How should Imatinib (Gleevec) be managed in patients with chronic myeloid leukemia or gastrointestinal stromal tumors at risk of or with active infections?

Imatinib and Infectious Clearance Management

Imatinib does not require routine interruption or dose modification for infection risk in CML or GIST patients, as the overall infection incidence is low (2%) and opportunistic infections are rare, but specific attention is needed for elderly patients, those with neutropenia, and patients at risk for hepatitis B or tuberculosis reactivation. 1

Baseline Infection Risk with Imatinib

• Imatinib has immunosuppressive effects through inhibition of T-cell proliferation and activation in vitro, but clinical infection rates remain low compared to second-generation TKIs 1
• In a series of 771 patients across all disease phases, the overall infection incidence was only 2%, with opportunistic infections being uncommon 1
• Bacterial and viral infections occur in approximately 13-16% of patients during 3.5 years of follow-up, with no significant difference between early and late chronic phase patients 2
• Opportunistic infections and Herpes Zoster reactivation occur at very low incidence during imatinib therapy 2

Specific Infectious Risks Requiring Attention

Hepatitis B Reactivation:

• Hepatitis B reactivation has been documented during imatinib treatment and requires prophylactic antiviral therapy 1
• Concomitant use of antiviral agents should be recommended for prevention of hepatitis B reactivation in at-risk patients 1

Tuberculosis Reactivation:

• Reactivation of pulmonary tuberculosis has been reported during imatinib therapy 1
• Two cases of granulomatous lymphadenitis have been described 1

Elderly Patients:

• One out of four elderly patients treated with imatinib developed infections, representing a significantly higher risk group 1
• Attention is most needed in elderly patients and in the presence of neutropenia 1

Vaccination Considerations

• Responses to vaccination against influenza and pneumococcus are blunted in TKI-treated patients 1
• Despite reduced vaccine efficacy, vaccination should still be pursued as part of preventive care 1

Management During Active Infection

Neutropenia-Associated Infections:

• For Grade 3-4 neutropenia (ANC <1,000/mm³), hold imatinib until ANC ≥1,500/mm³, then resume at starting dose of 400 mg 1
• If neutropenia recurs, hold drug until ANC ≥1,500/mm³, then resume at reduced dose of 300 mg 1
• Growth factors can be used in combination with imatinib for patients with resistant neutropenia 1

Infection Without Neutropenia:

• Imatinib does not require routine interruption for mild-to-moderate infections in patients with normal neutrophil counts 1
• Treatment decisions should be based on infection severity and clinical status rather than prophylactic drug holidays 1

Monitoring Strategy

During First 4-6 Weeks:

• Monitor blood counts weekly to detect early myelosuppression that could increase infection risk 1
• Peak incidence of myelosuppression occurs within the first 4-6 weeks after starting imatinib 1

Beyond Initial Period:

• Continue monitoring blood counts every 2-4 weeks if counts are stable 1
• The incidence of Grade 3-4 cytopenias decreases substantially after the first year, with only 1-2 percentage point increases beyond year one 1

Comparison with Other TKIs

• Dasatinib has more profound immunosuppressive effects due to broader kinase target spectrum and more potent off-target inhibition 1
• Large phase II/III studies show no significantly increased infection rates with dasatinib, nilotinib, or bosutinib compared to imatinib in first-line treatment 1
• Deaths due to infection in first-line therapy: dasatinib 1.9%, imatinib 0.4%, nilotinib and bosutinib 0% 1

Humoral Immune Effects

• Imatinib induces hypogammaglobulinemia in both CML and GIST patients, reaching severe levels in 10% of cases 3
• Significant reduction of gammaglobulin and immunoglobulin serum levels occurs during treatment 3
• Despite hypogammaglobulinemia, clinical infection rates remain relatively low, suggesting preserved cellular immunity 3, 2

Critical Pitfalls to Avoid

• Do not routinely discontinue imatinib for minor infections in non-neutropenic patients, as this risks loss of disease control without clear benefit 1
• Do not overlook hepatitis B screening and prophylaxis in at-risk populations before initiating therapy 1
• Do not assume all infections are treatment-related; elderly patients and those with advanced disease have baseline increased infection risk 1
• Do not reduce imatinib to subtherapeutic levels (<300 mg) for infection concerns, as maintaining adequate plasma concentration is essential for disease control 4