Should G-CSF be used to boost the immune system in patients with cancer and sepsis?
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Yes.
In certain settings.
Whether a patient has cancer or not, we are trained to reach into our toolbox for whatever therapies we may have to try to alleviate a patient’s situation. In that regard, it is easy to think of granulocyte colony-stimulating factor as one such tool that can be used for a patient with a severe infection.
There are longstanding associations between the depth of cytopenias and the risk for infection complications. I am a leukemia physician and many of my patients are at risk for febrile neutropenia. There are ongoing debates as to how to limit the risk for an initial infection or, once a patient is ill, how to minimize the clinical sequelae of infection or sepsis. In general, a blanket application for any therapy is uncommon — especially with sepsis, which can have wide variation in presentation and reversibility and can differ in severity from patient to patient.
At certain times it is important to administer G-CSF either as a preventive measure or for patients with cancer as an addition to their cancer therapy. For instance, a fair amount of data on patients with acute lymphoblastic leukemia aged 60 years and older suggest use of G-CSF to hasten count recovery during induction therapy can improve outcomes. We routinely consider using G-CSF in patients with ALL who are hospitalized with infection and sepsis. For patients who have myeloid neoplasms, cytopenias and sepsis, it is more difficult to know whether or not to use G-CSF. We often encounter a situation like this, where patients have leukemia and develop a dangerous infection. My general opinion is that G-CSF probably does not change whatever is in the bone marrow. If the bone marrow is healthy, G-CSF may help to recover hematopoiesis and improve neutrophil counts slightly faster and, in doing so, may resolve any ongoing infection. If there is underlying leukemia, the patient may not experience meaningful recovery.
G-CSF does not work instantly, but it can decrease the duration of neutropenia when used prophylactically and may be useful in the setting of certain severe infections. Like everything in medicine, however, its use and impact likely varies depending on the situation.
Andrew M. Brunner, MD, is assistant professor of medicine at Harvard Medical School. He can be reached at abrunner@partners.org.
No.
Sepsis, which induces a state of immunosuppression, remains a common, costly and frequently deadly condition — especially among patients with cancer. Sepsis is an extreme body response to infection, and clinicians usually employ intensive supportive care, including broad-spectrum antimicrobial agents, corticosteroids, vasopressors, tocilizumab [Actemra, Genentech], granulocyte transfusions (occasionally) and even intubation or dialysis. Sometimes immunostimulatory therapies such as recombinant G-CSF (filgrastim) or recombinant granulocyte-macrophage colony stimulating factor (GM-CSF; sargramostim) are given. These agents stimulate the bone marrow to produce and release granulocytes into the bloodstream and enhance the survival, proliferation, differentiation and function of precursor and mature neutrophils. G-CSF accounts for more than 95% of the use of molecularly cloned myeloid hematopoietic growth factors.
In a meta-analysis including 2,380 non-neutropenic patients with sepsis from 12 randomized clinical trials, Bo and colleagues found no evidence supporting routine use of G-CSF or GM-CSF in patients with sepsis. G-CSF can worsen patient outcomes from excessive neutrophil activation. Moreover, Takatsuka and colleagues reported five patients who developed acute respiratory distress syndrome (ARDS) when G-CSF was concomitantly given with chemotherapy or a hematopoietic stem cell transplant, suggesting this agent can worsen lung function by causing neutrophil infiltration. Finally, Orfali and colleagues observed a twofold increase in nonrelapse mortality and a 10% absolute decrement in survival among patients with AML and myelodysplastic syndrome who received allogeneic mobilized blood transplants performed with G-CSF administered early after transplant along with thymoglobulin.
On the other hand, GM-CSF, specifically sargramostim (yeast-derived rhuGM-CSF), has many pleiotropic and immunomodulatory properties. In a randomized, controlled trial in patients with severe sepsis or septic shock with sepsis-associated immune suppression, sargramostim increased monocyte HLA-DR levels, a marker of monocyte immune competence, thereby prolonging survival in patients with low HLA-DR monocyte expression. Further, sargramostim therapy has shown efficacy in multiple organ dysfunction syndrome, trauma and ARDS and increases monocyte killing of Staphylococcus aureus and Candida albicans in vitro in patients with solid cancers receiving chemotherapy. Additionally, sargramostim as an aerosol given via inhalation has efficacy in the treatment of COVID-19 by supporting alveolar macrophage function.
Thus, I argue to avoid using G-CSF in sepsis in patients with cancer. GM-CSF therapy should be pursued in randomized trials in patients with immunoparalyzed (low HLA-DR) mononuclear phagocytes, and sargramostim (GM-CSF) possibly should be considered to boost the immune system.
- References:
- Bo L, et al. Crit Care. 2011;doi:10.1186/cc10031.
- Damiani G, et al. Clin Immunol. 2020;doi:10.1016/j.clim.2019.108292.
- Efrimescu CI, et al. Curr Oncol Rep. 2021;doi:10.1007/s11912-021-01103-0.
- Lagu T, et al. Crit Care Med. 2012;doi:10.1097/CCM.0b013e318232db65.
- Lazarus HM, et al. Front Immunol. 2021;doi:10.3389/fimmu.2021.706186.
- Lazarus HM and Gale RP. Acta Haematol. 2021;doi:10.1159/000510352.
- Meisel C, et al. Am J Respir Crit Care Med. 2009;doi:10.1164/rccm.200903-0363OC.
- Monneret G, et al. Mol Med. 2008;doi:10.2119/2007-00102.
- Orfali N, et al. Transplant Cell Ther. 2021;doi:10.1016/j.jtct.2021.08.031.
- Takatsuka H, et al. Chest. 2002;doi:10.1378/chest.121.5.1716.
- Williams MD, et al. Crit Care. 2004;doi:10.1186/cc2893.
Hillard M. Lazarus, MD, FACP, is a professor of medicine at Case Western Reserve University. He can be reached at hillard.lazarus@case.edu.
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