Prolonged Duration of Systemic Immunosuppression after Allogeneic Hematopoietic Cell Transplantation Associates with the Use of Peripheral Blood Stem Cells, Severe Grade of Chronic Gvhd, Progressive Type Onset of Chronic Gvhd, Grade 2-4 Acute Gvhd and Older Age, but Not with T-Cell Depletion or Conditioning Regimen

Background: Prolonged systemic immunosuppression (SIS) post allogeneic hematopoietic cell transplantation (HCT) results in increased unnecessary complications. In our previous study of avascular necrosis (AVN; ASBMT 2015), one of common complications occurring after allogeneic HCT related to the use of prolonged immunosuppression including corticosteroids, we demonstrated a strong correlation between the duration of SIS and the risk of AVN. The probability of remaining on SIS was higher in the group developed AVN than those without episode of AVN (46.4% vs 11.7% at 4 years post-HCT). The question remains what are the risk factors related to prolonged SIS after allogeneic HCT. The present study attempted to evaluate potential risk factors for prolonged SIS.

Methods: A retrospective review of 845 consecutive patients ≥18 years of age who underwent alloHCT at Princess Margaret Cancer Centre from 2002 to 2013 was conducted to determine the probability of SIS discontinuation considering death and relapse as competing risks. Univariate and multivariate analyses were conducted using cumulative incidence method considering competing risk to identify the risk factors for failure from SIS discontinuation.

Results: Out of 845 patients, the probability of remaining on SIS, SIS discontinuation and death at 4 years is 19.6%, 30.5%, 49.9%, respectively. The median follow up duration among survivors was 3.5 years.

Univariate analysis for successful SIS cessation revealed following risk factors: aGVHD grade 2-4 (p<0.001, HR 0.53), cGVHD by NIH consensus criteria (p<0.001, HR 0.52), cGVHD severity (p<0.001,HR 0.44), progressive type onset of cGVHD (p<0.001, HR 0.62), stem cell source (p<0.001,HR 0.54 for PBSC), T cell depletion (p<0.001, HR 1.42), donor type (p=0.0028, HR 1.45 for matched related donor), HLA  match (p=0.0039, HR 0.30 for mismatched) and age (p<0.001, HR 0.98).

Multivariate analysis confirmed that younger age (p<0.001, HR 0.97), aGVHD grade 2-4 (p<0.001, HR 0.51), progressive type of cGVHD (p<0.001, HR 0.53), cGVHD by NIH consensus criteria (p<0.001, HR 0.53), stem cell source (p<0.001, HR 0.51 for PBSC) and use of matched related donor (p<0.001, HR 1.68) were significant risk factors. ROC analysis was performed which revealed an age ≤ 50 to be a categorical risk factor for SIS discontinuation.

A risk score model was generated assigning a score to each risk factor. A score of 1 was assigned to aGVHD grade 2-4, younger patient of age  ≤50 years, progressive type of cGVHD, cGVHD by NIH consensus criteria, PBSC stem cell source and the use of matched related donor. Total score was calculated with risk score 0 (n=16, 2%), risk score 1 (n=55, 7%), risk score 2 (n=109, 14%), risk score 3 (n=215, 28%), risk score 4 (n=232, 30 %), risk score 5 (n=119, 16%), risk score 6 (n=14, 1%). Three risk groups were created: low (score 0-2, n=181, 21.4%), intermediate (score 3, n=216, 25.6%) and high (score 4-6, n=365, 47%). This risk score group could stratify the patients according to their success rate of SIS cessation (p<0.0001): 48.0% in low vs. 40.8% in intermediate vs. 28.5% in high risk group for SIS discontinuation rate at 4 yrs.

Conclusions:  Younger age,  aGVHD grade 2-4, progressive type of cGVHD, cGVHD by NIH consensus criteria, peripheral stem cell source and use of matched sibling donor predicts for prolonged immunosuppression use post allogeneic transplant.