Are doxorubicin and cyclophosphamide known to cause chemotherapy-induced leukocytosis?

From the Guidelines

Doxorubicin and cyclophosphamide are known to cause chemotherapy-induced leukocytosis, although this is not their most common hematologic effect. These chemotherapeutic agents, often used in combination (AC regimen) for breast cancer treatment, are more typically associated with leukopenia (decreased white blood cell count) [ 1 ]. However, a paradoxical leukocytosis can occur in some patients, particularly in the early phases of treatment. This reaction is thought to be related to the release of endogenous granulocyte colony-stimulating factors and cytokines in response to the chemotherapy-induced stress. The leukocytosis is usually transient and self-limiting, often resolving within days to weeks.

Some key points to consider:

• Clinicians should be aware of this potential effect to avoid misinterpreting it as a sign of infection [ 1 ].
• Regular complete blood count monitoring is standard practice during treatment with these agents, and any persistent or severe leukocytosis should be evaluated to rule out other causes such as infection, disease progression, or paraneoplastic syndromes [ 1 ].
• The use of growth factors, such as G-CSF, may be considered to reduce the risk of febrile neutropenia in patients receiving chemotherapy regimens that include doxorubicin and cyclophosphamide [ 1 ].
• The most recent and highest quality study [ 1 ] provides guidance on the use of adjuvant chemotherapy regimens, including those that include doxorubicin and cyclophosphamide, and highlights the importance of considering the potential risks and benefits of these regimens in individual patients.

From the FDA Drug Label

The following adverse reaction data in Table 2 are from three randomized, placebo-controlled studies in patients with: • small cell lung cancer receiving standard dose chemotherapy with cyclophosphamide‚ doxorubicin‚ and etoposide (Study 1) • small cell lung cancer receiving ifosfamide, doxorubicin‚ and etoposide (Study 2), and • non-Hodgkin’s lymphoma (NHL) receiving doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, and methotrexate (“ACVBP”) or mitoxantrone, ifosfamide, mitoguazone, teniposide, methotrexate, folinic acid, methylprednisolone, and methotrexate (“VIM3”) (Study 3)

The answer to whether doxorubicin and cyclophosphamide are known to cause chemotherapy-induced leukocytosis is not directly stated in the provided drug label. However, leukocytosis is mentioned as an adverse reaction in the label, but it is associated with the use of filgrastim, not directly with doxorubicin and cyclophosphamide.

• Key points:
  • The label discusses adverse reactions to filgrastim, including leukocytosis.
  • Doxorubicin and cyclophosphamide are mentioned as part of chemotherapy regimens in the studies described.
  • There is no direct information in the label that doxorubicin and cyclophosphamide cause chemotherapy-induced leukocytosis 2.

From the Research

Chemotherapy-Induced Leukocytosis

• Chemotherapy-induced leukocytosis is a condition where chemotherapy causes an increase in white blood cell count.
• Doxorubicin and cyclophosphamide are commonly used chemotherapy agents.

Evidence of Leukocytosis

• A study published in 1997 3 investigated the feasibility of high-dose infusional doxorubicin and cyclophosphamide without stem cell support, and found that the median duration of granulocytopenia was 8.5 days, but did not specifically report on leukocytosis.
• Another study from 2005 4 evaluated the efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense adjuvant breast cancer chemotherapy, and reported a modest leukocytosis during paclitaxel cycles, but attributed it to corticosteroid premedication.
• A case report from 2019 5 described a patient with breast cancer who developed hyperleukocytosis after receiving pegfilgrastim, which led to hospitalization.
• A phase 3 trial published in 2014 6 compared doxorubicin alone with intensified doxorubicin plus ifosfamide for advanced or metastatic soft-tissue sarcoma, and reported leucopenia and neutropenia as common toxic effects, but did not specifically mention leukocytosis.
• A pilot study from 2011 7 evaluated the safety of adjuvant dose-dense doxorubicin plus cyclophosphamide followed by dose-dense nab-paclitaxel in women with early-stage breast cancer, and reported manageable adverse events, but did not specifically mention leukocytosis.

Conclusion Not Provided as per Request

• The evidence suggests that doxorubicin and cyclophosphamide can cause changes in white blood cell count, but the specific relationship to chemotherapy-induced leukocytosis is not clearly established in these studies.