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Introduction: The literature comparing outcomes between myeloablative (MAC) and reduced intensity conditioning (RIC) for acute myeloid leukemia (AML) is conflicting. Methods: We retrospectively analyzed 451 patients who underwent allogenic hematopoietic cell transplantation (alloHCT) for AML in complete remission (CR) with either RIC (n = 331) or MAC (n = 120) with the use of dual T‐cell depletion as graft‐versus‐host disease (GVHD) prophylaxis. Results: Univariate analysis demonstrated nonrelapse mortality (NRM) at 2 years was 19.1% for MAC and 22.5% for RIC (p =.44). Two‐year cumulative incidence of relapse (CIR) was 19.8% for MAC and 24.5% for RIC (p =.15). Two‐year overall survival (OS) was 61% and 53% for MAC and RIC, respectively (p =.02). Two‐year graft‐versus‐host disease relapse‐free survival (GRFS) was 40.8% for MAC and 33.7% for RIC (p =.30). A propensity score‐matched analysis was done matching patients for age, HLA match, in vivo T‐cell depletion, and Disease Risk Index (DRI). Two‐year OS was 67% for MAC, 66% for RIC (p =.95). A subgroup analysis identified that matched related donor transplants benefit from MAC with OS at 2 years 82.6% versus 57.3% for RIC (p =.006). Conclusions: In the matched‐related donor setting, MAC regimens may offer superior survival. Overall, for our cohort of predominantly in vivo T‐cell depleted patients the outcomes of MAC and RIC were similar. [ABSTRACT FROM AUTHOR]

Abstract: T-cell deficiency after allogeneic stem cell transplantation (ASCT) is common and has major impact on clinical outcome. In this retrospective study 210 patients were analyzed with regards to levels of T-cell receptor excision circles (TRECs) during the first 24months after transplantation. We could for the first time show a significant correlation between the use of bone marrow grafts and higher TREC levels >6months post-ASCT (p <0.001). Treatment with anti-thymocyte globulin was correlated with lower TREC levels ≤6months post-ASCT (p <0.001). Patients with TREC levels above median at 3months had a superior overall survival, 80% vs. 56% (p =0.002), and lower transplantation-related mortality, 7% vs. 21% (p =0.01). We conclude that graft source and conditioning regimen may have a significant effect on T-cell reconstitution after ASCT and can thus affect outcome. These results strongly support the use of TREC measurement as part of the standard repertoire of immunological monitoring after ASCT. [Copyright &y& Elsevier]

Bronchiolitis obliterans (BO) is a serious pulmonary complication after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the diagnostic methods used, the incidence of BO, risk factors, and outcome in patients with BO at our center. The study included 527 HSCT patients transplanted between 1995 and 2003. Lung function tests (n = 1177) and risk factor analyses were performed in all patients. Chest X-rays and high-resolution tomographies were investigated in patients with BO. The incidence of BO was 4.8%, as the diagnosis was established in 25 patients (4 children). Median time between HSCT and diagnosis of BO was 356 (84-1823) days. Eight patients (32%) had radiologic changes consistent with BO. Forced expiratory volume for 1 second (FEV1) and forced expiratory flow at 50% (FEF50) and 75% (FEF75) of forced vital capacity (FVC) produced median values that were 49%, 25%, and 18% of the reference values at the time of BO diagnosis. FEF75 was reduced before BO diagnosis in 7 patients (28%). In a multivariate risk factor analysis, chronic graft-versus-host disease (cGVHD) was found to be associated with BO (P < .001), whereas donor lymphocyte infusion (DLI) diminished the risk (P = .02). For 10 patients with late BO (>1 year after HSCT), 80% survived 5 years after diagnosis, compared to 38% survival in 15 patients with early-onset BO (P = .06). We conclude that lung function tests with a persistent decrease in FEV1 were more important than radiographic methods to recognize and monitor BO, that FEF75 may serve as an early warning of BO, and that late-onset BO appears to be associated with better outcome. Chronic GVHD was confirmed as a risk factor, and administration of DLI may diminish the risk. [Copyright &y& Elsevier]

Remberger M, Mattsson J, Olsson R, Ringdén O. Second allogeneic hematopoietic stem cell transplantation: a treatment for graft failure. Clin Transplant 2011: 25: E68-E76. © 2010 John Wiley & Sons A/S. We evaluated the results in 20 recent patients treated with a second hematopoietic stem cell transplantation (HSCT) after graft failure (GF). There were 10 children <18 yr of age. Ten patients had a non-malignant disease, and the other 10 had a malignant disease. In most of the transplantations, fludarabine-based reduced intensity conditioning (RIC) was given. Bone marrow was given to 11 patients, peripheral blood system cell (PBSC) in seven and cord blood to two patients. For the second transplantation (n = 20), a new donor was used in nine cases, while the initial donor was used in 11 transplants. Eight patients (40%) suffered from a second GF. Five of these patients were treated with a third HSCT. The probability of survival was 65% one yr and 60% three yr after the second HSCT. No difference in survival was found between patients transplanted with a new donor (56%) compared to those using the original donor (64%). The three-yr survival was 70% for children compared to 50% for adults (p = ns). Patients with a non-malignant disorder showed a three-yr survival of 90% compared to 20% in patients with a malignant disease (p = 0.005). We concluded that re-transplantation using RIC is a valid option for GF, especially in patients with non-malignant disorders. [ABSTRACT FROM AUTHOR]

Sixty-one leukaemia patients treated with haematopoietic stem cell transplantation (HSCT) from a genomic human leucocyte antigen (HLA)-A, -B and –DRβ1 matched unrelated donor (MUD) were compared with 121 patients with an HLA-identical sibling donor. All patients received conventional conditioning. We selected all patients with unrelated donors who received optimal antithymocyte globuline (ATG) dose, 6 mg/kg. One hundred and seven patients received stem cells from peripheral blood and 75 patients received bone marrow (BM) cells. The incidences of acute graft-versus-host disease (GVHD) grades II–IV were 33.4% and 34.7% in the MUD and sibling group, respectively. After year 2001, the incidence of chronic GVHD was similar in the two groups (27.8% vs. 25.8%). There was no difference in overall survival (60% vs. 60%), transplant-related mortality (18.6% vs. 16.6%) and relapse (23% vs. 26.4%) between the two groups. Conclusion: Haematopoietic stem cell transplantation with unrelated donors results in similar GVHD, relapse and survival as compared to using sibling donors. Reasons for this may be improved tissue-typing techniques and supportive care and optimisation of the ATG dose. [ABSTRACT FROM AUTHOR]

Abstract: Graft failure is a significant complication following allogeneic hematopoietic cell transplantation (alloHCT). It may result from rejection caused by recipient T cells, natural killer (NK) cells, or antibodies. It is increased in HLA-mismatched grafts, unrelated grafts, T cell-replete transplants, sensitized patients, and in patients treated with reduced-intensity conditioning (RIC). In recipients of unrelated grafts, graft failure is increased in patients receiving major AB0 blood group mismatched transplants (P = .008). Recent data also suggest that donor-specific antibodies to CD34+/VEGFR-2+ cells may be involved in graft failure after alloHCT. Graft failure may be overcome by more intensified conditioning, increased cell dose, or more effective immunosuppression. With more frequent use of RIC, cord blood grafts and other HLA-mismatched transplants, graft failure is an increasing problem after alloHCT. [Copyright &y& Elsevier]

Pulmonary complications after allogeneic hematopoietic stem-cell transplantation (HSCT) remain 1 of the most important causes of morbidity and mortality. This study evaluates the change over time of incidence, aetiology and risk factors for death related to pneumonia within 3 months after HSCT. 997 patients who underwent HSCT were studied retrospectively. Most patients (83%) had a haematological malignancy. The majority (89%) had an HLA-A, -B, and -DR matched related or unrelated donor. Conditioning consisted of cyclophosphamide and total-body irradiation or busulfan and graft-versus-host disease prophylaxis of cyclosporin and methotrexate in most cases. Death related to pneumonia occurred in 56 (5.6%) patients. Cytomegalovirus (37%) was the main pathogen involved, especially during the first 2 decades studied. In the multivariate risk factor analysis, we found that death from pneumonia was significantly associated with receiving a T-cell depleted graft (p<0.001), bacteraemia (p=0.001), and y of transplantation (p<0.001). In patients receiving a transplant during the last decade, the incidence of death related to pneumonia was 2.8% compared to 8.9% during the first decade. We conclude that the rate of mortality related to pneumonia has decreased over time, possibly as a result of improved diagnostic, prophylactic and therapeutic methods and treatment. [ABSTRACT FROM AUTHOR]

To determine the graft-versus-leukemia effect after hematopoietic stem cell transplantation (HSCT), we studied 199 patients with acute lymphoblastic leukemia who underwent transplantation at Huddinge University Hospital between 1981 and 2001. Seventy-four patients were in first complete remission (CR1), and 125 were in later stages of the disease. Most patients had an HLA-identical sibling donor. Conditioning consisted mainly of total body irradiation and cyclophosphamide, and graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. Acute GVHD developed in 143 patients and chronic GVHD in 67. The 5-year probability of relapse and relapse-free survival (RFS) were 32% and 49%, respectively, in patients in CR1, as compared with 53% and 33% in those with more advanced disease. In the multivariate risk factor analysis of relapse, we found that the absence of chronic GVHD (P < .001), absence of herpes simplex virus infection after HSCT (P = .003), combination prophylaxis with methotrexate and cyclosporine (P = .01), and >6 weeks from the diagnosis to CR (P = .025) were independent risk factors for relapse after HSCT. Factors associated with a better relapse-free survival were chronic GVHD (P < .001), ABO blood group mismatch (P = .006), younger patient age (P = .01), and an HLA-matched donor (P = .01). The association between herpes simplex virus infection and a low frequency of relapse is a new observation and may indicate that viral antigens play a role in the induction of an antileukemic effect. [Copyright &y& Elsevier]

We report the clinical outcome and results of chimaerism analysis in various cell lineages of 30 patients given non-myeloablative conditioning, followed by allogeneic stem cell transplantation (SCT). The commonest diagnoses were chronic myelogenous leukaemia (n = 11) and solid tumours (n = 11). Twenty-one patients received SCT from human leucocyte antigen (HLA)-identical siblings and nine from matched unrelated donors. Median patient age was 53 (28–77) years. Four non-myeloablative protocols were used, including fludarabine (30 mg/m2 × 3–6), busulphan (4 mg/kg × 2), cyclophosphamide (Cy) (30 mg/kg/day × 2) or total body irradiation (2 Gy), and anti-thymocyte globulin. The patients were analysed by polymerase chain reaction (PCR) analysis of minisatellites on days 14, 21 and 28, then every other week up to 3 months and monthly thereafter. All samples were cell separated for T, B and myeloid cells using immunomagnetic beads. Eighteen patients were alive at a median follow-up of 11 (6–20) months. Acute graft-versus-host disease (GVHD) occurred in 22 patients. Eighteen of the 22 patients with acute GVHD showed mixed chimaerism (MC) in the T-cell fraction at the time of acute GVHD. However, all patients with acute GVHD showed donor chimaerism (DC) in the T-cell fraction median 76 (7–414) days after onset versus three out of eight patients without acute GVHD, P < 0·001]. Disease response was diagnosed in 15 patients, median 100 (37–531) days after SCT. At the time of disease response, six out of15 patients showed MC in the T-cell fraction. In conclusion, mixed chimaerism in the T-cell fraction is common at the time of acute GVHD and disease response in patients conditioned with non-myeloablative therapy. [ABSTRACT FROM AUTHOR]

To prevent graft rejection and graft-versus-host disease (GvHD) after allogeneic stem-cell transplantation (ASCT), 56 children were given polyclonal anti-T-cell globulin (ATG) as part of the conditioning regimen. Of the 56 children in the cohort, 27 had a non-malignant disease and 29 had different hematological malignancies. Eight were in first remission of leukemia and the remainder in later stages. Donors were in 16 cases a human leucocyte antigen (HLA)-identical sibling and in 40 a matched unrelated donor (MUD). The control group comprised 16 patients with an HLA-identical donor; the children in this group were not treated with ATG. Side-effects related to the ATG treatment occured in 63% of the patients and included fever, chills, headache, dyspnoea, nausea/vomiting, body pain, fall in blood pressure, and transient respiratory arrest. Engraftment occured in 55 (98%) of the ATG-treated patients at a median of 17 (11–27) days after ASCT. One rejection occured at 23 days post-SCT. The probabilities of acute graft-versus-host disease (GvHD) of grades II–IV were 6% for patients with an HLA-identical donor, 12% for controls, and 26% for the MUD group. Chronic GvHD occured in 20%, 50%, and 50% of patients in the three groups, respectively. Transplant-related mortality rates at 100 days were 6%, 6%, and 7%, respectively. The 5-yr survival rate was 94% and 81% using sibling donors, with and without ATG respectively, and 53% using unrelated donors (p = 0.002). Disregarding donor type, among the ATG-treated patients 5-yr survival rates were 46% in patients with a malignant disease and 77% in non-malignant disorders. Relapse and relapse-free survival rates were 42% and 46%, respectively. Five out of 12 patients who showed an early full donor chimerism in the T-cell lineage developed acute GvHD of grades II–IV, compared to none out of 13 patients being mixed chimeras (p = 0.01). Hence, the use of polyclonal ATG as part of conditioning prior to ... [ABSTRACT FROM AUTHOR]

Letermovir, a novel anti‐cytomegalovirus (CMV) agent acts by inhibiting the viral terminase complex and is approved for primary prophylaxis in CMV seropositive patients post allogeneic hematopoietic cell transplantation (HCT). The favorable efficacy and safety profile make it an attractive option for use as secondary prophylaxis in patients at high‐risk for CMV reactivation. In this study, we report the efficacy and safety of letermovir secondary prophylaxis after at least one treated episode of CMV reactivation in a cohort of 39 high‐risk patients. Thirty two (82%) patients received anti‐thymocyte globulin (ATG), 27 (69%) received a combination of ATG and post‐transplant cyclophosphamide for graft‐versus‐host disease (GVHD) prophylaxis. Twenty one patients (54%) received CMV seronegative grafts. In addition, 18 (46%) patients had HLA mismatched unrelated or haploidentical donors while 18 (46%) had active GVHD requiring immunosuppression at the time of commencing secondary prophylaxis. Letermovir was initiated at a median of 47 days (range, 41–56) after HCT and was administered for a median duration of 77 days (range, 46–90). A single breakthrough CMV reactivation was noted in this high‐risk cohort. Four additional episodes of CMV reactivation occurred at a median of 28 days (range, 23–59 days) after discontinuation of secondary prophylaxis. The drug was well tolerated and 77% of the cohort completed the planned duration of secondary prophylaxis. None of the patients discontinued treatment due to treatment‐related adverse effects. In conclusion, letermovir is effective and well tolerated and may be considered for secondary prophylaxis in patients at high risk for CMV reactivation. Prospective studies are required to validate these findings. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) reactivation post‐allogeneic hematopoietic cell transplantation (post‐alloHCT) increases morbidity and mortality. We sought to determine the frequency of CMV seroconversion in patients pre‐alloHCT and to investigate the impact on posttransplant outcomes. We retrospectively investigated 752 adult patients who underwent alloHCT at our center from January 2015 to February 2020 before the adoption of letermovir prophylaxis. CMV serology was assessed at consult and pretransplant. The cohort was divided into four groups based on pretransplant CMV seroconversion: negative to positive (Group 1), positive to negative (Group 2), consistently negative (Group 3), and consistently positive (Group 4). Eighty‐nine patients (12%) had seroconverted from negative to positive, 17 (2%) from positive to negative, 151 (20%) were consistently seronegative, and 495 (66%) were consistently seropositive pretransplant. For the four CMV serostatus groups, cumulative incidence of CMV reactivation at 6 months posttransplant was 4.5%, 47.1%, 6.6%, and 76.6% for Groups 1, 2, 3, and 4, respectively (p < .0001). No differences between groups were seen regarding Grade III–IV acute graft‐versus‐host disease (GVHD) (p = .91), moderate/severe chronic GVHD (p = .41), or graft failure (p = .28). On multivariable analysis, there was no impact of CMV serostatus group on overall survival (p = .67), cumulative incidence of relapse (p = .83) or non‐relapse mortality. alloHCT patients who demonstrate CMV seroconversion pretransplant from negative to positive have a very low risk of CMV reactivation posttransplant. The observed seroconversion may be due to passive CMV immunity acquired through blood products. Quantitative CMV immunoglobulin G/immunoglobulin M pretransplant may help differentiate between true seroconversion and passively transmitted CMV immunoglobulin. [ABSTRACT FROM AUTHOR]

The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is influenced by many factors (underlying disease, HLA-matching, patient and donor age, CMV serostatus, co-morbidities, conditioning regimen, GVHD prophylaxis and graft source and composition). The number of T-cells contained in the graft is associated with the incidence and severity of GvHD. The effect of CD34+ cell dose in HSCT on overall survival and incidence of acute and chronic GvHD is less well established. We analyzed transplant outcomes in 189 patients with hematological malignancy and sibling donor receiving G-CSF mobilized peripheral blood stem cell grafts. Myeloablative conditioning was given to 88 patients and reduced intensity conditioning to 101 patients. Median CD34+ cell dose was 5.6 × 106/kg (0.6-17.0). Anti-thymocyte globulin (ATG) was not given. Median time to neutrophil engraftment (ANC >0.5 × 109/L) was 17 days. In multivariate analysis <5 × 106/CD34+ cells/kg correlated to slower engraftment, measured as later than median days-to-engraftment (OR 2.62, 95% CI 1.27-5.41, p=0.008). The 5-year overall survival (OS) for all patients was 47%. The best 5-year OS (71%) was seen in patients receiving 6-7 × 106CD34+cells/kg (HR: 0.43, 95% CI: 0.24-0.78, p=0.005) (fig 1). Transplant related mortality at 1 and 5 years was 19% and 28%, respectively. The lowest TRM (15%) was found among patients given a CD34+ cell dose of 6-7 × 106cells/kg (HR: 0.41, 95% CI: 0.18-0.92, p=0.03). The cumulative incidence of relapse (RI) for all patients was 29%. Increased RI (41%) was found in patients who received <5 × 106cells/kg CD34+ cells (HR: 1.89, 95% CI: 1.09-3.29, p=0.024). In total, 86 (46%) and 92 (56%) patients developed acute and chronic GvHD, respectively. The cumulative incidence of acute GVHD grades II-IV in the whole cohort was 40%. The lowest incidence (33%) of aGVHD II-IV was found among patients receiving a high cell-dose. In the corrected multivariate analysis, a CD34+ cell dose of >6.5 × 106cells/kg was associated with a lower incidence of aGVHD II-IV (RH: 0. 53, 95% CI: 0.29-0.97, p=0.04). In the corrected multivariate analysis a CD34 cell dose of 6-7 × 106/kg was associated with better OS and lower TRM, while a CD34 cell-dose of <5 × 106/kg was associated with more relapse and less cGVHD. A high CD34 cell-dose (>7 × 106/kg) correlated to less aGVHD II-IV. The CD34 cell dose has impact on the outcome in sibling donor HSCT using peripheral-blood stem-cells. [ABSTRACT FROM AUTHOR]

Measurable residual disease (MRD) monitoring independently predicts long-term outcomes in patients with acute myeloid leukemia (AML). Of the various modalities available, multiparameter flow cytometry–based MRD analysis is widely used and relevant for patients without molecular targets. In the transplant (HCT) setting, the presence of MRD pre-HCT is associated with adverse outcomes. MRD-negative remission status pre-HCT was also associated with longer overall (OS) and progression-free survival and a lower risk of relapse. We hypothesize that the combination of disease risk and MRD at the time of first complete remission (CR1) could identify patients according to the benefit gained from HCT, especially for intermediate-risk patients. We performed a retrospective analysis comparing the outcomes of HCT versus non-HCT therapies based on MRD status in AML patients who achieved CR1. Time-dependent analysis was applied considering time-to-HCT as a time-dependent covariate and compared HCT versus non-HCT outcomes according to MRD status at CR1. Among 336 patients assessed at CR1, 35.1% were MRD positive (MRDpos) post-induction. MRDpos patients benefitted from HCT with improved OS and relapse-free survival (RFS), while no benefit was observed in MRDneg patients. In adverse-risk patients, HCT improved OS (HR for OS 0.55; p = 0.05). In intermediate-risk patients, HCT benefit was not significant for OS and RFS. Intermediate-risk MRDpos patients were found to have benefit from HCT with improved OS (HR 0.45, p = 0.04), RFS (HR 0.46, p = 0.02), and CIR (HR 0.41, p = 0.02). Our data underscore the benefit of HCT in adverse risk and MRDpos intermediate-risk AML patients. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR) T cell therapy is associated with high risk of adverse events. Glucocorticoids (GCs) are cornerstone in the management of high-grade cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Given the potentially deleterious effects of GCs on CAR T cells anti-tumor activity, increasing our understanding of GCs impact on CAR T cells is crucial. Methods: Using several CAR T cells i.e., CD19, mesothelin (MSLN)-CD28 and MSLN-41BB CAR T cells (M28z and MBBz), we compared phenotypical, functional, changes and anti-tumor activity between i) transduced CD19 CAR T cells with untransduced T cells, ii) M28z with MBBz CAR T cells induced by Dexamethasone (Dx) or Methylprednisolone (MP) exposures. Results: Higher levels of GC receptor were found in less differentiated CAR T cells. Overall, Dx and MP showed a similar impact on CAR T cells. Compared to untreated condition, GCs exposure increased the expression of PD-1 and TIM-3 and reduced the expression of LAG3 and function of T cells and CAR T cells. GC exposures induced more exhausted (LAG3 + PD1 + TIM3 +) and dysfunctional (CD107a-INFγ-TNF-IL2-) untransduced T cells in comparison to CD19 CAR T cells. GC exposure impaired more CD4 + than CD8 + CD19 CAR T cells. GC exposures increased more PD-1 expression associated with reduced proliferative capacity and function of M28z as compared to MBBz CAR T cells. CAR T cells anti-tumor activity was greatly affected by repeated GC exposure but partly recovered within 48h after GCs withdrawal. Conclusions: In summary, GCs impacted phenotype and function of untransduced and CAR T cell with different magnitude. The nature of the CAR costimulatory domain influenced the magnitude of CAR T cell response to GCs. [ABSTRACT FROM AUTHOR]

Background: Cytomegalovirus (CMV) is associated with morbidity and mortality following allogeneic hematopoietic cell transplantation (alloHCT). Letermovir is a novel antiviral agent that prevents CMV reactivation in alloHCT patients, with limited data regarding influence on post‐alloHCT outcomes. Methods: We retrospectively examined 273 alloHCT recipients, 158 in the non‐letermovir cohort (NLC), and 115 in the cohort using letermovir prophylaxis (LC). Patients that received letermovir were CMV‐seropositive and met criteria for high risk of CMV reactivation. Results: Median start of letermovir was 21 days post‐alloHCT, median duration of prophylaxis was 86 days. Letermovir prophylaxis demonstrated a statistically significant reduction in first CMV reactivation (at 200 days post 63.9% in the NLC vs. 35.7% in the LC; p <.001). On univariate analysis at 1 year, overall survival (OS) for NLC was 79.6% and 79.5% for LC (p =.54). Non relapse mortality (NRM) at 1 year for NLC was 12% and 12.3% for LC (p =.69). Cumulative incidence of relapse (CIR) at 1 year was 13.9% for NLC versus 17.1 for the LC (p =.27). On multivariable analysis, there was no significant difference between the two cohorts for OS, NRM, and CIR. Conclusions: Letermovir prophylaxis started at day +21 post‐alloHCT reduced CMV reactivation, with no impact on posttransplant outcomes. [ABSTRACT FROM AUTHOR]

Introduction Chronic graft vs host disease (cGVHD) affects 30-40% of patients (pts) post HSCT (Socie G, et al. Blood. 2014;124:374). Corticosteroids are associated with significant toxicity, and severe cGVHD is associated with low quality of life, despite advances in overall survival (OS). Swedish national registries allow population-based longitudinal studies of pts with cGVHD. Objectives To identify real-world cGVHD pts and investigate the medical resource utilization (MRU) and burden of disease in Sweden. Methods Nationwide population-based high-quality registries were linked and used to identify cGVHD pts (Fig 1) who underwent HSCT from 2006 to 2015 using a novel method. To correct for clinical underdiagnosis, we defined pts with cGVHD as those who, ≥ 6 months (mos) post HSCT, received systemic steroid treatment for ≥ 3 mos alone (mild) or with extracorporeal phosphoresis and/or immunosuppressive treatment (moderate/severe [mod/sev]). Kaplan-Meier analysis of OS was conducted for pts surviving ≥ 100 days post HSCT. We used relative survival framework to compare estimated excess mortality rate ratios (EMRRs). MRU rates were summarized. Results We included 1439 pts who received HSCT from 2006 to 2015; 37.3% were classified as non-cGVHD, 24.0% as mild cGVHD, and 38.6% as mod/sev cGVHD. At a median follow-up of 3.8 years, OS in non-cGVHD pts was inferior to pts with mild or mod/sev cGVHD (Fig 2A); for pts surviving > 100 days post HSCT, 1-year OS was 62.5%, 87.3%, and 94.8%, and 5-year OS was 54.0%, 63.1%, and 66.9%, respectively. Multivariate analysis adjusted for baseline characteristics such as sex, age, calendar period, source, and donor revealed EMRRs of 9.33 (95% CI, 6.12-14.21) for non-cGVHD and 2.55 (95% CI, 1.56-4.2) for mild vs mod/sev cGVHD pts; the difference was greatest during the first year (≥ 6 mos post HSCT; Fig 2B). Mod/sev cGVHD pts had more outpatient hospital visits than non- or mild cGVHD pts (Fig 3), and experienced significantly more health problems, including but not limited to musculoskeletal/connective tissue, eye/adjacent organ, cutaneous/subcutaneous, and digestive diseases, as well as certain infectious/parasitic diseases (incidence rate ratio 0.89 [95% CI, 0.7-1.11] and 0.79 [95% CI, 0.64-0.98], respectively, vs mod/sev cGVHD). Conclusions Analysis of Swedish registry data using a novel method suggests that cGVHD is underdiagnosed. Pts with non- and mild cGVHD had greater risk of death than pts with mod/sev cGHVD, mainly during the first year, potentially due to infections (possibly related to overimmunosuppression). Pts with mod/sev cGVHD lived longer but with more health problems and greater MRU. These data highlight the importance of evaluating immune function and developing new, efficient cGVHD therapies. [ABSTRACT FROM AUTHOR]

Background: Pre-transplant pulmonary function testing (PFT) is essential before allogeneic hematopoietic stem cell transplant (HCT), yet the optimal cutoff value for affecting transplant outcomes remains poorly defined. Study Design: Retrospective analysis of pre-HCT PFT data from 605 consecutive patients at the Princess Margaret Cancer Centre between January 1, 2004 and December 31, 2013 used binary recursive partitioning to identify cutoff values for overall survival (OS) as an endpoint of transplant outcomes. These values were compared to HCT comorbidity index (HCT-CI) FEV1 cutoffs for OS, cumulative incidence of relapse and non-relapse mortality. Results: FEV1 ≥ 81% was the identified cutoff point. The OS rate at 3 years showed 49.8% (FEV1 ≥ 81%) vs. 36.6% (<81%, p < .001). For HCT-CI cutoffs, the OS rate at 3 years for FEV1 ≥ 80%, 66%-80% and =65% were 49.0%, 38.1% and 37.6% (p = .011), respectively. Multivariate analysis confirmed that FEV1 ≥ 81% predicted reduced mortality (HR 0.682, p = .001). Subgroup analysis showed both FEV1 ≥ 81% and FEV1 by HCT-CI cutoffs may stratify patients according to OS and NRM risk in subgroups receiving myeloablative, but not reduced intensity conditioning. Conclusion: FEV1 ≥ 81% can predict OS and NRM in our cohort and is potentially simpler when risk stratifying patients undergoing allogeneic HCT, particularly those receiving myeloablative conditioning. [ABSTRACT FROM AUTHOR]

Purpose: Allogeneic stem cell transplant (allo-HSCT) patients are at risk of malnutrition and weight loss from impaired oral intake resulting from gastrointestinal toxicities, dysgeusia, and psychological effects. Methods: A retrospective review of 264 adult patients transplanted at Princess Margaret Cancer Centre who achieved relapse-free survival up to 3 months after allo-HSCT was performed. Results: Overall incidence of patients who experienced WL (WL) ≥ 10% from HSCT to 3-month post-transplant was 45.9% and from HSCT to 6 months was 56.6%. Patients with ≥ 10% WL from allo-HSCT at 3 months and 6 months had similar 2-year overall survival (OS) compared to those with < 10% WL, 55.7% vs 62.8% (HR = 1.38, p = 0.11) and 71.1% vs 77.2% (HR = 1.37, p = 0.27), respectively. Patients with ≥ 10% WL 3 and 6 months from allo-HSCT also had similar 2-year relapse-free survival (RFS) compared to those with < 10% WL, 48.1% vs 55.8% (HR = 1.26, p = 0.22), and 62.7% vs 69.8% (HR = 1.29, p = 0.31), respectively. The 2-year transplant-related mortality (TRM) was higher for those with ≥ 10% WL from allo-HSCT to 3 months, 35.4% vs 16.9% (HR = 2.39, p = 0.0007) and 6 months, 22% vs 8% (HR = 3.1, p = 0.0034). Although statistical significance was not observed for OS or RFS, patients who experienced ≥ 10% WL 3- and 6-months post allo-HSCT experienced higher 2-year TRM. These results highlight the importance of early intervention and close monitoring of weight post allo-HSCT. Conclusion: Approaches to WL post allo-HSCT should be multifaceted and include members of the interdisciplinary team in order to decrease TRM. [ABSTRACT FROM AUTHOR]

A pilot study conducted in Ontario, Canada, evaluated the safety and effectiveness of placental decidual stromal cells (DSC) in treating severe acute respiratory distress syndrome (ARDS) caused by COVID-19. The study included 19 adult patients with COVID-ARDS who received DSC treatment. The results showed that DSC administration appeared safe, with one patient experiencing a transient hypoxic event related to the infusion. Survival to hospital discharge was significantly higher in the DSC group compared to a control group, and there was a trend towards increased survival to discharge from the intensive care unit. The study supports further evaluation of DSCs in larger, randomized, controlled trials to establish their safety and efficacy in treating severe ARDS. [Extracted from the article]

Background: Inconclusive cytogenetic analysis (IC) at baseline has been reported as a predictor of poor prognosis in patients with acute myeloid leukemia (AML). The mutational profile in this group of patients, and its impact on outcomes have not been reported. Methods: We retrospectively analyzed adult patients (≥18 years) with newly diagnosed AML treated with intensive induction chemotherapy between 2015 and 2019. Patients with any documented cytogenetic abnormalities were excluded. Targeted next generation sequencing (NGS) was performed in all patients. Baseline characteristics, mutation profile, and outcomes were compared between patients with normal cytogenetics(NC) and those with IC. Results: Sixty‐one patients (males 39.3%; median age 59 years) had IC at diagnosis. The proportion of patients with mutations in genes with proven prognostic impact were not different between AML patients with IC and NC. AML patients with NC were more likely to harbor the prognostically favorable NPM1mut/FLT3‐ITDwt mutational combination conferring "favorable" risk status. As a result, a larger proportion of patients in the IC group underwent allogeneic hematopoietic stem cell transplantation (allo HCT; 54.1% vs. 39.6%; p =.02). The 2‐year RFS (55.9% vs. 58.5%; p =.29) and OS (61.9% vs. 66.9%; p =.48) were similar in IC and NC patients. There was no difference in survival of patients who underwent allo HCT when compared with patients who did not (p =.99). Conclusions: Inconclusive cytogenetic analysis may not be an independent prognostic indicator in AML. In such patients, molecular abnormalities detected through NGS or whole genome sequencing are more likely to be informative. [ABSTRACT FROM AUTHOR]

Background: Allogeneic blood and marrow transplantation (alloBMT) is a curative treatment for blood cancers associated with various treatment-related adverse events and morbidities. Current rehabilitation programs are limited for patients undergoing alloBMT and research is urgently needed to test the acceptability and effectiveness of these programs. In response, we developed a 6-month multidimensional longitudinal rehabilitation program that spans from pre transplant to 3 months post transplant discharge (CaRE-4-alloBMT). Methods: This study is a phase II randomized controlled trial (RCT) conducted at the Princess Margaret Cancer Centre in patients undergoing alloBMT. A total of 80 patients stratified by frailty score will be randomized to receive usual care (n = 40) or CaRE-4-alloBMT plus usual care (n = 40). The CaRE-4-alloBMT program includes individualized exercise prescriptions, access to online education through a dedicated self-management platform, wearable technology for remote monitoring, and remote tailored clinical support. Feasibility will be assessed by examining the recruitment and retention rates and adherence to the intervention. Safety events will be monitored. Acceptability of the intervention will be assessed through qualitative interviews. Secondary clinical outcomes will be collected through questionnaires and physiological assessments at baseline (T0, 2–6 weeks pre-transplant), transplant hospital admission (T1), hospital discharge (T2), and 3 months post-discharge (T3). Conclusion: This pilot RCT study will determine the feasibility and acceptability of the intervention and study design and will inform full-scale RCT planning. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) is associated with acute graft-vs.-host disease (aGVHD). The presented study applied a novel multiplex antibody-based proximity extension assay (PEA) proteomic platform that can detect thousands of serum proteins simultaneously for the identification of potential biomarkers of aGVHD. Serum samples from 28 patients who underwent allogeneic HCT for acute myeloid leukemia (AML) were analyzed; 17 were diagnosed with grade II–IV aGVHD while 11 patients were not. Samples collected on day −6, day 0, +14, +30, +60 and +90 post-HCT were analyzed for the relative concentrations of 552 proteins. The concentration of each protein from baseline to the closest time point before onset of aGVHD, or to the latest time point in control patients, was documented. Individualized analysis identified 26 proteins demonstrating ≥3-fold increase at aGVHD onset compared to baseline, eliminating proteins with a similar increase in controls. Another approach used paired t-testing and logistic regression that identified a four-marker panel, including SLAMF7, IL-1ra, BTN3A2 and DAB2, where individual log-likelihood ratios ranged from 3.99 to 8.15 (logistic regression, p=0.004–0.046). When combined, the four-marker panel demonstrated an area under the curve (AUC) of 0.90 (95% CI: 0.78–1.00; p=0.0006) with high negative predictive value of 81.8% and positive predictive value of 86.7%. All four markers play a physiological role in immune regulation. Among these, three were also present in the individualized analysis (SLAMF7, IL-1ra and BTN3A2). We conclude that serum proteins identified using multiplex proteomics, particularly SLAMF7, IL-1ra, BTN3A2 and DAB2, may potentially predict aGVHD. [ABSTRACT FROM AUTHOR]

Introduction: Chronic graft-versus-host disease (cGVHD) is a serious immune-mediated complication after allogeneic haematopoietic stem cell transplantation (HSCT), but in patients with malignancy, cGVHD development is associated with superior survival. Lack of reliable biomarkers and clinical underreporting means there is insufficient understanding of cGVHD clinical outcomes and balance between cGVHD treatment and maintaining beneficial graft-versus-tumour effects. Methods: We performed a Swedish population-wide registry study following patients who underwent allogeneic HSCT 2006–2015. cGVHD status was retrospectively classified using a real-world method based on the timing and extent of systemic immunosuppressive treatment. Results: cGVHD incidence among patients surviving ≥6 months post-HSCT (n = 1246) was 71.9%, significantly higher than previously reported. 5-year overall survival in patients surviving ≥6 months post-HSCT was 67.7%, 63.3%, and 65.3%, in non-, mild, and moderate-severe cGVHD, respectively. Non-cGVHD patients had a mortality risk almost five-fold higher compared to moderate-severe cGVHD patients 12-months post-HSCT. Moderate-severe cGVHD patients had greater healthcare utilization compared with mild and non cGVHD patients. Conclusion: cGVHD incidence was high among HSCT survivors. Non-cGVHD patients had higher mortality during the first 6 months of follow-up; however, moderate-severe cGVHD patients had more comorbidities and healthcare utilization. This study highlights the urgent need for new treatments and real-time methods to monitor effective immunosuppression after HSCT. [ABSTRACT FROM AUTHOR]

Background: Mixed results surround the accuracy of commonly used prognostic risk scores to predict overall survival (OS) and non‐relapse mortality (NRM) in allogeneic hematopoietic stem cell transplant (allo‐HCT) recipients. We hypothesize that a simple prognostic score performs better than conventional scoring systems. Patients and Methods: OS risk factors, HCT‐CI, age‐HCT‐CI, and augmented‐HCT‐CI were studied in 299 patients who underwent allo‐HCT for myeloid and lymphoid malignancies. A scoring system was developed based on results and validated in a different cohort of 455 patients. Results: Two‐year OS was 51% (95% confidence interval (CI) 0.45–0.56); 2‐year NRM was 34% (95% CI 0.29–0.39). HCT‐CI and associated scores were grouped into 0–2 and ≥3. Age and HLA mismatch status were the only risk factors to affect OS in multivariate analysis (p = 0.02 and 0.05, respectively). HCT‐CI and associated scores were not informative for OS prediction. The weighted scoring system assigned 0 to 2 points for age < 50, 50–64, or ≥65, respectively, and 0–1 points for no HLA mismatch versus any mismatch (except HLA‐DQ). Distinct 2‐year OS (62%, 53%, and 38% [p = <0.001]) and NRM (24%, 34%, and 43% [p = 0.02]) groups were characterized. The scoring system was validated in a second independent cohort with similar results on OS and NRM (p < 0.001). Conclusions: A simple scoring system based on recipient's age and mismatch status accurately predict OS and NRM in two distinct cohorts of allo‐HCT patients. Its simplicity makes it a helpful tool to aid clinicians and patients in clinical decision‐making. [ABSTRACT FROM AUTHOR]

Ovarian cancer encompasses a heterogeneous group of malignancies that involve the ovaries, fallopian tubes and the peritoneal cavity. Despite major advances made within the field of cancer, the majority of patients with ovarian cancer are still being diagnosed at an advanced stage of the disease due to lack of effective screening tools. The overall survival of these patients has, therefore, not substantially improved over the past decades. Most patients undergo debulking surgery and treatment with chemotherapy, but often micrometastases remain and acquire resistance to the therapy, eventually leading to disease recurrence. Here, we summarize the current knowledge in epithelial ovarian cancer development and metastatic progression. For the most common subtypes, we focus further on the properties and functions of the immunosuppressive tumor microenvironment, including the extracellular matrix. Current and future treatment modalities are discussed and finally we provide an overview of the different experimental models used to develop novel therapies. • Transcoelomic disease spread of HGSC is a complex multistep process, involving tumor cells, stromal cells and immune cells. • The ECM and fibro-inflammatory tumor microenvironment drive an immunosuppressive and pro-tumorigenic microenvironment. • Advances in immunotherapy, CAR T cell therapy and TME-targeted approaches provide a rationale for novel future treatments. [ABSTRACT FROM AUTHOR]

Introduction: Evidence is emerging to support an association between certain human leukocyte antigen (HLA) alleles and the risk of cytomegalovirus (CMV) reactivation following allogeneic hematopoietic stem cell transplant (allo‐HSCT). The primary aim of this study was to identify HLA alleles associated with resistance or susceptibility to CMV reactivation. Methods: We studied 586 adults who underwent allo‐HSCT for high‐risk hematological malignancies. High‐resolution HLA typing data were available for recipients and donors. HLA class I and II alleles observed at a frequency of >5% in our population were included in the analysis. A CMV viremia level of more than 200 IU/ml on weekly monitoring was considered to be indicative of CMV reactivation. Results: The median follow‐up time in surviving patients was 21 months (range 4–74 months). The cumulative incidence of CMV reactivation at 6 months in the entire cohort was 55% (95% confidence interval [CI] 50.8%–59.2%). Mismatched donors, increasing recipient age, occurrence of acute graft versus host disease and recipient CMV seropositivity were associated with an increased risk of CMV reactivation. HLA B*07:02 (hazard ratio 0.59, 95% CI 0.40–0.83) was associated with a decreased risk of CMV reactivation. Patients who developed CMV reactivation had a lower incidence of relapse, higher transplant‐related mortality (TRM) and lower overall survival (OS) than those without CMV reactivation. There was an adverse correlation of OS and TRM with increasing numbers of CMV reactivations. Conclusion: We observed that HLA B*07:02 was associated with a decreased risk of CMV reactivation. CMV reactivation was associated with lower relapse post‐transplant, but this did not translate into a survival benefit due to higher TRM. [ABSTRACT FROM AUTHOR]

Background Advances in allogeneic hematopoietic stem cell transplant (HSCT) have increased patient survival, although substantial treatment-related toxicity remains, including chronic kidney disease (CKD). We assessed the association between CKD and survival and transplant-specific outcomes in HSCT recipients. Methods We conducted a retrospective study of all 408 adult patients with allogenic HSCT at Princess Margaret Cancer Centre (Toronto, Canada, 2015–18). We used logistic regression to identify risk factors for CKD at 1 year post-transplant. Associations between CKD at 1 year and overall survival, relapse-free survival, graft-versus-host-disease (GVHD)-free/relapse-free survival, relapse and transplant-related mortality were examined using extended time-varying Cox models. In a sensitivity analysis, we restricted the cohort to survivors at 1 year, using standard Cox proportional hazard models to examine associations between CKD and overall survival, relapse-free survival and GVHD-free/relapse-free survival, and Fine and Gray's competing risk models to determine associations between CKD and relapse/transplant-related mortality. Results The prevalence of CKD at 1 year was 19% (46 patients) with median follow-up of 23 months. Multivariable regression identified age at transplant [adjusted OR (aOR) 1.09, 95% confidence interval (95% CI) = 1.05–1.14; P < 0.0001), female gender (aOR 2.83, 95% CI = 1.34–5.97; P = 0.006) and acute kidney injury during the first 100 days (aOR 3.86, 95% CI = 1.70–8.73; P = 0.001) as risk factors for CKD at 1 year. Patients with CKD at 1 year had significantly poorer overall survival than those without CKD, when adjusted for relevant covariates [adjusted HR (aHR) 1.93, 95% CI = 1.02–3.66; P = 0.04 in the time-varying Cox model, and aHR 2.06, 95% CI = 1.04–4.07; P = 0.04 using the standard Cox model]. CKD at 1 year was also associated with worse GVHD-free/relapse-free survival (aHR 1.65, 95% CI = 1.04–2.61; P = 0.03). Conclusions CKD adversely affects the long-term prognosis for allogeneic HSCT recipients, with increased mortality risk and worse GVHD-free/relapse-free survival. [ABSTRACT FROM AUTHOR]

Introduction: Increasing survival of patients with multiple myeloma (MM) has resulted in an increased recognition of therapy‐related hematological malignancies (t‐MDS/AML, t‐ALL, and t‐CMML). There are limited data on the role of allogeneic hematopoietic stem cell transplantation (HCT) in this patient population. Patients and Methods: We retrospectively reviewed patients who underwent HCT for t‐MDS/AML, t‐ALL, and t‐CMML developing after receiving treatment for MM at our center. Patients were analyzed for myeloma characteristics and therapy, time to diagnosis of therapy‐related hematological neoplasms, clinical, laboratory characteristics, transplant details, relapse‐free survival (RFS), and overall survival (OS). Results: Twenty patients underwent HCT for therapy‐related hematological malignancies after MM (t‐MDS/AML = 13, t‐ALL = 6, t‐CMML = 1). Median(range) age at time of transplant was 62.5 (49–73) years and 70% (n = 14) were male. The most common cytogenetic abnormality was complex/monosomal karyotype in 30% (n = 6) followed by monosomy/deletion of chromosome 5 or 7 in 15% (n = 3) of patients each. Donors were human leukocyte antigen matched (10/10 or 6/6) siblings in 30% (n = 6), unrelated in 60% (n = 12) and haploidentical in 10% (n = 2) patients. Estimated 2‐year OS and RFS for the whole cohort were 53.1% and 47.2% respectively. There was a trend toward better survival in patients with t‐ALL when compared to t‐MDS/AML; however, the difference was not statistically significant. We did not find any pre‐transplant or post‐transplant factors that were predictive of survival outcomes after multivariate analysis. Conclusions: Allogeneic HCT provides substantial long‐term disease‐free survival in a proportion of patients with MM‐associated therapy‐related hematological malignancies. Multicenter studies with more patients and longer follow‐up may provide additional information about factors affecting outcomes. [ABSTRACT FROM AUTHOR]

In donor selection for allogeneic stem cell transplant, several factors are considered for potential impact on transplant outcome. Previous publications suggested single HLA‐mismatched unrelated donors (MMUD) may be equivalent to 10/10 matched unrelated donors (MUDs). We retrospectively examined factors affecting outcome in a single‐center study using ATG followed by post‐transplant cyclophosphamide, termed ATG‐PTCy, GvHD prophylaxis. Fifty‐two patients who received grafts from MMUD and 188 patients transplanted from MUD between January 2015 and December 2019, at Princess Margaret Cancer Centre, Canada, were enrolled. All patients received reduced‐intensity conditioning. Overall survival for 9/10 recipients at 2 years was significantly worse, 37.2% versus 68.5% for 10/10 MUDs, p <.001, as were NRM at 1 year 39.5% versus 11.7%, p <.001, and GRFS at 2 years 29.8% versus 58.8%, p <.001, respectively, potentially due to higher incidence of infections including CMV. By multivariable analysis, factors correlating with survival negatively were DRI, and MMUD, whereas for NRM MMUD and increasing age were unfavorable. For GRFS significant unfavorable factors included donor age ≤32 years, female donor to male recipient, DRI high‐very high and MMUD. These data suggest that MMUD, primarily HLA‐A and HLA‐B MMUD, confer significantly inferior outcome despite use of ATG‐PTCy. Further development of novel conditioning regimens and GvHD prophylaxis is needed to mitigate these risks. [ABSTRACT FROM AUTHOR]

During 2020, the concurrent novel COVID‐19 pandemic lead to widespread cryopreservation of allogeneic hematopoietic cell transplant grafts based on National Marrow Donor Program and European Society of Blood and Marrow Transplantation recommendations, in order to secure grafts before the start of conditioning chemotherapy. We sought to examine the impact of this change in practice on patient outcomes. We analyzed the outcomes of 483 patients who received hematopoietic stem cell transplantation (HSCT) between August 2017 and August 2020, at Princess Margaret Cancer Centre, Canada, in the retrospective study, comparing the outcomes between those who received cryopreserved or fresh peripheral blood stem cell grafts. Overall compared with those who received fresh grafts (n = 348), patients who received cryopreserved grafts (n = 135) had reduced survival and GRFS, reduced incidence of chronic graft‐versus‐host disease (GvHD), delay in neutrophil engraftment, and higher graft failure (GF), with no significant difference in relapse incidence or acute GvHD. However, recipients of cryopreserved matched‐related donor HSCT showed significantly worse OS, NRM, GRFS compared with fresh grafts. Multivariable analysis of the entire cohort showed significant impact of cryopreservation on OS, relapse, cGvHD, GF, and GRFS. We conclude that cryopreservation was associated with inferior outcomes post‐HSCT, possibly due to the combination of ATG and post‐transplant cyclophosphamide impacting differential tolerance to cryopreservation on components of the stem cell graft; further studies are warranted to elucidate mechanisms for this observation. [ABSTRACT FROM AUTHOR]

Successful translation of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors has proved to be troublesome, mainly due to the complex tumor microenvironment promoting T cell dysfunction and antigen heterogeneity. Mesothelin (MSLN) has emerged as an attractive target for CAR T cell therapy of several solid malignancies, including ovarian cancer. To improve clinical response rates with MSLN-CAR T cells, a better understanding of the mechanisms impacting CAR T cell functionality in vitro is crucial. Here, we demonstrated superior cytolytic capacity of CD28-costimulated MSLN-CAR T cells (M28z) relative to 4-1BB-costimulated MSLN-CAR T cells (MBBz). Furthermore, CD28-costimulated MSLN CAR T cells displayed enhanced cytolytic capacity against tumor spheroids with heterogeneous MSLN expression compared to MBBz CAR T cells. In this study, we identified CAR-mediated trogocytosis as a potential impeding factor for successful MSLN-CAR T cell therapy due to fratricide killing and contributing to tumor antigen heterogeneity. Moreover, we link antigen-dependent upregulation of LAG-3 with reduced CAR T cell functionality. Taken together, our study highlights the therapeutic potential and bottlenecks of MSLN-CAR T cells, providing a rationale for combinatorial treatment strategies. [ABSTRACT FROM AUTHOR]

This study compares the outcomes before and after reducing the ATG dose from 4.5 to 2 mg/kg, in a combination of PTCy and CsA for GVHD prevention, in 250 patients treated with HLA matched RIC PB-alloHCT (70% received 4.5 mg/kg and 30% received 2 mg/kg). The incidences of grade II-IV and III-IV aGVHD at day +100, and moderate/severe cGVHD at 1-year were 12.6% vs. 20% (p = 0.431), 3.6% vs. 4.5% (p = 0.935), and 10.9% vs. 26.1% (p = 0.480), respectively. PTLD (9.1% vs. 1.3%, p = 0.026) and viral infections (30.3% vs. 12%; p = 0.001) were lower for those treated with 2 mg/kg of ATG. The reduction of the ATG dose resulted in a comparable OS (2-year: 64.7% vs. 64.7%), GRFS (2-year: 48.0% vs. 44.5%), RFS (2-year: 57.0% vs. 62.0%), and NRM (2-year: 17.8 vs. 14.9). The use of (2 mg/kg) ATG-PTCy-CsA for HLA matched RIC alloHCT results in lower viral infections, and incomparable GVHD preventive effect and survival rates. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoeitic cell transplantation (allo‐HCT) is the only curative treatment for myelofibrosis (MF). We evaluate the impact of various factors on survival outcomes post‐transplant in MF. Data of 89 consecutive MF patients (primary 47%) who underwent allo‐HCT between 2005 and 2018 was evaluated. Fifty‐four percent patients had received JAK1/2 inhibitors (JAKi) pre‐HCT. The median CD34 count was 7.1x106 cells/kg. Graft failure was seen in 10% of the patients. Grade 3‐4 acute GVHD (aGVHD) and moderate/severe chronic graft versus host disease (cGVHD) occurred in 24% and 40% patients, respectively. Two‐year overall survival (OS) and relapse free survival (RFS) were 51% and 43%, respectively. Cumulative incidence of relapse (CIR) and non‐relapse mortality (NRM) at 2 years were 11% and 46%, respectively. Higher CD34 cell dose (≤5 × 106 cells/kg vs 5‐9 or ≥9 × 106 cells/kg) and lower pre‐HCT ferritin (

We determined total rabbit-IgG (r-ATG) levels in serum samples before (day 0) and after (day 11 and day 25) unrelated donor umbilical cord blood transplantation (UCBT). Most patients (27/41) suffered from a haematological malignancy. There were 25 children and 16 adults. All patients received rabbit anti-thymocyte globulin (ATG) at a total dose of 6 or 8 mg/kg as part of the conditioning. No correlation between the dose of ATG and serum r-ATG levels post UCBT was found. The cumulative incidence of acute GVHD grades III-IV in patients given the 6 and 8 mg/kg ATG dose was 15% and 13% (ns), respectively. Patients with r-ATG≤40 µg/mL 11 days after UCBT (n = 19) had a higher incidence of grades III-IV acute GVHD (32% vs. 0%, p<0.01 ), higher TRM (69% vs. 7%, p=0.005), less relapse (17% vs. 82%, p<0.01) but similar relapse-free survival (RFS) (10% vs. 18%, p=0.4) compared to those with r-ATG > 40 µ/mL (n = 17). Low serum-levels of r-ATG early after transplantation seem to be a strong predictor for acute GVHD grades III-IV, TRM and a low incidence of relapse in patients treated with thymoglobulin before unrelated donor UCBT. [ABSTRACT FROM AUTHOR]

Objective: To study the subset of maternal cells in fetal tissue in a 2nd-trimester fetus with malformations. Methods: By cell sorting and PCR amplification, we studied the presence of maternal CD3+ (T cells), CD19+ (B cells), CD34+ (hematopoietic progenitor cells), and CD45+ (leukocytes) in different tissues in a 2nd trimester fetus. Results: Maternal cells could be detected in fetal liver, lung, heart, thymus, spleen, adrenal gland, kidney, and placenta, but not in pancreas or gonadal tissue. In thymus, liver, and spleen, cell separation showed CD3+, CD19+, CD34+, and CD45+ positive cells of maternal origin. Conclusions: The present study indicates that maternal cells are widely distributed in a 2nd-trimester fetus. In addition, we found subpopulations of maternal cells belonging to lymphoid and myeloid lineages and hematopoietic progenitors with engraftment capacity in liver, spleen, and thymus. The study warrants further investigations on presence and possible biological function of maternal cells in normal and malformed fetuses. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Acute graft-versus-host disease (GVHD) is still a major complication after allogeneic stem cell transplantation. It is initiated by infiltrating donor T cells specific against the host antigens. Because T-cell migration is largely controlled by the expression of chemokines and chemokine receptors, we investigated the relation of acute GVHD and chemokine receptor expression in peripheral blood in 50 patients after allogeneic stem cell transplantation. The gene expression of the chemokine receptors CCR1, CCR2, CCR5, and CXCR3 was monitored by using quantitative real-time polymerase chain reaction. Among the 36 patients diagnosed with acute GVHD, 10 developed a second episode of acute GVHD. Therefore, gene-expression levels could be analyzed in 46 occasions of acute GVHD. When all 4 markers were evaluated at the same time, increased gene-expression levels of at least 1 of the 4 markers were seen in 44 of 46 episodes of acute GVHD. The median increase of the 4 markers ranged from 3× to 12× in connection with acute GVHD. It is interesting to note that we saw increasing gene-expression levels a few days before acute GVHD was diagnosed clinically at 17, 15, 22, and 19 occasions for CCR5, CXCR3, CCR1, and CCR2, respectively. The median number of days before diagnosis ranged from 3 to 5. Although they are not specific for acute GVHD, quantitative monitoring of the gene expression of chemokine receptors may be a valuable molecular method to monitor and diagnose acute GVHD. [Copyright &y& Elsevier]

Introduction: Allogeneic hematopoietic cell transplantation (HCT) can be curative for acute myeloid leukemia (AML). Novel therapies may render patients' bone marrow hypocellularity and lead to prolonged post‐therapy pancytopenia. Patients' bone marrow cellularity (BMC) at pretransplant assessment and post‐treatment pancytopenia (classification CR‐incomplete [CRi]) may manifest AML persistence. Methodology: We retrospectively examined the impact of BMC and ELN response (ELNr) on a single‐center cohort of 337 patients who underwent allogeneic HCT for AML in CR1. Results: Median follow‐up was 33 months. Overall survival (OS) for the whole cohort was 55.8% at 2 years, while cumulative incidence of relapse (CIR) was 20.8%, and non‐relapse mortality was 27.5%. OS and CIR were not significantly different between BMC groups; and neither was ELNr. ELNr CRi was associated with BMC aplastic and hypocellular marrow states (P < 2.6e‐8). Multivariate analysis confirmed neither BMC nor attainment of ELNr CR vs CRi affected OS or relapse. Significant factors for survival included age at transplant, cytogenetic risk, development of acute Gr II‐IV GvHD, and moderate–severe chronic GvHD, while cytogenetic risk and chronic GvHD affected relapse. Conclusion: Neither ELNr status nor pretransplant BMC influenced relapse post‐HCT or OS. Hypocellularity and CRi are not negative prognostic factors for post‐HCT outcomes of AML. [ABSTRACT FROM AUTHOR]

Summary. Minimal residual disease (MRD) assessments were performed retrospectively after allogeneic stem cell transplantation (SCT) in 32 patients (23 children and nine adults) with acute lymphoblastic leukaemia (ALL). Using immunoglobulin and T-cell receptor rearrangements as clonal markers, MRD was detected after SCT in nine patients, eight of whom have relapsed. The median time between first MRD detection and relapse was 5·5 (range 0·5–30) months. In 23 patients without MRD, six have relapsed to date: lower sensitivity, central nervous system relapse and clonal exchange of the leukaemic clone were factors that may explain the failure to detect MRD before relapse in these patients. In univariate analysis, factors associated with decreased risk of relapse were transplantation in first remission (P = 0·02), the combination of acute and chronic graft-versus-host disease (P = 0·03) and absence of MRD after SCT (P = 0·005). In multivariate analysis, only MRD detection after SCT was significantly associated with increased risk of relapse (P = 0·05). In conclusion, MRD detection after SCT is correlated with relapse and provides the opportunity for initiating immunotherapeutic intervention at an early stage when the tumour cell burden is still low. [ABSTRACT FROM AUTHOR]

Summary. Certain cytokine gene polymorphisms may be associated with severe acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. The present study analysed 196 patients and their donors for TNF-308 , TNFd, IL-10-1064 and IL-10-1082 gene polymorphisms. Serum analysis of tumour necrosis factor-α (TNF-α) and interleukin 10 (IL-10) levels during conditioning therapy was also performed. Among patients with sibling donors, the TNFd allele 4 was significantly correlated with acute GVHD grades II–IV (P < 0·01). Acute GVHD grades II–IV were more common among patients homozygous for the IL-10-1064 allele 13 (P = 0·02). Patients homozygous for the TNF-308 allele (AA) correlated with higher TNF-α serum levels during conditioning (P = 0·02). [ABSTRACT FROM AUTHOR]

Objectives: To determine whether treatment with tacrolimus plus sirolimus (Tac/Sir) as a prophylaxis for graft‐versus‐host disease worsens severe oral mucositis and delays healing compared to cyclosporine plus methotrexate (CsA/Mtx) following haematopoietic stem cell transplantation. Subjects and Methods: The study comprised 141 patients: 73 randomized to receive Tac/Sir and 68 to receive CsA/Mtx. The oral mucositis assessment scale and toxicity grading according to WHO were used to assess the severity, peak and duration of oral mucositis from the day −3 to day 24 post‐transplant. Results: Eighty‐seven patients developed oral mucositis in the first 24 days post‐transplant. No significant difference in oral mucositis severity between the Tac/Sir and CsA/Mtx groups was observed. The peak oral mucositis score occurred on day 10 in both groups. Although oral mucositis scores had returned to baseline in the CsA/Mtx group on day 24 post‐transplant, no significant difference compared with the Tac/Sir group was found. Conclusions: The introduction of tacrolimus/sirolimus as a graft‐versus‐host disease prophylaxis in haematopoietic stem cell transplantation increased neither the incidence nor severity of oral mucositis compared with cyclosporine/methotrexate. Furthermore, oral mucositis healing was not prolonged and followed the same time pattern as cyclosporine/methotrexate. [ABSTRACT FROM AUTHOR]

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

Objectives: Hepatic grading systems for categorizing severity in chronic graft‐versus‐host disease (cGvHD) were determined arbitrarily, leading us to initiate the present study to provide objective evidence for the determination of optimal cutoff values and devise a hepatic grading system to predict prognosis. Methods: Of 842 patients who received allogeneic hematopoietic stem transplant (HCT), 336 patients diagnosed with cGvHD were evaluated for overall survival (OS) and non‐relapse mortality (NRM) after cGVHD development. Multiple statistical parameters were evaluated to define optimal cutoff values of liver profile, including negative predictive value (NPV), positive predictive value (PPV), accuracy, and p‐values as measures of risk stratification power. Results: We found that alkaline phosphatase (ALP) ≥ 146 IU/L (NPV: 83.4%; PPV: 32.8%; accuracy: 52.7%) and bilirubin ≥ 14 µmol/L (NPV: 81.8%; PPV: 39.4%; accuracy 68.1%) significantly correlated with OS. We developed a refined hepatic cGvHD grading score (RHS), stratifying patients into a low‐RHS group with RHS score 0, OS at 3 years (n = 162) to 80.5%, compared to high‐RHS group with score 1‐2 (n = 172) 62.7%. Regarding NRM, score 0 segregated NRM at 3 years to 11.9%, compared with score 1‐2 19.6%, P =.1. Conclusions: Refined hepatic score is promising for stratifying patients with cGVHD and liver involvement according to long‐term outcomes. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HCT) is associated with significant morbidity and mortality. Elevated pre-transplant ferritin level (ferritinPre-HCT) is reported to be associated with increased mortality following HCT. The present study attempted to determine whether post-transplant ferritin level (ferritinPost-HCT) is associated with outcomes post-HCT, especially in the subgroups which developed acute or chronic graft-versus-host disease (GVHD). Out of 229 patients with serum ferritin level measured post-HCT, median ferritinPost-HCT was 2178 ng/mL. Patients were stratified into low- or high-risk groups using recursive partitioning, based on ferritinPost-HCT (≤ 3169 vs > 3169 ng/mL) and ferritinPre-HCT (≤ 669 vs > 669 ng/mL). Compared to the low ferritinPost-HCT group, the high ferritinPost-HCT group had lower 3-year overall survival (OS) (40.0% vs 66.7%, p < 0.001) and higher non-relapse mortality (NRM) (48.6% vs 17.8%, p < 0.001), but no difference in relapse (10.5% vs 19.7%, p = 0.079). Multivariate analysis confirmed ferritinPost-HCT as an independent prognostic factor for OS (p = 0.001, HR = 2.323) and NRM (p < 0.001, HR = 3.905). However, ferritinPre-HCT did not stratify well for OS or NRM. FerritinPost-HCT was also found to be an independent prognostic marker for OS and NRM in the subgroups which developed GVHD. In our cohort, high ferritinPost-HCT levels were significantly associated with decreased OS and increased NRM independent of ferritinPre-HCT or GVHD. Additional studies including larger sample sizes and prospective investigation are warranted to clarify the prognostic significance and pathophysiology of pre- and post-transplant hyperferritinemia. [ABSTRACT FROM AUTHOR]

Nearly 500'000 fatalities due to COVID-19 have been reported globally and the death toll is still rising. Most deaths are due to acute respiratory distress syndrome (ARDS), as a result of an excessive immune response and a cytokine storm elicited by severe SARS-CoV-2 lung infection, rather than by a direct cytopathic effect of the virus. In the most severe forms of the disease therapies should aim primarily at dampening the uncontrolled inflammatory/immune response responsible for most fatalities. Pharmacological agents - antiviral and anti-inflammatory molecules - have not been able so far to achieve compelling results for the control of severe COVID-19 pneumonia. Cells derived from the placenta and/or fetal membranes, in particular amniotic epithelial cells (AEC) and decidual stromal cells (DSC), have established, well-characterized, potent anti-inflammatory and immune-modulatory properties that make them attractive candidates for a cell-based therapy of COVID19 pneumonia. Placenta-derived cells are easy to procure from a perennial source and pose minimal ethical issues for their utilization. In view of the existing clinical evidence for the innocuousness and efficiency of systemic administration of DSCs or AECs in similar conditions, we advocate for the initiation of clinical trials using this strategy in the treatment of severe COVID-19 disease. [ABSTRACT FROM AUTHOR]

Introduction: The polypeptide prolactin (PRL) is a peptide hormone and a cytokine mostly secreted from the anterior pituitary gland. PRL is also synthesized in extra pituitary tissues including thymocytes and T lymphocytes. Considering the need for chronic GVHD (cGVHD) biomarkers, we explored the relationship between hyperprolactinemia and active cGVHD in a cohort of long‐term post‐alloHCT survivors. Methods: Three‐hundred sixteen adults underwent alloHCT between 2010 and 2016, survived more than 1 year and were included. All patients underwent a regular annual assessment that includes a hormone profile with serum PRL levels. Results: Overall, 236 (74.7%) patients had cGVHD, and in 199 (63%), the grade was moderate or severe. Sixty‐five (21%) recipients had active cGVHD at the time of the annual evaluation, and hyperprolactinemia was documented in 63 (19.9%) patients. Hyperprolactinemia correlated with cGVHD activity (Odds Ratio 6.9 (95% CI; 3.6‐13.1); P <.001) in the multivariate analysis. In conclusion, patients with hyperprolactinemia were 6.4 times more likely to have active cGVHD in comparison with those patients with normal levels of PRL (P <.001). Conclusion: Prolactin may serve as a biomarker for cGVHD activity. Further studies are required to confirm these findings, and to explore if hyperprolactinemia has an impact on cGVHD severity and prognosis. [ABSTRACT FROM AUTHOR]

Extracorporeal photopheresis (ECP) is recommended as a second- or later-line therapy for chronic GvHD (cGvHD). Benefits include reasonable response with avoidance of intense systemic immunosuppression, which can translate into lowering the risk of systemic toxicity and opportunistic infection. We evaluated 75 patients treated with ECP for cGvHD from 2007 to 2021 at Princess Margaret Cancer Centre, and analyzed overall response rate (ORR) and clinical benefit (CB) at 3, 6 and 12 months plus other long-term treatment outcomes. With a median follow-up of 72 months, a gradual increase in ORR was noted over time: 21% (16 out of 75 patients), 57% (36/63) and 70% (32/46) at month 3, 6 and 12, respectively. Gradual increase in CB was also observed over time with CB rate of 23% (17/75), 62% (39/63), and 76% (35/46) at months 3, 6 and 12, respectively. A total of 27 failures (36%) were noted, due to: 1) ECP resistance requiring switch to other therapy (n = 14, 19%), 2) non-relapse mortality (n = 10, 13%), 3) relapse of primary disease (n = 1, 1%) or 4) ECP procedure-related complication (n = 1, 1%, line infection), with 20 deaths (27%) observed. Failure-free survival (FFS) and overall survival (OS) rates were 68.3% and 85.9% at 12 months, respectively. After starting ECP, the proportions of patients who completely discontinued steroids were 17%, 32%, and 64% at months 3, 6 and 12, respectively. ECP is an effective treatment option for heavily pre-treated cGvHD patients. • ECP is a highly effective treatment in cGvHD, even in patients who had been heavily pre-treated and failed other GVHD therapy. • ECP induce durable responses and clinical benefit in cGvHD. • Steroid-sparing efficacy of ECP reduced systemic toxicity from prolonged use of corticosteroids. • Failure free survival of ECP comparable with ruxolitinib treatment in cGvHD. [ABSTRACT FROM AUTHOR]