Sabine Gerull

Evidence for a Bidirectional Relationship between Cytomegalovirus Replication and acute Graft-versus-Host Disease

Cytomegalovirus (CMV) infection and graft-versus-host disease (GVHD) are important complications after allogeneic hematopoietic stem cell transplantation (HSCT) with a clear link. Multiple studies show that GVHD and its treatment put patients at risk for CMV replication. Data on CMV replication as a cause of GVHD, in contrast, are controversial. We analyzed the reciprocal association of CMV replication with acute GVHD (aGVHD) in 515 patients treated with allogeneic HSCT between 1993 and 2008. Cumulative incidences at day 100 were 17% for CMV replication, 68% for aGVHD grade I-IV, and 48% for GVHD grade II-IV. Multivariate time-dependent analyses revealed that the presence of GVHD increased the risk of CMV replication in a dose-dependent manner: hazard ratio (HR) for CMV replication for patients with aGVHD grade I was 1.35 (95% confidence interval [CI] 0.82-2.21); HR for patients with aGVHD grade II-IV was 1.61 (95% CI 1.11-2.36, P-value for trend = .01). During phases of CMV replication, patients were at increased risk of developing aGVHD (HR 2.18, 95% CI 1.30-3.65, P < .01). These data confirm that GVHD and its therapy can induce CMV replication. They further demonstrate the reciprocal novel finding that patients are at significantly increased risk of developing aGVHD during CMV replication.

Lymphocyte subset recovery and outcome after T-cell replete allogeneic hematopoietic SCT.

Rapid recovery of lymphocytes after T-cell depleted hematopoietic SCT (HSCT) protects from relapse of myeloid malignancies. Whether lymphocyte reconstitution has a similar role after non-manipulated transplantation is controversial. We assessed numbers of CD4 and CD8 T-cells, natural killer (NK) cells and B-cells, before and 1, 3, 6, 12 and 24 months after T-cell replete transplantation in 345 patients. Lymphocyte subset counts up to 6 months post transplant had no effect on relapse. Elevated number of NK cells 12 months post transplant protected from relapse. As a novel finding, early recovery of NK cells was associated with significant protection from TRM already at the 3 and 6 months time points (P=0.03, P=0.02). In Cox multivariable models, patients with NK cells above 150/μL were significantly protected from TRM (hazard ratio (HR) 0.45, 95% confidence interval (95% CI) 0.21–0.95, P=0.03), an effect comparable in magnitude with that of carrying >200 CD4 T-cells/μL (HR 0.37, 95% CI 0.19–0.74, P=0.005). CD8 T-cell and B-cell recovery did not affect the rates of relapse or TRM. Early reconstitution of NK cells and CD4 T-cells in patients undergoing T-cell replete HSCT independently protected from TRM. Only a weak protection from disease relapse was noted for patients with high numbers of NK cells, and this occurred only late after transplantation.

Order of application and liver toxicity in patients given BU and CY containing conditioning regimens for allogeneic hematopoietic SCT

BU–CY is the established non-TBI-based myeloablative conditioning regimen for allogeneic hematopoietic SCT. However, liver toxicity and hepatic veno-occlusive disease (VOD) are frequent life-threatening complications. Pharmacological considerations suggest that BU can trigger toxicity of subsequent CY. Recent animal data confirmed this hypothesis. Less liver toxicity and better outcomes were observed when mice were treated with the reversed order of CY and BU. We analyzed in this study liver toxicity and outcome in patients receiving BU–CY (16 patients) or CY–BU (59 patients). Liver function differed significantly with higher levels of liver function tests between day +10 and +30, and a higher cumulative incidence of VOD in the BU–CY cohort (2/16 (12.5%) vs 0/59 (0%), P=0.006). TRM was significantly higher in patients receiving BU–CY (cumulative incidence BU–CY 45%, CY–BU 17%, P=0.02), without yet translating into a significant survival difference (incidence for survival: BU–CY 38%, CY–BU 63%; hazard ratio 1.19 for BU–CY, 95% confidence interval 0.29–4.82, P=0.80). Rates of engraftment and relapse were not different. These data support the concepts derived from animal models in favor of CY–BU compared with traditional BU–CY and form the basis for prospective controlled comparisons.

Prognostic impact of iron parameters in patients undergoing allo-SCT

Iron overload contributes to increased transplant-related mortality, and serum ferritin is typically used to detect iron overload. Other iron parameters have received limited attention. We studied serum ferritin, transferrin, transferrin saturation, iron, soluble transferrin receptor (sTfR) and C-reactive protein (CRP) levels in 230 consecutive patients undergoing myeloablative allo-SCT. All iron parameters were significantly associated with survival. When analyzed individually, both sTfR and transferrin saturation were superior in prognostic power to ferritin (areas under the curve in receiver operating characteristic analysis: 0.670, 0.715, and 0.657, respectively). A combination of ferritin and transferrin saturation had the highest prognostic power: Patients with ferritin below the 30th percentile (<802u2009ng/mL) showed excellent survival (70±6% at 5 years), while transferrin saturation above the 80th percentile (⩾69%) pointed to a high risk of transplant failure (5-year survival 5±5%). The remaining patients showed an intermediate outcome (5-year survival 52±5%). The prognostic impact of iron parameters was independent of other factors such as stage, conditioning regimen and CRP level, and operated similarly across diseases. Iron overload strongly influenced the outcome of allo-SCT. Low pre-transplant ferritin levels indicate a population at low risk, high transferrin saturations and a subgroup of patients with very poor outcome.

Syngeneic transplantation in aplastic anemia: pre-transplant conditioning and peripheral blood are associated with improved engraftment: an observational study on behalf of the Severe Aplastic Anemia and Pediatric Diseases Working Parties of the European Group for Blood and Marrow Transplantation

Aplastic anemia is usually treated with immunosuppression or allogeneic transplant, depending on patient and disease characteristics. Syngeneic transplant offers a rare treatment opportunity with minimal transplant-related mortality, and offers an insight into disease mechanisms. We present here a retrospective analysis of all syngeneic transplants for aplastic anemia reported to the European Group for Blood and Marrow Transplantation. Between 1976 and 2009, 88 patients received 113 transplants. Most transplants (n=85) were preceded by a conditioning regimen, 22 of these including anti-thymocyte globulin. About half of transplants with data available (39 of 86) were followed by posttransplant immunosuppression. Graft source was bone marrow in the majority of cases (n=77). Transplant practice changed over time with more transplants with conditioning and anti-thymocyte globulin as well as peripheral blood stem cells performed in later years. Ten year overall survival was 93% with 5 transplant-related deaths. Graft failure occurred in 32% of transplants. Risk of graft failure was significantly increased in transplants without conditioning, and with bone marrow as graft source. Lack of posttransplant immunosuppression also showed a trend towards increased risk of graft failure, while anti-thymocyte globulin did not have an influence. In summary, syngeneic transplant is associated with a significant risk of graft failure when no conditioning is given, but has an excellent long-term outcome. Furthermore, our comparatively large series enables us to recommend the use of pre-transplant conditioning rather than not and possibly to prefer peripheral blood as a stem cell source.

Forty years of haematopoietic stem cell transplantation: a review of the Basel experience

The purpose of this study was to examine changes in haematopoietic stem cell transplant (HSCT) characteristics and outcome in our combined paediatric and adult programme over the past four decades, since its implementation in 1973. The total number of transplant procedures rose from 109 in the first decade (1973-82) to 939 in the last decade (2003-12). Transplant characteristics changed significantly over time: patient age increased, peripheral blood largely replaced bone marrow as stem cell source, unrelated donors became an alternative to matched siblings, and patients are increasingly transplanted in more advanced disease stages. Advances such as improved supportive care and histocompatibility typing resulted in a steady decrease of transplant-related mortality after allogeneic HSCT (43% in the first decade, 22% in the last decade). Despite this, unadjusted survival rates were stable in the last three decades for allogeneic HSCT (approximately 50% 5-year survival) and in the last two decades for autologous HSCT (approximately 60% 5-year survival). After adjustment for covariates such as donor type, age and stage, the relative risk of treatment failure continuously dropped (for allogeneic HSCT: first decade 1.0, second decade 0.58, third decade 0.51, last decade 0.41). Collectively, these data suggest that improvements in peri- and post-transplant care have allowed considerable extension of transplant indications without having a negative impact on outcome.

Community-Acquired Respiratory Paramyxovirus Infection After Allogeneic Hematopoietic Cell Transplantation: A Single-Center Experience

Abstract Background Paramyxoviruses include respiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (MPV), which may cause significant respiratory tract infectious disease (RTID) and mortality after allogeneic hematopoietic cell transplantation (HCT). However, clinical data regarding frequency and outcome are scarce. Methods We identified all paramyxovirus RTIDs in allogeneic HCT recipients diagnosed by multiplex polymerase chain reaction between 2010 and 2014. Baseline characteristics of patients, treatment, and outcome of each episode were analyzed; ie, moderate, severe, and very severe immunodeficiency (verySID) according to HCT ≤6 months, T- or B-cell depletion ≤3 months, graft-versus-host disease, neutropenia, lymphopenia, or hypo-gammaglobulinemia. Results One hundred three RTID episodes in 66 patients were identified (PIV 47% [48 of 103], RSV 32% [33 of 103], MPV 21% [22 of 103]). Episodes occurred in 85% (87 of 103) at >100 days post-HCT. Lower RTID accounted for 36% (37 of 103). Thirty-nine percent (40 of 103) of RTID episodes required hospitalization and more frequently affected patients with lower RTID. Six percent progressed from upper to lower RTID. Overall mortality was 6% and did not differ between paramyxoviruses. Sixty-one percent (63 of 103) of episodes occurred in patients with SID, and 20.2% (19 of 63) of episodes occurred in patients with verySID. Oral ribavirin plus intravenous immunoglobulin was administered in 38% (39 of 103) of RTIDs, preferably for RSV or MPV (P ≤ .001) and for SID patients (P = .001). Patients with verySID frequently progressed to lower RTID (P = .075), required intensive care unit transfer, and showed higher mortality. Conclusion Paramyxovirus RTID remains a major concern in allogeneic HCT patients fulfilling SID and verySID, emphasizing that efficacious and safe antiviral treatments are urgently needed.

Calcineurin inhibitors in bronchiolitis obliterans syndrome following stem cell transplantation

Bronchiolitis obliterans is a complication after allogeneic haematopoietic stem cell transplantation (HSCT). Management of bronchiolitis obliterans comprises intensive immunosuppression, but treatment response is poor. We investigated the effect of cyclosporine A (CsA), tacrolimus (FK506), methylprednisolone (mPRED), mycophenolate mofetil (MMF) and everolimus on the proliferation of primary lung myofibroblasts from HSCT patients with bronchiolitis obliterans syndrome (BOS). Cells were isolated from surgical lung biopsies of eight HSCT patients with BOS. Proliferation was assessed by [3H]-thymidine incorporation. Biopsies revealed constrictive bronchiolitis obliterans in three patients and lymphocytic bronchiolitis in five patients. CsA and FK506 significantly induced proliferation of myofibroblasts. mPRED and MMF caused a significant inhibition of proliferation, whereas everolimus had no effect. Costimulation with FK506, mPRED and MMF significantly inhibited proliferation. Serial pulmonary function tests over 12 months after lung biopsy and under triple therapy demonstrated that patients with lymphocytic bronchiolitis had a significant improvement in forced expiratory volume in 1 s (FEV1), whereas FEV1 of patients with bronchiolitis obliterans was unchanged. Our data demonstrate a pro-proliferative effect of calcineurin inhibitors on primary human lung myofibroblasts obtained from patients with BOS after HSCT. In contrast, based on the observed antiproliferative capacity of MMF in vitro, MMF-based calcineurin inhibitor-free treatment strategies should be further evaluated in patients with bronchiolitis obliterans after HSCT. Calcineurin inhibitor-free regimens need further evaluation in bronchiolitis obliterans after stem cell transplantation http://ow.ly/qeKha

Allogeneic Stem Cell Transplantation for Relapsed or Refractory Lymphoma after Conditioning with BEAM/Fludarabine/TBI

Allogeneic stem cell transplant (SCT) after high-dose conditioning with BEAM/fludarabine/total body irradiation (TBI) in patients with relapsed or refractory lymphoma has shown promising results in a pilot study. In this trial, we treated 50 consecutive patients with refractory or relapsed lymphoma or chronic lymphocytic leukemia (CLL). The patients included were considered to have poor-prognosis disease (eg, one-third was chemo-refractory at transplantation and more than one-half had failed previous autologous or allogeneic SCT). All patients engrafted and achieved full donor chimerism. Grade II-IV acute graft-versus-host disease (aGVHD) occurred in 64% of patients (95% confidence interval [CI], 52% to 79%), and chronic GVHD (cGVHD) in 51% (95% CI, 36% to 66%). At 3 years, overall survival was 61% (95% CI, 46% to 75%). Progression-free survival was 55% (95% CI, 40% to 70%), with 30% (95% CI, 19% to 47%) transplantation-related mortality and a relapse incidence of 15% (95% CI, 7% to 32%). Disease classification and stage as well as remission status at transplantation and type of previous treatment (including previous SCT) had no significant impact on transplantation outcome. In conclusion, allogeneic SCT after BEAM/fludarabine/TBI provides excellent tumor control with complete and durable remissions in patients with poor-prognosis lymphoma and CLL. High rates of GVHD and GVHD-related mortality associated with this regimen are a major concern and warrant modification of the regimen in the future.

Cyclosporine levels and rate of graft rejection following non-myeloablative conditioning for allogeneic hematopoietic SCT.

Hematopoietic SCT (HSCT) after non-myeloablative conditioning is associated with reduced TRM, and increased risk of graft rejection. Although preclinical data have shown the importance of post transplant immunosuppression in achieving engraftment, little is known about the role of CSA in the clinical setting of non-myeloablative transplantation. In a retrospective analysis of patients treated with allogeneic HSCT after fludarabine and 2u2009Gy TBI, 15 of 77 evaluable patients (20%) experienced primary (n=2) or secondary graft rejection at a median of 66 days post transplant. Mean day 1–28 CSA trough levels were inversely associated with day 28 chimerism (median 99, 85 and 70% for mean CSA <300, 300–600 and >600u2009ng/mL, respectively; P=0.003). A similar association was observed for the cumulative incidence of graft rejection, which occurred in 8% (<300u2009ng/mL), 26% (300–600u2009ng/mL) and 50% (>600u2009ng/mL, P=0.005) of patients. The detrimental effect of high CSA levels on engraftment was confirmed in multivariable models and was found to operate comparably in sibling and unrelated donor transplants. Impairment of donor T-cell function by high serum levels of CSA might account for this finding, which should be verified in a larger patient group to better understand the role of CSA in non-myeloablative transplantation.