Efficacy and safety of Privigen® in patients with chronic inflammatory demyelinating polyneuropathy: results of a prospective, single-arm, open-label Phase III study (the PRIMA study)

This prospective, multicenter, single-arm, open-label Phase III study aimed to evaluate the efficacy and safety of Privigen (R) (10% liquid human intravenous immunoglobulin [IVIG], stabilized with l-proline) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Patients received one induction dose of Privigen (2g/kg body weight [bw]) and up to seven maintenance doses (1g/kg bw) at 3-week intervals. The primary efficacy endpoint was the responder rate at completion, defined as improvement of 1 point on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. The preset success criterion was the responder rate being 35%. Of the 31 screened patients, 28 patients were enrolled including 13 (46.4%) IVIG-pretreated patients. The overall responder rate at completion was 60.7% (95% confidence interval [CI]: 42.41%-76.43%). IVIG-pretreated patients demonstrated a higher responder rate than IVIG-naive patients (76.9% vs. 46.7%). The median (25%-75% quantile) INCAT score improved from 3.5 (3.0-4.5) points at baseline to 2.5 (1.0-3.0) points at completion, as did the mean (standard deviation [SD]) maximum grip strength (66.7 [37.24] kPa vs. 80.9 [31.06] kPa) and the median Medical Research Council sum score (67.0 [61.5-72.0] points vs. 75.5 [71.5-79.5] points). Of 108 adverse events (AEs; 0.417 AEs per infusion), 95 AEs (88.0%) were mild or moderate in intensity and resolved by the end of study. Two serious AEs of hemolysis were reported that resolved after discontinuation of treatment. Thus, Privigen provided efficacious and well-tolerated induction and maintenance treatment in patients with CIDP

Single-Molecule Sequencing Revealing the Presence of Distinct JC Polyomavirus Populations in Patients With Progressive Multifocal Leukoencephalopathy

Background. Progressive multifocal leukoencephalopathy (PML) is a fatal disease caused by reactivation of JC polyomavirus (JCPyV) in immunosuppressed individuals and lytic infection by neurotropic JCPyV in glial cells. The exact content of neurotropic mutations within individual JCPyV strains has not been studied to our knowledge. Methods. We exploited the capacity of single-molecule real-time sequencing technology to determine the sequence of complete JCPyV genomes in single reads. The method was used to precisely characterize individual neurotropic JCPyV strains of 3 patients with PML without the bias caused by assembly of short sequence reads. Results. In the cerebrospinal fluid sample of a 73-year-old woman with rapid PML onset, 3 distinct JCPyV populations could be identified. All viral populations were characterized by rearrangements within the noncoding regulatory region (NCCR) and 1 point mutation, S267L in the VP1 gene, suggestive of neurotropic strains. One patient with PML had a single neurotropic strain with rearranged NCCR, and 1 patient had a single strain with small NCCR alterations. Conclusions. We report here, for the first time, full characterization of individual neurotropic JCPyV strains in the cerebrospinal fluid of patients with PML. It remains to be established whether PML pathogenesis is driven by one or several neurotropic strains in an individual.Peer reviewe

Efficacy and safety of IVIG in CIDP : Combined data of the PRIMA and PATH studies

Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). To investigate the efficacy and safety of the IVIG IgPro10 (Privigen) for treatment of CIDP, results from Privigen Impact on Mobility and Autonomy (PRIMA), a prospective, open-label, single-arm study of IVIG in immunoglobulin (Ig)-naive or IVIG pre-treated subjects (NCT01184846, n = 28) and Polyneuropathy And Treatment with Hizentra (PATH), a double-blind, randomized study including an open-label, single-arm IVIG phase in IVIG pre-treated subjects (NCT01545076, IVIG restabilization phase n = 207) were analyzed separately and together (n = 235). Efficacy assessments included change in adjusted inflammatory neuropathy cause and treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score. Adverse drug reactions (ADRs) and ADRs/infusion were recorded. Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG pre-treated subjects) and 72.9% in PATH. In the pooled cohort (n = 235), INCAT response rate was 71.5%; median time to INCAT improvement was 4.3 weeks. No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21). In the pooled cohort, median change from baseline to last observation was -1.0 (interquartile range -2.0; 0.0) point for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score. In the pooled cohort, 271 ADRs were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion. This analysis confirms the efficacy and safety of IgPro10, a recently FDA-approved IVIG for CIDP, in a population of mainly pre-treated subjects with CIDP [Correction added on 14 March 2019 after first online publication: the INCAT response rate has been corrected.].Peer reviewe

Geriatric Rehabilitation as an Integral Part of Geriatric Medicine in the Nordic Countries

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenObjective: Firstly to outline the theoretical and practical framework for geriatric rehabilitation in Iceland and other Nordic countries and secondly to survey the scientific medical publications for evidence based geriatric rehabilitation. Methods: Brain storming on geriatric rehabilitation in a working group of Nordic teachers in geriatric medicine. Papers on scientific programs for geriatric rehabilitation from Internet sources were collected and analyzed. All articles describing randomized studies in geriatric rehabilitation were selected for overview. The papers were divided into four groups according to diseases, infirmity and resource settings; 1) stroke, 2) hip-fractures, 3) acute admissions and 4) programs conducted in nursing homes, day hospitals and home services. Results: A spectrum of biological and social events creates the conditions underlying most causes for illness and disability in old people. The process of established geriatric services promotes the efficiency of geriatric rehabilitation. The literature survey included 27 scientific studies (8586 patients) on randomized studies with valid endpoints. Geriatric rehabilitation programs for stroke patients in geriatric settings, six studies (1138 patients), reduced mortality and the need for nursing home placement but the outcome for ADL. Function and length of stay was more variable between the studies. The outcome of geriatric rehabilitation was even more decisive in the randomized hip-fracture studies, six studies (2171 patients). Eight studies were found comparing the outcome between acute admission of frail elderly to either geriatric (GEMU, GRU) or general medical wards. The outcome as regards to mortality rate at one year, placement to a nursing home, physical function, contentment with services, readmission rate and cost was all significantly better in the geriatric settings. Internal comparisons of geriatric programs in nursing homes, day hospitals and in home service, seven studies (1261 patient), revealed some differences in outcomes in function, contentment and costs. Conclusions: Specialized geriatric rehabilitation is complicated but effective when properly performed. Interdisciplinary teamwork, targeting of patients, comprehensive assessment and intensive and patient-targeted rehabilitation seem to characterize the most effective programs. Rehabilitation of frail elderly people poses a major challenge for the future and has to be developed further for the sake of quality of life of elderly people as well as for economic reasons.Markmið: Að gera úttekt á öldrunarendurhæfingu á Íslandi og öðrum Norðurlöndum, marka hinn hugmyndafræðilega grunn, tengja hann norrænum veruleika og taka saman vísindalegar niðurstöður um árangur öldrunarendurhæfingar. Aðferð: Hugarflugsfundir vinnuhóps kennara í öldrunarlækningum um öldrunarendurhæfingu. Sértæk leit í helstu læknatímarita á Medline í greinum sem fjalla um aðferðir og meðferðarleiðir endurhæfingar fyrir aldraða á vísindalegan hátt. Um er að ræða samantekt á rannsóknum sem notast við slembiúrtök og taka til elstu aldurshópa. Greinunum var skipt niður í fjóra flokka eftir sjúkdómum, færni og staðsetningu; 1) heilablóðfall, 2) mjaðmarbrot, 3) bráðveikir og hrumir, 4) prógrömm á hjúkrunarheimilum, dagspítölum og í heimaþjónustu. Niðurstöður: Lífeðlisfræðilegir og félagslegir þættir marka veikindaferli og fötlun aldraðra. Verklag öldrunarþjónustunnar skiptir miklu um árangur öldrunarendurhæfingar. Leit í 27 tímaritsgreinum náði til 8586 sjúklinga en þær báru saman slembiúrtök og höfðu haldbærar viðmiðanir. Endurhæfing aldraðra heilablóðfallssjúklinga á öldrunarlækningadeild, sex rannsóknir (1138 sjúklingar), dró úr dánarlíkum og minnkaði þörf fyrir stofnanavist en breyting á mælanlegri færni og legudagafjöldi varð ekki afgerandi hjá öllum. Enn betri árangur náðist við endurhæfingu eftir mjaðmarbrot, sex rannsóknir (2171 sjúklingur). Átta rannsóknir (4016 sjúklingar) báru saman árangur öldrunarlækningadeilda borið saman við almennar lyflæknisdeildir í meðhöndlun bráðveikra og hrumra sjúklinga. Niðurstöður voru flestar afgerandi betri á öldrunarlækningadeildum hvað varðar dánartíðni að ári, vistun á hjúkrunarheimili, líkamlega færni, ánægju, endurinnlagnir og kostnað. Innbyrðis samanburður á endurhæfingaraðferðum fyrir aldraða á hjúkrunarheimilum, dagspítölum og í heimaþjónustu, sjö rannsóknir (1261 sjúklingur), sýndu mun á nokkrum viðmiðunum í færniþáttum, ánægju og kostnaði. Ályktanir: Sérhæfð endurhæfing aldraðra er flókin en skilar árangri þegar rétt er á haldið. Bestur árangur næst með fjölfaglegri teymisvinnu, val á þeim sjúklingum sem mestu áhættuna hafa, alhliða öldrunarmati og virkri og einstaklingsmiðaðri endurhæfingu. Endurhæfing á hrumu gömlu fólki er og verður vaxandi viðfangsefni fyrir heilbrigðisþjónustuna og mikilvægt að hún nái því markmiði að auka lífsgæði aldraðs fólks. Benda rannsóknir einnig til að við það skapist einnig efnahagslegur ávinningur fyrir land og þjóð

Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

We generated ex vivo drug-response and multiomics profi ling data for a prospective series of 252 samples from 186 patients with acute myeloid leukemia (AML). A functional precision medicine tumor board (FPMTB) integrated clinical, molecular, and functional data for application in clinical treatment decisions. Actionable drugs were found for 97% of patients with AML, and the recommendations were clinically implemented in 37 relapsed or refractory patients. We report a 59% objective response rate for the individually tailored therapies, including 13 complete responses, as well as bridging five patients with AML to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled the identifi cation of drug response biomarkers, such as the association of IL15 overexpression with resistance to FLT3 inhibitors. Integration of molecular profi ling and large-scale drug response data across many patients will enable continuous improvement of the FPMTB recommendations, providing a paradigm for individualized implementation of functional precision cancer medicine. SIGNIFICANCE: Oncogenomics data can guide clinical treatment decisions, but often such data are neither actionable nor predictive. Functional ex vivo drug testing contributes signifi cant additional, clinically actionable therapeutic insights for individual patients with AML. Such data can be generated in four days, enabling rapid translation through FPMTB.Peer reviewe

Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

We generated ex vivo drug-response and multiomics profi ling data for a prospective series of 252 samples from 186 patients with acute myeloid leukemia (AML). A functional precision medicine tumor board (FPMTB) integrated clinical, molecular, and functional data for application in clinical treatment decisions. Actionable drugs were found for 97% of patients with AML, and the recommendations were clinically implemented in 37 relapsed or refractory patients. We report a 59% objective response rate for the individually tailored therapies, including 13 complete responses, as well as bridging five patients with AML to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled the identifi cation of drug response biomarkers, such as the association of IL15 overexpression with resistance to FLT3 inhibitors. Integration of molecular profi ling and large-scale drug response data across many patients will enable continuous improvement of the FPMTB recommendations, providing a paradigm for individualized implementation of functional precision cancer medicine. SIGNIFICANCE: Oncogenomics data can guide clinical treatment decisions, but often such data are neither actionable nor predictive. Functional ex vivo drug testing contributes signifi cant additional, clinically actionable therapeutic insights for individual patients with AML. Such data can be generated in four days, enabling rapid translation through FPMTB.Peer reviewe

Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH) : a randomised, double-blind, placebo-controlled, phase 3 trial

Mika Saarela työryhmän jäsenenä.Background Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. Methods Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0.2 g/kg or 0.4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1: 1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials. gov, number NCT01545076. Findings In this randomised, double-blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50-74]) patients on placebo, 22 (39% [27-52]) on low-dose SCIg, and 19 (33% [22-46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0.0007). Absolute risk reductions were 25% (95% CI 6-41) for low-dose versus placebo (p=0.007), 30% (12-46) for high-dose versus placebo (p=0.001), and 6% (-11 to 23) for high-dose versus low-dose (p=0.32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. Interpretation This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP.Peer reviewe

HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia

Peer reviewe