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Clinical practice guidelines on infectious complications of targeted drugs and biotherapies: European Conference on Infections in Leukaemia (ECIL)

Aug 18, 2022
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Learning objective: After reading this article, learners will be able to recall recommendations for the prevention and management of infectious complications of targeted drugs and biotherapies in acute leukemia.

Patients with hematologic malignancies such as acute myeloid leukemia (AML) are at an increased risk of infections, with associated morbidity and mortality. With the advent of small molecular inhibitors and immunotherapies, either as single agents or in combination with standard of care, the landscape of infectious complications seen with treatment for AML may change.1 Furthermore, any interactions between these novel agents and anti-infective drugs are not clearly understood, warranting recommendations for prevention and management of infectious complications in AML.1

At the 9th European Conference on Infections in Leukaemia (ECIL 9), the risk of infections and febrile neutropenia associated with molecular-targeted agents and immunotherapy for AML and acute lymphoblastic leukemia (ALL), was reviewed. The ECIL 9 meeting was a joint endeavor by the European Organisation for Research and Treatment of Cancer (EORTC), the International Immunocompromised Host Society (ICHS), and the European LeukemiaNet (ELN), to develop evidence-based recommendations for the prevention of infectious complications. Maschmeyer, et al.,1 reported a set of recommendations that were developed and discussed at the ECIL 9 meeting, for a rational clinical management of prevention and treatment of infections in leukemia patients treated with immunotherapeutic and molecular-targeted antineoplastic agents. The recommendations are summarized herein.

Methodology

The panel comprised experts in clinical hematology and oncology, infectious diseases, and clinical pharmacology. Evidence-based recommendations were developed and agreed upon reaching consensus by the ECIL 9 plenary members, using the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) grading system. Recommendations were made on diagnostic procedures, management strategies, and handling of drugs in the following classes (Table 1):

  • Novel antibody-based agents
  • Isocitrate dehydrogenases (IDH) inhibitors
  • FMS-like receptor tyrosine kinase 3 (FLT3) inhibitors
  • Hedgehog inhibitor
  • B-cell lymphoma 2 (BCL2) inhibitor

Recommendations

Novel antibody-based agents

Inotuzumab ozogamicin (InO) is a targeted antibody–drug conjugate, approved as a monotherapy for the treatment of adults with relapsed/refractory (R/R) CD22-positive B-cell precursor ALL, and binds with high affinity to CD22. When combined with chemotherapy, inotuzumab ozogamicin may cause febrile neutropenia, sepsis, and pneumonia; however, the risk of infection does not increase with inotuzumab ozogamicin monotherapy.

Gemtuzumab ozogamicin (GO) is a recombinant humanized anti-CD33 monoclonal antibody approved by the U.S. Food and Drug Administration (FDA), for the treatment of patients with AML with tumor cells expressing CD33. It is used in combination with daunorubicin and cytarabine, as well as a monotherapy. No risk of infection has been associated with gemtuzumab ozogamicin monotherapy, and in large comparative trials of chemotherapy plus gemtuzumab ozogamicin, it also showed no significant increase in neutropenic fever or infections. Infectious events reported in studies include fever of unknown origin, pneumonia, sepsis, and fungal infection.

Flotetuzumab is an investigational CD123 × CD3 bispecific, dual-affinity retargeting antibody granted orphan drug designation by the FDA for the treatment of AML. At clinical doses, flotetuzumab has not been found to cause prolonged suppression of normal hematopoiesis, and no specific risk of infection was associated with monotherapy.

IDH inhibitors

The IDH inhibitors enasidenib and ivosidenib are approved by the FDA for the treatment of R/R IDH2-positive AML, and newly diagnosed (ND) AML with a susceptible IDH1 mutation, respectively. Ivosidenib in combination with azacitidine was also recently approved by the FDA for the treatment of IDH1-mutated ND AML. No specific immunosuppressive effect or risk of infection was reported for enasidenib and ivosidenib monotherapy. However, when combined with intensive induction and consolidation treatment, both agents resulted in an increased rate of clostridia infections in some patients.

FLT3 inhibitors

Gilteritinib is a highly selective FLT3 inhibitor that acts against both the FLT3 mutation subtypes, internal tandem duplication (ITD) and tyrosine kinase domain (TKD). It is approved by the FDA and European Commission (EC) for the treatment of R/R FLT3-mutated AML. No evidence was found of any specific impact on the immune system caused by gilteritinib in patients with R/R AML, and infections reported included sepsis, febrile neutropenia, and pneumonia. Coadministration of gilteritinib with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers may alter gilteritinib levels; therefore, close monitoring in these situations is recommended (Table 1).

Midostaurin is approved by the FDA and the EC for the treatment of patients with ND FLT3-mutated AML, acting by inhibiting multiple tyrosine kinase receptors, inducing cell cycle arrest and apoptosis. Several studies reported febrile neutropenia and sepsis. The most common infection was pneumonia, followed by upper respiratory tract infection, cellulitis, and bacteremias.

Quizartinib, a potent FLT3 tyrosine kinase inhibitor with significant activity in FLT3-ITD-mutant AML, has FDA breakthrough therapy designation but has not been granted full approval in either the U.S. or Europe. It has been associated with frequent occurrence of febrile neutropenia, fever of unknown origin, and bacterial infections, mainly sepsis, urinary tract infection, and upper respiratory tract infection.

Hedgehog inhibitors

Glasdegib is approved by the FDA and the EC for the treatment of patients with ND de novo or secondary AML, who are not eligible for standard induction therapy. It inhibits the sonic hedgehog receptor smoothened, a key mediator of Hedgehog pathway signaling in leukemia stem cells. Febrile neutropenia and pneumonia have been reported in combination with low-dose cytarabine. Glasdegib is metabolized by CYP3A4/5 and, therefore, the concomitant use of other drugs which inhibit CYP3A has not been recommended (Table 1).

BCL2 inhibitors

Venetoclax, in combination with hypomethylating agents (azacitidine or decitabine), is approved by the FDA and the EC for the treatment of patients with ND AML who are not eligible for intensive chemotherapy. Venetoclax blocks the antiapoptotic BCL2 protein, leading to programmed cell death of leukemia cells. Venetoclax is also metabolized by CYP3A4/5 and, therefore, specific attention should be paid when combining venetoclax with other drugs, particularly CYP3A4 inhibitors. It is recommended to reduce the venetoclax dose by 75% if patients are also receiving posaconazole prophylaxis, since posaconazole is a strong CYP3A4 inhibitor (Table 1).

Table 1. ECIL recommendations for targeted drugs and biotherapies in acute leukemia*

Agent (class)

Recommendations

Inotuzumab ozogamicin
(anti-CD22 antibody–drug conjugate)

No specific antimicrobial prophylaxis required

No specific treatment recommendations for infection or fever

Take caution when combining with other agents prolonging the QT interval (e.g., levofloxacin or posaconazole)

Gemtuzumab ozogamicin
(anti-CD33 antibody–drug conjugate)

SOC diagnostic procedures and treatment in AML with neutropenic fever and/or infections

SOC prophylaxis in AML when given in combination or as a high dose for relapse

No systemic antimicrobial prophylaxis when given as monotherapy

Hepatotoxicity should be carefully monitored

Flotetuzumab
(CD123 × CD3 bispecific antibody)

SOC diagnostic procedures and treatment in AML with neutropenic fever and/or infections

No specific prophylaxis or drug handling recommendations due to lack of monotherapy data

Enasidenib; ivosidenib; olutasidenib
(IDH1/2 inhibitors)

SOC diagnostic procedures and treatment in AML with neutropenic fever and/or infections

No systemic antimicrobial prophylaxis when given as monotherapy

Gilteritinib
(FLT3 tyrosine kinase inhibitor)

SOC diagnostic procedures and treatment in AML with neutropenic fever and/or infections

No systemic antimicrobial prophylaxis when given as monotherapy

Monitor for QT interval prolongation when combining with strong CYP3A4 inhibitors

Avoid combinations with strong CYP3A4 inducers

Midostaurin
(FLT3 tyrosine kinase inhibitor)

SOC diagnostic procedures when given in combination with cytarabine/anthracycline chemotherapy

SOC antimicrobial prophylaxis when given in combination with cytarabine/anthracycline chemotherapy

No need for antibacterial or antifungal prophylaxis when given as monotherapy

Use of empirical antibiotic treatment during cytarabine/anthracycline chemotherapy plus midostaurin therapy in neutropenic fever and/or infections

Strong CYP3A4 inhibitors may increase exposure to midostaurin or its metabolites; consider alternatives that do not strongly inhibit CYP3A4 or monitor for increased risk of adverse reactions

Avoid concomitant use of strong CYP3A4 inducers (e.g., rifampin)

Quizartinib
(FLT3 tyrosine kinase inhibitor)

SOC diagnostic procedures in AML with neutropenic fever and/or infections

SOC antibiotic prophylaxis in AML when given in combination

Use an empirical antibiotic treatment approach in neutropenic fever and/or infections

Monitor for QT interval prolongation when combining with strong CYP3A4 inhibitors

Avoid combinations with strong CYP3A4 inducers

Glasdegib
(hedgehog pathway inhibitor)

SOC diagnostic procedures and treatment in AML with neutropenic fever and/or infections

SOC prophylaxis in AML when given in combination with chemotherapy

Reconsider concomitant erythromycin, clarithromycin, ciprofloxacin, itraconazole, posaconazole, ketoconazole, or voriconazole

Avoid combinations with strong CYP3A4 inducers

Venetoclax
(BCL2 inhibitor)

SOC diagnostic procedures and treatment in AML with neutropenic fever and/or infections

SOC prophylaxis as for AML treatment with intensive chemotherapy

Consider antibacterial and antifungal prophylaxis when combined with hypomethylating agents

In cases of infection/fever,
(1) consider venetoclax dose interruptions to allow for hematologic recovery in patients with a response;
(2) promote appropriate interruptions in venetoclax between treatment cycles to augment hematologic recovery;
(3) in patients with good response but severe neutropenia, consider venetoclax dose reduction in subsequent courses;
(4) if dose reduction is ineffective or not advised, consider prophylactic G-CSF during remission for subsequent courses

Ensure proper venetoclax dose adjustments when combined with antibacterial agents such as ciprofloxacin or macrolides

If given in combination with posaconazole, reduce venetoclax dosage by 75%

AML, acute myeloid leukemia; BCL2, B-cell lymphoma 2; CYP3A4, cytochrome P450 3A4; ECIL, European Conference on Infections in Leukaemia; G-CSF, granulocyte colony-stimulating factor; SOC, standard of care.
*Adapted from Maschmeyer, et al.1
The strength and quality of evidence was graded using the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) grading system.

Conclusion

The clinical practice guidelines developed and discussed at the ECIL meeting, in 2021, outline recommendations for the management of infectious complications of targeted drugs and biotherapies in acute leukemia. The reviewed evidence showed that most agents were not associated with a significantly increased risk of infections when used as monotherapy. However, careful consideration and monitoring were recommended with combination therapies, such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs, and midostaurin combined with conventional AML chemotherapy.

  1. Maschmeyer G, Bullinger L, Garcia-Vidal C, et al. Correction: Infectious complications of targeted drugs and biotherapies in acute leukemia. Clinical practice guidelines by the European Conference on Infections in Leukemia (ECIL), a joint venture of the European Group for Blood and Marrow Transplantation (EBMT), the European Organization for Research and Treatment of Cancer (EORTC), the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN). Leukemia. 2022;36(5):1450. DOI: 1038/s41375-022-01570-9

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