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Multiple myeloma (MM) is an incurable plasma cell malignancy. In the context of the current standard of care therapies in Canada, outcomes among patients with relapsed/refractory multiple myeloma (RRMM), particularly those with triple-class (or more) refractory disease remain poor. Immunotherapies have significantly changed the treatment landscape of MM. Since 2021, two BCMA-targeting CAR T-cell therapy products have been approved for RRMM—namely Idecabtagene vicleucel (Ide-cel) (ABECMA®) and Ciltacabtagene autoleucel (Cilta-cel) (CARVYKTI®), both of which are available in the US and Europe. Although they have shown unprecedented efficacy in RRMM, their clinical and logistical limitations must be acknowledged. MM CAR T-cell therapy is likely to be approved in Canada soon. Therefore, it is timely that we review the latest evidence for commercially available CAR T-cell therapy in multiple myeloma, with a focus on its relevance and impact in the Canadian setting. There will be challenges to access and strategies must be in place to ensure equitable care for all Canadians with MM. Alongside haematologists working in the immune effector cell therapy programs, providers in the community will also play a role in the ongoing monitoring and management of long-term side effects including opportunistic infections and late neurotoxicity. [ABSTRACT FROM AUTHOR]

Interim imaging with computed tomography (iCT) to assess response is common during frontline chemoimmunotherapy for follicular lymphoma (FL), but there is little evidence of its utility. We retrospectively reviewed outcomes of iCT in 190 patients with biopsy-proven FL who received first-line chemoimmunotherapy from 2003–2018. Most iCTs showed partial response (PR, 83%), with a minority showing complete response (CR, 8%) or stable disease (5%). Seven patients (4%) had radiographic disease progression (PD) on iCT; on repeat biopsy, four had another malignancy identified and three had transformation to DLBCL. Only one had asymptomatic PD. The 3-year PFS of all patients was 74% (median follow up 75 months). Patients with PR on iCT had similar 3-year PFS and OS as those with CR. In conclusion, iCT has limited utility in identifying patients with asymptomatic early progression during first-line treatment. Patients with PD mid-treatment warrant biopsy to identify histologic transformation or other malignancies. [ABSTRACT FROM AUTHOR]

Selinexor is a first-in-class, oral therapy that selectively inhibits nuclear export. The drug is active with an overall response rate (ORR) of approximately 30% in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL). Long-term patient follow-up has not been reported. Thirty-one NHL patients were treated between July 2012 and July 2018; 22 were evaluated for response. ORR was 32% (7/22). Two patients achieved complete remission (CR) and were alive and lymphoma-free at the end of follow-up. Fifteen patients (68%) progressed during treatment, most of them died within 3–10 months. The most common grade 3/4 adverse events were gastrointestinal and hematological. Median follow up was 50 months. Overall survival for the entire cohort was 16%. Selinexor monotherapy for r/r NHL is an active therapy with the potential for long-term disease control. It may serve as a 'bridge' to subsequent therapy. Additional studies are needed to identify predictive biomarkers and to evaluate combination approaches. [ABSTRACT FROM AUTHOR]

Avascular necrosis (AVN) is a debilitating complication of allogeneic hematopoietic cell transplantation (HCT). A retrospective review of 845 patients who underwent HCT was conducted. Cumulative incidence of AVN was 6.3% at 4 years. The following risk factors were significantly associated with AVN risk on univariate analysis: age < 45 (p=0.004), moderate to severe chronic GvHD (p<0.001), reduced intensity conditioning (p=0.02), and a diagnosis of acute leukemia (p=0.045). Multivariate analysis confirmed two risk factors: younger age (<45 years), 9.0% vs 4.4% (p=0.011, hazard ratio (HR) 2.134), and moderate-severe chronic GvHD, 15.4% vs 2.1% (p<0.001, HR 4.950). A risk score model was generated assigning a score to each risk factor. A score of 1 was assigned to moderate-severe GvHD or those with age <45. Total score was calculated, thus dividing patient into three groups: low (score 0, n=349, 41.3%), intermediate (score 1, n=379, 44.9%), and high risk (score 2; n=116, 13.7%). This risk score could stratify the patients according to AVN risk (p<0.001). The risk of AVN was 1.5% in the low risk, 6.2% in the intermediate risk, and 20.8% in the high risk groups. Moderate-severe chronic GvHD and younger age (<45 years) are key risk factors for AVN following allogeneic HCT. [ABSTRACT FROM AUTHOR]

Choosing Wisely encourages dialogue about reducing unnecessary procedures, tests, or treatments in healthcare. The American Society for Blood and Marrow Transplantation (ASBMT) and Canadian Blood and Marrow Transplant Group (CBMTG) established a Choosing Wisely BMT Task Force whose objective was to create a list of top 5 practices in blood and marrow transplantation to be questioned. The Task Force consisted of representatives from ASBMT's Quality Outcomes, Education, and Practice Guidelines committees; ASBMT's Pharmacy Special Interest Group; CBMTG Program Directors; and Center for International Blood and Marrow Transplant Research (CIBMTR). Suggestions for current transplantation practices to question were elicited from the CBMTG Program Directors; members of ASBMT's Quality Outcomes, Practice Guidelines, and Education committees; and chairs of the CIBMTR scientific working committees. We received 119 unique suggestions that were ranked based on their potential impact on harm reduction, cost reduction, necessity of the test or practice, and the strength of available evidence. Through a modified Delphi process, suggestions were narrowed down to 6, which were then subjected to systematic reviews. The final 5 recommendations focus on graft source for patients with aplastic anemia, corticosteroid dose for initial treatment of graft-versus-host-disease, optimal number of umbilical cord blood units for transplantation, graft source in matched unrelated donor transplantation, and use of prophylactic intravenous immunoglobulin in transplant recipients. These Choosing Wisely BMT recommendations are relevant to the current clinical practice of blood and marrow transplantation and focus on tests, treatments, or procedures that may be harmful, wasteful, or for which there is no apparent clinical benefit. [ABSTRACT FROM AUTHOR]

In the sowbug, Porcellio scaber Latreille, 1804 (Isopoda, Oniscidea), the genetics of carapace and eye colour were investigated. Carapace shield colours studied include white, dark grey/brown, light orange, and a variegated phenotype consisting of an orange background with darker brownish pigmented regions. Eye colours found include colourless, red, and black. Two loci, one with two alleles the other with three alleles, can explain the patterns of inheritance we found in the carapace shield and eyes. Alleles at a single locus with incomplete dominance appear to control carapace edge colour. Interactions between some alleles at different loci were discovered and correlations between eye and carapace colours are described. Variegation was limited to females and not expressed in males of similar genotype. [ABSTRACT FROM AUTHOR]

High dose chemotherapy followed by autologous stem cell transplant (ASCT) is a cornerstone of frontline therapy for multiple myeloma (MM) [[1]]. Four of the ten transplants were performed as second-line therapy, including two for relapsed disease 42 and 48 months after frontline ASCT (Patients #4 and #5 on Table 1) and one relapsing 47 months after frontline syngeneic transplant (Patient #3). GVHD was questioned in 2 patients (Patients #3 and #5), both receiving allogeneic-like conditioning and cyclosporine prophylaxis. Two of nine patients developed a secondary cancer during follow up (Patient #5 myelodysplastic syndrome 7 years post-syngeneic transplant; Patient #4 transitional cell carcinoma 11 years post-syngeneic transplant). [Extracted from the article]

Background: Hematopoietic cell transplantation (HCT) is an established therapy for hematologic malignancies and serious non-malignant blood disorders. Despite its curative potential, HCT is associated with substantial toxicity and health resource utilization. Effective delivery of HCT requires complex hospital-based care, which limits the number of HCT centres in Canada. In Canada, the quantity, indications, temporal trends, and outcomes of patients receiving HCT are not known. Methods: A retrospective cohort study of first transplants reported to the Cell Therapy Transplant Canada (CTTC) registry between 2000 and 2019. We determined overall survival (OS) and non-relapse mortality (NRM), categorizing the cohort into early (2000–2009) and later (2010–2019) eras to investigate temporal changes. Results: Of 18,046 transplants, 7571 were allogeneic and 10,475 were autologous. Comparing the two eras, allogeneic transplants increased in number by 22.3%, with greater use of matched unrelated donors in the later era. Autologous transplants increased by 10.9%. Temporal improvements in NRM were observed in children and adults. OS improved in pediatric patients and in adults receiving autologous HCT. In adults receiving allogeneic HCT, OS was stable despite the substantially older age of patients in the later era. Interpretation: HCT is an increasingly frequent procedure in Canada which has expanded to serve older adults. Noted improvements in NRM and OS reflect progress in patient and donor selection, preparation for transplant, and post-transplant supportive care. In allogeneic HCT, unrelated donors have become the most frequent donor source, highlighting the importance of the continued growth of volunteer donor registries. These results serve as a baseline measure for quality improvement and health services planning in Canada. [ABSTRACT FROM AUTHOR]

In this article, the author presents information on the maternal age restriction of 45 years related to the O-blood transfusion at women with trauma following the obstetric database review from a single institution. It mentions the national fill rate of 95.9 percent of the blood by the Canadian Blood Services (CBS) in comparison to the 99.6 percent by the other blood groups, and highlights the preferences of transfusion of O- blood for prevention of alloimmunization on the pregnant women.

Objectives: The prognostic value of kinetics of response to multiple myeloma (MM) therapy is controversial. We aimed to expand the knowledge on this topic by reviewing the kinetics of response to both first‐ and second‐line MM therapy, utilizing a homogeneously treated cohort and analyzing separately both M‐spike and light chain (LC) responses for each patient. Methods: We reviewed all patients who received first‐line cyclophosphamide, bortezomib and dexamethasone induction followed by autologous transplant with melphalan and lenalidomide maintenance in our center between 2007 and 2019. Results: Analyzing 360 patients, we observed no correlation between response kinetics to first‐ versus second‐line therapy at the individual patient level. Time to best response to first‐line therapy was not a predictor of outcome; however, longer time to best response was highly predictive of a favorable outcome in the second‐line setting, independent of other factors. Patients with IgA‐MM cleared their M‐spike faster than IgG‐MM, probably reflecting different half‐lives of these isotypes rather than disease biology, as the clearance of LC in both subtypes was similar. Conclusions: Analyzing both M‐spike and LC responses in a homogenously treated cohort, we identified important insights regarding the prognostic value of kinetic patterns. Prospective analysis may shed more light on unsolved questions. [ABSTRACT FROM AUTHOR]

Background: The prevalence of multiple myeloma is increasing and there is a need to evaluate escalating therapy costs (Canadian Cancer Statistics A, 2020). The MYX.1 phase II trial showed that high‐dose weekly carfilzomib, cyclophosphamide, and dexamethasone (wKCD) is efficacious in relapsed and refractory disease. We conducted a descriptive cost analysis, from the perspective of the Canadian public healthcare system, using trial data. Methods: The primary outcome was the mean total cost per patient. Resource utilization data were collected from all 75 trial patients over a trial time horizon. Costs are presented in Canadian dollars (2020). Results: The cost of treatment was calculated from the time of patient (pt) enrollment until the second data lock. The mean total cost was $203 336.08/pt (range $17 891.27‐$505 583.55) Canadian dollars (CAD, where 1 CAD = 0.67 Euro (EUR)) and $14 081.45/pt per cycle. The median number of cycles was 15. The predominant cost driver was the cost of chemotherapy accounting for an average of $179 332.78/pt or $12 419.17/pt per cycle. Carfilzomib acquisition accounted for the majority of chemotherapy costs – $162 471.65/pt or $11 251.50/pt per cycle. Fifty‐six percent (56%) of patients had at least one hospitalization during the trial period with an average cost of $12 657.86 per hospitalization. Three patients developed thrombotic microangiopathy (TMA) with an average cost of $18 863.32/pt including the cost of hospitalizations and therapeutic plasma exchange. Conclusions: High‐dose wKCD is an active triplet regimen for relapsed and refractory multiple myeloma (RRMM) associated with reduced total cost compared with twice‐weekly carfilzomib‐based regimens. [ABSTRACT FROM AUTHOR]

Background: Transfusion of 2 units of red blood cells (RBCs) for Hb ≤80 g/L is the prevailing liberal practice for patients undergoing intensive treatment for acute leukemia or hematopoietic transplant across North America. There is little evidence regarding optimal transfusion targets in these highly transfusion-dependent patient populations.Study Design and Methods: This was a retrospective pre-post cohort study of consecutive patients admitted to Kingston Health Sciences Center between April through December 2016 (pre) and April through December 2017 (post) for acute leukemia induction chemotherapy or high dose chemotherapy (HDCT) for autologous stem cell transplantation (ASCT). The pre-cohort was transfused using a liberal threshold (2 units of RBCs for Hb ≤80 g/L) and the post-cohort using a more restrictive threshold (1 unit RBCs for Hb ≤70 g/L), implemented with a computerized physician order entry form. Primary outcome was number of RBC units transfused per inpatient day. Secondary outcomes included inpatient mortality and select morbidity measures.Results: 124 patients underwent 134 treatment courses: 62 courses of induction chemotherapy (pre = 26, post = 36) and 72 courses of HDCT for ASCT (pre = 39, post = 33). There was a significant decrease in median RBC utilization per admission in both patient populations: 10.5 versus 6.7 in the leukemia group (p = 0.01) and 2.0 versus 1.0 in the ASCT group (p = 0.04). This reduction was seen without a difference in inpatient mortality, length of stay, falls, serious bleeds, requirement for ICU, or time to engraftment post ASCT.Conclusions: A restrictive transfusion strategy in patients receiving intensive chemotherapy for acute leukemia or ASCT decreased inpatient RBC usage without increasing adverse inpatient events. [ABSTRACT FROM AUTHOR]

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and nonmalignant diseases. Despite increasing survival rates, long-term morbidity after HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction after HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction after HCT. In this review we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Finally, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae after HCT. [ABSTRACT FROM AUTHOR]

Truncating mutations in Gli3, an intracellular effector in the SHH-SMO-GLI signaling pathway, cause renal aplasia/dysplasia in humans and mice. Yet, the pathogenic mechanisms are undefined. Here, we report the effect of decreased SHH-SMO signaling on renal morphogenesis, the expression of SHH target genes and GLI binding to Shh target genes. Shh deficiency or cyclopamine-mediated SMO inhibition disrupted renal organogenesis, decreased expression of GLI1 and GLI2 proteins, but increased expression of GLI3 repressor relative to GLI3 activator. Shh deficiency decreased expression of kidney patterning genes (Pax2 and Sall1) and cell cycle regulators (cyclin D1 and MYCN). Elimination of Gli3 in Shh-/- mice rescued kidney malformation and restored expression of Pax2, Sall1, cyclin D1, MYCN, Gli1 and Gli2. To define mechanisms by which SHH-SMO signaling controls gene expression, we determined the binding of GLI proteins to 5' flanking regions containing GLI consensus binding sequences in Shh target genes using chromatin immunoprecipitation. In normal embryonic kidney tissue, GLI1 and/or GLI2 were bound to each target gene. By contrast, treatment of embryonic kidney explants with cyclopamine decreased GLI1 and/or GLI2 binding, and induced binding of GLI3. However, cyclopamine failed to decrease Gli1 and Gli2 expression and branching morphogenesis in Gli3-deficient embryonic kidney tissue. Together, these results demonstrate that SHH-SMO signaling controls renal morphogenesis via transcriptional control of Gli, renal patterning and cell cycle regulator genes in a manner that is opposed by GLI3. [ABSTRACT FROM AUTHOR]

Objectives. To assess the effectiveness of IA corticosteroid (IAS) injections in PsA and to determine the association between macrophage migration inhibition factor (MIF) gene polymorphism and response to IAS injections. [ABSTRACT FROM PUBLISHER]

Busulfan (BU) has been used for approximatively four decades as a major component of chemotherapy-based conditioning before allo-HCT. At our center, IV-BU dose in MAC is 12.8 mg/kg (BU12.8) and in those not eligible for MAC, it is 9.6 mg/kg (BU9.6). The aim of this study was to compare the impact of BU9.6 to BU12.8 on outcomes in patients with acute leukemia (AL) or myelodysplastic syndromes (MDS) who received allo-HCT after BU-based conditioning from matched related or unrelated donors. This study included 181 patients: 134 AL [122 AML, 10 ALL and 2 biph. AL] and 47 (26%) MDS patients who received allo-HCT between Jan 2012 and Dec 2018 at the Ottawa Hospital. Median age at allo-HCT was 58 years (range: 18-73), 104 (57%) were males. At time of conditioning, among AL patients, 99 (74%) were in CR1, 19 (14%) in CR2 and 16 (12%) not in CR, and among MDS patients, 22 (47%) were not treated. All patients received PBSC from HLA matched related [N=68 (38%)] or unrelated [N=113 (62%)] donors. Patients were classified according to the refined Disease Risk Index (DRI): 94 (52%) intermediate, 81 (45%) high and 6 (3%) very high. GVHD prophylaxis consisted of tacrolimus and short course methotrexate for all patients. Rabbit antithymocyte globulin (rATG, Thymoglobulin) was used in all transplants from unrelated donors (n=113) and in BU12.8 transplants from related donors (n=28). Bu dose was 9.6 mg/kg for 74 (41%) patients and 12.8 mg/kg for 107 (59%). Ninety-eight % of the patients engrafted; GVHD requiring systemic immunosuppression was observed in 26/74 (35%) patients (4 acute, 22 chronic) after BU9.6, and in 45/107 (42%) patients (13 acute, 32 chronic) after BU12.8. With a median follow-up of 22 months (range: 5-74) for survivors, no significant difference in survival, relapse (REL) or NRM was observed between BU9.6 and BU12.8. Two-year OS, REL and NRM for the whole population were 65% (95%CI: 57-73), 29% (95%CI: 22-37) and 10.8% (95%CI: 6-16) respectively. When stratified according to DRI: intermediate, high and very high scores had 2-year OS of 76% (95%CI: 65-84), 53% (95%CI: 38-66) and 0% respectively, p=0.001; and 1-year REL rates of 12% (95%CI: 6-20), 31% (95%CI: 21-42) and 67% (95%CI: 12-92) respectively, p<0.001. In multivariable analysis adjusted for conditioning, DRI, the use of rATG and rATG dose, the only factors that significantly impacted OS were DRI [high-very high vs intermediate: HR=1.98 (95%CI: 1.15-3.4), p=0.013] and the use of ATG [No ATG vs ATG 4.5mg/kg: HR=2.2 (95% CI: 1.06-4.6), p=0.033], while only DRI [high-very high vs intermediate: HR=3.56 (95%CI: 1.86-6.8), p=0.0001] impacted on REL. Our results validate the efficacy of a reduced 9.6 mg/kg BU-based conditioning regimen for patients not suitable for traditional 12.8mg/kg dose. Relapse was not increased, in addition, we confirm the value of DRI in prognosticating both relapse and survival. [ABSTRACT FROM AUTHOR]