Myelodysplastic syndrome and acute myeloid leukemia after receipt of granulocyte colony‐stimulating factors in older patients with non‐Hodgkin lymphoma

Abstract

BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs), which are used for the prevention of complications from chemotherapy-related neutropenia, are linked to the risk of developing second primary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The objective of this study was to examine the correlation between using a specific G-CSF agent and the risk of MDS/AML among older patients with non-Hodgkin lymphoma (NHL). METHODS: This was a retrospective cohort study of adults aged >65 years who were diagnosed with first primary NHL between 2001 and 2011. With data from the Surveillance, Epidemiology, and End Results-Medicare-linked database, adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the risk of MDS/AML associated with the receipt of G-CSF(filgrastim and pegfilgrastim) in Cox proportional-hazards models, which were stratified according to treatment accounting for confounding by indication. RESULTS: Among 18,245 patients with NHL patients who had a median follow-up of 3.5 years, 56% received chemotherapy and/or immunotherapy, and G-CSF was most commonly used in those who received rituximab plus multiple chemotherapy regimens (77%). Subsequent MDS/AML diagnoses were identified in 666 patients (3.7%). A modest increased risk of MDS/AML was observed with the receipt of G-CSF (HR, 1.28; 95% CI, 1.01-1.62) and a trend was observed with increasing doses (P trend < .01). When specific agents were analyzed, an increased risk of MDS/AML was consistently observed with filgrastim (≥10 doses: HR, 1.67; 95% CI, 1.25-2.23), but not with pegfilgrastim (≥10 + doses: HR, 1.11; 95% CI, 0.84-1.45). CONCLUSIONS: A higher of MDS/AML was observed in patients with NHL risk among those who received G-CSF that was specific to the use of filgrastim (≥10 doses), but not pegfilgrastim. Neutropenia prophylaxis is an essential component of highly effective NHL treatment regimens. The differential risk related to the types of G-CSF agents used warrants further study given their increasing use and newly available, US Food and Drug Administration-approved, biosimilar products.

Maximizing Breast Cancer Therapy with Awareness of Potential Treatment-Related Blood Disorders

“…G-CSF and peg-G-CSF are thought to have the same mechanism of action but quite different pharmacokinetics. Therefore, if there is a true difference in leukemogenic potential between the two drugs, the mechanism is not clear at this time, unless peak drug blood levels or area-under-the-curve assessments are relevant to the degree of G-CSF exposure to susceptible patients [43].…”

Risk of secondary hematologic malignancies associated with breast cancer chemotherapy and G‐CSF support: A nationwide population‐based cohort

“…CI, 1.0-1.6). 28 There has always been a concern that growth factors could be leukemogenic 6,7 but had the G-CSF been responsible for a significant increase in AML or MDS, the risk would have been significantly higher after chemotherapy plus G-CSF compared to chemotherapy alone in our population-based cohort. The G-CSF may be simply playing the role of an innocent bystander.…”

“…A study of clonal hematopoiesis after neoadjuvant chemotherapy for BC did not either observe changes suggesting AML or MDS development 27 . However, in a study of patients treated for non‐Hodgkin lymphoma, a modest significant increased risk of MDS/AML was observed with the receipt of G‐CSF (HR, 1.28; 95% CI, 1.0‐1.6) 28 . There has always been a concern that growth factors could be leukemogenic 6,7 but had the G‐CSF been responsible for a significant increase in AML or MDS, the risk would have been significantly higher after chemotherapy plus G‐CSF compared to chemotherapy alone in our population‐based cohort.…”

“…Two previous SEER-Medicare database studies reported an increased MDS/AML risk that was exclusive to filgrastim and not observed with pegfilgrastim. 25,28 During their study period, the pegylated form of recombinant human G-CSF analog filgrastim (ie, pegfilgrastim) was introduced and the fil- One of our study's limitations was that intensity of chemotherapy and cumulative dose could not be assessed with our data. However, patients who receive dose-intense chemotherapy regimens are more likely to receive G-CSF support to prevent neutropenia and its complications.…”

“…In our analysis of G‐CSF use in terms of specific agents, we did not observe any significant difference in HMs risk that was specific to filgrastim, lenograstim or pegfilgrastim. Two previous SEER‐Medicare database studies reported an increased MDS/AML risk that was exclusive to filgrastim and not observed with pegfilgrastim 25,28 . During their study period, the pegylated form of recombinant human G‐CSF analog filgrastim (ie, pegfilgrastim) was introduced and the filgrastim biosimilars were not yet approved.…”