Prof. Sizhou Feng: Clinical application of antifungal drugs in the era of targeted therapy 2021 China Oncology Congress

Foreword With the vigorous development of targeted therapy for hematological malignancies in recent years, compared with traditional drugs, many targeted drugs can significantly improve the survival rate and remission rate of patients, and have excellent tolerance
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Most targeted drugs are metabolized by the liver, and most antifungal drugs are also metabolized by the liver, so they have moderate to severe interactions
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Therefore, in the context of the booming development of targeted therapy, how to prevent and treat invasive fungal disease (IFD) is crucial
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At the 2021 China Oncology Conference (CCO) held online from April 14 to 17, 2022, Professor Feng Sizhou from the Hospital of Hematology, Chinese Academy of Medical Sciences gave the title of "Clinical Application of Antifungal Drugs in the Era of Targeted Therapy".
Three parts are introduced
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Development of targeted drugs in various fields of hematological malignancies With the development of targeted drugs for hematological malignancies, targeted drugs with different mechanisms have emerged, such as immune checkpoint inhibitors in the field of lymphoma, CAR-T cell therapy, etc.
; acute Apoptosis pathway targeting drugs and mutation-specific targeting drugs in the field of myeloid leukemia/myelodysplastic syndrome (AML/MDS)
.

Specifically as shown in Figure 1
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Most of the above types of targeted drugs are metabolized by the liver, such as tyrosine kinase inhibitor (TKI) imatinib, nilotinib, dasatinib, and Bruton's tyrosine kinase (BTK) The inhibitor ibrutinib is metabolized by the liver cytochrome P450 (CYP450) family, and this metabolic pathway often affects the metabolism of antifungal drugs, thereby affecting the effect of fungal drugs
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In addition, a study published in Clinical MicroBiology and Infection showed that the reason why targeted drugs increase the risk of infection is that the target of drug action is usually an important element in physiological processes, and immune or inflammatory response pathways will block and regulate the resulting immune Impaired function
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Figure 1.
Different types of targeted drugs lead to infection events.
CD20 monoclonal antibody can clear B lymphocytes and reduce serum immunoglobulin levels, thereby directly or indirectly reducing the number of T cells, resulting in an increase in the incidence of infection
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Regarding CAR-T cell therapy, Professor Feng Sizhou said that CAR-T cell therapy has improved the remission rate and survival rate of patients with hematological tumors, but lymphocyte depletion chemotherapy before CAR-T cell infusion can cause cytopenia, and CAR-T cell therapy T cell therapy also depletes normal CD19+ B cells, resulting in hypogammaglobulinemia; and patients with more prior antitumor therapy, higher CAR-T cell infusions, and more severe cytokine release syndrome (CRS), The risk of infection is higher, so it needs to be taken seriously
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In addition, Professor Feng Sizhou said that when using the BTK inhibitor ibrutinib in patients with lymphatic system malignancies, attention should be paid to the occurrence of IFD, especially the possibility of invasive aspergillosis (IA)
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In addition, other targeted drugs, such as the histone deacetylation inhibitor Chidamide, the phosphatidylinositol-3 kinase inhibitor Copanlisib, and the proteasome inhibitor bortezomib, can also increase the risk of viral and fungal infections in patients
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Finally, Professor Feng Sizhou summarized the proportion of pathogenic bacteria in IFD of various hematological malignancies.
It can be seen that including AML, ALL, CLL, HL, NHL, etc.
, most of the IFDs are mainly IA and invasive candidiasis.
Specifically as shown in Figure 2
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Fig.
2 Diagnosis, prevention and treatment of IFD Prof.
Sizhou Feng introduced that the 2019 European Organization for Cancer Treatment Research/Fungal Treatment Research Group (EORTC/MSG) third edition guideline for invasive mycosis has been updated and released.
For the diagnosis of IFD, we must first find the IFD Evidence of infection, including inverse halo sign, wedge-shaped, phasic and lobar consolidation under lung CT; culture and microscopy results of sputum, bronchoalveolar lavage fluid, etc.
; galactomannan antigen (GM), etc.
Serology and cerebrospinal fluid examination
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Among them, culture, microscopy and antigen test are particularly important in the diagnosis of IFD infection
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The 2020 Guidelines for the Diagnosis and Treatment of Invasive Mycosis in Hematological Diseases/Malignancies (Sixth Revised Edition) further proposed a new model for the diagnosis and treatment of IFD, as shown in Figure 3 below
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Figure 3 For the primary prevention of IFD for neutropenia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or after chemotherapy, Professor Feng Sizhou said that we need to first carry out the risk of IFD in patients with agranulocytosis after allo-HSCT or after chemotherapy The high-risk criteria are: neutropenia >14 days; umbilical cord blood, HLA haploidentical after allo-HSCT; GVHD after allo-HSCT; AML, ALL, MDS induction and salvage treatment stage; intermediate-risk criteria For: 7-14 days of neutropenia; HLA homozygous allo-HSCT; AML, ALL, MDS consolidation and intensive treatment stage; low-risk criteria: neutropenia <7 days; autologous hematopoietic stem cell transplantation
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For high-risk patients with IFD, preventive medication is required.
According to the recommendations of the Infectious Diseases Society of America (IDSA), the European Society for Leukemia and Infection (ECIL), and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID), high-risk patients are the first choice for posaconazole tablets or Oral suspension; since the blood concentration of posaconazole > 0.
5mg/L can obviously take effect, during the application of posaconazole oral suspension, attention should be paid to proton pump inhibitors and steroid drugs for posaconazole blood.
effect of drug concentration
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For re-prevention, Prof.
Feng Sizhou said that at this time, drugs that are effective against fungal infections and have a broad antibacterial spectrum should be the first choice.
The dosage is the same as that of primary prevention.
In clinical practice, itraconazole, caspofungin and amphotericin are generally used.
drug
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For the treatment of IFD, the 2020 Guidelines for the Diagnosis and Treatment of Invasive Mycosis of Hematologic Diseases/Malignant Tumors recommend that for patients with high-risk persistent agranulocytosis and fever who are ineffective with broad-spectrum antibiotics for 4-7 days, empiric therapy should be initiated, and drugs including amphotericus should be considered.
Amphotericin B and its liposomes, caspofungin, voriconazole, and micafungin; for diagnosis-driven therapy in low-risk patients with IFD, consider drugs including amphotericin B and its liposomes, caspofungin, voriconazole, Micafungin
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However, for patients with Aspergillus infection with obvious diagnostic evidence, IDSA, ECIL, ESCMID and other organizations recommend voriconazole as class AI
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Professor Feng Sizhou said that although a large number of studies in recent years have shown that voriconazole has achieved good efficacy in patients with Aspergillus infection, voriconazole is metabolized by CYP450.
For patients with ultra-fast metabolism, voriconazole cannot reach effective blood levels.
The use of amphotericin B should be considered
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In addition, many recent studies have proved that the new drug isavuconazole has advantages compared with voriconazole, posaconazole, amphotericin B, etc.
For example, in the SECURE study, the researchers compared the efficacy of isavuconazole and voriconazole, Isavuconazole was found to be non-inferior to voriconazole in efficacy and significantly less toxic than voriconazole
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As mentioned above, many targeted drugs are metabolized by CYP450, and antifungal drugs are also metabolized by CYP450, so can targeted drugs and antifungal drugs be used together? Professor Feng Sizhou explained that most targeted drugs are not recommended to be used in combination with voriconazole and posaconazole.
Even if they are used in combination, the dose should be significantly reduced, and attention should be paid to ECG monitoring; The combination of targeted drugs is summarized in Figure 4
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Figure 4 Summary Professor Feng Sizhou finally concluded that hematological malignancies are in the era of targeted therapy, but the treatment and prevention of fungal infections cannot be relaxed.
We still need to strictly abide by relevant clinical guidelines and stratify patients accordingly.
, and take corresponding preventive measures as soon as possible; for patients with relevant signs of infection, the pathogenic bacteria should be identified as soon as possible, and then symptomatic medication should be given; for patients infected during targeted therapy drugs, antifungal drugs should be reduced.
For treatment, use antifungal drugs to control the infection
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Expert Profile Prof.
Feng Sizhou Doctor of Medicine, Chief Physician, Second-level Professor, Doctoral Supervisor, Peking Union Medical College, 1999.
7-2001.
7 Postdoctoral research at the University of Tokyo, Japan, Deputy Director, Hematopoietic Stem Cell Transplantation Center, Hematology Hospital, Chinese Academy of Medical Sciences, Chinese Pharmacological Society Deputy Director of the Professional Committee of the Chinese Medical Association Hematology Branch of the Chinese Medical Association Deputy Head of the Anti-Infection Group Vice Chairman of the Committee Member of the Standing Committee of the Expert Committee of the Anti-Leukemia Alliance of the Chinese Society of Clinical Oncology Member of the Standing Committee of the Professional Committee of Tianjin Integrative Medicine, Deputy Director of the Professional Committee of Hematology, Tianjin Association of Integrative Medicine, Vice Chairman of the Professional Committee of Critical Care Medicine of the Tianjin Association of Integrative Medicine, Editorial Board Member of the Journal of Clinical Hematology, Editorial Board Member of the Journal of Biomedical Engineering and Clinical, Emergency and Critical Care Medicine The editorial board of the journal, the editorial board of the Lymphoma & Leukemia Journal has published more than 150 core journal papers and SCI papers, and won 5 provincial and ministerial science and technology progress awards.