High incidence of severe chronic GvHD after HSCT with sibling donors. A single center analysis

For decades, HLA-identical sibling donor has been the gold standard for choice of donor. Many studies have compared HSCT using matched unrelated donors (URD) and HLA-identical sibling donors. Nowadays, the results of transplantation in these two groups are generally comparable. However, some studies have found a higher incidence of chronic GvHD when sibling donors were used, which is troublesome, as chronic GvHD in its most severe forms is potentially life-threatening and the factor most commonly associated with poor quality of life after HSCT.1 In this study we wanted to evaluate these two HSCT strategies: A) using sibling donors without anti-thymocyte globulin (ATG) and lower cyclosporine A (CsA) concentrations vs B) using URD including ATG and higher CsA concentrations for a longer time.

Furthermore, we wanted to determine the incidence, severity and risk factors for chronic GvHD after sibling donor and URD HSCT.

We studied 537 consecutive adult patients transplanted for a malignant disease between the years 2000 and 2014 either with an HLA-identical sibling donor not receiving ATG (n=187) or with an HLA-A, -B and -DR matched unrelated donor (URD) receiving ATG [Thymoglobulin, Genzyme, 4–8 mg/kg (n=350)]. The study was approved by the research ethics committee of Karolinska Institutet (DNR 425/97). Patient and donor characteristics are listed in Table 1.

Table 1 Patient and donor characteristics

The majority of patients received CsA and methotrexate as GvHD prophylaxis.2 During the first month, the target blood CsA levels were 100 ng/mL in patients with a sibling donor and at 200–300 ng/mL in patients with an URD. In the absence of GvHD, CsA was discontinued at 3 months if a sibling donor was used and at 6 months if a URD was used. Sirolimus, plasma target levels of 3–12 ng/mL, was discontinued at three months. Tacrolimus, plasma target concentration of 5–15 ng/mL, was discontinued at four months for sibling donor and at six months for URD transplants.

All patients and donors were typed using high-resolution molecular typing (that is, PCR-SSP) for HLA-A, -B, -C and -DR Ags (at the 4-digit level). In the URD cohort, 84 donors were HLA-C mismatched. Supportive care has been described in detail previously.3

Both acute GvHD and chronic GvHD were diagnosed on the basis of clinical symptoms and/or biopsies (skin, liver, gastrointestinal tract or oral mucosa) according to standard criteria.1, 4 Severity of chronic GvHD was assessed according to National Institutes of Health criteria and graded as mild, moderate or severe.5

Overall survival (OS) was calculated using the Kaplan–Meier method and it was compared using the log-rank test. Transplant-related mortality (TRM), GvHD and relapse were estimated using cumulative incidence curves. Univariate and multivariate risk-factor analyses for chronic GvHD were performed using the proportional subdistribution hazard regression model developed by Fine and Gray. Factors analyzed were patient and donor age, disease stage, donor type, graft cell-dose, graft source, conditioning, GvHD prophylaxis, AB0-compatibility, CMV-serology and female-donor-to-male recipient (FtoM). All multivariate analyses were corrected for a year of HSCT.

The main findings were that HSCTs with sibling donors resulted in significantly better 5-year OS (66 vs 58%, P<0.05) and relapse-free survival (60 vs 50%, P=0.025) compared to patients with a URD. However, TRM (17 vs 21%, P=0.48) and relapse (24 vs 30%, P=0.13) were similar. In contrast, other recent studies have found similar outcomes after URD HSCT compared to sibling donor HSCT.6, 7

The cumulative incidences of acute GvHD of grades II–IV and III–IV were 47 and 19% in patients with a sibling donor and 38 and 7% in patients with an URD (P=0.04 and P<0.001), respectively.

The cumulative 5-year incidence of chronic GvHD was higher in the sibling donor cohort (57 vs 28%, P<0.001) (Figure 1a). Also, the incidence of severe chronic GvHD was higher after sibling donor HSCT (12.4 vs 2.5%, P<0.001) (Figure 1a).

Figure 1
figure1

(a) Cumulative incidences of overall chronic GvHD (solid lines) and severe chronic GvHD (dotted lines) after HSCT in patients with sibling or unrelated donors. (b) Survival without relapse, severe acute and severe chronic GvHD (GRFS) after HSCT in patients with sibling or unrelated donors, (c) Cumulative incidence of severe chronic GvHD after HSCT in patients with sibling donors, according to the number of risk factors found in the multivariate analysis. Risk factors were a CD34+ cell-dose >9.5 × 106/kg, age <50 years, and immunized female-donor-to-male recipient, (d) Overall survival according to severity of chronic GvHD after HSCT in patients with sibling donors. Only patients surviving more than 100 days are included. A full color version of this figure is available at the Bone Marrow Transplantation journal online.

However, survival without relapse, severe acute and chronic GvHD (GRFS) was 49% in the sibling cohort and 48% in the URD cohort, P=0.80 (Figure 1b).

Presence of an HLA-C mismatch did not influence the incidence of chronic GvHD or any other outcomes among patients with URD. The reason for the lower incidence and severity of chronic GvHD after URD HSCT is therefore probably associated to the immunosuppressive concept used in the two cohorts. One part of this concept is that we have used ATG in URD HSCT.8 We chose to use ATG due to an expected higher risk for GvHD. This most likely led to a low incidence of GvHD at our center. Several studies have shown a strong effect of ATG on the incidence of cGvHD.9, 10, 11, 12, 13, 14 ATG removes T-cells from the graft, reducing the risk of both acute GvHD and chronic GvHD, but it may increase the risk of infections.12, 15 In our URD cohort, death due to infections was more common (11 vs 3% in the sibling cohort, P=0.005), which may be attributed to the use of ATG or to the higher ATG dose used in the early days of this study. The dose of ATG has been shown to be of crucial importance.8, 15

In the URD cohort, low dose ATG (<6.5 mg/kg, n=307) was associated to more acute GvHD grades II–IV (41 vs 16%, P=0.002) and a trend for less relapse-related mortality (18% vs 28%, P=0.09) compared to high dose ATG (6.5 mg/kg, n=43).

Another part of the used URD concept that may have resulted in the lower incidence of cGvHD is that patients with URDs receive longer immunosuppression, up to 6 months, as compared to 3 months in patients with sibling donors. Furthermore, the target CsA concentration was higher in patients with an URD.

Severe chronic GvHD was associated with a significantly higher incidence of TRM (30 vs 11% in all others, P<0.05). It is well known that these patients have an increased risk of fatal infections.16 Other possible fatal complications include severe malnutrition, bronchiolitis obliterans, secondary tumors or other types of severe organ failure.

Factors associated with severe chronic GvHD in multivariate analysis of the combined sibling and unrelated donor cohorts were the patient's age (per decade) (RH 0.73, 95% CI 0.53–0.99, P<0.05), immunized FtoM (ImmFtoM) (RH 3.11, 95% CI 1.40–6.90, P=0.005) and having a sibling donor (RH 4.40, 95% CI 1.83–10.5, P<0.001).

As well as, all grades as severe chronic GvHD were more common after sibling donor HSCT, we evaluated factors associated with chronic GvHD in this cohort of patients in more detail. Factors associated with severe chronic GvHD were patient age <50y (HR 3.11, 95% CI 1.03–9.32, P=0.04), CD34+ cell-dose >9.5 × 106/kg (3rd quartile)(HR 3.16, 95% CI 1.16–8.57, P=0.02) and ImmFtoM (HR 3.97, 95% CI 1.42–11.1, P<0.01).

The incidence of severe chronic GvHD in patients with two (n=49) and three (n=3) of these risk factors was 27%. In patients with none or one of these risk factors, the incidences of severe chronic GvHD were 4.5 and 8.2%, respectively (Figure 1c). Severe chronic GvHD decreased from 18% in the period between 2000 and 2004 to 7% in the period between 2010 and 2014. One reason for this may be the increasing number of older patients (>50 years), a group with low incidence of severe cGvHD in this study.

A high CD34+ cell dose was associated with an increased incidence of severe chronic GvHD. We have previously found that a high CD34+ dose was associated with a lower OS.17 As there were very few bone marrow grafts in the sibling cohort (n=13) the high CD34+ cell dose probably reflects the use of PBSC, a factor well known to be associated with the incidence and severity of chronic GvHD.18, 19, 20 The higher T-cell dose is probably one reason.

An ImmFtoM was associated with an increased risk of severe chronic GvHD, both in the entire cohort and in patients with sibling donors. A female donor was defined as being immunized if she had been pregnant or had received blood transfusions. These female donors had possibly developed an immune response to minor histocompatibility Ags, which are a group of Y chromosome-encoded proteins (H-Y) in male recipients that may be recognized by T-cells of female donors.21 The ‘ImmFtoM’ situation may be associated with a stronger immune response than the ‘FtoM’ situation. In our study ‘ImmFtoM’, but not ‘non-ImmFtoM’, was associated with severe chronic GvHD.

The female-to-male situation has previously been reported to be associated with an increased risk of acute and chronic GvHD, and also with less relapse and higher TRM.22, 23

The severity of chronic GvHD affected OS and RFS in the sibling cohort. The best OS and RFS values were seen in patients with mild or moderate cGvHD (Figure 1d).

Comparing these two HSCT strategies (sibling donor vs URD) with different immunosuppressive strategies indicate that we probably over-immunosuppress patients with URD (ATG+higher CsA conc. for longer time). In keeping with this we have now reduced the dosages of ATG and CsA in HSCT with URD.

In this study, we have isolated a subgroup of patients with high risk for severe chronic GvHD. As severe chronic GvHD is associated with considerable morbidity and mortality, actions to reduce the incidence among patients at high risk must be considered. However, since the OS is better for patients with sibling donors, any change should be done carefully in larger prospective studies.

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Acknowledgements

This study was supported by grants from the Swedish Cancer Society (CF2014-2016), the Swedish Children’s Cancer Foundation (PR2013-0022 and KF2013-0011), the Marianne and Marcus Wallenbergs Foundation (2013.0117) and grants provided by the Stockholm County Council (ALF-project 20140451).

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Correspondence to M Remberger.

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Remberger, M., Afram, G., Sundin, M. et al. High incidence of severe chronic GvHD after HSCT with sibling donors. A single center analysis. Bone Marrow Transplant 51, 1518–1521 (2016). https://doi.org/10.1038/bmt.2016.159

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