Transplant-related Characteristics Research Articles

Outcomes of Infliximab in Management of Steroid-Refractory Acute Graft Versus Host Disease

Corticosteroids are considered the standard first-line treatment for moderate/severe acute graft versus host disease (aGVHD), yet there is no consensus on the optimal management of patients that are steroid-refractory (SR). Infliximab is a chimeric monoclonal antibody with anti-TNF-α activity that has previously demonstrated efficacy in SR-aGVHD. We performed a retrospective review of 59 patients at Indiana University who underwent allogeneic stem cell transplantation and developed SR grade III-IV aGVHD from January 2007 to August 2018. Infliximab was administered 10 mg/kg weekly intravenously. Response criteria was in accordance with Martin et al (BBMT 2009; 12:777-784). Median age of treated patients was 49.5 years (range, 34.5-60) and median time from transplant to diagnosis of aGVHD was 106 days (range, 42-185) Patients received a median of 12 days (range, 8-20) of systemic steroids prior to infliximab. At the start of infliximab, 52 (88%) patients were on non-steroidal immunosupressants and 39 (66%) on non-absorbable steroids concurrently with systemic steroids. Patients received a median of 3 doses of infliximab with 37 (62.7%) patients receiving There was no significant difference between responders (n=16) and non-responders (n=43) in baseline demographic, transplant-related characteristics, initial GVHD prophylaxis regimen, number of non-steroidal systemic immunosuppressants at time of aGVHD diagnosis, or use of non-absorbable steroids. There was no difference in time from diagnosis of aGVHD to start of infliximab (median 16 vs. 11 days, P=0.06). Responders were less likely to have liver aGVHD involvement vs. non-responders (18% vs. 53%, P=0.016) and had slower tapering of systemic steroids, both at median time to 50% steroid dose (18 vs. 12 days, P=0.02) and 25% steroid dose (36 vs. 24 days, P=0.01). Responders had lower incidence of bacterial infection (44% vs. 74%, P=0.04), but not viral infections (56% vs. 47%, P=0.57). Responders had a longer overall survival (median 20.3 vs. 2.8 months, P=0.01). Our single center report of 59 patients with SR-aGVHD treated with infliximab is among the largest reported. The outcomes of response to SR-aGVHD are poor and there is an unmet need for better agents. Additional studies with greater patient numbers are needed to identify factors associated with improved response to infliximab.

Pulmonary Arterial Hypertension (PAH) Is Associated with Increased Non-Relapse Mortality after Allogeneic Hematopoietic Cell Transplantation (allo HCT) for Myelofibrosis

Background AlloHCT is the only curative therapy for primary and secondary myelofibrosis (MF). Pulmonary arterial hypertension (PAH) can be seen in 30% of patients with MF. PAH can eventually lead to right heart failure and may be associated with complications after alloHCT. The primary objective was to determine the association of PAH with alloHCT outcome in patients with MF. Secondary objectives included the effect of HCT on the underlying PAH as well as incidence of specific transplant-related complications in these patients. Methods All patients with MF who underwent alloHCT from 2008 to early 2018 at the City of Hope Medical Center with evaluable pre-HCT echocardiography were considered for this retrospective analysis. Pre and postHCT echocardiograms were reviewed to evaluate the pulmonary arterial systolic pressure (PASP). Descriptive statistics were used for baseline patient and transplant related characteristics stratified by PAH. Paired t-test was used to detect the change in the pulmonary vascular pressure after HCT. Kaplan-Meier and cumulative incidence curves were constructed for OS and NRM), respectively. Log-rank test and Gray's test were used whenever appropriate. Results 65 patients with MF that met the inclusion criteria were studied. Median age at HCT was 61 years with 36 (55%) males. 39 (60%) patients had intermediate 2 or high DIPPS score at the time of HCT. 37 (57%) had JAK2 positive MF. . Median PASP was 37.0 mmHg (range: 16.0-57.9) prior to HCT with 37 out of 65 patients (57%) meeting the diagnostic criteria for PAH. With median follow-up of 35.0 months (range: 3.3 – 119.4), PAH was significantly associated with inferior OS (58.9% vs. 88.8%, p=0.025), primarily due to increased NRM (21.6% vs. 7.1%, p= 0.007). 57% of deaths (8 of 14) in patients with PAH occurred within day 100 after HCT. In patients with available post-HCT echocardiogram (n=33) eight patients (24%) had persistent PAH with the median pulmonary artery pressure of 30mmHg. Compared with pre-HCT values pulmonary arterial pressure was significantly reduced after HCT (p Conclusion PAH is associated with inferior survival due to increased NRM in patients with MF undergoing alloHCT. About half of deaths in patients with PAH occurred within 100 days of HCT. PAH appears at least partially reversible after successful alloHCT. Based on our data, PAH should be considered a risk factor for early mortality after alloHCT and surveillance of pulmonary artery pressure in MF patients being considered for alloHCT may be useful.

Senescent Mesenchymal Stem Cells Present at the Early Post Allogeneic Hematopoietic Stem Cell Transplantation Period Are Associated with an Increased Incidence of Acute Graft-Versus Host Disease and Increased Plasma Levels of Fas Ligand

IntroductionMesenchymal stem cells (MSC) are a key component of the hematopoietic niche. In the allogeneic hematopoietic stem cell transplantation (allo-HSCT) setting, the bone marrow stroma, and thus, their MSC remain of host origin. In a preliminary study we observed that, some patients at the early post allo-HSCT period, presented senescent bone marrow (BM) MSC, a finding that has not been previously described nor studied.The aims of our current study were: a) To multiparametrically characterize BM MSC at the early post allo-HSCT period (day +21). b) To confirm senescence of MSC and correlate with clinical and biological parameters (including biomarkers). c) To compare these cells with those from healthy donors.MethodsWe obtained BM samples on the day +21 post allo-HSCT from 136 patients. MSC were isolated, ex-vivo expanded and characterized, according to the criteria of the International Society for Cellular Therapy. We also obtained samples from peripheral blood at same day +21, for the study of biomarkers, which were analyzed by Luminex technique. The data were correlated with information from complete blood counts (CBC), and the morphological study of the bone marrow the same day. MSC from healthy donors were used as control.ResultsPatient baseline and transplant related characteristics are detailed in table 1. MSC were expanded ex-vivo showing normal growth, which were cryopreserved in passage 3 in the 33% (n=45/136) of the patients (Group-MSC-N). On the other hand, the remaining 67% (n=91/136), MSC showed premature signs of senescence, thus, not reaching to passage 1 (Group-MSC-S). Full BM chimerism on day+21 was seen in both groups (p=0.03). Concerning acute graft versus-host disease (aGVHD), in the Group-MSC-S, the incidence was 73% compared to 44% in the Group-MSC-N (p=0.001). The median time of the onset of aGVHD was 43 and 37 days respectively (p=0.04). The majority of cases presented with grades I-II in both groups. Plasma levels of biomarkers showed increased levels of Fas Ligand in the Group-MSC-S (p=0.009). There were no statistically significant differences regarding mortality nor relapse rates.ConclusionsBone marrow Mesenchymal stem cells may be severely damaged in some allo-HSCT recipients early after transplantation (day+21). This fact strongly correlates with the risk of development of acute GVHD. [Display omitted] DisclosuresDíez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Pre-Engraftment Gut Colonization with Enterococcus Casseliflavus Improves Survival after Allogeneic Hematopoietic Cell Transplantation

▪Introduction: Gut bacteria modulate the immune system and influence outcomes of allogeneic hematopoietic cell transplantation (allo-HCT). The presence of Blautia, butyrate-producing Clostridia, and Eubacterium limosum in the stool has been associated with lower mortality after allo-HCT. We previously reported an unexpected association between pre-HCT gut colonization with intrinsically vancomycin-resistant enterococci (iVRE: E. gallinarum and E. casseliflavus) and improved overall survival (OS) due to decreased non-relapse mortality (NRM). In an expanded cohort, now also including patients who were iVRE-colonized early post-HCT (before day +14), we demonstrate that the iVRE association with improved OS is specific to E. casseliflavus.Patients and Methods: We studied allo-HCT recipients at our institution who had at least 1 positive rectal swab or stool culture for iVRE between days -14 and +14. New admissions for HCT were screened for gut VRE colonization weekly until discharge. SpectraTM VRE chromogenic agar medium (ThermoFisher Scientific) was used for species-level identification. Antimicrobial prophylaxis consisted of levofloxacin, acyclovir, and an azole. Cefepime was our empiric antibiotic for neutropenic fever.Results: 66 (23 with E. casseliflavus and 43 with E. gallinarum) of the 873 allograft recipients between 2011-2017 met our inclusion criteria. As expected from the constitutive, rather than acquired, vancomycin resistance of iVRE, the groups did not differ in their prior exposure to different classes of antibiotics. There were no significant differences between the groups in patient-, disease-, or transplant-related characteristics, except a higher frequency of sirolimus-based GVHD prophylaxis in the E. casseliflavus group (35% vs. 12%, P = 0.05). With a median follow up of 30 months, OS was significantly better in patients with E. casseliflavus (91% vs. 62% at 3 years, P = 0.04), due to lower NRM (0 vs. 18% at 3 years, P = 0.05) (Figures 1A and 1B). Only 2 patients with E. casseliflavus died within 3 years post-HCT, both due to relapse. In contrast, 14 patients with E. gallinarum died within 3 years post-HCT: 7 (50%) due to relapse, and 7 (50%) from NRM (4 GVHD, 1 infection, 1 graft failure, and 1 veno-occlusive disease). In multivariable analysis, E. casseliflavus gut colonization was significantly associated with reduced all-cause mortality (hazard ratio 0.20, 95% confidence interval 0.04-0.91, P = 0.04). There were no significant differences between the groups in 180-day acute grade II-IV GVHD (P = 0.19), 1-year chronic GVHD (P = 0.56), 100-day bacteremia (P = 0.59), or 100-day Clostridium difficile infection (P = 0.79). To probe the mechanism of this protection against mortality, we mined 15 E. casseliflavus and 8 E. gallinarum sequenced genomes for 14 shikimate and tryptophan metabolism enzymes. This analysis predicted that E. casseliflavus encodes a larger number of enzymes in the tryptophan metabolism pathway (Figure 1C). Several compounds in this pathway are ligands for the aryl hydrocarbon receptor (AhR). Signals downstream of AhR augment the gut barrier and modulate the immune system, potentially reducing pathogenic injury and inducing protective immune responses.Conclusions: Pre-engraftment gut colonization with E. casseliflavus, but not E. gallinarum, improves survival after allo-HCT. Future mechanistic studies of the interactions between E. casseliflavus and the host can guide the development of novel microbiota-oriented therapeutics in this high-risk patient population. DisclosuresWeisdorf:Seattle Genetics: Consultancy; FATE: Consultancy; SL Behring: Consultancy; Pharmacyclics: Consultancy; Equillium: Consultancy.

The Dilemma of Conditioning Intensity: When Does Myeloablative Conditioning Improve Outcomes for Allogeneic Hematopoietic Cell Transplantation

The impact of conditioning intensity on different disease risk index (DRI) groups has not been evaluated. We retrospectively analyzed acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) hematopoietic cell transplantation (HCT) recipients in 2 groups based on DRI, to assess the impact of conditioning intensity on overall survival (OS), disease free survival (DFS), relapse, and nonrelapse mortality (NRM).A total of 380 patients with either high/very high (n = 148) or low/intermediate DRI (n = 232) myeloid malignancy (AML, n = 278; MDS, n = 102) were included in the analysis. Median follow-up for survivors was 35 months. Median age was 58years (range, 18 to 75). Patient and transplant-related characteristics were 41% reduced-intensity conditioning (RIC), 59% myeloablative conditioning (MAC), 13% bone marrow graft, 29% matched related donor, 49% matched unrelated donor, 22% haploidentical donor, and 52% HCT-specific comorbidity index ≥ 3. Among patients with high/very high DRI, there was no difference in OS, DFS, relapse, and NRM between RIC and MAC conditioning groups. For low/intermediate risk DRI recipients of MAC had better 3-year OS estimate (69% versus 57%, P = .001), DFS (65% versus 51%, P = .003), and lower relapse (3-year cumulative incidence, 17% versus 32%; P = .01) but similar NRM (19% versus 17%, P = .04) to RIC recipients. On multivariable analysis MAC was associated with better DFS (hazard ratio [HR], .58; 95% confidence interval [CI], .39-.88; P = .01), lower relapse (HR, .56; 95% CI, .32 to .97; P = .038), and similar NRM (HR, 1.11; 95% CI, .54 to 2.26; P = .781) compared with RIC in the low/intermediate DRI group. Intensity had no impact on HCT outcomes in the high/very high DRI group.MAC improves DFS and relapse compared with RIC among AML/MDS patients with low/intermediate DRI. The finding of no such benefit in high/very high DRI needs to be further explored in a larger cohort with a longer follow-up.

Outcomes of Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Hodgkin Lymphomas: A Retrospective Multicenter Experience by the Rete Ematologica Pugliese (REP)

BackgroundHodgkin lymphoma (HL) is a potentially curable disease, and modern therapy is expected to successfully cure more than 80% of the patients. However, patients progressing after intensive treatments, such as autologous stem cell transplantation (SCT), have a very poor outcome. Allogeneic SCT offers the only strategy with a curative potential for these patients. This study reports a retrospective multicenter experience of the Rete Ematologica Pugliese (REP) over the past 17 years, aiming to define the impact of each patient’s disease and transplant-related characteristics on outcomes. Patients and MethodsWe retrospectively studied 72 patients with HL who received allogeneic SCT from 2000 to 2017. At the time of allogeneic SCT, 33 (46%) patients had chemosensitive disease, and 39 (54%) were chemo-refractory. All patients received reduced-intensity conditioning, 50% received grafts from a matched sibling donor, and 50% from a matched-unrelated donor. ResultsWith a median follow-up of 48 months (range, 3-195 months), 30 patients are alive, and 42 have died. The Kaplan-Meier estimates of overall survival and progression-free survival at 5 years were 35% and 34%, respectively. Following transplantation, 12 (17%) patients died of non-relapse mortality at a median of 90 days (range, 1 day-20 months). The causes of death included infection (n = 7), graft-versus-host disease (n = 3), and multi-organ failure (n = 2). ConclusionsAllogeneic SCT results extend survival in selected patients with relapsed/refractory HL, showing low treatment-related mortality. Patients with active disease at the time of allogeneic transplantation have poor outcomes. Allogeneic SCT may be an effective salvage strategy for patients who relapse after an autologous SCT.

Absence of early HHV-6 reactivation after cord blood allograft predicts powerful graft-versus-tumor effect.

Approximately 75% of cord blood transplant (CBT) recipients experience human herpes virus-6 (HHV-6) reactivation. Considering the immunomodulatory effects of HHV-6, we hypothesized that early HHV-6 reactivation may influence the risk of relapse of the underlying hematologic malignancy. In 152 CBT recipients with hematological malignancies, we determined the association between HHV-6 reactivation by day +28 and 2-year cumulative incidence of relapse. In univariate analysis, the absence of HHV-6 reactivation (n = 32) was associated with less relapse (26 [18-35]% vs. 7 [0-17]% in groups with vs. without HHV-6 reactivation, respectively; P = .03). This difference was due to a remarkably low relapse incidence among patients without HHV-6 reactivation. In multivariable analysis, the absence of HHV-6 reactivation was associated with less relapse (hazard ratio [95% confidence interval]: 0.2 [0.05-0.9], P = .03). This association was independent of patient-, disease-, and transplant-related characteristics known to influence the risk of relapse. Natural killer cell and T-cell reconstitution at day +28 were similar between patients with vs. without HHV-6 reactivation. Our results suggest that CB allografts not complicated by HHV-6 reactivation by day +28 have a powerful graft-versus-tumor effect. Knowledge about early HHV-6 reactivation may stratify patients at day +28 into low vs. high relapse risk groups.

The Frequency of Carpal Tunnel Syndrome in Hurler Syndrome After Peritransplant Enzyme Replacement Therapy: A Retrospective Comparison

Children with Hurler syndrome (HS) develop carpal tunnel syndrome (CTS) owing to glycosaminoglycan deposition secondary to enzyme deficiency. Advancement in the treatment of the underlying enzyme deficiency now commonly includes peritransplant intravenous enzyme replacement therapy (ERT). The primary objective of this study was to determine if the use of limited ERT in addition to hematopoietic stem cell transplantation (HCT) for the treatment of children with HS reduces the incidence of surgical intervention for CTS compared with a cohort of historical controls treated with HCT alone. The secondary objectives were to evaluate the impact of demographic and transplant-related characteristics on the incidence of CTS. Lastly, the results of surgical treatment of CTS in HS are reported. Medical records for a historical group of 43 HS patients who underwent HCT alone (group 1) were compared with 31 HS patients who underwent HCT+ ERT (group 2). Both groups were compared for genotype, age at transplant, sex, transplant graft source, median/ulnar nerve conduction study parameters as well as the incidence and treatment of CTS. Pre- and postoperative nerve conduction studies were compared for children treated surgically for CTS. The cumulative incidence of CTS at 5 years for HS children treated with HCT+ ERT was 51% compared with 47% for HS children treated with HCT alone. The incidence of CTS did not depend upon graft source, age at transplant, or sex. Median nerve conduction velocity for both sensory and motor potentials demonstrated significant improvement after carpal tunnel release. Although the administration of ERT prior to and for several months after HCT has become routine in our institution, our findings do not suggest this combined therapy is sufficient to decrease thedevelopment of CTS. Surgical intervention for median nerve compression remains the treatment of choice for CTS in HS children. Therapeutic IV.

Ureteric complications in recipients of kidneys from donation after circulatory death donors.

A large increase in the use of kidneys from donation after circulatory death (DCD) donors prompted us to examine the impact of donor type on the incidence of ureteric complications (UCs; ureteric stenosis, urinary leak) after kidney transplantation. We studied 1072 consecutive kidney transplants (DCD n=494, live donor [LD] n=273, donation after brain death [DBD] n=305) performed during 2008-2014. Overall, there was a low incidence of UCs after kidney transplantation (3.5%). Despite a trend toward higher incidence of UCs in DCD (n=22, 4.5%) compared to LD (n=10, 3.7%) and DBD (n=5, 1.6%) kidney transplants, donor type was not a significant risk factor for UCs in multivariate analysis (DCD vs DBD HR: 2.33, 95% CI: 0.77-7.03, P=.13). There was no association between the incidence of UCs and donor, recipient, or transplant-related characteristics. Management involved surgical reconstruction in the majority of cases, with restenosis in 2.7% requiring re-operation. No grafts were lost secondary to UCs. Despite a significant increase in the number of kidney transplants from DCD donors, the incidence of UCs remains low. When ureteric complications do occur, they can be treated successfully with surgical reconstruction with no adverse effect on graft or patient survival.

Structural Equation Modeling of Self-Management of Liver Transplant Recipients

The purpose of this study was to construct and test a structural equation model of self-management of liver transplant recipients based on self-determination theory. Participants were 275 outpatients who received liver transplantation. A structured self-report questionnaire was used to assess health care providers' autonomy support, transplant-related characteristics, illness consequence perception, autonomy, competence, family relatedness, depression and self-management. Collected data were analyzed using SPSS/WIN 24.0 and AMOS 24.0 program. The modified model showed a good fitness with the data: GFI=.96, RMSEA=.06, CFI=.96, NFI=.93, TLI=.93, PGFI=.43, PNFI=.49. The health care providers' autonomy support, competence, family relatedness and depression were factors with a direct influence on the self-management of liver transplant recipients. The health care providers' autonomy support and illness consequence perception had an indirect influence through competence, family relatedness and depression. However, the transplant-related characteristics and autonomy did not have a significant effect on self-management. This model explained 59.4% of the variance in self-management. The result suggests that continuous education must be done to promote the competence of liver transplant recipients and to encourage the patient to positively perceive their current health condition with a view that enhances one's self-management. Additionally, the liver transplant recipients should be screened for depression, which would affect self-management. Most of all, health care providers, who have the most influence on self-management, should improve therapeutic communication and try to form a therapeutic relationship with the liver transplant recipients.

Impact of Human Leukocyte Antigen (HLA) Alleles on Outcomes of Allogeneic Transplantation (Allo-HCT) for B-Cell Non-Hodgkin Lymphomas (B-NHL); A CIBMTR Analysis

Even in the modern era of targeted therapies, allo-HCT remains a strategy that offers a chance of extended survival in B-NHL who relapsed after, or are deemed ineligible for, autologous transplantation (auto-HCT). Moreover, it was shown that efficacy of auto-HCT in extending survival in patients with diffuse large B-cell lymphoma is limited in the post-rituximab era. The use of allo-HCT for salvage of relapsed/refractory B-NHL is likely to increase with the wide adoption of reduced intensity conditioning (RIC) since transplant-related mortality (TRM) is lower while preserving the benefit of graft vs lymphoma (GVL) effect. Further understanding of the factors likely to predict a more robust GVL response, and potentially better clinical outcomes, would be very useful in selecting patients with B-NHL who are likely to benefit from allo-HCT. Multiple prior studies have shown that the presence of certain human leukocyte antigen (HLA) alleles may be instrumental in modulating the outcomes of B-NHL after immunochemotherapy and/or allo-HCT. We hypothesized that certain HLA alleles may have superior ability to present antigens to cytotoxic T-cells or possibly modulate natural killer (NK) cell activity.We undertook a retrospective analysis of CIBMTR data to evaluate whether the presence of HLA-A2, HLA-C1C1, HLA-DRB1*01:01 or HLA-DRB1*13 alleles and HLA-A1+, HLA-A2- and HLA-B44- haplotypes were associated with outcomes of patients with relapsed/refractory B-NHL after transplantation from HLA-8/8 matched sibling (MRD) or unrelated (MUD) donors. The primary outcome was time to progression. Secondary outcomes included progression-free (PFS) and overall survival (OS), TRM, and incidence and severity of acute and chronic graft versus host disease (GVHD). Multivariate analyses were performed using Cox proportional hazards models adjusting for multiple disease and transplant related characteristics. HLA-A*02 was tested individually; HLA-DRB1*0101 and HLA-DRB1*13 were tested in 4 combinations; HLA-A1+/A2-, B44- vs. A2+ vs. neither. Because of multiple comparisons, p<0.01 is considered significant.The final analysis population was restricted to 1314 patients who received the first allo-HCT during the years of 1995-2012 for indolent (N=506), aggressive (N=514), and mantle (N=294) B-NHLs from MRD (N=708) or MUD (N=606) utilizing myeloablative; MA (N=636), RIC (N=434), non-myeloablative; NMA (N=196) or other (n=48) conditioning. The different HLA allele analysis groups were well-balanced for all disease, patient, transplant and donor characteristics. In multi-variate analysis, we have observed no significant association between any of the HLA alleles or combinations we tested with any of the primary or the secondary end-points. A power calculation suggested very large numbers would be needed to reach statistical significant based on the data analyzed so far. The marked heterogeneity of different lymphoma subtypes, conditioning regimens, donor choices, GVHD prophylaxis, supportive regimens or other center-related characteristics likely limited the ability to detect effects of differences in individual recipient HLA alleles. In conclusion, this study represents the largest reported series of allo-HCT outcomes of B-cell NHL patients based on HLA type. Further study of other variables will be required to delineate the immunologic impact of donor-host interactions on outcomes of allo-HCT for B-cell NHL. DisclosuresNo relevant conflicts of interest to declare.

Incidence of Cytomegalovirus (CMV) Reactivation after Autologous Peripheral Blood Stem Cell Transplantation (ASCT) in 324 Patients with Multiple Myeloma and Lymphoma: A Single-Center Study at the American University of Beirut Medical Center (AUBMC)

CONTEXT: Cytomegalovirus reactivation (R-CMV) is often diagnosed in allogeneic hematopoietic cell transplant recipients and could determine a CMV-related disease in these immunocompromised patients, involving any organ. R-CMV and end-organ disease after ASCT has not been studied thoroughly. Autograft recipients are generally considered to have low risk of R-CMV or end-organ disease.OBJECTIVE: Evaluate the incidence, risk factors, and outcome of R-CMV in adult patients with hematologic malignancies undergoing ASCT.DESIGN: Retrospective single center study.SETTING: This study was approved by the institutional review board of AUBMC and conducted at our institutionPATIENTS OR OTHER PARTICIPANTS: A total of 324 consecutive ASCT were performed at AUBMC between January 2005 and March 2016. All patients and transplant-related characteristics are listed on Table 1. CMV DNA load in blood was measured by quantitative polymerase chain reaction (PCR) weekly as a routine monitoring strategy in all patients. Irrespective of PCR results, some patients suspected to have gastrointestinal involvement were biopsied. Also, in the presence of symptomatic CMV reactivation, appropriate anti-CMV therapy was instituted.MAIN OUTCOMES MEASURES: The primary outcome is understanding the potential relationship between R-CMV and Overall Survival (OS). Secondary outcomes included the effect of CMV reactivation on transplant related mortality (TRM), and progression free survival (PFS).RESULTS: Overall, 53 (16%) patients had R-CMV and 38 (72%) required anti-CMV treatment. Five (1,5%) had CMV disease with positive PCR on colon biopsy, yet two had PCR negative in blood. After a median follow up of 21.5 months (range: 1 to 125 months), there was no significant difference in OS or PFS between patients with or without R-CMV. TRM has increased from 1.1% in patients with no R-CMV to 13% in patients with R-CMV (P=0.003). We didn't observe any impact for age, sex, type of disease, pre-transplant treatment types/lines on the incidence R-CMV following ASCT.CONCLUSIONS: Our data suggest that R-CMV is not uncommon in ASCT recipients and may contribute to increased TRM. Biopsy is recommended in case of high suspicion of R-CMV irrespective of PCR results. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Feasibility and Efficacy of High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation for HIV-Related Lymphoma: A Single-Institution Experience

Background: High dose therapy (HDT) followed by autologous hematopoietic cell transplantation (autoHCT) has been shown to be safe and effective in patients with HIV-related lymphoma (HRL). Data is limited to small case series, transplant registries and a single prospective multicenter observational study. Here we report our institutional experience with auto-HCT in patients with HRL.Patients and methods: Twenty patients with HRL [non-Hodgkin=14 (70%), Hodgkin=6 (30%)] and treatable HIV infection underwent HDT consisting of carmustine, etoposide, cytarabine and melphalan (BEAM) followed by peripheral blood auto-HCT from 04/2006 to 07/2015. In 2 cases rituximab was administered as part of the preparative regimen. Patient-, disease-, and transplant-related characteristics are summarized in Table 1.Results: Median age was 48 years (range 35-61). The median follow-up for surviving patients was 42 months (range 6-110). At transplant, median peripheral blood CD4 count was 226 cells/µl (range 41-761). HIV viral load was undetectable in 14 out of 20 patients and lower than 4 logs in all of them. The median time to neutrophil and platelet engraftment were 11 days (range 10-13) and 14 days (range 13-176), respectively. Response rates at day +100 post-autografting in 17 evaluable patients were as follows: complete remission (CR)=11/17 (65%), partial response (PR)=2/17 (12%), and relapse/progression=4/17 (24%). Median event-free survival (EFS) was 58.4 months. Median overall survival (OS) was 74.3 months. At 5-years post-transplantation, EFS and OS were 68% and 53%, respectively. Non-hematologic toxicities consisted of mucositis in 8 (grade 1=3, grade 2=5), and enteritis in 13 patients (grade 1=2, grade 2=3, and grade 3=8). There were 13 documented infections in 11 patients (bacterial=9, viral=2, fungal=2). Six patients died from disease relapse/progression (n=5) and infection (n=1). Non-relapse mortality was 0% at day 100 and 5% at 5 years.Conclusion: Patients with HRL and treatable HIV infection should be offered autoHCT if indicated. HIV infection is no longer a contraindication for autoHCT in this population. [Display omitted] DisclosuresChavez:Janssen: Speakers Bureau. Kharfan-Dabaja:Seattle Genetics: Speakers Bureau; Incyte: Speakers Bureau.

Incidence of Cytomegalovirus (CMV) Reactivation after Autologous Peripheral Blood Stem Cell Transplantation (ASCT) in 324 Patients with Multiple Myeloma and Lymphoma: a Single-Center Study at the American University of Beirut Medical Center (AUBMC)

Abstract CONTEXT: Cytomegalovirus reactivation (R-CMV) is often diagnosed in allogeneic hematopoietic cell transplant recipients and could determine a CMV-related disease in these immunocompromised patients, involving any organ. R-CMV and end-organ disease after ASCT has not been studied thoroughly. Autograft recipients are generally considered to have low risk of R-CMV or end-organ disease. OBJECTIVE: Evaluate the incidence, risk factors, and outcome of R-CMV in adult patients with hematologic malignancies undergoing ASCT. DESIGN: Retrospective single center study. SETTING: This study was approved by the institutional review board of AUBMC and conducted at our institution PATIENTS OR OTHER PARTICIPANTS: A total of 324 consecutive ASCT were performed at AUBMC between January 2005 and March 2016. All patients and transplant-related characteristics are listed on Table 1. CMV DNA load in blood was measured by quantitative polymerase chain reaction (PCR) weekly as a routine monitoring strategy in all patients. Irrespective of PCR results, some patients suspected to have gastrointestinal involvement were biopsied. Also, in the presence of symptomatic CMV reactivation, appropriate anti-CMV therapy was instituted. MAIN OUTCOMES MEASURES: The primary outcome is understanding the potential relationship between R-CMV and Overall Survival (OS). Secondary outcomes included the effect of CMV reactivation on transplant related mortality (TRM), and progression free survival (PFS). RESULTS: Overall, 53 (16%) patients had R-CMV and 38 (72%) required anti-CMV treatment. Five (1,5%) had CMV disease with positive PCR on colon biopsy, yet two had PCR negative in blood. After a median follow up of 21.5 months (range: 1 to 125 months), there was no significant difference in OS or PFS between patients with or without R-CMV. TRM has increased from 1.1% in patients with no R-CMV to 13% in patients with R-CMV (P=0.003). We didn't observe any impact for age, sex, type of disease, pre-transplant treatment types/lines on the incidence R-CMV following ASCT. CONCLUSIONS: Our data suggest that R-CMV is not uncommon in ASCT recipients and may contribute to increased TRM. Biopsy is recommended in case of high suspicion of R-CMV irrespective of PCR results. Download : Download high-res image (264KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.

Outcomes of allogeneic hematopoietic stem cell transplantation for lymphomas: a single-institution experience.

IntroductionAllogeneic hematopoietic stem cell transplantation offers the opportunity for extended survival in patients with Hodgkin's and non-Hodgkin lymphomas who relapsed after, or were deemed ineligible for, autologous transplantation. This study reports the cumulative experience of a single center over the past 14 years aiming to define the impact of patient, disease, and transplant-related characteristics on outcomes.MethodsAll patients with histologically confirmed diagnosis of Hodgkin's or non-Hodgkin lymphomas who received allogeneic transplantation from 2000 to 2014 were retrospectively studied.ResultsForty-one patients were reviewed: 10 (24%) had Hodgkin's and 31 (76%) had non-Hodgkin lymphomas. The median age was 50 years and 23 (56%) were male. The majority of patients (68%) had had a prior autologous transplantation. At the time of allogeneic transplantation, 18 (43%) patients were in complete and seven (17%) were in partial remission. Most (95%) patients received reduced-intensity conditioning, 49% received matched sibling donor grafts, 24% matched-unrelated donor grafts, and 27% received double umbilical cord blood grafts. The 100-day treatment-related mortality rate was 12%. After a median duration of follow up of 17.1 months, the median progression-free and overall survival was 40.5 and 95.8 months, respectively. On multivariate analysis, patients who had active disease at the time of transplant had inferior survival.ConclusionsAllogeneic transplantation results extend survival in selected patients with relapsed/refractory Hodgkin's and non-Hodgkin lymphomas with low treatment-related mortality. Patients who have active disease at the time of allogeneic transplantation have poor outcomes.

Cytogenetic Evolution and Its Effect on Survival of Patients with Relapse Myeloid Neoplasms after Allogeneic Hematopoietic Cell Transplantation

Survival of patients with myeloid neoplasms that relapsed after allogeneic hematopoietic cell transplantation (HCT) is poor. It is generally presumed that acquisition of increasing cytogenetic complexity may contribute to poor outcomes, but cytogenetic changes that accompany relapse are not well characterized. The role of cytotoxic chemotherapy in promoting mutagenic events has been proposed, however, the specific correlation between type and dose of chemotherapy with cytogenetic evolution has not been studied. A single institution, retrospective case cohort analysis of patients with myeloid malignancies who relapsed after an allogeneic HCT. Cytogenetic (CG) data at diagnosis and at relapse were compared with special emphasis on gain in abnormalities resulting in increasing cytogenetic complexity, known as cytogenetic evolution (CGE). Transplant-related characteristics were compared between patients who developed CGE and those who did not. Overall survival expressed in Kaplan-Meier curve, compared by log-rank test between the two groups. Of 506 patients undergoing allogeneic HCT transplanted for a myeloid malignancy at Mayo Clinic Arizona between 2006-2014, 92 patients relapsed post-transplantation, 49 cases met inclusion criteria; CGE was observed in 25, while 24 cases demonstrated unchanged cytogenetic results at relapse. Age was similar between groups (mean=49.4). Male to female ratio was equal in the CGE cohort (48% vs 52%), and a slight female predominance was observed in the non-CGE cohort (67% vs 33%). Patient disease spectrum included 27 de-novo AML, 19 MDS-MPN, and 3 CML. The ratio of MDS-MPN to de-novo AML was 12/11 in CGE cohort versus 7/16 in non-CGE cohort. High risk to intermediate disease risk ratio in CGE was 64.0/36.0 versus non-CGE 45.8/54.2. Both cohorts had similar median days from BMT to relapse and comparable induction and conditioning regimen exposures. Median OS was 1.35 months (95% CI: 0.69-2.76) in CGE cohort versus 5.65 (95% CI: 2.14-8.48) in the unchanged cohort, p<0.001. CG evolution, defined as gains in cytogenetic abnormalities resulting in increasing CG complexity, is common at relapse of myeloid malignancies after allogeneic HCT. CGE is associated with a significantly shorter survival after relapse compared to patients without CGE. The CGE cohort exhibits two major trends when compared to the non-CGE group: 1. a greater proportion of high-risk disease than intermediate-risk and 2. a larger proportion of MDS/MPN disease spectrum than de-novo AML. There was no association with myeloablative versus reduced intensity conditioning regimen or lines of salvage therapy received. The clear association of CGE and shorter survival suggests that new markers would be useful to identify patients with risk of cytogenetic instability at transplant, to enable more individualized therapy in this patient group.

The Impact of Graft/Recipient ABO Compatibility on Outcomes after Umbilical Cord Blood Transplant for Non-Malignant Disease

Background:Existing literature shows mixed conclusions regarding the impact of ABO incompatibility on outcomes following hematopoietic cell transplantation (HCT). As the future for umbilical cord blood (UCB) expansion technologies is bright, we assessed whether this typically-overlooked graft characteristic impacted various outcomes following UCB transplantation (UCBT) for non-malignant disorders (NMD).Patients and Methods:A prospectively maintained institutional BMT program database was queried for all patients undergoing first UCBT for NMD and their demographic, disease and transplant-related characteristics. For each transplant, UCB and recipient ABO compatibility was considered (1) matched, (2) major mismatched (recipient isoagglutinins against UCB antigen), (3) minor mismatched (UCB isoagglutinins against recipient antigen), or (4) bi-directional mismatched. In double UCBT, only the compatibility status of the dominant unit was considered.The impact of ABO incompatibility was assessed on the following outcomes using Kaplan-Meier and cumulative incidence functions: graft failure, aGvHD (grade II - IV and III - IV), cGvHD, platelet recovery, and overall survival. Cumulative red blood cell transfusion exposure per patient between HCT days 0 and +100 (c-RBC) was obtained from laboratory records. Donor hematopoietic chimerism values on the myeloid fraction of peripheral blood were reviewed at day +100 and most recent time assessed. HLA typing was at the antigen level for HLA-A and -B and allele level at -DRB1; in double UCBT, the matching status of the dominant unit was considered.Results:Through December 2014, 270 patients have undergone first UCBT for various NMD (inherited metabolic disorder = 165; marrow failure = 71; other = 34). The mean age at UCBT was 7.9 years (± 9.6). Most patients had a maximal performance score before UCBT (Lansky/Karnofsky of 100, n = 162; 60%) and were male (n = 164; 61%). Most patients received a single UCB unit (n = 225; 83%) and the majority of grafts were unrelated (n = 253; 94%). The average total nucleated cell dose was 8.0 x 107/kg (± 6). With respect to HLA-matching, 79 (29%) received matched, 133 (49%) single-mismatched and 57 (21%) two-mismatched grafts. Most patients received myeloablative conditioning (n = 209; 77%) and GvHD prophylaxis with cyclosporine and mycophenolate mofetil (n = 150; 56%). Negative CMV serostatus in both the graft and recipient was most common (n = 172; 64%).ABO compatibility for the cohort was as follows: matched, n = 93 (34%); major mismatch, n = 72 (27%); minor mismatch, n = 80 (30%); bi-directional mismatch, n = 23 (9%). ABO compatibility status was indeterminate in 2 transplants. Among all 4 ABO compatibility groups, no significant difference was seen in age, gender, NMD diagnosis category, conditioning intensity, HLA-matching, cell dose, number of UCB units, transplant era, performance score, GvHD prophylaxis, or CMV serostatus. Related UCB unit transplants were more likely to be ABO matched.Table 1 shows outcomes by ABO compatibility group with a median follow-up time of 4.5 years (range, 0.5 - 20). ABO compatibility status did not appear to impact any outcomes assessed, though a trend toward increased grade III - IV aGvHD was seen in recipients of major mismatched units.Table 1Outcomes after UCBT for NMD by ABO Compatibility StatusOutcomeABO Match (n=93)Minor Mismatch (n=80)Major Mismatch (n=72)Bidirectional Mismatch (n=23)P-valueOverall survival, 5 y estimate (95% CI)65% (53-74)72% (59-81)68% (54-78)76% (51-89)0.62aGVHD (II - IV) (95% CI)20% (12-29)25% (15-35)27% (16-38)28% (8-49)0.75aGVHD (III - IV) (95% CI)8% (2-15)8% (2-14)20% (10-29)5% (1-14)0.09cGVHD at 5 y (95% CI)8% (2-15)7% (1-13)8% (1-15)5% (1-15)0.96Graft failure (95% CI)19% (11-28)20% (11-29)25% (15-35)17% (2-34)0.83Platelet recovery at 1 y (95% CI)74% (65-83)75% (65-85)67% (55-78)70% (48-91)0.77Day 100 chimerism, ≥ 80% (95% CI)69% (58-79)70% (60-81)66% (54-78)75% (56-94)0.89Most recent chimerism, ≥ 80% (95% CI)79% (71-87)75% (65-84)66% (55-77)74% (56-92)0.33c-RBC (Day 0 to +100) median (inter-quartile range)11 (6-16)10 (6-20)10 (6-19)14 (8-21)0.75y = year; CI = confidence intervalConclusion:ABO compatibility status did not seem to impact outcomes following UCBT for our large NMD cohort. Further analysis of the cohort to exclude interference on some outcomes assessed will be needed for a more definitive conclusion. DisclosuresNo relevant conflicts of interest to declare.

Predictors of the Trajectory of Neurocognitive Functioning in the First Six Months after Allogeneic Hematopoietic Stem Cell Transplantation

Background: While most patients will not experience lasting neurocognitive effects from stem cell transplant, certain subgroups of patients may be particularly vulnerable to cognitive declines. The objective of this study was to identify factors that can predict the trajectory of neurocognitive functioning changes within the first six months after allogeneic hematopoietic stem cell transplantation (HCT).Methods: Adult patient scheduled for their first allogeneic HCT completed a neuropsychological test battery to assess neurocognitive functioning prior to transplant, and at 100 days and six months post-transplant. The neuropsychological testing battery consisted of six tests over 3 domains: learning/memory, psychomotor efficiency/processing speed, and executive functioning/working memory. Sociodemographic (e.g. intelligence quotient (IQ), years of education) and transplant-related (e.g. conditioning regimen, HCT-Comorbidity Index) characteristics were collected at baseline. Additional clinical characteristics were collected at each time point, including Karnofsky Performance Status, acute graft-versus-host disease (GVHD) graded using revised Glucksberg grading system, chronic GVHD graded with National Institutes of Health consensus criteria, and patient-reported outcomes of fatigue, depressive symptoms, and physical symptom distress. Raw scores were converted to standardized T-scores (Mean=50, SD=10) based on demographically-adjusted norms. Neurocognitive impairment was defined as performance of <1.5 SD on two tests or <2 SD on one test. Composite scores for each domain were tabulated based on average of scores on constituent tests. Participants who completed the baseline and at least one follow-up visit were included in the analysis. Unconditional growth models were used to assess for overall changes in neurocognitive functioning over time. Multivariate multilevel models were then specified to identify predictors of the trajectory of neurocognitive functioning. To address the issue of missing data, a sensitivity analysis was conducted in which all models were replicated using only the data from complete cases, or participants who were assessed at every time point.Results: 58 participants were included in the main analysis, 71% of whom provided data at all three time points. Missing data was mostly due to ill health preventing participation in study procedures. Mean age was 48.2 years; 47% were female; 81% of the sample was Caucasian. Mean years of formal education was 13.81 and the mean IQ was 114. The most frequent indications for allogeneic HCT included AML (34%), MDS (10%), CML (10%) and myelofibrosis (10%). 53% were treated with a myeloablative conditioning protocol. 46% of participants met the criteria for neuropsychological impairment prior to transplant. Mean T-scores of domain-specific neuropsychological performance prior to transplant were 39.93 (SD = 1.40) for learning/memory, 49.57 (SD = 1.26) for psychomotor efficiency/processing speed, and 49.37 (SD = 1.30) for executive functioning/working memory. Unconditional models specified overall improvements in learning/memory (3.64 units, p<.01), psychomotor efficiency/processing speed (3.44 units, p<.01), and executive functioning/working memory (3.82 units, p<.01) over the six months after transplant, that were not an effect of attrition. No significant change in the prevalence of overall impairment was detected over time. On multivariate analyses controlling for a range of sociodemographic and clinical predictors, Karnofsky Performance Status <80 was associated with worsening learning/memory over time (Figure 1); peak severity of acute GVHD higher than grade 2 was associated with worsening psychomotor efficiency/processing speed over time (Figure 2); and greater years of education predicted a faster improvement in psychomotor efficiency/processing speed over time. The effect of performance status and acute GVHD were maintained in subsequent sensitivity analyses.Conclusions: Overall, domain-specific neuropsychological performance demonstrated mild but statistically significantly improvement over the first six months after transplant. However, post-transplant outcomes, such as low functional status and severe acute GVHD, may influence the direction of change in neurocognitive functioning. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Association of Donor Killer Immunoglobulin-like Receptor (KIR) Genotype with Outcome after HLA-Matched Related Donor Hematopoietic Cell Transplantation for AML

Although outcomes after allogeneic hematopoietic cell transplantation (alloHCT) for AML have improved, this has mainly been attributed to a reduction in transplant-related mortality rather than reduced leukemia relapse. NK cell alloreactivity is regulated by inhibitory and activating signals mediated through cell-surface receptors including the killer immunoglobulin-like receptors (KIRs). Group A and B KIR haplotypes have distinct centromeric (Cen) and telomeric (Tel) gene-content motifs and donor Cen group B KIR haplotypes have been reported to be associated with decreased relapse and improved survival in AML patients undergoing unrelated donor alloHCT. We hypothesized that donor KIR genotype may also be predictive of outcomes after matched related donor (MRD) alloHCT. We evaluated 93 AML patients in CR1/CR2 who underwent T-cell replete alloHCT using HLA- matched related donors at our institution from 1/2000-3/2013. Sixty-six had myeloablative conditioning (MAC) that that was busulfan/cyclophosphamide-based and 27 had reduced-intensity conditioning (RIC) with fludarabine/total body irradiation or busulfan/fludarabine. Donors were KIR genotyped to assign haplotypes A/A vs. B/X and the distinctive Cen and Tel gene-content motifs of group A and B KIR haplotypes according to the presence or absence of one or more B haplotype-defining KIR genes. KIR B–content score for each KIR genotype was defined as the number of Cen and Tel gene-content motifs containing B haplotype–defining genes (range, 0-4). As compared to those with haplotypes B/X (n=40; B content scores of 1-4) those with haplotype A/A (n=25; B content score of 0) undergoing MAC had significantly lower 100-day, 6-, 12- and 24-month non-relapse mortality (NRM) (8% vs. 0%, 13% vs. 0%, 15% vs. 0%, 25% vs. 0%, respectively, Figure 1) which was confirmed on multivariable analysis (HR 9.19, p=0.03). There were no differences between these groups regarding patient and transplant-related characteristics, or for acute or chronic GVHD, relapse, or survival. The causes of death in the group with haplotypes B/X were most commonly attributed to infection and then GVHD. However, within the group with B/X haplotypes, the B motif content score (1-4) was not associated with significant differences in NRM (HR 0.79, p=0.56). No difference in outcomes was observed for those undergoing RIC. The number of donor activating KIR genes (2SD1, 2DS2, 2DS3, 2DS4, 2DS5, and 3DS1) was then assessed. As compared to those with 3-6 activating KIR genes (n=20) those with 0-2 (n=41) undergoing MAC had significantly lower 100-day, 6-, 12- and 24-month non-relapse mortality (NRM) (15% vs. 0%, 15% vs. 5%, 15% vs. 5%, 29% vs. 8%, respectively, Figure 2) which was confirmed on multivariable analysis (HR 4.07, p=0.01). There were no differences in other post-transplant outcomes when comparing these groups or when considering those undergoing RIC. An increase of 1 donor activating KIR also was highly associated with NRM (HR 1.37, p=0.008). Overall, these results suggest that in the MRD MAC alloHCT setting donor KIR genotype may be predictive of increased NRM risk, particularly for those with B/X haplotypes and greater numbers donor activating KIRs. No comparable effects were observed in the RIC setting. Future strategies to further enhance immune reconstitution post-transplant may be appropriate to pursue for these higher risk patients. These results may have potential implications to improve donor selection for those AML patients with multiple HLA-matched related donors and need to be validated in larger cohorts. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risk Factors Associated With Lung Retransplantation: Evaluation of a Nationwide Registry Over a Quarter Century

The relative paucity of donors heightens the debate and scrutiny surrounding retransplantation. To date, risk factors associated with retransplantation are poorly characterized in the literature. We sought to identify those risk factors that may independently serve to predict lung retransplantation. We performed a retrospective evaluation of the United Network for Organ Sharing data over 25 years from 1987 to 2012. Competing risk analysis was used to evaluate the cohort for cumulative incidence of retransplantation. Recipient-related, donor-related, and transplant-related characteristics were assessed using Cox regression to identify risk factors associated with lung retransplantation. We identified 23,180 adult lung transplant recipients, of which 791 (3.4%) had also undergone retransplantation. Factors associated with lung retransplantation at 1 year included recipient age (hazard ratio [HR], 0.97; p=0.005), admission to the intensive care unit (HR, 2.89; p=0.002), donor age (HR, 1.02; p=0.004), and bilateral lung transplantation (HR, 0.41; p<0.001). Moreover, predictors of 5-year risk of retransplantation included recipient age (HR, 0.95; p<0.001), intensive care unit hospitalization (HR, 1.87; p=0.005), and bilateral lung transplant (HR, 0.46; p<0.001), as well as recipient body mass index of 25 to 29 kg/m2 (HR, 1.29; p=0.04) and a diagnosis of chronic obstructive pulmonary disease (HR, 0.68; p=0.008). We identified factors associated with retransplantation that may afford a better prediction of graft failure and need for retransplantation. These may further serve to better guide donor selection and assist in the development and validation of a risk-scoring model to further guide preoperative counseling.