Allogeneic Hematopoietic Stem Cell Transplantation Patients Research Articles

Lymphocyte counts may predict a good response to mesenchymal stromal cells therapy in graft versus host disease patients.

Steroid-resistant GvHD is one of the most significant causes of mortality following allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Treatment with mesenchymal stromal cells (MSC) seems to be a promising solution, however the results from clinical studies are still equivocal. Better selection of candidate patients and improving monitoring of patients following MSC administration can increase treatment effectiveness. In order to determine which characteristics can be used to predict a good response and better monitoring of patients, blood samples were taken prior to therapy, one week and one month after therapy, from 26 allogeneic HSCT patients whom contracted GvHD and were treated with MSCs. Samples were examined for differential blood counts, bilirubin levels and cell surface markers. Serum cytokine levels were also measured. We found that the level of lymphocytes, in particular T and NK cells, may predict a good response to therapy. A better response was observed among patients who expressed low levels of IL-6 and IL-22, Th17 related cytokines, prior to therapy. Patients with high levels of bilirubin prior to therapy showed a poorer response. The results of this study may facilitate early prediction of success or failure of the treatment, and subsequently, will improve selection of patients for MSC therapy.

Xenon-129 MRI detects ventilation deficits in paediatric stem cell transplant patients unable to perform spirometry.

Early detection of pulmonary morbidity following haematopoietic stem cell transplantation (HSCT) remains an important challenge for intervention, primarily due to the insensitivity of spirometry to early change, and in paediatrics, patient compliance provides additional challenges. Regional lung ventilation abnormalities in paediatric HSCT patients were quantified using hyperpolarised xenon-129 (129Xe) magnetic resonance imaging (MRI) and compared to spirometry. Medically stable, paediatric allogeneic HSCT patients (n=23, ages 6-16 years) underwent an outpatient MRI scan where regional ventilation was quantified with a breath-hold of hyperpolarised 129Xe gas. Ventilation deficits, regions of the lung that ventilate poorly due to obstruction, were quantified as a ventilation defect percentage (VDP) and compared to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio, and forced expiratory flow at 25-75% of FVC (FEF25-75%) from spirometry using linear regression. The mean±sd 129Xe VDP was 10.5±9.4% (range 2.6-41.4%). 129Xe VDP correlated with FEV1, FEV1/FVC ratio and FEF25-75% (p≤0.02 for all comparisons). Ventilation deficits were detected in patients with normal spirometry (i.e. FEV1 >80%), supporting the sensitivity of 129Xe MRI to early obstruction reported in other pulmonary conditions. Seven (30%) patients could not perform spirometry, yet ventilation deficits were observed in five of these patients, detecting abnormalities that otherwise may have gone undetected and untreated until advanced. Lung ventilation deficits were detected using hyperpolarised 129Xe gas MRI in asymptomatic paediatric HSCT patients and in a subgroup who were unable to perform reliable spirometry. 129Xe MRI provides a reliable imaging-based assessment of pulmonary involvement in this potentially difficult to diagnose paediatric population.

Patients with Transplantation-Associated Thrombotic Microangiopathy Demonstrate Elevated Levels of Ba Protein That Correlate with Renal Function

Introduction Transplantation-associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic stem cell transplant (HSCT) characterized by hemolytic anemia, thrombocytopenia, and microvascular thrombosis that leads to multiple end-organ injury. The kidney is most uniformly affected. The disease is challenging, as it is difficult to diagnose, the pathogenesis is poorly understood, and therapies are limited, resulting in long-term complications and mortality as high as 80%. TA-TMA has been associated with genetic abnormalities in the alternative complement pathway (AP), part of the innate immune system (Fig. 1). In this study, we hypothesized that TA-TMA patients would demonstrate markers of AP activation. We aimed to measure the AP activation products C3a, C5a, and Ba in HSCT patients with TA-TMA in order to assess if the degree of AP activation correlated with renal function in these individuals. Methods Allogeneic HSCT patients with elevated lactate dehydrogenase and renal dysfunction (doubling of creatinine, proteinuria, and/or hypertension) were eligible for enrollment. Plasma samples were collected for measurement of C3a, C5a, and Ba at enrollment and intervals up to 6 months. Estimated glomerular filtration rate (eGFR), an assessment of renal function, was calculated by the Schwartz equation. 17 patients met eligibility criteria and were enrolled over a 2.5-year period. 10 of these met full criteria for TA-TMA based on our institutional guidelines, and 7 recovered without developing TA-TMA and served as controls. Results Ba levels were higher in TA-TMA patients compared to control patients at enrollment (P=0.001, Fig. 2 and Table 1) and remained higher throughout study duration. eGFR levels were lower in TA-TMA patients at enrollment (P=0.016), and remained lower throughout the study (Fig. 2). There were no differences in C3a or C5a between patient populations at enrollment (Table 1) or at any interval. In patients with more than one measurement, eGFR decreased as Ba levels increased over time. Among the 10 TA-TMA patients, 6 were treated with therapeutic plasma exchange (TPE) plus the complement C5 inhibitor, eculizumab, 2 were treated with TPE alone, 1 was treated with eculizumab alone, and 1 did not receive any treatment prior to a rapid decompensation and death. 1/7 (14%) control patients died, and 7/10 (70%) TA-TMA patients died. Conclusions In comparison to controls, TA-TMA patients demonstrated higher Ba levels at enrollment and throughout study, consistent with AP activation. Ba protein, therefore, may serve as a beneficial diagnostic marker for TA-TMA. Furthermore, renal function was worse in the TA-TMA group compared to the control group throughout study, and Ba levels inversely correlated with eGFR. Components generated early during AP activation, therefore, may be directly involved in the pathogenesis of renal endothelial injury in TA-TMA.

Implementation of Required Electronic Learning Modules to Enhance Nursing Pharmacotherapy Knowledge of Select Hematopoietic Stem Cell Transplant Topics

Background The care of hematopoietic stem cell transplant (HSCT) patients is complex. Both autologous and allogeneic HSCT patients require high level, expert nursing care to help attain optimal outcomes. For smaller transplant programs, nursing exposure to these complex patients and their potentially devastating complications is often rare. In order to increase nursing awareness on these topics, especially as it relates to pharmacotherapeutic interventions, supplementary education is necessary to maintain a high level of knowledge and understanding. Methods Multidisciplinary collaboration was imperative to the implementation of required electronic learning modules to enhance nursing pharmacotherapy knowledge. Attending physicians, transplant administrators, and most importantly bedside nurses were supportive of the endeavor. A survey was sent to nursing staff to obtain information on the topics they would find most beneficial. Based on a needs assessment survey, 3 initial electronic learning modules were developed which focused on pharmacotherapy surrounding conditioning regimens, acute graft versus host disease, and sinusoidal obstructive syndrome. Each module was developed in collaboration with an electronic learning developer as a 15-20 minute presentation with a test following each session. Nurses were allowed 3 attempts at each test, with a passing score set at 80%. If a nurse failed to pass a test after 3 attempts, they were required to meet with the nurse educator. Completion of each module was required for nurses to continue to care for HSCT patients at the institution. Results Of nurses surveyed, 100% were supportive of the development of required electronic learning modules. Three electronic modules have been developed and implemented thus far. Thirty two nurses have completed each of the 3 modules successfully. The average scores for the conditioning regimen module, acute graft versus host disease module, and sinusoidal obstructive syndrome module were 89%, 87%, and 87% respectively. No nurse timed out of the modules by failing 3 attempts at the test. Based on nursing surveys, additional modules have been identified including but not limited to treatment of viral infections, treatment of fungal infections, transplant associated thrombotic microangiopathy, and neutropenic fever. Conclusions Implementation of electronic learning modules has been successful at enhancing nursing pharmacotherapy knowledge of select HSCT topics. These modules serve as a successful means for providing annual competency and comfort for nurses in a smaller transplant program, especially when their exposure to certain complications is low.

α4β7 Integrin Is Upregulated on CD8+ Effector Memory T-Cells in Children with Gut Gvhd Prior to Clinical Symptoms and Represents a Therapeutic Target in Pediatric Allogeneic HSCT Patients

Background α4β7 integrin is expressed on T-cells which migrate to gut-associated lymphoid tissues. Expression of α4β7 integrin is elevated on memory T-cells in adult hematopoietic stem cell transplant (HSCT) recipients at diagnosis of GI GVHD. No pediatric data exist regarding α4β7 integrin expression before or at onset of GVHD. We hypothesized that α4β7 integrin expression on effector memory T-cells (TEMs) would be elevated in patients before acute GI GVHD symptoms compared to patients without GVHD and may be a useful therapeutic target for the prevention of acute GI GVHD. Methods Cryopreserved T-cells were characterized in 48 children who developed acute GI GVHD (n=22), isolated skin GVHD (n=12) and no GVHD (n=14). In patients with GVHD, T-cells were characterized prior to HSCT, one week before GVHD and at GVHD diagnosis. In patients without GVHD, samples were analyzed at baseline and day+30 after HSCT. Samples were incubated with fluorochrome conjugated monoclonal antibodies directed against CD3, CD8, CCR7, α4β7 integrin and CD45RA. TEMs were defined as CD3+, CCR7-, CD45RA- lymphocytes. Co-expression of trafficking markers implicated in GI GVHD (CCR5, CCR9), and liver GVHD (CXCR6 and CCR5) were also assessed. Samples were analyzed on an LSR Fortessa flow cytometer (BD Biosciences). Data were analyzed using FCS Express (De Novo Software). Surface expression of all markers were compared using the Mann Whitney U-test. Patients with skin GVHD and no GVHD were grouped for analysis. Patients with at least 200 absolute CD8+ T-cell events were deemed evaluable. Results Twenty patients with GI GVHD, 8 with skin GVHD and 10 patients without GVHD had at least 200 absolute CD8+ events and were evaluable. Demographics of patients are shown in Figure 1. Expression of α4β7 integrin on CD8+ TEMs was upregulated in patients with GI GVHD compared to the No GI GVHD (skin GVHD + no GVHD) group one week prior to clinical symptoms (p=0.02; Figure 2A). Co-expression of CCR5 and CCR9 with α4β7 integrin was also higher on CD8+ TEM cells in the GI GVHD group compared to No GI GVHD group (p Conclusion α4β7 integrin is elevated on CD8+ TEMs prior to acute GI GVHD symptoms and co-expression of intestinal trafficking-specific markers such as CCR5 and CCR9 are also elevated prior to acute GVHD in pediatric patients. Our data suggest a rationale for the blockade of α4β7 integrin or the dual blockade of α4β7 integrin and CCR5 with clinically available therapeutics (maraviroc and vedolizumab) for acute GI GVHD prevention in pediatric allogeneic HCT patients.

Allogeneic hematopoietic stem cell transplantation in a 76-year-old woman with relapsed acute myeloid leukemia

Acute myeloid leukemia (AML) is commonly diagnosed in the elderly. Treatment of AML frequently requires hematopoietic stem cell transplantation (HSCT), which is associated with significant treatment-related toxicity and is considered to be too intense for older patients. However, with the development of reduced intensity conditioning, patients of increasing age are now considered for HSCT. We present a case of relapsed AML in a 76-year-old woman who was successfully treated with allogeneic stem cell transplantation. She endured the process without significant complications and achieved a durable treatment response, demonstrating the feasibility of allogeneic HSCT in patients with very advanced age.

Minimal Residual Disease in Ovarian Biopsies Collected in Patients with Bone Marrow Complete Remission of Acute Lymphoblastic Leukemia

▪The last three authors contributed equally to this work.Introduction:Allogeneic hematopoietic stem cell transplantation (HSCT) may improve long-term survival of patients with acute lymphoblastic leukemia (ALL) at high risk of relapse. However, ovarian failure is observed in 70 to 90% of patients who received myeloablative HSCT. Autotransplantation of cryopreserved ovarian cortex harvested before gonadotoxic treatments has been shown to re-establish the menstrual cycles and lead to the birth of healthy children (Donnez J. N Engl J Med, 2018). In patients treated for acute leukemia, concern has been expressed about the risk of leukemia recurrence after the ovarian autotransplantation due to the potential presence of residual leukemic cells in the ovarian tissue (Dolmans MM. Blood, 2010). To date, there were only few studies evaluating the presence of leukemic cells in cryopreserved ovarian tissue, and in most cases ovarian tissues were harvested at diagnosis of ALL or early after onset of chemotherapy. The present study prospectively investigated, in the context of fertility preservation, the presence of leukemic cells in cryopreserved ovarian samples harvested before allogeneic HSCT in patients in complete remission (CR) of ALL.Patients and Methods:From October 2015 to May 2018, all female patients with ALL who had a leukemia specific marker and underwent ovarian cryopreservation before allogeneic HSCT as part of preservation fertility program in 3 centers were included in the study. Consents were obtained from the guardians and/or age appropriate patients. The specific local ethical committees approved the study. Ovariectomy was performed after patients achieved CR, mostly in the weeks preceding HSCT. Ovarian cortex was separated into several fragments and cryopreserved as previously described (Poirot C. Human Reprod, 2002). When more than 14 cortical fragments were obtained, one was dedicated to molecular analysis, as well as the ovarian medulla. MRD quantification was performed by quantitative PCR of clonal rearrangements of immunoglobulin/T-cell receptor genes (Ig/TCR) or oncogenic fusion genes, according to EuroMRD and European Against Cancer (EAC) guidelines. MRD in ovarian samples were compared to MRD in bone marrow (BM) sample obtained at the same time point.Results:Fourteen patients were included in the study: 12 with B-cell precursor ALL, 1 with T-cell ALL and 1 with mixed phenotype acute leukemia. MRD marker was Ig/TCR rearrangement in 12 cases, M-BCR-ABL transcript in 1 case and genomic MLL-AF4 in 1 case. Median age at transplant was 18.2 years (range 1.1 - 35.2 years). Criteria for HSCT were poor early response to treatment (N=8), Philadelphia positive ALL (N=1), or previous relapse (N=5). With a median follow-up after HSCT of 8.1 months (range 0.8 - 29.8 months), all patients are disease-free.At the time of ovariectomy, 7/14 (50%) patients had undetectable MRD in ovarian samples, 6 had low positivity below 10-4 and one had positive MRD higher than 10-4. Unexpectedly of the 7 patients with positive ovarian MRD, 4 were undetectable in BM. One of the 7 patients with undetectable MRD in ovarian samples was positive in bone marrow. Concordant results were observed between the cortex and medulla samples in 10 of the 11 cases where both could be tested.Conclusions:To our knowledge, this series is the largest cohort evaluating MRD in ovarian samples from patients with ALL in complete remission after full chemotherapy regimen. We detected low levels of residual leukemic cells in ovarian tissues in half of the patients, some of them having no detectable MRD in BM at the time of ovariectomy, suggesting that leukemic cells could preferentially persist in ovary. Our results warrant further analyses of an extended cohort and longer post-transplant follow-up to better assess the potential presence of leukemic cells in ovarian samples and evaluate the impact of ovarian MRD status on post HSCT relapse. Still, autotransplantation of cryopreserved ovarian cortex could be discussed after allogeneic HSCT in patients with undetectable ovarian MRD.Table 1. MRD evaluation in bone marrow and ovarian samples.BM, bone marrow; BCP-ALL, B-cell precursor ALL; Ph-positive ALL, ALL with Philadelphia chromosome; NA: not available. Undetectable MRD means negative result obtained with a sensitivity of 10-4 or 10-5. BCR-ABL1 MRD results are expressed as the BCR-ABL1/ABL1 transcripts ratio. DisclosuresNo relevant conflicts of interest to declare.

Treosulfan, Fludarabine and Cytarabine As Conditioning before Allogeneic Hematopoietic Stem Cell Transplantation

Background: The combination of treosulfan witth fludarabine was successfully introduced into toxicity-reduced conditioning regimens for hematopoietic stem cell transplantation (HCT). However, the risk of post-HCT relapse remains of concern. Here we report for the first time on the results of an individual treatment approach with treosulfan, fludarabin and cytarabine as conditioning for allogeneic HCT in patients with AML, MPN or MDS.Methods: 22 patients were treated with fludarabine 30 mg/m² given on day -6 to day -2, treosulfan 14 g/m² administered on days -4 to day -2 and cytarabin 2g/m² given on days -6 and -5. GvHD-prophylaxis consisted of cyclosporine A and methotrexate or MMF. In addition, antithymocyte globulin was applied in case of an unrelated donor. One patient received bone marrow and the remaining patients received peripheral blood stem cells from matched related donors (9%), matched unrelated donors (73%) or mismatched unrelated donors (18%). All patients were considered to have high risk of relapse because of unfavourable cytogenetic features and/or insufficient or missing response to previous treatment. Three patients (14 %) with CML after blast crisis received the combination because of the reported high relapse rate (46%) after three-day scheduled conditioning with treosulfan [1]. In addition, patients were considered to be ineligible for myeloablative standard conditioning because of multi-morbidity (n = 4; 18% with HCT-CI >2) and/or age >55 years (n = 14; 64%).Results: The median age of patients was 59 (35-68) years. Patients suffered from acute myeloid leukemia (n = 14, 64%), myeloproliferative neoplasia (n = 6, 27%) or myelodysplasic syndrome (n = 2, 9%). The conditioning regime was well tolerated and nearly all patients engrafted and achieved complete donor-type chimerism, except for one who died very early from sepsis. Another patient with underlying myelofibrosis suffered from secondary graft failure on day 100. Two patients developed aGVHD °III/ IV. None of the patients suffered from veno-occlusive disease or severe chronic GVHD. Overall survival and event-free survival at one year reached 60.2% and 59.6%, respectively. Six patients died from infectious disease, two from relapse and one patient from acute GVHD °IV.Conclusion: The combination of cytarabine with the established conditioning of treosulfan and fludarabine is feasible in patients with high risk of relapse and ineligible for myeloablative standard conditioning.Holowiecki J, Giebel S, Wojnar J et al. Treosulfan and fludarabine low-toxicity conditioning for allogeneic 334 haematopoietic stem cell transplantation in chronic myeloid leukaemia. Br J Haematol 335 2008; 142(2): 284-92. DisclosuresHilgendorf:Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Frietsch:Deutsche Krebshilfe: Research Funding. Scholl:Abbivie: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Deutsche Krebshilfe: Research Funding; Alexion: Other: Travel support. Hochhaus:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Casper:Medac: Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding.

Outcome of Patients with Acute Myeloid Leukemia (AML) Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Beyond First Complete Remission (CR1)

Abstract Introduction Despite substantial progress in the treatment of newly diagnosed AML, 20% to 40% of patients do not achieve remission with conventional induction chemotherapy. In addition, 50% to 70% of patients with CR1 are expected to relapse within 3 years. Currently, allogeneic HSCT is thought to be the most reliable curative option for patients with relapsed and/or refractory (r/r) disease. Compared to HSCT in CR1 allogeneic HSCT beyond CR1 is associated with lower survival rates. So far, different predictive factors influencing survival in r/r AML have been identified. However, pretransplantation variables delineating prognostic subgroups after allogeneic HSCT beyond CR1 are less well known and the total number of patients in trials addressing this issue has been limited. Methods We analyzed the outcome after allogeneic HSCT in non-APL-AML patients transplanted with either subsequent 2nd complete remission (CR2), r/r AML or with persisting cytopenia (PC, including patients with hematologic complete remission with incomplete hematologic recovery and patients with persisting bone marrow hypoplasia) after induction or salvage therapy. Of 3989 patients who enrolled into a multicenter clinical trial (AMLCG1999; NCT00266136) of the German Acute Myeloid leukemia Cooperative Group (AMLCG) we identified 498 subjects aged 17 to 74 years who underwent allogeneic HSCT beyond first CR. Before transplantation, all patients received first line treatment either with 6-Thioguanine, cyararabine, daunorubicin (TAD) and high-dose cytarabine, mitoxantrone (HAM) or HAM/HAM. After induction failure (n=97) or relapse (n=401) patients either received salvage chemotherapy (n=299) or directly underwent allogeneic HSCT (n=199). Overall survival (OS) and relapse free survival (RFS) after allogeneic HSCT were the main endpoints for this analysis. Kaplan-Meier analysis was performed to estimate survival probabilities in subgroups. Log-rank tests were used to compare survival groups. Relative hazard rates and differences in subgroups were calculated using cox regression analysis. Results At a median follow-up of 6.5 years for surviving patients, OS and RFS rates were 32% (95% CI 28-36%) and 30% (95% CI 26-34%), respectively. Subgroup analysis revealed an OS of 49% in 128 patients with allogeneic HSCT in CR2. In comparison, 73 patients who underwent allogeneic HSCT with PC after induction (n = 42) / salvage treatment (n = 31) and 297 patients with refractory disease (RD) exhibited an OS of 39% and 23%, respectively (Figure 1). The corresponding cumulative incidences (CI) at 1/6.5 years for death in remission after allogeneic HSCT were 25%/31% for patients transplanted in CR2, 29%/41% for patients transplanted with PC and 30%/46% for patients transplanted with RD, respectively. The cumulative incidence of relapse (CIR) after 6.5 years was 58% for patients transplanted with RD compared to 34% for patients transplanted in CR2 and 31% for patients with PC. Main prognostic factors for survival outcome were remission status prior to allogeneic HSCT and cytogenetic risk category at diagnosis. By contrast, patient age, donor, graft source, remission status after induction therapy and CMV status had no significant impact on survival outcome. Conclusions Long-term OS rates after allogeneic HSCT for patients with r/r AML are considered to range between 20 and 40%. Our analysis indicates that a substantial fraction of patients who received similar first line treatment within one prospective trial is able to achieve long term survival when transplanted beyond CR1. In addition, remission upon salvage therapy prior to allogeneic HSCT might be a relevant prognostic factor for patients with r/r AML. However, whether remission induction prior to HSCT can provide an overall survival benefit in patients with r/r disease is still elusive and is currently being evaluated in a prospective randomized clinical trial (ETAL3-ASAP; NCT02461537). Disclosures Beelen: Medac: Consultancy, Other: Travel Support. Scheid:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria. Lenz:Celgene Corp.: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Research Funding; Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria. Hiddemann:Bayer: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stelljes:MSD: Consultancy; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding.

Epidemiology of Second Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Relapsed Myelodysplastic Syndrome

IntroductionMyelodysplastic syndrome (MDS) represent a group of clonal myeloid stem cell disorder with a heterogeneous spectrum of presentation. Although allogeneic hematopoietic stem cell transplantation (HSCT) was the well-studied and only curative treatment option for patients with MDS, relapse remains a major drawback like other hematological malignancies because it is associated with poor survival in general. The efficacy of second allogeneic HSCT was reported for patients with various hematological diseases. However, even fundamental epidemiological data of second allogenic HSCT after relapsed MDS is still lacking. The aim of this study was to investigate the epidemiology in patients who received second allogenic HSCT after relapsed MDS, and then to evaluate prognostic factor of second allogeneic HSCT by comparing and identifying the difference between first and second allogeneic HSCT in patients with MDS.MethodsThe present study included 3340 adult patients with MDS who received first allogeneic HSCT from January 1990 to December 2015 (Total population) from the Japanese Data Center for Hematopoietic Cell Transplantation. Among total population, 627 patients experienced recurrence of MDS and 101 patients underwent second allogenic HSCT for the treatment of relapsed MDS after allogenic HSCT (Recurrent population). We defined a relapse more than 18 months after allogeneic HSCT as a “late relapse” and the others as an “early relapse.” Active disease was defined when the blast in bone marrow was greater than 5% and or presence of blast in peripheral blood. Performance Status (PS) was defined according to Eastern Cooperative Oncology Group and categorized into two group (i.e., good PS: 0-1 and poor PS: 2-4).We set the primary endpoint as the 5-year overall survival (5yOS) which was evaluated by using log-rank test. We defined 5yOS as the time from first HSCT in total population and second HSCT in recurrent population to any cause of death. Other endpoints were evaluated by using Gray's method. To evaluate the risk factors for the primary endpoint, we employed multivariable Cox proportional hazards model. Adjusted covariates were selected clinically based on previous reports, and those for recurrent and total population were shown in Table.ResultsWe analyzed 101 patients in recurrent population and 3340 patients in total population. In recurrent population, median age was 53 years old (interquartile: 45-59) and 58 patients (57.4%) were male. Eighty patients (82.5%) relapsed within 18 month after first allogeneic HSCT. The median duration between first and second HSCT was 281 days (interquartile: 145-610). Before second allogeneic HSCT, 71 (71.0%) patients had active disease and 31 patients (32.0%) had poor PS. About stem cell source, 35 (34.7%) received cord blood transplantation.Regarding primary endpoint, 5yOS after allogeneic HSCT was 24.7% (15.8-34.7%) in recurrent population (Figure 1A) and 49.9% (95%CI: 48.0-51.7%) in total population (Figure 1B). Regarding secondary endpoints, 5-year cumulative incidence of relapse was 45.2% (35.0-54.9%) and 22.6% (21.1-24.1%), 5-year cumulative incidence of non-relapse mortality was 33.4 (23.2-43.4%) and 29.5 (27.9-31.2%), and 5-year cumulative incidence of tumor-related mortality was 41.5% (31.1-51.5%) and 20.0% (18.6-21.5%) in recurrent population and total population, respectively.For analysis of prognostic factors influencing 5yOS in recurrent population, early relapse (HR: 2.82, 95%CI: 1.12-7.13, p=0.028) and poor PS (HR: 3.27, 95%CI: 1.79-5.97, p=0.001) were identified as significant independent predictors for 5yOS (Table). Ad-hoc subgroup analysis considering early relapse and poor PS demonstrated that the 5yOS were significantly worse in patients who had early relapse and poor PS as compared with other groups with median survival of only 57 days (p<0.001) (Figure 2). On the other hand, higher age, male gender, active disease, poor karyotype, poor PS and cord blood transplantation were associated with worse 5yOS in total population (Table).ConclusionIn the present study, we revealed epidemiology of second allogeneic HSCT for relapsed MDS and prognostic factor that could aid the identification of patients who may benefit from second allogeneic HSCT. Patients who relapsed earlier than 18 months and had poor PS were recommended not to receive second allogeneic HSCT. [Display omitted] DisclosuresMori:SHIONOGI: Honoraria; Ono: Honoraria; Taisho Toyama Pharmaceutical Co: Honoraria; Celgene: Honoraria; Asahi Kasei: Research Funding; Novartis Pharma: Research Funding; MSD: Research Funding; Astella Pharma: Honoraria; Janssen: Honoraria; MSD: Honoraria; Novartis Pharma: Honoraria; CHUGAI: Honoraria; Eisai: Honoraria; Pfizer: Honoraria; Japan Blood Products Organization: Honoraria; Shire Japan: Honoraria; Kyowa Hakko Kirin: Honoraria. Ichinohe:CSL Behring: Research Funding; Eisai Co.: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Celgene: Honoraria; Chugai Pharmaceutical Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; JCR Pharmaceuticals: Honoraria; Taiho Pharmaceutical Co.: Research Funding; Novartis.: Honoraria; Mundipharma: Honoraria; Zenyaku Kogyo Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Astellas Pharma: Research Funding. Ishiyama:Alexion Pharmaceuticals, Inc.: Honoraria.

Socioeconomic Status and Outcomes Among Mexican Patients Undergoing Allogeneic Stem Cell Transplantation

Background: Some specific patient and donor demographic factors have been described and associated with outcomes of hematopoietic stem cell transplantation (HSCT). However, associations with the socioeconomic status (SES) remain controversial as some studies including allogeneic HSCT (allo-HSCT) patients have reported that SES associates with worse long-term outcomes and other studies, including both, allogeneic and autologous HSCT have not found an association between SES and overall survival (OS), non-relapse mortality (NRM) or other outcomes. More importantly, these studies have been performed in developed countries and data from developing regions remains scarce.Objective: To associate the SES with outcomes in Mexican patients undergoing allo-HSCT at a National Institute of Health located in Mexico City.Patients and Methods: A retrospective study was performed including 124 consecutive patients undergoing allo-HSCT at the National Institute of Medical Sciences and Nutrition “Salvador Zubiran”, from May 1999 to March 2018. SES was established according to the classification assigned by the Department of Social Work (levels I-VII); the lowest level corresponds to 7% out-of-pocket expense (93% subsidized by the Institution) and the highest to 120% (private health insurances). Patients were dichotomized into low SES (levels I-II) and high SES (levels ≥ III). Disease risk index was classified as low, intermediate or high using standard definitions and the HCT-CI score was assigned to each patient. Graft-versus-host disease (GVHD) was evaluated according to NIH guidelines. Endpoints included OS and NRM.Results: Patient characteristics by SES are shown in Table 1. Age, educational attainment, employment status, and financial support were the sociodemographic characteristics that differed between both groups. There were no differences in GVHD between the two groups. For all the cohort, 30, 100-days, and 1-year NRM was 3.2%, 8.8%, and 14.5%, respectively. Figure 1 shows NRM and OS by SES group.Conclusion: Although there were differences regarding diagnosis between the two groups (low and high SES), the DRI was the same between them, as well as the HCT-CI. Further, there were no differences between low and high SES in NRM or OS, demonstrating that our HSCT approaches are standardized and all patients can benefit from them despite their financial status, also highlighting that patients with low SES probably had good outcomes as a result of substantial governmental, NGO, and/or institutional subsidy. DisclosuresNo relevant conflicts of interest to declare.

2055. Utility of Aspergillus Galactomannan Assay in Allogeneic Stem Cell Transplant Recipients

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is a valuable treatment option for patients with some blood/malignant disorders. However, this procedure may be complicated by life-threatening infections, including invasive aspergillosis (IA). Diagnosis of IA is challenging due to nonspecific symptoms that present similar to other infections; and delays in initiation of treatment are associated with poor outcomes. The galactomannan assay (GM) is a widely used test for the early diagnosis of IA and allows for prompt initiation of antifungal therapy. However, a positive (+) GM result requires further workup for a definitive diagnosis. Furthermore, false-positives can lead to unnecessary treatment with expensive and potentially toxic antifungal medications. At UC San Diego Health, allogeneic HSCT patients not on mold-active agents for antifungal prophylaxis have GM tested weekly until 100 days post-HSCT. This study aims to describe the utility of routine GM assays in this HSCT population.MethodsThis is a retrospective single-center study of patients >18 years of age post-allogeneic HSCT at UC San Diego Health from January 2015 to December 2016 with GM results reported in the electronic medical record. Data includes patient demographics, GM results up to 100 days post-HSCT, antifungal prophylaxis, further testing performed, diagnosis of possible, probable and proven IA, and outcome of infection.ResultsIn total, 108 patients met criteria for enrollment in this study. There were a total of 1,354 GM results, of which only 2.8% (38) were positive (≥1 +GM) in 25 patients (23% of all patients). Of these, 20 of 25 (80%) were found to be false-positives. In total, 7 of 108 patients had a diagnosis of possible or probable IA. Of the seven, two had 0 +GM, and two had 1 +GM. In the two with 1+GM, IA diagnosis was notably made prior to the +GM result. In only three of the seven cases did +GM screening lead to diagnosis of IA; of these, two patients had acute GVHD and one developed infection during neutropenia, in the first 2 weeks post-HSCT.ConclusionRoutine GM testing adds to cost and is not a useful predictor of IA infection in the studied population. Studies to determine what populations, if any, would most benefit from routine pre-emptive GM or other fungal screening are needed.Disclosures R. Taplitz, U.C.S.D.: Scientific Advisor, Consulting fee.

Human pegivirus persistence in human blood virome after allogeneic haematopoietic stem-cell transplantation

ObjectivesBecause commensal viruses are defined by the immunologic tolerance afforded to them, any immunomodulation, such as is received during haematopoietic stem-cell transplantation, may shift the demarcation between innocuous viral resident and disease-causing pathogen. MethodsWe analysed by deep-sequencing the plasma virome of 40 allogeneic haematopoietic stem-cell transplantation patients 1 month after transplantation. Because human pegivirus (HPgV) was highly prevalent, we performed a 1-year screening of 122 plasma samples by specific real-time reverse transcription PCR assay. We used the log-rank test and the Gray test to assess association with outcomes, and the Mann-Whitney test and multivariable linear regression model to assess association with T-cell reconstitution. ResultsPolyomaviruses (PyV) (20/40 patients), anelloviruses (16/40), pegiviruses (14/40) and herpesviruses (14/40) were most frequently identified, including ten cytomegalovirus; three Epstein-Barr virus; two herpes simplex virus type 1; one human herpesvirus 6b and one human herpesvirus 7; 18 Merkel cell–PyV; two BK-PyV; three PyV-6; and one JC-PyV. Papillomavirus and adenovirus were identified in 11 and two patients, respectively. The HPgV specific real-time reverse transcription PCR screening identified 51 of 122 positive samples, high virus loads and persistent infections up to 1 year after transplantation. Comparison between patients with or without HPgV infection at time of transplantation did not reveal a significant difference in infections, engraftment, survival, graft vs. host disease, relapse or immune reconstitution. ConclusionsThe blood virome after allogeneic haematopoietic stem-cell transplantation includes several DNA viruses, notably herpesviruses and PyV. Among RNA viruses, HPgV is highly prevalent and persists for several months, and it thus may deserve special attention in further research on immune reconstitution.

Increased Incidence of Nocardial Infections in an Era of Atovaquone Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Nocardial infections have been rare after allogeneic hematopoietic stem cell transplantation (HSCT). We report 10 recent cases of late-onset nocardiosis (median time of onset of 508 days after transplantation) primarily in patients on high doses of corticosteroids for graft-versus-host disease. All 10 patients had pulmonary infection caused by Nocardia species susceptible to trimethoprim-sulfamethoxazole (TMP-SMX). At time of diagnosis 8 of 10 patients were not receiving TMP-SMX for prophylaxis of Pneumocystis jiroveci pneumonia (PJP; 7 on atovaquone, 1 on i.v. pentamidine). After the initiation of atovaquone prophylaxis for PJP in place of TMP-SMX for many UCLA allogeneic HSCT patients in 2012, 9 cases of nocardiosis occurred in 411 patients (2.2%) over the next 6 years (2012 to 2017) compared with only 1 case in 575 patients (0.17%) during the previous 12 years (2000 to 2011). Although there were no deaths directly related to nocardial infection treated primarily with TMP-SMX, overall mortality in this group of patients was 40%. Based on this experience, the use of atovaquone for PJP prophylaxis in place of TMP-SMX may be associated with an increased risk for previously rare nocardial infections after allogeneic HSCT.

Enlarged spleen is associated with low neutrophil and platelet engraftment rates and poor survival after allogeneic stem cell transplantation in patients with acute myeloid leukemia and myelodysplastic syndrome.

Primary graft failure can be a cause of early morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), as it leads to a high risk of severe infections and bleeding. Splenomegaly is associated with primary graft failure in patients of myelofibrosis, but the association between splenomegaly and outcomes after HSCT in patients with myeloid malignancies has not been previously evaluated. The aim of this study was to investigate the effect of spleen volume on engraftment kinetics in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We enrolled 85 patients. The median spleen volume was 146cm3 (quartile 88-201cm3). The adjusted hazard ratios for neutrophil and platelet engraftments were 0.17 (0.07-0.40, p < 0.001) and 0.19 (0.05-0.69, p = 0.011), respectively, for the high-risk group, at a cutoff splenic volume of 320cm3. Overall survival at 3years after HSCT was significantly poor in the high-risk group with an adjusted hazard ratio of 13.8 (2.61-72.4, p = 0.002). Enlarged spleen was associated with low neutrophil and platelet engraftment rates and poor survival after allogeneic HSCT in patients of AML and MDS.

Caregiver Sleep and Patient Neutrophil Engraftment in Allogeneic Hematopoietic Stem Cell Transplant: A Secondary Analysis.

Caregiving for allogeneic hematopoietic stem cell transplant (Allo-HSCT) patients can be significantly burdensome. Caregiver well-being often mirrors patients' suffering. However, to our knowledge, this dyadic relationship has not been linked to patient outcome. Caregiver's objective and subjective sleep and overall distress before transplantation were hypothesized to be related to patient's time to engraftment in secondary analyses. Dyads (N = 124) were Allo-HSCT patients (mean [SD] age, 49.2 [12.7] years) and their caregivers (mean [SD] age, 52.7 [12.3] years). Caregiver's subjective sleep quality was measured via the Pittsburgh Sleep Quality Index, objective sleep was measured by actigraphy, and distress was measured by combining validated psychological measures. Both caregiver reports of worse sleep (β = .22; P < .05) and objective measurement of caregiver sleep patterns (higher sleep efficiency; less time awake after sleep onset) collected before engraftment significantly predicted shorter time to patient engraftment (β values = -.34 and .29, respectively; P values < .05). Caregiver distress was unrelated to engraftment (β = .14; P = .22). Despite limitations in available patient data, these findings appear to link caregiver well-being to patient outcome. This underscores the interrelatedness of the patient-caregiver dyad in Allo-HSCT. Future research should examine psychological and biomedical mediators. Given that caregiver well-being during the peritransplantation period was associated with patient outcome in this study, such findings highlight the need to address caregiver and patient well-being during Allo-HSCT. There may be potential to improve patient outcome by focusing on the caregiver, which nursing staff is well positioned to monitor.

Cytomegalovirus Reactivation and Disease amongst Patients with Allogeneic Haematopoietic Stem Cell Transplantation in Eastern India: Epidemiology, Outcome and Healthcare Cost

Purpose: Data from developing countries about incidence, prognosis and healthcare cost of cytomegalovirus (CMV) reactivation amongst patients with allogeneic hematopoietic stem cell transplantation (AHSCT) remain scarce. The purpose of the study was to describe the epidemiology, outcome and cost implications of CMV reactivation and CMV disease amongst patients with AHSCT in cancer hospital in Eastern India. Materials and Methods: The study design was a retrospective audit of clinical records. Results: Ninety-nine per cent of patients and 94% of the donors were found to be CMV seropositive. CMV reactivation rate was 43.8% amongst patients with AHSCT (n = 130 patients). CMV reactivation occurred 118 days after AHSCT (median; range: 28–943 days). Patients with any grade of graft-versus-host disease (GVHD) had higher CMV reactivation rate than patients without GVHD. Patients with CMV reactivation had more frequent GVHD than patients without CMV reactivation. Use of steroids was associated with CMV reactivation. We found no differences in overall survival of patients with or without CMV reactivation. The cost of in-house CMV-polymerase chain reaction at our centre was USD $57 (Rs. 3650), cost for intravenous ganciclovir was USD $26 (Rs. 1665) per infusion and oral valganciclovir USD $8 (Rs. 512)/900 mg tablet. The median duration of anti-CMV therapy was 14 days (interquartile range: 14–28 days) and the average cost per patient per month directed towards CMV management ranged between USD $800 and USD $1,300 (Rs. 51,238–Rs. 83,264). Three patients (2.3%) in this series had CMV disease, all of whom died. Conclusion: In an increasingly globalised world, where medical tourism is common, data from developing countries regarding cost and outcome of CMV infections in AHSCT patients are of relevance.

Dyslipidemia and lipid-lowering treatment in a hematopoietic stem cell transplant cohort: 25 years of follow-up data

Dyslipidemia is common after hematopoietic stem cell transplantation (HSCT). Few data regarding the time course of lipid profiles after HSCT, the effect of multiple transplantations, and efficacy and safety of lipid-lowering treatments are available. The objective of the study was to determine the prevalence and treatment of dyslipidemia over a 25-year period in a large, single-center cohort. One thousand one hundred ninety-six adult patients (≥16years) who underwent HSCT during 1973 to 2013 and who survived ≥100days were studied retrospectively. The prevalence of dyslipidemia before transplantation was 36% and 28% in the autologous and allogeneic groups, respectively (P<.001). Three months after HSCT, the prevalence rose to 62% and 74% (P<.001), and at 25years, it was 67% and 89%. Lipid profiles were similar after first and subsequent transplants. Baseline dyslipidemia (odds ratio [OR]= 2.72), allogeneic transplant (OR= 2.44), and age≥35years (OR= 2.33) were independent risk factors for dyslipidemia at 1 year. Lipid-lowering treatment was given to 223 (19%) patients, primarily in the form of statins (86%) and was associated with a decrease in total cholesterol from 246 to 192mg/dL (P<.01) and from 244 to 195mg/dL (P<.001) in the autologous and allogeneic groups, respectively. There were 10 cases (4%) of muscle symptoms prompting cessation of lipid-lowering therapy, including 1 case of rhabdomyolysis. The OR for dyslipidemia among patients who suffered a cardiovascular event (conditional logistic regression) was 3.5 (95% confidence interval= 1.6-7.7, P=.002). This study confirms that dyslipidemia is a common and long-lasting phenomenon among both allogeneic and autologous HSCT patients. Statins are effective, generally well-tolerated and should be highly recommended for the management of post-HSCT dyslipidemia.

High human herpesvirus 6 viral load in pediatric allogeneic hematopoietic stem cell transplant patients is associated with detection in end organs and high mortality.

Human Herpes Virus 6 (HHV-6) reactivation occurs in approximately half of patients following allogeneic hematopoietic stem cell transplant (HSCT). While encephalitis and delayed engraftment are well-documented complications of HHV-6 following HSCT, the extent to which HHV-6 viremia causes disease in children is controversial. We performed a retrospective review of HHV-6 reactivation and possible manifestations in pediatric allogeneic HSCT patients at a single institution. Of 89 children and young adults who underwent allogeneic HSCT over a three-and-a-half-year period, 34 patients reactivated HHV-6 early post-transplant. Unrelated donor stem cell source and lack of antiviral prophylaxis were risk factors for the development of HHV-6 viremia. Viremia correlated with the presence of acute graft-versus-host disease, but not chronic graft-versus-host disease. We identified two subgroups within the viremic patients-a high-risk viremic and tissue-positive group that reactivated HHV-6 and had suspected end-organ disease and a low-risk viremic but asymptomatic group that reactivated HHV-6 but did not exhibit symptoms or signs of end-organ disease. Peak viral load was found to be strongly associated with mortality. Prospective studies in larger numbers of patients are needed to further investigate the role of HHV-6 in causing symptomatic end-organ disease as well as the association of viral load with mortality.

Incidence and Risk Factors for Nontuberculous Mycobacterial Infection after Allogeneic Hematopoietic Cell Transplantation

Allogenic hematopoietic stem cell transplant (HCT) recipients are at risk of many infections. Nontuberculous mycobacteria (NTM) are increasingly recognized as clinically significant pathogens in this population. We investigated the incidence and risk factors for NTM infection after allogeneic HCT. This retrospective cohort study included all patients with allogeneic HCT at our institution during 2001 to 2013. Patients who developed significant NTM infection (NTM disease) were identified. Multivariable modeling was used to identify risk factors for NTM disease, and a risk score model was constructed to identify high-risk patients. Of 1097 allogeneic HCT patients, 45 (4.1%) had NTM isolated and 30 (2.7%) had NTM disease (28 [93.3%] exclusively pulmonary, 2 [6.7%] pulmonary plus another site). Incidence of NTM infection by competing risk analysis was 2.8% at 5 years (95% CI, 1.9% to 4.0%). The median time to diagnosis was 343 days (range, 19 to 1967). In Fine-Gray proportional hazards modeling, only global severity of chronic graft-versus-host disease (cGVHD) (HR, 1.99; 95% CI, 1.12 to 3.53; P = .019,) and cytomegalovirus (CMV) viremia (HR, 5.77; 95% CI, 1.71 to 19.45; P = .004) were significantly associated with NTM disease. Using these variables a risk score was calculated: 1 point for CMV viremia or moderate cGVHD and 2 points for severe cGVHD. The score divided patients into low risk (0 to 1 points, n = 820 [77.3%], 3-year NTM risk 1.2%), intermediate risk (2 points, n = 161 [15.4%], 3-year NTM risk 7.1%), and high risk (3 points, n = 56 [5.4%], 3-year NTM risk 14.3%). NTM disease after allogeneic HCT is common. Severe cGVHD and CMV viremia are associated with increased risk, permitting risk stratification.