Autologous Graft Versus Host Disease: An Emerging Complication in Patients with Multiple Myeloma

Abstract

Autologous graft versus host disease (autoGVHD) is a recently recognized, rare transplant complication with significant morbidity and mortality. Pathogenesis and risk factors for autoGVHD are poorly understood. We hypothesized that patients with multiple myeloma might be predisposed to autoGVHD through disregulation of immune response resulting from their treatment with immunomodulatory agents (IMiDs) and chemotherapeutic mobilization regimens. We identified 8 patients with multiple myeloma treated between 2005- 2013 with biopsy-proven autoGVHD after transplant. We identified 2 non-autoGVHD controls per autoGVHD patient matched by the time of hematopoietic progenitor cell (HPC) collection (within 15 days). Reference samples from HPC products of autoGVHD, non-autoGVHD myeloma patients, and 7 healthy controls were thawed and examined for cell surface marker expression of CD3, CD4, CD8, CD25, and CD56 and intracellular expression of FoxP3 by multicolor flow cytometry. Information on the following variables was collected: number of transplants prior to developing autoGVHD, mobilization regimens, exposure to a proteosome inhibitor, bortezomib, and IMiDs (thalidomide, lenalidomide and pomalidomide), and human leukocyte class I antigens (HLA A and B). Myeloma patients with and without autoGVHD were well matched for age (60 ± 5.3 and 62.1 ± 7.8 years) and sex (50% and 43.8% male). Regulatory T-cells were decreased, but not significantly, in patients with autoGVHD (1.6 ± 1.4%) compared to non-autoGVHD patients (2.1 ± 1.7%).There was no difference in the NK cell population in the 2 groups. CD3+ cell percentage was significantly lower in autoGVHD (46.6 ± 12.4%) than the non-autoGVHD patients (59.1 ± 14.4%, p = 0.047). On subset analysis of CD3+ cells, CD8+ cells were found to be significantly lower in patients with autoGVHD (12.9 ± 6.9% versus 24.4 ± 13.7%, p = 0.038) but not CD4+ cells. There was a trend towards higher number of transplants in patients who developed autoGVHD (2.1 ± 0.4%) compared to those who did not (1.6 ± 0.7%, p= 0.072). There was no difference between these groups with respect to mobilization regimens, exposure to bortezomib and the IMiDs. HLA B55 positivity was significantly associated with the development of autoGVHD (p=0.028). While there was a trend towards a higher number of transplants being associated with the development of autoGVHD in myeloma patients, no differences were seen in the use of bortezomib, IMiDs and mobilization regimens. However, lower percentages of CD3+ and CD8+ T-cells in HPC products were significantly associated with autoGVHD, suggesting that increased immunosuppression following mobilization may be a predisposing factor for developing autoGVHD in myeloma patients, particularly in the setting of HLA B55 positivity.