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 fever

Luis-Gerardo Rodríguez-Lobato, Alexandra Martínez-Roca, Sandra Castaño-Díez, Alicia Palomino-Mosquera, Gonzalo Gutiérrez-García, Alexandra Pedraza, María Suárez-Lledó, Montserrat Rovira, Carmen Martínez, Carlos Fernández de Larrea, María-Teresa Cibeira, Laura Rosiñol, Ester Lozano, Pedro Marín, Joan Cid, Miquel Lozano, Ana Belén Moreno-Castaño, Marta Palomo, Maribel Díaz-Ricart, Cristina Gallego, Adelina Hernando, Susana Segura, Enric Carreras, Álvaro Urbano-Ispizua, Joan Bladé, Francesc Fernández-Avilés, Luis-Gerardo Rodríguez-Lobato, Alexandra Martínez-Roca, Sandra Castaño-Díez, Alicia Palomino-Mosquera, Gonzalo Gutiérrez-García, Alexandra Pedraza, María Suárez-Lledó, Montserrat Rovira, Carmen Martínez, Carlos Fernández de Larrea, María-Teresa Cibeira, Laura Rosiñol, Ester Lozano, Pedro Marín, Joan Cid, Miquel Lozano, Ana Belén Moreno-Castaño, Marta Palomo, Maribel Díaz-Ricart, Cristina Gallego, Adelina Hernando, Susana Segura, Enric Carreras, Álvaro Urbano-Ispizua, Joan Bladé, Francesc Fernández-Avilés

Abstract

Background: Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT.

Methods: Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT.

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 prospective randomized clinical trial.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Cumulative incidence of neutrophil engraftment…
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.
Fig 2
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.
Fig 3
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.

References

    1. Cavo M, Terpos E, Bargay J, Einsele H, Cavet J, Greil R, et al. The multiple myeloma treatment landscape: international guideline recommendations and clinical practice in Europe. Expert Rev Hematol. 2018;11(3):219–37. 10.1080/17474086.2018.1437345
    1. Ludwig H, Miguel JS, Dimopoulos MA, Palumbo A, Garcia Sanz R, Powles R, et al. International Myeloma Working Group recommendations for global myeloma care. Leukemia. 2014. May;28(5):981–92. 10.1038/leu.2013.293
    1. Moreau P, San Miguel J, Sonneveld P, Mateos MV, Zamagni E, Avet-Loiseau H, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol. 2017. July 1;28(suppl_4):iv52–61.
    1. 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. August;50(8):1037–56. 10.1038/bmt.2015.6
    1. Majhail NS, Farnia SH, Carpenter PA, Champlin RE, Crawford S, Marks DI, et al. Indications for Autologous 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. November;21(11):1863–9.
    1. McCarthy PL, Hahn T, Hassebroek A, Bredeson C, Gajewski J, Hale G, et al. Trends in use of and survival 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. July;19(7):1116–23. 10.1016/j.bbmt.2013.04.027
    1. 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.
    1. Fernández-Avilés F, Carreras E, Urbano-Ispizua A, Rovira M, Martínez 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. October 20;24(30):4855–61. 10.1200/JCO.2006.06.4238
    1. 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. August;51(8):1032–40. 10.1038/bmt.2016.79
    1. 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. April;47(4):549–55. 10.1038/bmt.2011.126
    1. 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. April;19(4):547–51. 10.1016/j.bbmt.2012.12.006
    1. 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. July;50(7):947–53. 10.1038/bmt.2015.46
    1. 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. February;93(2):299–307. 10.1007/s00277-013-1872-4
    1. Satlin MJ, Vardhana S, Soave R, Shore TB, Mark TM, Jacobs SE, et al. Impact of Prophylactic Levofloxacin 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. October;21(10):1808–14.
    1. 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 10.1186/s12885-017-3137-4
    1. Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2009. October;15(10):1143–238.
    1. 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 diseases society of america. Clin Infect Dis Off Publ Infect Dis Soc Am. 2011. February 15;52(4):e56–93.
    1. Gutiérrez-García G, Rovira M, Magnano L, Rosiñol L, Bataller A, Suárez-Lledó M, et al. Innovative strategies minimize engraftment syndrome in multiple myeloma patients with novel induction therapy following autologous hematopoietic stem cell transplantation. Bone Marrow Transplant. 2018;53(12):1541–7. 10.1038/s41409-018-0189-2
    1. 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 Transplant. 2011. July;46(7):956–61. 10.1038/bmt.2010.233
    1. Cox JE, Campos S, Wu J, May R, Liu H, Ramos CA, et al. Efficacy of deferred dosing of granulocyte colony-stimulating factor in autologous hematopoietic transplantation for multiple myeloma. Bone Marrow Transplant. 2014. February;49(2):219–22. 10.1038/bmt.2013.149
    1. Maiolino A, Biasoli I, Lima J, Portugal AC, Pulcheri W, Nucci M. Engraftment syndrome following autologous hematopoietic stem cell transplantation: definition of diagnostic criteria. Bone Marrow Transplant. 2003. March;31(5):393–7. 10.1038/sj.bmt.1703855
    1. Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001. May;27(9):893–8. 10.1038/sj.bmt.1703015
    1. Carreras E, Fernández-Avilés F, Silva L, Guerrero M, Fernández de Larrea C, Martínez 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. September;45(9):1417–22. 10.1038/bmt.2009.363
    1. Spitzer TR. Engraftment syndrome: double-edged sword of hematopoietic cell transplants. Bone Marrow Transplant. 2015. April;50(4):469–75. 10.1038/bmt.2014.296
    1. 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 Haematol. 2008. May;80(5):397–406. 10.1111/j.1600-0609.2008.01037.x
    1. 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. December;21(12):2061–8. 10.1016/j.bbmt.2015.08.030
    1. Carreras E, Diaz-Ricart M. The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant. 2011. December;46(12):1495–502. 10.1038/bmt.2011.65
    1. Palomo M, Diaz-Ricart M, Carbo C, Rovira M, Fernandez-Aviles F, Escolar G, et al. The release of soluble factors contributing to endothelial activation and damage after hematopoietic stem cell transplantation 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.
    1. Palomo M, Diaz-Ricart M, Carbo C, Rovira M, Fernandez-Aviles F, Martine C, et al. Endothelial dysfunction 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. July;16(7):985–93. 10.1016/j.bbmt.2010.02.008
    1. Gale RP, Lazarus HM. Engraftment syndrome, the Emperor’s new clothes and the artist formerly known as Prince. Bone Marrow Transplant. 2015. April;50(4):483–4. 10.1038/bmt.2014.317
    1. Mossad S, Kalaycio M, Sobecks R, Pohlman B, Andresen S, Avery R, et al. Steroids prevent engraftment syndrome after autologous hematopoietic stem cell transplantation without increasing the risk of infection. Bone Marrow Transplant. 2005. February;35(4):375–81. 10.1038/sj.bmt.1704769
    1. 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 autologous peripheral blood stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2013. September;19(9):1368–73. 10.1016/j.bbmt.2013.06.017
    1. Martínez-Cibrian N, Magnano L, Gutiérrez-García 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. April;51(4):593–5. 10.1038/bmt.2015.287
    1. Gutiérrez-García G, Cibeira MT, Rovira M, Fernández de Larrea C, Tovar N, Rodríguez-Lobato LG, et al. Improving security of autologous hematopoietic stem cell transplant in patients with light-chain amyloidosis. Bone Marrow Transplant. 2019. August;54(8):1295–303. 10.1038/s41409-019-0447-y
    1. 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. 10.1053/bbmt.2002.v8.pm12064360
    1. Rodríguez-Lobato LG, Martínez-Roca A, Moreno DF, Gutiérrez-García G, Suárez-Lledó M, Rovira M, et al. Impact of intensifying primary antibiotic prophylaxis in at-home autologous stem cell transplantation program for lymphoma patients. Leuk Lymphoma. 2020. July;61(7):1565–74. 10.1080/10428194.2020.1742901
    1. Scrucca L, Santucci A, Aversa F. Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplant. 2007. August;40(4):381–7. 10.1038/sj.bmt.1705727
    1. Scrucca L, Santucci A, Aversa F. Regression modeling of competing risk using R: an in depth guide for clinicians. Bone Marrow Transplant. 2010. September;45(9):1388–95. 10.1038/bmt.2009.359
    1. Delgado J, Pereira A, Villamor N, López-Guillermo A, Rozman C. Survival analysis in hematologic malignancies: recommendations for clinicians. Haematologica. 2014. September;99(9):1410–20. 10.3324/haematol.2013.100784
    1. 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. September;15(9):536–40. 10.1016/j.clml.2015.05.006
    1. 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. March;56(3):801–4. 10.3109/10428194.2014.931952
    1. 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. November;85(11):863–7. 10.1002/ajh.21855
    1. 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. July;36(1):59–65. 10.1038/sj.bmt.1705005
    1. 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. 10.1038/bmt.2016.207
    1. Gutiérrez-García 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. 10.1038/s41409-019-0768-x

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever