Role of polyomavirus in emerging secondary hypofunction of marrow graft following allogeneic bone marrow transplantation in adults

Summary

Background

Poor function of haematopoietic transplant is considered an important complication following allogeneic bone marrow transplantation (allo-HSCT). According to different reports, incidence of BK polyomavirus (BKV) reactivation following allo-HSCT can be as high as 33-54% (1). Relation between BK viruria (or viremia) and the risk of hemorrhagic cystitis is well studied in HSCT patients (1-3). Cases of BKV-associated encephalitis and pneumonitis have been also reported (2). Some studies suggest correlation between BK virus reactivation and cytopenia in both renal (1) and bone marrow transplant recipients (2-4). Taking into account susceptibility of different cell types to BKV infection, including peripheral leukocytes (4), one may suggest a clinical form of BKV disease manifesting as bone marrow transplant insufficiency.

Objective

The aim of our study was to assess a role of BKV infection in the development of secondary graft hypofunction following allogeneic HSCT.

Materials and methods

We carried out a retrospective analysis of 328 patients with different oncohematological disorders (18 to 77 y.o., a median of 31 years), who underwent allogeneic HSCT (matched related donors, 89; matched unrelated donors, 211; haploidentical donors, 28) during the period from 2014 to 2016. Myeloablative conditioning regimen was applied in 75 patients (23% of total), reduced-intensity regimens were used in 253 cases (77% of total). Characteristics of the group are shown in Table 1.

Over the posttransplant period 219 patients were tested for BKV in different body fluids including blood plasma,urine, bone marrow aspirates, CSF etc. (Fig.1), using qualitative gene-specific PCR. BKV testing was carried out both in cases of local clinical symptoms (cystitis, encephalitis, graft failure etc.), and as a routine screening. Tests were positive in 166 (78%) cases and negative in 45 patients (2%). Altered graft functioning was evaluated as follows: primary graft failure (PGF) was identified in absence of donor hematopoiesis without clinical relapse; secondary graft hypofunction (SGH) was determined as post-engraftment cytopenia with sustained donor chimerism, or as a persisting dependence on transfusions and CSF injections with full donor chimerism and no signs of tumor relapse.

Results

Poor graft function was observed in 194 patients (59% of total); primary graft failure (PGF) was documented in 21 cases (6.4%); secondary graft hypofunction (SGH) was revealed in 172 patients (52.4%). BKV reactivation was found in 163 patients, including 42 cases with normally functioning graft, primary graft failure was diagnosed in 10 cases, whereas 111 patients exhibited SGH. BKV detection in bone marrow was a risk factor for SGH, as shown by a single-factor analysis. In the patients with BKV reactivation (n=163), PGF and SGH frequency was respectively 6.8% (n=11) and 68% (n=112). Among patients without BKV reactivation (n=56), PGF was reported in 1.7% (n=1), and SGH, in 46.4% (n=26, p < 0.002), as shown in Fig.2. In SGH cases, the median time for BKV detection was 46 days, thus preceding the onset of graft hypofunction (a median of 52 days). BKV reactivation episodes were observed within 14 days before the onset, or during graft hy ofunction in 74 patients (43% of the SGH group, or 22.5% of the total HSCT cohort). Meanwhile, bone marrow samples were positive for BKV in 46 patients, i.e., 27% of all SGH cases, or 14% of total allo-HSCT cohort. However, BKV reactivation (including bone marrow affection) did not correlate with total survival after HSCT.

Conclusion

Post-transplant BKV infection may be a predisposing or triggering factor in the development of hematopoietic graft hypofunction. Further studies are required in order to obtain more detailed information about BKV replication in bone marrow and its potential effects upon post-HSCT survival.

References

1. Erard V, Storer B, Corey L, Nollkamper J, Huang M-L, Limaye A, et al. BK virus infection in hematopoietic stem cell transplant recipients: frequency, risk factors, and association with postengraftment hemorrhagic cystitis. Clin Infect Dis 2004; 39: 186

2. Reploeg MD, Storch GA, Clifford DB. BK virus: a clinical review. Clin Infect Dis 2001; 33:191-202.

3. Pambrun E, Mengelle C, Fillola G, Laharrague P, Esposito L, Cardeau-Desangles I, Del Bello A, Izopet J, Rostaing L, Kamar N. An association between BK virus replication in bone marrow and cytopenia in kidney-transplant recipients. J Transplant 2014; 2014:252914. doi: 10.1155/2014/252914.

4. Dropulic LK, Jones RJ. Polyomavirus BK infection in blood and marrow transplant recipients. Bone Marrow Transplantation 2008; 41:11–18

Keywords

Allogeneic hematopoietic cell transplantation, bk polyomavirus, reactivation, graft insufficiency