Linezolid Use Early After Stem Cell Transplant - A Cautionary Tale

Background:  Linezolid (LZ) is an oxazolidinone antimicrobial often used to treat resistant gram-positive bacteria and has been associated with mild, reversible, time-dependent myelosuppression, including thrombocytopenia (common), anemia (common), leukopenia, and pancytopenia.  Generally, these effects occur with treatment durations of ≥ 14 days.  Patients with underlying hematologic abnormalities may be more at risk for the development of LZ-induced myelosuppression, but this is controversial. We hypothesized that LZ use before engraftment may delay hematopoietic recovery following stem cell transplant (SCT), and performed a matched controlled analysis to investigate this hypothesis.

Methods: With institutional review board approval, we retrospectively evaluated 24 patients who received LZ and compared them to 60 controls who did not receive LZ from 1/1/1997 to 1/1/2010. Our SCT database was utilized to find matched controls and matching was based on: diagnosis; transplant type; cell source; transplant conditioning regimen; and age +/- 10 years. Patients in the LZ group were included if LZ was administered at any time from day 0 through engraftment of white cells but for a minimum of 72 consecutive hours.  Patients 1 year of age or older were included.  The data were analyzed for the effects of LZ on time to neutrophil (ANC > 500 for 3 days) and platelet engraftment (platelet count > 20,000 for 7 days without transfusion), and the cumulative incidence of engraftment of both neutrophil and platelets within the first 100 days post-transplant.

Results:  The LZ and control groups were similar with respect to age (median 44 vs. 41 years), gender (50% vs. 58% male and 50% vs. 42% female), diagnosis (29% vs. 25% had AML/MDS), cell source (67% vs. 63% apheresis product), transplant type (67% vs. 63% allogeneic), ablative vs. non-ablative conditioning (79% vs. 83% myeloablative), and cell dose (median CD34 dose 4.52 x 10⁶/kg vs. 4.34 x 10⁶/kg). Median time to neutrophil engraftment was the same for LZ and control groups (12 days). The median time to neutrophil plus platelet engraftment for LZ group and control group was 50 days (11 patients censored) vs. 15.5 days (10 patients censored). Neutrophil engraftment failure occurred in 16% of LZ patients vs. 7% of controls. Forty-six percent of LZ patients vs. 13% of controls failed to achieve platelet engraftment.   The cumulative incidence of engraftment of neutrophils plus platelets (using death without engraftment as the competing risk) was lower in the LZ group (54%) vs. the control group (83%) (p=0.005). Day 100 survival rates were 58% for the LZ group vs. 92% for controls. Survival probability is shown in figure 1.

Conclusions: LZ does not significantly affect time to neutrophil engraftment, but does appear to prolong time to platelet engraftment when compared to patients who did not receive LZ. LZ should be used cautiously early after stem cell transplantation.