The Effect of Natural Killer Cell Killer Ig-Like Receptor Alloreactivity on the Outcome of Bone Marrow Stem Cell Transplantation for Severe Combined Immunodeficiency (SCID)

Natural killer (NK) cell alloreactions against recipient cells in the setting of bone marrow transplantation have been associated with decreased rates of graft-versus-host disease (GVHD) and improved survival in transplant recipients with myeloid leukemia. These alloreactions are predicted by the absence of recipient HLA class I ligands for donor inhibitory killer Ig-like receptors (KIR). We hypothesized that donor NK cell alloreactions against recipient cells may affect the development of T and B-cell functions and incidence of GVHD in infants with severe combined immunodeficiency (SCID). Of the 156 patients with SCID who had received related bone marrow transplants without pretransplant chemotherapy or posttransplant GVHD prophylaxis, 137 patient-donor pairs were evaluated for the absence of recipient HLA class I ligands for donor inhibitory KIR. Analysis showed that the absence of a KIR ligand had no effect on the incidence or severity of GVHD (RR [corrected] = 0.95, p = 0.84), development of T-cell function (RR [corrected] = 1.05, p = 0.69), production of IgA (p = 0.46) or IgM (p = 0.33), or on 5-year survival (RR [corrected] = 1.21, p = 0.10). Further, in patients possessing native NK cells, the absence of KIR ligands in donors for recipient-inhibitory KIR did not alter transplantation outcomes. This study suggests that inhibitory KIR/HLA interactions do not play a significant role in bone marrow transplantation for SCID.     

Validation of the Disease Risk Index for Outcome of Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation after T Cell Depletion

Identification of pretransplantation risk factors is important in evaluating patient outcomes after hematopoietic stem cell transplantation. Current scoring schemes, such as the European Group for Blood and Marrow Transplantation risk score or the Hematopoietic Cell Transplantation-Specific Comorbidity Index, may under-rate disease and disease status at the time of transplantation. The recently published Disease Risk Index (DRI) specifically investigates these aspects by defining 4 risk groups (low, intermediate, high, very high) with significant differences in overall survival (OS). We retrospectively investigated whether the DRI could be applied at the transplantation center of Geneva's University Hospitals (Geneva, Switzerland), where 64% of patients are underwent transplantation with T cell–depleted grafts (TDEP). We analyzed 409 patients with various hematological malignancies who underwent transplantation between January 1998 and October 2012. Using the DRI, the 4-year OS for the low, intermediate, high, and very high groups was 82%, 53%, 27%, and 31%, respectively (P < .0001). For TDEP patients, the 4-year OS for low, intermediate, and high overall risk groups was 86%, 53%, and 33%, respectively (P < .0001). As patients in the very high overall risk group are usually not eligible for TDEP, our group comprised too few patients (n = 3) for meaningful analysis. For non-TDEP patients, the 4-year OS for low, intermediate, high, and very high overall risk groups was 63%, 54%, 22%, and 18%, respectively (P < .0001). Our results confirm the prognostic value of the DRI in a cohort with a majority of TDEP patients.     

The Emerging Role of Gemcitabine in Conditioning Regimens for Hematopoietic Stem Cell Transplantation

The specific combination for conditioning regimens in hematopoietic stem cell transplantation continues to be a premier area of focus in research. Although conditioning regimens have significantly evolved over time, obstacles continue to persist, including regimen-related toxicities, graft-versus-host disease, and disease relapse. Gemcitabine (2’,2’-difluoro 2’-deoxycytidine, dFdC) is a pyrimidine nucleoside analog that distinguishes itself from other agents in the class by possessing a favorable pharmacokinetic and cytotoxic profile, while maintaining acceptable toxicities. Given the desirable properties, gemcitabine has garnered much attention and been assessed in several conditioning regimens. In this article, we review the pharmacology of gemcitabine with other nucleoside analogs and report the findings of pivotal trials conducted in both autologous and allogeneic transplantation. The positive results suggest a potential future role for gemcitabine and necessitate the need to conduct studies to further define its role.     

Lymphocyte Subset Recovery and Outcome after Autologous Hematopoietic Stem Cell Transplantation for Plasma Cell Myeloma

Rapid immune reconstitution—particularly of natural killer cells (NK cells)—after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with protection from relapse. Whether such an association also exists after autologous stem cell transplantation is less clear. We retrospectively assessed lymphocyte subsets after autologous HSCT in 114 patients and correlated lymphocyte recovery with outcome. CD8 T cell and NK cell counts recovered rapidly to pretransplantation levels, whereas B cell and CD4 T cell recovery were delayed. Compared with patients with low NK cells (<100/uL), high NK cell count at 1 month after HSCT was associated with significantly prolonged progression-free survival: for NK cells 100 to 200/uL hazard ratio [HR], .33 (95% confidence interval [CI]; .16 to .80; P = .004); for NK cells > 200/μL HR, .27 (95% CI, .13 to .58; P = .001). No significant protective effects were associated with rapid recovery of any other lymphocyte subset. None influenced overall survival (OS) or time to next treatment. Early NK cell recovery is associated with better progression-free survival after autologous HSCT. The failure to detect an effect on OS might be due to the salvage strategies available to these patients.     

Differential Expression of the Ly49GB6, but Not the Ly49GBALB,Receptor Isoform during Natural Killer Cell Reconstitution after Hematopoietic Stem Cell Transplantation

Inhibitory natural killer (NK) cell receptors specific for major histocompatibility complex class I (MHC-I) molecules include Ly49 receptors in mice and killer immunoglobulin-like receptors (KIR) in humans. The “licensing” or “arming” models imply that engagement of these receptors to self MHC-I molecules during NK cell development educates NK cells to be more responsive to cancer and viral infection. We recently reported that hematopoietic stem cell transplantation (HSCT) induced rapid and preferential expansion of functionally competent Ly49G⁺, but not other Ly49 family, NK cells independent of NK cell licensing via Ly49–MHC-I interactions. We now extend these studies to evaluate expression of the two Ly49G receptor isoforms Ly49G^B6 and Ly49G^BALB, using mice with different MHC-I haplotypes that express one or both of the isoforms. NK cells from CB6F₁ (H-2^bxd) hybrid mice express two different alleles for Ly49G receptor, Ly49G^B6 and Ly49G^BALB. We found that CB6F₁ mice had more Ly49G^B6+ NK cells than Ly49^BALB+ NK cells, and that only Ly49G^B6+ NK cells increased in relative numbers and in Ly49G mean fluorescence intensity values after HSCT similar to the B6 parental strain. We further observed that Ly49G⁺ NK cells in BALB/c (H-2^d) and BALB.B (H-2^b) mice, which have the same background genes, recover slowly after HSCT, in contrast to Ly49G⁺ NK cells in B6 (H-2^b) recipients. The difference in expression of Ly49G^B6 relative to Ly49G^BALB was linked to differences in the activity of the Pro1 promoter between the two alleles. Thus, we conclude that the Ly49G^B6 receptor dominates Ly49G expression on NK cells after HSCT in strains in which that allele is expressed. The data suggest that Ly49 allelic polymorphism within a particular Ly49 family member can differentially affect NK cell recovery after HSCT depending on the background genes of the recipient, not on the MHC-I haplotype.     

Evaluation of a Test Dose Strategy for Pharmacokinetically-Guided Busulfan Dosing for Hematopoietic Stem Cell Transplantation

Targeted busulfan dosing helps limit chemotherapy-related toxicity and optimize disease outcomes in hematopoietic stem cell transplantation (HCT). The objective of this study was to evaluate busulfan exposure from a pharmacokinetic (PK)-guided dosing strategy using a test dose. This retrospective evaluation included adult patients who underwent HCT at our institution with busulfan-based myeloablative (>9 mg/kg) conditioning between January 2014 and October 2015. A weight-based test dose of 0.8 mg/kg was used with PK assessments to predict area under the curve (AUC_pred) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUC_target). PK from the test dose was then used to calculate a PK-guided first myeloablative busulfan dose. PK assessments were also done after the first dose to assess if the goal area under the curve (AUC) had been achieved (AUC_first). A PK-guided first dose resulted in achievement of target AUC with target ranges of ±10% in 50% of patients, ±15% in 75%, and ±20% in 94%. This was an improved rate of target achievement compared with the 33%, 44%, and 63% of patients who achieved the desired AUC for these respective target ranges when using weight-based dosing (P?=?.12, .004, and <.001, respectively). The PK-guided strategy also decreased the variability of AUC from 3.6-fold in AUC_pred from the weight-based test doses (2700.8 to 9631 µM*minute; SD, 1211.6 µM*minute) to 1.8-fold in AUC_first from the PK-guided first doses (3672.1 to 6609.8 µM*minute; SD, 574.7 µM*minute). This reflects a 2-fold improvement in AUC variability with a PK-guided dosing strategy. This is also improved from the 3-fold variability in AUC reported in other studies. Weight and body surface area were significantly associated with the likelihood of AUC_first being within the ±10% target range (P?=?.04 for both associations). There was no significant association between AUC_first and death, relapse, or a composite of the two. These results demonstrate a significant improvement in target AUC attainment and less interpatient variability with PK-guided dosing using a test dose strategy compared with weight-based dosing.     

Effect of Antithymocyte Globulin Source on Outcomes of HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Severe Aplastic Anemia

We wanted to evaluate efficacy of porcine antithymocyte globulin (ATG) in HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation (MSD-HSCT) for patients with severe aplastic anemia (SAA). The clinical data of 113 SAA patients who received MSD-HSCT from January 2005 to November 2016 were analyzed retrospectively. Of these, 58 patients received rabbit ATG as a part of conditioning regimen (R-ATG group), whereas the other 55 patients received porcine ATG (P-ATG group). Patient baseline characteristics and donor conditions of the 2 groups were similar, except patients were older and more received peripheral blood stem cell transplantation in the P-ATG group. All patients engrafted in 2 groups. There were significant differences in the incidence of acute (20.7%?±?5.3% versus 43.4%?±?7.0%, P?=?.015) and chronic graft-versus- host disease (GVHD; 20.1%?±?5.8% versus 46.0%?±?7.9%, P?=?.003) between the R-ATG and P-ATG groups. However, there were no significant differences in terms of 3-year overall survival (93.1%?±?3.3% versus 84.4%?±?5.7%, P?=?.235), grades III to IV acute GVHD (3.4%?±?2.4% versus 12.3%?±?4.7%, P?=?.098), moderate to severe chronic GVHD (12.6%?±?4.9% versus 11.5%?±?4.9%, P?=?.905), or graft rejection (7.4%?±?3.6% versus 5.5%?±?3.1%, P?=?.852). There was also no significant difference with regard to the incidence of severe bacterial infection (P?=?.075), invasive fungal disease (P?=?.701), or cytomeglovirus viremia (P?=?.770). P-ATG showed satisfactory efficacy and safety compared with R-ATG in the setting of MSD-HSCT for SAA patients. P-ATG could be a potential alternative preparation for R-ATG, further offering the advantage of lower costs.     

The Art of Transplantation: Conditioning Intensity for Allogeneic Hematopoietic Stem Cell Transplantation

The search for the optimal conditioning regimen before allogeneic hematopoietic stem cell transplantation (HCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) has been ongoing for decades. In this issue, Solh et al present an original analysis evaluating the impact of conditioning intensity on different disease risk index (DRI) groups of patients with AML and MDS. An impressive difference was observed in outcomes between reduced-intensity conditioning and myeloablative conditioning (MAC) regimens in the low/intermediate-risk disease groups, supporting the use of MAC in this population. Further prospective trials in this population are encouraged.     

Antigen and Lymphopenia-Driven Donor T Cells Are Differentially Diminished by Post-Transplantation Administration of Cyclophosphamide after Hematopoietic Cell Transplantation

Administration of cyclophosphamide after transplantation (post-transplantation cyclophosphamide, PTC) has shown promise in the clinic as a prophylactic agent against graft-versus-host disease (GVHD). An important issue with regard to recipient immune function and reconstitution after PTC is the extent to which, in addition to diminution of antihost allo-reactive donor T cells, the remainder of the nonhost allo-reactive donor T cell pool may be affected. To investigate PTC's effects on nonhost reactive donor CD8 T cells, ova-specific (OT-I) and gp100-specific Pmel-1 T cells were labeled with proliferation dyes and transplanted into syngeneic and allogeneic recipients. Notably, an intermediate dose (66 mg/kg) of PTC, which abrogated GVHD after allogeneic HSCT, did not significantly diminish these peptide-specific donor T cell populations. Analysis of the rate of proliferation after transplantation illustrated that lymphopenic-driven, donor nonhost reactive TCR Tg T cells in syngeneic recipients underwent slow division, resulting in significant sparing of these donor populations. In contrast, after exposure to specific antigens at the time of transplantation, these same T cells were significantly depleted by PTC, demonstrating the global susceptibility of rapidly dividing T cells after an encounter with cognate antigen. In total, our results, employing both syngeneic and allogeneic minor antigen-mismatched T cell replete models of transplantation, demonstrate a concentration of PTC that abrogates GVHD can preserve most cells that are dividing because of the accompanying lymphopenia after exposure. These findings have important implications with regard to immune function and reconstitution in recipients after allogeneic hematopoietic stem cell transplantation.     

CD34+-Selected Stem Cell Boost without Further Conditioning for Poor Graft Function after Allogeneic Stem Cell Transplantation in Patients with Hematological Malignancies

We retrospectively analyzed outcomes of a CD34⁺-selected stem cell boost (SCB) without prior conditioning in 32 patients (male/22; median age of 54 years; range, 20 to 69) with poor graft function, defined as neutrophils ≤1.5 x 10⁹/L, and/or platelets ≤30 x 10⁹/L, and/or hemoglobin ≤8.5 g/dL). The median interval between stem cell transplantation and SCB was 5 months (range, 2 to 228). The median number of CD34⁺ and CD3⁺ cells were 3.4 x 10⁶/kg (.96 to 8.30) and 9 x 10³/kg body weight (range, 2 to 70), respectively. Hematological improvement was observed in 81% of patients and noted after a median of 30 days (range, 14 to 120) after SCB. The recipients of related grafts responded faster than recipients of unrelated grafts (20 versus 30 days, P = .04). The cumulative incidence of acute (grade II to IV) and chronic graft-versus-host disease (GVHD) after SCB was 17% and 26%, respectively. Patients with acute GVHD received a higher median CD3⁺ cell dose. The 2-year probability of overall survival was 45%. We suggest that SCB represents an effective approach to improve poor graft function post transplantation, but optimal timing of SCB administration, anti-infective, and GVHD prophylaxis needs further evaluation.     

Microbiologic Diagnostic Workup of Acute Respiratory Failure with Pulmonary Infiltrates after Allogeneic Hematopoietic Stem Cell Transplantation: Findings in the Era of Molecular- and Biomarker-Based Assays

Allogeneic hematopoietic stem cell transplantation (HSCT) recipients frequently develop acute respiratory failure (ARF) with pulmonary infiltrates. Molecular- and biomarker-based assays enhance pathogen detection, but data on their yield in this population are scarce. This was a retrospective single-center study of 156 consecutive HSCT recipients admitted to the intensive care unit (ICU) between May 2013 and July 2017. Findings from a microbiologic diagnostic workup using currently available methods on bronchoalveolar lavage (BAL) and blood samples from 66 patients (age, 58 years [range, 45 to 64]; HSCT to ICU, 176 days [range, 85 to 407]) with ARF and pulmonary infiltrates were analyzed. In 47 patients (71%) a causative pathogen was identified (fungal, n?=?28; viral, n?=?26; bacterial, n?=?18). Polymicrobial findings involving several pathogen groups occurred in 20 patients (30%). Culture (12/16, 75%), galactomannan (13/15, 87%), and Aspergillus-PCR (8/9, 89%) from BAL but not serum galactomannan (6/14, 43%) helped to diagnose invasive aspergillosis (n?=?16, 24%). Aspergillus-PCR detected azole resistance in 2 cases. Mucorales was found in 7 patients (11%; BAL culture, n?=?6; Mucorales-PCR, n?=?1). Patients with identified pathogens had higher Simplified Acute Physiology Score II scores (P?=?.049) and inferior ICU survival (6% versus 37%, P?<?.01), which largely related to the presence of an invasive fungal infection. Eight patients (12%) had 1 or more viruses with uncertain lung pathogenicity as the sole microbiologic finding. A diagnostic microbiologic workup incorporating molecular- and biomarker-based assays identified pathogens in most HSCT recipients with ARF and pulmonary infiltrates admitted to the ICU. Implications of polymicrobial infection and pathogen patterns in these patients warrant further investigation.     

Status of Natural Killer Cell Recovery in Day 21 Bone Marrow after Allogeneic Hematopoietic Stem Cell Transplantation Predicts Clinical Outcome

Rapid immune recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is important for clinical outcome prediction. In most studies, immune recovery after allo-HSCT is monitored via peripheral blood. However, few reports regarding the status of absolute lymphocyte subsets in the bone marrow (BM) microenvironment have been undertaken. Therefore, we evaluated the clinical impact of immune recovery in the early period following allo-HSCT using BM samples. We showed that delayed natural killer cell recovery was independently associated with a poor prognosis for overall survival (hazard ratio [HR], 3.07; 95% confidence interval [CI], 1.37- 6.89; P?=?.007), progression-free survival (HR, 3.42; 95% CI, 1.47-7.94; P?=?.004), and nonrelapse mortality (HR, 6.68; 95% CI, 1.82-25.0; P?=?.004) by multivariate analysis. In addition, low NK cell counts were associated with the presence of 1 or more bacterial, viral, or fungal infections. Our results indicate that investigating absolute lymphocyte subsets in BM in the early phase following allo-HSCT can be useful for predicting and improving survival outcomes.     

Impact of Cytomegalovirus Replication and Cytomegalovirus Serostatus on the Outcome of Patients with B Cell Lymphoma after Allogeneic Stem Cell Transplantation

Cytomegalovirus (CMV) replication after allogeneic hematopoietic stem cell transplantation (HSCT) was historically associated with increased nonrelapse mortality (NRM). More recently, different groups have reported an association between CMV replication and reduced risk of acute myeloid leukemia (AML) relapse. Given the conflicting results, we evaluated the impact of CMV replication and other covariates on the outcome of a retrospective cohort of 265 adults with B cell lymphoma receiving allogeneic HSCT from HLA-identical siblings or alternative donors. In time-dependent multivariate analysis, CMV replication, evaluated by pp65 antigenemia, had no independent effect on the risk of relapse (hazard ratio [HR], 1.0; 95% confidence interval [CI], .6 to 1.6; P = .9), although it was associated with a reduced overall survival (HR, 2.0; 95% CI, 1.3 to 3.2; P = .001) and an increased NRM (HR, 2.5; 95% CI, 1.1 to 5.3; P = .01). Consistently, donor and/or recipient CMV seropositivity were not associated with a different outcome relative to CMV double-negative serostatus. In multivariate models, a diagnosis of follicular lymphoma (P < .0001) and pretransplantation complete remission status (P < .0001) were the main independent predictors for improved relapse-free survival. In summary, contrary to what is observed in patients with AML, this report identifies no independent role for CMV replication or serostatus on the relapse of patients with B cell lymphomas undergoing allogeneic HSCT.     

Outcome and Prognostic Factors for Patients Who Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Disease relapse remains a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HSCT), yet little is known about the relevant prognostic factors after relapse. We studied 1080 patients transplanted between 2004 and 2008, among whom 351 relapsed. The 3-year postrelapse overall survival (prOS) rate was 19%. Risk factors for mortality after relapse included shorter time to relapse, higher disease risk index at HSCT, myeloablative conditioning, high pretransplantation comorbidity index, and graft-versus-host disease (GVHD) occurring before relapse. Important prognostic factors did not vary by disease type. Based on this, we could stratify patients into 3 groups, with 3-year prOS rates of 36%, 14%, and 3% (P < .0001). This score was validated in an historical cohort of 276 patients. Postrelapse donor lymphocyte infusion or repeat HSCT was associated with improved prOS, as was the development of GVHD after relapse. These differences remained significant in models that accounted for other prognostic factors and in landmark analyses of patients who survived at least 2 months from relapse. The results of this study may aid with prognostication and management of patients who relapse after HSCT and motivate the design of clinical trials aimed at relapse prevention or treatment in higher-risk patients.     

Impact of Thrombotic Microangiopathy on Renal Outcomes and Survival after Hematopoietic Stem Cell Transplantation

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT). We characterized the incidence, risk factors, and long-term outcomes associated with TA-TMA by performing a comprehensive review of all adult patients (n?=?1990) undergoing allogeneic HSCT at the Dana Farber Cancer Institute/Brigham and Women's Hospital between 2005 and 2013. Using the City of Hope criteria, we identified 258 patients (13%) with “definite” TMA and 508 patients (26%) with “probable” TMA. Mismatched donor transplantation (subdistribution hazard ratio [sHR], 1.79; 95% confidence interval [CI], 1.17 to 2.75; P?=?.007), sirolimus-containing graft-versus-host disease prophylaxis (sHR, 1.73; 95% CI, 1.29 to 2.34; P?<?.001), myeloablative conditioning (sHR, 1.93, 95% CI, 1.38 to 2.68; P?<?.001), and high baseline lactate dehydrogenase (LDH) level (sHR, 1.64; 95% CI, 1.26 to 2.13; P?<?.001) were associated with definite TMA. Moreover, positive cytomegalovirus serostatus (sHR, 1.41; 95% CI, 1.16 to 1.71; P?<?.001), high and very high disease risk index (sHR, 1.48; 95% CI, 1.12 to 1.96, P?=?.007), and high baseline LDH level (sHR, 1.25; 95% CI, 1.05 to 1.49; P?=?.011) were associated with probable TMA. In multivariable analyses, definite and probable TMA were each independently associated with higher mortality (HR, 5.24; 95% CI, 4.43 to 6.20 and HR, 2.12; 95% CI, 1.84 to 2.44, respectively), and long-term kidney dysfunction (HR, 5.43; 95% CI, 4.61 to 6.40 and HR, 2.20; 95% CI, 1.92 to 2.51, respectively). Definite and probable TMA were also independently associated with an increased risk of nonrelapse mortality and shorter progression-free survival. Our findings indicate that TA-TMA is common following HSCT and is independently associated with increased risk of death and kidney dysfunction.     

Comparable Outcomes after HLA-Matched Sibling and Alternative Donor Hematopoietic Cell Transplantation for Children with Fanconi Anemia and Severe Aplastic Anemia

Fanconi anemia (FA)-associated severe aplastic anemia (SAA) requires allogeneic hematopoietic cell transplantation (HCT) for cure. With the evolution of conditioning regimens over time, outcomes of alternative donor HCT (AD-HCT) have improved dramatically. We compared outcomes of HLA-matched sibling donor HCT (MSD-HCT; n?=?17) and AD-HCT (n?=?57) performed for FA-associated SAA at a single institution between 2001 and 2016. Overall survival at 5 years was 94% for MSD-HCT versus 86% for AD-HCT, neutrophil engraftment was 100% versus 95%, platelet recovery was 100% versus 89%, grade II-IV acute graft-versus-host disease (GVHD) was 6% versus 12%, grade III-IV acute GVHD was 6% versus 4%, and chronic GVHD was 0 versus 7%, with no statistically significant differences by type of transplant. The use of UCB was associated with decreased rates of neutrophil recovery in AD-HCT and platelet recovery in both MSD-HCT and AD-HCT. A trend toward a higher serious infection density before day +100 post-HCT was observed in AD-HCT compared with MSD-HCT (P?=?.02). These data demonstrate that AD-HCT should be considered at the same time as MSD-HCT for patients with FA-associated SAA.     

Novel Ultrasonographic Scoring System of Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation

Sinusoidal obstruction syndrome (SOS)/hepatic veno-occlusive disease (VOD) is a well-documented complication after hematopoietic stem cell transplantation (HSCT). Transabdominal ultrasonography (US) enables the visualization of blood flow abnormalities and is therefore useful for the diagnosis of SOS/VOD. We herein prospectively evaluated accuracy of a novel US diagnostic scoring system of SOS/VOD based on US findings. We carried out US in 106 patients on day 14 and when SOS/VOD was suspected after allogeneic HSCT. Among 106 patients, 10 patients (9.4%) were diagnosed as SOS/VOD by Baltimore or Seattle criteria. According to univariate analysis of 17 US findings (US-17 screening), we established a novel scoring system (HokUS-10) consisting of 10 parameters, such as gallbladder wall thickening, ascites, and blood flow signal in the paraumbilical vein. The sensitivity and specificity were 100% and 95.8%, respectively. Diagnostic performance of the HokUS-10 was significantly better than US-17 screening. In 4 of 10 patients US detection of SOS/VOD preceded to clinical diagnosis. The HokUS-10 scoring system is useful in the diagnosis of SOS/VOD; however, our results should be validated in other cohorts.     

Risk-Factor Analysis of Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation

The objective of this study was to investigate the main risk factors for poor graft function (PGF) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), to allow the improvement of transplantation outcomes through preventive measures. Clinical data for 124 patients who received allo-HSCT were analyzed retrospectively. There were 83 males (66.9%) and 41 females (33.1%) with a median age of 28 years (4-60 years). The median follow-up time was 7 months (1-116 months). Factors analyzed included age, gender, disease diagnosis, source of hematopoietic stem cells, donor type, human leukocyte antigen (HLA) matching, conditioning regimen, numbers of infused mononuclear cells and CD34⁺ cells, donor-recipient sex and blood-type matching, prophylactic treatment of graft-versus-host disease (GVHD), grades of GVHD, Epstein-Barr virus or cytomegalovirus (CMV) infection, post-transplantation lymphoproliferative disorders and hepatic veno-occlusive disease. Data were analyzed by univariate and multivariate conditional logistic regression analyses. Among the 124 patients who underwent allo-HSCT, 15 developed PGF (12.1%). Univariate logistic regression analysis identified age, donor-recipient blood type and CMV infection (in 30 days) as potential risk factors for PGF. Multivariate analysis of factors with P<0.1 in univariate analysis showed that age, donor-recipient blood type and CMV infection (in 30 days) were significant risk factors for PGF. Patients were divided into subgroups based on age <20, 20-30, 30-40, and >40 years. The risk of PGF increased 2.747-fold (odds ratio (OR)=2.625, 95% confidence interval: 1.411-5.347) for each increment in age level. Patients with mismatched blood type (OR=4.051) or CMV infection (OR=9.146) had an increased risk of PGF. We conclude that age, donor-recipient blood-type matching and CMV infection are major risk factors for PGF after allo-HSCT.     

Combination of High-Dose Methylprednisolone and Defibrotide for Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplant Recipients

Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplant (HSCT), with high mortality in severe cases and until recently very limited therapeutic options consisting largely of supportive care. Defibrotide was recently approved in the United States for the treatment of severe VOD in patients with renal or pulmonary dysfunction after HSCT. Our group previously published on the use of high-dose methylprednisolone (500?mg/m² per dose every 12 hours for 6 doses) in patients with VOD, showing good success. A small subset of these individuals were also treated with defibrotide, but additional studies using the combination of high-dose methylprednisolone and defibrotide for the treatment of VOD are lacking. We present a single-institution retrospective chart review of 15 HSCT patients with VOD treated with the combination of high-dose methylprednisolone and defibrotide. VOD developed at a median of 17 days post-HSCT, and combination therapy was initiated within 1 day of VOD diagnosis. Twelve of 15 patients (80%) had multiorgan failure. Our single-center experience using both high-dose methylprednisolone and defibrotide showed a day +100 survival rate of 73% and an overall VOD complete resolution rate of 66.7%, higher than the rates reported in the recent literature using defibrotide alone (40% to 50% day +100 overall survival). These data suggest that the combination of high-dose steroids and defibrotide may be superior to defibrotide alone and warrant further investigation.