Editor's Note
In 2021, under the overall planning of the Guidelines Working Committee of the Chinese Society of Clinical Oncology, due to the guidance of Academician Jin Ming, Academician Martin, Academician Xu Binghe and Professor Shen Zhixiang, written by Professor Qin Shukui and Professor Ma Jun, on the basis of the 2017 "Guidelines for the Standardized Management of Neutropenia Related to Tumor Radiotherapy and Chemotherapy", combined with the national conditions of the mainland and the latest evidence-based medical evidence, the "Guidelines for the Standardized Management of Neutropenia Related to Tumor Radiotherapy and Chemotherapy of the Chinese Society of Clinical Oncology (CSCO)" (2021) was formulated. (Referred to as the CSCO Whitening Guide v2021, the same below), is an important supplement to the CSCO guidance series. "Physician Daily" closely follows the forefront and practices the norms, and specially invites Professor Shen Zhixiang (Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine), Professor Qiu Lugui (Hematology Hospital of Institute of Hematology, Chinese Academy of Medical Sciences), Professor Zhang Qingyuan (Affiliated Cancer Hospital of Harbin Medical University) and Professor Xu Wei (First Affiliated Hospital of Nanjing Medical University) of the guideline expert group to interpret the relevant content of the new version of the guidelines.
Professor Shen Zhixiang: The risk of G-CSF inducing a second tumor is low
Whether hematopoietic growth factors (such as G-CSF) will induce a second tumor is a matter of clinical concern, Professor Shen Zhixiang showed that chemotherapy drugs have caused more reports of second tumors, but there is no clear evidence to support that hematopoietic growth factor can lead to the occurrence of second tumors.
A randomized, prospective follow-up study in 2020 included 192 patients with severe aplastic anemia who received G-CSF treatment ± the standard immunosuppressive regimen, with a median follow-up of 11.7 years, with a total of 9 patients developing MDS or AML, 10 patients developing clonal cytogenetic abnormalities, 7 patients developing solid tumors, and no significant difference in the incidence of secondary tumors and chromosomal abnormalities in patients receiving or not receiving G-CSF. The cumulative incidence of MDS, AML, or isolated cytogenetic abnormalities found in the G-CSF group at 15 years of follow-up was 8.5±3%, compared with 8.2±3% in the non-G-CSF group, and P =0.90. ¹ This study confirmed that G-CSF caused no difference in the risk of a second tumor from the blank group. Conversely, the fear that not using G-CSF for second tumors will lead to extreme neutrophil decline, and the mortality rate will increase in the near future. Professor Shen Zhixiang stressed that clinicians should rationally apply G-CSF under the guidance of the CSCO Whitening Guideline v2021 to reduce the risk of FN and avoid patients dying of severe infections during treatment, and not to worry too much about secondary tumors.
Professor Qiu Lugui: Bendamostine is included in the risk category of FN, and G-CSF prevention improves the final efficacy
Table 1 Risk of FN in common hematologic tumor chemotherapy regimens
With the aging of mainland society, the incidence of lymphoma, especially inert B-cell lymphoma, is gradually increasing, and the bendamustine± rituximab (B±R) regimen is an important targeted drug combination chemotherapy regimen. One study showed that the incidence of FN in patients treated with NHL in B±R regimen was as high as 16.8%²², the NCCN guidelines have listed NHL's B±R regimen as a risk in FN, and the CSCO Whitening Guideline v2021 also includes NHL's bendamustine regimen in the FN risk category (Table 1). At the same time, malignant hemato-lymphatic disease is a clear FN risk factor for CSCO, and patients treated with bendamustine regimen in NHL who meet the "high risk factors for taking a risk chemotherapy regimen in FN and combining an increased risk of FN" require primary prevention of G-CSF.
Targeted drug combination chemotherapy has significantly improved the prognosis of hematological tumors, and more attention needs to be paid to whether the risk of infection is increased when combining multiple drugs. Infections during treatment may lead to delays in treatment, which in turn can affect the patient's efficacy, and regardless of the option chosen, adequate treatment according to the course of treatment can ensure efficacy. Professor Qiu Lugui suggested that patients treated with targeted drugs combined with chemotherapy regimens should be prophylaxis with long-acting G-CSF 24 hours after the application of cytotoxic drugs to reduce the risk of FN or treatment delay, reduce hospital stays, and improve final efficacy. In addition, NHL-related studies have shown that interrupting G-CSF prevention in patients with high risk of FN significantly increases the incidence of FN³, so the CSCO Whitening Guideline v2021 states that high-risk patients need to use G-CSF per cycle to prevent and avoid interruption.
Professor Zhang Qingyuan: During the use of G-CSF, it is found that the white blood cells are extremely elevated and need to be carefully identified
Leukemia-like reactions refer to the > of the white blood cell count 50X10⁹/L, and hematological tumors are particularly necessary to distinguish between the primary disease and the elevated white blood cells caused by G-CSF. When the application of G-CSF in the treatment of tumors occurs rapidly elevated white blood cells, the infection should be ruled out first, and it is easy to have bacterial infection during tumor chemotherapy, and if sepsis occurs, the white blood cell count can reach more than 100×10⁹/L. Secondly, it should be excluded that the patient is in the recovery period of agranulocytosis, and naïve granulocytes can appear in peripheral blood during G-CSF treatment, and occasionally the white blood cell count reaches 50×10⁹/L or more and lasts for 1-3 weeks. Finally, other tests such as flow cytometry and genetics are needed to rule out poor control or recurrence of blood diseases.
Professor Zhang Qingyuan pointed out that the elevated white blood cells found during G-CSF treatment generally do not require special treatment. Leukemia-like reactions are rare adverse reactions of G-CSF added in the CSCO Whitening Guideline v2021, and the peripheral blood leukocytes in patients can reach more than 50×10⁹/L, and the white blood cell count can return to normal after G-CSF is discontinued. The use of G-CSF basically does not directly lead to a white blood cell count exceeding 100x10⁹/L, and the occurrence of difficult to manage hyperleukocyticemia can be considered to avoid leukocyte stasis. Clinically, careful identification and precise treatment are required.
Professor Xu Wei: The incidence of FN in hematological tumors is high, and the management level needs to be further improved
FN is more common in hematologic tumors, with the incidence of FN in patients with hematopoietic malignancies ≥ 1 course of chemotherapy exceeding 80%, and the cumulative incidence of fever when the hypochondria persists for 21 days is as high as 81.9% (Figure 1) ⁴. Infection fever occurs in almost 100% of patients with hematologic tumors with central venous catheterization, gastrointestinal mucositis, exposure to broad-spectrum antimicrobials within 90 days, or a duration of granular defects > 7 days.
Figure 1 Cumulative incidence of neutrophilia with fever in patients with hematological diseases
At present, there are still many deficiencies in the management of blood tumor granule deficiency. Professor Xu Wei proposed that in many cases, doctors do not fully understand the relationship between bone marrow suppression and chemotherapy, and the prediction of bone marrow suppression after chemotherapy is insufficient. There are still ways to reduce the dose of chemotherapy in China to deal with bone marrow suppression after chemotherapy, the reduction of chemotherapy dose caused by the decline in efficacy is not enough attention, it is necessary to recognize that neutrophil deficiency is still the main reason for the reduction of chemotherapy dose or delay in chemotherapy, and G-CSF should be used rationally to ensure the smooth progress of chemotherapy.
The CSCO Whitening Guideline v2021 recommends that hematological tumor granule deficiency fever be managed according to FN risk stratification, but in practice, it may still be affected by external conditions such as drug accessibility, patient economic conditions, and insurance coverage. In the past, the dose and timing of G-CSF use were more arbitrary, and there were cases where different doses were given in response to weight, commercial dosage forms, or elevated white blood cells. It is believed that with the update and implementation of the "CSCO Whitening Guide v2021", the use of G-CSF will be more standardized.
Professor Shen Zhixiang concluded
G-CSF is at low risk of inducing a second tumor, and clinicians should apply G-CSF appropriately under the CSCO Whitening Guideline v2021 to reduce the risk of FN and avoid death from severe infection during treatment. The CSCO Whitening Guidelines v2021 include the NHL's bendamustine regimen in the FN risk category, emphasizing the importance of G-CSF per cycle in high-risk patients to prevent and avoid disruption. Although leukemia-like reactions may occasionally be seen during G-CSF treatment, they need to be carefully distinguished from infection, disease recurrence, etc., and generally do not require special treatment. The update of the CSCO Whitening Guideline v2021 is more detailed and accurate than the old version, and proposes a more in-depth and clinically suitable FN risk stratification and management plan, which effectively promotes the development of FN management in the blood field.
Expert Profiles
Professor Shen Zhixiang
Tenured professor, professor of internal medicine, chief physician and doctoral supervisor of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine
Former Chairman of the National Society of Hematology of the Chinese Medical Association, Fu Is the Editor-in-Chief of the Chinese Journal of Hematology, and the editorial board of the Chinese Medical Journal (English Edition) and other journals
Professor Shen has published more than 100 papers and monographs in domestic and foreign journals, and has edited eight monographs such as "Malignant Blood Disease", "Lymphoma", "Concise Clinical Hematology", "Advances in Hematology Research", and participated in the preparation of more than 10 monographs. He has won the second prize of the National Natural Science Award, the third prize of the Science and Technology Progress Award, the second prize of the Chinese Medical Science and Technology Award, the second prize of the Shanghai Medical Achievement Award, the third prize of the Medical Achievement Award, and the third place in the number of citations of a single international paper in 1999. In 2004, he won the first prize of the Chinese Medical Science and Technology Award, the first prize of the 2004 Shanghai Medical Award, and the second prize of the National Natural Science Award in 2004. First Prize of Shanghai Science and Technology Award in 2006
Professor Shen has long been engaged in clinical medicine and clinical research in the field of internal medicine and hematology, especially in the malignant tumors of the blood system, hemostasis diseases and severe anemia, and has accumulated rich clinical practice experience
Professor Qiu Lugui
Professor/Chief Physician of Chinese Academy of Medical Sciences and Peking Union Medical College, Doctoral Supervisor
Director of the Lymphoma Center of the Hematology Hospital of the Chinese Academy of Medical Sciences,
Director of Tianjin Cord Blood Hematopoietic Stem Cell Bank
Main research directions:
Molecular genetics and pathogenesis of lymphomas and effective treatment strategies
Hematopoietic stem cell transplantation related foundations, stem cell engineering
Main Academic Positions:
Member of the Expert Committee of the International Myeloma Working Group (IMWG).
Member of the International Myeloma Society (IMS) Conference Committee
Chairman of the Hematology and Tumor Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of The Lymphoma Research Alliance of the Chinese Society of Clinical Oncology
Vice Chairman of the Hematology Committee of the Association of Integrative Physicians
Vice Chairman of the Hematology Professional Committee of the China Medical Education Association
Chairman of the Hematology and Tumor Professional Committee of Tianjin Anti-Cancer Association
He is a member of the editorial board/standing editorial board of 6 core journals, including Blood Advances and Chinese Journal of Hematology
He has published more than 450 papers, including more than 120 SCI papers in GOOD, JCI and LEUKEMIA journals
Professor Zhang Qingyuan
Chief physician, second-level professor, doctoral supervisor, provincial famous teacher
Director of Heilongjiang Institute of Cancer Prevention and Control
Vice President of the Affiliated Cancer Hospital of Harbin Medical University
Leader of the National Key Specialty of Oncology
National Millions of Talents Project Inductees
Young and middle-aged experts with outstanding contributions to the state
He is the chairman-elect of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Chemotherapy Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Breast Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
Professor Xu Wei
Deputy Director of the Department of Hematology of the First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People's Hospital), doctoral supervisor
Vice Chairman of the Hematology and Tumor Professional Committee of the Chinese Anti-Cancer Association, leader of the Lymphoma Group
Vice Chairman of the Lymphoma Professional Committee of the Chinese Geriatric Health Care Association
Vice Chairman of the Lymphoma Branch of the Chinese Medical Education Association
Standing Committee Member of CSCO China Anti-Lymphoma Alliance
Member of the Standing Committee of the Hematology Branch of the Chinese Geriatrics Society
Member of the Standing Committee of the Blood Professional Committee of the Chinese Association of Women Physicians
Member of the Standing Committee of the Lymphohematology-Oncology Professional Committee of the Chinese Geriatric Oncology Society
Member of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association
Member of the Experimental Hematology Committee of the Chinese Society of Pathophysiology
Member and Secretary of the Integrative Hematology Professional Committee of the Integrative Medical Physician Branch of the Chinese Medical Doctor Association
Vice Chairman of the Hematology Society of Jiangsu Medical Association
Vice President of Hematology Physician Branch of Jiangsu Medical Doctor Association
Chairman of the Lymphoma Professional Committee of Jiangsu Research Hospital Association
Chairman of Jiangsu Anti-Lymphoma Alliance
Vice Chairman of the Blood and Tumor Professional Committee of Jiangsu Anti-Cancer Association
Member of the Standing Committee of the Lymphoma Professional Committee of Jiangsu Anti-Cancer Association
Vice Chairman of Nanjing Hematology Society
He is a member of the editorial boards of Chinese Journal of Hematology, Chinese Journal of Experimental Hematology, International Journal of Blood Transfusion and Hematology, Leukemia/Lymphoma, and BLOOD Chinese Edition
References: (Swipe to view)
1. Yan Z H, Xu T, Zheng X Y, et al. Multicenter and prospective epidemiological study of neutrophil deficiency with fever in Patients with Hematological Diseases in China. Chinese Journal of Hematology,2016,37(3): 177-182.
2. Li Y, Family L, Yang SJ, et al Neutropenia Associated With Select Myelosuppressive Chemotherapy Regimens in a Large Community-Based Oncology Practice. J Natl Compr Canc Netw. 2017 Sep;15(9):1122-1130.
3. Weycker D, Li X, Barron R, et al. Risk of chemotherapy-induced febrile neutropenia with early discontinuation of pegfilgrastim prophylaxis in US clinical practice. Support Care Cancer. 2016 Jun;24(6):2481-90.
4.Tichelli A, de Latour RP, Passweg J, et al. Long-term outcome of a randomized controlled study in patients with newly diagnosed severe aplastic anemia treated with antithymocyte globulin and cyclosporine, with or without granulocyte colony-stimulating factor: a Severe Aplastic Anemia Working Party Trial from the European Group of Blood and Marrow Transplantation. Haematologica. 2020;105(5):1223-1231.