Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA).

BACKGROUND: Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future. DESIGN: The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field. RESULTS: Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues. CONCLUSIONS: We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic.

Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL.

Blinatumomab can induce a complete haematological remission in patients in 46.6% with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) resulting in a survival benefit when compared with chemotherapy. Only bone marrow blast counts before therapy have shown a weak prediction of response. Here we investigated the role of regulatory T cells (Tregs), measured by CD4/CD25/FOXP3 expression, in predicting the outcome of immunotherapy with the CD19-directed bispecific T-cell engager construct blinatumomab. Blinatumomab responders (n=22) had an average of 4.82% Tregs (confidence interval (CI): 1.79-8.34%) in the peripheral blood, whereas non-responders (n=20) demonstrated 10.25% Tregs (CI: 3.36-65.9%). All other tested markers showed either no prediction value or an inferior prediction level including blast BM counts and the classical enzyme marker lactate dehydrogenase. With a cutoff of 8.525%, Treg enumeration can identify 100% of all blinatumomab responders and exclude 70% of the non-responders. The effect is facilitated by blinatumomab-activated Tregs, leading to interleukin-10 production, resulting in suppression of T-cell proliferation and reduced CD8-mediated lysis of ALL cells. Proliferation of patients' T cells can be restored by upfront removal of Tregs. Thus, enumeration of Treg identifies r/r ALL patients with a high response rate to blinatumomab. Therapeutic removal of Tregs may convert blinatumomab non-responders to responders.

Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia.

We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20-27%) and a median OS of 3.3 months (95% CI: 2.8-3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36-50%) and a median OS of 6.1 months (95% CI: 4.2-7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67-4.31) and improved OS (HR=0.536, 95% CI: 0.394-0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.

[52 year-old patient with severe heart failure due to multiple myeloma]. / 52-jähriger Patient mit schwerer Herzinsuffizienz bei multiplem Myelom.

Cardiac amyloidosis represents a prognostically relevant comorbidity in multiple myeloma. We report the case of a patient in whom severe heart failure symptoms as a consequence of cardiac AL-amyloidosis resolved after tandem high-dose melphalan therapy followed by autologous blood-stem cell transplantation. Partial regression of cardiac amyloid deposits and improvement of cardiac function were objectified.

[Heat shock protein 90 alpha und beta are overexpressed in multiple myeloma cells and critically contribute to survival]. / Die Hitzeschockproteine 90 alpha und beta sind im mutiplen Myelom überexprimiert und tragen zum Tumorzellüberleben bei.

HSP90's are overexpressed in different cancer types and they probably are required to sustain aberrant signalling in malignant cells. Recently, pharmacological inhibition of HSP90 was found to suppress growth of myeloma cell lines and in primary myeloma cells. Therefore, we wanted to investigate the role of HSP90alpha and HSP90beta in the pathogenesis of malignant myeloma (MM) in more detail. Immunohistochemistry was employed to examine the expression of HSP90alpha and HSP90beta in MM. The importance of HSP90 for survival of MM -cells was investigated by SiRNA-mediated knockdown of HSP90 and blockade of the IL-6R/STAT3 and the MAPK signaling pathways in vitro. HSP90alpha and HSP90beta were overexpressed in majority of investigated MM cases, but not in MGUS or in normal plasma cells. SiRNA-mediated knockdown of HSP90 or treatment with the novel HSP90 inhibitor 17-DMAG attenuated the levels of STAT3 and phospho-ERK and decreased the viability of MM cells. The knockdown of HSP90alpha was sufficient to induce apoptosis. This effect was strongly increased when both HSP90s were targeted, indicating a cooperation of both. HSP90 critically contributes to myeloma survival in the context of its microenvironment and therefore strengthen the potential value of HSP90 as a therapeutic target.

Correlations of structure and rates of energy transfer for through-bond energy-transfer cassettes.

Fluorescent DNA-labeling cassettes are designed to have a common absorbing chromophore matched to a single exciting laser wavelength, but up to four different emitters. Experiments reported here have examined the energy-transfer rates and fluorescence polarization characteristics for two different types of cassette, involving three distinct relative orientations of the donor and acceptor transition moments and the axis of the rigid linker. Energy-transfer times range from <200 fs to approximately 20 ps, the fastest transfer times occurring when the transition moments of the donor and acceptor species are aligned parallel to the linker axis. Experimental evidence is presented that supports a through-bond energy-transfer mechanism, in contrast with a commercial DNA-labeling agent, which exhibits much slower transfer times controlled by FRET. These rigid cassettes also exhibit polarized fluorescence from the acceptor species, so that this particular type of DNA-labeling probe has some of the advantages of single-molecule probes such as rhodamine and coumarin dyes.

Case gender and severity in cerebral palsy varies with intrauterine growth.

BACKGROUND: There is an unexplained excess of cerebral palsy among male babies. There is also variation in the proportion of more severe cases by birth weight. It has recently been shown that the rate of cerebral palsy increases as intrauterine size deviates up or down from an optimum about one standard deviation heavier than population mean weight-for-gestation. AIMS: To determine whether the gender ratio or the severity of cases also varies with intrauterine size. METHODS: A total of 3454 cases of cerebral palsy among single births between 1976 and 1990 with sufficient data to assign case severity (based on intellectual impairment and walking ability) and to compare weight-for-gestation at birth to sex specific fetal growth standards, were aggregated from nine separate registers in five European countries. RESULTS: The greater the degree to which growth deviates either up or down from optimal weight-for-gestation at birth, the higher is the rate of cerebral palsy, the larger is the proportion of male cases, and the more severe is the functional disability. Compared to those with optimum growth the risk of more severe cerebral palsy in male babies is 16 times higher for those with a birth weight below the 3rd centile and four times higher when birth weight is above the 97th centile. In contrast, for mild cerebral palsy in female babies the excess risks at these growth extremes are about half these magnitudes. CONCLUSIONS: Among singleton children with cerebral palsy, abnormal intrauterine size, either small or large, is associated with more severe disability and male sex.

Frecuencia del polimorfismo E4154K del gen de la apolipoproteína B en individuos chilenos con perfil de riesgo para enfermedad coronaria / Frequency of the E4154K polymorphism at the apolipoprotein B gene in chilean individuals with high risk for coronary artery disease

Las enfermedades cardiovasculares son la principal causa de morbimortalidad en Chile. El conocimiento de los factores de riesgo asociados a estas patologías, puede ser importante en la prevención. Los objetivos del presente estudio fueron: a)evaluar la frecuencia del polimorfismo E4154K (EcoRI) del gen de la apolipoproteína B (APOB) en 60 individuos con perfil de riesgo para enfermedad coronaria (grupo de estudio, GE) y 120 controles (GC) de la ciudad de Temuco (Chile) y b) determinar el efecto de esta alteración molecular sobre las concentraciones plasmáticas de lípidos. La genotipificación del polimorfismo EcoRI fue realizada mediante la técnica de PCR, seguida de restricción enzimática. Nuestros resultados mostraron que el genotipo homocigoto E+E+ para el polimorfismo EcoRI fue significativamente mayor en los individuos del grupo GE (77 por ciento vs. 56 por ciento, p=0.018). Se observó también, que los individuos del grupo GE portadores del genotipo E+E+, presentaron mayores niveles de colesterol total (p=0.003), y bajos valores de HDL-C )p=0.008). En conclusión, nuestros datos demuestran una importante asociación entre el polimorfismo EcoRI del gen APOB y marcadores biológicos de riesgo cardiovascular.

The Danish Cerebral Palsy Registry. A registry on a specific impairment.

Cerebral palsy (CP) is the commonest disabling impairment in childhood, with a prevalence of 2-3 per 1000 live births. The Danish Cerebral Palsy Registry is a research registry that contains cases of CP from birth year 1925 and has estimated the birth prevalence since 1950. Data on children with CP are collected from paediatric departments and one special institution for disabled children. The children are included by a child neurologist and an obstetrician, and information on pregnancy, birth, neonatal period, impairments and demographic data on the child and mother are registered in a standard form. The uptake area is eastern Denmark, covering about 50% of the population, but the rest of Denmark is planned to be included from 2001. The Registry is large, well established and validated, and the definitions and collection procedures have not changed through several decades. It therefore has great research potential. Birth prevalence is estimated continuously, and changes over time are analysed and correlated with pre- and perinatal conditions. A correlation between increased survival of preterm babies and an increased prevalence was found previously, and a decreased prevalence in very preterm infants was later associated with less use of mechanical ventilation. A study correlating CP and maternal infection is ongoing. Collaboration between 14 European CP registries allows the true differences in prevalence between different countries to be studied. Linkage to other individually based registries in Denmark will allow the social consequences of CP to be described.

Cerebral palsy births in eastern Denmark, 1987--90: implications for neonatal care.

The Cerebral Palsy Register in eastern Denmark has collected cases using a uniform data sampling procedure since birth year 1979. We have investigated changes in the rate of cerebral palsy, related to gestational age, mortality and perinatal risk factors in children born 1983--90. The total cerebral palsy birth prevalence decreased from 3.0 in the birth year period 1983--86 to 2.4 per 1000 live births (P < 0.01) in 1987--90, owing to a decrease among all preterm infants (29--19 per 1000, P < 0.001). The perinatal and early neonatal mortality in preterm infants was unchanged from 1983--86 to 1987--90. The rate of cerebral palsy in term infants was 1.5 per 1000 in all birth-year periods from 1979--90. Among the cerebral palsy infants, the proportion of very preterm babies treated with mechanical ventilation in the neonatal period decreased from 95% in 1983--86 to 61% in 1987--90 (P < 0.001), while the group treated with CPAP among the moderately preterm babies increased from 61% to 78% (P < 0.05). The significant decline in cerebral palsy rate in preterm infants born 1987--90 may be due to a change in treatment at the neonatal intensive care units using less mechanical ventilation, a hypothesis which needs further investigation.

Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells.

NKG2D is an activating receptor that stimulates innate immune responses by natural killer cells upon engagement by MIC ligands, which are induced by cellular stress. Because NKG2D is also present on most CD8alphabeta T cells, it may modulate antigen-specific T cell responses, depending on whether MIC molecules--distant homologs of major histocompatibility complex (MHC) class I with no function in antigen presentation--are induced on the surface of pathogen-infected cells. We found that infection by cytomegalovirus (CMV) resulted in substantial increases in MIC on cultured fibroblast and endothelial cells and was associated with induced MIC expression in interstitial pneumonia. MIC engagement of NKG2D potently augmented T cell antigen receptor (TCR)-dependent cytolytic and cytokine responses by CMV-specific CD28- CD8alphabeta T cells. This function overcame viral interference with MHC class I antigen presentation. Combined triggering of TCR-CD3 complexes and NKG2D induced interleukin 2 production and T cell proliferation. Thus NKG2D functioned as a costimulatory receptor that can substitute for CD28.

The relation of breech presentation at term to cerebral palsy.

OBJECTIVE: To examine the relation between breech delivery and cerebral palsy, considering the influence of intrauterine growth, low Apgar score at birth, and mode of delivery. DESIGN: Register-based, case-control study. POPULATION: A cohort of infants with cerebral palsy born between 1979 and 1986 in East Denmark, identified by linkage of the cerebral palsy register with the national birth register. Discharge letters from births of breech infants with cerebral palsy were reviewed. MAIN OUTCOME MEASURES: Presentation, mode of delivery, gestational age, birthweight, Apgar score, type of cerebral palsy, severity of handicap. RESULTS: Breech presentation at term was associated with a borderline significantly higher risk of cerebral palsy than vertex presentation (OR 1.56; 95% CI 0.9-2.4). Breech presentation infants more often had a lower Apgar score (< 7 at 5 minutes) and were smaller for gestational age (SGA < 2 SD) than were those with vertex presentation; infants with a low Apgar score, or who were small for gestational age, had a higher risk of cerebral palsy. After stratification by being small for gestational age the risk of cerebral palsy was not related to presentation. There were no differences between breech and vertex infants with cerebral palsy in terms of low Apgar score, being small for gestational age, mode of delivery, and severity of the handicap. Breech presentation infants were more often classified as diplegic (77.8% versus 42.3% in cephalic infants). CONCLUSION: The risk of cerebral palsy among term breech presentation infants does not seem to be related to mode of delivery, but is more likely linked to a higher rate of being small for gestational age in breech infants.

Trend in cerebral palsy birth prevalence in eastern Denmark: birth-year period 1979-86.

To investigate changes in cerebral palsy birth prevalence and perinatal mortality rate by different gestational age groups, 1979-86, cerebral palsy cases in eastern Denmark were identified from the Danish Cerebral Palsy Register, and information on birth and mortality rates was sought in the Danish Medical Birth Register. From 1979-82 to 1983-86, the birth prevalence of cerebral palsy increased from 2.6 to 3.0 per 1000 (P < 0.05). The rate for infants of 31 weeks' gestation or more did not change, whereas a significant increase was observed in infants below 31 weeks (85-123 per 1000, P < 0.05). In the same periods, perinatal mortality in eastern Denmark decreased significantly from 8.6 to 7.8 per 1000. The decrease in stillbirth rate was significant in all subgroups of gestational ages except in those of 28-30 weeks' gestation. The early neonatal mortality rate decreased significantly only in infants below 31 weeks (282-239 per 1000, P < 0.05). Thus, in eastern Denmark, cerebral palsy birth prevalence has increased from birth-year period 1979-82 to 1983-86 because of an increased rate in preterm infants below 31 weeks, who at the same time had a reduced risk of early neonatal death.