➔ Viral infections: ◆ Cytomegalovirus (CMV). Allogeneic stem cell transplantation (allo-HCT). ● No recommendation can be given regarding which viral load cut-off should be used to switch to preemptive therapy (PET). ● Letermovir (LMV) is recommended as the strategy of choice for preventing CMV for CMV primary prophylaxis for CMV seropositive adult allo-HCT recipients. ● There is no controlled data to support primary LMV prophylaxis in patients with CMV-negative status. Regardless of the donor serostatus and it is not recommended. ● Sequential monitoring of Interferon (IFN)-γ-producing CMV-specific T-cells may provide potentially useful information for managing CMV infection after allo-HCT, which may be used to personalize PET. ● Extended prophylaxis should be considered in patients at high risk for CMV disease and can continue for at least 200 days after transplantation. ● For some individuals, prophylaxis for longer than 200 days after transplantation can be considered if, in the treating physician’s judgment, the benefit is stronger than the risk. ● So called LMV blips (single test low level DNA positivity in plasma or whole blood samples occurring especially early during LMV prophylaxis) are common, and it is not recommended to interrupt LMV prophylaxis unless there are repeated positive samples showing increased viral load. ● After discontinuation of prophylaxis, “secondary” prophylaxis with LMV can be considered in the following situations: ○ After successful treatment (negative quantitative nucleic acid testing [qNAT]) of a CMV reactivation in patients perceived to be at increased risk for CMV disease. ○ In patients who, for some reason, have not received primary prophylaxis and who have reactivated CMV that has been successfully treated. ● LMV is not indicated for the treatment of CMV reactivations or disease due to the high risk for resistance development and possible underdosing since a treatment dose has not been determined. ● Either intravenous (IV) ganciclovir or foscarnet can be used for first line preemptive therapy. Valganciclovir can be used instead of IV ganciclovir or foscarnet (except in patients with severe gastrointestinal graft-versus-host disease [GVHD]). ● Maribavir can be considered in patients with neutropenia or renal function impairment not appropriate for therapy with valganciclovir or foscarnet. ● The choice of drug depends on time after transplant, risk of toxicity, and previous antiviral drug exposure but is not influenced by whether a patient has received LMV prophylaxis. ● Genotyping should be performed in any case of non-response to allow adjustment of further therapy. ● Repeated genotyping is recommended if the viral load does not improve within two weeks of appropriate therapy. ● Genotyping results should be combined with clinical interpretation to guide clinical decisions. ● Maribavir is not indicated for CMV disease involving the central nervous system (CNS) and the eyes. ● Foscarnet is an alternative therapy for refractory/resistant (R/R) CMV infections, in particular in the CNS and eyes, but is associated with significant toxicity. ● Cidofovir is an option for the treatment of CMV retinitis. ● CMV-specific T-cells are an option for treating R/R CMV infection/disease, if available. ● Combination therapy for R/R CMV infections could be considered. The combination of maribavir and val(ganciclovir) should not be used.
◆ CMV. Chimeric antigen receptor (CAR) T-cell therapies. ● CMV monitoring is only required in patients being CMV-seropositive before CAR T-cell therapy. ● In CMV-seropositive patients, a viral load determination should be performed before the start of lymphodepletion. If the tests show evidence of CMV replication, close monitoring is recommended. ● Risk factors for CMV reactivation after CAR T-cell therapy are cytokine release syndrome (CRS) grade 3-4, receiving corticosteroids >3 days, persistent lymphocytopenia < 200/µl, or receiving ≥2 immunosuppressants. Such patients should be regarded as high-risk patients for CMV reactivation. ● Active monitoring for CMV-DNA testing should be considered between 2 and 6 weeks after cell infusion in high-risk CAR T-cell recipients. ● Preemptive antiviral treatment could be considered in case of “high level”/rapidly increasing level of CMV-DNA-emia. ● It is currently unclear whether CAR T-cells directed against different antigens have the same risk for CMV reactivation, so the same strategy should be employed. ● LMV prophylaxis is not recommended.
◆ CMV. T-cell-engaging antibodies. ● Currently, there is a lack of good data allowing risk assessment regarding CMV reactivation and CMV disease in this patient population. The recommendations should, therefore, be seen as provisional. ● CMV testing is only required in patients being CMV-seropositive before treatment with bispecific antibodies. ● In CMV-seropositive patients, a viral load determination could be performed before therapy with bispecific antibodies. ● If the tests show evidence of CMV replication, close monitoring is recommended. ● Risk factors for CMV reactivation after T-cell engaging therapy are CRS grade ≥ 2, corticosteroids >3 days, or combination therapy with Anti-CD38 antibodies, immunomodulators (IMiDs), and proteasome inhibitors. Such patients should be regarded as high-risk patients for CMV reactivation. ● Testing for CMV-DNA-emia could be considered in febrile patients who have received bispecific antibodies for > 4 weeks. ● Antiviral treatment could be considered in cases of symptoms and a “high level”/rapidly increasing level of CMV-DNA-emia.
➔ Antifungal prophylaxis.
◆ Recommendations in allo-HCT recipients: pre-engraftment ● No significant changes, only: 1. The introduction of isavuconazole (can be used as second-line mould active prophylaxis, in case of intolerance to posaconazole/voriconazole, or QTc prolongation). Based on observational studies. 2. Haplo-HCT with cyclophosphamide post-transplant should be considered “low risk.” “High risk” includes active leukemia, cord blood transplantation, and unrelated donors. ● Emphasis on monitoring azole levels (posaconazole, itraconazole, voriconazole).
◆ Recommendations in allo-HCT recipients: post-engraftment ● The same change is the introduction of isavuconazole.
◆ CAR T-cell. Panel proposes to endorse these recommendations
● Mold-active prophylaxis in: ○ Pre-infusion neutropenia, invasive mold infection within 6 months, recent allo-HCT, acute leukemia. ○ Post-infusion grade ≥3 CRS/immune effector cell–associated neurotoxicity syndrome, OR ≥7 days of corticosteroids (≥0.1mg/kg dexamethasone or equivalent), OR ≥3 weeks of neutropenia, OR other immunosuppressive agent. ● Yeast-active prophylaxis and consider pre-emptive monitoring for molds (pre-emptive therapy consists of diagnostics such as fungal biomarkers and surveillance radiographic imaging). ➔ Neutropenic patient with severe sepsis.
◆ Revision of recommendations for empirical antibiotic therapy: Escalation approach. ● Uncomplicated presentation ● No known colonization with resistant bacteria ● No previous infection with resistant bacteria ● In centers where infections due to resistant pathogens are rarely seen at the onset of febrile neutropenia ● Options for initial antibiotic therapy: ○ Anti-pseudomonal cephalosporin (cefepime, ceftazidime; avoid if extended-spectrum beta-lactamases are prevalent). ○ Piperacillin-tazobactam ○ Other possible options include cefoperazone-sulbactam or piperacillin plus gentamicin.
◆ Revision of recommendations for empirical antibiotic therapy: De-escalation approach. ● Sepsis/septic shock ● Known colonization with resistant bacteria ● Previous infection with resistant bacteria ● In centers where resistant pathogens are regularly seen at the onset of febrile neutropenia. ● Options for initial antibiotic therapy: ○ Carbapenem monotherapy. ○ Combination of anti-pseudomonal beta-lactam + aminoglycoside (e.g., sepsis/septic shock, pneumonia, local epidemiology, previous use of carbapenems within 30 days). ○ Beta-lactam targeting the suspected colonizing pathogen based on susceptibility testing. Situations for which novel anti-Gram-negative beta-lactams are indicated as the empirical regimen: a. KPC-producers: ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, cefiderocol. b. OXA-48-producers: ceftazidime-avibactam, cefiderocol. c. MBL-producers: ceftazidime-avibactam plus aztreonam, cefiderocol. d. Difficult-to-treat Pseudomonas aeruginosa: high dose ceftolozane-tazobactam, ceftazidime-avibactam, imipenem/cilastatin/relebactam, cefiderocol. - Screening for resistant bacteria should be performed in high-risk setting. - Coverage against invasive streptococcal infections should be considered if antibiotics with limited activity against Gram-positive organisms are used (e.g., ceftazidime with or without avibactam or cefiderocol).
◆ Addition of anti-Gram-positive agents. ● Hemodynamic instability, or other evidence of sepsis, septic shock or pneumonia in patients (especially in those with known methicillin-resistant Staphylococcus aureus [MRSA] colonization). ● Colonization with MRSA. ● Suspicion of severe/serious catheter-related infection (e.g., chills or rigors with infusion through catheter and cellulitis around the catheter exit site). ● Skin or soft-tissue infection at any site.
◆ Recommended strategies for de-escalation approach: Patient stable at presentation and stable at 72-96 h, fever of unknown origin (FUO). ○ Stop any aminoglycoside, or anti-Gram positive agent if given in combination. ○ Switch to a narrower-spectrum agent, e.g., cefepime, ceftazidime, piperacillin/tazobactam, cefoperazone/sulbactam, if carbapenem or novel beta-lactam were used initially. ** Irrespective of fever status at re-evaluation.
◆ Revision of recommendation for discontinuation of antibiotic treatment in neutropenic patients with FUO: ● Empiric antibiotic therapy (EAT) can be discontinued at ≥ 72 hours of treatment in hemodynamically stable patients since presentation and who are afebrile ≥48 hours, irrespective of neutrophil count or expected duration of neutropenia. ● They recommend continuing EAT in stable, high- or intermediate-risk neutropenic patients with FUO and persistent fever. Diagnostic efforts should be continued to search for an infectious focus or alternative explanation of fever. ● Discontinuation of EAT can be considered later when the bacterial infectious source was reasonably excluded by microbiological tests and imaging. ● They do not recommend adding coverage against resistant Gram-positive, or Gram-negative bacteria in a stable patient with persistent fever.
◆ Antibiotic therapy can be discontinued before recovery from neutropenia in patients with clinically documented infections or microbiologically documented infections (CDI/MDI) after completion of intended course of treatment, who are hemodynamically stable and afebrile for ≥72 h, with resolution of all clinical signs and symptoms and microbiological eradication of infection (when re-sampling possible). ● In patients with Gram-negative bloodstream infections, we recommend a duration of antibiotic treatment of at least 7 days with recovery of neutropenia or without recovery of neutropenia. |
