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T-replete HLA-matched Grafts vs T-depleted HLA-mismatched Grafts in Inborn Errors of Immunity
Haematopoietic cell transplantation (HCT) has become standard of care for an increasing number of inborn errors of immunity (IEI). This is the first report to compare the transplant outcomes according to T-replete HLA-matched grafts using alemtuzumab (n=117) and T-depleted HLA-mismatched grafts using TCR αβ/CD19 depletion (n=47) in children with IEI who underwent first HCT between 2014 and 2019. All patients received treosulfan-based conditioning except patients with DNA repair disorders. For T-replete grafts, the stem cell source was marrow in 25 (21%) patients, PBSC in 85 (73%) and CB in 7 (6%). TCR αβ/CD19 depletion was performed on PBSC from 45 haploidentical parental donors and 2 mismatched unrelated donors. The 3-year OS and EFS for the entire cohort were 85% (77-90%) and 79% (69-86%) respectively. Analysis by age at transplant revealed a comparable 3-year OS between T-replete grafts (88%, 76-94%) and T-depleted grafts (87%, 64-96%) in younger patients (<5 years of age at HCT). For older patients more than 5 years of age, the OS was significantly lower in T-depleted grafts (55%, 23-78%), compared to T-replete grafts (87%, 68-95%) (p=0.03). Grade III-IV aGvHD was observed in 8% of T-replete marrow, 7% of T-replete PBSC, 14% of T-replete CB and 2% of T-depleted PBSC (p=0.73). Higher incidence of viraemia (p<0.001) and delayed CD3 reconstitution (p=0.003) were observed after T-depleted graft HCT. These data indicate that mismatched donor transplant after TCR αβ and CD19 depletion represents an excellent alternative for younger children with IEI in need of an allograft.
Abstract Introduction Allogeneic hematopoïetic stem cell transplantation (HSCT) is the only established curative therapy for patients (pts) with sickle cell disease (SCD). It is mostly performed in children 1, due to higher risk of graft-versus-host disease (GVHD) and transplant related mortality in adults. Different approaches have been developped to improve tolerance of transplant in adults: use of reduced intensity conditioning (RIC) regimens 2 and intensive immunosuppression to avoid GVHD. Here, we have studied the impact of such approaches on immune reconstitution in adolescents and adults transplanted for SCD. Patients and methods We report 39 transplants in adolescents and adults, performed in Saint Louis hospital from 2008 to 2020: 25 were matched related transplants (MRT) and 14 haplo-identical related transplant (HRT). In MRT, conditioning was myeloablative (MAC) in 15 pts (busulfan, cyclophosphamide, rabbit anti-thymoglobulin (ATG) 20 mg/kg) and non myeloablative (NMA) in 10 pts (alemtuzumab 1 mg/kg, 3 Gy total body irradiation (TBI)). In MAC transplants, stem cell source was bone marrow and post-transplant immunosuppression was methotrexate and cyclosporine. In NMA transplants, stem cell source was peripheral blood cells with post-transplant immunosuppression by sirolimus. In the 14 HRT, the conditioning was reduced (cyclophosphamide, thiotepa, fludarabine, 2 Gy TBI, ATG 4.5 mg/kg), stem cell source was bone marrow and GVHD prophylaxis was ensured by post-transplant cyclophosphamide (100 mg/kg), sirolimus and mycophenolate mofetil. Results Median age at transplant was 17 years (y) old (range (r) 14-39). With a median follow-up of 3.6 y, the 2-y overall survival and survival without SCD were 97% (IC95%: 0.92-1) and 92% (IC95%: 0.83-1) respectively: no event after MRT, 1 death of GVHD and 2 graft rejections after HRT. The acute GVHD grade II-IV rate was 33%: 21% after HRT, 13% after MAC MRT and 0% after NMA MRT. Chronic GVHD occured in 3 pts (8%): severe in 1 HRT and mild in 2 MAC MRT. At 6 months, the blood chimerism evaluated in the 36 patients alive without rejection, was more often mixed (5 to 95% of donor) after NMA MRT (100%) versus MAC MRT (40%, p = 0.003) and HRT (18%, p < 0.001). Total lymphocytes (TL) counts increased rapidly in HRT and MAC MRT with a normalization from 3 months post-transplant. In contrast, NMA MRT experienced a slower recovery: at 6 months, median count was 1039/mm3 (r 463-1767) compared to 2071/mm3 (r 882-5985, p = 0.002) after MAC MRT and 2382/mm3 (r 676-3978, p = 0.005) after HRT. After NMA MRT, TL counts remained lower than normal values up to 12 months with a median of 1195/mm3 (r 870-3210) (Figure 1A). HRT displayed a rapid normalization of CD4 counts with a 3-month median count of 645/mm3 (r 350-1076) higher than reported after MRT (p < 0.001). Evolution of CD4 counts was similar after NMA and MAC MRT. They were lower than normal values during the first 12 months: median 364/mm3 and 388/mm3 respectively at 12 months (p = 0.25) (Figure 1B). From 3 months post-transplant, CD8 counts reached normal values after MAC MRT (314/mm3, r 108-2175) and were superior to normal after HRT (1335/mm3, r 66-4529), with a significant difference between HRT and MRT (p = 0.003). After NMA MRT, there was a trend for lower 3-month CD8 counts compared to MAC MRT: median of 107/mm3 (r 18-631, p = 0.08). CD8 counts remained under normal values after NMA MRT up to 12 months post-transplant (Figure 1C). From 3 to 6 months, CD4 and CD8 were mostly memory, with only 3.2% (r 0.1%-20.6%) and 6.2% (r 2.1%-11.2%) of CD45RA+ CCR7+ naïve CD8+ and CD4+ respectively. In the 3 groups NK cell counts reached normal values after 3 months. B lymphocytes counts normalized in the first months post-transplant except for patients who received rituximab for EBV reactivation. From 3 to 6 months, B lymphocytes were mostly naive: 98% of CD27- (r 92%-99%). Gammaglobuline levels were normal from 3 months in the 3 groups. Twelve (31%) pts were treated for a CMV and 6 (15%) for an EBV reactivation. No patient had CMV or adenovirus disease, or post-transplant lymphoproliferative disorder. Infections according to transplant types are detailed in figure 1D. Conclusion NMA MRT were associated with a delayed CD4 and CD8 recovery probably due to alemtuzumab. As previously reported 3, HRT displayed a rapid immune reconstitution. Despite use of serotherapy in the three modalities of transplant, the rate of viral infections remained acceptable without severe episode. Figure 1 Figure 1. Disclosures Pondarré: ADDMEDICA: Honoraria. Peffault De Latour: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Boissel: CELGENE: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria.
Abstract Graft failure (GF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HCT). The incidence of GF after HCT using human leukocyte antigen (HLA) matched donors is lower than 5%; however, a higher incidence is observed when considering HLA mismatched donors or alternative donor sources and the use of reduced intensity conditioning (RIC) regimens. In the absence of autologous recovery, a second HCT is necessary to attempt preventing death due to prolonged pancytopenia. Previous studies describing outcomes of second HCT performed after a GF with different types of donor sources report a wide range of overall survival (OS) and transplant related mortality (TRM), however studies including a large number of patients receiving a second transplant with umbilical cord blood (UCB) are scarce. In this retrospective study, using registry data from Eurocord and the European Society for Blood and Marrow Transplantation (EBMT), we report the outcomes of 247 umbilical cord blood transplants (UCBT) performed after GF following a previous HCT. Data were analyzed separately for patients with malignant (n=141) and non-malignant diseases (n=106). UCB was the most frequent stem cell source that resulted in GF (65.0% and 68.9%, for malignant and non-malignant diseases, respectively), and most of the reported GF occurred within 100 days after HCT (92.3% and 85.9%). The most frequent diagnosis in malignant diseases was acute leukemia (64.5%), mainly acute myeloid leukemia (AML). In non-malignant diseases, the diagnoses most often reported were inborn error of metabolism (IEM) (37.7%), followed by bone marrow failure syndrome (BMF) (34.0%) and primary immune deficiency (PID) (21.7%). In malignant and non-malignant diseases, we observed a similar cumulative incidence of neutrophil engraftment of 59.1% (95% CI 51.4- 67.9%) and 60.4% (95% CI 51.7- 70.6%), in a median time of 23 and 24 days, and a 3-year OS of 28.9% (95% CI 21.8- 37.3%) and 49.1% (95% CI 39.5- 58.8%). TRM at 100 days and at 3 years for malignant diseases was 39.9% (95%CI 32.5 - 49.1%), and 57.5% (95%CI 49.4 - 66.8%). In multivariate analyses, none of the characteristics were statistically significantly associated with engraftment or overall survival. Although survival for patients requiring a second transplant is not optimal, UCB remains a valid life-saving option for some patients with GF as it is an immediately available source of stem cells in severely ill patients. The most appropriate stem cell source for salvage transplants remains controversial, as it depends on multiple factors including center choice, donor availability, underlying disease and existing comorbidities. Disclosures Peffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding.
Abstract Introduction: World Marrow Donor Association (WMDA) promotes global collaboration for the benefit of stem cell donors and transplant patients. WMDA activities include recording the number of unrelated hematopoietic stem cell (HSC) donations globally. Because the COVID-19 pandemic also has an impact on the treatment of patients with other diseases, we hypothesise that it also impacted the practice of unrelated hematopoietic stem cell transplantation (HSCT). We used the 2020 WMDA data to examine the trends in unrelated HSC donations during the COVID-19 pandemic globally, per continent and per country/region. Methods: Donor registries (DRs) and cord blood banks (CBBs) from 61 countries participated in the 2020 survey, compared to 59 countries in the 2019. Slight differences in participation between the data sets of 2019 and 2020 do not explain the trends we observe in HSC donations. Country/region-specific COVID-19 data on cases and deaths were obtained from the data repository operated by the Johns Hopkins University Center for Systems Science and Engineering(https://github.com/CSSEGISandData/COVID-19, accessed July 12, 2021); and population data were retrieved from the Worldometer website(https://www.worldometers.info/, accessed July 12, 2021). Results: HSC donations from unrelated donors (peripheral blood stem cells (PBSC) and bone marrow (BM)) decreased from 20,330 in 2019 to 19,623 in 2020 (-3.5%), compared to an average annual growth rate of 3.9% from 2015 to 2019 (figure 1). The 3.5% decrease is composed of a 29.0% decrease for BM and a 2.6% increase for PBSC, resulting in a drop in the BM share of unrelated HSC donations from 19.3% in 2019 to 14.2% in 2020. The number of cord blood unit (CBU) shipments globally decreased with 3.5% from 2,851 to 2,750. The percentage of national use of HSC products (PBSC and BM) increased from 51.2% to 53.5%. When considering the continent on which the patient is transplanted (table 1), the change rate of use of HSC donated products in 2020 vs. 2019 ranged from -28.0% in South America to +18.2% in Africa. In absolute numbers, the largest decrease of HSC donations occurred for patients in Asia (n=-485) followed by Europe (n=-205), and the largest increase occurred in North America (n=+88) followed by Oceania (n=+25). The share of HSC donations requiring intercontinental transport decreased from 24.6% in 2019 to 21.9% in 2020. In terms of the country/region of transplant (table 2), the largest percentage decrease occurred in Colombia (-90,5%) followed by Russia (-55,5%). In absolute numbers, the largest decrease occurred in Turkey (-147), with Japan following (-128, although Japan saw an increase of CBU use of +106). The highest growth rate was observed in Iran (+28,7%), followed by South Africa (+28,2%). In absolute figures, the greatest increase occurred in Italy (+67). The two countries receiving the largest HSC donation numbers showed no major changes versus the previous year: USA: +0.6% (although a decrease for CBU of -21,0% was observed) and Germany: -2.4%. We did not find any significant correlation between the numbers of COVID-19 cases or COVID-19-related deaths per 1 million inhabitants with the HSC donation numbers (Spearman's r=0.05 for cases and =0.08 for deaths). Discussion: The decline in the number of unrelated HSC donations in 2020 suggests an impact of the COVID-19 pandemic on HSC donation and unrelated HSCT. The significant decrease in BM collections and intercontinental/cross-border shipments can be explained by logistically complex processes, as well the increased risk to the donor of being exposed to an operative procedure. CBU as a stem cell source potentially circumvents these logistical complications. However, on a global scale our data does not show increased use of CBU suggesting that decisions to use CBU as a stem cell source did not change in the pandemic . We were unable to demonstrate a correlation between country/region-specific severity of the pandemic and HSC donation numbers. We suspect this is due to the data quality of reported number of COVID-19 cases and COVID-19-related deaths. Also, we did not gather monthly data and therefore could not specify pandemic waves. In conclusion, we would like to point out the fact that global exchanges of HSC products continued and only decreased slightly is an extraordinary achievement of DRs, CBBs and their donors and is a testament to the importance of international collaborations in the WMDA. Figure 1 Figure 1. Disclosures Devine: Orca Bio: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding; Be the Match: Current Employment. Shaw: Orca bio: Consultancy; mallinkrodt: Other: payments. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.
Abstract Introduction: The role of allogeneic hematopoietic cell transplantation (allo-HCT) in Philadelphia-positive chronic myeloid leukemia (Ph+ CML) changed profoundly after the introduction of tyrosine kinase inhibitors (TKIs). Nevertheless, allo-HCT still represents the preferred treatment option for selected high-risk patients in Europe, with TKI resistance as the most common indication in first chronic phase (CP1). Reported survival outcomes for patients transplanted in CP1 with matched related (MRD), matched unrelated (MUD) and mismatched unrelated donors (MMUD) are generally good, but there are no published data on transplants from haploidentical donors (HD). In this retrospective study, we aimed to compare HD outcomes with those using MRD/MUD/MMUD. Patients and Methods: Patients who had received a first allo-HCT for Ph+ CML between 2012 and 2019 were selected from the EBMT database. Following the exclusion of patients transplanted using MRD, MUD, or MMUD and who received post-Cy GvHD prophylaxis, 1686 patients were included in the analysis. The impact of donor type on overall survival (OS) and relapse-free survival (RFS) was assessed using the Kaplan-Meier method; the cumulative incidence of relapse (REL) and non-relapse mortality (NRM) were estimated as competing events. Univariate comparisons were tested by log-rank or Gray's test, as appropriate. Cox proportional hazard models were applied to compare the risk of OS, RFS, REL and NRM in patients transplanted from MRD, MUD, MMUD and HD, adjusted for baseline disease and transplant characteristics, and to analyze the cause-specific hazard of NRM and REL. Two-sided p values of p<0.05 were considered statistically significant. Results: Overall, the median age at transplant was 46 years (range 18-74). 62% were male. The median interval from diagnosis to transplant was 17.5 months. Disease status at transplant was CP1 in 43%, CP2 or later in 27%, accelerated phase (AP) in 12%, and blast phase (BP) in 18%. Karnofsky Performance Status (KPS) was ≥90 in 78% of patients. Donor was MRD in 661 patients (39.2%), MUD in 677 (40.2%), MMUD in 212 (12.6%) and HD in 136 (8%). The stem cell source was peripheral blood (PB) in 84% (52% in HD, p<0.001). Reduced intensity conditioning (RIC) was used in 33%. Median time to neutrophil engraftment was 18 days in HD, and 16 days in MRD/MUD/MMUD transplants. Median time to platelet (>20 x 10 9/L) engraftment was 25 days in HD, 14 days in MRD/ MUD and 15 days in MMUD transplants. 53% of patients were serologically CMV positive pre-transplant. The cumulative incidence of grade II-IV acute GvHD at Day +100 was 25%, 27%, 31% and 39% in HD, MRD, MUD and MMUD, respectively (p=0.008). Chronic GvHD at +60 months was observed in 36%, 49%, 40% and 48% in HD, MRD, MUD and MMUD transplants (p=0.006), respectively. With regard to transplant outcomes at 60 months in HD, MRD, MUD and MMUD, OS was 51%, 51%, 62% and 58% (p=0.22), RFS was 42%, 46%, 51% and 45% (p=0.03, Fig.1), REL was 37%, 35%, 28% and 31% (p=0.064), NRM was 21%, 20%, 21% and 24% (p=0.34), and GVHD-free/relapse-free survival (GRFS) was 23%, 22%, 32% and 26% (p<0.001, Fig.2), respectively. By multivariable analyses (1,482 patients included), poorer OS was associated with older age (HR per 10 year increase 1.12, 95% CI 1.03-1.21, p=0.008), KPS <90 (HR vs ≥90 1.83, 1.51-2.23, p<0.0001), CMV+ status (HR 1.27 1.04-1.55, p=0.02), more advanced disease vs CP1 (p<0.0001); shorter RFS associated with KPS <90 (HR vs ≥90 1.51 1.27-1.80, p<0.0001), RIC (HR vs MAC 1.25, 1.05-1.50, p=0.01), disease status at transplant other than CP1 (overall p<0.0001), and BP vs AP (HR 1.33, 1.01-1.75, p=0.04); higher REL was predicted by KPS <90 (HR 1.54, 1.23-1.93, p<0.0001), RIC (HR vs MAC 1.31, 1.04-1.64, p=0.02) and disease status at transplant ≥CP2 vs CP1 and BP vs AP (p<0.0001); higher NRM was associated with older age (HR per 10 year increase 1.17, 1.05-1.31, p<0.005), KPS <90 (HR 1.47, 1.10-1.96, p<0.001), and PB as stem cell source (HR 1.61, 1.04-2.50, P=0.03). Table 1 shows the hazard ratio of OS, RFS, REL and NRM after transplants in MRD, MUD and MMUD compared to HD. Conclusions: Apart from confirming the stage of disease at transplant as being a major prognostic factor, this study identified a trend to better RFS and GRFS in patients with Ph+ CML transplanted using MUD when compared to MRD/HD/MMUD. These results should be interpreted with caution given the limited number of patients who had HD. Figure 1 Figure 1. Disclosures Byrne: Incyte: Honoraria. Apperley: Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau; Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ganser: Novartis: Honoraria; Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria. Hayden: Amgen: Honoraria; Jansen, Takeda: Other: Travel, Accomodation, Expenses. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.
Abstract We are in the midst of a pandemic with the COVID-19 virus, a pathogen with potential severe manifestations. A major clinical question is whether it is safe to undergo hematopoietic stem cell transplantation (HSCT) shortly after COVID-19 infection. A total of 21 patients received HSCT following a diagnosis of COVID-19 infection at our institution between 7/30/2020 and 4/14/2021. The majority (n=13, 62%) received an allogeneic (ALLO) HSCT from an HLA-matched related (n=5), -matched unrelated (n=6), or haploidentical (n=2) donor. The remaining 8 patients received autologous (AUTO) HSCT. Among ALLO-HSCT recipients, 4 (31%), 5 (38%), 3 (23%), and 1 (8%) patients had grade 1, 2, 3, and 4, manifestations respectively, scored according to the WHO COVID-19 infection severity grading system. Among AUTO-HSCT recipients, 5 (62%), 1 (12%), and 2 (25%) patients had grade 0, 1, and 2 manifestations, respectively. All patients had resolution of COVID-19 symptoms before HSCT. In recipients of ALLO-SCT, the median time from diagnosis of the COVID infection to HSCT was 134 (range: 55-311) days. Median age of recipients was 53 (range: 17-71) years and the majority (69%) of patients were male. Only one patient was <18 years old, and 38% were >60 years. Patients received ALLO-HSCT for treatment of acute myeloid leukemia or myelodysplastic syndrome (n=7, 54%), acute lymphoblastic leukemia (n=2, 15%), chronic lymphoblastic leukemia (n=2, 15%), and Hodgkin's (n=1, 8%) or non-Hodgkin's lymphoma (n=1, 15%). Most (62%) patients were not in remission at the time of HSCT. The median hematopoietic cell transplant-co-morbidity index (HCT-CI) score was 3 (range 0-6); one patient had a history of diabetes and another of hypertension before HSCT. Conditioning regimen was myeloablative in 61%, and stem cell source was peripheral blood (PB) in 92% of transplants. Median time to neutrophils engraftment was 15 (range: 10-20) days. With a median follow-up of 3.5 (range: 0.4-8) months since ALLO-HSCT, two patients died and another two experienced progression of the underlying malignancy. Three patients were diagnosed with grade 2 and none with grade 3 or 4 acute graft-versus-host disease (GvHD). The deaths occurred among patients with COVID-19 infection grade 2 and 3. The primary cause of death was attributed to alveolar hemorrhage/pneumonitis (no organism identified) and acute GvHD, respectively. Overall survival was 89% (95% confidence interval [CI]:43-98) and 76% (95% CI 33-93) at 3 and 6 months, respectively. In recipients of AUTO-HSCT, the median time from diagnosis of the COVID-19 infection to HSCT was 55 (range: 20-157) days. Median age of recipients was 55 (range: 34-75) years, and the majority (62%) of patients were male. One (12%) patient was >60 years. Patients received AUTO-HSCT for treatment of Hodgkin's (n=1, 15%) or non-Hodgkin's (n=4, 50%) lymphoma, or multiple myeloma (n=3, 37%). Six (75%) patients were in remission at the time of HSCT. The median HCT-CI score was 2 (range 0-6). None of the patients had a history of diabetes or hypertension before transplant. Conditioning regimen was myeloablative and stem cell source was PB for all patients. Median time to neutrophils engraftment was 10 (range: 9-13) days. With a median follow-up of 4 (range: 0.8-9) months since AUTO-HSCT, one patient with grade 1 COVID infection died as a result of a candida/cytomegalovirus infection, and none of the patients experienced progression of the underlying malignancy. Overall survival was 100% and 75% (95% CI 13-96) at 3 and 6 months respectively. After HSCT, one ALLO and two AUTO asymptomatic patients had a positive nasal swab COVID-19 PCR assay possibly due to delayed shedding of the virus. None of the 21 patients developed active COVID infections post-transplant. In conclusion, allogeneic and autologous hematopoietic transplantation can be performed in patients after COVID-19 infection. Two of 13 allogeneic and one of 8 autologous recipients experienced non-relapse mortality, none directly related to COVID-19 infection. Patients recovering from COVID-19 infection should be considered eligible for hematopoietic transplantation as clinically indicated. Disclosures Shpall: Magenta: Honoraria; Affimed: Patents & Royalties; Novartis: Honoraria; Navan: Consultancy; Magenta: Consultancy; Axio: Consultancy; Adaptimmune: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Novartis: Consultancy; Takeda: Patents & Royalties. Chemaly: Other: Other: Compensation: I am a consultant and advisor on companies who are developing new agents such as Merck, Ansun, and Janssen.
Glaucoma is one of the leading causes of vision loss worldwide, characterised with irreversible optic nerve damage and progressive vision loss. Primary open-angle glaucoma (POAG) is a subset of glaucoma, characterised by normal anterior chamber angle and raised intraocular pressure (IOP). Reducing IOP is the main modifiable factor in the treatment of POAG, and the trabecular meshwork (TM) is the primary site of aqueous humour outflow (AH) and the resistance to outflow. The structure and the composition of the TM are key to its function in regulating AH outflow. Dysfunction and loss of the TM cells found in the natural ageing process and more so in POAG can cause abnormal extracellular matrix (ECM) accumulation, increased TM stiffness, and increased IOP. Therefore, repair or regeneration of TM’s structure and function is considered as a potential treatment for POAG. Cell transplantation is an attractive option to repopulate the TM cells in POAG, but to develop a cell replacement approach, various challenges are still to be addressed. The choice of cell replacement covers autologous or allogenic approaches, which led to investigations into TM progenitor cells, induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs) as potential stem cell source candidates. However, the potential plasticity and the lack of definitive cell markers for the progenitor and the TM cell population compound the biological challenge. Morphological and differential gene expression of TM cells located within different regions of the TM may give rise to different cell replacement or regenerative approaches. As such, this review describes the different approaches taken to date investigating different cell sources and their differing cell isolation and differentiation methodologies. In addition, we highlighted how these approaches were evaluated in different animal and ex vivo model systems and the potential of these methods in future POAG treatment.
Background: Allogeneic blood or marrow transplant (BMT) recipients are at risk for venous-thromboembolism (VTE) because of high-intensity therapeutic exposures, comorbidities and a pro-inflammatory state due to chronic graft vs. host disease (GvHD). The long-term risk of VTE in allogeneic BMT survivors remains unstudied. Methods: Participants were drawn from the BMT Survivor Study (BMTSS), a retrospective cohort study that included patients who underwent transplantation between 1974 and 2014 and survived ≥2y after BMT. The BMTSS survey collected information on sociodemographics, health behaviors and chronic health conditions along with age at diagnosis. Details regarding primary cancer diagnosis, transplant preparative regimens, type of transplant and stem cell source were obtained from institutional databases and medical records. We analyzed the risk of VTE in 1,554 2y survivors of allogeneic BMT compared to 907 siblings. Using backward variable selection guided by minimizing Akaike's information criterion, we created a prediction model for risk of late-occurring VTE. Results: Allogeneic BMT survivors had a 7.3-fold higher risk of VTE compared to siblings (95%CI: 4.69-11.46, p<0.0001). After a median follow-up of 11y (inter-quartile range: 6-18y), and conditional on surviving the first 2y after BMT, the cumulative incidence of late-occurring VTE was 2.4% at 5y, 4.9% at 10y and 7.1% at 20y after BMT. Older age at BMT (hazard ratio [HR]=1.02/y, 95%CI=1.01-1.04, p=0.002), use of immunosuppressive medications (HR=2.28, 95%CI=1.41-3.38, p=0.0008), obesity (HR=1.06/unit increase in body mass index, 95%CI=1.02-1.10, p=0.002), history of stroke (HR=3.71, 95%CI=1.66-8.27, p=0.001), chronic GvHD (HR=1.62, 95%CI=1.00-2.60, p=0.049), and use of peripheral blood stem cells (PBSCs) as source of stem cells compared to bone marrow (HR=2.73, 95%CI=1.65-4.50, p<0.0001) were associated with increased VTE risk. The final model for VTE risk applied at 2y post-BMT ("HiGHS2") included History of stroke, chronic GvHD, Hypertension, Sex (male vs. female) and Stem cell source (PBSCs vs. other) (corrected C-statistics: 0.73; 95%CI=0.67-0.79), and was able to classify patients at high and low VTE risk (10y cumulative incidence 9.3% vs. 2.4%, p<0.0001). Conclusions: The BMTSS HiGHS2 risk model when applied at 2y post-BMT can be used to inform targeted prevention strategies for patients at high risk for late-occurring VTE.
AbstractBetween 2008 and 2019, 58,914 hematopoietic stem cell transplantations (HSCTs) were reported to the Chinese Blood and Marrow Transplantation Registry Group (CBMTRG) throughout China. In this report, we focus on 2019 data and describe current trends in HSCT in China. There was continued growth in transplant activity in China, with a rapid increase in haploidentical HSCT. In 2019, a total of 12,323 cases of HSCT were reported from 149 transplant teams, 78% (9597 cases) were allogeneic HSCTs. Haploidentical donor (HID) HSCT accounted for 60% (5771 cases) of allogeneic HSCT. The most common indications for allogeneic HSCT for malignant disease were acute myeloid leukemia (AML) (37%) and acute lymphoblastic leukemia (ALL) (24%), and the largest proportion of non-malignant diseases comprised aplastic anemia (AA) (13%). Multiple stem cell source composed 70% of HID and 28% of MSD, which was typical in China. The BuCy based regimen (59%) was the most popular conditioning regimen for allogeneic HSCT, followed by the BuFlu based regimen (23%) and TBI-based regimen (12%). This survey clearly shows comprehensive information about the current state and recent trends for HSCT in China. Further efforts should be made to obtain detailed information.
AbstractPredisposition to mycobacterial infection is a key presenting feature of several rare inborn errors of intrinsic and innate immunity. Hematopoietic stem cell transplantation (HSCT) can be curative for such conditions, but published reports are few. We present a retrospective survey of the outcome of 11 affected patients (7 males, 4 females) who underwent HSCT between 2007 and 2019. Eight patients had disseminated mycobacterial infection prior to transplant. Median age at first transplant was 48 months (9 -192); three patients were successfully re-transplanted due to secondary graft failure. Donors were matched family (1), matched unrelated (3), and mismatched unrelated and haploidentical family (5 each). Stem cell source was peripheral blood (9), bone marrow (4), and cord blood (1). TCRαβ/CD19 + depletion was performed in 6. Conditioning regimens were treosulfan, fludarabine (4), with additional thiotepa (in 8), and fludarabine, melphalan (2); all had serotherapy with alemtuzumab (8) or anti T-lymphocyte globulin (6). Median hospital stay was 113 days (36–330). Three patients developed acute grade I-II skin and one grade IV skin graft versus host disease. Four patients had immune-reconstitution syndrome. Two reactivated cytomegalovirus (CMV), 1 Epstein-Barr virus, and 3 adenovirus post HSCT. Nine are alive, 1 died early post-transplant from CMV, and the other was a late death from pneumococcal sepsis. Patients with active mycobacterial infection at HSCT continued anti-mycobacterial therapy for almost 12 months. In conclusion, HSCT is a successful treatment for patients with mycobacterial susceptibility even with disseminated mycobacterial infection and in the absence of an HLA matched donor.
