ABSTRACT
Patients undergoing treatment for haematological malignancies have been shown to have reduced antibody responses to vaccination against SARS-COV2. This is particularly important in patients who have undergone allogeneic haemopoietic stem cell transplantation (HSCT), in whom there is limited data about vaccine efficacy. In this retrospective single-centre analysis, we present data on serologic responses following one, two, three or four doses of either Pfizer-BioNTech (PB), AstraZeneca (AZ) or Moderna (MU) SARS-CoV- 2 vaccines from a series of 75 patients who have undergone allogeneic HSCT within 2 years from the time they were revaccinated. The seroconversion rates following post-HSCT vaccination were found to be 50.7%, 78%, 79% and 83% following the first, second, third and fourth primary post -HSCT vaccine doses, respectively. The median time from allograft to first revaccination was 145 days (range 79-700). Our findings suggest that failure to respond to the first SARS-CoV- 2 vaccine post-HSCT was associated with the presence of acute GVHD (p = 0.042) and treatment with rituximab within 12 months of vaccination (p = 0.019). A statistical trend was observed with the presence of chronic GVHD and failure to seroconvert following the second (p = 0.07) and third (p = 0.09) post-HSCT vaccine doses. Patients who had received one or more SARS-CoV- 2 vaccines prior to having an allogeneic stem cell transplant were more likely to demonstrate a positive antibody response following the first dose of revaccination against Sars-CoV- 2 (p = 0.019) and retained this seropositivity following subsequent doses. The incidence of confirmed COVID-19 diagnosis among this cohort at the time of analysis was 16%. 17% of these were hospitalised and there was one recorded death (8%) secondary to COVID-19 in a patient who was 15.7 months post allogeneic transplant. In summary, this study suggests that despite the initial low seroconversion rates observed postallogeneic transplant, increasing levels of antibody response are seen post the second primary vaccine dose. In addition, there seems to be lower risk of mortality secondary to COVID-19 in this vaccinated population, compared to what was reported in the earlier phases of the pandemic prior to use of SARS-COV2 vaccination. This adds support to the widely adopted policy of early full revaccination with repeat of primary vaccine doses and boosters post-HSCT to reduce mortality in this population. Finally, we have identified rituximab use and active GVHD as potential risk factors influencing serological responses to SARS-COV2 vaccination and further work should focus on further characterising this risk and optimum dosing schedule both pre-and post-transplant.
ABSTRACT
Background: Tixagevimab(Txg)/cilgavimab (Cgv) was given emergency use authorization (EUA) to provide passive immunity against COVID-19(CoV) for immunocompromised (IC) pts who may not mount an adequate response to CoV vaccination [1]. Recipients of allogeneic hematopoietic cell transplant (Allo-HCT) are amongst the most IC. Due to high risk of mortality and complications of CoV in this population, Txg/ Cgv was used as pre-exposure prophylaxis (PrEP) under EUA without prior study. Our study aims to assess efficacy and adverse events (AE) of Txg/Cgv administration in this cohort of patients to help guide future practice. Method(s): We retrospectively investigated Allo-HCT recipients who received Txg/Cgv as PrEP. Data were gathered including changes in blood counts, incidence of graft-vs-host-disease (GVHD), history of prior CoV infection and vaccination status. Pts who developed CoV infection after PrEP were assessed for supplemental oxygen(O2) need and hospitalization. Data cutoff date was 9/30/2022. Result(s): A total of 18 Allo-HCT recipients received Txg/Cgv. Table 1 summarizes patient and transplant characteristics. Thirteen (72.2%) pts received 2 doses of 150mg of Txg / Cgv, while 4 pts received 1 dose of 300mg, and one patient received one dose of 150mg. Median time to first dose was 213 days [range 22-3660] post-transplant. Two pts had lab confirmed CoV, one at 24 days post dosing and the 2nd patient at 22 days post dose. Neither required supplemental O2;one was hospitalized for fever. Prior to dosing, 44.4% (8/18) of pts had GVHD. (Table Presented) (Figure Presented) (Figure Presented) Of these, 62.5% (5/8) had no changes in the severity of their GVHD. Two of 8 (25%) pts with pre-existing chronic GVHD had a flare of symptoms. Two (25%) had improvement of GVHD. Two pts developed new onset acute GVHD following Txg/Cgv administration, one requiring 1mg/kg prednisone and the other topical steroids (2/18, 11%). Figure 1 summarizes GVHD patterns observed. Hematologic parameters did not change significantly, see Figure 2. None of the pts reported any subjective AE following dosing. Summary: Txg/Cgv was found to be safe and effective for Allo-HCT pts, without significant toxicity. Two patients had new onset GVHD and 2 patients had progressive GVHD. Whether there is a true association between Txg/Cgv and development of GVHD should be investigated in a larger cohort and then investigated for possible underlying mechanisms.Copyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
Background: The emergence of the COVID-19 pandemic saw an increased use of cryopreserved (cryo) peripheral blood (PB) grafts for allogeneic hematopoietic stem cell transplantation (HSCT). Outcomes of patients receiving either fresh or cryo grafts have yielded heterogeneous results. Herein, we retrospectively compared the outcomes of patients receiving fresh and cryo grafts at a single center.(Table Presented)Methods: Between 2019 and 2021, we reviewed data from 380 patients;167 (44%) received a fresh, and 213 (56%) received a cryo graft. Patients underwent myeloablative or nonmyeloablative HSCT from either matched or mismatched, related or unrelated donors. Cell doses were determined by number of donor cells collected and recipient weight at infusion. Engraftment, disease risk (DR) and acute GVHD were classified based on established criteria. Donor chimerism was collected at approximately day 28 and day 80 after HSCT. Unadjusted and adjusted estimates of overall survival (OS), relapse, and non-relapse mortality (NRM) as a function of time were obtained. The adjusted odds (grades III-IV acute GVHD) and the adjusted cause-specific hazard of failure (all other outcomes) were compared between the 2 groups. with the use of logistic (Figure Presented) or Cox regression, respectively. These models were adjusted for various factors known to be associated with each outcome. Result(s): The characteristics of patients between the 2 groups are shown in Table 1. There was a higher proportion of patients with high/very high DR in the fresh graft group (Table 1). Median time to neutrophil engraftment was 17 and 18 days in fresh vs. cryo, respectively. The adjusted hazard ratio (HR) of neutrophil engraftment (fresh vs. cryo) was 1.07 (95% CI, 0.86-1.34, p=0.54). Median time to platelet engraftment was 13 and 15 days, respectively, and the adjusted HR of platelet engraftment was 1.32 (1.06-1.65, p=0.01). Day 28 chimerism data were available for 272 patients (113 fresh and 159 cryo). At day 28, donor CD3 chimerism was below 50% in 5 out of 113 (4.4%) and 17 out of 159 (10.7%) patients receiving fresh and cryo grafts, respectively (p= 0.06). At day 80, 3 out of 121 (2.5%) patients in the fresh group and 4 out of 165 (2.4%) in the cryo group had CD3 chimerism below 50%. The adjusted HRs (fresh vs. cryo) for death and NRM were 0.83 (0.54-1.28, p=0.40) and 0.71 (0.38-1.33, p=0.29), respectively (Figures 1 and 2). The adjusted HR for relapse was 0.65 (0.42-0.99, p=0.05) (Figure 3). The adjusted odds ratio (fresh vs. cryo) for grades III-IV GVHD was 1.65 (0.94-2.9, p=0.07). Conclusion(s): In this single-center retrospective study we observed numerically better outcomes with fresh grafts relative to cryo grafts for all examined endpoints with the exception of grades III-IV aGVHD, although none of the differences were definitive with the possible exception of relapse and platelet engraftment. Further studies are needed to confirm our observations.Copyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
Background: The use of cryopreservation for stem cell grafts for both autologous stem cell and allogeneic cord blood transplant has been utilized for years. For other allogeneic stem cell transplant sources, the use of fresh collected grafts has been preferred due to concerns that cryopreservation may result in impaired graft function. With the onset of the COVID-19 pandemic a shift was made at our institution to exclusive use of cryopreservation Methods: In this retrospective single-center analysis a total of 133 patients undergoing allogeneic stem cell transplant at the University of Minnesota between 1/2018-6/2021 for a variety of malignancies were included, with 62 patients receiving fresh stem cell product and 71 patients receiving frozen stem cell product. Univariate statistical analysis was performed. Result(s): There was no significant difference between the two groups with regards to product type, sex, age, diagnosis (acute leukemia vs other), disease risk index, conditioning regimen, Karnofsky score, co-morbidity index, or cell dose (Table 1). Donor type was notably different between the two groups (p<0.01): matched sibling grafts were more commonly used for fresh products than frozen (85% vs. 35%), while matched unrelated donors were used more frequently for frozen than for fresh products (54% vs. 6%). Use of frozen product was associated with delayed neutrophil and platelet engraftment compared to fresh (median days to engraftment 15 vs 12 for neutrophils, 23 vs 17 for platelets, p<0.01 for both). Two-year relapse rates were significantly lower for frozen products (4%) than fresh (24%) (Table 2). This may be partially attributable to differences in follow up between the groups, as fresh products had a total of 910 days of follow up vs 432 for frozen products (P<0.0001). The difference in follow up remained statistically significant if the data was censored at 730 days (P<0.0001). Of note, the use of frozen products was associated with a lower rate of chronic graft-versus-host disease at one year post-transplant (p<0.01). There was no significant difference in the rates of acute GVHD between the groups. There were significant differences in GVHD prophylaxis regimens between the fresh and frozen groups (p<0.01). (Figure Presented)Two-year overall survival did not differ between groups (p=0.96). Conclusion(s): Use of cryopreserved stem cell products is associated with similar efficacy and outcomes as those seen with the use of fresh stem cell products. Although the data presented here suggest novel finding of decreased risk of relapse and chronic GVHD with the use of frozen stem cell products, additional follow up may abrogate these differences. Regardless, the logistical benefits of cryopreservation make this an attractive option for continued use in allogeneic transplants and our data presented here suggests that cryopreserved products remain an appropriate option for allogeneic stem cell transplant.Copyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
Allogeneic hematopoietic stem cell transplantation (allo- HSCT) has traditionally involves administering fresh peripheral blood or bone marrow stem cells. At onset of the COVID-19 pandemic in March 2020, the National Marrow Donor Program (NDMP) mandated cryopreservation of all unrelated peripheral blood stem cell (PBSC) products to prevent interruptions in transplant plans by donor COVID-19 infection after recipient's start of conditioning chemotherapy. Since the lifting of this mandate, many centers have continued to cryopreserve grafts prior to initiation of conditioning, but the longer-term clinical outcomes of this practice including chronic graft versus host disease (cGVHD) rates of patients receiving cryopreserved stem cells have not been previously well described. Prior work has raised concern for a deleterious effect of cryopreservation on overall survival and non-relapse mortality (PMID: 33865804). However, heterogeneity in the patient population and reason for cryopreservation suggest that further study is needed to assess these outcomes. Here we report our single-institution experience of clinical outcomes using cryopreserved versus fresh URD PBSCs for allo-HSCT. We examined long-term outcomes in 387 patients who received unrelated donor (URD) PBSCs (136 cryopreserved, 251 fresh) between January 1, 2019 and July 31, 2021. The cohorts had similar baseline characteristics including donor/recipient age/sex, disease, conditioning regimen/intensity, and GVHD prophylaxis regimens. Two-year OS, PFS, relapse, NRM, and acute GVHD rates were not different between recipients of fresh versus cryopreserved PBSCs. Strikingly, 2-year incidence of cGVHD (28% vs 52%, p=0.00001) and moderate/severe cGVHD (9% vs 24%, p=0.00016) was substantially lower in recipients of cryopreserved PBSCs compared to fresh, respectively (Figure 1). This difference was only noted in patients receiving a GVHD prophylaxis regimen without post-transplantation cyclophosphamide (PTCY) (no PTCY 2-year cGVHD incidence cryopreserved vs fresh: 29% vs 57%, p=0.000016), moderate/severe cGVHD 16% vs 34%, p=0.0006) (Figure 2). For patients receiving a PTCY-containing GVHD prophylaxis regimen, there was no difference in cGVHD incidence (cGVHD cryopreserved vs fresh: 24% vs 27%, p=0.56, moderate/severe cGVHD 7% vs 9.3%, p=0.3, Figure 3). (Figure Presented) (Figure Presented) (Figure Presented) While survival and relapse rates are not different, cryopreservation is associated with a marked reduction in cGVHD rates in the setting of non-PTCy based GVHD prophylaxis. Larger multicenter or registry analyses are needed to confirm these observations and may prompt a re-assessment of the role of cryopreservation of stem cell products in clinical practice. If confirmed, it will be critical to understand the immunologic consequences of cryopreservation and how they might influence the clinical impact on chronic GVHDCopyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
The Hermanos Ameijeiras Hospital (HAH) in Havana is the only center performing allogeneic hematopoietic stem cell transplantation (HSCT) in adult patients in Cuba. Because transplants from unrelated donors are not possible due to political restrictions and economic embargo, in 2016 HAH and University of Illinois at Chicago (UIC) started a collaboration to support the training of a physician, annual educational programs and exchange of guidelines and protocols to perform haploidentical transplants. The first haploidentical transplant was performed at HAH in 2016. Because of limited resources, disease risk stratification is based on morphologic assessment, as cytogenetic is tested on an irregular basis. Peripheral blood stem cells (PBSC) were infused based on total nucleated cell count (TNC) due to lack of reagents for flow cytometry. Posttransplant chimerism and CMV monitoring cannot be performed. Transplant activity was stopped in 2020 due to high expenses allocated for COVID19 pandemic in Cuba. From 2016 to 2020, 16 haploidentical HSCT in 15 patients (9 males/ 6 females) were completed at HAH. The median age of patients was 34 years (range:21-54). Diagnoses included: acute leukemia, n=12, myelodysplastic syndrome, n=1, Hodgkin disease, n=1, and severe aplastic anemia, n=1. At the time of transplant, 11 patients were in morphologic remission and 5 had active disease. Conditioning regimens utilized were myeloablative (Flu/Bu) in 10 cases and at reduced intensity (Flu/Cy/ TBI200 +/- ATG) in 6 cases, and GVHD prophylaxis was standard PTCy on D3 and 4, CsA and mycophenolate. The donors were mother (n=10), father (n=1), child (1), or sibling (n=3) and the median age was 48 years (range: 26-68). All patients received fresh stem cells from PBSC(n=13) or bone marrow (n=3). Median cell dose infused was 5.5x108 TNC/kg (range: 2.2-8). All patients but 1 engrafted and median time to neutrophil and platelet engraftment was 17 days (range:12-28) and 16 days (range:11-30), respectively. Acute graft-versus-host disease (GVHD) grade 2-3 occurred in 50% of patients and chronic GVHD in 2 out of 8 that were evaluable. Day 100 and 2-year overall survival rates were 73% and 40%, respectively. With a medium follow-up of 18.8 months (range: 0.3-64), 5 of 15 patients (30%) are alive and complete remission. Causes of death in the remaining 10 patients included relapse of original disease, n= 4;bacterial infection, n=2;brain hemorrhage, n=1;VOD, n=1;graft failure, n=1;and multi-organ failure, n=1. Despite significant difficulties, HAH implemented a haploidentical transplant program for adult patients in Cuba. Among future steps, improving access to molecular testing and using younger donors will be pursued to improve on the results. The partnership between HAH and UIC has been instrumental in building clinical and research capacity and continues to support HAH in its mission to provide care to patients in Cuba.(Figure Presented)Copyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
The World Health Organization (WHO) declared COVID-19 a pandemic in March 2020. Since then, logistical challenges arose regarding the procurement of allogeneic (allo) hematopoietic stem cell (HSC) donor grafts. Little data was available on transplant outcomes using cryo haploidentical (haplo) HSC grafts with post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis. We retrospectively analyzed patients who received a first PTCy-based haplo hematopoietic stem cell transplant (Haplo HCT) at a single outpatient transplant center between January 2015 and December 2021. We identified 294 patients, 179 received a fresh graft and 115 received a cryo graft (Table 1). Both cohorts were similar in terms of median age, diagnoses, HCT-CI score and DRI. Out of 179 fresh haplo grafts, 160 (89.4%) were from peripheral blood stem cells (PBSC) and 19 (10.6%) were bone marrow grafts (BM). There were no cryo BM grafts used. Conditioning intensity were similar amongst both cohorts, with 43% myeloablative, 41.9% non-myeloablative and 15.1% RIC regimens used for fresh Haplo HCT and 39.1% myeloablative, 42.6% non-myeloablative and 18.3% RIC cryo Haplo HCT. Median time to engraftment was 16 days for fresh Haplo HCT and 17 days for cryo HCT (p=0.18). Median time to platelet engraftment was 27 days for fresh Haplo HCT and 27.5 days for cryo HCT (p=0.96). Since March 2020, only 8 transplants performed at our institution were from fresh haplo HSC grafts. Cryo grafts performed after March 2020 accounted for 73 (63.5%) of 115 total cryo Haplo HCT performed in the period reviewed. Using a Cox model to evaluate the effect of graft type and adjusting for significant variables, we found no difference in overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM) and relapse rates between fresh and cryo Haplo HCT performed (Figure 1). While we found no difference in grades III-IV aGVHD (Table Presented) (Figure Presented) between fresh vs cryo Haplo HCT, we found a statistically significant higher incidence of grades II-IV aGVHD (p=0.033). There was no difference in all-grade cGVHD (p=0.53) or moderate- severe cGVHD (p=0.86) (Figure 2).(Figure Presented) The National Marrow Donor Program (NMDP) released a statement requiring cryopreservation of unrelated donor grafts at the start of the COVID-19 pandemic. The cryopreservation of all types of allo HSC grafts has been adopted by many transplant programs including ours. Our results mimic a CIBMTR analysis published at the start of the pandemic, where survival outcomes using fresh vs cryo haplo HSC grafts with PTCy as GVHD prophylaxis were similar. Contrary to other reports, we did not see differences in graft failure or rates of cGVHD between fresh and cryo Haplo HCT. The use of cryopreserved HSC grafts for Haplo HCT with PTCy results in favorable outcomes in an outpatient transplant setting. Further studies are needed to determine the cost-effectiveness of this practice in the post-pandemic era.Copyright © 2023 American Society for Transplantation and Cellular Therapy
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OBJECTIVE: To evaluate the effectiveness of ruxolitinib on acute graft-versus-host disease (aGVHD) prophylaxis and its impact on graft-versus-leukemia (GVL) effect in patients after modified donor lymphocyte infusion (mDLI). METHODS: We retrospectively included patients with relapsed leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) who received ruxolitinib prophylaxis between October 2018 and April 2020. The incidence of aGVHD, disease-free survival (DFS), overall survival (OS), and treatment safety were evaluated. RESULTS: Seventeen patients were followed up for a median time of 8 months (range: 1-26 months). The incidence of aGVHD on Day 30 after mDLI was 41.2% and ranged from Grade 1 to 4; ten of 17 patients (58.8%) achieved a complete response (CR), and two (11.8%) had a partial response (PR). Cytomegalovirus (CMV) reactivation rate was 23.5%, and the median time from mDLI to CMV reactivation was 48.5 days. The mean DFS and OS after mDLI were 1.0 (95% CI 0.0-3.5) and 9.0 (95% CI 1.2-16.8) months, respectively. The causes of death for 10 patients were leukemia relapse (n = 5), aGVHD and septic shock (n = 3), intracranial lesion (n = 1), and COVID-19 (n = 1). CONCLUSIONS: We reported encouraging results of ruxolitinib monotherapy in the prevention of aGVHD and maintenance of GVL for post-transplantation relapsed patients, even though being at high risk with poor initial prognosis.
ABSTRACT
Background: HIV persistence during antiretroviral therapy (ART), prevents HIV eradication or control. Mechanisms responsible for HIV persistence, including in tissues, are not well understood. Here we investigated persistence of HIV-infected cells in tissues for >200 days in an individual who had successful allogeneic hematopoietic cell transplant (Allo-HCT;donor CCR5 wild-type) but developed acute lymphocytic interstitial pneumonia after COVID vaccination and expired. Method(s): Clinical and autopsy records were reviewed. HIV in tissue samples and mononuclear cells (prepared by ficoll from lung and spleen) were studied by single genome sequencing (SGS, 1.1 kb gag) and single-copy PCR for HIV DNA. Result(s): Study participant was a 38 yo man with HIV/AIDS on ART with HIV RNA<50 c/ml for >3 years who had reducedintensity conditioning, HLA-mismatched unrelated donor allo-HCT for primary refractory ALK-negative anaplastic large cell lymphoma. His course was remarkably uncomplicated:100% engraftment of donor CD3 and myeloid subsets confirmed by day +42 post-HCT;100% donor cells (CD4, CD8, CD19, CD14, CD56) confirmed by day +100. Per protocol, he was off all immunosuppression on day +60, did not develop acute graft-versus-host disease (GVHD), and maintained ART with HIV RNA<20 c/ml. Immune reconstitution was robust: NK, CD8, and B cells within normal range, CD4=172 cells/muL at d+100. He received SARS-CoV2 mRNAvaccine (Moderna) on days +107 and +144. On d+155, he developed dyspnea, hypoxia with acute lymphocytic interstitial pneumonia, presumed vaccinerelated, with no signs of GVHD, pulmonary infection, or lymphoma. HIV-1 RNA remained <20 except 21 c/ml noted shortly before expiring on d+207. Postmortem notable only for diffuse alveolar damage with fibrosis and a small white pulpdepleted spleen. Single copy assay detected HIV DNA in brain (thalamus, frontal lobe, midbrain), lymph node, and jejunum (1.6-16 copies/106 tissue cells) but not liver, spleen, or affected lung (<0.2 copies/106 cells). SGS revealed HIV sequences were non-identical, demonstrating multiple distinct populations of infected cells were present. Conclusion(s): HIV populations are diverse in tissues even after extensive lymphodepleting chemotherapy and allo-HCT. Complete donor engraftment in tissues, including brain, may take significantly longer than engraftment measured in peripheral blood. Eradication strategies will require evaluation of tissue compartments. Copyright © 2022 Elsevier Ltd
ABSTRACT
BACKGROUND: Acute graft-versus-host disease is one of the major complications of allogeneic hematopoietic stem cell transplantation, and it is also the key to the success of transplantation, which is particularly important to find specific biomarkers of acute graft-versus-host disease for the early diagnosis and treatment. The immune function of children is imperfect, and the changes of plasma biomarkers after acute graft-versus-host disease have their own characteristics. OBJECTIVE: To explore the correlation of plasma levels of soluble growth stimulation expressed gene 2 (sST2), regenerating islet-derived protein 3 alpha (REG3α), tumor necrosis factor receptor 1 (TNFR1), interleukin 6 (IL6), and interleukin 8 (IL8) with acute graft-versus-host disease in children after allogeneic hematopoietic stem cell transplantation. It is expected to provide reliable detection biomarkers for early diagnosis of acute graft-versus-host disease and prediction of therapy effect and prognosis. METHODS: Samples were collected from 127 pediatric patients who underwent allogeneic hematopoietic stem cell transplantation from March 2019 to December 2020 in the Department of Pediatrics, Nanfang Hospital. The plasma was collected at multiple time points, including 10 days before transplantation, 0, 7, 14, 28, and 90 days after transplantation, at the onset of acute graft-versus-host disease symptoms, 1, 2, and 4 weeks after acute graft-versus-host disease therapy. The plasma concentrations of sST2, REG3α, TNFR1, IL6 and IL8 were detected by the Luminex technology. RESULTS AND CONCLUSION: (1) Plasma samples were collected from 100 of 127 patients at the point of occurrence of acute graft-versus-host disease. Sixty cases never developed acute graft-versus-host disease symptoms;40 cases presented acute graft-versus-host disease, among which 9 cases developed II-IV gastrointestinal acute graft-versus-host disease according to EBMT-NIH-CIBMTR classification standard. (2) The plasma concentrations of sST2 and REG3α at onset point in patients were significantly higher in the acute graft-versus-host disease group compared with the non-acute graft-versus-host disease group (P < 0.05). sST2 was significantly increased at 7 days after transplantation in the acute graft-versus-host disease group than that in the non-acute graft-versus-host disease group (P < 0.05). The sST2 and REG3α levels were significantly higher in the II-IV gastrointestinal acute graft-versus-host disease group than those in the non-gastrointestinal acute graft-versus-host disease group (P < 0.01;P < 0.05). There were no significant differences in TNFR1, IL6 and IL8 levels at onset point and 7 days after transplantation in patients between the acute graft-versus-host disease group and the non-acute graft-versus-host disease group (P > 0.05). (3) In all acute graft-versus-host disease patients, the plasma concentrations of sST2 and REG3α in the steroid-resistant acute graft-versus-host disease group showed increasing tendency compared with steroid-sensitive acute graft-versus-host disease group. (4) It is concluded that the increate of plasma sST2 and REG3α levels at onset point after transplantation suggests the incidence of acute graft-versus-host disease. sST2 and REG3α in plasma can be helpful for the early prediction of acute graft-versus-host disease. By analyzing the levels of biomarkers at 1, 2, and 4 weeks after treatment, no decrease in the sST2 and REG3α levels in patients with acute graft-versus-host disease after treatment may be related to poor prognosis. (English) [ FROM AUTHOR] 背景：急性移植物抗宿主病是造血干细胞移植最主要的并发症之一，也是影响移植成败的关键，寻找其特异性生物学标记物对于疾病的早 期诊断及治疗尤为重要。婴幼儿时期免疫功能不完善，其急性移植物抗宿主病发生后血浆生物标记物的变化有其自身特点。 目的：研究异基因造血干细胞移植儿童患者血浆可溶性生长刺激表达基因2、胰岛再生衍生因子3α、肿瘤坏死因子受体1、白细胞介素6 和白细胞介素8水平变化与急性移植物抗宿主病的关系，以期为急性移植物抗宿主病的早期诊断、预测治疗效果和预后提供可靠的检测指 标。 方法：南方医院儿科2019年3月至2020 年12月行异基因造血干细胞移植共计127例患儿，采集移植前10 d、移植后第0，7，14，28，90 天、临床急性移植物抗宿主病症状出现时、急性移植物抗宿主病药物干预后1，2，4周患儿外周血，采用Luminex方法检测血清可溶性生长 刺激表达基因2、胰岛再生衍生因子3α、肿瘤坏死因子受体1、白细胞介素6和白细胞介素8水平。 结果与结论：①在127例患儿中有100例在急性移植物抗宿主病发生点采集血浆标本，按照EBMT-NIH-CIBMTR 分级标准未发生急性移植物抗 宿主病60例，发生急性移植物抗宿主病有40例，其中有9例Ⅱ-Ⅳ度肠道急性移植物抗宿主病。②急性移植物抗宿主病组发生点的血浆可 溶性生长刺激表达基因2和胰岛再生衍生因子3α水平高于无急性移植物抗宿主病组，差异均有显著性意义(P < 0.05)。与无急性移植物抗宿 主病组相比，急性移植物抗宿主病组移植后7 d的血浆可溶性生长刺激表达基因2水平显著增加(P < 0.05)。单纯Ⅱ-Ⅳ度肠道急性移植物抗 宿主病组发生点的血浆可溶性生长刺激表达基因2和胰岛再生衍生因子3α水平高于非肠道急性移植物抗宿主病组，差异均有显著性意义(P< 0.01；P < 0.05)。在发生点和造血干细胞移植后7 d时，急性移植物抗宿主病组和非急性移植物抗宿主病组间肿瘤坏死因子受体1、白细胞 介素6和白细胞介素8水平无显著差异(P > 0.05)。③在所有急性移植物抗宿主病患者中，与激素敏感组相比，激素耐药组的血浆可溶性生长 刺激表达基因2和胰岛再生衍生因子3α水平呈上升趋势。④结果表明，移植后发生点的血浆可溶性生长刺激表达基因2和胰岛再生衍生因 子3α水平升高提示急性移植物抗宿主病的发生，二者有助于急性移植物抗宿主病的早期预测。通过分析用药后1，2，4周的生物标记物水 平，急性移植物抗宿主病患者治疗后血浆可溶性生长刺激表达基因2和胰岛再生衍生因子3α水平不降低可能与预后不良相关。 (Chinese) [ FROM AUTHOR] Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo zu zhi gong cheng yan jiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. 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ABSTRACT
Introduction: The use of high-dose post-transplant cyclophosphamide (PTCY) has revolutionized graft-versus-host disease (GVHD) prophylaxis and allowed to successfully reconsider haplotransplant in recent years. As this strategy significantly reduces the incidence of both acute and chronic GVHD, PTCY has been thereafter considered not only in matched settings but also as sole GVHD prophylaxis, at least when considering myeloablative allotransplant using matched sibling (MSD) or unrelated (MUD) donors and bone marrow as source of graft. Here, PTCY, as a sole GVHD prophylaxis, was tested in a reduced-intensity conditioning (RIC) setting, using peripheral blood stem cells (PBSC) as source of graft considering that this platform is currently broadly used worldwide in adults. Methods: This prospective monocentric phase 2 study was designed with the main objective to demonstrate the feasibility and safety of using only PTCY (without cyclosporine A nor mycophenolate mofetyl after transplant) in adults (18-70 years old) eligible for a RIC PBSC transplant with MSD or MUD. The Baltimore platform with 2 days of PTCY 50mg/kg/day on days 3 and 4 post infusion was considered as conditioning regimen, using fludarabine for lymphoid disease or clofarabine for myeloid disease. The primary objective was to appreciate the incidence of corticosteroid-resistant acute grade 3-4 GVHD (CR 3-4 GVHD) within 100 days post-transplant. According to statistical rules, patients have to be included in a step by step fashion (3, 3, 6, 15, 15 and 17 patients) for a total of 59 evaluable patients (meaning having received PTCY), in order to stop the protocol soon enough in case of excessive rate of deleterious severe acute GVHD (graded according to Mount Sinai International Consortium). Thus, the trial had to be stopped in case of documentation of > 2 CR 3-4 GVHD for the first 3 patients, >3 CR 3-4 GVHD for the first 6 patients, > 4 CR 3-4 GVHD for the first 12 patients, > 6 3-4 CR GVHD for the first 27 patients, > 8 CR 3-4 GVHD for the first 42 patients and finally as soon as > 9 CR 3-4 GVHD for the last included patients. All patients gave informed consent. The trial was registered at ClinicalTrials.gov Identifier: NCT03263767. Results: The results of the first 27 first patients (males n=17 and female n=10;median age: 59 years old (yo), range: 26-70) are reported here. They were included between February 2018 and November 2020. Diagnoses were AML (N=8), MDS (N=5), CMML (N=2), myelofibrosis (N=5), CML (N=1), DLBCL (N=1), T-cell lymphoma (N=1), Philadelphia positive B-ALL (N=1), CLL (N=1), lymphoblastic lymphoma (N=1) and mixed phenotype acute leukemia (N=1). Donors were MSD in 10 cases and MUD in 17. Only one primary graft failure was documented in a 61 yo MDS patient with active disease at transplant. He is however still alive in response after autologous reconstitution. With a median follow-up of 17.6 months (range: 10-42) for alive patients at the time of analysis (July 2021), 1-year and 2-year survivals were 80.9+7% and 74.7+9%, respectively, for both OS et DFS. GVHD-free/relapse-free survival (GRFS) at 1-year and 2-year was 58.7+9% and 52.2+10%, respectively. Three relapses (11%) and 6 deaths occurred. Deaths were due to acute GVHD in 4 patients (including 1 with sepsis and 1 with SARS-COVID 19 infection) and relapse in 2. Grade 2, 3 and 4 acute GVHD occurred in 11, 1 and 4 patients, respectively, for a total of 59% of grade 2-4 acute GVHD. CR 3-4 GVHD was observed in all of 5 patients with acute grade 3-4 GVHD and 4 died related to GVHD. Moderate/severe chronic GVHD occurred in 5/22 (22.7%) evaluable patients, including 4 still on immunosuppressive therapy at 40, 28, 25 and 16 months post-transplant. Overall non-relapse mortality (NRM) was 14.8% and related to acute GVHD. However, the number of cases conducting to stop the protocol was not reached. Conclusion: PTCY as a sole GVHD prophylaxis is here demonstrated as possible and relatively safe for adults receiving a matched PBSC Baltimore-based RIC allograft. The very good survivals reported he e may be related to a strong GVL effect associated with the high incidence of acute GVHD. However, because of this high incidence and the fact that NRM was related to GVHD after this first analysis, we have now made an amendment to test the addition to PTCY of one day of anti-thymoglobulin (ATG) 2.5 mg/kg on day-2 for the next 32 patients to be included. This second cohort receiving PTCY+ATG as a sole prophylaxis is ongoing.
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 in ection 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.
ABSTRACT
CD6 is a co-stimulatory receptor predominantly expressed on T cells that acts as a crucial regulator of T-cell activation and is implicated in the pathogenesis of multiple autoimmune diseases. Activated leukocyte cell adhesion molecule (ALCAM), a CD6 ligand, is expressed on antigen-presenting cells, as well as epithelial and endothelial cells of acute GVHD target organs, including the skin and the GI tract.1,2 Previous studies in patients receiving alloHCT showed that ex vivo depletion of donor CD6-positive T cells lowered the incidence of acute GVHD, providing a rationale for therapeutically targeting CD6 in acute GVHD.3 Itolizumab, a humanized immunoglobulin G1 monoclonal antibody undergoing evaluation as treatment for acute GVHD, binds CD6 and blocks interaction with ALCAM to inhibit T-cell activity and trafficking.4 Dr John Koreth presented interim study results from EQUATE, an ongoing phase 1b/2 study of itolizumab in combination with corticosteroids for newly diagnosed severe acute GVHD (grade 3-4) after first alloHCT.5 The phase 1b portion is an open-label, 3+3 dose-escalation study evaluating doses of 0.4, 0.8, 1.6, and 2.4 mg/kg administered intravenously every 2 weeks through day 57. As of November 13, 2020, 10 patients completed treatment: 4 with 0.4 mg/kg, 3 with 0.8 mg/kg, and 3 with 1.6 mg/kg. All patients received corticosteroids at an initial dose of 1 to 2 mg/kg/day. Their mean age was 48 years (standard deviation, 15.7 years), 90% were male, and 90% were white. The graft source was peripheral blood for 80% and bone marrow for 20%, and 80% had an HLA-matched donor. The mean time to onset of GVHD was 43 days, and 100% of patients had GI involvement. At day 57, the ORR was 50% with 0.4 mg/kg, 100% with 0.8 mg/kg, and 100% with 1.6 mg/kg.5 The median percent corticosteroid dose reduction at day 85 was 93%, 87%, and 91% for the 0.4, 0.8, and 1.6 mg/kg groups, respectively (Figure 6). Itolizumab decreased the CD6 levels on T cells in a dose-dependent manner within 24 hours of the first dose, a reduction that was maintained throughout the treatment period. Across the dosing cohorts, all patients developed at least 1 AE. Most AEs were mild to moderate in severity.5 The most common AEs were hypomagnesemia (n=3) and peripheral edema (n=3). One mild infusion reaction was noted. Six patients had serious AEs, including recurrent GVHD (n=1), sepsis (n=2;1 event was considered a dose-limiting toxicity), fever (n=1), COVID-19 (n=1), and disseminated nocardia (n=1).
ABSTRACT
Four decades ago, Hal Broxmeyer demonstrated that umbilical cord blood (CB) contained hematopoietic stem cells (HSC) and hypothesized that CB could be used as a source of donor HSC for rescue of myeloablated bone marrow. In 1988, Gluckman et al reported the first successful cord blood transplant (CBT) of a child with Fanconi Anemia using matched sibling CB. This patient survives and 35 years later still has durable hematopoiesis from the CB donor graft. In 1991, Rubinstein et al established an unrelated donor (UD) CB bank and in 1993 the first UD CBT was using a unit from this bank. Since that time, >40,000 CBTs have been performed worldwide. We hypothesized that changes in cord blood banking (increased size, diversity, and quality of banked units enabling selection of units with higher cell doses and closer HLA matching) and in transplantation (less use of steroids, availability of newer therapies for prophylaxis and treatment of graft versus host disease [GVHD], improved antifungal and antiviral detection and therapeutics) have improved outcomes of CBT today. To address this hypothesis, we performed a retrospective study combining data from Eurocord and Duke University in a large cohort of children transplanted with a single UD CB unit (CBU) from 1993-2019. Standard transplant outcomes (overall survival [OS], disease free survival [DFS], acute and chronic GVHD, treatment related mortality [TRM], and relapse) and changes in outcomes over 3 time periods (1:<2005, n=1297;2:2005-2010, n=1735;and 3:>2010, n=1802) were studied. Relative contributions of cell dose and HLA matching to transplant outcomes over time were assessed. A total of 4834 patients (4015 from Eurocord and 819 from Duke) were analyzed. The majority of patients, (59%, n=2839) had malignant diagnoses including 1422 with ALL, 887 with AML and 167 with MDS. Of the 1995 with non-malignant diagnoses, 761 had inborn errors of metabolism, 644 had primary immunodeficiency, 325 had a bone marrow failure syndrome and 206 had a histiocytic disorder. Half of the patients had positive serologies for CMV prior to transplant. The median age of the cohort fell from 5.2 to 3.25 years over time. In patients with malignancies, use of total body irradiation decreased over time. The median total nucleated cell (TNC) and CD34+ cell doses administered were 8.07x10e7 and 6.17x10e5 cells/kg and increased over time. HLA matching and transplantation of patients in earlier disease states also increased over time, p<0.001 for both. The probability of 5-year OS in the entire cohort was 53.48% and improved over time: 42%;57.4%;and 60.4%, in periods 1,2,3 respectively (p<0.0001). OS improved with closer HLA matching, higher cell dose, myeloablative conditioning, and negative pre-transplant CMV serologies. For patients with malignancies, DFS increased and TRM and acute GVHD decreased over time. In contrast, leukemic relapse did not change throughout the years. OS was higher in patients with inborn errors of metabolism and also improved over time with 57.8% surviving before 2005, 69.4% from 2005-2010, and 71% after 2010 (p=0.0141). Similar results were seen in the cohort with immune deficiencies. In the entire cohort, the median time to neutrophil engraftment decreased from 25 days (period 1) to 19 days (period 3). In multivariate analysis for engraftment, a higher TNC dose (p=0.001) up to but not beyond the median cell dose (8.07x10e7 cells/kg), total body irradiation, and the use of ATG improved engraftment. Acute GVHD decreased from 35% before 2005 to 27.1% after 2010 (p=0.0556) while the incidence of chronic GvHD was stable. The use of ATG reduced the risk of acute GVHD and closer HLA matching reduced the risk of both acute and chronic GVHD. In this population of patients receiving high cell doses, outcomes were predominantly influenced by HLA matching and increasing cell dose did not abrogate HLA mismatching. In conclusion, we analyzed the largest cohort of pediatric patients undergoing CBT over the past 3 decades. OS, DFS and engraftment have improved over time accompanied b decreases in TRM and acute GVHD. Relapse and chronic GVHD were stable and remain low. These improvements are explained by the increased availability of high quality banked CBUs enabling selection of closer HLA matching and units with higher cell doses. The numbers of CBTs have decreased in the past decade, but these results support the ongoing use of CBT in children lacking matched related or unrelated donors. [Formula presented] Disclosures: Kurtzberg: Neurogene: Consultancy;CryoCell: Patents & Royalties: Duke licensed IP, and data and regulatory packages for manufacturing and use of cord blood and cord tissue MSCs in the treatment of patients with hypoxic ischemic encephalopathy, cerebral palsy, autism, acute ischemic stroke, COVID-ARDS, and COVID-MIS-C.;Sinocell: Patents & Royalties: Duke licensed IP, data, and regulatory packages for use of autologous and sibling cord blood to treat children with cerebral palsy.;Celularity: Current holder of stock options in a privately-held company. Troy: SinoCell: Patents & Royalties;CryoCell: Patents & Royalties;Bristol Myers Squibb: Research Funding;Synthetic Biologics: Honoraria;Gamida Cell: Consultancy;The EMMES Corporation: Consultancy;The Community Data Roundtable: Consultancy;AegisCN: Consultancy.
ABSTRACT
The introduction of post-transplant cyclophosphamide (PTCy) has circumvented the need for T-cell depletion following haploidentical stem cell transplantation (SCT). By expanding the donor pool for patients from certain ethnic minorities, this has addressed to some degree an important health care disparity issue in SCT. However, a recent registry study showed increased incidence GvHD and inferior outcomes in patients receiving haploidentical SCT with PTCy, tacrolimus and mycophenolate mofetil for GvHD prevention as opposed to matched unrelated donor SCT with PTCy-based GvHD prevention. Seeking to improve the results of GvHD prevention in the setting of haploidentical SCT, we examined a combination of PTCy, abatacept and a short course of tacrolimus (CAST). Abatacept is a recombinant soluble fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) fused to the Fc region of IgG1. Abatacept blocks CD28-CD80I86 axis and prevents T-cell co-stimulation. In early studies, abatacept has shown promising results when added to methotrexate and tacrolimus in matched and mismatched donor SCT. We initiated a phase Ib-II clinical trial for patients with hematological malignancies undergoing haploidentical SCT. Patients received G-CSF mobilized peripheral blood grafts from related haploidentical donors. GvHD prevention consisted of PTCy 50mg/kg IV on day +3 and +4 with forced hydration, abatacept 10mg/kg IV on day +5, +14 and +28 and tacrolimus. Tacrolimus was started on day +5 at 0.02mg/kg/day by continuous IV and adjusted thereafter to maintain a trough level of 5-12ng/mL. Tacrolimus taper was planned to begin on day +60 and complete by day +90 in the absence of GvHD. All patients received standard supportive care including levofloxacin until neutrophil engraftment, posaconazole until day +75, acyclovir for 1 year and, if CMV positive by serology, letermovir until day +100. Pneumocystis Jiroveci prophylaxis was started after neutrophil engraftment and continued until 6 months post-transplant. G-CSF was administered routinely until neutrophil engraftment. Since September 2020, 19 patients were enrolled. Three patients are too early in their post-transplant course and were excluded from this analysis. Patients' characteristics are summarized in the table. All but 2 patients received cryopreserved products. Median times to ANC and platelet engraftment were 18.5 days (14-30) and 28.5 (16-61). All 16 patients achieved full whole blood donor chimerism by day +30. There was no secondary graft failure. With a median follow-up was 149.5 days (41-308) with 10 patients having >120 days and 8 >180 days of follow-up, 4 patients developed skin acute GvHD (all grade I). No patient developed grade II-IV acute GvHD. Two patients developed skin chronic GvHD (limited, both moderate). Both cases were diagnosed following COVID-19 vaccination. Fifteen patients completed tacrolimus taper by day +90. Two patients received systemic steroids, one for treatment of cGvHD. The remaining patients required no further immunosuppressive therapy beyond day +90. CMV activation rate was 25%. One patient had EBV reactivation and required preemptive therapy with 2 weekly rituximab doses. There were no cases of adenovirus, HHV-6 virus or BK virus reactivation. Four patients developed renal insufficiency (3 in the setting of acute sepsis and 1 with thrombotic microangiopathy, which resolved after tapering off tacrolimus. One patient with adult T-cell leukemia/lymphoma relapsed and died. All other patients are alive and well. In summary, our preliminary results suggest that CAST with shortened course of tacrolimus is feasible and seems to offer very promising outcomes with low rates of acute GvHD. The study is accruing actively and the results of a larger cohort with longer follow-up will be presented at the meeting. If confirmed, by improving the outcomes of haploidentical SCT, this regimen may further address a health care disparity issue, offering almost every patient in need of allogeneic SCT an alternative donor op ion with equal outcomes. [Formula presented] Disclosures: Al-Homsi: Daichii Sanyko: Consultancy;Celyad: Other: Advisory Board. Abdul-Hay: Abbvie: Consultancy;Servier: Other: Advisory Board, Speakers Bureau;Jazz: Other: Advisory Board, Speakers Bureau;Takeda: Speakers Bureau;Amgen: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Abatacept - off label use as GvHD prevention Cyclophosphamide - off label use as GvHD prevention
ABSTRACT
[Formula presented] Introduction: During the COVID-19 pandemic, concerns regarding travel logistics and donor safety necessitated a substantial increase in the use of cryopreserved hematopoietic stem cell (HSC) grafts from both related (RD) and unrelated donors (URD) to ensure patients have a graft available prior to the start of conditioning for hematopoietic cell transplantation (HCT). However, pre-pandemic data beyond single center or small multi-center reports are lacking to reassure clinicians that cryopreservation of allogeneic grafts does not adversely impact post-HCT outcomes including hematopoietic engraftment and overall survival (OS). The Center for International Blood and Marrow Transplant Research (CIBMTR) has recently published three retrospective analyses of outcomes in recipients of cryopreserved compared to fresh grafts administered prior to the pandemic. Results have been conflicting and reasons for receipt of cryopreserved grafts were not routinely collected, rendering interpretation of the impact of cryopreservation on clinical outcomes problematic. Since the pandemic provided a unifying rationale (including mandatory cryopreservation required by the National Marrow Donor Program (NMDP) and other major registries) for the majority of patients to receive cryopreserved allografts, we sought to evaluate early post-HCT clinical outcomes in patients reported to the CIBMTR database who received a first allogeneic HCT using cryopreserved grafts from March through August 2020. Methods: Key study endpoints were hematopoietic engraftment and overall survival (OS). We compared these outcomes to those in patients allografted using fresh products transplanted between March through August 2019. Additional patient selection criteria included: 1) recipients in US only, 2) peripheral blood stem cell (PBSC) or bone marrow (BM) grafts, 3) consented to research, and 4) availability of both CIBMTR product infusion and post-HCT day 100 (D100) follow-up form. The Pearson chi-square test was used for comparing discrete variables;the Kruskal-Wallis test was used for comparing continuous variables. Multivariate analysis (MVA) using a Cox proportional hazards model was performed for OS after adjusting for confounders and testing the proportional hazards assumption. Neutrophil engraftment by D28 and platelet engraftment by D100 were analyzed using multivariate logistic regression. Results: This study included 959 and 2,499 recipients of cryopreserved and fresh products, respectively. Patient characteristics are presented in Table 1. Recipients of cryopreserved grafts were older, more likely to receive URD grafts, PBSC as the graft source and post-transplant cyclophosphamide (PTCy) for graft versus host disease (GVHD) prophylaxis. They received lower infused PBSC and BM cell doses. Due to differences in duration of follow-up between the cohorts, follow up for the OS analysis was censored at Days 100 and 180. MVA results are presented in Table 2. No impact of cryopreservation on OS at either D100 (HR 0.93, p=0.72) or D180 (HR 1.10, p=0.34) post HCT was detected (see also Figure 1). When we performed the MVA for OS limiting the analysis to URD recipients only, the results were unchanged. Median time to neutrophil and platelet engraftment were both delayed by 1 day in recipients of cryopreserved grafts (16 vs. 15 days and 21 vs. 20 days, respectively) but there was no difference in the risk of primary graft failure by D28 (OR 1.38, p=0.96). Some delay in D100 platelet engraftment was observed in recipients of cryopreserved grafts (OR 0.67, p<0.005). There were no interactions identified between donor or graft type for OS or engraftment. Other important clinical outcomes such as secondary graft failure, acute GVHD, and early relapse are being analyzed and will be included at the time of presentation. Conclusion: The shift in clinical practice to cryopreserved products necessitated during the pandemic did not adversely impact early post HCT OS or risk of primary graft failure. We caution that follow up is short and it ill be critical to follow this cohort and subsequent recipients of cryopreserved grafts for much longer periods to determine the ultimate impact of cryopreservation on outcomes. Nevertheless, this large multi-center study will be useful to inform clinical decision making both during and following the pandemic. [Formula presented] Disclosures: Devine: Sanofi: Consultancy, Research Funding;Magenta Therapeutics: Current Employment, Research Funding;Tmunity: Current Employment, Research Funding;Vor Bio: Research Funding;Kiadis: Consultancy, Research Funding;Johnsonand Johnson: Consultancy, Research Funding;Orca Bio: Consultancy, Research Funding;Be the Match: Current Employment. Stefanski: Novartis: Honoraria. Shaw: mallinkrodt: Other: payments;Orca bio: Consultancy.
ABSTRACT
Background During 2020, the novel COVID-19 pandemic lead to cryopreservation of allogeneic hematopoietic stem cell (HSCT) grafts based on NMDP and EBMT recommendations, to secure grafts before start of conditioning chemotherapy. We examined the impact of this change in practice on patient outcomes. Methods We retrospectively analyzed the outcomes of 483 patients who received HSCT between Aug 2017 and Aug 2020, at Princess Margaret Cancer Centre, Canada, comparing the outcomes between those who received cryopreserved (CRYO, n=135) or fresh peripheral blood stem cell grafts (FRESH, n=348). Median follow-up: 12.3 months. Probability of overall survival (OS) was calculated using the Kaplan-Meier product-limit method and heterogeneity of time-to-event distribution functions were compared by the log-rank test. Cumulative incidences of aGvHD and cGvHD, relapse, and non-relapse mortality (NRM) were estimated using the cumulative incidence method considering competing risk, and groups were compared using Gray's test. Death was considered as a competing event for relapse, aGvHD and cGvHD, and relapse was considered a competing event for NRM, aGvHD and cGvHD. Results Median age was 58y;54.5% were males. Acute myeloid leukemia was commonest HSCT indication (n=248, 49.1%). Donors: MUD 10/10 n=233;MUD 9/10 (MMUD) n=48, matched related donor (MRD) n=112, Haploidentical n=88. Transplant conditioning: 79 (23%) and 23 (17%) patients received myeloablative conditioning (MAC) in the FRESH and the CRYO groups, respectively (p ns). In the FRESH group, 253 (73%) patients and 114 (84%) patients in the CRYO group received ATG followed by posttransplant cyclophosphamide (PTCy) and Cylosporine GvHD prophylaxis. OS at the 2y timepoint, FRESH group (n=348), was 67.0% (61.1-72.3%), compared to 48.7% (38.1-58.4%) for patients in the CRYO group (n=135), p=0.002, Figure 1a. This was mainly due to MRD cohort outcomes: 2y OS in MRD FRESH group (n=65), was 85.2% (73.3-92.0%), compared to 45.1% (29.9-59.1%) in MRD CRYO group (n=47), p<0.001, Figure 2a. Multivariate analysis (MVA) for OS, significant factors were increasing patient age, DRI high/v.-high, HCT-CI ≥ 3, Donors: Haplo and MMUD, cryopreservation, Table 1. NRM at 1y for FRESH (n=348) 17% (13.2-21.2) vs CRYO (n=135) 22.1 % (14.8-30.4), p ns. However, in the MRD cohort, NRM at 1y for FRESH group (n=65), was 1.5% (0.1-7.4%), compared to 15.4% (6.6-27.4%) for CRYO group (n=47), p=0.003, Figure 2b. On MVA, NRM adverse significant factors were patient age, DRI high/v.-high, Donors: Haplo and MMUD, Table 1. Cumulative incidence (CI) of relapse at 2y for FRESH 22.4% (17.5-27.7) vs CRYO 27.0 % (18.8-35.9) p=0.07. The CI of moderate-severe cGvHD at 1y for FRESH group (n=315) was 21.5% and 10.8% in the CRYO group, p=0.027, Figure 1c. Patients with FRESH 10/10 MUDs (n=180), had CI of moderate-severe cGvHD at 1y of 20.6%, compared to CRYO 10/10 MUDs (n=35), 6.0% p ns for MUDs;FRESH MRD (n=64) CI was 30.1%;and CRYO MRD (n=43) 10.3%, p=0.008 for MRD, Figure 1d. On MVA, significant adverse factors for chronic GvHD were increasing donor age, male recipient/female donor, whilst graft CRYO was protective, Table 1. GvHD-and Relapse free Survival (GRFS) at 2y for FRESH 54.0% (47.9-59.6) vs CRYO 43.4% (33.4-53.0) p<0.05, Figure 1b. However, in the MRD cohort, GRFS at 2y in FRESH group (n=65), was 74.2% (61.3-83.4%), compared to 40.7% (26.3-54.6%) for CRYO group (n=47), p=0.001;other donor types no difference, Figure 1c. On MVA, significant factors correlated with worse GRFS were: DRI high and very-high, cryopreservation, Donors: Haplo and MMUD, Table 1. Compared to FRESH group, CRYO group experienced reduced cGvHD, delay in neutrophil engraftment, higher graft failure and increased CMV reactivation, with no difference in relapse incidence or acute GvHD. Conclusion Cryopreservation was associated with inferior outcomes post-HSCT particularly in the MRD cohort, possibly due to combination ATG and post-transplant cyclophosphamide impacting differential tolerance to cryopreservation on components of the stem ce l graft;further studies are warranted to elucidate mechanisms for this observation. [Formula presented] Disclosures: Law: Novartis: Consultancy;Actinium Pharmaceuticals: Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding. Kim: Bristol-Meier Squibb: Research Funding;Paladin: Honoraria, Research Funding;Pfizer: Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mattsson: MattssonAB medical: Current Employment, Current holder of individual stocks in a privately-held company.
ABSTRACT
Background: In November 2020, the U.S. Food and Drug Administration (FDA) issued emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild to moderate COVID-19 who are at high risk for disease progression. These mAbs reduce the risk of hospitalization in the general population. However, its efficacy and safety in immunocompromised hematology patients are not known. Methods: From November 9th, 2020, until February 28th, 2021, all adult hematology patients with mild to moderate COVID-19 disease who received monoclonal antibodies within 10 days of symptoms onset were included. Patients who were asymptomatic, had severe or critical COVID-19 disease, or were hospitalized at the time of COVID-19 diagnosis were excluded. Baseline demographic, clinical outcomes, and hematologic-related data were extracted. All statistical analysis was performed using SAS statistical software. Results: Thirty-eight hematology patients with mild to moderate COVID-19 disease who received mAb therapy under EUA were included in this study. Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab-imdevimab. Baseline characteristics prior to mAB administration include: 53% female, median age of 51 years (range: 21-80), with 18% above 65 years old. Twenty-eight (74%) patients received cellular therapy: 18 (47%) had undergone allogeneic hematopoietic cell transplantation (HCT), 9 (24%) autologous HCT, and 1 (3%) chimeric antigen receptor T-cell (CAR T) therapy. Among the 17 patients who had COVID-19 disease after HCT, the median time to COVID-19 diagnosis was 22.8 months (range: 2.6-274.4) from HCT to COVID-19 diagnosis. Twelve out of 17 (71%) alloHCT patients were being managed for active graft-vs-host disease (GvHD) at the time of COVID-19 diagnosis (chronic GVHD: n=11 [mild: 4, moderate: 4, severe: 3], acute GVHD (grade 2): n=1). Ten (59%) alloHCT patients were on immunosuppressant therapy at the time of COVID-19 diagnosis. Fifteen (39%) patients were on active treatment for their hematologic malignancy (HM) at the time of COVID-19 diagnosis with a mean of 3 previous lines of treatment (range: 1-6). Additional patient characteristics are shown in Table 1. mAb therapy under EUA was well tolerated in this patient population with only 1 (3%) patient having experienced an adverse reaction characterized as headache. Four (11%) patients were hospitalized due to COVID-19, and 2 (5%) progressed to severe disease. All four patients had received bamlanivimab. The median time for hospitalization from diagnosis of COVID-19 to admission date was 8 days (range: 1-20) while median time from mAB infusion to hospitalization was 7.5 days (range: 0-17). One patient (3%) died within 30 days of COVID-19 diagnosis;the cause of death was COVID-19 disease. Most patients (n=34, 89%) ultimately tested negative for SARS-CoV-2 by PCR after mAb infusion. 34% of patients (n=13) cleared the virus within 2 weeks of receiving mAb infsuion. The median time to clearance of viral shedding was 25.5 days (range: 7-138). After mAb infusion, most patients (10/15;67%) who were previously on active treatment for HM prior to diagnosis of COVID-19 resumed therapy for their HM with a median delay of 21.5 days (range: 12-42). We observed a significant difference in hospitalization was amongst patients who received a HCT vs. non-HCT (0%, 0/26 and 36%, 4/11 respectively;p<0.01). None of the other patient characteristics, which included: gender, ethnicity, age, BMI, smoking, obesity, chronic kidney disease, diabetes mellitus, hypertension, coronary vascular disease, and lung disease, were associated with significantly increased rate of hospitalization. Conclusion: This study demonstrates that SARS-COV2 specific mAb use in malignant hematology patients under EUA was safe and may reduce hospitalization as reported in the literature amongst those at high risk for disease progression. Thus, the access to SARS-COV2 mAb in this population who is at increased risk for complications from SARS-COV2 infection is critical in reducing progression to severe COVID-19 disease and hospitalization. [Formula presented] Disclosures: Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;CTI BioPharma: Membership on an entity's Board of Directors or advisory committees;BMS: Speakers Bureau. Aribi: Seagen: Consultancy. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Koller: Novartis: Consultancy. Nikolaenko: Rafael Pharmaceuticals: Research Funding;Pfizer: Research Funding. Shouse: Beigene: Honoraria;Kite Pharma: Speakers Bureau. Stein: Amgen: Consultancy, Speakers Bureau;Celgene: Speakers Bureau;Stemline: Speakers Bureau. Marcucci: Abbvie: Other: Speaker and advisory scientific board meetings;Novartis: Other: Speaker and advisory scientific board meetings;Agios: Other: Speaker and advisory scientific board meetings. 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. Dadwal: AlloVir: Research Funding;Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Astellas: Speakers Bureau;Shire/Takeda: Research Funding;Aseptiscope: Consultancy;Janssen: Other: Investigator;Karius: Other: Investigator. Al Malki: CareDx: Consultancy;Rigel Pharma: Consultancy;Jazz Pharmaceuticals, Inc.: Consultancy;Neximmune: Consultancy;Hansa Biopharma: Consultancy.
ABSTRACT
Use of Cryopreserved Allogeneic PBSC Results in Delayed Engraftment And Increased Incidence of Poor Graft Function Introduction: During COVID Pandemic, national and international transplant centres agreed to use cryopreserve the donor PBSC as a safer option to deliver allogeneic transplants. Published data suggests that use of cryopreserved allogeneic PBSC is safe and comparable to use of fresh PBSC but cryopreservation of stem cells may lead to cell loss and hence efficacy. During COVID pandemic, use of cryopreserved allogeneic PBSC was adopted as policy on 01/06/2020. This look back analysis evaluates the impact of change in policy. Aims: Evaluate Engraftment time, compare with historical data, blood component support, and use of growth factors Methods and Materials: Data was collected from health records (paper and electronic) and laboratory records. Transplant features and engraftment kinetics were analysed. Results: Group A June 2020 to November 2020, 19 patients [M: 13;F: 6;median age: 50yr (range: 23-69)] who received cryopreserved allogeneic PBSC were compared to 35 patients [M:24;F:11;median age: 59yr (range: 21-71)] receiving fresh allogeneic PBSC for engraftment kinetics. There were no differences between two groups regarding underlying diagnosis (p=0.31), sex mismatch, CMV mismatch, blood group mismatch, reduced intensity conditioning [RIC](p=0.28), type of donor (p=0.98) or use of Alemtuzumab (p=0.88). Median infused Cell dose in group A was 5.3 (3.4-7.16) and in group B 4.9 (1.03-6.85), [p=0.11]. Neutrophil engraftment was significantly faster with fresh PBSC as compared to cryopreserved PBSC (16d vs. 25d, p=0.0025) predominantly with MUD (18d vs. 27d, p=0.009) and RIC (16d vs. 25d, p=0.009). Platelet engraftment to 25 was faster with fresh PBSC (13d vs. 20d, p=0.021) with delayed engraftment in MUD (20d vs. 13d, p=0.006) and RIC (23d vs. 13d, p=0.039). Day to engraftment per unit CD34 was shorter with fresh PBSC for neutrophils (median: 3.2, range: 2.0-7.7 vs. 5.3, range: 2.5-16.7;p=0.006) and platelets (median: 2.4, range: 1.7-25 vs. 3.8, range: 2.2-25;p=0.001) but only for MUD. This suggests 35-40% less efficiency with use of cryopreserved PBSC. There was no difference in the need for transfusion support [RBCs (6 units vs. 3 units, p=0.32);platelets (5 pools vs. 7 pools, p=0.33)]. G-CSF use was higher with cryopreserved PBSC in RIC (54% vs. 20%, p=0.031). Two patients experienced TRM before day 90 (3.7%). At day 90, 17/52 (32.7%) had cytopenia in one lineage and 8/52 (16%) had cytopenia in more than one lineage. Delayed engraftment was observed in 10 of 33 patients (30.3%) transplanted in 2020 and the only significant association was use of cryopreserved PBSC (0% vs. 53%, p=0.001). There was no difference in the incidence of aGVHD, hepatic VOD, microangiopathy and bacterial infections. Numbers are not sufficient to make disease specific comparisons. Conclusion: Cryopreserved PBSC result in delayed neutrophil and platelet engraftment predominantly with MUDS and RIC. Incidence of delayed engraftment and poor graft function is higher. Per unit CD34 dose, cryopreserved PBSC are 30-40% less efficient to achieve engraftment. Delayed engraftment with cryopreserved PBSC especially in MUD raises the possibility that time from harvest to cryopreservation contributes to reduced efficacy. Based on these findings it was decided to infuse higher CD34 dose (6-7x10