Steep Neutrophil Recovery following Unrelated Bone Marrow Transplantation is a Major Risk Factor for the Development of Acute Graft-Vs-Host Disease
Transplant international : official journal of the European Society for Organ Transplantation. 2020
The speed of neutrophil recovery following allogeneic hematopoietic cell transplantation (allo-HCT) varies widely among patients. We retrospectively evaluated the slope of neutrophil recovery (N slope) in 120 patients who underwent a first unrelated bone marrow transplantation with granulocyte-colony stimulating factor support between 2009 and 2018. The median N slope was 205.5 /µL/day. We classified patients into low (n = 59) and high (n = 61) N slope groups with a cut-off value of 200 /µL/day. The high N slope group correlated with older patients, RIC regimen, high CD34+ cells and recent transplantation. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was significantly higher in the high N slope group than in the low N slope group (44.3% vs. 16.9%, P < 0.001). In multivariate analysis, high N slope was identified as a significant independent risk factor for grade II to IV aGVHD, irrespective of the involved organs. There were no differences in relapse, non-relapse mortality, or overall survival between the two groups. In conclusion, the difference in N slope after allo-HCT may predict the risk of aGVHD. Prevention and treatment of GVHD according to the changes in the neutrophil count may improve post-transplant complications.
Functional and phylogenetic alterations in gut microbiome are linked to graft-versus-host disease severity
Blood advances. 2020;4(9):1824-1832
Acute graft-versus-host disease (aGVHD) is the main complication of hematopoietic stem cell transplantation (HSCT). Changes in gut microbiota composition have been associated with subsequent aGVHD, and reconstitution of healthy microbiota is currently being explored as a therapeutic approach. However, the specific actors in the intestinal ecosystem involved in the pathologic process at the time of aGVHD onset are not yet fully known. We prospectively collected stool samples from patients who underwent allogeneic HSCT. Patients sampled at aGVHD onset were compared with non-GVHD patients. To identify phylogenetic and functional signatures of the disease process, we determined fecal short-chain fatty acid (SFCA) profiles and used high-throughput DNA sequencing and real-time quantitative polymerase chain reaction to assess the microbiota composition. Microbiota alterations were highly specific of gastrointestinal (GI) aGVHD severity. Bacterial biomass and alpha-diversity were lower in severe aGVHD. We identified several bacterial signatures associated with severe aGVHD at disease onset; a negative correlation was observed with anaerobic bacteria of the Lachnospiraceae, especially the Blautia genus, and Ruminococcaceae families. In parallel, in severe aGVHD patients, we showed a dramatic decrease in the levels of the main SFCAs: acetate (75.8%), propionate (95.8%), and butyrate (94.6%). Mild aGVHD patients were characterized by conserved levels of propionate and Blautia propionate producers. Butyrate was significantly decreased in all GI aGVHD stages, representing a potential diagnostic marker of the disease. Specific microbiota and metabolic alterations were thus associated with aGVHD severity and may be useful for diagnostic and pathophysiologic purposes.
Post-transplant cyclophosphamide versus anti-thymocyte globulin for graft-versus-host disease prevention in haploidentical transplantation for adult acute lymphoblastic leukemia
Graft-versus-host disease (GVHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation (haplo-HCT) include post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing EBMT registry, we compared ATG versus PTCy based GVHD prophylaxis in adult acute lymphoblastic leukemia (ALL) patients undergoing haplo-HCT. Included were 434 patients; ATG (n=98) and PTCy (n=336). Median follow-up was ~2 years. Baseline characteristics were similar between the groups except that the ATG-group was more likely to have relapsed/refractory ALL (P=0.008), non-TBI conditioning (P<0.001), peripheral blood graft source (P=<0.001) and transplanted at an earlier time-period (median year of HCT 2011 vs. 2015). The 100-day grade II-IV and III-IV acute-GVHD was similar between ATG and PTCy, as was 2-year chronic-GVHD. On multivariate analysis (MVA), leukemia-free survival (LFS) and overall survival (OS) was better with PTCy compared to ATG prophylaxis. Relapse incidence (RI) was lower in the PTCy group (P=0.03), while non-relapse mortality (NRM) was not different. Advanced disease and lower performance score were associated with poorer LFS and OS and advanced disease with inferior GVHD-free/relapse-free survival (GRFS). Peripheral grafts were associated with higher GVHD compared to bone marrow grafts. In ALL patients undergoing unmanipulated haplo-HCT, PTCy for GVHD prevention resulted in lower RI and improved LFS and OS compared to ATG.
Differential microRNAs expression in acute graft-versus-host disease as potential diagnostic biomarkers
Bone marrow transplantation. 2020
Retrospective multicenter study of extracorporeal photopheresis in steroid-refractory acute and chronic graft-versus-host disease
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
BACKGROUND Extracorporeal photopheresis (ECP) is an established treatment strategy in steroid-refractory GvHD. This study's main objectives were to analyze the clinical response and impact of ECP therapy in steroid dose reduction. STUDY DESIGN AND METHODS A retrospective observational series of 113 patients from 7 transplant centers was analyzed. 65 patients (58%) had acute GvHD (aGvHD) and 48 (42%) chronic GvHD (cGvHD). All ECP procedures were performed with the off-line system. RESULTS The median number of procedures until initial response was 3, for both aGvHD and cGvHD. ECP was the second-line therapy in 48% of aGvHD cases and 50% in cGvHD. 71% of the cases of aGvHD were grade 3-4 and 69% of the cases of cGvHD were severe. The overall response rate on day 28 in aGvHD was 53% (CR 45%), whereas in cGvHD it was 67% (CR 23%). Skin was the most involved organ, with a response rate of 58% (CR 49%) in aGvHD and 69% (CR 29%) in cGvHD. At the end of ECP treatment, 60% of patients treated for aGvHD that responded were able to stop steroids, with a median dose reduction of 100%. Significant OS differences were observed for patients responding to ECP in aGvHD (HR=4.3, p<0.001) and cGvHD (HR=4.8, p=0.003) patients. CONCLUSIONS ECP is a valid therapeutic alternative in patients with steroid-refractory acute and chronic GvHD, permitting significant steroid dose reductions.
Patients with haematological malignancies, with steroid-refractory GvHD following allo-SCT (n=113)
Patients with acute GvHD (aGvHD, n=65) were compared with patients with chronic GvHD (cGvHD, n=48)
The overall response rate on day 28 in aGvHD was 53% (CR 45%), whereas in cGvHD it was 67% (CR 23%). Skin was the most involved organ, with a response rate of 58% (CR 49%) in aGvHD and 69% (CR 29%) in cGvHD. At the end of ECP treatment, 60% of patients treated for aGvHD that responded were able to stop steroids, with a median dose reduction of 100%. Significant OS differences were observed for patients responding to ECP in aGvHD and cGvHD patients.
Extracorporeal photopheresis for graft versus host disease: A literature review and treatment guidelines proposed by the Nordic ECP Quality Group
European journal of haematology. 2020
Extracorporeal photopheresis (ECP) is one of the most used and established therapies for steroid-refractory graft versus host disease (GvHD), with a good effect to side effect profile. In this review we present a summary of present literature and provide evidence-based treatment guidelines for ECP in GvHD. The guidelines constitute a consensus statement formed by the Nordic ECP Quality Group representing all ECP centres in the Nordic countries, and aims to facilitate harmonization and evidence based practise. In developing the guidelines, we firstly conducted a thorough literature search of original articles and existing guidelines. In total, we identified 26 studies for ECP use in acute GvHD and 36 in chronic GvHD. The studies were generally small, retrospective and heterogeneous regarding patient characteristics, treatment schedule and outcome assessment. In general, a majority of patients achieved partial response or better, but response rates varied by the organs affected. Head to head comparisons to other treatment modalities were lacking. Overall, we consider the quality of evidence to be low-moderate (GRADE) and encourage future prospective multi-armed trials to strengthen the present recommendations. However, despite limitations in evidence strength, standardized treatment schedules and regular follow-up are imperative to ensure the best possible patient outcome.
Role of HLA-DP Expression in Graft-Versus-Host Disease After Unrelated Donor Transplantation
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;:Jco2000265
PURPOSE The main aim of this study was to evaluate the significance of HLA-DPB1 expression in acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) from HLA-A, -B, -C, -DRB1, -DQB1-matched and -mismatched unrelated donors. PATIENTS AND METHODS Between January 1, 2017, and January 10, 2019, we assessed 19,136 patients who received HCT from an HLA-A, -B, -C, -DRB1, -DQB1-matched or -mismatched unrelated donor performed in Australia, the European Union, Japan, North America, and the United Kingdom between 1988 and 2016. Among transplant recipients with one HLA-DPB1 mismatch, the patient's mismatched HLA-DPB1 allotype was defined as low or high expression. Multivariable regression models were used to assess risks of GVHD associated with high expression relative to low expression HLA-DPB1 mismatches. The effect of increasing numbers of HLA-DPB1 mismatches on clinical outcome was assessed in HLA-mismatched transplant recipients. RESULTS In HLA-A, -B, -C, -DRB1,-DQB1-matched transplant recipients, donor mismatching against one high-expression patient HLA-DPB1 increased moderate (odds ratio [OR], 1.36; P = .001) and severe acute GVHD (OR, 1.32; P = .0016) relative to low-expression patient mismatches, regardless of the expression level of the donor's mismatched HLA-DPB1. Among transplant recipients with one HLA-A, -B, -C, -DRB1, or -DQB1 mismatch, the odds of acute GVHD increased with increasing numbers of HLA-DPB1 mismatches (OR, 1.23 for one; OR, 1.40 for two mismatches relative to zero mismatches for moderate GVHD; OR, 1.19 for one; OR, 1.40 for two mismatches relative to zero for severe GVHD), but not with the level of expression of the patient's mismatched HLA-DPB1 allotype. CONCLUSION The level of expression of patient HLA-DPB1 mismatches informs the risk of GVHD after HLA-A, -B, -C, -DRB1, -DQB1-matched unrelated HCT, and the total number of HLA-DPB1 mismatches informs the risk of GVHD after HLA-mismatched unrelated HCT. Prospective consideration of HLA-DPB1 may help to lower GVHD risks after transplantation.
Nilotinib in steroid-refractory cGVHD: prospective parallel evaluation of response, according to NIH criteria and exploratory response criteria (GITMO criteria)
Bone marrow transplantation. 2020
We conducted a phase I-II study to evaluate Nilotinib (NIL) safety and pharmacokinetics in 22 SR-cGVHD patients; we also evaluated ORR by using in parallel NIH criteria and an exploratory approach, combining objective improvement (OI) without failure criteria (GITMO criteria). Results: 22 patients were enrolled. After dose escalation up to 600 mg/day, MTD was not reached. Main toxicities were asthenia, headache, nausea, pruritus, cramps, and mild anemia. Mean and median plasma concentrations of NIL (C-NIL) were 817 (SD +/- 450) and 773 ng/ml. ORR at 6 months, according to 2005 and 2014 NIH and GITMO criteria were 27.8%, 22.2%, and 55.6% respectively; close correspondence has been observed for ORR, according to 2014 NIH criteria, both assessed in a conventional way and assisted by dedicated software (CROSY). At 48 months OS was 75% while FFS, according to NIH and GITMO criteria, was 30 and 25%. In conclusion the safety profile of NIL and long-term outcome makes NIL an attractive option in SR-cGVHD. Exploratory GITMO criteria could represent an alternative tool for easy response evaluation in patients with prevalent skin and lung involvement, but require validation in a larger population; CROSY software showed excellent reliability in capturing ORR according to the 2014 NIH criteria.
Weight-based Mycophenolate Mofetil Dosing Predicts Acute GVHD and Relapse after Allogeneic Hematopoietic Cell Transplantation
European journal of haematology. 2020
OBJECTIVES Higher MMF dose can reduce acute GVHD risk after allogeneic hematopoietic cell transplantation (HCT). We examined the effect of MMF dose, relative to patient actual body weight (mg/kg/day), on outcomes of 680 adults after HCT. METHODS MMF was combined with cyclosporine (n=599) or sirolimus (n=81). We divided MMF dose/kg/day in quartiles. RESULTS The median time to grade II-IV acute GVHD was 32 days. The incidence of grade II-IV acute GVHD at day 30 was 30% in 1st (<29), 20% in 2nd (29-34), 16% in 3rd (35-41), and 19% in 4th (≥42) quartile (p<0.01). Corresponding relapse incidence at 1 year was 16%, 25%, 27%, and 31%, respectively (p=0.01). In multivariate analysis, as compared to 1st quartile, higher dose of weight-based MMF reduced grade II-IV acute GVHD (HR=0.64 for 2nd, HR=0.48 for 3rd, and HR=0.55 for 4th quartile), but increased the risk of relapse (HR=1.63 for 2nd, HR=1.75 for 3(rd) , and HR=2.31 for 4th quartile). CONCLUSIONS Weight-based MMF dose had no significant impact on engraftment, chronic GVHD or survival. These data suggest that higher weight-based MMF dose reduces the risk of acute GVHD at the expense of increased relapse and support conducting prospective studies to optimize MMF dosing after HCT.
Trajectories of acute graft-versus-host disease and mortality in critically ill allogeneic-hematopoietic stem cell recipients: the Allo-GRRR-OH score
Bone marrow transplantation. 2020
Acute graft-versus-host disease (aGVHD) is a major cause of morbidity mortality in critically ill hematopoietic stem cell transplantation recipients. We assessed aGVHD trajectories in 191 allogeneic-HSCT recipients (age 42 (27-46)) admitted to our ICU between 2005 and 2015. aGVHD affected 130 (68%) patients (including 90% who underwent steroid therapy at a dose of 2 (2-2) mg/kg) and was graded 3 or 4 in 31% of the patients. Trajectories of aGVHD were clustered in four groups: (1) no aGVHD, (2) controlled aGVHD, (3) uncontrolled aGVHD (active, stable, or worsening), and (4) newly diagnosed and untreated aGVHD. Patients with controlled aGVHD and those admitted at the onset of aGVHD had similar survival than patients who never experienced aGVHD. By multivariable analysis, the dynamic assessment of aGVHD was independently associated with 90-day mortality, in addition to the admission to the ICU for acute respiratory failure, acute kidney injury or acute liver failure, and sepsis-related organ failure assessment score at admission. In conclusion, these findings suggest that GVHD cannot be assessed as a binary variable and at a single time point. Patients in whom GVHD is not uncontrolled with corticosteroids should have the same goals of ICU care than patients without GVHD.