A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells

Chimeric antigen receptor (CAR) T-cells are an emerging therapy for the treatment of relapsed/refractory B-cell malignancies. While CD19 CAR-T cells have been FDA-approved, CAR T-cells targeting CD22, as well as dual-targeting CD19/CD22 CAR T-cells, are currently being evaluated in clinical trials. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of CD22-targeting CAR T-cell therapies. We searched MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials from inception to March 3rd 2022 for full-length articles and conference abstracts of clinical trials employing CD22-targeting CAR T-cells in acute lymphocytic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL). The primary outcome was best complete response (bCR). A DerSimonian and Laird random-effects model with arcsine transformation was used to pool outcome proportions. From 1068 references screened, 100 were included, representing 30 early phase studies with 637 patients, investigating CD22 or CD19/CD22 CAR T-cells. CD22 CAR T-cells had a bCR of 68% [95% CI, 53-81%] in ALL (n= 116), and 64% [95% CI, 46-81%] in NHL (n= 28) with 74% and 96% of patients having received anti-CD19 CAR T-cells previously in ALL and NHL studies respectively. CD19/CD22 CAR T-cells had a bCR rate of 90% [95% CI, 84-95%] in ALL (n= 297) and 47% [95% CI, 34-61%] in NHL (n= 137). The estimated incidence of total and severe (grade ≥3) CRS were 87% [95% CI, 80-92%] and 6% [95% CI, 3-9%] respectively. ICANS and severe ICANS had an estimated incidence of 16% [95% CI, 9-25%] and 3% [95% CI, 1-5%] respectively. Early phase trials of CD22 and CD19/CD22 CAR T-cells show high remission rates in ALL and NHL. Severe CRS or ICANS were (1)rare and dual-targeting did not increase toxicity. Variability in CAR construct, dose, and patient factors amongst studies limits comparisons, with long-term outcomes yet to be reported.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42020193027

Assessing the Completeness of Reporting in Preclinical Oncolytic Virus Therapy Studies

Irreproducibility of preclinical findings could be a significant barrier to the “bench-to-bedside” development of oncolytic viruses (OVs). A contributing factor is the incomplete and non-transparent reporting of study methodology and design. Using the NIH Principles and Guidelines for Reporting Preclinical Research, a core set of seven recommendations, we evaluated the completeness of reporting of preclinical OV studies. We also developed an evidence map identifying the current trends in OV research. A systematic search of MEDLINE and Embase identified all relevant articles published over an 18 month period. We screened 1,554 articles, and 236 met our a priori-defined inclusion criteria. Adenovirus (43%) was the most commonly used viral platform. Frequently investigated cancers included colorectal (14%), skin (12%), and breast (11%). Xenograft implantation (61%) in mice (96%) was the most common animal model. The use of preclinical reporting guidelines was listed in 0.4% of articles. Biological and technical replicates were completely reported in 1% of studies, statistics in 49%, randomization in 1%, blinding in 2%, sample size estimation in 0%, and inclusion/exclusion criteria in 0%. Overall, completeness of reporting in the preclinical OV therapy literature is poor. This may hinder efforts to interpret, replicate, and ultimately translate promising preclinical OV findings

Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease

BACKGROUND: Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. METHODS: We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56. RESULTS: A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]). CONCLUSIONS: Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy

The impact of prolonged storage of red blood cells on cancer survival.

The duration of storage of transfused red blood cells (RBC) has been associated with poor clinical outcomes in some studies. We sought to establish whether prolonged storage of transfused RBC in cancer patients influences overall survival (OS) or cancer recurrence.Patients diagnosed with cancer at The Ottawa Regional Cancer Centre between January 01, 2000 and December 31, 2005 were included (n = 27,591) where 1,929 (7.0%) received RBC transfusions within one year from diagnosis. Transfused RBC units were categorized as "new" if stored for less than 14 days, "intermediate" if stored between 14 and 28 days and "old" if stored for more than 28 days. Baseline characteristics between the comparative groups were compared by ANOVA test. Categorical variables and continuous variables were compared using Chi-squared and Wilcoxan rank-sum tests respectively. Overall survival was not associated with duration of storage of transfused RBC with a median survival of 1.2, 1.7, 1.1 years for only new, intermediate and old RBC units respectively (p = 0.36). Cancer recurrence was significantly higher in patients who received a RBC transfusion than those who did not (56.3% vs 33.0% respectively; p<0.0001) but was not affected by the duration of storage of transfused RBC (p = 0.06). In multivariate analysis, lung cancer, advanced stage, chemotherapy, radiation, cancer-related surgery and cancer recurrence were associated with inferior OS (p<0.05), while age, advanced stage, lung cancer, and more than 6 units of blood transfused were associated with cancer recurrence (p<0.05). The duration of storage of RBC before transfusion was not associated with OS or cancer recurrence in multivariate analysis.In patients diagnosed with cancer, the duration of storage of transfused RBC had no impact on OS or cancer recurrence. This suggests that our current RBC storage policy of providing RBC of variable duration of storage for patients with malignancy is safe

Modelling Improvements in Cell Yield of Banked Umbilical Cord Blood and the Impact on Availability of Donor Units for Transplantation into Adults

Umbilical cord blood (UCB) is used increasingly in allogeneic transplantation. The size of units remains limiting, especially for adult recipients. Whether modest improvements in the yield of cells surviving storage and thawing allow more patients to proceed to transplant was examined. The impact of improved cell yield on the number of available UCB units was simulated using 21 consecutive anonymous searches. The number of suitable UCB units was calculated based on hypothetical recipient weight of 50 kg, 70 kg, and 90 kg and was repeated for a 10%, 20%, and 30% increase in the fraction of cells surviving storage. Increasing the percentage of cells that survive storage by 30% lowered the threshold of cells needed to achieve similar engraftment rates and increased numbers of UCB units available for patients weighing 50 (P=0.011), 70 (P=0.014), and 90 kg (P=0.003), controlling for differences in HLA compatibility. Moreover, if recipients were 90 kg, 12 out of 21 patients had access to at least one UCB unit that met standard criteria, which increased to 19 out of 21 patients (P=0.035) when the fraction of cells surviving storage and thawing increased by 30%. Modest increases in the yield of cells in banked UCB units can significantly increase donor options for adult patients undergoing HSCT

Efficacy, Safety, and Practicality of Tacrolimus Monitoring after Bone Marrow Transplant: Assessment of a Change in Practice

Pharmacy residents have the opportunity to complete a research project during their residency training, which provides them with skills on how to conduct and manage a research project. Projects often represent an area of interest and need that has been recognized by the host institution’s pharmacy department. Projects are presented as a poster at an annual CSHP Ontario Branch Residency Research Night, and many eventually go on to be published in a peer-reviewed journal.Background: Currently, there is no standardized approach to the frequency of monitoring tacrolimus levels in patients who have undergone hematopoietic stem cell transplant (HSCT). Previously, the practice at the study hospital was to monitor tacrolimus levels daily throughout a patient’s admission. A recent institutional study suggested that measurement of tacrolimus level is more frequent than needed to achieve consistent time in the therapeutic range (TTR), particularly after the first 7 days. As a result, tacrolimus monitoring was changed to daily measurement for the initial week of therapy, followed by measurements on Monday, Wednesday, and Friday in subsequent weeks. Objective:To confirm the safety and efficacy of the recent practice change. Methods: This retrospective chart review of HSCT patients admitted to The Ottawa Hospital involved 68 patients in the pre–practice change group and 43 patients in the post–practice change group. Data on tacrolimus measurement were collected for up to 21 days after initiation of this medication. The proportion of TTR was compared between the 2 groups. Differences in the incidence and severity of renal dysfunction and the incidence of acute graft versus host disease (GVHD) were determined and described. Results: In the pre–practice change cohort, the median proportion of TTR for tacrolimus was 40.5% for days 1–7, 65.1% for days 8–14, and 78.9% for days 15–21, similar to the values for the post–practice change group (46.6% [p = 0.09], 62.9% [p = 0.93], and 70.0% [p = 0.22], respectively, for the same periods). The incidence of acute GVHD within 100 days after HSCT was 24% and 33% for the pre– and post–practice change cohorts, respectively. The incidence and severity of renal dysfunction were similar between the 2 groups. Conclusion:The proportion of TTR for tacrolimus was not significantly affected by the recent practice change. Similarly, the incidence and severity of renal dysfunction and the incidence of acute GVHD did not appear to differ between the pre– and post–practice change groups

Efficacy, Safety, and Practicality of Tacrolimus Monitoring after Bone Marrow Transplant: Assessment of a Change in Practice

ABSTRACTBackground: Currently, there is no standardized approach to the frequency of monitoring tacrolimus levels in patients who have undergone hematopoietic stem cell transplant (HSCT). Previously, the practice at the study hospital was to monitor tacrolimus levels daily throughout a patient’s admission. A recent institutional study suggested that measurement of tacrolimus level is more frequent than needed to achieve consistent time in the therapeutic range (TTR), particularly after the first 7 days. As a result, tacrolimus monitoring was changed to daily measurement for the initial week of therapy, followed by measurements on Monday, Wednesday, and Friday in subsequent weeks.Objective:To confirm the safety and efficacy of the recent practice change.Methods: This retrospective chart review of HSCT patients admitted to The Ottawa Hospital involved 68 patients in the pre–practice change group and 43 patients in the post–practice change group. Data on tacrolimus measurement were collected for up to 21 days after initiation of this medication. The proportion of TTR was compared between the2 groups. Differences in the incidence and severity of renal dysfunction and the incidence of acute graft versus host disease (GVHD) were determined and described.Results: In the pre–practice change cohort, the median proportion of TTR for tacrolimus was 40.5% for days 1–7, 65.1% for days 8–14, and 78.9% for days 15–21, similar to the values for the post–practice change group (46.6% [p = 0.09], 62.9% [p = 0.93], and 70.0% [p = 0.22], respectively, for the same periods). The incidence of acute GVHD within 100 days after HSCT was 24% and 33% for the pre– and post–practice change cohorts, respectively. The incidence and severity of renal dysfunction were similar between the 2 groups.Conclusion:The proportion of TTR for tacrolimus was not significantly affected by the recent practice change. Similarly, the incidence and severity of renal dysfunction and the incidence of acute GVHD did not appear to differ between the pre– and post–practice change groups.RÉSUMÉContexte : Il n’existe actuellement aucune approche standardisée portant sur la fréquence des contrôles des valeurs du tacrolimus pour les patients ayant subi une greffe de cellules souches hématopoïétiques (GCSH). Dans le passé, la pratique à l’hôpital où s’est déroulée l’étude consistait à les contrôler quotidiennement durant tout le séjour du patient. Une récente étude institutionnelle a laissé entendre que cette mesure était plus fréquente que nécessaire pour obtenir une marge thérapeutique régulière (TTR), particulièrement après les sept premiers jours. Par conséquent, une modification du contrôle des valeurs du tacrolimus préconise désormais des mesures quotidiennes pendant la première semaine de la thérapie, suivies de mesures le lundi, le mercredi et le vendredi au coursdes semaines suivantes.Objectif : Confirmer la sécurité et l’efficacité du récent changement apporté à la pratique.Méthode : Cet examen rétrospectif des dossiers des patients GCSH admis à l’Hôpital d’Ottawa concernait 68 patients du groupe « avant le changement de pratique » et 43 du groupe « après le changement de pratique ». Les données relatives aux mesures des valeurs du tacrolimus ont été recueillies pendant les 21 premiers jours après le début de l’administration de ce médicament. La comparaison entre les deux groupes portait sur la proportion de TTR. Les différences d’incidence et de gravité du dysfonctionnement rénal et l’apparition de réaction aiguë du griffon contre l’hôte (GVHD) ont été définies et décrites.Résultats : Dans la cohorte « avant le changement de pratique », la proportion moyenne de TTR du tacrolimus était de 40,5 % du 1er au 7e jour; de 65,1 % du 8e au 14e jour et de 78,9 % du 15e au 21e jour. Ces valeurs sont similaires à celles du groupe « après le changement de pratique » (respectivement 46,6 % [p = 0,09], 62,9 % [p = 0,93] et 70,0 % [p = 0,22] pendant les mêmes périodes). L’incidence de réaction aiguë du greffon contre l'hôte dans les 100 jours après la GCSH se montait respectivement à 24 % et à 33 % dans les cohortes « avant et après le changement de pratique ». L’incidence et la gravité du dysfonctionnement rénal étaient similaires dans les deux groupes.Conclusion : La proportion de TTR relative au tacrolimus n’a pas été modifiée de manière significative par le changement récent de pratique. De même, l’incidence et la gravité du dysfonctionnement rénal et l’incidence de réaction aiguë du greffon contre l’hôte ne semblaient pas différer entre les groupes avant et après le changement de pratique

Overall survival of cancer patients.

<p>Overall survival of cancer patients.</p

Baseline Patient Characteristics.

<p>Baseline Patient Characteristics.</p