Recognizing subclinical hyposplenism Seftel, Matthew D., MD MPH
CMAJ. Canadian Medical Association journal,
01/2019, Letnik:
191, Številka:
1
Journal Article
Background
Human leukocyte antigen (HLA)‐matched unrelated donors are not available for some patients considered for allogeneic hematopoietic cell transplantation, particularly among certain ethnic ...groups. Simulated recruitment modeling can inform efforts to find new matches for more patients.
Methods
Simulated recruits were generated by assigning a pair of donor HLA haplotypes from historical data files and matched against HLA data of patient searches in the Canadian Blood Services Stem Cell Registry. Recruitment cohorts reflected the proportion of five specific ethnic groups in the 2016 Canadian census data.
Results
Novel 8/8 HLA matches between simulated recruits and patients increased linearly with larger recruitment cohorts. The proportion of novel 8/8 HLA matches from Caucasian, Hispanic, and Native American/First Nations recruits was equal to or greater than their relative proportion in the recruited cohort (match to: recruit ratio (MRR) ≥ 1). In contrast, African American and Asian & Pacific Islander recruits represented a smaller proportion of novel matches relative to their percentage of the recruited cohort (MRR <1). The proportion of novel 7/8 HLA‐matches from each ethnic group was approximately the same as their proportion in the recruited cohort (MRR ~ 1) and high rates of 7/8 HLA‐matching already exist within the Canadian Blood Services registry for all ethnic groups.
Conclusion
Continued large recruitment cohorts are needed to add new 8/8 HLA matches to registry inventories. Likelihoods of novel HLA matches varied across ethnic groups, reflecting varied HLA haplotype frequencies across groups. Simulated cohort modeling can inform recruitment strategies that will generate new donor options for patients.
Cellular immunotherapy is a novel therapy where the body's own immune cells are harnessed for their anticancer effect. One of the most exciting of these approaches is chimeric antigen receptor T-cell ...therapy (CAR-T). This therapy is now standard of care for relapsed or refractory B-cell acute lymphoblastic leukemia, the most common malignancy of childhood, and in high-grade B-cell lymphomas, the most common lymphoma in Canada. CAR-T is undergoing clinical trials in other cancers. Here, Brown et al discuss the CAT-T.
Promising efficacy results of chimeric antigen receptor (CAR) T-cell therapy have been tempered by safety considerations. Our objective was to comprehensively summarize the efficacy and safety of ...CAR-T cell therapy in patients with relapsed or refractory hematologic or solid malignancies. MEDLINE, Embase, and the Cochrane Register of Controlled Trials (inception – November 21, 2017). Interventional studies investigating CAR-T cell therapy in patients with malignancies were included. Our primary outcome of interest was complete response (defined as the absence of detectable cancer). Two independent reviewers extracted relevant data, assessed risk of bias, and graded the quality of evidence using established methods. A total of 42 hematological malignancy studies and 18 solid tumor studies met were included (913 participants). Of 486 evaluable hematologic patients, 54.4% 95% CI, 42.5%-65.9% experienced complete response in 27 CD19 CAR-T cell therapy studies. Of 65 evaluable hematologic patients, 24.4% 95% CI, 9.4%-50.3% experienced complete response in seven non-CD19 CAR-T cell therapy studies. Cytokine release syndrome was experienced by 55.3% 95% CI, 40.3%-69.4% of patients and neurotoxicity 37.2% 95% CI, 28.6%-46.8% of patients with hematologic malignancies. Of 86 evaluable solid tumor patients, 4.1% 95% CI, 1.6%-10.6% experienced complete response in eight CAR-T cell therapy studies. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. There was a strong signal for efficacy of CAR-T cell therapy in patients with CD19+ hematologic malignancies and no overall signal in solid tumor trials published to date. These results will help inform patients, physicians, and other stakeholders of the benefits and risks associated with CAR-T cell therapy.
•CAR-T cell therapy is most effective in DLBCL and CD19-positive ALL patients.•There is limited evidence of efficacy of CAR-T cell therapy in solid malignancies.•This study provides a comprehensive summary of the efficacy CAR-T cell therapy.
Background
The utility of unrelated donor registries that support allogeneic hematopoietic cell transplantation could be optimized through greater understanding of redundancy and rareness of HLA ...phenotypes.
Methods
HLA phenotype rareness was determined using known HLA haplotype frequencies. Donor redundancy was determined through pairwise comparison of donor HLA profiles within an inventory.
Results
Among 61,730 registrants in the Canadian Blood Services (CBS) Stem Cell Registry (SCR) with high resolution HLA typing at 5 loci, 6.6% of HLA phenotypes were redundant with variation across ethnic groups (8.3% of Caucasian phenotypes; 8% of Native American/First Nations, 4.4% of Asia‐Pacific Islanders (API), 2.1% of Hispanic, 0.7% of African‐American (AFA), and 4.5% of other ethnicities). A total of 18.5% of registrants had redundant HLA phenotypes with variation across ethnic groups. All 3716 cord blood units in the CBS's cord blood bank (CBB) had high resolution HLA typing at 5 loci and 202 units were redundant (5.4%) comprising 78 HLA phenotypes, with varying rareness. Repeated HLA phenotypes were from Caucasian donors (77%), multiple ethnicity (13%), API (9%), and AFA (1%). Registrants and CBUs with AFA ethnicity had the rarest phenotypes while Caucasian ethnicity was associated with the most common HLA phenotypes.
Conclusions
Redundancy was greater in the SCR compared to the CBB and was most common with CAU ethnicity. Recruiting non‐Caucasian registrants and continued cord blood banking should reduce redundancy. A sub‐inventory of redundant donors and cord blood units could support new uses for donor‐supported cellular therapies that do not require HLA matching.
For patients with Mantle Cell Lymphoma (MCL), there is no recognized standard of care for relapsed/refractory (R/R) disease after treatment with a Bruton's tyrosine kinase inhibitor (BTKi). ...Brexucabtagene autoleucel (brexu-cel) represents a promising new treatment modality in MCL. We explored whether brexu-cel was cost-effective for the treatment of R/R MCL. We developed a partitioned survival mixture cure approach to model the costs and outcomes over a lifetime horizon. The clinical data were derived from the ZUMA-2 clinical trial. The costs were estimated from the publicly available Canadian databases, published oncology literature, and pan-Canadian Oncology Drug Review economic guidance reports. The health state utilities were sourced from the ibrutinib submission to the National Institute for Health and Care Excellence for R/R MCL and supplemented with values from the published oncology literature. In the base case over a lifetime horizon, brexu-cel generated an incremental 9.56 life-years and an additional 7.03 quality-adjusted life-years compared to BSC, while associated with CAD 621,933 in additional costs. The resultant incremental cost-utility ratio was CAD 88,503 per QALY gained compared with BSC. Based on this analysis, we found brexu-cel to be a cost-effective use of healthcare resources relative to BSC for treatment of adult patients with R/R MCL previously treated with a BTKi in Canada, though additional research is needed to confirm these results using longer follow-up data.
In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥70 years with hematologic malignancies across the United States. Adults ≥70 years ...with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% 95% confidence interval (CI), 21% to 33% in 2000-2007 to 39% 95% CI, 35% to 42% in 2008-2013, P < .001; PFS: 22% 16% to 28% in 2000-2007 to 32% 95% CI, 29% to 36% in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time (P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥3 (hazard ratio HR, 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant.
•Over the last decade, allogeneic HCT has been increasingly administered in the United States to adults aged 70 and older with hematologic malignancies.•Allogeneic transplant outcomes were reasonable; high comorbidity and ablative conditioning regimens were associated with inferior outcomes.
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