Safety of Disease-Modifying Therapies for Highly Active Relapsing-Remitting Multiple Sclerosis

MS-tautia eli pesäkekovettumatautia hoidetaan taudinkulkua muuntavilla lääkehoidoilla. Näiden hoitojen tarkoitus on vähentää MS-taudin tulehduksellista tautiaktiivisuutta ja sitä kautta estää toimintakyvyn heikkenemistä. Osalla MS-tautia sairastavista henkilöistä tauti on kuitenkin poikkeuksellisen aktiivinen, jolloin usein turvaudutaan kaikista tehokkaimpina pidettyihin lääkehoitoihin. Tehokkaiden lääkkeiden käyttöön liittyy kuitenkin erityisiä turvallisuusriskejä. Jotta nämä riskit osattaisiin ottaa huomioon jo lääkehoitoa suunniteltaessa, tarvitaan tosielämän potilasaineistoihin perustuvaa tutkimustietoa eri lääkehoitojen turvallisuudesta. Tämän väitöskirjan tavoitteena oli tutkia neljän eri MS-tautilääkkeen turvallisuutta. Tutkituista lääkkeistä natalitsumabi ja fingolimodi ovat niin sanottuja soluliikennöinnin estäjiä, kun taas alemtutsumabi ja kladribiini ovat niin sanottuja immuunirekonstituutiohoitoja. Väitöskirjaan kuuluu neljä osatyötä. Ensimmäisessä osatyössä tutkittiin natalitsumabin lopettamisen jälkeistä tautiaktiivisuuden lisääntymistä. Toisessa osatyössä tutkittiin veren rasva-arvojen muutoksia fingolimodin käytön aikana. Kolmannessa osatyössä tutkittiin alemtutsumabin haittavaikutuksia. Neljännessä osatyössä tutkittiin kladribiinin käyttöä, tehoa ja haittavaikutuksia. Tutkimusaineistot kerättiin sairaaloiden potilastietojärjestelmistä ja Suomen MS-rekisteristä. Ensimmäisen osatyön otos kattoi 89 natalitsumabin keskeyttänyttä potilasta, joilla seuranta-aika oli 12 kuukautta. Toisen osatyön otos kattoi 72 fingolimodin aloittanutta potilasta, joilla seuranta-ajan mediaani oli 12 kuukautta. Kolmannen osatyön otos kattoi 121 alemtutsumabin aloittanutta potilasta, joilla seuranta-ajan mediaani oli 30.3 kuukautta. Neljännen osatyön otos kattoi 179 kladribiinin aloittanutta potilasta, joilla seuranta-ajan mediaani oli 19.0 kuukautta. Ensimmäisessä osatyössä osoitimme kliinisen tautiaktiivisuuden palaavan 20 % ja 30 % potilaista kuuden ja 12 kuukauden kuluessa natalitsumabin lopettamisesta, kun päätemuuttujana käytettiin kortisonihoidettuja pahenemisvaiheita. Ylipäätään pahenemisvaiheita todettiin vastaavasti 27 % ja 36 % potilaista kuuden ja 12 kuukauden kuluessa. Tautiaktiivisuuden lisääntymisen riski oli koholla niillä potilailla, joilla oli ollut useita pahenemisvaiheita tai alentunut toimintakyky ennen natalitsumabin aloitusta (Expanded Disability Status Scale [EDSS] -pisteet vähintään 5.5). Uutta lääkehoitoa aloitettaessa yli kolmen kuukauden varoaika oli yhteydessä suurentuneeseen taudin aktivoitumisen riskiin verrattuna niihin potilaisiin, jotka eivät aloittaneet mitään uusia lääkehoitoja. Toisessa osatyössä havaitsimme, että kokonaiskolesterolin ja HDL-kolesterolin (high-density lipoprotein) pitoisuudet kohosivat hieman fingolimodin käytön aikana, kun taas LDL-kolesterolin (low-density lipoprotein) ja triglyseridien pitoisuudet eivät. Seuranta-ajan keston mediaani oli 12 kuukautta, ja tutkittuna ajanjaksona kokonaiskolesterolin pitoisuus nousi keskimäärin 0.40 mmol/L/vuosi ja HDL- kolesterolin pitoisuus nousi keskimäärin 0.17 mmol/L/vuosi. Kolmannessa osatyössä osoitimme, että vakavia infuusioreaktioita ilmeni 11 % alemtutsumabia saaneista potilaista ensimmäisen hoitokerran yhteydessä, mutta vain 0-3 % toisen hoitokerran yhteydessä. Muita vakavia haittoja ilmeni yhteensä 23 % potilaista 30 kuukauden mediaaniseurannan aikana. Tutkimuksessa raportoitiin muun muassa autoimmuunisairauksia, infektioita, maksa- ja sappiperäisiä haittoja sekä syöpiä. Neljännessä osatyössä havaitsimme, että niillä potilailla, jotka olivat käyttäneet aiemmin kahta tai useampaa lääkehoitoa, tuli nopeammin pahenemisvaihe kladribiinin aloittamisen jälkeen verrattuna niihin potilaisiin, jotka olivat käyttäneet korkeintaan yhtä aiempaa hoitoa. Alaryhmäanalyysin perusteella tämän katsottiin selittyvän fingolimodista kladribiiniin siirtyneillä potilailla, joista suurella osalla todettiin pahenemisvaihe pian fingolimodin lopettamisen jälkeen. Yleisimpiä kladribiinin haittavaikutuksia olivat päänsärky, Herpes simplex -infektio ja pahoinvointi. Koska natalitsumabin ja fingolimodin lopetukseen liittyy taudin aktivoitumisen riski, tarvitaan yhteisesti sovittuja ohjeistuksia siitä, miten näitä lääkehoitoja lopetettaessa tulisi menetellä. Natalitsumabin käytön lopettamisen yhteydessä tulisi huomioida potilaan aiempi tautiaktiivisuus ja toimintakyky ennen natalitsumabin aloitusta. Vaikka toisen osatyön tulosten perusteella onkin epätodennäköistä, että fingolimodi vaikuttaisi merkittävästi valtimonkovettumataudin riskiin, tulisi asiaa tutkia vielä muilla vastaavan vaikutusmekanismin omaavilla MS-lääkkeillä erikseen. Alemtutsumabin ja kladribiinin käytön jälkeen ilmaantuneet haitat vastasivat enimmäkseen aiempaa tutkimusnäyttöä. Vakavien haittojen ilmaantuvuus alemtutsumabia saaneilla MS-tautipotilailla oli kuitenkin niin suuri, että hoitoa voidaan pitää riskialttiina.The treatment of multiple sclerosis (MS) includes using disease-modifying therapies (DMTs) to prevent inflammatory disease activity. Patients with a highly active disease are at elevated risk for neurologic disability and are treated using DMTs with the highest expected efficacy. However, the use of these DMTs is limited by safety concerns. Measures to reduce medication-related harm in people with MS need to be further examined in the post marketing setting. The aim of this thesis was to investigate the safety of four different DMTs for highly active relapsing-remitting MS in Finland using real-world patient data. The DMTs assessed in this thesis included the two anti-trafficking therapies, natalizumab (NTZ) and fingolimod (FNG), as well as the two immune reconstitution therapies, alemtuzumab (ALEM) and cladribine (CLAD) tablets. The specific aims of the four studies in this thesis included assessing disease reactivation after NTZ discontinuation (Study I), lipid profile alterations during FNG treatment (Study II), adverse events (AEs) after ALEM treatment (Study III) and clinical outcomes and treatment sequencing in patients treated with CLAD tablets (Study IV). Real-world data were acquired from patient information archives and the Finnish MS registry. Study I included data on 89 patients who had discontinued NTZ and had been followed-up for at least 12 months afterwards. Study II included data on 72 patients who had initiated FNG with a median follow- up of 12 months. Study III included data on 121 patients who had initiated ALEM with a median follow-up of 30.3 months. Study IV included data on 179 patients who had initiated CLAD tablets with a median follow-up of 19.0 months. In Study I, we demonstrated that corticosteroid-treated relapses occurred in 20% and 30% of patients after six and 12 months after discontinuing NTZ respectively, whereas any relapse was observed in 27% and 36% of patients respectively. A higher number of relapses and an EDSS score of 5.5 or above prior to initiating NTZ predicted the risk of reactivation at six months. Initiating a subsequent DMT after a washout period longer than three months was associated with an increased risk for reactivation at six months when compared to not initiating any subsequent DMTs. In Study II, we observed minor elevation in the concentrations of total cholesterol (0.40 mmol/L/year) and high-density lipoprotein (0.17 mmol/L/year) during a median follow-up of 12 months after the initiation of FNG. No statistically significant alterations in the concentrations of low-density lipoprotein or triglycerides were observed. In Study III, we showed that serious infusion-associated reactions (IARs) were observed in 11% of patients during the first course of ALEM, and in 0-3% of patients during subsequent courses. Serious adverse events (SAEs) other than IARs occurred in 23% of patients during a median follow-up of 30 months after the initiation of ALEM. Autoimmune AEs, infections, hepatobiliary AEs and malignancies were reported. In Study IV, we found that median time to first relapse was shorter in patients switching to CLAD tablets after receiving at least two previous DMTs when compared to patients with 0-1 previous DMTs prior to CLAD tablets. A subgroup analysis showed that this was most likely due to disease reactivation in patients switching from FNG. The most frequent AEs reported after receiving treatment with CLAD tablets were headache, Herpes simplex and nausea. The main contributions of this thesis include describing disease reactivation after anti-trafficking therapies as well as safety issues associated with the use of immune reconstitution therapies. Exit strategies for patients discontinuing anti- trafficking therapies need to be developed, and the newly proposed risk factor for predicting the risk of reactivation after NTZ discontinuation based on EDSS should be taken into account when discontinuing NTZ in patients with early disability. We confirmed existing safety findings regarding the use of immune reconstitution therapies, but according to the results from Study III, considered ALEM a risky approach in the treatment of MS. Finally, the findings from Study II suggest that the overall risk of atherosclerosis may be unaltered by the small alterations in lipid concentrations observed during FNG treatment. However, more research is warranted to explore whether other similar drugs could have an effect on the lipoprotein concentrations or the risk of atherosclerosis in people with MS

Surgically Treated Unsuspected N2-Positive NSCLC : Role of Extent and Location of Lymph Node Metastasis

The role of positive lymph node location in non-small-cell lung cancer (NSCLC) patients and effects on survival was assessed. A total of 88 operated patients with unsuspected N2 disease or station 10 lymph nodes were included. No difference was found in survival between inferior positive mediastinal N2 node patients compared to multilevel N2 disease patients. The survival of patients with positive hilar disease was similar to the inferior mediastinal positive N2 group. Background: The role of surgery in the treatment of non-small-cell lung cancer that has spread to ipsilateral mediastinal or hilar lymph nodes (LNs) is controversial. We examined whether the location of LNs positive for non-small-cell lung cancer in mediastinum or hilum influences the survival of these patients. Patients and Methods: We reviewed data from 881 patients and analyzed those with unsuspected N2 disease or hilar (station 10) LNs. The patients were stratified into the following groups: group A, positive hilar Naruke 10; group B, superior mediastinal and aortic nodes (Naruke 1, 2, 3, 4, 5, and 6); group C, inferior mediastinal nodes (Naruke 7, 8, and 9), and multilevel group D (2 or more positive N2 levels). Results: A total of 69 pN2 and 19 pN1 patients were included. Progression-free survival (PFS) was statistically significant better in group B versus group C (P = .044) and group B versus group D (P = .0086). The overall survival (OS) of group A did not differ from that of group C. A statistically significant better OS was found between groups B and D (P= .051). Conclusion: Inferior positive mediastinal N2 node patients seem to have an OS and PFS as poor as multilevel N2 disease patients. The OS and PFS of patients with positive hilar disease are similar to those in the inferior mediastinal positive N2 group. Superior positive mediastinal N2 node patients have better OS and PFS than the inferior mediastinal positive N2 group. (C) 2018 Elsevier Inc. All rights reserved.Peer reviewe

Thoracotomy and VATS Surgery in Local Non-Small-Cell Lung Cancer : Differences in Long-Term Health-Related Quality Of Life

Very long-term health-related quality of life (HRQoL) is an important end point in operated early stage non-small-cell lung cancer with good prognosis. The results for very long-term HRQoL after minimally invasive video-assisted thoracoscopic surgery (VATS) has not been evaluated and compared to thoracotomy. Surprisingly, inferior overall HRQoL was evident for patients operated with VATS, independent of preoperative factors including age, comorbidities, and pulmonary function tests. Background: As a result of routine low-dose computed tomographic screening, lung cancer is more frequently diagnosed at earlier, operable stages of disease. In treating local non-small-cell lung cancer, video-assisted thoracoscopic surgery (VATS), a minimally invasive surgical approach, has replaced thoracotomy as the standard of care. While short-term quality-of-life outcomes favor the use of VATS, the impact of VATS on long-term health-related quality of life (HRQoL) is unknown. Patients and Methods: We studied patients who underwent lobectomy for the treatment of non-small-cell lung cancer from January 2006 to January 2013 at a single institution (n = 456). Patients who underwent segmentectomy (n = 27), who received neoadjuvant therapy (n = 13), or who were found to have clinical stage > T2 or > NO disease (n = 45) were excluded from analysis. At time of HRQoL assessment, 199 patients were eligible for study and were mailed the generic HRQoL instrument 15D. Results: A total of 180 patients (90.5%) replied; 92 respondents underwent VATS while 88 underwent open thoracotomy. The VATS group more often had adenocarcinoma (P = .006), and lymph node stations were sampled to a lesser extent (P = .004); additionally, hospital length of stay was shorter among patients undergoing VATS (P = .001). No other clinical or pathologic differences were observed between the 2 groups. Surprisingly, patients who underwent VATS scored significantly lower on HRQoL on the dimensions of breathing, speaking, usual activities, mental function, and vitality, and they reported a lower total 15D score, which reflects overall quality of life (P <.05). Conclusion: In contrast to earlier short-term reports, long-term quality-of-life measures are worse among patients who underwent VATS compared to thoracotomy. (C) 2019 Elsevier Inc. All rights reserved.Peer reviewe

Finnish multiple sclerosis patients treated with cladribine tablets : a nationwide registry study

Background: Cladribine tablets for adult patients with highly active relapsing multiple sclerosis (MS) have been available in Finland since 2018. Real-world data from different genetic and geographical backgrounds are needed to complement data from clinical trials.Methods: We investigated the use of cladribine tablets in Finland in a non-interventional cohort study, based on real-world data from the nationwide Finnish MS registry. All eligible patients who had initiated treatment with cladribine tablets in 2018-2020 were included. Descriptive analyses for outcomes were conducted using summary statistics. Time-dependent endpoints were analyzed using cumulated events analysis based on 1-Kaplan-Meier estimates and curves. Subgroups were analyzed separately according to the number of previous disease-modifying therapies (DMTs) and the most common last preceding therapies.Results: Data of 179 patients were analyzed. Median follow-up time was 19.0 months (interquartile range [IQR] 12.0-26.2). Of the 134 patients who were followed for at least 12 months, 112 patients (83.6%) remained relapse-free during follow-up. Mean annualized relapse rate (ARR) was 1.0 (standard deviation [SD] 0.89) at baseline, and 0.1 (SD 0.30) at follow-up. Patients with two or more previous DMTs had shorter time to first relapse (median 2.5 months, IQR 0.6-9.3) when compared to patients with 0-1 previous DMTs (median 11.4 months, IQR 8.7-13.1) (p=0.013). After excluding patients switching from fingolimod (n=33), a statistically significant difference in time to first relapse was no longer observed between the two groups (p=0.252). Adverse events (AEs) were reported in 30 patients (16.8%). The most frequent AE was headache (n=14, 7.8%). One patient (0.6%) died of cardiac arrest. Discontinuation of cladribine tablets was reported in nine patients (5.0%).Conclusion: The mean ARR observed in this cohort was similar to what has been reported in clinical trials. Approximately half of the patients had used two or more previous DMTs before cladribine tablets. These patients had a shorter time to first relapse when compared to patients with 0-1 previous DMTs, mostly driven by early relapses in patients switching from fingolimod.Peer reviewe

Finnish multiple sclerosis patients treated with cladribine tablets: a nationwide registry study

BACKROUNDCladribine tablets for adult patients with highly active relapsing multiple sclerosis (MS) have been available in Finland since 2018. Real-world data from different genetic and geographical backgrounds are needed to complement data from clinical trials.METHODSWe investigated the use of cladribine tablets in Finland in a non-interventional cohort study, based on real-world data from the nationwide Finnish MS registry. All eligible patients who had initiated treatment with cladribine tablets in 2018-2020 were included. Descriptive analyses for outcomes were conducted using summary statistics. Time-dependent endpoints were analyzed using cumulated events analysis based on 1-Kaplan-Meier estimates and curves. Subgroups were analyzed separately according to the number of previous disease-modifying therapies (DMTs) and the most common last preceding therapies.RESULTSData of 179 patients were analyzed. Median follow-up time was 19.0 months (interquartile range [IQR] 12.0-26.2). Of the 134 patients who were followed for at least 12 months, 112 patients (83.6%) remained relapse-free during follow-up. Mean annualized relapse rate (ARR) was 1.0 (standard deviation [SD] 0.89) at baseline, and 0.1 (SD 0.30) at follow-up. Patients with two or more previous DMTs had shorter time to first relapse (median 2.5 months, IQR 0.6-9.3) when compared to patients with 0-1 previous DMTs (median 11.4 months, IQR 8.7-13.1) (p=0.013). After excluding patients switching from fingolimod (n=33), a statistically significant difference in time to first relapse was no longer observed between the two groups (p=0.252). Adverse events (AEs) were reported in 30 patients (16.8%). The most frequent AE was headache (n=14, 7.8%). One patient (0.6%) died of cardiac arrest. Discontinuation of cladribine tablets was reported in nine patients (5.0%).CONCLUSIONThe mean ARR observed in this cohort was similar to what has been reported in clinical trials. Approximately half of the patients had used two or more previous DMTs before cladribine tablets. These patients had a shorter time to first relapse when compared to patients with 0-1 previous DMTs, mostly driven by early relapses in patients switching from fingolimod.</p

Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients

Background Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice. Objectives To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients. Methods In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files. Results Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented. Conclusions SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.Peer reviewe

Finnish multiple sclerosis patients treated with cladribine tablets : a nationwide registry study

Background: Cladribine tablets for adult patients with highly active relapsing multiple sclerosis (MS) have been available in Finland since 2018. Real-world data from different genetic and geographical backgrounds are needed to complement data from clinical trials. Methods: We investigated the use of cladribine tablets in Finland in a non-interventional cohort study, based on real-world data from the nationwide Finnish MS registry. All eligible patients who had initiated treatment with cladribine tablets in 2018-2020 were included. Descriptive analyses for outcomes were conducted using summary statistics. Time-dependent endpoints were analyzed using cumulated events analysis based on 1-Kaplan–Meier estimates and curves. Subgroups were analyzed separately according to the number of previous disease-modifying therapies (DMTs) and the most common last preceding therapies. Results: Data of 179 patients were analyzed. Median follow-up time was 19.0 months (interquartile range [IQR] 12.0-26.2). Of the 134 patients who were followed for at least 12 months, 112 patients (83.6%) remained relapse-free during follow-up. Mean annualized relapse rate (ARR) was 1.0 (standard deviation [SD] 0.89) at baseline, and 0.1 (SD 0.30) at follow-up. Patients with two or more previous DMTs had shorter time to first relapse (median 2.5 months, IQR 0.6-9.3) when compared to patients with 0-1 previous DMTs (median 11.4 months, IQR 8.7-13.1) (p=0.013). After excluding patients switching from fingolimod (n=33), a statistically significant difference in time to first relapse was no longer observed between the two groups (p=0.252). Adverse events (AEs) were reported in 30 patients (16.8%). The most frequent AE was headache (n=14, 7.8%). One patient (0.6%) died of cardiac arrest. Discontinuation of cladribine tablets was reported in nine patients (5.0%). Conclusion: The mean ARR observed in this cohort was similar to what has been reported in clinical trials. Approximately half of the patients had used two or more previous DMTs before cladribine tablets. These patients had a shorter time to first relapse when compared to patients with 0-1 previous DMTs, mostly driven by early relapses in patients switching from fingolimod.publishedVersionPeer reviewe

Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients

Background Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice. Objectives To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients. Methods In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files. Results Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented. Conclusions SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.</p

Patient features predicting long-term survival and health-related quality of life after radical surgery for non-small cell lung cancer

Background: This study presents a retrospective evaluation of patient, disease, and treatment features predicting long-term survival and health-related quality of life (HRQoL) among patients who underwent surgery for non-small cell lung cancer (NSCLC). Methods: Between January 2000 and June 2009, 586 patients underwent surgery at the Helsinki University Hospital. The 276 patients still alive in June 2011 received two validated quality of life questionnaires (QLQ): the generic 15D and the cancer-specific EORTC QLQ-C30 + QLQ-LC13. We used binary and linear regression analysis modeling to identify patient, disease, and treatment characteristics that predicted survival and long-term HRQoL. Results: When taking into account patient, disease, and treatment characteristics, long-term survival was quite predictable (69.5% correct), but no long-term HRQoL (R-2 between 0.041 and 0.119). Advanced age at the time of surgery, male gender, comorbidity (measured with the Charlson comorbidity index), clinical and pathological stages II-IV, and postoperative infectious complications predicted a lower survival rate. Features associated with poorer long-term HRQoL (measured with the 15D) were comorbidity, postoperative complications, and the use of the video-assisted thoracoscopic surgery (VATS) technique. Conclusions: Long-term HRQoL is only moderately predictable, while prediction of long-term survival is more reliable. Lower HRQoL is associated with comorbidities, complications, use of the VATS technique, and reduced pulmonary function, while adjuvant therapy is associated with higher HRQoL.Peer reviewe