than 40 years had significantly higher OS (55.1%, p = 0.023) and DFS (48.6%, p = 0.020). In conclusion, high-dose TBI is feasible in younger patients providing better survival. The choice between TBI- or Bu-conditioning regimens remains challenging.

Treatment with Mannitol is Associated with Increased Risk for In-Hospital Mortality in Patients with Acute Ischemic Stroke and Cerebral Edema.

BACKGROUND: Current guidelines state that osmotic therapy is reasonable in patients with clinical deterioration from cerebral infarction-related cerebral edema. However, there are limited data on the safety and efficacy of this therapy. We aimed to evaluate the effect of mannitol on the outcome of ischemic stroke-related cerebral edema. METHODS AND RESULTS: We prospectively studied 922 consecutive patients admitted with acute ischemic stroke. Patients who showed space-occupying brain edema with tissue shifts compressing the midline structures received mannitol. The outcome was assessed with dependency rates at discharge (modified Rankin Scale grade 2-5) and in-hospital mortality. Rates of dependency were higher in patients treated with mannitol (n = 86) than in those who were not (97.7 and 58.5%, respectively; p < 0.001). Independent predictors of dependency were age, history of ischemic stroke and National Institutes of Health Stroke Scale (NIHSS) score at admission. Rates of mortality were higher in patients treated with mannitol than in those who were not (46.5 and 5.6%, respectively; p < 0.001). Independent predictors of in-hospital mortality were diastolic blood pressure [relative risk (RR) 1.05, 95% confidence interval (CI) 1.02-1.08, p < 0.001], NIHSS score at admission (RR 1.19, 95% CI 1.14-1.23, p < 0.001) and treatment with mannitol (RR 3.45, 95% CI 1.55-7.69, p < 0.005). CONCLUSIONS: Administration of mannitol to patients with ischemic stroke-related cerebral edema does not appear to affect the functional outcome and might increase mortality, independently of stroke severity.

Effect of antihypertensive treatment on the long-term outcome of patients discharged after acute ischemic stroke.

We aimed to evaluate the effects of the five main classes of antihypertensive agents on the long-term outcome of 313 consecutive patients discharged after acute ischemic stroke (36.4% males, age 78.5 ± 6.3 years). One year after discharge, the functional status [evaluated with the modified Rankin scale (mRS)], the occurrence of cardiovascular events, and vital status were recorded. Patients prescribed angiotensin receptor blockers (ARBs) had lower mRS than patients not prescribed ARBs (1.7 ± 2.0 vs. 2.9 ± 2.5, respectively; p = 0.006). The rates of adverse outcome (mRS 2-6) and cardiovascular events did not differ between patients prescribed each one of the major classes of antihypertensive agents and those not prescribed the respective class. Patients who were prescribed ARBs had lower risk of death during follow-up than patients who did not receive ARBs (9.4 and 26.9%, respectively; p < 0.05). In binary logistic regression analysis, the only independent predictor of all-cause mortality during follow-up was the mRS at discharge (relative risk 1.69, 95% confidence interval 1.25-2.28; p < 0.001). In conclusion, in patients discharged after acute ischemic stroke, administration of ARBs appears to have a more beneficial effect on long-term functional outcome and all-cause mortality than treatment with other classes of antihypertensive agents.

Stress hyperglycemia and acute ischemic stroke in-hospital outcome.

BACKGROUND AND AIMS: Stress hyperglycemia is frequent in patients with acute ischemic stroke. However, it is unclear whether stress hyperglycemia only reflects stroke severity or if it is directly associated with adverse outcome. We aimed to evaluate the prognostic significance of stress hyperglycemia in acute ischemic stroke. METHODS: We prospectively studied 790 consecutive patients who were admitted with acute ischemic stroke (41.0% males, age 79.4±6.8years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Stress hyperglycemia was defined as fasting serum glucose levels at the second day after admission ≥126mg/dl in patients without type 2 diabetes mellitus (T2DM). The outcome was assessed with adverse outcome rates at discharge (modified Rankin scale between 2 and 6) and with in-hospital mortality. RESULTS: In the total study population, 8.6% had stress hyperglycemia. Patients with stress hyperglycemia had more severe stroke. Independent predictors of adverse outcome at discharge were age, prior ischemic stroke and NIHSS at admission whereas treatment with statins prior to stroke was associated with favorable outcome. When the NIHSS was removed from the multivariate model, independent predictors of adverse outcome were age, heart rate at admission, prior ischemic stroke, log-triglyceride (TG) levels and stress hyperglycemia, whereas treatment with statins prior to stroke was associated with favorable outcome. Independent predictors of in-hospital mortality were atrial fibrillation (AF), diastolic blood pressure (DBP), serum log-TG levels and NIHSS at admission. When the NIHSS was removed from the multivariate model, independent predictors of in-hospital mortality were age, AF, DBP, log-TG levels and stress hyperglycemia. CONCLUSION: Stress hyperglycemia does not appear to be directly associated with the outcome of acute ischemic stroke. However, given that patients with stress hyperglycemia had higher prevalence of cardiovascular risk factors than patients with normoglycemia and that glucose tolerance was not evaluated, more studies are needed to validate our findings.

Prognostic significance of major lipids in patients with acute ischemic stroke.

Although dyslipidemia increases the risk for ischemic stroke, previous studies reported conflicting data regarding the association between lipid levels and stroke severity and outcome. To evaluate the predictive value of major lipids in patients with acute ischemic stroke. We prospectively studied 790 consecutive patients who were admitted with acute ischemic stroke (41.0 % males, age 79.4 ± 6.8 years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Moderate/severe stroke was defined as NIHSS ≥5. The outcome was assessed with dependency rates at discharge (modified Rankin scale between 2 and 5) and with in-hospital mortality. Independent predictors of moderate/severe stroke were age (relative risk (RR) 1.05, 95 % confidence interval (CI) 1.02-1.08, p < 0.001), atrial fibrillation (RR 1.71, 95 % CI 1.19-2.47, p < 0.005), heart rate (RR 1.02, 95 % CI 1.01-1.04, p < 0.001), log-triglyceride (TG) levels (RR 0.24, 95 % CI 0.08-0.68, p < 0.01) and high-density lipoprotein cholesterol (HDL-C) levels (RR 0.97, 95 % CI 0.95-0.98, p < 0.001). Major lipids did not predict dependency at discharge. Independent predictors of in-hospital mortality were atrial fibrillation (RR 2.35, 95 % CI 1.09-5.04, p < 0.05), diastolic blood pressure (RR 1.05, 95 % CI 1.02-1.08, p < 0.001), log-TG levels (RR 0.09, 95 % CI 0.01-0.87, p < 0.05) and NIHSS at admission (RR 1.19, 95 % CI 1.14-1.24, p < 0.001). Low-density lipoprotein cholesterol levels were not associated with stroke severity or outcome. Lower TG and HDL-C levels are associated with more severe stroke. Lower TG levels also appear to predict in-hospital mortality in patients with acute ischemic stroke.

Treatment with Clopidogrel Prior to Acute Non-Cardioembolic Ischemic Stroke Attenuates Stroke Severity.

BACKGROUND: Clopidogrel reduces the risk of non-cardioembolic ischemic stroke, but it is unclear whether it affects the severity and outcome of stroke. We aimed at evaluating the effect of prior treatment with clopidogrel on acute non-cardioembolic ischemic stroke severity and in-hospital outcome. METHODS: We prospectively studied 608 consecutive patients (39.5% males, age 79.1 ± 6.6 years) who were admitted with acute ischemic stroke. The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Severe stroke was defined as NIHSS ≥21. The outcome was assessed using the dependency rates that prevailed at the time of discharge (i.e. modified Rankin scale between 2 and 5) and with in-hospital mortality. RESULTS: At admission, 397 patients did not have atrial fibrillation or heart valve disease. Among these 397 patients, 69 were receiving monotherapy with clopidogrel prior to stroke, 69 were receiving monotherapy with aspirin and 236 patients were not on any antiplatelet treatment. The prevalence of severe stroke was lower in patients who were receiving clopidogrel than in patients who were receiving aspirin and patients who were not on antiplatelets (1.4, 13.0 and 11.0%, respectively; p < 0.05). Independent predictors of severe stroke at admission were male gender (relative risk (RR) 0.31, 95% CI 0.12-0.78, p < 0.05) and treatment with clopidogrel prior to stroke compared with no antiplatelet treatment (RR 0.13, 95% CI 0.02-0.97, p < 0.05). Treatment with aspirin prior to stroke did not predict severe stroke compared with no antiplatelet treatment (RR 1.24, 95% CI 0.51-2.98, p = NS). The rate of dependency at discharge did not differ between patients who were receiving clopidogrel, patients who were receiving aspirin and those who were not on antiplatelets (57.9, 47.8 and 59.7%, respectively; p = NS). Independent predictors of dependency at discharge were age (RR 1.12, 95% CI 1.05-1.19, p < 0.001) and NIHSS at admission (RR 1.67, 95% CI 1.46-1.92, p < 0.001). In-hospital mortality rate also did not differ between patients who were receiving clopidogrel, patients who were receiving aspirin and those who were not on antiplatelets (4.3, 4.3 and 5.0%, respectively; p = NS). The only independent predictor of in-hospital mortality was NIHSS at admission (RR 1.22, 95% CI 1.14-1.30, p < 0.001). CONCLUSIONS: Treatment with clopidogrel prior to acute non-cardioembolic ischemic stroke attenuates the severity of stroke at admission but does not appear to affect the functional outcome at discharge or the in-hospital mortality of these patients.

Adequacy of preadmission oral anticoagulation with vitamin K antagonists and ischemic stroke severity and outcome in patients with atrial fibrillation.

It is unclear whether vitamin K antagonists affect stroke severity and outcome in patients with atrial fibrillation (AF). We aimed to evaluate this association. We prospectively studied 539 consecutive patients admitted with acute ischemic stroke (41.2 % males, age 78.9 ± 6.6 years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). The outcome was assessed with dependency rates at discharge (modified Rankin scale 2-5) and with in-hospital mortality. 177 patients had a history of AF. The median NIHSS at admission did not differ between patients on acenocoumarol with INR 2.0-3.0, on acenocoumarol with INR < 2.0, on single antiplatelet treatment, on dual antiplatelet treatment, or on no treatment [4 (range 0-26), 13 (0-39), 8 (0-33), 3 (2-23) and 7 (0-33), respectively; p = 0.433]. Dependency rates were lower in patients on acenocoumarol with INR 2.0-3.0 or on dual antiplatelet treatment than in those on acenocoumarol with INR < 2.0, single antiplatelet treatment, or no treatment (20.0, 22.2, 61.5, 58.7 and 68.0 %, respectively; p = 0.024). Independent predictors of dependency were age, NIHSS at admission and history of ischemic stroke. In-hospital mortality did not differ between patients on acenocoumarol with INR 2.0-3.0, on acenocoumarol with INR < 2.0, on single antiplatelet treatment, on dual antiplatelet treatment, or on no treatment (7.7, 18.2, 16.1, 16.7 and 22.2 %, respectively; p = 0.822). In conclusion, optimally anticoagulated patients with AF have more favorable functional outcome after stroke and a trend for less severe stroke whereas patients with subtherapeutic anticoagulation have similar stroke severity and outcome with those on no treatment.

Acenocoumarol vs. low-dose dabigatran in real-world patients discharged after ischemic stroke.

The aim of this study was to compare the efficacy of dabigatran 110 mg twice daily and acenocoumarol in patients with atrial fibrillation discharged after ischemic stroke. We prospectively studied 436 consecutive patients who were discharged after acute ischemic stroke (39.2% males, age 78.6 ±â€Š6.7 years). Approximately 1 year after discharge, the functional status was assessed with the modified Rankin scale (mRS). Adverse outcome was defined as mRS between 2 and 6. The occurrence of ischemic stroke, myocardial infarction (MI) and death during the 1-year follow-up was also recorded. At discharge, 142 patients had atrial fibrillation. Acenocoumarol and dabigatran 110 mg twice daily were prescribed to 52.1 and 6.3% of these patients, respectively. At 1 year after discharge, there was a trend for patients treated with acenocoumarol to have lower mRS than patients prescribed dabigatran (2.3 ±â€Š2.4 and 4.1 ±â€Š2.2, respectively; P = 0.060). Adverse outcome rates and the incidence of stroke during follow-up did not differ between the two groups. The incidence of MI was almost three times higher in patients prescribed dabigatran than in those prescribed acenocoumarol, but this difference did not reach significance (11.1 and 4.0%, respectively; P = 0.254). The incidence of cardiovascular death was also almost three times higher in the former, but again this difference was not significant (33.3 and 12.2%, respectively; P = 0.237). In real-world patients with acute ischemic stroke, dabigatran 110 mg twice daily is as effective as acenocoumarol in preventing stroke but appears to be associated with worse long-term functional outcome and higher incidence of MI.

No Association Observed Between Blood Pressure Variability During the Acute Phase of Ischemic Stroke and In-Hospital Outcomes.

BACKGROUND: Recent data suggest that blood pressure (BP) variability confers increased cardiovascular risk independently of BP. We aimed to evaluate the association between BP variability during the acute phase of ischemic stroke and the in-hospital outcome. METHODS: We prospectively studied 608 consecutive patients admitted with acute ischemic stroke (39.5% males, age: 79.1±6.6 years). Variability in BP was assessed with the SD and with the coefficient of variation of systolic (SBP) and diastolic BP (DBP) during the first 2 and the first 3 days of hospitalization. The outcome was assessed with dependency rates at discharge and with in-hospital mortality. RESULTS: Patients who were dependent at discharge did not differ from patients who were independent in any index of BP variability. Independent predictors of dependency at discharge were age (relative risk (RR) 1.17, 95% confidence interval (CI) 1.09-1.25, P < 0.001), history of prior ischemic stroke (RR 2.08, 95% CI 1.02-4.24, P = 0.04), and National Institutes of Health Stroke Scale (NIHSS) at admission (RR 1.64, 95% CI 1.44-1.86, P < 0.001). Patients who died during hospitalization did not differ in any index of BP variability from patients who were discharged. DBP at admission was independently and directly associated with in-hospital mortality (RR 1.06, 95% CI 1.03-1.09, P < 0.001). Other independent predictors of in-hospital mortality were history of atrial fibrillation (RR 3.30, 95% CI 1.46-7.49, P = 0.004) and NIHSS at admission (RR 1.18, 95% CI 1.13-1.23, P < 0.001). CONCLUSIONS: Our data do not support the hypothesis of an association between BP variability and in-hospital outcomes among patients admitted for ischemic stroke.

Comparative effects of more versus less aggressive treatment with statins on the long-term outcome of patients with acute ischemic stroke.

BACKGROUND AND AIMS: There are no studies that compared the effects of different intensities of statin treatment on the long-term outcome of patients with recent ischemic stroke. We aimed to evaluate these effects. METHODS: We prospectively studied 436 consecutive patients who were discharged after acute ischemic stroke (39.2% males, age 78.6 ± 6.7 years). Statin treatment was categorized in equipotent doses of atorvastatin. One year after discharge, the functional status was assessed with the modified Rankin scale (mRS). Adverse outcome was defined as mRS between 2 and 6. The occurrence of ischemic stroke, myocardial infarction and death was recorded. RESULT: Adverse outcome rates were lower in patients treated with atorvastatin 20 mg/day or more potent doses of statins than in patients treated with atorvastatin 10 mg/day (63.5, 38.2 and 48.2%, respectively; p = 0.004). In binary logistic regression analysis, independent predictors of adverse outcome were the mRS at discharge (relative risk (RR) 2.33, 95% confidence interval (CI) 1.77-3.07, p < 0.001) whereas more aggressive treatment with statins independently predicted favorable outcome (atorvastatin 20 vs. 10 mg/day, RR 0.30, 95% CI 0.11-0.87, p = 0.026; atorvastatin 40 mg/day or more potent dose of statins vs. atorvastatin 10 mg/day, RR 1.66, 95% CI 0.62-4.44, p = NS). The incidence of cardiovascular events and all-cause mortality showed a trend for being lower in patients treated with atorvastatin 40-80 mg/day or rosuvastatin 10-40 mg/day than in those treated with less potent doses of statins. CONCLUSION: More aggressive statin treatment improves the long-term functional outcome of patients with acute ischemic stroke more than less aggressive treatment.