PLOS ONE RESEARCH ARTICLE The avoidance of G-CSF and the addition of prophylactic corticosteroids after autologous stem cell transplantation for multiple myeloma patients appeal for the at-home setting to reduce readmission for neutropenic a1111111111 fever a1111111111 Luis-Gerardo Rodrı́guez-Lobato ID1,2,3*, Alexandra Martı́nez-Roca1, Sandra Castaño- a1111111111 Dı́ez1, Alicia Palomino-Mosquera1, Gonzalo Gutiérrez-Garcı́a1,3, Alexandra Pedraza1, a1111111111 Marı́a Suárez-Lledó1,3, Montserrat Rovira1,3, Carmen Martı́nez1,3, Carlos Fernández de a1111111111 Larrea2,3, Marı́a-Teresa Cibeira2,3, Laura Rosiñol1,2,3, Ester Lozano2,3, Pedro Marı́n4, Joan Cid ID3,4, Miquel Lozano3,4, Ana Belén Moreno-Castaño5,6, Marta Palomo3,5,6,7, Maribel Dı́az-Ricart3,5,6, Cristina Gallego1, Adelina Hernando1, Susana Segura1, Enric Carreras6,7, Álvaro Urbano-Ispizua1,3, Joan Bladé2,3, Francesc Fernández-Avilés1,3 OPEN ACCESS 1 Department of Hematology, Home Care and Bone Marrow Transplantation Unit, Hospital Clı́nic of Barcelona, Barcelona, Spain, 2 Department of Hematology, Amyloidosis and Multiple Myeloma Unit, Hospital Citation: Rodrı́guez-Lobato L-G, Martı́nez-Roca A, Clı́nic of Barcelona, Barcelona, Spain, 3 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Castaño-Dı́ez S, Palomino-Mosquera A, Gutiérrez- Barcelona, Spain, 4 Department of Hemotherapy and Hemostasis, Apheresis and Cellular Therapy Unit, Garcı́a G, Pedraza A, et al. (2020) The avoidance of Hospital Clı́nic of Barcelona, Barcelona, Spain, 5 Department of Hematopathology, Laboratory of Hemostasis G-CSF and the addition of prophylactic and Eritropathology, Biomedical Diagnosis Center (CDB), Hospital Clı́nic of Barcelona, Barcelona, Spain, corticosteroids after autologous stem cell 6 Barcelona Endothelium Team (BET), Josep Carreras Leukemia Research Institute, Barcelona, Spain, transplantation for multiple myeloma patients 7 Josep Carreras Leukemia Research Institute, Hospital Clı́nic/University of Barcelona Campus, Barcelona, Spain appeal for the at-home setting to reduce readmission for neutropenic fever. PLoS ONE * lgrodriguez@clinic.cat 15(11): e0241778. https://doi.org/10.1371/journal. pone.0241778 Editor: Senthilnathan Palaniyandi, University of Kentucky, UNITED STATES Abstract Received: July 28, 2020 Background Accepted: October 20, 2020 Autologous stem cell transplantation (ASCT) remains the standard of care for young multi- Published: November 4, 2020 ple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever Copyright: © 2020 Rodrı́guez-Lobato et al. This is an open access article distributed under the terms (NF) and hospital readmissions continue to pose as the most important limitations in the out- of the Creative Commons Attribution License, patient setting. It is possible that the febrile episodes may have a non-infectious etiology, which permits unrestricted use, distribution, and and engraftment syndrome could play a more significant role. The aim of this study was to reproduction in any medium, provided the original author and source are credited. analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Methods Funding: The author(s) received no specific Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were funding for this work. managed at-home beginning +1 day after ASCT. Three groups were established: Group A Competing interests: The authors have declared (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; that no competing interests exist. group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 1 / 16 PLOS ONE At-home ASCT in myeloma patients Results The incidence of NF among the groups was reduced (64%, 44%, and 24%; P<0.001), with a non-significant decrease in hospital readmissions as well (12%, 6%, and 2%; P = 0.07). The most important variables identified for NF were: HCT-CI >2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P<0.001); and for hospital readmission: age �60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05). Conclusions G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospec- tive randomized clinical trial. Introduction The multiple myeloma (MM) treatment landscape has evolved dramatically over the last few years with the emergence of a next-generation proteasome inhibitor (carfilzomib), an immu- nomodulatory drug (pomalidomide) and monoclonal antibodies (daratumumab and elotuzu- mab) [1]. However, most guidelines continue to support high-dose therapy followed by autologous stem cell transplantation (ASCT) as the standard of care for newly diagnosed patients without severe comorbidities [2–5]. This treatment is considered a safe procedure with an extremely low transplant-related mortality (TRM) (<3%), due to improvements that include the use of peripheral blood-derived hematopoietic stem cell products and post-trans- plantation administration of granulocyte colony-stimulating factor (G-CSF) [6,7]. In recent years though, due to extensive waiting lists and an ever-growing concern about the proper use of health care resources, many groups have implemented outpatient ASCT pro- grams. Such an approach has resulted in considerably acceptable outcomes in terms of hematopoietic recovery, toxicity and TRM; as well as improvements in cost and resource use, risk of infections, length of hospital admission and quality of life [8–12]. Nevertheless, neutro- penic fever (NF) continues to pose as the most important limitation in the outpatient setting with an estimated incidence of 80–100%, which in most cases acts as a main driver for hospital readmissions [8,13–15]. In light of such an observation, the use of antibiotic prophylaxis dur- ing chemotherapy-induced neutropenia is recommended [16,17]. Since 2002, our group has enhanced infectious prophylaxis in the outpatient setting by adding ceftriaxone to levofloxa- cin, reducing the incidence of NF to 76% with a bacteremia rate of 26% and 8% in hospital readmissions [8]. It is possible that the high incidence of NF in spite of antibiotic prophylaxis could be a consequence of non-infectious causes [18]. Recently, the usefulness of G-CSF has been questioned; indeed, some transplant groups have stopped using it, observing no changes in relevant transplant outcomes and avoiding potential adverse effects including fatigue, bone pain, fever, engraftment syndrome (ES), and capillary leak syndrome [19,20]. In January 2011, our group too decided to follow suit and stop the routine use of G-CSF. Engraftment syndrome is a syndromic entity occurring in the peri-engraftment period within the context of ASCT. It is characterized by non-infectious fever, skin rash, and diarrhea, resulting in less frequent hepatic dysfunction, transient encephalopathy, and capillary leak syn- drome [21–23]. While symptoms are usually mild and transient, some patients may, however, develop complications, delay hospital discharge, require intensive care treatment or experience death [24]. The exact pathogenesis is not well understood; it is probable that the syndrome PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 2 / 16 PLOS ONE At-home ASCT in myeloma patients may arise in response to a release of pro-inflammatory cytokines (IL-2, TNF-α, IFN-γ, IL-8 and IL-6), associated with endothelial damage (high levels of vWF, sVCAM-1, sICAM-1, sTNFRI and low levels of ADAMTS-13 activity) and high levels of C-reactive protein [23–29]. The estimated incidence of ES ranged between 5% and 72% [30,31] depending on the diagnos- tic criteria implemented [21,22]. The onset of ES has been associated with ASCT for solid tumors (breast cancer), autoimmune diseases (multiple sclerosis) and monoclonal gammopa- thies (MM, AL amyloidosis and POEMS syndrome) that included the use of post-ASCT G-CSF, a high infused CD34+ cell dose, earlier and more rapid granulocyte recovery and the introduction of bortezomib and immunomodulatory drugs as induction therapy in MM [18,23–26,32–34]. The most important aspect in managing ES is early recognition, ruling out alternative causes, and the use of corticosteroids (methylprednisolone 1 to 1.5 mg/Kg/day for two or three days) following a quick tapering regimen [26]. Due to the dramatic response to corticosteroids, some authors have encouraged the pre-emptive or prophylactic use of such drugs [21,31,35]. In observance of such aspect, our ASCT team established primary corticoste- roid prophylaxis after ASCT in January 2014. The aim of this study was to analyze the outcomes of different prophylactic policies to reduce NF, ES and hospital readmissions in our at-home ASCT program for patients with MM in order to increase the safety of those treatments by which these patients undergo. First: the standard G-CSF administration after ASCT; second: the withdrawal of G-CSF after ASCT; and third: the addition of primary prophylaxis for ES with corticosteroids after ASCT. Materials and methods Patients The clinical records of 853 consecutive ASCT for hematological malignancies at Hospital Clı́nic of Barcelona between January 2002 and August 2018 were reviewed. Patients who received ASCT in the in-patient setting were excluded (n = 539). Two hundred and three patients were excluded for being non-MM patients. The final study population was comprised of 111 MM patients (S1 Fig). Some of the patients were included in a previous publication (18); however, the series has increased and only outpatients have been included in the analysis. The study was approved by the Ethics Committee of the Hospital Clı́nic of Barcelona, and was in accordance with the Declaration of Helsinki. The eligibility criteria for at-home transplanta- tion included ECOG�2; travel time from home to the hospital <60 minutes; permanent care- giver availability. All patients signed an informed consent form. At-home ASCT program Our at-home ASCT program is based on the early-discharge outpatient model and has been published elsewhere [8,36]. Data on prior induction treatment and peripheral stem cell mobili- zation regimen was collected. All patients received conditioning regimen with intravenous melphalan 200 mg/m2; they were discharged from hospital the day after stem cell infusion. Hematology nurses visited patients once a day and performed laboratory tests three times a week. Prevention of chemotherapy-induced nausea and vomiting, and prophylaxis for oral mucositis (OM) followed standard international supportive care protocols. Proton pump inhibitors or H2 antagonists were used in all patients. Red blood cell and platelet transfusion were administered when hemoglobin concentration was <8 g/dL and platelet count was �10 x 109/L, respectively. All patients received antimicrobial prophylaxis with fluoroquinolone, flu- conazole, acyclovir (if herpes serology was positive), aerosolized pentamidine and enhanced antimicrobial prophylaxis with ceftriaxone [8] (1 g/day) from day +1 until the appearance of fever or neutrophil engraftment. At the onset of the first episode of NF, clinical evaluation, PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 3 / 16 PLOS ONE At-home ASCT in myeloma patients collection of blood and urine cultures and X-ray/CT scan were performed, along with empirical antimicrobial therapy with meropenem (1 g IV t.i.d.). Treatment with teicoplanin was added in cases when WHO grade � 2 mucositis and signs of central venous access (CVA) infection existed. Empirical antimicrobial therapy was maintained until patients were afebrile for at least three days with no signs of infection and an absolute neutrophil count (ANC) of �1x109/L. When ES was suspected, methylprednisolone 1 mg/Kg/12h was administered for 3 days and then tapered over 7–8 days. Indications for hospital readmission were WHO grade 4 mucositis, uncontrolled vomiting or diarrhea, hemodynamic instability, respiratory distress, and willing- ness of caregiver or patient. At-home program discharge criteria consisted of an ANC of �1x109/L and afebrile status without antibiotic administration for a minimum of 48 hours. Prophylactic strategies to reduce neutropenic fever Patients were divided into three groups in the outpatient setting during three different time periods established in our transplant unit per the NF. Group A (January 2002 to December 2010) included all patients who received standard G-CSF (filgrastim) 5 μg/Kg/day beginning on post-transplant day +7 until ANC reached 1x109/L for three consecutive days; group B (January 2011 to December 2013) included patients who did not receive G-CSF post-trans- plant; and group C (January 2014 to August 2018) included patients who avoided G-CSF post- transplant, but did undergo primary prophylaxis with corticosteroids for ES with oral predni- sone 0.5 mg/Kg/day from day+7 until their ANC reached 0.5x109/L for three consecutive days. Definitions Neutrophil and platelet engraftment were defined as the first of three consecutive days, in which an ANC >0.5x109/L and platelet count >20x109/L without platelet transfusion were achieved, respectively. NF was defined as a newly observed temperature �38˚C with an ANC of <0.5x109/L and bacteremia as isolation of bacteria from a blood culture with fever or symp- toms and/or signs of infection. ES was defined using Maiolino clinical criteria [21]. Non-infec- tious fever was defined as a new fever without clinical or microbiological documentation or response to antimicrobials. Skin rash was defined as macular-papular exanthema mimicking acute graft versus host disease involving >25% of body surface area. Pulmonary infiltrates were considered secondary to ES in the absence of clinical and laboratory evidence of infec- tion, cardiac failure, or pulmonary embolism. Diarrhea was defined as �2 episodes of liquid stool per day without microbiologically documented infection. Weight gain was defined >2.5% increase from baseline body weight. Hepatic and renal dysfunction was defined by either an elevation in serum bilirubin �2mg/dL or an increase in serum AST or ALT of �2 times the upper limit of normal (ULN) and serum creatinine of �2 times the ULN. Transient encephalopathy was defined as confusion not secondary to any other etiology. Statistical analysis Descriptive statistical analysis was performed. Median and range were used for continuous variables; meanwhile, frequency and percentage were used for categorical variables. Patient variables and outcomes were compared using Fisher’s exact test or χ2 test for categorical vari- ables, as well as t-test or Wilcoxon rank-sum test for continuous variables. Univariate and mul- tivariate binary logistic regression models were used to identify factors associated with NF, ES, and hospital readmission. Logistic regression analysis was performed by a backward stepwise method. The cumulative incidence of NF, ES, and hospital readmission were calculated with Gray’s test, as well as the Fine and Gray proportional hazard model for the analysis of the sub- distribution of competitive risks [37,38]. The probability of progression-free survival (PFS) PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 4 / 16 PLOS ONE At-home ASCT in myeloma patients and overall survival (OS) was calculated with the Kaplan-Meier estimator; survival curves were compared with the log-rank test. The starting point for time-to-event analysis was the date of ASCT [39]. All p values were two-sided with statistical significance evaluated at the 0.05 alpha level. All analyses were performed using R.3.6.1 (R Foundation for Statistical Computing, Vienna, Austria, http://www.R-project.org). Results Patient characteristics Patient demographics and clinical characteristics are summarized in Table 1. The median age was 56 years (range: 25–70) and 70 patients (63%) were males. As expected, the most frequent isotypes of heavy and light chain produced were IgG (49%) and Kappa (62%), respectively. Most patients had an International Staging System (ISS) of I (63%). Bortezomib-based schemes were received as an induction regimen in 84% of patients and 26% received �2 treat- ment lines before ASCT. The underlying disease was in complete response in 36% of the patients; meanwhile, 64% were in very good partial response or worse. Twenty-four patients (22%) had a hematopoietic cell transplantation-comorbidity index (HCT-CI) score of >2. The Table 1. Main patient characteristics. Characteristics Total group (n = 111) Group A (n = 33) Group B (n = 32) Group C (n = 46) P A vs. B B vs. C A vs. C Age (range) 56 (25–70) 51 (25–67) 57 (40–69) 58 (39–70) 0.03 0.71 0.06 Gender, male (%) 70 (63) 20 (61) 18 (56) 32 (69.6) 0.72 0.23 0.41 Immunological subtype 0.89 0.36 0.85 IgG (%) 54 (49) 17 (52) 18 (56) 19 (41.3) IgA (%) 29 (26) 8 (24) 9 (28) 12 (26.1) Bence Jones (%) 25 (23) 7 (21) 5 (16) 13 (28.4) Light chain isotype, Kappa (%) 69 (62) 19 (58) 17 (53) 33 (71.7) 0.71 0.14 0.23 ISS 0.55 0.04 0.003 I (%) 70 (63) 27 (82) 23 (72) 20 (43.5) II (%) 28 (25) 4 (12) 7 (22) 17 (37.09) III (%) 13 (12) 2 (6) 2 (6) 9 (19.5) Number of pre-ASCT lines � 2 (%) 29 (26) 8 (24) 8 (25) 13 (28.3) 1.00 0.8 0.8 Pre-transplant therapy 0.002 0.16 <0.001 Chemotherapy (%) 18 (16) 14 (42) 3 (9) 1 (2.2) Bortezomib-based schemes (%) 93 (84) 19 (58) 29 (91) 45 (97.8) Response before ASCT 0.23 0.53 0.64 CR (%) 40 (36) 15 (46) 8 (25) 17 (37.0) VGPR/PR (%) 65 (59) 16 (49) 22 (69) 27 (58.7) MR/progression (%) 6 (5) 2 (5) 2 (6) 2 (4.3) Mobilization 0.20 0.10 0.08 G-CSF (%) 92 (83) 31 (94) 26 (82) 35 (76) G-CSF + cyclophosphamide (%) 5 (5) 2 (6) 3 (9) 0 (0) Plerixafor (%) 14 (12) 0 (0) 3 (9) HCT-CI >2 (%) 24 (22) 4 (12) 8 (25) 12 (26.1) 0.18 0.91 0.13 CD34+ x106/Kg (range) 3.3 (1.7–9.4) 3.2 (1.9–6.4) 3.0 (1.9–9.4) 3.6 (1.7–7.2) 0.57 0.51 0.14 Group A: G-CSF without corticosteroids; Group B: No G-CSF without corticosteroids; Group C: No G-CSF adding corticosteroids. ASCT: autologous stem cell transplantation; CR: complete response; HCT-CI: hematopoietic cell transplantation-comorbidity index; ISS: international staging system; MR: minimal response; PR: partial response; VGPR: very good partial response. https://doi.org/10.1371/journal.pone.0241778.t001 PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 5 / 16 PLOS ONE At-home ASCT in myeloma patients median infused CD34+ cell dose was 3.3 x 106/Kg (range, 1.7–9.4). Thirty-three patients (30%) received G-CSF post-ASCT (group A); 32 patients (29%) did not receive G-CSF post-ASCT (group B), and 46 patients (41%) avoided G-CSF post-ASCT and received primary prophylaxis with corticosteroids (group C). The groups were similar in most basal characteristics. How- ever, we observed more ISS grade III patients in group C in comparison to group A (A: 6% vs. C: 19.5%; P = 0.003) and a greater number of patients in group B and C received bortezomib- based schemes (A: 58%, B: 91% and C: 98%; P<0.001). The median time of prednisone pro- phylaxis in group C was 8 days (range 1–14). While in the subgroup of patients who did not develop and did develop ES, the median time of prednisone prophylaxis were 9 days (range 5–14) and 2 days (range 1–4), respectively. Thirty-nine patients (39%) developed ES; their dis- tributions according to symptoms were: fever (100%), diarrhea (86%), skin rash (28%), and pulmonary infiltrates (7%). The median follow-up of all patients was 39.8 months. Patient outcomes The most important clinical outcomes are summarized in Table 2. There was a significant dif- ference in duration of severe neutropenia between patients that received G-CSF and those who did not, with a median of 8, 11, and 10 days in group A, B and C, respectively (A vs. B; P = 0.005 and A vs. C; P = 0.04). The 10-day cumulative incidence of neutrophil engraftment was 88% (95% confidence interval (CI), 70–95%) in group A, 47% (95%CI, 26–62%) in group B, and 59% (95%CI, 42–71%) in group C (P = 0.005) (Fig 1). There were no differences among groups in either platelet engraftment or their requirement for platelet transfusions. Neutropenic fever There was a significant reduction in NF incidence between group A and group C (64% vs. 24%; P<0.001), with a relative risk reduction of 0.38 (95%CI, 0.21–0.67; P<0.001) and a num- ber needed to treat of 2.52 (95%CI, 1.7–5.1). Onset and duration of NF were similar among groups. In the multivariate binary logistic regression analysis for NF, HCT-CI >2 was a risk factor (odds ratio (OR) 6.1; P = 0.002), while the avoidance of G-CSF and the addition of corti- costeroids (group C) were protective (OR 0.1; P<0.001) (Table 3). The 10-day cumulative inci- dence of NF were 61% in group A, 41% in group B, and 24% in group C (P = 0.001) (Fig 2A). In the competing risk regression model for NF, the avoidance of G-CSF and the addition of corticosteroids retained their independent protective factor (hazard ratio (HR) 0.53; P<0.001) and HCT-CI >2 as risk factor (HR 2.24; P<0.01). Regarding bacteremia, there were no differ- ences in the number of positive blood cultures in all three groups (A: 2 isolations; B: 2 isola- tions; C: 1 isolation), and all were positive for coagulase-negative Staphylococcus. During follow-up, there was a case of Clostridioides difficile-associated diarrhea in each two groups (A and C), which responded to oral vancomycin treatment. Regarding the ES, its incidence decreased with the non-administration of G-CSF and the addition of prophylactic corticosteroids (group A: 58% vs, group C: 22%; P = 0.001). The 10-day cumulative incidence of ES was 52% in group A, 38% in group B, and 17% in group C (P = 0.002) (Fig 2B). In the multivariate analysis, the most important variables related to the development of ES were female gender (OR 2.3; P = 0.05), HCT-CI >2 (OR 4.0; P = 0.01), and group C (OR 0.2; P = 0.02) (Table 3). The use of corticosteroids in group C did not increase the incidence of viral and fungal infections. Antibiotic use Patients who received G-CSF (Group A) and did not develop NF received fewer days of pro- phylactic antibiotic compared with Group B and C (A: 8 days; B: 11 days; C: 10 days; A vs. B or PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 6 / 16 PLOS ONE At-home ASCT in myeloma patients Table 2. Clinical outcomes. Characteristics Group A (n = 33) Group B (n = 32) Group C (n = 46) P A vs. B B vs. C A vs. C Engraftment First day of neutropenia � 0.5x109/L (range) 4 (0–5) 4 (1–5) 4 (3–6) 0.31 0.07 0.009 9 Duration of neutropenia � 0.5x10 /L (range) 8 (5–22) 11 (6–18) 10 (7–21) 0.005 0.24 0.04 Duration of thrombocytopenia � 20,000x109/L (range) 12 (0–37) 12 (9–17) 11 (0–34) 0.37 0.58 0.27 Fever Neutropenic fever (�38˚C) (%) 21 (64) 14 (44) 11 (24) 0.11 0.07 0.0004 First day with fever (range) 7.5 (4–12) 8 (3–11) 8 (5–9) 0.47 0.34 0.75 Duration of fever (range) 2 (1–5) 1 (1–5) 3 (1–5) 0.09 0.05 0.56 Positive blood cultures (%) 2/21 (10) 2/14 (14) 1/11 (2) 1.00 1.00 1.00 Engraftment syndrome 19 (58) 14 (44) 10 (22) 0.27 0.04 0.001 Fever (%) 19 (100) 14 (100) 10 (100) Rash (%) 5 (26) 4 (29) 3 (30) Diarrhea (%) 15 (79) 12 (86) 10 (100) Pulmonary infiltrates (%) 3 (16) 0 (0) 0 (0) Antibiotic use Days with antibiotic prophylaxis, median (range) 8 (5–11) 11 (6–16) 10 (7–21) <0.001 0.44 <0.001 Without further presence of fever 4 (0–9) 4 (0–8) 4 (0–6) 0.18 0.23 0.79 Further presence of fever 0.3 0.2 0.09 <0.001 <0.001 <0.001 Days with antibiotic treatment 0.09 0.08 0.02 0.56 <0.001 <0.001 Meropenem daily dose/outpatient-days� 0.04 0 0.004 <0.001 0.27 <0.001 Teicoplanin daily dose/outpatient-days� Amikacin daily dose/outpatient-days� Toxicity Mucositis � 2 (%) 2 (6) 0 (0) 2 (4) 0.49 0.51 1.00 Cutaneous � 2 (%) 0 (0) 0 (0) 0 (0) 1.00 1.00 1.00 Diarrhea � 2 (%) 1 (3) 0 (0) 9 (20) 1.00 1.00 0.08 Nausea and vomiting � 2 (%) 0 (0) 0 (0) 1 (2) 1.00 1.00 1.00 Hospital readmission Readmissions (%) Duration of readmission 4 (12) 2 (6) 1 (2) 0.35 0.66 0.07 (range) 8 (4–13) 2.5 (2–39) 12 0.06 - - Group A: G-CSF without corticosteroids; Group B: No G-CSF without corticosteroids; Group C: No G-CSF adding corticosteroids. � Total sum of antibiotic days in the sample/total sum of days of sample follow-up. https://doi.org/10.1371/journal.pone.0241778.t002 C; P<0.001) related to the duration of neutropenia. Respecting antibiotic treatment in patients who presented NF, Groups A and B received more days of antibiotic compared with group C (expressed in daily dose/outpatient-days) (meropenem: 0.3 vs. 0.2 vs. 0.09; P<0.001; teicopla- nin: 0.09 vs. 0.08 vs. 0.02; P<0.001; amikacin: 0.04 vs. 0 vs. 0.004; P<0.001; Table 2). Toxicity and hospital readmission The non-administration of G-CSF with the addition of prophylactic corticosteroids did not modify the incidence and grade of mucositis, or other subtypes of toxicities including cutane- ous, diarrhea, nausea, and vomiting (Table 2). Hospital readmission was necessary for four patients (12%) within group A, two patients (6%) within group B, and one patient (2%) within group C (A vs. C; P = 0.07). The causes of readmissions were ES (n = 3) and respiratory PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 7 / 16 PLOS ONE At-home ASCT in myeloma patients Fig 1. Cumulative incidence of neutrophil engraftment comparing group A (G-CSF without corticosteroid), group B (avoiding G-CSF and corticosteroid), group C (avoiding G-CSF and adding corticosteroid) during the first 30 days after autologous stem cell transplantation. https://doi.org/10.1371/journal.pone.0241778.g001 syncytial virus (RSV) pneumonia (n = 1) in group A; ES (n = 1) and RSV pneumonia in group B; and human metapneumovirus infection (n = 1) in group C. In the multivariate analysis for hospital readmission, age � 60 years was a risk factor (OR 14.6; P = 0.04); meanwhile, the avoidance of G-CSF with the administration of corticosteroid retained an independent protec- tive factor (OR 0.07; P = 0.05) (Table 3). Regarding adverse events related to prednisone pro- phylaxis in group C, no cases of suppression of the hypothalamic-pituitary-adrenal axis were found, nor was it observed toxicity �2 at the metabolic and cardiovascular levels. In the one- year follow-up, we did not observe an increase in the incidence of viral and fungal infections in those patients who received prophylactic prednisone. PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 8 / 16 PLOS ONE At-home ASCT in myeloma patients Table 3. Multivariate regression model for neutropenic fever, engraftment syndrome, and hospital readmission. Characteristic OR 95% CI P Neutropenic fever Gender, female 1.8 0.7–4.6 0.2 HCT-CI > 2 6.1 1.9–19.4 0.002 Novel drugs� 0.7 0.2–2.6 0.6 No G-CSF with corticosteroid 0.1 0.02–0.4 0.0007 Engraftment syndrome Gender, female 2.3 0.9–5.6 0.07 HCT-CI > 2 4.0 1.4–11.4 0.01 Novel drugs� 0.4 0.1–1.3 0.1 No G-CSF with corticosteroid 0.2 0.1–0.8 0.02 Hospital readmission Age � 60 years 14.6 1.1–19.9 0.04 No G-CSF with corticosteroid 0.07 0.01–0.99 0.05 � Proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide and lenalidomide). https://doi.org/10.1371/journal.pone.0241778.t003 Transplant outcomes The one-year TRM in the whole series was 0.9% with no statistically significant differences among groups. The only death recorded occurred in group B on day +35 due to RSV pneumo- nia. There were no differences in PFS or OS between patients with and without NF, ES, and the avoidance of G-CSF with the addition of corticosteroids. However, there was a substantial and expected improvement in group C PFS probably due to the use of novel drugs in the induction regimen (Fig 3A–3D). Discussion This study shows that patients with MM who received high-dose chemotherapy with melpha- lan and peripheral ASCT in the outpatient setting observe an increase in safely managing and Fig 2. A. Cumulative incidence of neutropenic fever comparing group A (G-CSF without corticosteroid), group B (avoiding G-CSF and corticosteroid), group C (avoiding G-CSF and adding corticosteroid) during the first 30 days after autologous stem cell transplantation. B. Cumulative incidence of engraftment syndrome comparing group A (G-CSF without corticosteroid), group B (avoiding G-CSF and corticosteroid), group C (avoiding G-CSF and adding corticosteroid) during the first 30 days after autologous stem cell transplantation. C. Cumulative incidence of hospital readmission comparing group A (G-CSF without corticosteroid), group B (avoiding G-CSF and corticosteroid), group C (avoiding G-CSF and adding corticosteroid) during the first 30 days after autologous stem cell transplantation. https://doi.org/10.1371/journal.pone.0241778.g002 PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 9 / 16 PLOS ONE At-home ASCT in myeloma patients Fig 3. A. Progression-free survival comparing group A, group B, and group C; B. Progression-free survival in all patients with and without engraftment syndrome; C. Overall survival comparing group A, group B, and group C; D. Overall survival in all patients with and without engraftment syndrome. https://doi.org/10.1371/journal.pone.0241778.g003 reducing the incidence of NF. Such changes to support that conclusion include enhanced anti- biotic prophylaxis with levofloxacin plus ceftriaxone; avoidance of G-CSF; and the addition of primary prophylaxis with corticosteroids after transplantation. The withdrawal of G-CSF and the use of corticosteroids did not increase the rate of infections nor did they modify transplant outcomes. PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 10 / 16 PLOS ONE At-home ASCT in myeloma patients NF remains one of the most important concerns associated with ASCT in the outpatient setting. Despite the use of peripheral blood-derive hematopoietic stem cells and enhanced infectious prophylaxis, the incidence of NF and hospital readmissions in patients with MM remains high (30–80% and 8–33%, respectively) [11,14,15,40,41]. Our group has incorporated the combination of levofloxacin plus ceftriaxone into the prophylactic antibiotic armamentar- ium, reducing the incidence of NF and hospital readmission to 76% and 8%, respectively [8]. Trying to bolster at-home strategies to reduce these complications and assuming that febrile episodes may have a non-infectious etiology, we decided to withdraw the use of G-CSF and add corticosteroids after ASCT. Studies published 25 years ago that validate the use of G-CSF cannot be taken into account to support its use today; the value of growth factors must be reevaluated with current supportive care [19]. In this study, the duration of severe neutropenia was longer in those groups who did not receive G-CSF post-ASCT, with a difference of two days. However, avoiding G-CSF did not modify the platelet engraftment, transfusion support, number of infections, or chemotherapy-related toxicity, which is consistent with other publi- cations where the use of G-CSF is rationalized [18–20]. The introduction of the two preventive measures (group C) led to a 90% decrease in odds for NF onset, entailing that 2.5 patients would need to avoid G-CSF and receive corticosteroids in order to reduce one episode of NF and make it a useful strategy in the outpatient setting. Risk factors associated with NF are diverse; nonetheless, in many series there is a strong correlation with older age, advanced stage disease, infusion of <5x106 CD34+/Kg, CVA infections, and OM [42]. In this regard, the mul- tivariate analysis revealed an HCT-CI >2 as risk factor, hinting that patients with greater num- ber and severity of comorbidities are at greater risk of developing fever. The incidence of ES in the group A of patients was 58% while in group C, it was 22%. Our new policy of G-CSF avoidance post-transplant and the use of primary prophylaxis with corti- costeroids have remarkably reduced ES incidence. These results are consistent with those pub- lished by Mossad et al., in which ES was reduced from 57% to 6% [31]. Although the physiopathology of ES is not fully understood, it is possible that some pro-inflammatory risk factors for developing ES, such as older age, HCT-CI >2 and pre-ASCT treatment �2 lines could be associated with the development of this complication [18]. In contrast to other stud- ies, we did not observe any association among the amount of infused CD34+ cell dose, mobili- zation regimen, and use of novel anti-MM drugs in the development of ES. The avoidance of G-CSF and the administration of corticosteroids did not boost the inci- dence of viral and fungal infections; it is likely due to the small variation in the number of days of severe neutropenia among groups and due to short use of corticosteroids. Regarding bacte- rial infections, the most frequently isolated bacteria was coagulase-negative Staphylococcus in all three groups, with these results being similar to those of other publications [12,43]. Regard- ing Clostridioides difficile-associated diarrhea, we observed two cases, which agree with the 0 and 13% incidence rates published by other groups [8,12,14,15,43]. In terms of toxicity, the non-administration of G-CSF and the addition of corticosteroid did not modify the incidence and grade of OM, ratifying the importance of better oral health care and cryotherapy [44]. The observed hospital readmission rate was quite low in all groups. We were only able to observe a trend to reduce it in group C. It is difficult to carry out ade- quate comparisons with other published series, since the incidence of hospital readmission is very variable (8–87%), dependent on the model of outpatient transplant program, ECOG, comorbidities, subtype of hematological disease and proficiency of the at-home unit, among other elements [8,10–12,15]. This study has some limitations as a retrospective, non-randomized, single-center-based study. The study spans a long period and we could not assess the continuous improvement in supportive care and enhanced proficiency of physicians and nurses who care for these patients. PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 11 / 16 PLOS ONE At-home ASCT in myeloma patients However, patients in group C were older, with worse ISS, and had the same infused CD34+ cell dose compared with group A. Notwithstanding, we observed a decrease in the incidence rate of NF and in hospital readmission, with no noted increase in adverse effects. We could not per- form economic analysis; however, currently the median cost per day in our at-home ASCT program is €117, while the median hospital cost per day is €862, which represents important savings resulted mainly from lower hospitalization charges. Another benefit of our at-home transplant program is the ability to decrease the number of ward patients receiving an ASCT, and thus implement complex procedures, including haploidentical hematopoietic cell trans- plants and chimeric antigen receptor T-cells without increasing the number of hospital beds [45]. Finally, the outpatient setting could become a potential approach to maintaining hemato- poietic transplants during the COVID-19 pandemic. In conclusion, this study suggests that for patients with multiple myeloma in at-home ASCT, the avoidance of G-CSF and the addition of primary prophylaxis with corticosteroids after ASCT minimize the incidence rates of NF and ES. This preventive policy might not com- promise transplant outcomes or increase the infection rate, and could provide clinicians with greater safety in the outpatient management of these patients. This approach should be explored in a prospective randomized multicenter study to confirm the results. Major con- founding factors not accounted for in this small study may have led to the results. Supporting information S1 Fig. Flowchart of patient inclusion. (PDF) S1 Database. (PDF) Author Contributions Conceptualization: Luis-Gerardo Rodrı́guez-Lobato, Gonzalo Gutiérrez-Garcı́a, Francesc Fernández-Avilés. Data curation: Luis-Gerardo Rodrı́guez-Lobato, Sandra Castaño-Dı́ez, Alicia Palomino-Mos- quera, Alexandra Pedraza. Formal analysis: Luis-Gerardo Rodrı́guez-Lobato, Alexandra Martı́nez-Roca, Sandra Cas- taño-Dı́ez, Alicia Palomino-Mosquera, Alexandra Pedraza, Ester Lozano, Ana Belén Moreno-Castaño. Investigation: Luis-Gerardo Rodrı́guez-Lobato, Alexandra Martı́nez-Roca, Gonzalo Gutiér- rez-Garcı́a, Marı́a Suárez-Lledó, Carmen Martı́nez, Ester Lozano, Ana Belén Moreno-Cas- taño, Marta Palomo, Maribel Dı́az-Ricart, Cristina Gallego, Adelina Hernando, Susana Segura, Francesc Fernández-Avilés. Methodology: Luis-Gerardo Rodrı́guez-Lobato, Alexandra Martı́nez-Roca, Gonzalo Gutiér- rez-Garcı́a, Montserrat Rovira, Carmen Martı́nez, Ana Belén Moreno-Castaño, Marta Palomo, Maribel Dı́az-Ricart, Enric Carreras, Francesc Fernández-Avilés. Project administration: Gonzalo Gutiérrez-Garcı́a, Marı́a Suárez-Lledó, Montserrat Rovira, Carlos Fernández de Larrea, Cristina Gallego, Adelina Hernando, Susana Segura, Álvaro Urbano-Ispizua, Francesc Fernández-Avilés. Resources: Pedro Marı́n, Joan Cid, Miquel Lozano, Joan Bladé, Francesc Fernández-Avilés. PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 12 / 16 PLOS ONE At-home ASCT in myeloma patients Supervision: Alexandra Martı́nez-Roca, Gonzalo Gutiérrez-Garcı́a, Marı́a Suárez-Lledó, Montserrat Rovira, Carmen Martı́nez, Carlos Fernández de Larrea, Marı́a-Teresa Cibeira, Laura Rosiñol, Pedro Marı́n, Joan Cid, Miquel Lozano, Enric Carreras, Álvaro Urbano-Ispi- zua, Joan Bladé, Francesc Fernández-Avilés. Validation: Alexandra Martı́nez-Roca, Gonzalo Gutiérrez-Garcı́a, Montserrat Rovira, Carlos Fernández de Larrea, Marı́a-Teresa Cibeira, Laura Rosiñol, Pedro Marı́n, Joan Cid, Miquel Lozano, Ana Belén Moreno-Castaño, Álvaro Urbano-Ispizua, Joan Bladé, Francesc Fernán- dez-Avilés. Visualization: Luis-Gerardo Rodrı́guez-Lobato. Writing – original draft: Luis-Gerardo Rodrı́guez-Lobato, Alexandra Martı́nez-Roca. Writing – review & editing: Gonzalo Gutiérrez-Garcı́a, Alexandra Pedraza, Marı́a Suárez- Lledó, Montserrat Rovira, Carmen Martı́nez, Carlos Fernández de Larrea, Marı́a-Teresa Cibeira, Laura Rosiñol, Ester Lozano, Pedro Marı́n, Joan Cid, Miquel Lozano, Ana Belén Moreno-Castaño, Marta Palomo, Maribel Dı́az-Ricart, Cristina Gallego, Adelina Her- nando, Susana Segura, Enric Carreras, Álvaro Urbano-Ispizua, Joan Bladé, Francesc Fer- nández-Avilés. References 1. Cavo M, Terpos E, Bargay J, Einsele H, Cavet J, Greil R, et al. The multiple myeloma treatment land- scape: international guideline recommendations and clinical practice in Europe. Expert Rev Hematol. 2018; 11(3):219–37. https://doi.org/10.1080/17474086.2018.1437345 PMID: 29415570 2. Ludwig H, Miguel JS, Dimopoulos MA, Palumbo A, Garcia Sanz R, Powles R, et al. International Mye- loma Working Group recommendations for global myeloma care. Leukemia. 2014 May; 28(5):981–92. https://doi.org/10.1038/leu.2013.293 PMID: 24177258 3. Moreau P, San Miguel J, Sonneveld P, Mateos MV, Zamagni E, Avet-Loiseau H, et al. Multiple mye- loma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol. 2017 Jul 1; 28(suppl_4):iv52–61. 4. Sureda A, Bader P, Cesaro S, Dreger P, Duarte RF, Dufour C, et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015. Bone Marrow Transplant. 2015 Aug; 50(8):1037–56. https://doi.org/10.1038/bmt.2015.6 PMID: 25798672 5. Majhail NS, Farnia SH, Carpenter PA, Champlin RE, Crawford S, Marks DI, et al. Indications for Autolo- gous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2015 Nov; 21(11):1863–9. 6. McCarthy PL, Hahn T, Hassebroek A, Bredeson C, Gajewski J, Hale G, et al. Trends in use of and sur- vival after autologous hematopoietic cell transplantation in North America, 1995–2005: significant improvement in survival for lymphoma and myeloma during a period of increasing recipient age. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2013 Jul; 19(7):1116–23. https://doi.org/ 10.1016/j.bbmt.2013.04.027 PMID: 23660172 7. Faussner F, Dempke WCM. Multiple myeloma: myeloablative therapy with autologous stem cell support versus chemotherapy: a meta-analysis. Anticancer Res. 2012 May; 32(5):2103–9. PMID: 22593496 8. Fernández-Avilés F, Carreras E, Urbano-Ispizua A, Rovira M, Martı́nez C, Gaya A, et al. Case-control comparison of at-home to total hospital care for autologous stem-cell transplantation for hematologic malignancies. J Clin Oncol Off J Am Soc Clin Oncol. 2006 Oct 20; 24(30):4855–61. https://doi.org/10. 1200/JCO.2006.06.4238 PMID: 17001069 9. Martino M, Lemoli RM, Girmenia C, Castagna L, Bruno B, Cavallo F, et al. Italian consensus conference for the outpatient autologous stem cell transplantation management in multiple myeloma. Bone Marrow Transplant. 2016 Aug; 51(8):1032–40. https://doi.org/10.1038/bmt.2016.79 PMID: 27042841 10. Faucher C, Le Corroller Soriano AG, Esterni B, Vey N, Stoppa AM, Chabannon C, et al. Randomized study of early hospital discharge following autologous blood SCT: medical outcomes and hospital costs. Bone Marrow Transplant. 2012 Apr; 47(4):549–55. https://doi.org/10.1038/bmt.2011.126 PMID: 21725375 PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 13 / 16 PLOS ONE At-home ASCT in myeloma patients 11. Holbro A, Ahmad I, Cohen S, Roy J, Lachance S, Chagnon M, et al. Safety and cost-effectiveness of outpatient autologous stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2013 Apr; 19(4):547–51. https://doi.org/10.1016/j. bbmt.2012.12.006 PMID: 23253556 12. Graff TM, Singavi AK, Schmidt W, Eastwood D, Drobyski WR, Horowitz M, et al. Safety of outpatient autologous hematopoietic cell transplantation for multiple myeloma and lymphoma. Bone Marrow Transplant. 2015 Jul; 50(7):947–53. https://doi.org/10.1038/bmt.2015.46 PMID: 25867651 13. Piñana JL, Montesinos P, Martino R, Vazquez L, Rovira M, López J, et al. Incidence, risk factors, and outcome of bacteremia following autologous hematopoietic stem cell transplantation in 720 adult patients. Ann Hematol. 2014 Feb; 93(2):299–307. https://doi.org/10.1007/s00277-013-1872-4 PMID: 23995612 14. Satlin MJ, Vardhana S, Soave R, Shore TB, Mark TM, Jacobs SE, et al. Impact of Prophylactic Levo- floxacin on Rates of Bloodstream Infection and Fever in Neutropenic Patients with Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2015 Oct; 21(10):1808–14. 15. Lisenko K, Sauer S, Bruckner T, Egerer G, Goldschmidt H, Hillengass J, et al. High-dose chemotherapy and autologous stem cell transplantation of patients with multiple myeloma in an outpatient setting. BMC Cancer. 2017 22; 17(1):151. https://doi.org/10.1186/s12885-017-3137-4 PMID: 28228122 16. Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infec- tious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2009 Oct; 15(10):1143–238. 17. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious dis- eases society of america. Clin Infect Dis Off Publ Infect Dis Soc Am. 2011 Feb 15; 52(4):e56–93. 18. Gutiérrez-Garcı́a G, Rovira M, Magnano L, Rosiñol L, Bataller A, Suárez-Lledó M, et al. Innovative strat- egies minimize engraftment syndrome in multiple myeloma patients with novel induction therapy follow- ing autologous hematopoietic stem cell transplantation. Bone Marrow Transplant. 2018; 53(12):1541– 7. https://doi.org/10.1038/s41409-018-0189-2 PMID: 29706650 19. Gertz MA, Gastineau DA, Lacy MQ, Dispenzieri A, Hayman SR, Kumar SK, et al. SCT without growth factor in multiple myeloma: engraftment kinetics, bacteremia and hospitalization. Bone Marrow Trans- plant. 2011 Jul; 46(7):956–61. https://doi.org/10.1038/bmt.2010.233 PMID: 20972466 20. Cox JE, Campos S, Wu J, May R, Liu H, Ramos CA, et al. Efficacy of deferred dosing of granulocyte col- ony-stimulating factor in autologous hematopoietic transplantation for multiple myeloma. Bone Marrow Transplant. 2014 Feb; 49(2):219–22. https://doi.org/10.1038/bmt.2013.149 PMID: 24096822 21. Maiolino A, Biasoli I, Lima J, Portugal AC, Pulcheri W, Nucci M. Engraftment syndrome following autolo- gous hematopoietic stem cell transplantation: definition of diagnostic criteria. Bone Marrow Transplant. 2003 Mar; 31(5):393–7. https://doi.org/10.1038/sj.bmt.1703855 PMID: 12634731 22. Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001 May; 27(9):893–8. https://doi.org/10.1038/sj.bmt.1703015 PMID: 11436099 23. Carreras E, Fernández-Avilés F, Silva L, Guerrero M, Fernández de Larrea C, Martı́nez C, et al. Engraftment syndrome after auto-SCT: analysis of diagnostic criteria and risk factors in a large series from a single center. Bone Marrow Transplant. 2010 Sep; 45(9):1417–22. https://doi.org/10.1038/bmt. 2009.363 PMID: 20062097 24. Spitzer TR. Engraftment syndrome: double-edged sword of hematopoietic cell transplants. Bone Mar- row Transplant. 2015 Apr; 50(4):469–75. https://doi.org/10.1038/bmt.2014.296 PMID: 25581406 25. Dispenzieri A, Lacy MQ, Hayman SR, Kumar SK, Buadi F, Dingli D, et al. Peripheral blood stem cell transplant for POEMS syndrome is associated with high rates of engraftment syndrome. Eur J Haema- tol. 2008 May; 80(5):397–406. https://doi.org/10.1111/j.1600-0609.2008.01037.x PMID: 18221391 26. Cornell RF, Hari P, Drobyski WR. Engraftment Syndrome after Autologous Stem Cell Transplantation: An Update Unifying the Definition and Management Approach. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2015 Dec; 21(12):2061–8. https://doi.org/10.1016/j.bbmt.2015.08.030 PMID: 26327628 27. Carreras E, Diaz-Ricart M. The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant. 2011 Dec; 46(12):1495–502. https://doi.org/10.1038/bmt.2011.65 PMID: 21460864 28. Palomo M, Diaz-Ricart M, Carbo C, Rovira M, Fernandez-Aviles F, Escolar G, et al. The release of solu- ble factors contributing to endothelial activation and damage after hematopoietic stem cell transplanta- tion is not limited to the allogeneic setting and involves several pathogenic mechanisms. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2009 May; 15(5):537–46. PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 14 / 16 PLOS ONE At-home ASCT in myeloma patients 29. Palomo M, Diaz-Ricart M, Carbo C, Rovira M, Fernandez-Aviles F, Martine C, et al. Endothelial dys- function after hematopoietic stem cell transplantation: role of the conditioning regimen and the type of transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2010 Jul; 16 (7):985–93. https://doi.org/10.1016/j.bbmt.2010.02.008 PMID: 20167280 30. Gale RP, Lazarus HM. Engraftment syndrome, the Emperor’s new clothes and the artist formerly known as Prince. Bone Marrow Transplant. 2015 Apr; 50(4):483–4. https://doi.org/10.1038/bmt.2014. 317 PMID: 25642762 31. Mossad S, Kalaycio M, Sobecks R, Pohlman B, Andresen S, Avery R, et al. Steroids prevent engraft- ment syndrome after autologous hematopoietic stem cell transplantation without increasing the risk of infection. Bone Marrow Transplant. 2005 Feb; 35(4):375–81. https://doi.org/10.1038/sj.bmt.1704769 PMID: 15640827 32. Cornell RF, Hari P, Zhang M-J, Zhong X, Thompson J, Fenske TS, et al. Divergent effects of novel immunomodulatory agents and cyclophosphamide on the risk of engraftment syndrome after autolo- gous peripheral blood stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2013 Sep; 19(9):1368–73. https://doi.org/10.1016/j.bbmt.2013.06. 017 PMID: 23806770 33. Martı́nez-Cibrian N, Magnano L, Gutiérrez-Garcı́a G, Andrade X, Correa JG, Suárez-Lledó M, et al. At- home autologous stem cell transplantation in multiple myeloma with and without G-CSF administration: a comparative study. Bone Marrow Transplant. 2016 Apr; 51(4):593–5. https://doi.org/10.1038/bmt. 2015.287 PMID: 26595072 34. Gutiérrez-Garcı́a G, Cibeira MT, Rovira M, Fernández de Larrea C, Tovar N, Rodrı́guez-Lobato LG, et al. Improving security of autologous hematopoietic stem cell transplant in patients with light-chain amyloidosis. Bone Marrow Transplant. 2019 Aug; 54(8):1295–303. https://doi.org/10.1038/s41409- 019-0447-y PMID: 30664727 35. Openshaw H, Nash RA, McSweeney PA. High-dose immunosuppression and hematopoietic stem cell transplantation in autoimmune disease: clinical review. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2002; 8(5):233–48. https://doi.org/10.1053/bbmt.2002.v8.pm12064360 PMID: 12064360 36. Rodrı́guez-Lobato LG, Martı́nez-Roca A, Moreno DF, Gutiérrez-Garcı́a G, Suárez-Lledó M, Rovira M, et al. Impact of intensifying primary antibiotic prophylaxis in at-home autologous stem cell transplanta- tion program for lymphoma patients. Leuk Lymphoma. 2020 Jul; 61(7):1565–74. https://doi.org/10. 1080/10428194.2020.1742901 PMID: 32208787 37. Scrucca L, Santucci A, Aversa F. Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplant. 2007 Aug; 40(4):381–7. https://doi.org/10.1038/sj.bmt.1705727 PMID: 17563735 38. Scrucca L, Santucci A, Aversa F. Regression modeling of competing risk using R: an in depth guide for clinicians. Bone Marrow Transplant. 2010 Sep; 45(9):1388–95. https://doi.org/10.1038/bmt.2009.359 PMID: 20062101 39. Delgado J, Pereira A, Villamor N, López-Guillermo A, Rozman C. Survival analysis in hematologic malignancies: recommendations for clinicians. Haematologica. 2014 Sep; 99(9):1410–20. https://doi. org/10.3324/haematol.2013.100784 PMID: 25176982 40. Paul TM, Liu SV, Chong EA, Luger SM, Porter DL, Schuster SJ, et al. Outpatient Autologous Stem Cell Transplantation for Patients With Myeloma. Clin Lymphoma Myeloma Leuk. 2015 Sep; 15(9):536–40. https://doi.org/10.1016/j.clml.2015.05.006 PMID: 26141214 41. Martino M, Russo L, Martinello T, Gallo GA, Fedele R, Moscato T, et al. A home-care, early discharge model after autografting in multiple myeloma: results of a three-arm prospective, non-randomized study. Leuk Lymphoma. 2015 Mar; 56(3):801–4. https://doi.org/10.3109/10428194.2014.931952 PMID: 24913501 42. Eleutherakis-Papaiakovou E, Kostis E, Migkou M, Christoulas D, Terpos E, Gavriatopoulou M, et al. Prophylactic antibiotics for the prevention of neutropenic fever in patients undergoing autologous stem- cell transplantation: results of a single institution, randomized phase 2 trial. Am J Hematol. 2010 Nov; 85(11):863–7. https://doi.org/10.1002/ajh.21855 PMID: 20882526 43. Solano C, Gutierrez A, Martinez F, Gimeno C, Gómez C, Muñoz I, et al. Prophylaxis of early bacterial infections after autologous peripheral blood stem cell transplantation (PBSCT): a matched-pair study comparing oral fluoroquinolones and intravenous piperacillin-tazobactam. Bone Marrow Transplant. 2005 Jul; 36(1):59–65. https://doi.org/10.1038/sj.bmt.1705005 PMID: 15908979 44. Marchesi F, Tendas A, Giannarelli D, Viggiani C, Gumenyuk S, Renzi D, et al. Cryotherapy reduces oral mucositis and febrile episodes in myeloma patients treated with high-dose melphalan and autologous stem cell transplant: a prospective, randomized study. Bone Marrow Transplant. 2017; 52(1):154–6. https://doi.org/10.1038/bmt.2016.207 PMID: 27526285 PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 15 / 16 PLOS ONE At-home ASCT in myeloma patients 45. Gutiérrez-Garcı́a G, Rovira M, Arab N, Gallego C, Sánchez J, Ángeles Álvarez M, et al. A reproducible and safe at-home allogeneic haematopoietic cell transplant program: first experience in Central and Southern Europe. Bone Marrow Transplant. 2020 May; 55(5):965–73. https://doi.org/10.1038/s41409- 019-0768-x PMID: 31932656 PLOS ONE | https://doi.org/10.1371/journal.pone.0241778 November 4, 2020 16 / 16