Choice of Conditioning Regimen Influences Risk of Thymoglobulin Infusion Reactions in Allogeneic Hematopoietic Cell Transplantation

Background

Thymoglobulin (Genzyme, Mass., USA) is used in allogeneic hematopoietic cell transplantation (alloHCT) for graft-versus-host disease (GVHD) prophylaxis. Infusion-related reactions are common and challenging to manage. We explored characteristics of Thymoglobulin infusion reactions (TIRs), predictors of TIR and the relevance of TIR to outcomes after alloHCT.

Method

We reviewed records of all patients who received Thymoglobulin prior to alloHCT for hematologic malignancy between the years 2007 and 2013 inclusive. We defined TIR as fever (temperature ≥ 38°C); rigors; or two or more episodes of heart rate > 120, respiratory rate > 26, oxygen saturation < 92%, systolic blood pressure < 90 mmHg, occurring within 24 hours of commencement of Thymoglobulin infusion, without bacteremia.

Results

One hundred and thirteen patients were studied (male 62%, median age 43, range 17-61). The most common indication for alloHCT was acute leukemia (n = 69) followed by chronic lymphoproliferative disorder (n = 22) and myelodysplastic syndrome (n = 10). All patients received an initial infusion of 0.5 mg/kg over 6 hours on day -3. Day -2 and -1 doses were 2 mg/kg then 2 mg/kg (n = 77); 1.5 mg/kg then 4 mg/kg (n=16); 1.5 mg/kg then 2 mg/kg (n = 16); 1 mg/kg then 2 mg/kg (n = 1); or unknown (n = 7). All patients received premedication with acetaminophen, an antihistamine, and methylprednisolone 1 mg/kg, approximately one hour prior to each Thymoglobulin infusion. Fifty-one patients (45%) experienced TIR after the first infusion. Of these, 88% first developed features of TIR during the infusion. Features of TIR were fever in 90%, rigors in 58%, tachycardia in 34%, hypotension in 18%, tachypnea in 16% and hypoxia in 10%. Median time from start of first Thymoglobulin infusion to onset of TIR was 265 minutes (range, 15 to 705). Four patients had subsequent Thymoglobulin doses omitted due to TIR (two after first dose, two after second dose). Twelve patients had first onset of TIR after second infusion, and eleven after the third infusion. No patients required intensive care transfer. On univariate analysis (Fisher exact test), age over 30, choice of conditioning regimen, and alloHCT for chronic lymphoproliferative disorder, were significantly associated with day -3 TIR, whereas conditioning intensity, alloHCT in remission, and day -3 absolute lymphocyte count and white cell count were not associated with day -3 TIR. On multivariate analysis (logistic regression), only choice of conditioning remained significant. The influence of conditioning remained significant after adjustment for age and disease type. Incidences of day -3 TIR were 13% (2/16) for total body irradiation (TBI)/etoposide (VP16), 19% (5/26) for busulfan/cyclophosphamide (BuCy), 60% (18/30) for fludarabine-based reduced intensity regimens (without TBI; mostly fludarabine and melphalan, n = 23), and 63% (26/41) for cyclophosphamide/TBI (CyTBI). Compared to CyTBI, BuCy (odds ratio 0.1, 95% CI 0.0-0.4, P=.001) and TBI-VP16 (odds ratio 0.1, 95% CI 0.0-0.3, P = .002) were associated with markedly reduced incidence of day -3 TIR. The presence of day -3 TIR did not significantly influence survival, non-relapse mortality, relapse or acute or chronic GVHD.

Conclusion

TIR in alloHCT, is a predictable toxicity which is manageable and varies in incidence with particular conditioning agents.