This study demonstrates that patients with MM who received high-dose chemotherapy with melphalan and peripheral ASCT in the outpatient setting observe an increase in safely managing and reducing the incidence of NF. Such changes to support that conclusion include enhanced antibiotic 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.
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 armamentarium, 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 publications 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 multivariate analysis revealed an HCT-CI >2 as risk factor, hinting that patients with greater number 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 corticosteroids have remarkably reduced ES incidence. These results are consistent with those published 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 studies, we did not observe any association among the amount of infused CD34+ cell dose, mobilization 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 incidence 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 bacterial 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). Regarding 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 adequate 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. 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 perform 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 transplants 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 hematopoietic 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 strategy does not compromise transplant outcomes or increase the infection rate. Notably, this preventive policy could provide clinicians with greater safety in the outpatient management of these patients.