Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute ...myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age.
In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs.
Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ≥ 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ≥ 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61).
Our results support that de novo AML, sAML, and tAML are biologically and prognostically distinct subtypes of AML. Patients with non-MDS-sAML have dismal outcomes, independent of age and cytogenetics. Previous myeloid disorder, age, and cytogenetics are crucial determinants of outcomes and should be integrated in treatment recommendations for these patients.
T-cell receptor (TCR) γδ cells are perceived as innate-like effector cells with the possibility of mediating graft-vs. -tumor (GVT) without causing graft-vs.-host disease (GVHD) in the setting of ...hematopoietic allogeneic stem cell transplantation (HSCT). We conducted a prospective study to assess the clinical impact of TCR γδ cell immune reconstitution on overall survival, relapse-free-survival, relapse and GVHD. The impact of CD3, CD4, and CD8 T cells together with NK cells including subtypes were analyzed in parallel. A total of 108 patients with hematological malignancies transplanted with HLA-matched, T cell replete stem cell grafts were included for analyses of absolute concentrations of CD3, CD4, and CD8 positive T cells and NK cells together with a multi-color flow cytometry panel with staining for TCRαβ, TCRγδ, Vδ1, Vδ2, CD3, CD4, CD8, HLA-DR, CD196, CD45RO, CD45RA, CD16, CD56, CD337, and CD314 at 28, 56, 91, 180, and 365 days after transplantation. Immune reconstitution data including subsets and differentiation markers of T and NK cells during the first year after transplantation was provided. Patients with TCR γδ cell concentrations above the median value of 21 (0-416) × 10
cells/L 56 days after transplantation had significantly improved overall survival (
= 0.001) and relapse-free survival (
= 0.007) compared to patients with concentrations below this value. When day 56 cell subset concentrations were included as continuous variables, TCR γδ cells were the only T cell subsets with a significant impact on OS and RFS; the impact of TCR γδ cells remained statistically significant in multivariate analyses adjusted for pre-transplant risk factors. The risk of death from relapse was significantly decreased in patients with high concentrations of TCR γδ cells 56 days after transplantation (
= 0.003). Also, the risk of acute GVHD was significantly lower in patients with day 28 TCR γδ cell concentrations above the median of 18 × 10
cells/L compared to patients with low concentrations (
= 0.01). These results suggest a protective role of TCR γδ cells in relapse and GVHD and encourage further research in developing adaptive TCR γδ cell therapy for improving outcomes after HSCT.
Spouses have a key position in the treatment of patients with acute leukemia (AL) who are increasingly managed in an outpatient setting. Patients live at home but appear at the hospital every second ...day for follow-up visits. Patients must adhere to specific precautions due to an impaired immune system, which challenges and influence the life of the whole family. This qualitative study, based on individual and group interviews with spouses to AL patients in curative intended treatment, elucidates how the intense and substantial caregiver role affects the everyday lives of spouses to AL patients in curative intended treatment.
Qualitative semi-structured group interviews (n = 6) and individual interviews (n = 5) with spouses to AL patients were conducted at different time points during the whole course of treatment. Theories of everyday life served as the theoretical framework.
The spouses described their life as a constant state of vigilance and attention as a consequence of the responsibility they felt arising from the treatment in the outpatient setting. These made them experience their role as a burden. The social life of the spouses and the families suffered substantially due to the precautions that were instated in the home. However, many experienced that relations in the family were developed positively.
Close relatives experience additional psychosocial burdens instigated by the outpatient management regimens. This is important knowledge for the health care system to include in future development of AL outpatient settings, to prioritize and support offers to the relatives that recognize their sense of burden. This could apply not only to relatives of AL patients but to the relatives of other severely ill patients as well.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mature immunocompetent cells from the stem cell graft as well as early robust immune reconstitution are essential for the graft-vs. -tumor (GVT) effect to eliminate residual malignant cells after ...allogeneic hematopoietic stem cell transplantation (HSCT). In this prospective study we characterized graft composition of T- and NK cell subsets in 88 recipients of peripheral blood stem cell grafts with multicolor flowcytometry. Our primary aim was to analyze the impact of graft composition on immune reconstitution and clinical outcomes after transplantation. Patients transplanted with graft NK cell doses above the median value of 27 × 10
/kg had significantly increased relapse-free-survival compared to patients transplanted with lower doses, HR 2.12 (95% CI 1.01-4.45,
= 0.04) Peripheral blood concentrations of NK cells obtained from donors before G-CSF mobilization were significantly correlated to graft NK cell doses (Spearman's ρ 0.53,
= 0.03). The dose of transplanted NK cells/kg correlated significantly with NK cell concentrations in patients early after transplantation (Spearman's ρ 0.26,
= 0.02, and ρ = 0.35,
= 0.001 for days 28 and 56, respectively). Early immune reconstitution above median values of NK cells was significantly associated with improved relapse-free survival (HR 2.84 95% CI 1.29-6.28,
= 0.01, and HR 4.19 95% CI 1.68-10.4,
= 0.002, for day 28 and 56, respectively). Early concentrations above the median value of the mature effector CD56dim NK cell subset were significantly associated with decreased relapse incidences at 1 year, 7% (95% CI 1.8-17) vs. 28% (95% CI 15-42),
= 0.04, and 7% (95% CI 1.8-18) vs. 26% (95% CI 14-40) %,
= 0.03, for days 28 and 56, respectively. The results suggest a protective effect of high doses of NK cells in grafts and during early immune reconstitution and support the perception of NK cells as innate effector cells with anti-tumor effects in the setting of allogeneic stem cell transplantation.
Myeloid neoplasms (MNs) with germline predisposition have recently been recognized as novel entities in the latest World Health Organization (WHO) classification for MNs. Individuals with MNs due to ...germline predisposition exhibit increased risk for the development of MNs, mainly acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Setting the diagnosis of MN with germline predisposition is of crucial clinical significance since it may tailor therapy, dictate the selection of donor for allogeneic hematopoietic stem cell transplantation (allo‐HSCT), determine the conditioning regimen, enable relevant prophylactic measures and early intervention or contribute to avoid unnecessary or even harmful medication. Finally, it allows for genetic counseling and follow‐up of at‐risk family members. Identification of these patients in the clinical setting is challenging, as there is no consensus due to lack of evidence regarding the criteria defining the patients who should be tested for these conditions. In addition, even in cases with a strong suspicion of a MN with germline predisposition, no standard diagnostic algorithm is available. We present the first version of the Nordic recommendations for diagnostics, surveillance and management including considerations for allo‐HSCT for patients and carriers of a germline mutation predisposing to the development of MNs.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction: Accurate assessment of the risk of non-relapse mortality (NRM) is important for making the shared decision about treatment with allogeneic hematopoietic cell transplantation (allo-HCT). ...We have shown that the pre-transplantation plasma level of suppression of tumorigenicity 2 (ST2)-a protein that is released to the bloodstream upon inflammation, cellular stress and endothelial damage-was associated with NRM after myeloablative allo-HCT Gjærde et al., ASH Annual Meeting 2020, abstract #1524. In an expanded cohort of both myeloablative- and non-myeloablative conditioned patients, we aimed to validate the value of pre-transplant ST2 in predicting 1-year NRM after allo-HCT.
Methods: Pre-transplantation plasma ST2 levels were measured by enzyme-linked immunosorbent assays in 374 adult patients who underwent allo-HCT at Rigshospitalet between July 2015 and December 2019 (Table 1), using stored plasma samples collected at a median (Q1, Q3) of 23 (21, 24) days before allo-HCT. All patients were followed-up for at least 1 year after transplant. NRM was defined as all deaths in relapse-free patients. Given our sample size and outcome proportion, we could include four parameters in a logistic regression model of 1-year NRM to avoid severe overfitting Riley et al., BMJ, 2020. Based on our current clinical risk assessment practice, we included age (linear), comorbidity index (HCT-CI Sorror et al., Blood, 2005, linear) and conditioning intensity (myeloablative vs. non-myeloablative) in a base model, to which we added the pre-transplantation ST2 level (linear) and assessed its incremental prognostic value Steyerberg et al., Epidemiology, 2019. The internal validity of the full model was estimated by bootstrapping Steyerberg et al., J Clin Epidemiol, 2001.
Results: The median (Q1, Q3) pre-transplantation plasma ST2 level was 20.4 (15.2, 27.2) ng/mL. NRM at 1-year was 9% (N = 33). The main causes of NRM were organ failure (39%), infection (23%) and acute graft-versus-host disease (21%). Relapse risk at 1-year was 18%. The patients who constituted the 33 cases of 1-year NRM had a 2.7 ng/mL higher median pre-transplantation ST2 level than the remaining 341 patients (95% bootstrap confidence interval CI of the difference: -1.9, 6.2 ng/mL, Figure Panel A). In the full logistic regression model-including age, HCT-CI, conditioning intensity and ST2-ST2 was associated with 1-year NRM with an odds ratio of 1.32 (CI: 1.05, 1.65) per 10 ng/mL increase. Adding ST2 to the base model increased the model likelihood ratio χ 2 from 12.1 to 17.3 (p = 0.02), i.e. ST2 added a fraction of 30% (12.1/17.3) of new predictive information to age, HCT-CI and conditioning intensity. However, the ability of the full model to discriminate cases of NRM at 1-year remained poor with minimal improvement after adding ST2 (AUC up to 0.675 from 0.674 in the base model). The bootstrap-corrected AUC (the expected AUC of the full model used in a new population) was 0.63. Moreover, bootstrap-corrected estimates of predicted vs. observed risk revealed slight model miscalibration: lower predicted risks were generally underestimated, while higher predicted risks were overestimated (Figure Panel B).
Conclusion: Pre-transplantation plasma levels of ST2 was a prognostic biomarker of 1-year NRM after allo-HCT, adding new predictive information to age, HCT-CI and conditioning intensity. However, internal validation of the full ST2-based prediction model revealed poor overall performance, precluding further validation and use of the model in clinical practice. When identifying prognostic biomarkers, investigation of overall predictive performance (in addition to already known prognostic factors) is needed before clinical usefulness can be evaluated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose Previous US studies have shown that socioeconomic status (SES) affects survival in acute myeloid leukemia (AML). However, no large study has investigated the association between education or ...income and clinical characteristics, treatment, and outcome in AML. Methods To investigate the effects of education and income in a tax-supported health care system, we conducted a population-based study using individual-level SES and clinical data on all Danish patients with AML (2000 to 2014). We compared treatment intensity, allogeneic transplantation, and response rates by education and income level using logistic regression (odds ratios). We used Cox regression (hazard ratios HRs) to compare survival, adjusting for age, sex, SES, and clinical prognostic markers. Results Of 2,992 patients, 1,588 (53.1%) received intensive chemotherapy. Compared with low-education patients, highly educated patients more often received allogeneic transplantation (16.3% v 8.7%). In intensively treated patients younger than 60 years of age, increased mortality was observed in those with lower and medium education (1-year survival, 66.7%; adjusted HR, 1.47; 95% CI, 1.11 to 1.93; and 1-year survival, 67.6%; adjusted HR, 1.55; CI, 1.21 to 1.98, respectively) compared with higher education (1-year survival, 76.9%). Over the study period, 5-year survival improvements were limited to high-education patients (from 39% to 58%), increasing the survival gap between groups. In older patients, low-education patients received less intensive therapy (30% v 48%; adjusted odds ratio, 0.65; CI, 0.44 to 0.98) compared with high-education patients; however, remission rates and survival were not affected in those intensively treated. Income was not associated with therapy intensity, likelihood of complete remission, or survival (high income: adjusted HR, 1.0; medium income: adjusted HR, 0.96; 95% CI, 0.82 to 1.12; low income: adjusted HR, 1.06; CI, .88 to 1.27). Conclusion In a universal health care system, education level, but not income, affects transplantation rates and survival in younger patients with AML. Importantly, recent survival improvement has exclusively benefitted highly educated patients.
Introduction: Suppression of tumorigenicity 2 (ST2) is a prognostic plasma marker of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT) when measured at day ...+14 Vander Lugt MT et al., N Engl J Med, 2013 and at day +7 in combination with regenerating islet-derived 3α (REG3α) Hartwell MJ et al., JCI Insight, 2017. We hypothesized that also pre-transplantation ST2 levels would be associated with NRM in the first 6 months after allo-HCT.
Methods: We studied 112 adult patients who underwent allo-HCT with myeloablative conditioning at Rigshospitalet between July 2015 and August 2018 (Table 1). ST2 levels were measured by enzyme-linked immunosorbent assays using stored EDTA plasma samples obtained at the patients’ scheduled pre-transplantation visit around day -23 (±11 days) and post-transplantation at days +7 and +14 (±3 days, n = 76 and 66). Univariable linear models and Spearman’s ρ were used to evaluate associations and correlations between pre-transplantation ST2 levels and patient characteristics and other prognostic markers, respectively. Cause-specific Cox regression models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for NRM in the first 6 months after allo-HCT (relapse as competing risk) and grade II-IV acute graft-versus-host disease (GvHD) in the first 100 days after allo-HCT (NRM and relapse as competing risks) according to pre-transplantation ST2 levels. Gray’s test was used to test differences in the cumulative incidence of NRM in the first 6 months after allo-HCT according to quartiles of pre-transplantation ST2 levels.
Results: The median pre-transplantation plasma ST2 level was 19.9 ng/mL (inter-quartile range: 14.6-25.7 ng/mL, Figure Panel A); levels were higher in males (β = 8.7 ng/mL, p < 0.01), but did not differ by age (p = 0.81) or by being transplanted for acute leukemia (p = 0.89). ST2 was correlated with C-reactive protein (ρ = 0.24, p = 0.01), the endothelial activation and stress index (EASIX, calculated as creatinine x lactate dehydrogenase/thrombocytes, ρ = 0.27, p < 0.01) and ferritin (ρ = 0.28, p < 0.01). Longitudinally, pre-transplantation ST2 levels were strongly correlated with ST2 levels on day +7 (ρ = 0.57, p < 0.01) and day +14 (ρ = 0.48, p < 0.01). The cumulative incidence of NRM at 6 months was 11% (n = 12); causes of death were organ failure (75%), acute graft-versus-host disease (GvHD, 17%) and infection (8%). Higher pre-transplantation ST2 levels were associated with increased hazard of NRM in the first 6 months after allo-HCT (HR 1.73 per 10 ng/mL increase, 95% CI: 1.28-2.33, p < 0.01, area under the receiver operating characteristics curve = 0.61). Despite a significantly higher NRM in patients with pre-transplantation ST2 levels in the highest quartile (cumulative incidence at 6 months: 21% vs. 7% in patients with levels in the three lower quartiles, p = 0.03), there was no overall significant difference in NRM according to quartiles of pre-transplantation ST2 levels (p = 0.15, Figure Panel B). No significant association was found between pre-transplantation ST2 levels and grade II-IV acute GvHD (HR 0.88, 95% CI: 0.61-1.26, p = 0.48).
Conclusion: Pre-transplantation ST2 levels were associated with increased NRM in the first 6 months after myeloablative allo-HCT, mainly driven by higher NRM in patients with pre-transplantation ST2 levels in the highest quartile. Larger studies are warranted to validate pre-transplantation ST2 levels as a prognostic marker of NRM after allo-HCT, which potentially could be used to support the choice of conditioning intensity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) yet the major ...cause of death remains relapse after transplantation which occurs in 30-70% of patients for whom the prognosis is dismal. Since the 1990's donor lymphocyte infusion (DLI) has been proven able to induce remission after allo-HSCT and the use of therapeutic DLI at relapse has widely increased. The immunological mechanism in DLI is primarily T-cell-mediated graft-versus-leukemia (GVL) effect driven by genetic differences between donor and recipient in minor and major histocompatibility antigens. DLI treatment at relapse can additionally reverse T-cell exhaustion and increase T-cell receptor diversity, both of which are GVL-enhancing mechanisms. Risks and complications with DLI-treatment are primarily graft-versus-host disease (GVHD). Though dose escalation schedules have been suggested to increase the GVL-effect while minimizing the risk of GVHD, uniform therapeutic algorithms are still lacking, treatment is often individually scheduled, and outcome results are often disappointing with reported 2-year overall survival rates at 14-29% in AML relapse patients (Greiner J, Götz M, Bunjes D, Hofmann S, Wais V. Immunological and Clinical Impact of Manipulated and Unmanipulated DLI after Allogeneic Stem Cell Transplantation of AML Patients. J Clin Med. 2019;9(1):39). During the last decade, treatment with the hypomethylating agent azacitidin (Aza) has become another potential treatment in patients with myeloid malignancies. Immunological mechanisms of GVL in Aza-treatment for relapse include epigenetically reactivation of pro-apoptotic pathways and demasking of tumor-antigens while increased expression of regulatory T-cells protects from GVHD. In recent years DLI and Aza have been used for synergistical effect post-HSCT relapse both in patients who are un-fit to receive high-dose cytoreductive therapy as well as consolidation after reinduction. The aim of this analysis is to report results of retrospective single center-study of patients treated with DLI +/- Aza over a period of twenty years.
Methods: Between 2001 and 2020 50 adult patients with relapse after allo-HSCT for AML(n=38) or MDS (n=12) were treated with DLI at the Department of Hematology, Transplant Unit, at Rigshospitalet, Copenhagen University Hospital, table 1. Only patients free from active GVHD were selected as DLI-candidates. Median follow-up time was 57 (1-170) months. Reinduction with high-dose chemotherapy was administered in 35 (70%) of patients prior to DLI and 34 (68%) patients were in complete morphological remission (CR) before DLI. DLI-products were unmanipulated and obtained from leukapheresis of unstimulated peripheral blood in matched related or unrelated donors of the original stem cell graft. Patients received a median of 3 (1-5) doses of DLI with median total doses of 6,1x10 7 (5x10 6- 4,65x10 8) CD3 postive T-cells per kg. Aza was used together with DLI from 2012 and administrered in 28 (56%) patients with a median of 6 (2-20) cycles. Reported outcomes are overall survial (OS) and relapse-free survival (RFS) in patients in CR prior to DLI.
Results: At end of follow-up 20 patients were alive, 11 of these in CR and 2 in partial remission. In 7 patients, DLI was discontinued due to the development of GVHD after 1-2 doses, 6/7 of these patients had unrelated donors. Overall, 2 (4%) patients died from GVHD after DLI. Seven patients received a second HSCT after DLI treatment and were censored at this date in survival analyses. Figure 1a+b shows OS in all patients (n=50) and RFS in patients in CR prior to DLI (n=34). 2-year OS was approximately 59% and 5-year OS was 20%. 2-year RFS was approximately 32% and 5-year RFS was 8%. None of the analyzed baseline factors showed significant associations to the probability of OS, table 2, or RFS (data not shown). Reinduktion before first DLI and increasing doses of transplanted CD3 T cell per kg showed trends towards superior survival probability but failed to reach significant levels, possibly due to the limited patient number.
Conclusion: Treatment vith DLI +/- Aza is effective and safe as relapse-treatment after allo-HSCT in myeloid diseases. In selected patients, a short-term (2-year) overall survival of 59% is achieved, and 20% of the patients remain long term survivors.
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Fischer-Nielsen: A.F.N. is employee and shareholder of StemMedical A/S, a biotech company working with cell-enriched fat grafting.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Donor lymphocyte infusion (DLI) is used to induce remission in patients who relapse after allogeneic stem cell transplantation (allo-HSCT). During the last decade, the hypomethylating agent ...Azacitidine has been used together with DLI for a synergistic graft-versus-leukemia (GVL) effect. Here, we report results of DLI/Azacitidine treatment from a retrospective single-center study.
Fifty AML/MDS patients treated for relapse after allo-HSCT between 2001 and 2020 with DLI at the Department of Hematology, at Rigshospitalet, Copenhagen University Hospital were included for analyses. A subgroup of patients who obtained complete remission (CR) after reinduction chemotherapy, received DLI in combination with low-dose (32 mg/m2) Azacitidine.
Overall survival in all patients after DLI treatment was 59% at 2 years and 20% at 5 years. Relapse-free survival in patients in CR prior to DLI was 32% after 2 years and 7% after 5 years. In the DLI + low-dose-Azacitidine group, 5-year relapse-free survival was 40%.
DLI remains an effective treatment in post-transplant relapse leaving one-fifth of patients' long-term survivors. Our results support the concomitant use of low-dose Azacitidine in the future use of DLI in order to enhance the GVL effect of donor lymphocytes.
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