Pulmonary function is a strong predictor of 2-year overall survival and non-relapse mortality after allogenic hematopoietic cell transplantation.

OBJECTIVES: The purpose of the study was to assess the validity of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and of pulmonary comorbidity prior to HCT in terms of predicting non-relapse mortality (NRM) and overall survival (OS). METHODS: In this retrospective single-center study of 663 consecutive adult recipients of HCT, we stratified patients into groups by pulmonary comorbidity: low-risk, intermediate-risk, and high-risk. The predictive value of this pulmonary comorbidity score (PCS) was compared to HCT-CI. RESULTS: In univariate analysis, the HCT-CI and the PCS were associated with OS after transplantation when comparing patients in high-risk groups with patients in low-risk groups. Using the PCS, the hazard ratios (HRs) of the 2-year OS in the entire population and in the myeloablative conditioning (MAC) group were 1.98 (p < .001) and 3.27 (p < .001), respectively, whereas the HRs using the HCT-CI were 1.83 (p < .001) and 2.57 (p = .002). The 2-year NRM incidence in the three risk-groups in the entire population was significant using both indexes. In the MAC group, the 2-year NRM was significant using the PCS (p = .003), but not using the HCT-CI (p = .23). CONCLUSIONS: Our study suggest that pulmonary function alone is a strong predictor of 2-year OS and NRM after HCT.

Donor Lymphocyte Infusion Is a Feasible Way to Improve Survival in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Who Relapse after Allogeneic Stem Cell Transplantation.

INTRODUCTION: 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. METHODS: 50 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. RESULTS: 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-years relapse-free survival was 40%. CONCLUSION: 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.

Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen-mismatched donors.

This trial aimed to evaluate the efficacy of sirolimus in addition to cyclosporine (CSP) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after nonmyeloablative conditioning for HLA class I or II mismatched hematopoietic cell transplantation (HCT). Eligible patients had hematologic malignancies treatable by allogeneic HCT. Conditioning consisted of fludarabine (90 mg/m2) and 2 to 3 Gy total body irradiation. GVHD prophylaxis comprised cyclosporine, mycophenolate mofetil, and sirolimus. The primary objective was to determine whether the cumulative incidence of grade 2 to 4 acute GVHD could be reduced to <70% in HLA class I or II mismatched HCT. The study was closed on December 20, 2018. Seventy-seven participants were recruited between April 14, 2011, and December 12, 2018, of whom 76 completed the study intervention. Median follow-up was 47 months (range, 4-94 months). The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 36% (95% confidence interval [CI], 25-46), meeting the primary end point. The cumulative incidence of nonrelapse morality, relapse/progression, and overall survival was 18% (95% CI, 9-27), 30% (interquartile range, 19-40), and 62% (95% CI, 50-73) after 4 years. In conclusion, the addition of sirolimus to cyclosporine and mycophenolate mofetil resulted in a lower incidence of acute GVHD, thus translating into superior overall survival compared with historical results. This trial was registered at www.clinicaltrials.gov as #NCT01251575.

Functional immune reconstitution early after allogeneic haematopoietic cell transplantation: A comparison of pre- and post-transplantation cytokine responses in stimulated whole blood.

We aimed to use a novel standardized whole-blood stimulation system to evaluate differences in the functional immune reconstitution in patients early after allogeneic haematopoietic cell transplantation (HCT). Between April and September 2018, 30 patients undergoing HCT had whole blood samples collected around day -21 (day 0 being the day of haematopoietic cell infusion) and day +28. Whole blood was transferred to TruCulture assays comprising prefilled incubation tubes with cell culture medium and a standardized stimulus. We used a panel of four stimuli (lipopolysaccharide, resiquimod, heat-killed Candida albicans and polyinosinic:polycytidylic acid) and a blank, designed to evaluate the function of critical extra- and intracellular immunological signalling pathways. For each stimulus, the cytokine response was assessed by the concentration of interferon-γ, interleukin (IL)-12p40, IL-10, IL-1ß, IL-6, IL-8, IL-10, IL-12p40, IL-17A and tumour necrosis factor-α using a multiplex Luminex assay. Pre-HCT cytokine responses were globally decreased across several different stimuli. Despite patients receiving immunosuppressive prophylaxis at the time, post-HCT cytokine responses were higher and less intercorrelated than pre-HCT responses, also after adjusting for differences in the leukocyte differential counts. For the resiquimod and heat-killed Candida albicans stimuli, we identified a cluster of patients in whom post-HCT responses were lower than average across several cytokines, indicating a possible functional immune deficiency. Our findings suggest that the standardized whole blood stimulation system can be used to reveal heterogeneity in the in vitro cytokine responses to various stimuli after HCT. Larger studies are needed to address if the functional immune reconstitution after HCT can predict the risk of infections.

Vitamin E and acute graft-versus-host disease after myeloablative allogeneic hematopoietic cell transplantation.

OBJECTIVES: Vitamin E has antioxidant and immunomodulatory effects that might influence the development of acute graft-versus-host disease (GvHD). We investigated the association between plasma vitamin E levels and acute GvHD. METHODS: We studied 115 adults who underwent myeloablative allogeneic hematopoietic cell transplantation between July 2015 and August 2018. Vitamin E was measured by high-performance liquid chromatography in stored plasma samples obtained pre-transplantation at day -23 (±15 days) and post-transplantation at day +28 (±3 days). RESULTS: Pre-transplantation vitamin E levels were inversely associated with grade II-IV acute GvHD (hazard ratio 0.68 per 10 µmol/L increase, 95% confidence interval [CI]: 0.47-0.98). The association remained after adjustment for known prognostic factors for acute GvHD. Patients with levels below the median had a cumulative incidence of grade II-IV acute GvHD of 46% (CI: 33-59%) versus 21% (CI: 10-32%) in patients with levels above the median. No clear association with non-relapse mortality, relapse, or chronic GvHD was found. Post-transplantation vitamin E levels (measured in 72 [63%] patients) were correlated with pre-transplantation levels (ρ = .31) but were not associated with subsequent grade II-IV acute GvHD. CONCLUSIONS: High pre-transplantation vitamin E levels were associated with less acute GvHD.

Improved Outcomes after Allogenic Hematopoietic Stem Cell Transplantation with Fludarabine/Treosulfan for Patients with Myelodysplastic Syndromes.

While allogeneic hematopoietic stem cell transplantation (allo-HCT) currently offers the only curative option for patients with myelodysplastic syndrome (MDS), there is still a high risk of relapse or transplant-related complications. We collected data on all patients who had undergone allo-HCT at our center (Copenhagen University Hospital) between 2000 and 2018. In total, 215 patients with MDS (n = 196) or chronic myelomonocytic leukemia (n = 19) were included. Estimated 1-year overall survival (OS) was 70.3% (95% confidence interval [CI], 64.2% to 77.0%), and the median survival was 7.7 years (95% CI, 4.7 to indeterminable). There was a significant improvement in OS over time (P = .011, comparing 2000 to 2010, 2010 to 2014, and 2014 to 2018). Treatment was standardized throughout the study period, allowing comparison between patients receiving nonmyeloablative (NMA, n = 124), standard myeloablative (SMA, n = 36), and fludarabine and treosulfan (FluTreo, n = 55) conditioning. FluTreo has myeloablative properties but lower toxicity and replaced standard myeloablative conditioning at our center in 2014. The FluTreo group was significantly older and had more comorbidities than the SMA group but similar disease severity. One-year OS was 84.0% (95% CI, 74.3% to 94.9%), 58.3% (95% CI, 44.3% to 76.9%), and 68.3% (95% CI, 60.2% to 77.5%) for FluTreo, SMA, and NMA, respectively (P = .04). In univariate analysis, Revised International Scoring System (IPSS-R) (high versus low), donor sex mismatch, and cytomegalovirus status mismatch were significant factors for OS. In multivariate analysis of OS including age, IPSS-R, and HCT specific comorbidity index, NMA was borderline inferior to FluTreo (P = .073) while SMA was significantly inferior to FluTreo with a hazard ratio of 6.89 (95% CI, 2.53 to 18.77, P < .001). The introduction of FluTreo allowed us to administer a myeloablative regimen to a broader patient group and shows promising results.

Mononuclear Cell Telomere Attrition Is Associated with Overall Survival after Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies.

After allogeneic hematopoietic cell transplantation (allo-HCT), transplanted cells rapidly undergo multiple rounds of division. This may cause extensive telomere attrition, which could potentially prohibit further cell division and lead to increased mortality. We therefore characterized the development in telomere length after nonmyeloablative allo-HCT in 240 consecutive patients transplanted because of hematologic malignancies and tested the hypothesis that extensive telomere attrition post-transplant is associated with low overall survival. Telomere length was measured using quantitative PCR in mononuclear cells obtained from donors and recipients pretransplant and in follow-up samples from recipients post-transplant. Telomere attrition at 9 to 15 months post-transplant was calculated as the difference between recipient telomere length at 9 to 15 months post-transplant and donor pretransplant telomere length, divided by donor pretransplant telomere length. Although allo-HCT led to shorter mean telomere length in recipients when compared with donors, recipients had longer mean telomere length 9 to 15 months post-transplant than they had pretransplant. When compared with donor telomeres, recipients with extensive telomere attrition at 9 to 15 months post-transplant had low overall survival (10-year survival from 9 to 15 months post-transplant and onward: 68% in the tertile with least telomere attrition, 57% in the middle tertile, and 39% in the tertile with most attrition; log-rank P = .01). Similarly, after adjusting for potential confounders, recipients with extensive telomere attrition had high all-cause mortality (multivariable adjusted hazard ratio, 1.84 per standard deviation of telomere attrition at 9 to 15 months post-transplant; 95% confidence interval, 1.25 to 2.72; P = .002) and high relapse-related mortality (subhazard ratio, 2.07; 95% confidence interval, 1.14 to 3.76; P = .02). Taken together, telomere attrition may be a clinically relevant marker for identifying patients at high risk of mortality.

C-Reactive Protein Levels at Diagnosis of Acute Graft-versus-Host Disease Predict Steroid-Refractory Disease, Treatment-Related Mortality, and Overall Survival after Allogeneic Hematopoietic Stem Cell Transplantation.

Acute graft-versus-host disease (aGVHD) remains a cause of excessive morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Primary treatment consists of high-dose corticosteroids, but a small group of patients develop steroid-refractory disease, and their prognosis is especially poor. There is experimental evidence that coexisting inflammation aggravates aGVHD. Because C-reactive protein (CRP) is a systemic inflammatory marker, we aimed to investigate whether plasma CRP concentrations at the diagnosis of aGVHD can predict the risk of failing first-line therapy and developing steroid-refractory disease. We retrospectively studied 461 patients who underwent HSCT between 2010 and 2015. aGVHD grade II-IV was diagnosed in 148 patients (32%). CRP level and total white blood cell, lymphocyte, and neutrophil counts were available for all patients at the time of aGVHD diagnosis. According to local protocol, patients with failed response to high-dose steroid therapy (2 mg/kg) were treated with the TNF-α inhibitor infliximab and categorized as having steroid-refractory disease. Of 148 patients with grade II-IV aGVHD, 28 (19%) developed steroid-refractory disease. In these patients, plasma CRP concentration at diagnosis ranged between <1 and 253 mg/L. CRP levels were significantly higher in patients who developed steroid-refractory disease compared with those who responded to high-dose corticosteroid therapy (odds ratio, 1.50; 95% confidence interval, 1.18-1.93; P = .001). This translated into significantly increased transplantation-related mortality and decreased overall survival in the patients with high CRP levels. Total white blood cell, lymphocyte, and neutrophil counts were not associated with steroid resistance in the patients with aGVHD. These results suggest that CRP level at diagnosis is a valid predictor of the development of steroid-refractory disease in patients who develop grade II-IV aGVHD after HSCT.

Toll-like receptor polymorphisms in allogeneic hematopoietic cell transplantation.

To assess the impact of the genetic variation in toll-like receptors (TLRs) on outcome after allogeneic myeloablative conditioning hematopoietic cell transplantation (HCT), we investigated 29 single nucleotide polymorphisms across 10 TLRs in 816 patients and donors. Only donor genotype of TLR8 rs3764879, which is located on the X chromosome, was significantly associated with outcome at the Bonferroni-corrected level P ≤ .001. Male hemizygosity and female homozygosity for the minor allele were significantly associated with disease-free survival (hazard ratio [HR], 1.47 [95% confidence interval {CI}, 1.16 to 1.85]; P = .001). Further analysis stratified by donor sex due to confounding by sex was suggestive for associations with overall survival (male donor: HR, 1.41 [95% CI, 1.09 to 1.83], P = .010; female donor: HR, 2.78 [95% CI, 1.43 to 5.41], P = .003), disease-free survival (male donor: HR, 1.45 [95% CI, 1.12 to 1.87], P = .005; female donor: HR, 2.34 [95% CI, 1.18 to 4.65], P = .015), and treatment-related mortality (male donor: HR, 1.49 [95% CI, 1.09 to 2.04], P = .012; female donor: HR, 3.12 [95% CI, 1.44 to 6.74], P = .004). In conclusion, our findings suggest that the minor allele of TLR8 rs3764879 of the donor is associated with outcome after myeloablative conditioned allogeneic HCT.

Durable donor engraftment after radioimmunotherapy using α-emitter astatine-211-labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation.

To reduce toxicity associated with external γ-beam radiation, we investigated radioimmunotherapy with an anti-CD45 mAb labeled with the α-emitter, astatine-211 ((211)At), as a conditioning regimen in dog leukocyte antigen-identical hematopoietic cell transplantation (HCT). Dose-finding studies in 6 dogs treated with 100 to 618 µCi/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) without HCT rescue demonstrated dose-dependent myelosuppression with subsequent autologous recovery, and transient liver toxicity in dogs treated with (211)At doses less than or equal to 405 µCi/kg. Higher doses of (211)At induced clinical liver failure. Subsequently, 8 dogs were conditioned with 155 to 625 µCi/kg (211)At-labeled anti-CD45 mAb (0.5 mg/kg) before HCT with dog leukocyte antigen-identical bone marrow followed by a short course of cyclosporine and mycophenolate mofetil immunosuppression. Neutropenia (1-146 cells/µL), lymphopenia (0-270 cells/µL), and thrombocytopenia (1500-6560 platelets/µL) with prompt recovery was observed. Seven dogs had long-term donor mononuclear cell chimerism (19%-58%), whereas 1 dog treated with the lowest (211)At dose (155 µCi/kg) had low donor mononuclear cell chimerism (5%). At the end of follow-up (18-53 weeks), only transient liver toxicity and no renal toxicity had been observed. In conclusion, conditioning with (211)At-labeled anti-CD45 mAb is safe and efficacious and provides a platform for future clinical trials of nonmyeloablative transplantation with radioimmunotherapy-based conditioning.

A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation.

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m(2) fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 - tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 - tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 - tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001).

Effect of non-pharmacological interventions on symptoms and quality of life in patients with hematological malignancies - A systematic review.

BACKGROUND: Non-pharmacological interventions have the potential to enhance health-related quality of life (HRQoL) through symptom management. This systematic review aims to identify, collate, and assess randomized controlled trials investigating the effect of non-pharmacological interventions on symptoms and HRQoL within hematology. METHODS: MEDLINE/PUBMED, EMBASE, CINAHL, PSYCINFO and COCHRANE were searched up to April 2021. Outcomes were changes in symptoms and HRQoL. RESULTS: Sixty-five studies were categorized into five intervention types: Mind/body (n=9), Web-based (n=9), Music/art (n=6), Consultation-based (n=4), and Physical activity (n=37). We found significantly reduced fatigue (n=12 studies), anxiety (n=8) and depression (n=7), with 11 studies showing significant improvements in HRQoL. CONCLUSIONS: The evidence for non-pharmacological interventions shows substantial variation in efficacy and methodological quality. While specific symptoms and HRQoL outcomes significantly favored the intervention, no particular intervention can be emphasized as more favorable, given the inability to conduct a meta-analysis.

ECP versus ruxolitinib in steroid-refractory chronic GVHD - a retrospective study by the EBMT transplant complications working party.

Ruxolitinib has become the new standard of care for steroid-refractory and steroid-dependent chronic GVHD (SR-cGVHD). Our aim was to collect comparative data between ruxolitinib and extracorporeal photophoresis (ECP). We asked EBMT centers if they were willing to provide detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient. 31 centers responded positively and we included all patients between 1/2017-7/2019 treated with ECP or ruxolitinib for moderate or severe SR-cGVHD. We identified 84 and 57 patients with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-cGVHD (steroid dependent vs. refractory vs. intolerant to steroids). At day+180 after initiation of treatment for SR-cGVHD the odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.35 (95% CI = [0.64; 2.91], p = 0.43). In line, we detected no statistically significant differences in overall survival, progression-free survival, non-relapse mortality and relapse incidence. The clinical significance is limited by the retrospective study design and the current data can't replace prospective studies on ECP in SR-cGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-cGVHD.

Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial.

The risks and benefits of adding fludarabine to a 2-Gy total body irradiation (TBI) nonmyeloablative regimen are unknown. For this reason, we conducted a prospective randomized trial comparing 2-Gy TBI alone, or in combination with 90 mg/m(2) fludarabine (FLU/TBI), before transplantation of peripheral blood stem cells from HLA-matched related donors. Eighty-five patients with hematological malignancies were randomized to be conditioned with TBI alone (n = 44) or FLU/TBI (n = 41). All patients had initial engraftment. Two graft rejections were observed, both in the TBI group. Infection rates, nonrelapse mortality, and graft-versus-host disease (GVHD) were similar between groups. Three-year overall survival was lower in the TBI group (54% versus 65%; hazard ratio [HR], .57; P = .09), with higher incidences of relapse/progression (55% versus 40%; HR, .55; P = .06), relapse-related mortality (37% versus 28%; HR, .53; P = .09), and a lower progression-free survival (36% versus 53%; HR, .56; P = .05). Median donor T cell chimerism levels were significantly lower in the TBI group at days 28 (61% versus 90%; P < .0001) and 84 (68% versus 92%; P < .0001), as was NK cell chimerism on day 28 (75% versus 96%; P = .0005). In conclusion, this randomized trial demonstrates the importance of fludarabine in augmenting the graft-versus-tumor effect by ensuring prompt and durable high-level donor engraftment early after transplantation.

Pretransplantation Plasma ST2 Level as a Prognostic Biomarker of 1-Year Nonrelapse Mortality in Allogeneic Hematopoietic Cell Transplantation.

Soluble ST2 is established as a prognostic biomarker of nonrelapse mortality (NRM) when measured early after allogeneic hematopoietic cell transplantation (HCT). However, less is known about the prognostic value of ST2 measured before transplantation. We hypothesized that pretransplantation plasma ST2 level was associated with 1-year NRM and could add to our current prognostic assessment. Moreover, we aimed to investigate the associations between pretransplantation plasma ST2 levels and patient characteristics and other plasma biomarkers and to reproduce previous associations between post-transplantation plasma ST2 levels and outcomes of HCT. We conducted this cohort study of 374 adults who underwent allogeneic HCT at our center between July 2015 and December 2019 (median age, 59 years; 55% with a nonmyeloablative conditioning regimen). ST2 levels were measured by enzyme-linked immunosorbent assay in stored plasma samples obtained at a median of 23 days before HCT and also in samples obtained on days +7 and +14 post-HCT. A logistic regression model of 1-year NRM was fitted using an a priori defined set of covariates consisting of age, Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI), and conditioning intensity (myeloablative versus nonmyeloablative), to which the pretransplantation ST2 level was added as a variable to assess its incremental prognostic value. Models also were fitted of 1-year all-cause mortality, relapse, and grade II-IV acute graft-versus-host disease (GVHD) for pretransplantation and post-transplantation ST2 levels. The median pretransplantation plasma ST2 level was 20.4 ng/mL (interquartile range, 15.2 to 27.2 ng/mL). Pretransplantation ST2 levels were higher in males compared with females (median, 22.2 ng/mL versus 18.1 ng/mL; P < .001) and were correlated with HCT-CI (Spearman ρ = .18; P < .001), body mass index (ρ = .10; P = .05), and plasma levels of C-reactive protein (ρ = .34; P < .001), creatinine (ρ = .17; P = .001), and albumin (ρ = -.17; P < .001). Pretransplantation ST2 levels added prognostic information about 1-year NRM to age, HCT-CI, and conditioning intensity (adjusted odds ratio [OR] of 1-year NRM per 10 ng/mL increase in ST2, 1.32; 95% confidence interval [CI], 1.05 to 1.65; P = .02). Although adding pretransplantation ST2 levels did not notably improve model discrimination (.674 to .675, ΔAUC = .001), it increased the diversity of the predicted risks (P = .02, likelihood ratio test). Pretransplantation ST2 levels also were prognostic of 1-year all-cause mortality (adjusted OR per 10-ng/mL increase, 1.23; 95% CI, 1.02 to 1.48; P = .03), but not of relapse (P = .47) or acute GvHD (P = .81). Plasma ST2 levels at day +7 were prognostic of 1-year NRM, all-cause mortality, relapse, and acute GVHD, whereas levels at day +14 were prognostic of 1-year NRM and all-cause mortality. Our results show that pretransplantation plasma ST2 levels added prognostic information about 1-year NRM to age, HCT-CI, and conditioning intensity, and suggest that ST2 has potential as a biomarker of pretransplantation vulnerability and should be considered in future developments of prediction models of NRM after allogeneic HCT.

Triple-Drug Graft-versus-Host Disease Prophylaxis after HLA-Matched Unrelated Donor Nonmyeloablative Allogenic Hematopoietic Stem Cell Transplantation.

Adding sirolimus to graft-versus-host disease (GVHD) prophylaxis with cyclosporin and mycophenolate mofetil (MMF) reduced the risk of grade II-IV acute GVHD after nonmyeloablative (NMA) allogenic hematopoietic stem cell transplantation (HSCT) with an HLA-matched unrelated donor in a randomized clinical trial. We analyzed real-life data to investigate the impact of implementing the triple-drug regimen with cyclosporin, MMF and sirolimus as standard GVHD prophylaxis after NMA HSCT with an HLA-matched unrelated donor at our institution. We studied all adult patients (age ≥18 years) who underwent NMA HSCT with an HLA-matched unrelated donor at Rigshospitalet, Copenhagen University Hospital, Denmark between 2018 and 2021 and received GVHD prophylaxis with cyclosporin, MMF and sirolimus (triple-drug group [TDG]). Comparisons were made with a historical cohort who received tacrolimus and MMF as GVHD prophylaxis after HLA-matched unrelated donor NMA HSCT between 2014 and 2017 (control group [CG]). Outcomes were grade II-IV and grade III-IV acute GVHD, chronic GVHD, relapse, nonrelapse mortality (NRM) and overall survival (OS). A total of 264 patients were included (TDG, n = 137; CG, n = 127). Median age was 66 years (interquartile range [IQR], 58 to 69 years) in the TDG and 63 years (IQR, 57 to 68 years) in the CG. Acute myeloid leukemia and myelodysplastic syndrome were the most frequent indications for HSCT in both groups (TDG, 33% and 23%, respectively; CG, 36% and 22%, respectively). The cumulative incidence at day +110 of grade II-IV GVHD was 17% (95% confidence interval [CI] 11% to 23%) in the TDG versus 29% (95% CI, 21% to 37%) in the CG (P = .02, Gray's test) and that of grade III-IV acute GVHD was 3% (95% CI, 0 to 6%) versus 5% (95% CI, 1% to 8%), respectively (P = .4, Gray's test). In a Cox regression model adjusted for age, donor age and female donor to male recipient the risk of grade II-IV acute GVHD was lower in the TDG compared to the CG (hazard ratio [HR], .51; 95% CI .30 to .86; P = .01). The 2-year OS was 77% (95% CI, 70% to 84%) in the TDG and 69% (95% CI, 61% to 77%) in the CG (P = .04), and this difference remained significant after adjustment for age and Karnofsky Performance Status (HR, .65; 95% CI, .42 to .99; P = .04). The 2-year cumulative incidences of chronic GVHD, relapse and NRM were 60% (95% CI, 51% to 69%), 21% (95% CI, 13% to 28%), and 12% (95% CI, 6% to 17%), respectively, in the TDG and 62% (95% CI, 54% to 71%), 27% (95% CI, 19% to 35%) and 14% (95% CI, 8% to 20%), respectively, in the CG. Multivariable analyses revealed no difference in the risk of chronic GVHD (HR, .91; 95% CI, .65 to 1.26; P = .56), relapse (HR, .70; 95% CI, .42 to 1.15; P = .16) or NRM (HR, .56; 95% CI, .31 to 1.05; P = .07). After changing the standard GVHD prophylaxis in patients undergoing NMA HSCT with an HLA-matched unrelated donor from tacrolimus and MMF to cyclosporin, MMF and sirolimus, we observed a reduction in the incidence of grade II-IV acute GVHD and improved 2-year OS.

ECP versus ruxolitinib in steroid-refractory acute GVHD - a retrospective study by the EBMT transplant complications working party.

Introduction: Extracorporal Photophoresis (ECP) is in clinical use for steroid-refractory and steroid-dependent acute GVHD (SR-aGVHD). Based on recent Phase-III study results, ruxolitinib has become the new standard of care for SR-aGVHD. Our aim was to collect comparative data between ruxolitinib and ECP in SR-aGVHD in order to improve the evidence base for clinical decision making. Methods: We asked EBMT centers if they were willing to participate in this study by completing a data form (Med-C) with detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient. Results: 31 centers responded positively (14%) and we included all patients receiving alloSCT between 1/2017-7/2019 and treated with ECP or ruxolitinib for SR-aGVHD grades II-IV from these centers. We identified 53 and 40 patients with grades II-IV SR-aGVHD who were treated with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-aGVHD (steroid dependent vs. refractory). At day+90 after initiation of treatment for SR-aGVHD we found no statistically significant differences in overall response. The odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.13 (95% CI = [0.41; 3.22], p = 0.81). In line, we detected no statistically significant differences in overall survival, progression-free survival, non-relapse mortality and relapse incidence. Discussion: The clinical significance is limited by the retrospective study design and the current data can't replace prospective studies on ECP in SR-aGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-aGVHD.

Reagents for astatination of biomolecules. 6. An intact antibody conjugated with a maleimido-closo-decaborate(2-) reagent via sulfhydryl groups had considerably higher kidney concentrations than the same antibody conjugated with an isothiocyanato-closo-decaborate(2-) reagent via lysine amines.

We are investigating the use of an (211)At-labeled anti-CD45 monoclonal antibody (mAb) as a replacement of total body irradiation in conditioning regimens designed to decrease the toxicity of hematopoietic cell transplantation (HCT). As part of that investigation, dose-escalation studies were conducted in dogs using (211)At-labeled anticanine CD45 mAb, CA12.10C12, conjugated with a maleimido-closo-decaborate(2-) derivative, 4. Unacceptable renal toxicity was noted in the dogs receiving doses in the 0.27-0.62 mCi/kg range. This result was not anticipated, as no toxicity had been noted in prior biodistribution and toxicity studies conducted in mice. Studies were conducted to understand the cause of the renal toxicity and to find a way to circumvent it. A dog biodistribution study was conducted with (123)I-labeled CA12.10C12 that had been conjugated with 4. The biodistribution data showed that 10-fold higher kidney concentrations were obtained with the maleimido-conjugate than had been obtained in a previous biodistribution study with (123)I-labeled CA12.10C12 conjugated with an amine-reactive phenylisothiocyanato-CHX-A″ derivative. The difference in kidney concentrations observed in dogs for the two conjugation approaches led to an investigation of the reagents. SE-HPLC analyses showed that the purity of the CA12.10C12 conjugated via reduced disulfides was lower than that obtained with amine-reactive conjugation reagents, and nonreducing SDS-PAGE analyses indicated protein fragments were present in the disulfide reduced conjugate. Although we had previously prepared closo-decaborate(2-) derivatives with amine-reactive functional groups (e.g., 6 and 8), a new, easily synthesized, amine-reactive (phenylisothiocyanate) derivative, 10, was prepared for use in the current studies. A biodistribution was conducted with coadministered (125)I- and (211)At-labeled CA12.10C10 conjugated with 10. In that study, lower kidney concentrations were obtained for both radionuclides than had been obtained in the earlier study of the same antibody conjugated with 4 after reduction of disulfide bonds.

Single-institution long-term outcomes for patients receiving nonmyeloablative conditioning hematopoeitic cell transplantation for chronic lymphocytic leukemia and follicular lymphoma.

Non-myeloablative conditioning hematopoietic cell transplantation (NMC-HCT) has improved the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). In a cohort of 85 patients (45 with CLL and 40 with FL), we observed 5-yr overall survival (OS) and progression-free survival (PFS) of 53% and 38% in the CLL group and 81% and 76% in the FL group. In the both the CLL group and the FL group, a strong trend toward better OS and PFS was observed among patients in complete remission (CR) at HCT. Within the FL group, sixteen patients had at one or more time points in their disease history had transformed FL. In contrast to the poor survival found in patients with transformed FL in previous studies, the 5-yr OS was almost identical in patients with transformed and non-transformed FL, 83% and 78%, respectively. In conclusion, our study supports that NMC-HCT is a safe and efficacious treatment that can provide long-term survival in elderly, heavily pretreated patients with FL and CLL. Especially patients with FL, and also transformed FL, seemed to have a great benefit of NMC-HCT, and CR at the time of HCT was an important prognostic factor.