Prophylactic Use of a Combination of an Anticoagulant and Ursodeoxycholic Acid for Sinusoidal Obstruction Syndrome after Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation

Sinusoidal obstruction syndrome (SOS) is a life-threatening early complication after hematopoietic stem cell transplantation (HSCT), and until now, examinations about the influence of genetic risk factors are extremely rare. The purpose of this study was to identify an association between heparanase (HPSE) single nucleotide polymorphisms (SNPs) and SOS in children undergoing allogeneic HSCT. We retrospectively analyzed the distribution of the both HPSE SNPs rs4693608 and rs4364254 and the occurrence of SOS after allogeneic HSCT in 160 children with malignant and non-malignant diseases. Patients with HPSE genotypes GG or AG of rs4693608 (G>A) had a significantly reduced incidence of SOS on day 100 after HSCT compared to patients with genotype AA (4.7 vs. 14.3 %, P = 0.038). In addition, incidence of SOS in patients with genotype CC or CT of rs4364254 (C>T) was significantly decreased in comparison with patients with genotype TT (2.3 vs. 14.7 %, P = 0.004). Interestingly, no patient with genotype CC developed SOS. Because both SNPs co-occur in vivo, we generated subsets: AA-TT, GG-CC, and a group with remaining SNP combinations. We found significant differences between all three patient groups (P = 0.035). Patients with AA-TT showed the highest incidence of SOS (16.7 %), while SOS did not appear in patients with GG-CC (0 %) and residual combinations were numerically in-between (4.9 %). An impact caused by main patient and donor characteristics, established risk factors for SOS, and conditioning regimen could be excluded in multivariate analyses. HPSE polymorphisms turned out to be significant independent risk factors (P = 0.030) for development of SOS and should be evaluated in further trials.

Aim: Acute renal failure (ARF) after hematopoietic stem cell transplantation (HSCT) is a widespread complication leading to considerable morbidity and mortality. The present study aims to determine the incidence and risk factors of ARF and to investigate whether there exists a relationship between the renal injury indicators and quantity of the transplanted stem cells in a uniform patient population after allogeneic myeloablative HSCT. Methods: Patients undergoing myeloablative allogeneic HSCT from 2007 to 2008 were monitored prospectively in terms of their renal functions during the first 100 days after transplantation. ARF was defined as a twofold rise in serum creatinine concentration of baseline value or a >50% decrease in creatinine clearance and classified into three grades. Results: ARF occurred in 51.3% of patients over a period of 100 days after HSCT. ARF developed in 12 (60.0%) patients within the first 2 weeks, whereas in 8 (40.0%) of them ARF development was observed within 2–4 weeks. No correlation was found between ARF development and the quantity of the infused hematopoietic stem cells. Additionally, we were not able to identify a particular cause which was significantly associated with the occurrence of ARF after HSCT. Conclusion: A 51.3% incidence of ARF was found in patients after myeloablative allogeneic HSCT. ARF in HSCT patients could not be linked to a single cause. Rather a combination of multiple risk factors seems to be responsible for ARF development.

The aim of this study is to evaluate the incidence of sinusoidal obstruction syndrome (SOS) of the liver and the clinical outcome after hematopoietic stem cell transplantation (HSCT) based on several modifications in our protocols. We retrospectively investigated 372 patients undergoing myeloablative conditioning with oral busulfan (Bu) and cyclophosphamide before allogeneic HSCT during 1990–2015. Patients' supportive care was changed in order to reduce the regimen‐related toxicities. Norethisterone use was terminated in 1998, therapeutic drug monitoring of Bu was initiated in 2000, and the use of liver supportive drugs, such as ursodeoxycholic acid and N‐acetyl‐L‐cysteine, were started in 2002 and 2009, respectively. In total, 26 patients (7.0%) developed SOS at a median of 19 days after transplantation. Of these 26 patients, 20 died at a median of 119 days after HSCT and 102 days after the diagnosis of SOS. The incidence of SOS decreased over time in accordance with the improvements in supportive care. The highest incidence of SOS was during 1995–1999 (16.2%) compared with 2.3% during 2010–2015. Overall survival for patients with SOS was 62%, 46%, and 27% at 100 days, 1 year, and 5 years after HSCT, respectively, compared with 92%, 77%, and 66% for those who did not develop SOS (P < 0.001). In conclusion, the incidence of SOS and related deaths were significantly decreased over the last years. Our institution pursues massive preventative and personalized measures for SOS. This strategy may also be applicable in other conditioning protocols in order to reduce the incidence of SOS and, hence, improve the clinical outcome.

The Risk of Sinusoidal Obstruction Syndrome (SOS) in Allogeneic Hematopoietic Stem Cell Transplantation after Prior Gemtuzumab Ozogamicin Treatment: A Retrospective Study on Behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Costs of Complications after Allogeneic Myeloablative Stem Cell Transplantation.

Hepatic sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD) is a complication after allogenic hematopoietic stem-cell transplantation (allo-HSCT) with high mortality. The purpose of this study was to assess the incidence and outcome of SOS in patients after allo-HSCT with the impact of ursodeoxycholic acid (UDCA) and low-dose heparin as SOS prophylaxis. Out of 1016 patients, 23 developed SOS, with a cumulative incidence of 2.3% (95% CI 1.3–3.3) 6 months after HSCT. Approximately one quarter of these patients (26.1%) had late-onset SOS. A high proportion were very severe SOS cases (74%), and 83% of the patients were treated with defibrotide (DF). In multivariate analysis, advanced disease (p = 0.003), previous HSCT (p = 0.025) and graft versus host disease (GvHD) prophylaxis by post-transplant cyclophosphamide (PTCy) (p = 0.055) were associated with the development of SOS. The 1-year overall survival (OS) was significantly lower in the SOS group compared to patients without SOS (13% versus 70%, p = 0.0001). In conclusion, we found a low incidence of SOS in patients receiving low-dose heparin and UDCA prophylactically, but among SOS patients, a high mortality. Low-dose heparin and UDCA might be a prophylactic approach for SOS.

The Incidence of Veno-Occlusive Disease Following Allogeneic Hematopoietic Stem Cell Transplantation Has Diminished and the Outcome Improved over the Last Decade

NCI First International Workshop on the Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Cell Transplantation: Report from the Committee on Prevention of Relapse Following Allogeneic Cell Transplantation for Hematologic Malignancies

Cyclophosphamide Followed By Intravenous Busulfan (Cy-Bu) As Myeloablative Conditioning: Impact on Venoocclusive Disease and Transplant Outcomes, Real World Experience

A Phase 2 Trial of Inotuzumab Ozogamicin (InO) in Children and Young Adults with Relapsed or Refractory (R/R) CD22+ B-Acute Lymphoblastic Leukemia (B-ALL): Results from Children's Oncology Group Protocol AALL1621

Iron Overload in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation: Quantification of Iron Burden by a Superconducting Quantum Interference Device (SQUID) and Therapeutic Effectiveness of Phlebotomy

Role of Hematopoietic Stem Cell Transplantation As Salvage Treatment of Acute Promyelocytic Leukemia Initially Treated with All-Trans-Retinoic Acid: A Retrospective Analysis of the Japan Adult Leukemia Study Group (JALSG) APL97 Study

Analysis of Laboratory Parameters before the Occurrence of Hepatic Sinusoidal Obstruction Syndrome in Pediatric Patients after Hematopoietic Stem Cell Transplantation

BackgroundThe binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation.MethodsWe conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis.ResultsThirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls.ConclusionsOur study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted.Trial registrationClinicalTrials.gov NCT01280955

This retrospective study was conducted in Japan to determine the incidence, risk factors and outcomes of sinusoidal obstruction syndrome (SOS) after allogeneic hematopoietic stem cell transplantation (HSCT). Among 4290 patients undergoing allogeneic HSCT between 1999 and 2010, 462 were diagnosed with SOS according to the Seattle criteria (cumulative incidence, 10.8%). The cumulative incidence of SOS diagnosed by the modified Seattle criteria was 9.3%. Of 462 patients, 107 met the Baltimore criteria and 168 had severe SOS with renal and/or respiratory failure. The median onset for SOS was 12 days after HSCT (range, -2-30). Overall survival at day 100 was 32% for SOS and 15% for severe SOS. Multivariate analyses showed that significant independent risk factors for SOS were the number of HSCTs, age, performance status, hepatitis C virus-seropositivity, advanced disease status and myeloablative regimen. SOS was highly associated with overall mortality (hazard ratio, 2.09; P<0.001). Our retrospective survey showed that the cumulative incidence of SOS in Japan was 10.8%, similar to that previously reported in Western countries, and that the overall survival of patients who developed SOS was low. Furthermore, several risk factors were identified. Preventive and therapeutic strategies for high-risk SOS patients must be established to improve overall survival.