Introduction A high CD4/CD8 T cell ratio in hematopoietic stem cell transplant (HSCT) allografts was observed to predict graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) but has not been comparatively examined in settings of various GVHD-prophylaxis regimens.Methods This retrospective monocentric study included all consecutive HSCT performed with peripheral blood stem cells between January 2000 and June 2021. The impact of the graft CD4/CD8 ratio was analyzed in three cohorts with different GVHD-prophylaxis platforms.Results In the cyclosporine/mycophenolate-mofetil (CSA/MMF) cohort (n = 294, HLA-matched HSCT), a high (>75th percentile) CD4/CD8 ratio was associated with increased overall mortality (HR: 1.56; p = .01), increased NRM (HR: 1.85; p = .01) and GVHD-associated mortality (HR: 2.13; p = .005). In the post-transplant cyclophosphamide (PTCy)/tacrolimus/MMF cohort (n = 113, haploidentical-related or mismatched-unrelated HSCT), a high CD4/CD8 ratio was associated with increased overall mortality (HR 2.07; p = .04) and aGVHD3-4 (HR: 2.24; p = .02). By contrast, in the CSA/methotrexate (CSA/MTX) cohort (n = 185, HLA-matched HSCT) the CD4/CD8 ratio had no significant impact on any of the investigated endpoints.Conclusion A high CD4/CD8 ratio in the allograft has an adverse impact on GVHD and survival in CSA/MMF- and PTCy-based HSCT, while MTX-based prophylaxis may largely alleviate this important risk factor.

Abstract Background T-DXd is a novel antibody-drug conjugate with high activity in HER2-positive metastatic breast cancer. The prospective, single-arm, single-centre phase II TUXEDO-1 trial showed clinically relevant activity of T-DXd in HER2-positive BC pts with active BM with an intracranial response rate of 73.3%. This biomarker sub-study of TUXEDO-1 aimed to investigate changes in the extent of metastases-induced brain damage in patients with and without response to therapy by measuring the serum levels of two proteins constitutively expressed in the human brain and measurable upon brain damage in the blood serum: NSE and S100. Material and Methods We assessed serum NSE (sNSE) and serum S100 (sS100) levels in a total of 37 blood samples drawn at cycles 1, 4 and end of treatment (EOT) in all patients of the intent-to-treat population of the TUXEDO-1 trial using commercially available ELISA assays. Intracranial radiological response was centrally assessed by a board-certified neuro-radiologist using RANO criteria. sNSE and sS100 levels were compared between responders and non-responders using the Mann Whitney U test and a significance level of 0.05. Results At baseline, we detected no significant difference of sNSE or sS100 levels between T-DXd responders and non-responders, respectively. Baseline median sNSE level was 10.6 ng/ml (interquartile range (IQR) 8.6-12.2) in T-DXd responders as compared with median 12.5 ng/ml (IQR 12.2-12.9) in the non-responder group (n.s.). At cycle 4, corresponding numbers were 8.1 ng/ml in responding patients (IQR 7-11.2) and 12.7 ng/ml (IQR 12.2-12.9) in non-responders, respectively (p=0.009). No differences in sS100 levels were observed between the groups at any time point. Conclusion In patients showing intracranial objective response to T-Dxd, sNSE levels were significantly lower at cycle 4 as compared with non-responders, suggesting a reduction in metastases-induced brain damage as a direct treatment effect. sNSE may be a clinically useful biomarker for longitudinal assessment of brain metastasis burden.

Maintaining quality-of-life (QoL) and neurocognitive function is a main goal in the setting of brain metastases (BM) in HER2-positive breast cancer (BC) patients (pts). TUXEDO-1 investigated QoL and neurocognitive function during trastuzumab-deruxtecan (T-DXd) therapy in HER2-positive BC BM pts.

Brain metastases (BM) are a frequent and devastating complication of HER2-positive breast cancer (BC). T-DXd is an antibody-drug conjugate with high activity in pretreated pts but information regarding activity in active BM is limited. Therefore, the prospective, single-arm, phase II TUXEDO-1 trial investigated T-DXd in HER2-positive BC pts with active BM. TUXEDO-1 included adult pts with HER2-positive BC and newly diagnosed untreated BM or BM progressing after local therapy, prior exposure to trastuzumab and pertuzumab, and no indication for immediate local therapy. The primary endpoint was intracranial response rate (RR) centrally assessed by Response Assessment in Neuro-Oncology (RANO)-BM criteria. Secondary endpoints consisted of extracranial RR, progression-free survival (PFS), overall survival, safety, and quality-of-life. Based on a Simon’s two-stage design (RR under alternative hypothesis >60%; RR under null hypothesis <26%), a total number of 15 pts were enrolled. The null hypothesis was to be rejected with a type I error rate of 5% and a power of 80% if at least 7 responses were observed. As of December 29th, 2021, all 15 pts had received at least one dose of T-DXd (60% progressive BM, 70% prior T-DM1). One patient initially assessed as having parenchymal BM was found to have dural metastasis upon restaging and was excluded from efficacy analyses. In the intention-to-treat population, intracranial RR was 73.3% (11/15) (per protocol population: 78.6% [11/14]). At 11 months median follow-up, PFS was 14 months (95% CI 8.48-19.52); two pts died from disease progression. Main non-haematological toxicities consisted of grade 1/2 fatigue (86.7%), nausea (46.7%), and diarrhoea (26.7%). Dose reductions were required in 9 pts; 4 pts had serious adverse events. Grade 2 interstitial lung disease and a symptomatic drop of left-ventricular ejection fraction were observed in one patient each. In the TUXEDO-1 study, T-DXd yielded high intracranial response rates. Data suggest that T-DXd achieves significant therapeutic effects in the central nervous system and should thus be further explored in this context.

Brain metastases (BM) are frequently diagnosed in HER2-positive breast cancer (BC) and add to morbidity and mortality. Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate approved for the treatment of HER2-positive metastatic BC but has not been specifically investigated in the context of BM. Here, we present preliminary results of the prospective, single-centre, single-arm, phase II TUXEDO-1 trial investigating T-DXd in HER2-positive BC patients (pts) with active BM.

Although the risk for nonrelapse mortality (NRM) associated with early cytomegalovirus (CMV) reactivation (CMVR) after allogeneic hematopoietic stem cell transplantation (HSCT) is well established, debate is ongoing on whether CMVR may reduce the risk of primary disease relapse. The aim of this study was to evaluate relapse protection following early CMV reactivation after HSCT in the context of the recipient HLA-C killer cell immunoglobulin-like receptor ligands (KIRLs). In this retrospective bicentric study, 406 matched related or unrelated donor transplantations for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) were stratified by HLA-C KIRL group (homozygous versus heterozygous) and analyzed separately for the impact of early CMVR on the cumulative incidences of relapse, NRM, and acute and chronic graft-versus-host-disease (GVHD) using landmark and multistate analyses. By landmark analysis of patients alive and relapse-free at 45 days post-HSCT, HLA-C KIRL homozygous recipients (C1/1 or C2/2) had a lower risk of subsequent relapse if CMVR occurred before this landmark (subhazard ratio [sHR], 0.36; P=.002). In contrast, in HLA-C KIRL heterozygous (C1/2) recipients, early CMVR had no impact on subsequent relapse (sHR, 0.88; P =.63). NRM (sHR, 3.31; P<.001) and grade III-IV acute GVHD (sHR, 2.60; P=.04) were significantly increased after early CMVR in the homozygous cohort, but not in the heterozygous cohort (NRM: sHR, 1.23; P=.53; grade III-IV acute GVHD: sHR, 1.40; P=.50). Multivariable landmark analyses and a multistate model confirmed the limitation of the relapse-protective effect of early CMVR to the homozygous cohort. Chronic GVHD and overall survival were not influenced in neither cohort. An antileukemic effect of early CMVR after HSCT for AML/MDS was significant but strictly limited to recipients homozygous for HLA-C KIRL. However, particularly in this cohort, CMVR had an adverse impact on aGVHD and NRM. (C) 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Background: The interstitial deletion of the long arm of chromosome 5—del(5q)—is the most common cytogenetic abnormality in MDS occurring either as a sole aberration or as a part of complex karyotypes (CK). MDS with isolated del(5q) are associated with a favorable outcome while MDS with CK relate to poor prognosis. Extent of deleted segment is highly variable. However, it remains unclear whether its size matters for the different MDS phenotypes. Aims: The aim was to compare the extent of deletion in 264 MDS patients [116 with isolated del(5q) and 148 with del(5q) involved in CK] and to assess the relationship of del(5q) extent and TP53 gene mutation. Methods: Extent of del(5q) was analyzed using I-FISH (Abbott, MetaSystems), mBAND (MetaSystems) and array CGH/SNP (CytoChip Cancer SNP 180K, Illumina or SurePrint G3 Cancer CGH+SNP 4x180K, Agilent). CK were analyzed with mFISH (MetaSystems). Sequence analysis of TP53 gene was performed in 84 cases using amplicon deep sequencing (exons 4–11) on a 454 GS Junior system (Roche) or with TruSight Myeloid Panel Kit on MiSeq sequencing instruments (Illumina). Results: In the group with isolated del(5q), the most frequently deleted segment ranged between the bands 5q14 and 5q33.3, with the smallest deletion encompassing the 5q31.1–5q31.3 region (18.527 Mb). The TP53 mutation was proved in 19.4% cases. The size of the deletion did not significantly differ in patients with and without TP53 mutation. In the group with CK, the deletion often involved entire long arm including the telomeric region. In some cases, a part of short arm was also deleted, but we never observed the loss of the entire chromosome 5. The commonly conserved region (CCR) was localized in bands 5p12 to 5p14.1. In this group, the mutation of TP53 and/or LOH17p was detected in 49% of patients. The commonly deleted regions (CDR) were in the band 5q31.1 (5.522 Mb) in cases with isolated del(5q) and between the bands 5q31.1 and 5q31.3 (18.527 Mb) in patients with CK. Summary/Conclusion: Patients with isolated del(5q) had a smaller size of the deleted segment. More extensive 5q deletion was associated with higher karyotype complexity, increased frequency of TP53 aberrations and worse prognosis. Accurate analysis of breakpoints and range of del(5q) points out to the correlation of deletion size with increasing genomic instability in MDS and contributes to a better understanding of the MDS pathogenesis. Supported by RVO-VFN64165, GACR P302/12/G157, ProgresQ28/LF1, MHCR 00023736.

Seit 2014 ist in den gespag Krankenhäusern, den beiden Häusern des Ordensklinikums Linz und im Krankenhaus der Barmherzigen Schwestern in Ried, die gemeinsam rund 60% der jährlich neuerkrankten Patientinnen in Oberösterreich betreuen, eine einheitliche „medizinische Leitlinie Mammakarzinom“ etabliert. Trotz der Tatsache, dass seit Jahren regelmäßig auch physikalisch- rehabilitative Maßnahmen bei unterschiedlichen im Verlauf der Behandlung auftretenden Gesundheitsstörungen durchgeführt werden, Evidenz zur Wirksamkeit solcher Maßnahmen vorliegen und darüber hinaus die Vorhaltung entsprechender Leistungen für die EUSOMA Zertifizierung nachgewiesen werden muss, haben bisher einschlägige Empfehlungen keine Aufnahme in diese Leitlinien gefunden.