Tirabrutinib

Tirabrutinib

Tirabrutinib (brand name Velexbru) is a drug used for the treatment of autoimmune diseases and hematological malignancies.

Tirabrutinib was approved in March 2020 in Japan for the treatment of recurrent or refractory primary central nervous system lymphoma.

In addition, tirabrutinib is in clinical development by Ono Pharmaceutical and Gilead Sciences in the United States, Europe, and Japan for autoimmune disorders, chronic lymphocytic leukemia, B cell lymphoma, Sjogren’s syndrome, pemphigus, and rheumatoid arthritis.

Tirabrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase.

The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL).

Methods: Patients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II.

Results: Forty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types.

Conclusion: These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL 1).

Yoshioka et al. reported that tirabrutinib was administered via nasogastric tubes to treat an elderly patient with primary central nervous system lymphoma (PCNSL). The patient was a 76-year-old woman who underwent endoscopic biopsy of multiple intracerebral masses, which resulted in the diagnosis of diffuse large B-cell lymphoma. The patient was diagnosed with PCNSL and was started on an induction regimen of systemic chemotherapy with rituximab in combination with high-dose methotrexate. However, after the second cycle of chemotherapy, the tumor grew rapidly, and the patient went into a coma. As a result, the treatment was changed to nasogastric tube administration of tirabrutinib suspension. After 1 week of tirabrutinib administration, the patient’s level of consciousness improved, and furthermore, after 2 weeks of tirabrutinib administration, the patient was able to take tirabrutinib orally. Although oral administration is the standard route of administration for tirabrutinib, this case study showed that the nasogastric tube administration of tirabrutinib suspension is a therapeutic option for patients with impaired consciousness or dysphagia 2)


A 64-year-old patient with recurrent PCNSL enrolled in the phase I/II clinical trial of tirabrutinib, a second-generation BTK inhibitor designed for treating relapsed/refractory PCNSL. The left cerebellum lesions on magnetic resonance imaging disappeared one month after tirabrutinib treatment. The patient died because of suspected pneumocystis pneumonia and acute exacerbation of interstitial pneumonia 43 days after starting tirabrutinib. An autopsy confirmed no viable tumor cells in the entire brain, including the left cerebellum lesion, confirming complete obliteration of tumor cells by tirabrutinib. This letter pathologically confirms the effect of tirabrutinib on relapsed/refractory PCNSL for the first time in humans.Trial registration: JapicCTI-173646. Registered 14 July 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-173646 3).


Recovery from coma of a patient having acute progression of primary central nervous system lymphoma using tirabrutinib and methylprednisolone 4).


1)

Narita Y, Nagane M, Mishima K, Terui Y, Arakawa Y, Yonezawa H, Asai K, Fukuhara N, Sugiyama K, Shinojima N, Kitagawa J, Aoi A, Nishikawa R. Phase I/II study of tirabrutinib, a second-generation Bruton’s tyrosine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma. Neuro Oncol. 2021 Jan 30;23(1):122-133. doi: 10.1093/neuonc/noaa145. PMID: 32583848; PMCID: PMC7850159.
2)

Yoshioka H, Okuda T, Nakao T, Fujita M, Takahashi JC. Experience with nasogastric tube administration of tirabrutinib in the treatment of an elderly patient with primary central nervous system lymphoma. Int Cancer Conf J. 2021 Jun 5;10(4):290-293. doi: 10.1007/s13691-021-00491-1. PMID: 34567940; PMCID: PMC8421486.
3)

Okita Y, Kano-Fujiwara R, Nakatsuka SI, Honma K, Kinoshita M. Histological verification of the treatment effect of tirabrutinib for relapsed/refractory primary central nervous system lymphoma. Exp Hematol Oncol. 2021 Apr 26;10(1):29. doi: 10.1186/s40164-021-00222-5. PMID: 33902692; PMCID: PMC8077707.
4)

Satow T, Horiguchi S, Komuro T. Recovery from coma of a patient having acute progression of primary central nervous system lymphoma using tirabrutinib and methylprednisolone. Neurooncol Adv. 2020 Nov 27;2(1):vdaa164. doi: 10.1093/noajnl/vdaa164. PMID: 33409497; PMCID: PMC7770517.

SCAT5

SCAT5

Sports Concussion Assessment Tool 5 (SCAT5) is a standardized concussion assessment, available as a pdf or online , used by healthcare providers when a concussion is suspected in athletes ages 12 and older.


The Fifth International Conference on Concussion in Sport was held in Berlin in October 2016. A series of 12 questions and subquestions was developed and the expert panel members were required to perform a systematic review to answer each question. Following presentation at the Berlin meeting of the systematic review, poster abstracts and audience discussion, the summary Consensus Statement was produced. Further, a series of tools for the management of sport-related concussion was developed, including the Sport Concussion Assessment Tool Fifth edition (SCAT5), the Child SCAT5, and the Concussion Recognition Tool Fifth edition 1).


PDF


Online


The SCAT5 cannot be performed correctly in less than 10 minutes.

The revision of the SCAT3 (first published in 2013) culminated in the SCAT5. The revision was based on a systematic review and synthesis of current research, public input and expert panel review as part of the 5th International Consensus Conference on Concussion in Sport held in Berlin in 2016. The SCAT5 is intended for use in those who are 13 years of age or older. The Child SCAT5 is a tool for those aged 5-12 years, which is discussed elsewhere 2).


The Sports Concussion Assessment Tool-5th Edition (SCAT5) and the child version (Child SCAT5) are the current editions of the SCAT and have updated the memory testing component from previous editions.


To achieve consensus, via an international panel of SRC experts, on which athlete/player and parent/caregiver demographic variables should be considered for inclusion in future editions of the SCAT/Child SCAT respectively.

Methods: A two-round modified Delphi technique, overseen by a steering committee, invited 41 panellists to achieve expert consensus (≥80% agreement). The first round utilised open questions to generate demographic variables; the second round used a five-point ordinal item to rank the importance of including each variable in future editions of the SCAT/Child SCAT.

Results: 15 experts participated in at least one Delphi round. 29 athlete/player and eight parent/caregiver variables reached consensus for inclusion in the SCAT, whereas two parent/caregiver variables reached consensus for exclusion. 28 athlete/player and four parent/caregiver variables reached consensus for the Child SCAT, whereas two parent/caregiver variables reached consensus for exclusion. Key categories of variables included the following: concussion/sport details, personal medical conditions and family medical history.

Conclusion: This study provides a list of athlete/player and parent/caregiver demographic variables that should be considered in future revisions of the SCAT/Child SCAT. By considering (and ultimately likely including) a wider and standard set of additional demographic variables, the Concussion in Sport experts will be able to provide clinicians and researchers with data that may enhance interpretation of the individual’s data and the building of larger datasets 3).


In a prospective observational study, the ability of the SCAT5 and ChildSCAT5 to differentiate between children with and without a concussion was examined. Concussed children (n=91) and controls (n=106) were recruited from an emergency department in three equal-sized age bands (5-8/9-12/13-16 years). Analysis of covariance models (adjusting for participant age) were used to analyze group differences on components of the SCAT5. On the SCAT5 and ChildSCAT5, respectively, youth with concussion reported a greater number (d=1.47; d=0.52) and severity (d=1.27; d=0.72) of symptoms than controls (all p<0.001). ChildSCAT5 parent-rated number (d=0.98) and severity (d=1.04) of symptoms were greater for the concussion group (all p<0.001). Acceptable levels of between-group discrimination were identified for SCAT5 symptom number (AUC=0.86) and severity (AUC=0.84) and ChildSCAT5 parent-rated symptom number (AUC=0.76) and severity (AUC=0.78). The findings support the utility of the SCAT5 and ChildSCAT5 to accurately distinguish between children with and without a concussion 4).


A study aimed to validate this new memory component against the Rey Auditory Verbal Learning Test (RAVLT) as the validated standard. This prospective, observational study, carried out within The Royal Children’s Hospital Emergency Department, Melbourne, Australia, recruited 198 participants: 91 with concussion and 107 upper limb injury or healthy sibling controls. Partial Pearson correlations showed that memory acquisition and recall on delay aspects of the SCAT5 were significantly correlated with the RAVLT equivalents when controlling for age (p < 0.001, r = 0.565 and p < 0.001, r = 0.341, respectively). Factor analysis showed that all RAVLT and SCAT5 memory components load on to the same factor, accounting for 59.13% of variance. Logistic regression models for both the RAVLT and SCAT5, however, did not predict group membership (p > 0.05). Receiver operating curve analysis found that the area under the curve for all variables and models was below the recommended 0.7 threshold. This study demonstrated that the SCAT5 and Child SCAT5 memory paradigm is a valid measure of memory in concussed children 5).


The two-week test-retest reliability of the SCAT5 baseline scores varied from moderate to high. However, there was considerable individual variability on the SAC and mBESS scores and most players have notable short-term fluctuation on performance even if uninjured. Recommendations for interpreting change on the SCAT5 are provided 6).


1)

Davis GA, Ellenbogen RG, Bailes J, Cantu RC, Johnston KM, Manley GT, Nagahiro S, Sills A, Tator CH, McCrory P. The Berlin International Consensus Meeting on Concussion in Sport. Neurosurgery. 2018 Feb 1;82(2):232-236. doi: 10.1093/neuros/nyx344. PMID: 29106653.
2)

Echemendia RJ, Meeuwisse W, McCrory P, Davis GA, Putukian M, Leddy J, Makdissi M, Sullivan SJ, Broglio SP, Raftery M, Schneider K, Kissick J, McCrea M, Dvořák J, Sills AK, Aubry M, Engebretsen L, Loosemore M, Fuller G, Kutcher J, Ellenbogen R, Guskiewicz K, Patricios J, Herring S. The Sport Concussion Assessment Tool 5th Edition (SCAT5): Background and rationale. Br J Sports Med. 2017 Jun;51(11):848-850. doi: 10.1136/bjsports-2017-097506. Epub 2017 Apr 26. PMID: 28446453.
3)

Shanks MJ, McCrory P, Davis GA, Echemendia RJ, Gray AR, Sullivan SJ. Developing common demographic data elements to include in future editions of the SCAT and Child SCAT: a modified international Delphi study. Br J Sports Med. 2020 Aug;54(15):906-912. doi: 10.1136/bjsports-2018-100482. Epub 2019 Oct 11. PMID: 31604697.
4)

Babl FE, Anderson V, Rausa VC, Anderson N, Pugh R, Chau T, Clarke C, Fabiano F, Fan F, Hearps S, Parkin G, Takagi M, Davis G. Accuracy of Components of the SCAT5 and ChildSCAT5 to Identify Children with Concussion. Int J Sports Med. 2021 Aug 16. doi: 10.1055/a-1533-1700. Epub ahead of print. PMID: 34399426.
5)

Shapiro JS, Hearps S, Rausa VC, Anderson V, Anderson N, Pugh R, Chau T, Clarke C, Davis GA, Fabiano F, Fan F, Parkin GM, Takagi M, Babl FE. Validation of the SCAT5 and Child SCAT5 Word-List Memory Task. J Neurotrauma. 2021 May 10. doi: 10.1089/neu.2020.7414. Epub ahead of print. PMID: 33765839.
6)

Hänninen T, Parkkari J, Howell DR, Palola V, Seppänen A, Tuominen M, Iverson GL, Luoto TM. Reliability of the Sport Concussion Assessment Tool 5 baseline testing: A 2-week test-retest study. J Sci Med Sport. 2021 Feb;24(2):129-134. doi: 10.1016/j.jsams.2020.07.014. Epub 2020 Aug 5. PMID: 32868203.

Low-frequency deep brain stimulation

Low-frequency deep brain stimulation

Patients with Parkinson’s disease can develop axial symptoms, including speechgait, and balance difficulties. Chronic high-frequency deep brain stimulation (>100 Hz) can contribute to these impairments while low-frequency stimulation (<100 Hz) may improve symptoms but only in some individuals.

DBS at frequencies below 100 Hz is a therapeutic option in select cases of Parkinson’s disease with freezing of gait and other axial symptoms, and in select patients with dystonia and other hyperkinetic movements, particularly those requiring an energy-saving strategy 1).

In ten studies with 132 patients, the pooled results showed no significant difference in the total Unified Parkinson Disease Rating Scale part III (UPDRS-III) scores (mean effect, -1.50; p = 0.19) or the rigidity subscore between HFS and LFS. Compared to LFS, HFS induced a greater reduction in the tremor subscore within the medication-off condition (mean effect, 1.01; p = 0.002), while no significance was shown within the medication-on condition (mean effect, 0.01; p = 0.92). LFS induced greater reduction in akinesia subscore (mean effect, -1.68, p = 0.003), the time to complete the stand-walk-sit (SWS) test (mean effect, -4.84; p < 0.00001), and the number of freezing of gait (FOG) (mean effect, -1.71; p = 0.03). These results suggest that two types of frequency settings may have different effects, that is, HFS induces better responses for tremor and LFS induces greater response for akinesia, gait, and FOG, respectively, which are worthwhile to be confirmed in a future study, and will ultimately inform the clinical practice in the management of PD using STN-DBS 2).

Vijiaratnam et al. from the Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Unit of Functional Neurosurgery, the National Hospital for Neurology and Neurosurgery, London, Unit of Neurology of Ospedale “M. Bufalini” of Cesena, Cesena, Italy Department of Neurology, the Walton Centre NHS Foundation Trust, Liverpool recruited patients who developed axial motor symptoms while using high-frequency stimulation and objectively assessed the short-term impact of low-frequency stimulation on axial symptoms, other aspects of motor function and quality of life. A retrospective chart review was then conducted on a larger cohort to identify which patient characteristics were associated with not only the need to trial low-frequency stimulation but also those which predicted its sustained use. Among 20 prospective patients, low-frequency stimulation objectively improved mean motor and axial symptom severity and quality of life in the short term. Among a retrospective cohort of 168 patients, those with less severe tremor and those in whom axial symptoms had emerged sooner after subthalamic nucleus deep brain stimulation were more likely to be switched to and remain on long-term low-frequency stimulation. These data suggest that low-frequency stimulation results in objective mean improvements in overall motor function and axial symptoms among a group of patients, while individual patient characteristics can predict sustained long-term benefits. Longer follow-up in the context of a larger, controlled, double-blinded study would be required to provide definitive evidence of the role of low-frequency deep brain stimulation 3).


To investigate whether LF-SNr-DBS combined with standard HF stimulation of the subthalamic nucleus (STN) is clinically relevant in improving gait disorders that no longer respond to levodopa in PD patients, compared with HF-STN or LF-SNr stimulation alone.

Methods: Patients received LF-SNr or HF-STN stimulation alone or combined (COMB) stimulation of both nuclei (crossover design). The nucleus to be stimulated was randomly assigned and clinical evaluations performed by a blinded examiner after three months follow-up for each. Clinical assessment included the Freezing of Gait questionnaire, Tinetti Balance and Walking Assessing tool, and Unified Parkinson’s Disease Rating.

Results: We included six patients (mean age 59.1 years, disease duration 16.1 years). All patients suffered motor fluctuations and dyskinesias. The best results were obtained with COMB in four patients (who preferred and remained with COMB over 3 years of follow-up) and with HF-STN in two patients. SNr stimulation alone did not produce better results than COMB or STN in any patient.

Conclusion: COMB and HF-STN stimulation improved PD-associated gait disorders in this preliminary case series, sustained over time. Further multicenter investigations are required to better explore this therapeutic option 4).


Sidiropoulos et al. studied the effects of low-frequency stimulation (LFS) (≤80 Hz) for improving speech, gait, and balance dysfunction in the largest patient population to date. PD patients with bilateral STN-DBS and resistant axial symptoms were switched from chronic 130 Hz stimulation to LFS and followed up to 4 years. Primary outcome measures were total motor UPDRS scores, and axial and gait subscores before and after LFS. Bivariate analyses and correlation coefficients were calculated for the different conditions. Potential predictors of therapeutic response were also investigated. Forty-five advanced PD patients who had high-frequency stimulation (HFS) for 39.5 ± 27.8 consecutive months were switched to LFS. LFS was kept on for a median period of 111.5 days before the assessment. There was no significant improvement in any of the primary outcomes between HFS and LFS, although a minority of patients preferred to be maintained on LFS for longer periods of time. No predictive factors of response could be identified. There was overall no improvement from LFS in axial symptoms. This could be partly due to some study limitations. Larger prospective trials are warranted to better clarify the impact of stimulation frequency on axial signs 5).


1)

Baizabal-Carvallo JF, Alonso-Juarez M. Low-frequency deep brain stimulation for movement disorders. Parkinsonism Relat Disord. 2016 Oct;31:14-22. doi: 10.1016/j.parkreldis.2016.07.018. Epub 2016 Jul 30. PMID: 27497841.
2)

Su D, Chen H, Hu W, Liu Y, Wang Z, Wang X, Liu G, Ma H, Zhou J, Feng T. Frequency-dependent effects of subthalamic deep brain stimulation on motor symptoms in Parkinson’s disease: a meta-analysis of controlled trials. Sci Rep. 2018 Sep 27;8(1):14456. doi: 10.1038/s41598-018-32161-3. PMID: 30262859; PMCID: PMC6160461.
3)

Vijiaratnam N, Girges C, Wirth T, Grover T, Preda F, Tripoliti E, Foley J, Scelzo E, Macerollo A, Akram H, Hyam J, Zrinzo L, Limousin P, Foltynie T. Long-term success of low-frequency subthalamic nucleus stimulation for Parkinson’s disease depends on tremor severity and symptom duration. Brain Commun. 2021 Jul 28;3(3):fcab165. doi: 10.1093/braincomms/fcab165. PMID: 34396114; PMCID: PMC8361419.
4)

Valldeoriola F, Muñoz E, Rumià J, Roldán P, Cámara A, Compta Y, Martí MJ, Tolosa E. Simultaneous low-frequency deep brain stimulation of the substantia nigra pars reticulata and high-frequency stimulation of the subthalamic nucleus to treat levodopa unresponsive freezing of gait in Parkinson’s disease: A pilot study. Parkinsonism Relat Disord. 2019 Mar;60:153-157. doi: 10.1016/j.parkreldis.2018.09.008. Epub 2018 Sep 5. PMID: 30241951.
5)

Sidiropoulos C, Walsh R, Meaney C, Poon YY, Fallis M, Moro E. Low-frequency subthalamic nucleus deep brain stimulation for axial symptoms in advanced Parkinson’s disease. J Neurol. 2013 Sep;260(9):2306-11. doi: 10.1007/s00415-013-6983-2. Epub 2013 Jun 9. PMID: 23749331.
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