We analyzed patient-reported QoL, CF, and symptoms of depression and anxiety in patients with primary or secondary AML who received their 1st allo-HSCT with TBI-based protocols at the Department of Hematology of the University Hospital Regensburg between 1999 and 2017. All patients had a follow-up time of at least 2 years and were relapse-free for at least 2 years. The 2 year follow up was chosen since the primary aim was long term outcome and reports have indicated a protracted recovery of neurocognitive function [3]. Donors included matched sibling donors (MSD), matched unrelated donors (MUD), mismatched unrelated donors (MMUD) and haploidentical/mismatched related donors (MMRD). Source of stem cells were peripheral blood, bone marrow or cord blood. Patients completed the Functional Assessment of Cancer Therapy-Bone marrow transplant (FACT-BMT, version 4), the FACT-Cognition Function (FACT-Cog, version 3), the Patient Health Questionaire-4 (PHQ-4) and a questionnaire about sociodemographic data. All patients visited the Department of Hematology of the University Hospital Regensburg for routine follow-up visits. Clinical data including cGvHD status were abstracted from the medical charts of the Departments of Hematology and Radiation Oncology of the University Hospital Regensburg. Transplantation variables included gender, diagnosis, patient age, Karnofsky performance score (KPS), hematopoietic cell transplantation-comorbidity index (HCT-CI), as described by Sorror et al. [4], 2017 European LeukemiaNet (ELN) genetic risk stratification, as described by Döhner et al. [5], disease status, stem cell source, intensity of conditioning regimen, chemotherapeutic regimen, recipient and donor characteristics (donor type, donor age, HLA-compatibility, gender match, cytomegalovirus serostatus), GvHD prophylaxis and the use of rabbit anti-thymocyte globulin (ATG). Data closing was April 2021. The local Ethics Board of the University of Regensburg approved this study (Number 20-1810_1-101).

The choice of conditioning regimen was based on the oncologists´ discretion and dependent on patient age, disease risk and comorbidities. All patients included in the analysis received TBI as part of a complex conditioning regimen. TBI was performed in a consistent manner with an average dose rate of 4 cGy/min to the total body and lung shielding in case of doses > 8 Gy. Over the years, four treatment protocols were used (8 Gy TBI/Cyclophosphamide/Fludarabine, FLAMSA-RIC/Cyclophosphamide/4Gy TBI, 12 Gy TBI/Cyclophosphamide and 8 Gy TBI/Fludarabine). From 2000 to 2013, two Siemens Primus linear accelerators (Siemens Medical Systems, Inc., Concord, CA) were used for TBI, and from 2013 to 2017 two linear accelerators of type Elekta Synergy ™ with an Agility ™ head (Elekta Ltd, Crawley, UK) were applied. We proved clinically good dose distributions and similar parameters with both linear accelerators [6]. All patients received 6 megavoltage (MV) photon beams. Patients were treated with a twice-daily fractionation and a minimum of 6 h between fractions. Patients were lying down on a couch at the floor level in supine and prone positions to extend the source-to-skin distance. A plate of Makrolon® polycarbonate of 1 cm thickness was placed on a stand above of the patient to neutralize the skin sparing by the buildup effect. The low diameter in the neck region was compensated by using a bolus of plastic modeling mass. Eight rotational arcs were used per patient position. The average time to deliver each fraction was 50–60 min per side (supine and prone). Additional fixed beams were used in cranial and caudal direction to compensate for the effects of inverse square variation with increasing distance. Two individual lung shields of MCP96 of calculated thickness were designed in case of doses > 8 Gy to reduce the total dose to the center of the lung to 3.5 Gy in supine and prone positions (total dose of 7 Gy). Radio-oncologists contoured two individual lung blocks for each patient on a CT scan with a 1–2 cm margin between the edge of the lung on the CT film and the edge of the block. Lung blocks were tailored to avoid shielding of the vertebrae. MV-imaging verified the shielding positions. Areas of the chest wall that were shielded by the blocks were supplemented once a day with electron beams to achieve the full dose to the thoracic walls. The electron fields delivered a supplemented dose of 5 Gy for 12 Gy regimens. In vivo dosimetry was used to verify the dose delivery on several points on the patient´s body, demonstrating the uniformity of the dose distribution [6].

The FACT-BMT (Version 4.0) is a self-report questionnaire. The FACT-BMT combines the 27-item FACT-G total score (score range 0–108), an assessment of physical well-being (PWB, score range 0–28), social/family well-being (SWB, score range 0–28), emotional well-being (EWB, score range 0–24) and functional well-being (FWB, score range 0–28) with a 10 item Bone Marrow Transplant subscale (BMTS, score range 0–40) to evaluate self-reported concerns after transplantation. Patients rate on five-point Likert scale the frequency with which each concern was recognized in the past 7 days. The FACT-BMT-Trial Outcome Index (FACT-BMT-TOI, score range 0–96) is the sum of PWB, FWB and the BMTS-score. The FACT-BMT total score (score range 0–148) is the sum of the BMTS score and of the FACT-G total score. Higher scores indicate better QoL. The FACT-Cog (Version 3.0) is a validated measurement to analyze self-reported cognitive complaints in cancer patients. It includes perceived cognitive impairments (FACT-CogPCI, score range 0–72), impact of perceived cognitive impairments on quality of life (FACT-CogQoL, score range 0–16), comments from others (FACT-CogOth, score range 0–16) and perceived cognitive abilities (FACT-CogPCA, score range 0–28). Patients rate on five-point Likert scale the frequency of each complaint in the past 7 days. Higher scores indicate better QoL. All data are analyzed and expressed as mean according to the FACIT recommendations. The Patient Health Questionnaire-4 (PHQ-4) analyzes symptoms of depression and anxiety over the last 2 weeks on a 4 point Likert-type scale. Patients indicate if they feel nervous, anxious or on edge (item 1), if they are not able to stop and control worrying (item 2), if they have little interest or pleasure in doing things (item 3) and if they feel down, depressed or hopeless (item 4). The anxiety subscale (GAD-2) is the sum of the items 1 und 2 and the depression subscale (PHQ-2) is the sum of the items 3 and 4. In summary, there are four categories of psychological distress (None = 0–2, mild = 3–5, moderate = 6–8 and severe = 9–12). Patients with a GAD2 or PHQ2 of ≥ 3 are categorized as present for anxiety or depression. The presence and absence of cGvHD was extracted from the database of the Department of Hematology. Acute GvHD and cGvHD were defined according to described standard criteria [7,8,9]. Acute GvHD is classified as clinically significant at grade II-IV aGvHD. Patients have clinically active cGvHD (Group 1: Currently active inflammatory manifestations of cGvHD independently of the use of immunosuppression), resolved cGvHD (Group 2: All signs of clinically activity of cGvHD have disappeared, past history of cGvHD, no use of immunosuppression) or never had signs of cGvHD (Group 3: Never having cGvHD). The overall rate of completion was 100% for the FACT-Cog and the PHQ-4 as well as 98.1% for the FACT-BMT (Missing answers referred to satisfaction with sexual functioning).

Transplant-related characteristics were presented as absolute and relative frequencies for categorical variables and as median and interquartile range (IQR) for continuous variables. The Mann–Whitney U-test was used for comparisons of continuous variables and the chi-square test of independence for categorical variables. Spearman's rank correlation coefficients were calculated to analyze the association of the FACT-BMT, FACT-Cog and PHQ-4. One-way analyses of variance (ANOVA) were performed to explore the effect of cGvHD on QoL outcomes. Post hoc group comparisons were done using the Tukey-test. Median follow-up time was estimated by using the reverse Kaplan-Meier method. Normative data (unadjusted means and standard deviations) of a general U.S. adult population of Brucker et al. [10] were used for comparisons with the FACT-G and normative data (means and standard deviations) of a French healthy population of Lange et al. [11] for comparisons with the FACT-Cog. We excluded AML patients < 30 years of age (n = 4) for comparisons with the normative data of Lange et al. [11] because of missing reference values for patients < 30 years of age. Comparisons between the normative data and the patient population were made using the one-sample t-test. A minimum clinically important difference (MCID) in QoL scores was defined as half of standard deviation (0.5 SD), as reported by Norman et al. [12]. Missing data were treated according to the manual scoring guidelines. We used the cutpoints of van Dyk et al. [13] to discriminate cancer-related cognitive impairment (Perceived cognitive impairment-score, FACT-CogPCI < 54) from the healthy population (FACT-CogPCI ≥ 54). All p-values were two-sided and p-values < 0.05 were considered as significant. Statistical analysis was performed using SPSS 26.0 (SPSS Inc., Chicago, IL, USA) and graphics were performed with Excel (2013, Microsoft Office).